4

10-month retrospective study on compliance and tolerability of the drospirenone-only pill

Objective: The current study evaluated menstrual bleeding profiles, compliance and tolerability in women using a drospirenone (DRSP)-only pill. Patients and methods: This is a non-interventional, retrospective, multi-center study on healthy female adults [n=276, aged between 18 and 53 years and premenopausal using a DRSP-only pill for at least six months with a mean duration of 10.4 months (+/-SD 4.0) months]. 75.6% used other contraceptives than POP before starting with the DRSP-only pill. A questionnaire was used to evaluate the bleeding profile. 56.5% of the women had associated cardiovascular risk factors. Results: Two hundred and sixty-two (262) women (mean age of 32.5 ± 9.1 years; mean BMI of 23.1 ± 3.8 kg/m²) were eligible for analysis. 42.6% of the users had a scheduled bleeding, 33,3% unscheduled bleeding and 48% no bleeding during the last evaluable cycle. 75.4% evaluated the bleeding profile in the last cycle as very good or good, 13.8% said there was no change since starting the medication, 8.4% declared the profile was bad and 2.3% as very bad. 87.8% of the users evaluated the general satisfaction of the contraception as very good or good, whereas only 8.8% and 3.4% said there was no change or that it was bad. No women evaluated the general satisfaction as very bad. Conclusions: These data demonstrate that the DRSP-only pill is associated with a very high satisfaction as a contraceptive in general and in the individual bleeding profile. These aspects reaffirm the acceptability not only in women with cardiovascular risk factors.

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Autores
Palacios S, Colli E, de Diego MV, Regidor PA.

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María Elena Aguilar-Mora, Joaquín Darío Treviño-Báez,Marisela Castañeda-Díaz,Victoria Martínez-Gaytán, Luis Oswaldo de la O-Pérez Efecto y tolerancia gastrointestinal de mioinositol vs metformina en el control metabólico y hormonal

OBJETIVO: Evaluar el efecto de las cápsulas de soft-gel de mioinositol en la reducción del índice de HOMA, el control metabólico y hormonal en pacientes con síndrome de ovario poliquístico versus metformina y la tolerabilidad gastrointestinal de ambos. MATERIALES Y MÉTODOS: Estudio clínico prospectivo, de etiqueta abierta, controlado no aleatorizado vs activo de referencia, con diseño de grupos paralelos efectuado en el servicio de Biología de la Reproducción Humana de la Unidad Médica de Alta Especialidad 23, IMSS, Monterrey NL, de agosto 2019 a octubre 2020, en pacientes con resistencia a la insulina asociada con síndrome de ovario poliquístico e infertilidad. RESULTADOS: Se estudiaron 83 pacientes: 33 que recibieron 600 mg de mioinositol en cápsulas soft-gel por vía oral cada 12 h y 50 que tomaron 850 mg de metformina cada 12 h durante 12 semanas. Completaron el estudio 75 pacientes. El grupo tratado con mioinositol tuvo una reducción del índice de HOMA de 1.49 ± 1.05 (con valor delta de cambio) versus el grupo tratado con metformina de 0.42 ± 0.40 (con igual valor delta de cambio). La diferencia entre ambos grupos fue estadísticamente significativa. Otros parámetros metabólicos y hormonales también tuvieron desenlaces favorables en ambos grupos, pero con una tendencia superior en el grupo de mioinositol. CONCLUSIONES:Se demostró la ventaja del tratamiento con mioinositol en la reducción del índice de HOMA y otros parámetros metabólicos y hormonales en pacientes con resistencia a la insulina asociada con síndrome de ovario poliquístico e infertilidad, con buena tolerabilidad gastrointestinal.

Elisa Lepore, Rosa Lauretta, Marta Bianchini, Marilda Mormando, Cherubino Di Lorenzo, Vittorio Unfer, et al. Inositols depletion and resistance: Principal mechanisms and therapeutic strategies

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.

Simona Dinicola, Vittorio Unfer, Fabio Facchinetti, Christophe O Soulage, et al. Inositols: From Established Knowledge to Novel Approaches

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

Weixuan Chen, Yanli Pang Metabolic Syndrome and PCOS: Pathogenesis and the Role of Metabolites

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases among women of reproductive age and is associated with many metabolic manifestations, such as obesity, insulin resistance (IR) and hyperandrogenism. The underlying pathogenesis of these metabolic symptoms has not yet been fully elucidated. With the application of metabolomics techniques, a variety of metabolite changes have been observed in the serum and follicular fluid (FF) of PCOS patients and animal models. Changes in metabolites result from the daily diet and occur during uncommon physiological routines. However, some of these metabolite changes may provide evidence to explain possible mechanisms and new approaches for prevention and therapy. This article reviews the pathogenesis of PCOS metabolic symptoms and the relationship between metabolites and the pathophysiology of PCOS. Furthermore, the potential clinical application of some specific metabolites will be discussed.

Giovanni Monastra, Ivana Vucenik, Abdel Halim Harrath, Saleh H Alwasel, Zdravko A Kamenov, Antonio Simone Laganà, Noemi Monti 6, Valeria Fedeli, Mariano Bizzarri  PCOS and Inositols: Controversial Results and Necessary Clarifications. Basic Differences Between D-Chiro and Myo-Inositol

Myo-Inositol (myo-Ins) and its phosphate derivatives—including inositol phosphates (InsPs), inositol pyrophosphates (IPPs) and phosphatidyl-inositol phosphate (PtdIns)—are credited to act as second messengers, which accumulate rapidly and transiently in response to external or endocrine signals, a phenomenon that allows signaling to be discrete and regulated (1, 2). Noticeably, inositol is involved in the transduction of several endocrine signals, including insulin (3, 4), thyroid hormones (5), gonadotropins (6), lipids with hormone-like activity (as prostaglandins) (7), and many other endocrine systems (8). Namely, in the last decade, a growing body of clinical and experimental research provided robust evidence about the efficiency of inositol in reversing a few clinical, metabolic, and endocrine features of the Polycystic Ovary Syndrome (PCOS). Myo-inositol, alone or in combination with its isomer D-Chiro-Inositol (DChiro-Ins), showed to exert a variable—albeit significant—effect in improving both symptoms and outcome in PCOS patients (9). Experimental and pilot clinical studies pointed out that a combination of both isomers could provide a reliable rationale for establishing a proper treatment strategy, as first suggested by Beemster’s seminal study (10, 11).

L Pkhaladze, M Russo, V Unfer, M Nordio, S Basciani, A Khomasuridze Treatment of lean PCOS teenagers: a follow-up comparison between Myo-Inositol and oral contraceptives

Objective: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder widely diffused and diagnosed in women of reproductive age. The pathology exhibits alteration of the reproductive functions, including conditions as hyperandrogenism, menstrual cycle irregularity, type 2 diabetes. These conditions are visible in the patients through phenotypical manifestations as hirsutism, acne, and obesity. Even if the syndrome is characterized by common features among both adult and adolescent women, the diagnostic criteria are different for the two age categories and to date still controversial. We investigated different treatments in PCOS adolescents with non-severe metabolic conditions, to evaluate which could be the appropriate therapeutical approach for these patients.Patients and methods: We enrolled lean teenagers with PCOS, and we divided the patients in two age ranges: 13-16 years old and 17-19 years old. They were treated for 3 months either with oral contraceptive pills (OCP) drospirenone/ethinylestradiol (group A), myo-Inositol (myo-Ins) (group B), or OCP plus myo-Ins (group C). Data were analyzed with a descriptive statistics summarizing quantitative variables including median, 25th and 75th percentiles.Results: We pointed out that the group of 13-16 years old lean teenagers treated with myo-Ins exhibit a significant decrease of weight and body mass index (BMI), and an effective improvement the metabolic and hormonal parameters achieved with a non-pharmacological treatment. In the older teenagers aged 17-19 years, data highlights that myo-Ins treatment in combination with OCP prevents the increases of weight and BMI, improves the metabolic profile of the patients, and strongly ameliorates the hormonal parameters analyzed.Conclusions: The results indicate a different scenario in the two age ranges considered and interestingly suggest an important role of myo-Ins in the PCOS context. A therapy based on this natural compound alone or in combination with OCP seems effective to improve both metabolic and hormonal parameters of PCOS adolescents and thus could represent a novel and valid option to consider for the treatment of this syndrome.

Watkins OC, Selvam P, Pillai RA, Cracknell-Hazra VKB, Yong HEJ, Sharma N, Cazenave-Gassiot A, Bendt AK, Godfrey KM, Lewis RM, Wenk MR, Chan SY. Myo-inositol moderates maternal BMI and glycemia related variations in in-vitro placental 13C-DHA-metabolism, altering their relationships with birthweight

Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with 13C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized 13C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most 13C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased 13C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased 13C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.

Laganà AS, Vitagliano A, Noventa M, Ambrosini G, D'Anna R. Myo‑inositol supplementation reduces the amount of gonadotropins and length of ovarian stimulation in women undergoing IVF: a systematic review and meta‑analysis of randomized controlled trials

Purpose: To evaluate whether oral myo-inositol supplementation (MI) is able to reduce the amount of gonadotropins (GA) and the length of controlled ovarian hyperstimulation (SL) in both Polycystic Ovarian Syndrome (PCOS) and non-PCOS women undergoing in vitro fertilization (IVF). Methods: We performed a systematic review (PROSPERO ID: CRD42017069439) of randomized controlled trials (RCTs). We searched articles published in English between January 1985 to August 2017, using the combination of the Medical Subject Headings "Inositol" with "Ovulation Induction", "follicle-stimulating hormone, human, with HCG C-terminal peptide", "Reproductive Techniques, Assisted", and "Fertilization in Vitro". We collected data about GA and SL comparing MI to no treatment or D-Chiro-Inositol (DCI) supplementation (controls). A subgroup analysis was performed to evaluate selected outcomes in PCOS and non-PCOS women. Results: We included 8 studies embedding 812 participants. We found a reduction in GA (p < 0.00001) and SL (p = 0.0007) in patients receiving MI with respect to controls. MI was effective in both PCOS (p < 0.00001) and non-PCOS women (p = 0.02) in reducing GA; conversely, MI supplementation decreased the SL only in PCOS women (p < 0.00001). Conclusion: During IVF, MI is effective in both PCOS and non-PCOS women in saving gonadotropins, but reduces efficiently SL only in PCOS women.

Otoya Chaves F, León Quirós S, Rodríguez Morera M. Manejo de infertilidad por anovulación en síndrome de ovario poliquístico

La infertilidad por anovulación es una complicación común asociada al síndrome de ovario poliquístico. La optimización de la salud constituye el primer paso en el abordaje de esta patología, principalmente con cambios en estilo de vida e índice de masa corporal óptimo. En lo referente a farmacoterapia, el citrato de clomifeno es ampliamente utilizado a nivel mundial como primera línea para inducir la ovulación. No obstante, el letrozol y la metformina en combinación con citrato de clomifeno, son terapias con evidencia prometedora que han demostrado ser superiores al citrato de clomifeno en monoterapia, en lo que respecta a fertilidad. Sin embargo, no existe consenso, y se siguen considerando terapias de segunda línea. Las gonadotropinas exógenas y la perforación laparoscópica del ovario son utilizadas cuando hay resistencia a la primera línea. La fertilización in vitro es una opción cuando tanto la primera, como la segunda línea, no son exitosas. Otros medicamentos se encuentran en estudio para determinar su eficacia en esta patología, como los agonistas del receptor del péptido similar al glucagón tipo 1 y esteroisómeros del inositol, empero, aún requieren estudios de mejor calidad.

Andrea R. Genazzani, Lourdes Ibáñez, Andrzej Milewicz, Duru Shah Impact Of Polycystic Ovary Metabolic Syndrome and Obesity on Women Health

This volume comprehensively focuses on polycystic ovary, metabolic syndrome and obesity and their impact on women’s health, reproduction and quality of life from adolescence to old age. PCOS is analyzed form the early origins - highlighting the importance of diagnosis, management and treatment starting from the high-risk period of adolescence - throughout infertility PCOS-related issues, pregnancy and menopause transition. All aspects of this syndrome are covered also in relation with endocrine and metabolic features that affects women’s health.This book is a very useful tool for gynecologists, endocrinologists, obstetricians, reproductive medicine and general practitioners and is an important resource for all physicians involved in women’s health.

Asimakopoulos G, Pergialiotis V, Anastasiou E, Antsaklis P, Theodora M, Vogiatzi E, Kallergi A, Sindos M, Loutradis D, Daskalakis G. Effect of dietary myo-inositol supplementation on the insulin resistance and the prevention of gestational diabetes mellitus: study protocol for a randomized controlled trial

Background: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance with onset or first recognition during pregnancy, which is characterized by an increased insulin resistance. Gestational diabetes mellitus is associated with pregnancy-related maternal and fetal morbidity (both antenatal and perinatal). Myo-inositol has been suggested to improve insulin resistance in women with polycystic ovary syndrome. The aim of this study is to examine the impact of myo-inositol supplementation during pregnancy on the incidence of gestational diabetes mellitus.Methods: We will conduct a single-center, open-label, randomized controlled trial. A total of 160 healthy pregnant women with singleton pregnancy at 11-13+6 weeks of gestation will be randomly allocated in two groups: intervention group (N = 80) and control group (N = 80). The intervention group will receive myo-inositol and folic acid (4000 mg myo-inositol and 400 mcg folic acid daily) from 11 to 13+6 weeks of gestation until 26-28 weeks of gestation, while the control group will receive folic acid alone (400 mcg folic acid daily) for the same period of time as intervention group. The primary outcome will be gestational diabetes incidence rate at 26-28 weeks of gestation, according to the results of a 75 g oral glucose tolerance test held at 26-28 weeks of gestation. The secondary outcomes will include fasting blood glucose levels, glycated hemoglobin levels, insulin resistance level (evaluated by homeostasis model assessment of insulin resistance and Matsuda Index), and incidence rate of diet-treated gestational diabetes and diabetes requiring insulin therapy at 26-28 weeks of gestation. Discussion: This trial will provide evidence for the effectiveness of myo-inositol supplementation during pregnancy in reducing the incidence of gestational diabetes mellitus.

Carmona-Ruiz IO, Saucedo-de-la-Llata E, Moraga-Sánchez MR,3Romeu- Sarrió A Mioinositol en combinación con D-chiro-inositol: resultados preliminares en el tratamiento de primera línea de pacientes con síndrome de ovario poliquístico

OBJETIVO: evaluar el efecto de la combinación de mioinositol y D-chiro-inositol en el perfil metabólico y endocrino de mujeres con síndrome de ovario poliquístico. MATERIALES Y MÉTODOS: estudio experimental, prospectivo y longitudinal efectuado en pacientes con diagnóstico de síndrome de ovario poliquístico (criterios de Rotterdam) sin tratamiento o intervención previa. Diariamente se administraron, por vía oral, 2000mg de mioinositol y 400 mg de D-chiro-inositol, durante 90 días. Se evalúan y comparan el perfil clínico y metabólico de cada paciente antes y después de la intervención. RESULTADOS: se estudiaron 61 pacientes con síndrome de ovario poliquístico, con una diferencia estadísticamente significativa en los valores de la escala Ferriman-Gallwey (6.06 ± 2.0 y 5.57 ± 1.1; p = 0.003 pre y postratamiento, respectivamente); volumen ovárico izquierdo (7.76 ± 3.2 y 7.18 ± 2.3; p = 0.005, pre y postratamiento, respectivamente). La cuenta de folículos antrales del ovario izquierdo fue de 10.65 ± 6.4 y 10.20 ± 5.7; p=0.029 pre y postratamiento, respectivamente. La cuenta de folículos antrales del ovario derecho fue: 12.11 ± 6.5 y 11.75 ± 6.1; p=0.048 pre y postratamiento, respectivamente. Hubo mejoría en los valores del HOMA (1.85 ± 1.0 y 1.67 ± 0.7; p=0.015 pre y postratamiento, respectivamente. En la proporción LH-FSH: 1.13 ± 0.8 y 0.99 ± 0.6; p=0.018 pre y postratamiento, respectivamente. CONCLUSIÓN: los resultados del estudio muestran un efecto positivo de la administración combinada de mioinositol y D-chiro-inositol en el perfil clínico y metabólico de pacientes con síndrome de ovario poliquístico. La mejora en las concentraciones séricas de andrógenos, de la proporción LH-FSH y la regularización de los ciclos menstruales puede contribuir al aumento de la fertilidad en pacientes con síndrome de ovario poliquístico y factor ovárico.

Chan KY, Wong MMH, Pang SSH, Lo KKH. Dietary supplementation for gestational diabetes prevention and management: a meta-analysis of randomized controlled trials

Purpose: The use of supplement to prevent and ease gestational diabetes (GDM) progression has been examined in various studies, but the results were inconclusive, and studies evaluated dietary supplements separately. The present review aimed to evaluate the efficacy of various dietary supplementation on GDM risk and the surrogate markers for cardiometabolic risk of pregnant women with GDM. Methods: A comprehensive search on multiple databases were performed to identify randomized controlled trials. Random-effects model was used to pool the results in relative risk (RR) or mean difference. Results: Fifty-three randomized controlled studies with 9443 pregnant women were included. Vitamin D (5 studies, RR 0.64; 95% CI 0.44, 0.94) and myo-inositol (4 studies, RR 0.34, 95% CI 0.20, 0.58) supplementation significantly reduced the risk of GDM. Myo-inositol, probiotics, and vitamin D showed significant intervention effect on surrogate markers related to glycemic control, lipid profile, inflammatory, and oxidative stress. However, the majority of included studies were clustered to Iran and Italy, which might convey a generalizability bias. Conclusion: Dietary supplementation including vitamin D and myoinositol supplementation has the potential in primary prevention and management of GDM, whereas probiotics demonstrated its ability in GDM management by improving the levels of surrogate markers for cardiometabolic risk. The potential for dietary supplement in preventing GDM or managing cardiometabolic risk of pregnant women should receive more attentions.

De Diego MV, Gómez-Pardo O, Groar JK, López-Escobar A, Martín-Estal I, Castilla-Cortázar I, Rodríguez-Zambrano MÁ. Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study

Purpose: To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). Methods: This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). Results: Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. Conclusions: Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.

Soldat-Stanković V, Popović-Pejičić S, Stanković S, Prtina A, Malešević G, Bjekić-Macut J, Livadas S, Ognjanović S, Mastorakos G, Micić D, Macut D. The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial

Purpose: To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). Methods: In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. Results: After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). Conclusion: Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women.

Minisha Sood, Susan B. Zweig, Marsha C. Tolentino, Marina Strizhevsky, and Leonid Poretsky Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting approximately 5–10 % of reproductive-age women. PCOS isconsidered the most common cause of anovulatory infertility. PCOS is widely accepted as a combination of ovulatory dysfunction, androgen excess, and polycystic ovaries with the exclusion of specific disorders that may lead to similar phenotypes. Genetic variants have also been identified which result in PCOS. PCOS is associated with insulin resistance, type 2 diabetes mellitus, dyslipidemia, and visceral obesity. The treatment of PCOS is multifaceted, including the use of oral contraceptives, insulin sensitizers, antiandrogen agents, and other medications; PCOS therapy is tailored to patient-specific physiological conditions and treatment goals

Minisha Sood, Susan B. Zweig, Marsha C. Tolentino, Marina Strizhevsky, and Leonid Poretsky PCOS Therapy

Gynecologists usually treat PCOS only as an endocrine disorder, without recognition of the very important part that insulin resistance plays in the syndrome. In this section, the way to treat PCOS from a metabolic point of view, without dwelling on the use of oral contraceptives and antiandrogen drugs, will be discussed. Lifelong strategies that improve the care of women with PCOS are essential, because of the chronic nature of the syndrome and the young age at which all the symptoms begin to manifest [ 1 ]. A valid therapeutic protocol for PCOS includes diet, physical exercise, and insulin- sensitizing agents such as metformin and inositol. For example, in fact, a normal BMI is associated with a positive fertility outcome, and fertility specialists recommend achieving this BMI before IVF (in vitro fertilization): in fact, these techniques are invasive and expensive and have low success rates, so it seems logical to improve BMI and to support hormonal balance through diet, exercise, and nutrition supplements

Tabatabaie M, Amiri S, Golestan Jahromi M, Sene AA, Zandieh Z, Mehdizadeh M, Amjadi F. The effect of Myo-Inositol supplement on molecular regulation of folliculogenesis, steroidogenesis, and assisted reproductive technique outcomes in patients with polycystic ovarian syndrome

Research question: The mechanism of Myo-Inositol, as an adjuvant, on key signaling pathways related to oocyte maturation, fertilization rate, and embryo quality as well as ovarian steroidogenesis in cumulus cells of PCOS patients, is still unclear. Design: Infertile patients who were candidates for ART cycles were divided into three groups (n = 30 in each group), including group 1: PCOS patients only receiving folic acid, group 2: PCOS patients receiving daily Myo-Inositol combined with folic acid, and a control group (group 3): normal ovulatory women without PCOS receiving only folic acid from 1 month prior to IVF cycle until the day of ovum pick up. During the ART procedure, oocytes maturation, fertilization rate, and embryo quality were assessed. The gene expressions of FSHR, LHR, CYP11A1, CYP19A1, 3β-HSD2, and StAR were also analyzed using qRT-PCR. Western blot analysis was performed for the evaluation of AKT, ERK, CREB, and AMPK phosphorylation. Result: Despite equal number of retrieved oocytes, the percentages of MII oocytes, fertilization rate, and embryo quality were found to be significantly higher in group 2 due to the administration of inofolic. The expressions of all the studied genes were significantly higher in the cumulus cells of group 1 compared to the group 2. Higher phosphorylation of ERK1/2 was found in the groups 2 and 3 compared to the group 1. On the other hand, p-Akt has significantly decreased in the group 2 compared to the group 1. Conclusion: Our study provides new insight into the molecular mechanism underlying the positive effect of Myo-Inositol on intrinsic ovarian defects in PCOS, steroidogenesis, oocyte maturation, fertilization rate, and embryo quality.

Zeng L, Yang K. Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis

Purpose: To assess the effectiveness and safety of myoinositol for patients with PCOS. Methods: In this meta-analysis, data from randomized controlled trials are obtained to assess the effects of myoinositol vs. placebo or western medicine in women with PCOS. The study's registration number is CRD42017064563. The primary outcomes included total testosterone, estradiol (E2) and the homeostatic model assessment (HOMA) of insulin resistance. Result: Ten trials involving 573 patients were included. The meta-analysis results show that: compared with the control group, myoinositol may improve HOMA index (WMD -0.65; 95% CI -1.02, -0.28; P = 0. 0005) and increase the E2 level (WMD 16.16; 95% CI 2.01, 30.31; P = 0. 03); while there is no enough strong evidence that the myoinositol has an effect on the total testosterone level (WMD -16.11; 95% CI -46.08, 13.86; P = 0. 29). Conclusion: Based on current evidence, myoinositol may be recommended for the treatment of PCOS with insulin resistance, as well as for improving symptoms caused by decreased estrogen in PCOS.

Pintaudi B, Di Vieste G, Bonomo M. The Effectiveness of Myo-Inositol and D-Chiro Inositol Treatment in Type 2 Diabetes

Inositol has been used as a supplement in treating several pathologies such as PCOS, metabolic syndrome, and gestational diabetes. Both myo-inositol and its isomer d-chiro-inositol showed insulin mimetic effects in conditions of insulin resistance. Type 2 diabetes (T2DM) is a condition typically caused by insulin resistance. There is a lack of evidence of inositol use in T2DM. We evaluated the effectiveness and safety of myo-inositol and d-chiro-inositol treatment in T2DM. This was a pilot study involving a consecutive sample of patients with T2DM with suboptimal glycemic control (HbA1c 7.0-10.0%) already treated with glucose-lowering agents. Patients (23.1% males, mean age of 60.8 ± 11.7 years) took for three months a combination of myo-inositol (550 mg) and d-chiro-inositol (13.8 mg) orally twice a day as add-on supplement to their glucose-lowering drugs. Possible occurrence of side effects was investigated. After three months of treatment fasting blood glucose (192.6 ± 60.2 versus 160.9 ± 36.4; p = 0.02) and HbA1c levels (8.6 ± 0.9 versus 7.7 ± 0.9; p = 0.02) significantly decreased compared to baseline. There was no significant difference in blood pressure, lipid profile, and BMI levels. None of the participants reported side effects. In conclusion, a supplementation with a combination of myo- and d-chiro-inositol is an effective and safe strategy for improving glycemic control in T2DM.

Zavatta A, Parisi F, Mandò C, Scaccabarozzi C, Savasi VM, Cetin I. Role of Inflammaging on the Reproductive Function and Pregnancy

During female lifetime and pregnancy, inflammation and cellular senescence are implicated in physiological processes, from ovulation and menstruation, to placental homeostasis and delivery. Several lifestyles, nutritional, and environmental insults, as well as long-lasting pregestational inflammatory diseases may lead to detrimental effects in promoting and sustaining a chronic excessive inflammatory response and inflammaging, which finally contribute to the decay of fertility and pregnancy outcome, with a negative effect on placental function, fetal development, and future health risk profile in the offspring. Maladaptation to pregnancy and obstetric disease may in turn increase maternal inflammaging in a feedback loop, speeding up aging processes and outbreak of chronic diseases. Maternal inflammaging may also impact, through transgenerational effects, on future adult health. Hence, efficacious interventions should be implemented by physicians and healthcare professionals involved in prevention activities to reduce the modifiable factors contributing to the inflammaging process in order to improve public health.

Vanhees K, Vonhögen IG, van Schooten FJ, Godschalk RW. You are what you eat, and so are your children: the impact of micronutrients on the epigenetic programming of offspring

The research field of fetal programming has developed tremendously over the years and increasing knowledge suggests that both maternal and paternal unbalanced diet can have long-lasting effects on the health of offspring. Studies implicate that macronutrients play an important role in fetal programming, although the importance of micronutrients is also becoming increasingly apparent. Folic acid and vitamins B2, B6 and B12 are essential for one-carbon metabolism and are involved in DNA methylation. They can therefore influence the programming of the offspring's epigenome. Also, other micronutrients such as vitamins A and C, iron, chromium, zinc and flavonoids play a role in fetal programming. Since it is estimated that approximately 78 % of pregnant women in the US take vitamin supplements during pregnancy, more attention should be given to the long-term effects of these supplements on offspring. In this review we address several different studies which illustrate that an unbalanced diet prior and during pregnancy, regarding the intake of micronutrients of both mother and father, can have long-lasting effects on the health of adult offspring.

Saunders, C., dos Santos, K. Nutritional Aspects of Gestation and Puerperium

This chapter is organized into two major sections that address issues about the nutritional aspects of (1) gestation and (2) puerperium, based on the best scientific evidence. The recommended tools and methods for nutritional assessment and weight management followed by nutritional requirements during pregnancy and lactation are presented at each section. Adequacy of gestational weight gain and interventions to reduce postpartum weight retention are opportunely contextualized in the present obesity scenario. Recommendations for common situations in prenatal or postnatal care such as digestive symptoms, nutritional deficiencies, pica, hypertensive disorders of pregnancy, diabetes mellitus, and prescription of nutritional supplements are critically discussed. The main nutritional guidelines for adult and adolescent pregnant or lactating women are summarized for use by health professionals in clinical practice. Current topics emerging in the field of maternal and child nutrition are introduced in this chapter: chrononutrition, vegetarianism, DASH diet, e-Health, and early life programming.

Oakes, J.L., Ideraabdullah, F.Y. Maternal Nutrition and Epigenetic Perturbation: Modeling Trends to Translation

Maternal nutrition plays an essential role in offspring health and development. Critical stages include: (1) preconception, affecting oocyte development and uterine environment preparation; (2) gestation, affecting uterine environment and placental nutrient transfer and (3) postnatal, through lactation. It remains debatable which stage is most important, but arguably, the most complex cellular events occur during gestation. During this time, embryo development requires a well orchestrated and tightly regulated cascade of genetic, molecular and biochemical events. Among these are epigenetic events necessary for gene expression regulation. These produce heritable yet often reversible states established based on transcriptional needs of the cell. A growing body of research highlights the role of maternal nutrition in determining epigenetic states important for pre- and postnatal development. Here, we discuss recent findings addressing epigenetic response to nutrition with relevance to developmental origins of phenotypic outcome.

Nordgren TM, Lyden E, Anderson-Berry A, Hanson C. Omega-3 Fatty Acid Intake of Pregnant Women and Women of Childbearing Age in the United States: Potential for Deficiency?

Omega-3 fatty acids play critical roles during fetal growth and development with increased intakes associated with improved maternal-fetal outcomes. Omega-3 fatty acid intake in Western diets is low, and the impact of socioeconomic factors on omega-3 fatty acid intake in pregnant women and women of childbearing age has not been reported. We used the National Health and Nutrition Examination Survey (NHANES) cycles 2003-2012 to assess the relationship between omega-3 fatty acid intake and socioeconomic factors in women of childbearing age. Out of 7266 eligible participants, 6478 were women of childbearing age, while 788 were identified as pregnant at the time of the survey. Mean EPA+DHA intake of the population was 89.0 mg with no significant difference between pregnant and non-pregnant women. By univariate and multivariate analyses adjusting for confounders, omega-3 fatty acid intake was significantly associated with poverty-to-income ratio, race, and educational attainment. Our results demonstrate that omega-3 fatty acid intake is a concern in pregnant women and women of childbearing age in the United States, and that socioeconomically disadvantaged populations are more susceptible to potential deficiencies. Strategies to increase omega-3 fatty acid intake in these populations could have the potential to improve maternal and infant health outcomes.

Broś-Konopielko M, Białek A, Johne M, Czajkowski K. Increased LC PUFA Levels in the Serum of Pregnant Women and Their Children as a Result of Dietary Supplementation with ‘Omega’ Fatty Acids

Essential fatty acids (EFA) and long-chain polyunsaturated fatty acids (LC PUFA) are considered the most valuable bioactive fatty acids (FA) of the greatest importance for the mother's and child's health (e.g., placentation process, labor course, development of the central nervous system, visual acuity, cognitive functions), which results in dietary recommendations concerning EFA and LC PUFA intake in the diet of pregnant women. In this study, we aimed to evaluate the frequency of different food products consumption and 'omega' dietary supplements usage in groups of pregnant women. We also measured n-3 and n-6 FA content in serum samples of pregnant women and their children with the GC-FID technique, estimated the efficacy of applied supplementation, and compared the usefulness of different dietary supplements dedicated for pregnant women. 'Omega' dietary supplements effectively increased LC PUFA in the maternal blood (EPA, p = 0.0379; DHA p &lt; 0.0001; n-3 PUFA, p &lt; 0.0001), which penetrated the umbilical cord (EPA, p = 0.0131; DHA, p = 0.0288). If fish and seafood consumption is not enough, dietary supplements of the highest quality may provide sufficient LC PUFA without apprehension of MetHg contamination. 'Omega' dietary supplementation seems the most efficient way of providing an optimal supply of LC PUFA for the developing child from the earliest stages of development, which will bring advantages in the child's future life and its health.

Khanjari Z, Iravani M, Abedi P, Ghanbari S.  Effect of Omega-3 fatty acid supplementation on sexual function of pregnant women: a double blind randomized controlled trial

The aim of this study was to evaluate the effect of omega-3 fatty acid supplementation on female sexual function during pregnancy. The present study was a double-blind randomized controlled clinical trial performed on 124 pregnant women (62 people in each group) at 16-22 weeks of gestation who referred to health centers in Ilam in 2020 to receive prenatal care. The intervention group received 300 mg of omega-3 supplements and the control group received placebo once a day for 8 weeks. Data collection tools in this study included a demographic questionnaire, three 24-h dietary recall (24HR), female sexual function index (FSFI), and Van den Bergh Pregnancy-Related Anxiety Questionnaire (PRAQ). Before intervention, the total score of sexual function in the intervention group and control groups, showed no statistically significant difference (P = 0.123). However, 4 and 8 weeks after intervention, the mean total score of sexual function in the intervention group was significantly higher than that of the control group after intervention (P < 0.0001). Before intervention, the total score of gestational anxiety in the intervention and control groups, showed no statistically significant difference (P = 0.149). However, 4 and 8 weeks after intervention, the mean total score of gestational anxiety in the intervention group was significantly lower than that of the control group (P < 0.0001). Based on three 24-h dietary recall, regardless of daily intake of 300 mg of omega-3 supplement, the percentage of polyunsaturated fatty acid (PUFA) intake from daily energy intake was not statistically significant between the intervention and control groups from baseline to follow-up (P > 0.01). Based on the results of this study, omega-3 supplementation could improve sexual function in pregnant women by preventing increased pregnancy anxiety. However, more studies are needed to prove the effectiveness of omega-3s on female sexual function during pregnancy.

Harris MA, Reece MS, McGregor JA, Wilson JW, Burke SM, Wheeler M, Anderson JE, Auld GW, French JI, Allen KG. The Effect of Omega-3 Docosahexaenoic Acid Supplementation on Gestational Length: Randomized Trial of Supplementation Compared to Nutrition Education for Increasing n-3 Intake from Foods.

Objective: DHA supplementation was compared to nutrition education to increase DHA consumption from fish and DHA fortified foods. Design: This two-part intervention included a randomized double-blind placebo controlled DHA supplementation arm and a nutrition education arm designed to increase intake of DHA from dietary sources by 300 mg per day. Setting: Denver Health Hospitals and Clinics, Denver, Colorado, USA. Population: 871 pregnant women aged 18-40 were recruited between 16 and 20 weeks of gestation of whom 564 completed the study and complete delivery data was available in 505 women and infants. Methods: Subjects received either 300 or 600 mg DHA or olive oil placebo or nutrition education. Main outcome variable: Gestational length. Results: Gestational length was significantly increased by 4.0-4.5 days in women supplemented with 600 mg DHA per day or provided with nutrition education. Each 1% increase in RBC DHA at delivery was associated with a 1.6-day increase in gestational length. No significant effects on birth weight, birth length, or head circumference were demonstrated. The rate of early preterm birth (1.7%) in those supplemented with DHA (combined 300 and 600 mg/day) was significantly lower than in controls. Conclusion: Nutrition education or supplementation with DHA can be effective in increasing gestational length.

Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancy

Background: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. Objectives: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. Selection criteria: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. Data collection and analysis: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. Main results: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega-3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. Authors' conclusions: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3. There was a possibly reduced risk of perinatal death and of neonatal care admission, a reduced risk of LBW babies; and possibly a small increased risk of LGA babies with omega-3 LCPUFA.For our GRADE quality assessments, we assessed most of the important perinatal outcomes as high-quality (e.g. preterm birth) or moderate-quality evidence (e.g. perinatal death). For the other outcome domains (maternal, child/adult and health service outcomes) GRADE ratings ranged from moderate to very low, with over half rated as low. Reasons for downgrading across the domain were mostly due to design limitations and imprecision.Omega-3 LCPUFA supplementation during pregnancy is an effective strategy for reducing the incidence of preterm birth, although it probably increases the incidence of post-term pregnancies. More studies comparing omega-3 LCPUFA and placebo (to establish causality in relation to preterm birth) are not needed at this stage. A further 23 ongoing trials are still to report on over 5000 women, so no more RCTs are needed that compare omega-3 LCPUFA against placebo or no intervention. However, further follow-up of completed trials is needed to assess longer-term outcomes for mother and child, to improve understanding of metabolic, growth and neurodevelopment pathways in particular, and to establish if, and how, outcomes vary by different types of omega-3 LCPUFA, timing and doses; or by characteristics of women.

Nordgren TM, Anderson Berry A, Van Ormer M, Zoucha S, Elliott E, Johnson R, McGinn E, Cave C, Rilett K, Weishaar K, Maddipati SS, Appeah H, Hanson C. Omega-3 Fatty Acid Supplementation, Pro-Resolving Mediators, and Clinical Outcomes in Maternal-Infant Pairs; Salud Materna y Epigenómica

Omega (n)-3 fatty acids are vital to neonatal maturation, and recent investigations reveal n-3 fatty acids serve as substrates for the biosynthesis of specialized pro-resolving lipid mediators (SPM) that have anti-inflammatory and immune-stimulating effects. The role SPM play in the protection against negative maternal-fetal health outcomes is unclear, and there are no current biomarkers of n-3 fatty acid sufficiency. We sought to ascertain the relationships between n-3 fatty acid intake, SPM levels, and maternal-fetal health outcomes. We obtained n-3 fatty acid intake information from 136 mothers admitted for delivery using a food frequency questionnaire and measured docosahexaenoic acid (DHA)-derived SPMs resolvin D1 (RvD1) and RvD2 in maternal and cord plasma. We found significantly elevated SPM in maternal versus cord plasma, and increased SPM levels were associated with at-risk outcomes. We also identified that increased DHA intake was associated with elevated maternal plasma RvD1 (p = 0.03; R² = 0.18) and RvD2 (p = 0.04; R² = 0.20) in the setting of neonatal intensive care unit (NICU) admission. These findings indicate that increased n-3 fatty acid intake may provide increased substrate for the production of SPM during high-risk pregnancy/delivery conditions, and that increased maternal plasma SPM could serve as a biomarker for negative neonatal outcomes.

Miles EA, Calder PC. Can Early Omega-3 Fatty Acid Exposure Reduce Risk of Childhood Allergic Disease?

A causal link between increased intake of omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and increased incidence of allergic disease has been suggested. This is supported by biologically plausible mechanisms, related to the roles of eicosanoid mediators produced from the n-6 PUFA arachidonic acid. Fish and fish oils are sources of long chain omega-3 (n-3) PUFAs. These fatty acids act to oppose the actions of n-6 PUFAs particularly with regard to eicosanoid synthesis. Thus, n-3 PUFAs may protect against allergic sensitisation and allergic manifestations. Epidemiological studies investigating the association between maternal fish intake during pregnancy and allergic outcomes in infants/children of those pregnancies suggest protective associations, but the findings are inconsistent. Fish oil provision to pregnant women is associated with immunologic changes in cord blood. Studies performed to date indicate that provision of fish oil during pregnancy may reduce sensitisation to common food allergens and reduce prevalence and severity of atopic eczema in the first year of life, with a possible persistence until adolescence. A recent study reported that fish oil consumption in pregnancy reduces persistent wheeze and asthma in the offspring at ages 3 to 5 years. Eating oily fish or fish oil supplementation in pregnancy may be a strategy to prevent infant and childhood allergic disease.

Amaral YN, Marano D, Silva LM, Guimarães AC, Moreira ME.  Are There Changes in the Fatty Acid Profile of Breast Milk with Supplementation of Omega-3 Sources? A Systematic Review

Purpose To evaluate the effect of supplementation with omega-3 sources on the fatty acid composition of human milk. Methods The review consisted of the search for articles published in PubMed, Biblioteca Virtual de Saúde (Virtual Health Library[VHL]) and Web of Science databases using the following keywords: fatty acids, omega-3, human milk and supplementation; for this purpose, we have used the program of research to integrate the services for the maintenance of autonomy (PRISMA) checklist. The following selection criteria were used: articles in English, Portuguese, Spanish or Italian, published between 2000 and 2015, and about studies performed in humans. We found 710 articles that met the established criteria; however, only 22 of them were selected to be part of this study. Results All studies found a positive relationship between the consumption of omega-3 sources and their concentration in human milk. The differences in the findings are due to the distinct methods used, such as the specific time of the omega-3 supplementation, the type of omega-3 source offered, as well as the sample size. Conclusion Although the studies were different in several methodological aspects, it was possible to observe the importance of omega-3 supplementation during gestation and/or the puerperium.

Tummala, L.S., Agrawal, A. & Lundberg, G. Management Considerations for Lipid Disorders During Pregnancy

Purpose of review. Dyslipidemias including familial hypercholesterolemia and elevated lipoprotein (a) are not uncommon in young women who may desire pregnancy. In all women, abnormal lipid metabolism has been linked to adverse outcomes during pregnancy, including hypertensive disease of pregnancy, gestational diabetes mellitus, and preterm birth. Optimal management of dyslipidemias in pregnant women remains undefined, as statins are contraindicated in this group. Recent findings. Recent literature questions this traditional avoidance of statins, however, as well as explores their potential benefit in pre-eclampsia specifically. Summary In this review, the arsenal of nutrition, bile acid resins, omega-3 fatty acids, and low-density lipoprotein cholesterol apheresis is explored, as are newer therapies like mipomersen and proprotein convertase subtilisin/kexin type 9 inhibitors, for the management of dyslipidemias during pregnancy.

Guéant, JL., Guéant-Rodriguez, RM Maternal Folate, Methyl Donors, One-Carbon Metabolism, Vitamin B12 and Choline in Foetal Programming.

Experimental and human population studies have established links between the deficit in dietary methyl donors (MDD) of one-carbon metabolism (1-CM) during pregnancy and foetal programming. This review on MDD foetal programming is focused on the mechanisms dissected in animal models and the associations with outcomes of obesity, metabolic syndrome and cognition in population studies. 1-CM plays a central role in the influence of metabolic and nutritional factors on DNA methylation and regulation of gene expression through its role on the synthesis of S-adenosylmethionine (SAM), which is needed for methylation of DNA, RNA and histones, the activation of nuclear receptor pathways and the adaptation to cellular stress. This complex metabolic network is regulated by a number of genes and requires micronutrients such as folate, vitamins B12 and B6 and choline to function properly. Experimental and epidemiological studies have clearly demonstrated an association between dietary and metabolic markers of the 1-CM and birth weight and age-related manifestations of foetal programming, including neurodevelopment and cognition, in which epigenomic mechanisms may play a central role. Some of the MDD foetal programming effects are exerted by altered methylation of differentially methylated region (DMR) and imprinted genes. These associations illustrate the need to perform further integrated analyses associating epigenomic and transcriptomic analyses and metabolic and nutritional factors that influence the outcomes of MDD foetal programming.

Khaire, A., Joshi, S. Maternal Long-chain Polyunsaturated Fatty Acids and Pregnancy Outcome

The mother provides various vital nutrients to the growing fetus during pregnancy. Maternal nutrient levels and fatty acids are critical for normal fetal growth and development. All fatty acids provide energy, but structural and metabolic functions primarily require the long-chain polyunsaturated fatty acids (LCPUFA). The biologically most active LCPUFA are docosahexaenoic acid (22:6, omega-3), eicosapentaenoic acid (20:5, omega-3), and arachidonic acid (AA, 20:4 omega-6) which are synthesized from their essential fatty acid precursors, alpha-linolenic acid (18:3, omega-3), and linoleic acid (18:2, omega-6). LCPUFA and their eicosanoid metabolites such prostaglandins and prostacyclins play a vital role in determining the length of gestation, initiation of labor, and placental growth and development. Storage of LCPUFA in maternal fat depots during early pregnancy serves as a sole source of LCPUFA for the growing fetus as the fetus has a limited capacity to synthesize LCPUFA due to lack of desaturases. Therefore, the amount of LCPUFA transported from the mother to fetus depends on maternal LCPUFA intake, metabolism, and placental uptake/transport of fatty acids. Accretion of maternal LCPUFA during pregnancy may reduce the risk of pregnancy complications such as preterm birth, intrauterine growth restriction, gestational diabetes mellitus, and preeclampsia. Maternal DHA and AA status positively influence fetal growth and brain development and also reduce the risk of developing non-communicable diseases in the offspring in adult life. This chapter describes the role of maternal LCPUFA in reducing the risk of adverse pregnancy outcomes.

Koemel NA, Skilton MR. Epigenetic Aging in Early Life: Role of Maternal and Early Childhood Nutrition

Purpose of review: Early life presents a pivotal period during which nutritional exposures are more likely to cause epigenetic modifications, which may impact an individual's health during adulthood. This article reviews the current evidence regarding maternal and early childhood nutritional exposures and their role in epigenetic aging. Recent findings: Maternal and early life consumption of diets higher in fiber, antioxidants, polyphenols, B vitamins, vitamin D, and ω-3 fatty acids is associated with slower epigenetic aging. Conversely, diets higher in glycemic load, fat, saturated fat, and ω-6 fatty acids demonstrate a positive association with epigenetic aging. Maternal and early life nutrition directly and indirectly influences epigenetic aging via changes in one-carbon metabolism, cardiometabolic health, and the microbiome. Clinical trials are warranted to determine the specific foods, dietary patterns, and dietary supplements that will normalize or lower epigenetic aging across the life course.

McKeating DR, Fisher JJ, MacDonald T, Walker S, Tong S, Bennett WW, Kaitu'u-Lino TJ, Perkins AV. Circulating trace elements for the prediction of preeclampsia and small for gestational age babies

Introduction: Poor gestational outcomes due to placental insufficiency can have lifelong consequences for mother and child. Objective: There is a need for better methods of diagnosis, and elemental metabolomics may provide a means to determine the risk of gestational disorders. Methods: This study used blood plasma samples collected at 36 weeks' gestation from women who later developed preeclampsia (n = 38), or small-for-gestational age babies (n = 91), along with matched controls (n = 193). Multi-element analysis was conducted by inductively coupled plasma mass spectrometer (ICP-MS), allowing simultaneous measurement of 28 elements. Results: Women who later developed PE, exhibited significantly increased concentrations of K, Rb and Ba. For SGA pregnancies, there was a significant increase in Cu and a decrease in As concentrations. Despite significant differences in single elements, the elemental profile of groups indicated no clustering of control, PE, or SGA samples. Positive predicative values correctly identified approximately 60% of SGA and 70% of PE samples. Conclusion: This is the first-time elemental metabolomics has been used to predict SGA and PE at 36 weeks. Though significant changes were identified, routine clinical use may be limited but may contribute to a multi marker test. Future analysis should include other biomarkers, metabolic data or clinical measurements made throughout gestation.

Patel, S., Choksi, A., Pant, R., Alam, A., Chattopadhyay, S. Nutritional Programming of Metabolic Syndrome: Role of Nutrients in Shaping the Epigenetics

Increased prevalence of metabolic syndrome like obesity, heart diseases, and diabetes is an emerging public health problem. Susceptibility to such diseases has always been attributed to environmental and genetic factors which certainly play a pivotal role but cannot be the sole causal factor leading to metabolic syndrome. Epigenetics – a mediator between genetics and environment – is emerging as a potential candidate to explain the increase in the prevalence of such metabolic diseases. Changes in the epigenetic landscape marked by DNA methylation, histone methylation, and acetylation can lead to obesity, insulin resistance, diabetes, and vascular dysfunction in both animals and humans. Nutritional programming during early stages of life can manipulate the metabolism and the physiology of the organism. This is where the importance of optimal maternal nutrition comes into play. Both maternal under- and overnutrition have the potential to adversely affect the etiology of metabolic disorders in the developing fetus by changing the epigenetic marks. Various macronutrients and micronutrients in the maternal diet have also been shown to be exhibiting specific effect on the future health of the offspring. Though the role of epigenetics in fetal programming of metabolic syndrome is constantly being well understood, research on the therapeutic aspect is still in its infancy. Interventions and manipulation of dietary supplementation which potentially can make changes in the epigenetic marks can be the future therapeutic targets for chronic metabolic syndrome.

Saghazadeh, A., Mahmoudi, M., Rezaei, N. Nutriepigenomic Immunity

Epigenetic mechanisms and regulatory factors organize a flexible machinery by means of which multicellular organisms generate a heritable alteration in gene expression with respect to the fluctuating external environment. Epigenetic modifications by clever manipulation of maternal dietary and care can transpire independent of DNA sequences to shape a baby and future adult rich not only in immunity to physical diseases – particularly from chronic non-communicable (metabolic and cardiovascular diseases, cancers, and aging) diseases point of view – but also to brain and behavioral disorders. Therefore, despite the book’s dictum to discuss the link between nutrition and immune system function from different aspects, the present chapter first goes beyond to reach that the maternal diet does not leave indiscriminate marks on the offspring epigenome but does plan to manipulate it in a careful pattern and then ends with a nudge to nutriepigenomic immunity.

Shayganfard M. Are Essential Trace Elements Effective in Modulation of Mental Disorders? Update and Perspectives

The emergence of mental disorders is associated with several risk factors including genetic and environmental susceptibility. A group of nutrients serves an especially important role in a number of essential neurodevelopmental processes through brain areas promoting the high degree of brain metabolism during early life, although almost all nutrients are needed. These include macronutrients and micronutrients (e.g., iron, magnesium, zinc, copper, selenium). Numerous nutritional psychiatry trials have been performed to examine the correlation of many individual nutrients with mental health, such as essential trace elements. The increased accumulation or lack of such components will facilitate an alternative metabolic pathway that can lead to many diseases and conditions of neurodevelopment. Mental functions have biochemical bases, so the impairment of such neurochemical mechanisms due to lack of trace elements can have mental effects. In psychological conditions such as depression, anxiety, schizophrenia, and autism, scientific studies demonstrate the putative role of trace element deficiency. Therefore, given the critical roles played by essential trace elements in the neurodevelopment and mental health, the effect of these elements' intake on the modulation of psychological functioning is reviewed.

Skalny AV, Tinkov AA, Voronina I, Terekhina O, Skalnaya MG, Kovas Y. Hair Trace Element and Electrolyte Content in Women with Natural and In Vitro Fertilization-Induced Pregnancy

The objective of the present study was to perform comparative analysis of hair trace element content in women with natural and in vitro fertilization (IVF)-induced pregnancy. Hair trace element content in 33 women with IVF-induced pregnancy and 99 age- and body mass index-matched control pregnant women (natural pregnancy) was assessed using inductively coupled plasma mass spectrometry. The results demonstrated that IVF-pregnant women are characterized by significantly lower hair levels of Cu, Fe, Si, Zn, Ca, Mg, and Ba at p < 0.05 or lower. Comparison of the individual levels with the national reference values demonstrated higher incidence of Fe and Cu deficiency in IVF-pregnant women in comparison to that of the controls. IVF pregnancy was also associated with higher hair As levels (p < 0.05). Multiple regression analysis revealed a significant interrelation between IVF pregnancy and hair Cu, Fe, Si, and As content. Hair Cu levels were also influenced by vitamin/mineral supplementation and the number of pregnancies, whereas hair Zn content was dependent on prepregnancy anthropometric parameters. In turn, planning of pregnancy had a significant impact on Mg levels in scalp hair. Generally, the obtained data demonstrate an elevated risk of copper, iron, zinc, calcium, and magnesium deficiency and arsenic overload in women with IVF-induced pregnancy. The obtained data indicate the necessity of regular monitoring of micronutrient status in IVF-pregnant women in order to prevent potential deleterious effects of altered mineral homeostasis.

Deswal R, Narwal V, Dang A, Pundir CS. The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review

Background: Polycystic ovary syndrome (PCOS), the major endocrinopathy among reproductive-aged women, is not yet perceived as an important health problem in the world. It affects 4%-20% of women of reproductive age worldwide. The prevalence, diagnosis, etiology, management, clinical practices, psychological issues, and prevention are some of the most confusing aspects associated with PCOS. Aim: The exact prevalence figures regarding PCOS are limited and unclear. The aim of this review is to summarize comprehensively the current knowledge on the prevalence of PCOS. Materials and methods: Literature search was performed through PubMed, ScienceDirect, Cochrane Library, and Google Scholar (up to December 2019). All relevant articles published in English language were identified following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Our analysis yielded 27 surveys with a pooled mean prevalence of 21.27% using different diagnostic criteria. The proportion of women with PCOS also increased in the last decade. Conclusion: The current review summarizes and interprets the results of all published prevalence studies and highlights the burden of the syndrome, thereby supporting early identification and prevention of PCOS in order to reverse the persistent upward trend of prevalence.

Hu C, Pang B, Ma Z, Yi H. Immunophenotypic Profiles in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductive-metabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.

Xu Y, Wu Y, Huang Q.  Comparison of the effect between pioglitazone and metformin in treating patients with PCOS:a meta-analysis

Background: Pioglitazone was used to treat patients of PCOS in many researches, but the treatment has not been recognized by public or recommended by all the guidelines. Method: We conducted a meta-analysis of the related literatures to objectively evaluate the clinical effectiveness and safety by comparing pioglitazone with metformin administrated by PCOS patients. Searches were performed in Cochrane Library, EMBASE and PubMed (last updated December 2016). Results: Eleven studies among 486 related articles were identified through searches. Fixed effects and random effects models were used to calculate the overall risk estimates. The results of the meta-analysis suggest that improvement of the menstrual cycle and ovulation in pioglitazone treatment group was better than metformin group [OR = 2.31, 95% CI (1.37, 3.91), P < 0.001, I 2 = 41.8%]. Improvement of the F-G scores in metformin treatment group was better than pioglitazone group [SMD = 0.29, 95% CI (0.0, 0.59), P = 0.048, I 2 = 0.0%]. BMI was more elevated in pioglitazone group than in metformin group [SMD = 0.83, 95% CI (0.24, 1.41), P = 0.006, I 2 = 82.8%]. There were no significant differences of the other data between the two groups. Conclusions: This meta-analysis indicated that pioglitazone ameliorated menstrual cycle and ovulation better than metformin and metformin ameliorated BMI and F-G scores better than pioglitazone in treating patients with PCOS. Pioglitazone might be a good choice for the patients with PCOS who were intolerant or invalid to metformin for the treatment.

Montanino Oliva M, Buonomo G, Calcagno M, Unfer V. Effects of myo-inositol plus alpha-lactalbumin in myo-inositol-resistant PCOS women

Background: Myo-inositol (MI), successfully used in polycystic ovary syndrome (PCOS), was administered with α-LA to exploit its action of favouring the passage of other molecules through biological barriers, and also considering its anti-inflammatory effect. Methods: PCOS patients, according to the Rotterdam ESHRE-ASRM criteria, with anovulation and infertility > 1 year, were included in this open and prospective study. The preliminary phase was aimed at determining a set of MI-resistant PCOS patients. This treatment involved 2 g MI, taken twice per day by oral route, for three months. The Homeostasis Model Assessment (HOMA) index and MI plasma levels were measured. In the main phase, previously selected MI-resistant patients received the same daily amount of MI plus 50 mg α-LA twice a day, for a further three months. Ovulation was assessed using ultrasound examination on days 12, 14 and 20 of the cycle. The HOMA index, lipid, hormone and MI plasma levels were detected at baseline and at the end of this phase. Results: Thirty-seven anovulatory PCOS subjects were included in the study. Following MI treatment, 23 of the 37 women (62%) ovulated, while 14 (38%) were resistant and did not ovulate. In the latter group, MI plasma levels did not increase. These MI-resistant patients underwent treatment in the main phase of the study, receiving MI and α-LA. After this combined treatment, 12 (86%) of them ovulated. Their MI plasma levels were found to be significantly higher than at baseline; also, a hormone and lipid profile improvement was recorded. Conclusion: The combination of MI with α-LA allowed us to obtain significant progress in the treatment of PCOS MI-resistant patients. Therefore, this new formulation was able to re-establish ovulation, greatly increasing the chances of desired pregnancy.

Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, Ling Y, Fu H, Dong W, Shen J, Reeves A, Greenberg AS, Zhao L, Peng Y, Ding X. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain-gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3-V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain-gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes.

Ravanos K, Monastra G, Pavlidou T, Goudakou M, Prapas N. Can high levels of D-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality?

Objective: It was previously shown that higher concentrations of myo-inositol in human follicular fluid improve oocyte and embryo quality, whereas D-chiro-inositol seems to worsen oocyte quality and ovarian response in polycystic ovary syndrome patients. Our study was the first one aiming to test whether different myo-inositol and D-chiro-inositol concentration in follicular fluids correlate with blastocyst quality in healthy young women. Patients and methods: Eight egg donors and eleven couples undergoing in vitro fertilization, were involved in a prospective observational study. Myo-inositol/D-chiro-inositol ratio was calculated in the follicular fluids and associated with different blastocyst grades. Donors were homogeneous and followed the same standard stimulation protocol. Results: The ratio between myo-inositol and D-chiro-inositol was significantly higher in the specimens rated as good quality blastocysts, compared to those rated as poor-quality blastocysts. In this study, almost all the transferred blastocysts were graded as good quality and were correlated to lower D-chiro-inositol content in the follicular fluid; the implantation rate and pregnancy rate were satisfying. Our data suggest that the reduction of such ratio in follicular fluid seems to play a negative role in follicular development. Conclusions: We found a correlation between myo-inositol/D-chiro-inositol ratio in follicular fluid and blastocyst quality. The value of this ratio may represent a new biomarker for estimating the good features of blastocysts, and a prognostic factor of embryo implantation and pregnancy success. Moreover, the pre-treatment with myo-inositol in women undergoing in vitro fertilization (IVF) may improve oocyte quality and ART outcome.

Muscogiuri G, Palomba S, Laganà AS, Orio F. Inositols in the Treatment of Insulin-Mediated Diseases

A growing body of research is currently focused on the role of inositol isomers and in particular myo-inositol (MYO-INS) and D-chiroinositol (DCI) in the treatment of insulin resistance states. Both isomers have been shown to exert insulin-mimetic action and to lower postprandial glucose. Further, insulin resistance-related diseases were associated to derangements in inositol metabolism. Thus, the aim of this review is to provide current evidence on the potential benefits of inositol isomers (MYO-INS and DCI) in the treatment of disease associated to insulin resistance such as polycystic ovary syndrome (PCOS), gestational diabetes, and metabolic syndrome. Finally, molecular insights into inositol insulin-sensitizing effects will be covered focusing on the possible role of inositol glycans as insulin second messengers.

Jouanne M, Oddoux S, Noël A, Voisin-Chiret AS. Nutrient Requirements during Pregnancy and Lactation

A woman's nutritional status during pregnancy and breastfeeding is not only critical for her health, but also for that of future generations. Nutritional requirements during pregnancy differ considerably from those of non-pregnant women. Thus, a personalized approach to nutritional advice is recommended. Currently, some countries recommend routine supplementation for all pregnant women, while others recommend supplements only when necessary. Maternal physiological adaptations, as well as nutritional requirements during pregnancy and lactation, will be reviewed in the literature examining the impacts of dietary changes. All of these data have been studied deeply to facilitate a discussion on dietary supplement use and the recommended doses of nutrients during pregnancy and lactation. The aim of this review is to evaluate the knowledge in the scientific literature on the current recommendations for the intake of the most common micronutrients and omega-3 fatty acids during pregnancy and lactation in the United States, Canada, and Europe. Taking into account these considerations, we examine minerals, vitamins, and omega-3 fatty acid requirements. Finally, we conclude by discussing the potential benefits of each form of supplementation.

Politano CA, López-Berroa J. Omega-3 Fatty Acids and Fecundation, Pregnancy and Breastfeeding

Long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as the eicosapentaenoic and docosahexaenoic acids, have been linked to human health in all stages of life, from fetal development to aging. These PUFAs act as precursors for various metabolites involved in the prevention of certain diseases. The recognizable effects of these supplements prior to pregnancy (oocyte maturation), during pregnancy (improvement in the risk of premature delivery, among others) and in the offspring (in terms of cognitive function and the approach to neurodevelopmental disorders) are described in the present narrative review. We concluded that the diffusion of these supplements may improve the prognosis of these patients in a simple, effective way, and with high safety rates.

National Institutes of Health Datos sobre la vitamina D

La vitamina D es un nutriente necesario para la salud. Ayuda al cuerpo a absorber el calcio, una de las principales sustancias necesarias para tener huesos fuertes. Junto con el calcio, la vitamina D contribuye a prevenir la osteoporosis, una enfermedad que hace que los huesos se vuelvan más delgados y débiles y sean más propensos a fracturas. Además, al cuerpo le hace falta la vitamina D para otras funciones. Los músculos la necesitan para el movimiento y los nervios para transmitir mensajes entre el cerebro y otras partes del cuerpo. La vitamina D es indispensable para que el sistema inmunitario pueda combatir las bacterias y los virus que lo atacan.

OMS-OPS Menopausia

La menopausia representa un punto en el continuo de las etapas vitales de las mujeres, y marca el final de sus años reproductivos. Tras la menopausia, una mujer no se puede quedar embarazada, salvo algunos casos excepcionales en los que se aplican tratamientos especializados de fecundidad. La mayoría de las mujeres[1] experimentan la menopausia entre los 45 y los 55 años como un episodio natural fruto del envejecimiento biológico. La menopausia viene causada por la pérdida de la función folicular de los ovarios y la disminución de los niveles de estrógenos en la sangre. La transición menopáusica puede ser un fenómeno gradual y suele comenzar con cambios en el ciclo menstrual. El término «perimenopausia» se refiere al periodo que transcurre desde la primera vez que se observan estos signos hasta un año después del último periodo menstrual. La perimenopausia puede durar varios años y afectar al bienestar físico, emocional, mental y social. Existen diversos tipos de intervenciones hormonales y no hormonales que pueden ayudar a aliviar los síntomas de la perimenopausia.[2] La menopausia puede ser una consecuencia de determinados procedimientos quirúrgicos o médicos.

Carranza-Lira, Sebastián, López-Chávez, Melissa, Díaz de León-de Luna, Alejandra, Rosales-Ortiz, Sergio, & Méndez-González, Guadalupe J. Relación de la concentración de vitamina D en sangre con la masa muscular y la función cognitiva en mujeres posmenopáusicas

Introducción: Las concentraciones bajas de vitamina D se han asociado con la pérdida de masa muscular y la alteración de la función cognitiva. Objetivo: Conocer la relación de la concentración sanguínea de vitamina D con la masa muscular y la función cognitiva en mujeres posmenopáusicas. Materiales y métodos: Se estudiaron 99 mujeres posmenopáusicas ≥ 50 años. Se midió la circunferencia de la pantorrilla, los pliegues cutáneos tricipital, bicipital, subescapular y suprailíaco. Se calcularon: el área muscular del brazo, el área muscular libre de hueso y la masa muscular total. Se realizó la prueba corta de desempeño físico (PCDF), se aplicó el cuestionario de diagnóstico rápido de sarcopenia (SARC-F) y el Mini Examen del Estado Mental (MMSE). Se tomó una muestra de sangre para medir la concentración de vitamina D en sangre. Para el análisis estadístico se utilizó la prueba U de Mann-Whitney y análisis de correlación de Spearman. Resultados: Se encontró que a mayor edad hubieron mayores concentraciones de vitamina D y mayor puntaje SARC-F. Las concentraciones de vitamina D se correlacionaron negativamente con la fuerza de agarre, la PCDF y la puntuación total del MMSE. Conclusiones: La vitamina D no tuvo una influencia positiva sobre la masa muscular. Se observó un mejor desempeño en el MMSE en aquellas con concentraciones más bajas de vitamina D.

De Franciscis P, Colacurci N, Riemma G, Conte A, Pittana E, Guida M, Schiattarella A. A Nutraceutical Approach to Menopausal Complaints

The menopausal transition, or perimenopause, is characterized by menstrual irregularities, vasomotor symptoms, sleep disturbances, mood symptoms, and urogenital tract atrophy. These changes can also affect the quality of life and one's self-esteem. Hormone replacement therapy (HRT) is considered the best option to achieve therapeutic relief of different menopausal symptoms but is usually restricted to moderate or severe symptoms. Moreover, many women refuse HRT for a variety of reasons concerning the fear of cancer and other adverse effects. According to these considerations, new topics are emerging: Dissatisfaction with drug costs and conventional healthcare, desire for personalized medicines, and the public perception that "natural is good". In this context, nonhormonal therapies are mostly evolving, and it is not unusual that women often request a "natural" approach for their symptoms. The aim of this study is to investigate nonhormonal therapies that have been identified to reduce the menopausal symptoms.

Štulíková K, Karabín M, Nešpor J, Dostálek P. Therapeutic Perspectives of 8-Prenylnaringenin, a Potent Phytoestrogen from Hops

Hop (Humulus lupulus L.), as a key ingredient for beer brewing, is also a source of many biologically active molecules. A notable compound, 8-prenylnaringenin (8-PN), structurally belonging to the group of prenylated flavonoids, was shown to be a potent phytoestrogen, and thus, became the topic of active research. Here, we overview the pharmacological properties of 8-PN and its therapeutic opportunities. Due to its estrogenic effects, administration of 8-PN represents a novel therapeutic approach to the treatment of menopausal and post-menopausal symptoms that occur as a consequence of a progressive decline in hormone levels in women. Application of 8-PN in the treatment of menopause has been clinically examined with promising results. Other activities that have already been assessed include the potential to prevent bone-resorption or inhibition of tumor growth. On the other hand, the use of phytoestrogens is frequently questioned regarding possible adverse effects associated with long-term consumption. In conclusion, we emphasize the implications of using 8-PN in future treatments of menopausal and post-menopausal symptoms, including the need for precise evidence and further investigations to define the safety risks related to its therapeutic use.

Gao Q, Kou T, Zhuang B, Ren Y, Dong X, Wang Q. The Association between Vitamin D Deficiency and Sleep Disorders: A Systematic Review and Meta-Analysis

Epidemiology studies have investigated the association between vitamin D and the risk of sleep disorders, but the results remain controversial. Therefore, we conducted this meta-analysis with the goal of clarifying the association between vitamin D and sleep disorders risk. All relevant studies were searched using PubMed, EMBASE, and Web of Science from inception to January 2018. Pooled odds ratios (ORs) and 95% confidence interval (CIs) were calculated using a fixed-effect model A total of nine studies (6 cross-sectional, 2 case-control, and 1 cohort studies) involving 9397 participants were included. By comparing the lowest verse highest levels of serum vitamin D, we found that participants with vitamin D deficiency (VDD) had a significantly increased risk of sleep disorders (OR: 1.50, 95% CI: 1.31, 1.72). Subgroup analysis showed that VDD also was associated with poor sleep quality (OR: 1.59, 95% CI: 1.23, 2.05), short sleep duration (OR: 1.74, 95% CI: 1.30, 2.32), and sleepiness (OR: 1.36, 95% CI: 1.12, 1.65). Subgroup analyses further indicated that serum 25(OH)D <20 ng/mL could significantly increase the risk of unhealthy sleep. This meta-analysis suggest that vitamin D deficiency is associated with a higher risk of sleep disorders. More high-quality cohort studies and randomized controlled trials (RCTs) are needed to verify this association.

Shanmugan S, Loughead J, Cao W, Sammel MD, Satterthwaite TD, Ruparel K, Gur RC, Epperson CN. Impact of Tryptophan Depletion on Executive System Function during Menopause is Moderated by Childhood Adversity

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Preclinical literature suggests latent effects of early life adversity on serotonin function may play a role in this phenomenon. However, evidence in human participants regarding the mechanisms by which loss of estradiol contributes to this vulnerability is lacking. Here we examined the impact of tryptophan depletion (TD) and adverse childhood experiences (ACE) on brain activation during a working memory task in menopausal women. We hypothesized that an interactive effect between ACE and TD would be observed when women were hypogonadal, and that treatment with estradiol would attenuate this effect. Thirty-three women underwent functional imaging at four time points (123 total scans) in this double-blind, placebo controlled, cross-over study. The effects of TD, ACE, and TD × ACE were evaluated using a voxel-wise, mixed-effects, 2 × 2 ANOVA. In the absence of exogenous estradiol, a TD by ACE interaction was observed on BOLD signal in the right DLPFC such that TD increased activation in high ACE subjects but decreased activation in low ACE subjects. While a similar interaction was observed with placebo treatment, treatment with estradiol attenuated the effects of ACE and TD such that no between or within group differences were observed. Together, these results suggest that early life adversity may have a lasting impact on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause.

ranco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, Oliver-Williams C, Muka T. Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis

Importance: Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms. Objective: To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness. Data sources: The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies. Study selection: Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness. Data extraction: Data were extracted by 2 independent reviewers using a predesigned data collection form. Main outcomes and measures: Hot flashes, night sweats, and vaginal dryness. Results: In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, -1.31 [95% CI, -2.02 to -0.61]) and vaginal dryness score (pooled mean difference of changes, -0.31 [95% CI, -0.52 to -0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, -2.14 [95% CI, -5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, -0.79 [-1.35 to -0.23]) and vaginal dryness score (pooled mean difference of changes, -0.26 [-0.48 to -0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality. Conclusions and relevance: This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.

Abdi F, Mobedi H, Roozbeh N. Hops for Menopausal Vasomotor Symptoms: Mechanisms of Action

Menopause is a critical stage of women's life associated with various complaints and distresses. Vasomotor symptoms (VMS), such as hot flushes, night sweats, sleep disturbances, and fatigue, are the most common menopause symptoms affecting about 50% to 80% of middle-aged women. Obviously, these symptoms, resulting from estrogen deficiency during menopause, can exert negative effects on women's health and quality of life and thus require to be managed through approaches such as hormone replacement therapy (HRT). Many herbal treatments for menopause symptoms contain and its components such as 8-prenylnaringenin, 6-PN, isoxanthohumol and xanthohumol. Recent in-vivo studies have highlighted the ability of 8-prenylnaringenin to reduce serum-luteinizing hormone (LH) and follicle-stimulating hormone (FSH), to increase serum prolactin levels and uterine weight, and to induce vaginal hyperplastic epithelium. Previous research has shown that hops extract can strongly bind to both estrogen receptors, stimulate alkaline phosphatase activity in Ishikawa cells, and upregulate presenelin-2 and progesterone receptor mRNA in Ishikawa cells. Numerous clinical trials have documented significant reductions in the frequency of hot flushes following the administration of hop-containing preparations. Nevertheless, further clinical trials with larger sample size and longer follow-up are warranted to confirm such benefits.

Gaudard AM, Silva de Souza S, Puga ME, Marjoribanks J, da Silva EM, Torloni MR. Bioidentical hormones for women with vasomotor symptoms

Review question This Cochrane review evaluates the effectiveness and safety of bioidentical hormone treatment (BHT) compared to no treatment or non- bioidentical hormone treatment (HT) for vasomotor symptoms experienced during the menopausal transition period. Background Various hormone therapies (HT) are available to treat menopausal vasomotor symptoms. Bioidentical hormones are chemically identical to those produced by the human body, and several types are well-tested and available on prescription. Many women have opted for bioidentical hormone therapy (BHT) on the assumption that it would be safer than other forms of HT. However, as it is unclear whether BHT is better or safer than other forms of HT, we evaluated the evidence. Study characteristics This review includes 23 randomised controlled trials conducted up to July 2015. These studies included a total of 5779 women who were in the menopausal transition period and suffered from hot flushes. Most of the studies (20/23) included only women with moderate to severe hot flushes. None of the studies reported night sweats as a separate outcome. Key results There is low to moderate quality evidence that BHT in various forms and doses is more effective than placebo in decreasing the frequency of moderate to severe hot flushes in women in the menopausal transition period. There was low to moderate quality evidence of higher rates of adverse effects such as headache, vaginal bleeding, breast tenderness and skin reactions in the BHT group. There is some evidence to suggest that higher doses of BHT are associated with more effectiveness but also higher risk of adverse effects. No data are yet available about the safety of BHT with regard to long-term outcomes such as heart attack, stroke and breast cancer. All women with a uterus who are taking any form of estrogen require co-administration of a progestogen, as unopposed estrogen is associated with endometrial hyperplasia. There is no good evidence of a difference in effectiveness between BHT and CEE, and findings with regard to adverse effects are inconsistent. The quality of the evidence is too low to reach any firm conclusions for this comparison. Quality of the evidence The main limitations in the quality of the evidence were study risk of bias (mainly due to poor reporting of methods), imprecision and lack of data suitable for analysis.

Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis; Terapia de remplaso hormonal

The serotonergic system forms a diffuse network within the central nervous system and plays a significant role in the regulation of mood and cognition. Manipulation of tryptophan levels, acutely or chronically, by depletion or supplementation, is an experimental procedure for modifying peripheral and central serotonin levels. These studies have allowed us to establish the role of serotonin in higher order brain function in both preclinical and clinical situations and have precipitated the finding that low brain serotonin levels are associated with poor memory and depressed mood. The gut-brain axis is a bi-directional system between the brain and gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral functioning of the digestive tract. An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to tryptophan and serotonin, producing a possibility that alterations in the gut may be important in the pathophysiology of human central nervous system disorders. In this review we will discuss the effect of manipulating tryptophan on mood and cognition, and discuss a possible influence of the gut-brain axis.

Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms

Review question: This Cochrane review has evaluated whether phytoestrogen treatments reduce the number and severity of hot flushesand whether they are safe and acceptable.Background: Hormone therapy is an effective treatment for controlling the most common menopausal symptoms—hot flushes and nightsweats. However, it is now recommended only in low doses given for the shortest possible time because of concerns about increased risk ofsome chronic diseases. Many women have started to use therapies that they perceive as 'natural' and safe, but they oGen do not have goodinformation about the potential benefits and risks. Some of these therapies contain phytoestrogens—a group of plant-derived chemicalsthat are thought to prevent or treat disease. Phytoestrogens are found in a wide variety of plants, some of which are foods, particularlysoy, alfalfa and red clover.Study characteristics: This review found 43 RCTs conducted up to July 2013 that included 4,084 participants with hot flushes who wereclose to the menopause or were menopausal. Evidence obtained is current to July 2013.Key results: Some trials reported a slight reduction in hot flushes and night sweats with phytoestrogen-based treatment. Extractscontaining high levels of genistein (a substance derived from soy) appeared to reduce the number of daily hot flushes and need to beinvestigated further. Overall no indication suggested that other types of phytoestrogens work any better than no treatment. No evidencewas found of harmful effects on the lining of the womb, stimulation of the vagina or other adverse effects with short-term use.Quality of the evidence: Many of the trials in this review were small, of short duration and of poor quality, and the types of phytoestrogensused varied substantially

Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: current state of knowledge and future research directions

A tight control of magnesium homeostasis seems to be crucial for bone health. On the basis of experimental and epidemiological studies, both low and high magnesium have harmful effects on the bones. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting on the secretion and the activity of parathyroid hormone and by promoting low grade inflammation. Less is known about the mechanisms responsible for the mineralization defects observed when magnesium is elevated. Overall, controlling and maintaining magnesium homeostasis represents a helpful intervention to maintain bone integrity.

Hajirahimkhan A, Simmler C, Yuan Y, Anderson JR, Chen SN, Nikolić D, Dietz BM, Pauli GF, van Breemen RB, Bolton JL. Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms

The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERβ selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical supplements. Although hops shows strong estrogenic properties via ERα, licorice might have different estrogenic activities due to its ERβ selectivity, partial estrogen agonist activity, and non-enzymatic conversion of isoliquiritigenin to liquiritigenin.

Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM, de Villiers TJ; STRAW + 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging

Objective: The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period. Methods: Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus. Results: STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage -3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage -1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics. Conclusions: STRAW + 10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW + 10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified

Bravo R, Matito S, Cubero J, Paredes SD, Franco L, Rivero M, Rodríguez AB, Barriga C. Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans

Melatonin and serotonin rhythms, which exhibit a close association with the endogenous circadian component of sleep, are attenuated with increasing age. This decrease seems to be linked to sleep alterations in the elderly. Chrononutrition is a field of chronobiology that establishes the principle of consuming foodstuffs at times of the day when they are more useful for health, improving, therefore, biorhythms and physical performance. Our aim was to analyze whether the consumption of cereals enriched with tryptophan, the precursor of both serotonin and melatonin, may help in the reconsolidation of the sleep/wake cycle and counteract depression and anxiety in 35 middle-aged/elderly (aged 55-75 year) volunteers in a simple blind assay. Data were collected for 3 weeks according to the following schedule: The control week participants consumed standard cereals (22.5 mg tryptophan in 30 g cereals per dose) at breakfast and dinner; for the treatment week, cereals enriched with a higher dose of tryptophan (60 mg tryptophan in 30 g cereals per dose) were eaten at both breakfast and dinner; the posttreatment week volunteers consumed their usual diet. Each participant wore a wrist actimeter that logged activity during the whole experiment. Urine was collected to analyze melatonin and serotonin urinary metabolites and to measure total antioxidant capacity. The consumption of cereals containing the higher dose in tryptophan increased sleep efficiency, actual sleep time, immobile time, and decreased total nocturnal activity, sleep fragmentation index, and sleep latency. Urinary 6-sulfatoxymelatonin, 5-hydroxyindoleacetic acid levels, and urinary total antioxidant capacity also increased respectively after tryptophan-enriched cereal ingestion as well as improving anxiety and depression symptoms. Cereals enriched with tryptophan may be useful as a chrononutrition tool for alterations in the sleep/wake cycle due to age.

Joo EH, Kim YR, Kim N, Jung JE, Han SH, Cho HY. Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.

Salehi B, Berkay Yılmaz Y, Antika G, Boyunegmez Tumer T, Fawzi Mahomoodally M, Lobine D, Akram M, Riaz M, Capanoglu E, Sharopov F, Martins N, Cho WC, Sharifi-Rad J. Insights on the Use of α-Lipoic Acid for Therapeutic Purposes

α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.

Costantino M, Guaraldi C, Costantino D. Resolution of subchorionic hematoma and symptoms of threatened miscarriage using vaginal alpha lipoic acid or progesterone: clinical evidences

Objective: Alpha Lipoic Acid (ALA) is a safe natural molecule that exerts a selective immunomodulating activity with antioxidant and anti-inflammatory properties. This randomized controlled clinical trial (RCT) tested the effect of the vaginal administration with ALA or Progesterone, in subchorionic hematoma resorption in women with threatened miscarriage. Patients and methods: 400 mg of vaginal Progesterone or 10 mg of vaginal ALA were administered to sixty-two pregnant women, in the first trimester of gestation with threatened miscarriage and subchorionic hematoma. Controls were patients who chose not to receive any treatment. Results: In the ALA group the subchorionic hematoma was reabsorbed more quickly in comparison with the progression detected in Progesterone group (p ≤ 0.05). The other parameters checked (pelvic pain and vaginal bleeding) did not show any significant difference and a smaller number of miscarriages was recorded in the ALA group, compared to Progesterone group. Conclusions: Our data provides the first evidence of the efficacy of ALA, administered by vaginal route, in the healing process of patients with threatened miscarriage, thus supporting the normal course of pregnancy.

Schatz F, Guzeloglu-Kayisli O, Arlier S, Kayisli UA, Lockwood CJ.  The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding

Background: Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the decidualized endometrium, modification of spiral arteries and post-partum processes. However, decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Methods: We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. Results: Progestin-induced decidualization of estradiol-primed human endometrial stromal cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. Conclusion: Perivascular decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.

Giakoumelou S, Wheelhouse N, Cuschieri K, Entrican G, Howie SE, Horne AW. The role of infection in miscarriage

Background: Miscarriage is the spontaneous loss of a pregnancy before 12 weeks (early miscarriage) or from 12 to 24 weeks (late miscarriage) of gestation. Miscarriage occurs in one in five pregnancies and can have considerable physiological and psychological implications for the patient. It is also associated with significant health care costs. There is evidence that potentially preventable infections may account for up to 15% of early miscarriages and up to 66% of late miscarriages. However, the provision of associated screening and management algorithms is inconsistent for newly pregnant women. Here, we review recent population-based studies on infections that have been shown to be associated with miscarriage. Methods: Our aim was to examine where the current scientific focus lies with regards to the role of infection in miscarriage. Papers dating from June 2009 with key words 'miscarriage' and 'infection' or 'infections' were identified in PubMed (292 and 327 papers, respectively, on 2 June 2014). Relevant human studies (meta-analyses, case-control studies, cohort studies or case series) were included. Single case reports were excluded. The studies were scored based on the Newcastle - Ottawa Quality Assessment Scale. Results: The association of systemic infections with malaria, brucellosis, cytomegalovirus and human immunodeficiency virus, dengue fever, influenza virus and of vaginal infection with bacterial vaginosis, with increased risk of miscarriage has been demonstrated. Q fever, adeno-associated virus, Bocavirus, Hepatitis C and Mycoplasma genitalium infections do not appear to affect pregnancy outcome. The effects of Chlamydia trachomatis, Toxoplasma gondii, human papillomavirus, herpes simplex virus, parvovirus B19, Hepatitis B and polyomavirus BK infections remain controversial, as some studies indicate increased miscarriage risk and others show no increased risk. The latest data on rubella and syphilis indicate increased antenatal screening worldwide and a decrease in the frequency of their reported associations with pregnancy failure. Though various pathogens have been associated with miscarriage, the mechanism(s) of infection-induced miscarriage are not yet fully elucidated. Conclusions: Further research is required to clarify whether certain infections do increase miscarriage risk and whether screening of newly pregnant women for treatable infections would improve reproductive outcomes.

Porcaro G, Brillo E, Giardina I, Di Iorio R. Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: preliminary clinical results; PazOB; Salud Materna y Epigenómica

Objective: The clinic use of alpha Lipoic Acid (ALA) is linked to its capability to exert antioxidant effects and, more interestingly, to counteract the pathologic changes of complex networks of cytokines, chemokines and growth factors, restoring their physiological state. The aim of this randomized controlled clinical trial was to test the contribution of oral supplementation of ALA to the standard treatment with Progesterone vaginal suppositories, in healing subchorionic hematomas in patients with threatened miscarriage. Controls were administered only Progesterone suppositories. Patients and methods: Nineteen pregnant women in the first trimester of gestation, with threatened miscarriage and ultrasound evidence of subchorionic hematoma, were included in the trial and randomly divided in two groups: controls, treated with 400 mg Progesterone (200 mg 2 times per day), given by vaginal suppositories, and case study treated with the same Progesterone dosage, plus ALA, given orally at the dose of 600 mg (300 mg 2 times per day, DAV®, Lo.Li. Pharma srl, Italy). Sixteen patients completed the trial. Treatment was performed until complete resolution of the clinical picture. Results: In both groups, the subjects improved significantly but, in general, a better and faster evolution in the major signs of threatened miscarriage was observed in the subjects treated with ALA and Progesterone. In these patients, the speed of resorption of subchorionic hematoma was significantly (p ≤ 0.05) superior compared to controls. The ALA and Progesterone group showed a faster decrease or disappearance of all symptoms than that observed in the control group, however the difference was not significant. Conclusions: These preliminary results suggest that ALA supplementation significantly contributes to speed up the process of restoration of physiological conditions in threatened miscarriage and ameliorates the medical conditions of both the mothers and the foetus, probably modulating the networks of cytokines, growth factors and other molecules.

North RA, McCowan LM, Dekker GA, Poston L, Chan EH, Stewart AW, Black MA, Taylor RS, Walker JJ, Baker PN, Kenny LC. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort

Objectives: To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Design: Prospective multicentre cohort. Setting: Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. Participants: 3572 "healthy" nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Main outcome measure: Pre-eclampsia defined as ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks' gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37(+0) weeks' gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Results: Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks' gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. Conclusions: The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added.

Clissold SP, Heel RC. Tioconazole. Tioconazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses

Tioconazole is a substituted imidazole antimicrobial agent structurally related to other drugs in this group. It has been shown to have a broad spectrum of activity in vitro against dermatophytes and yeasts, as well as against some chlamydia, trichomonads and Gram-positive bacteria. Both open and controlled clinical trials have clearly demonstrated the efficacy and safety of topical preparations of tioconazole for treating superficial dermatophyte or yeast infections of the skin and vaginal candidiasis. In comparative studies it was at least as effective as alternative imidazole antifungal drugs, and in a few trials significantly greater efficacy has been reported for tioconazole, compared with clotrimazole, miconazole, econazole and systemic ketoconazole. Preliminary studies in other clinical areas suggest tioconazole may be useful for treating onychomycosis (in a special nail formulation), napkin-rash due to Candida albicans, impetigo, and vaginal trichomoniasis, although comparative studies are needed in each of these settings to clearly assess its relative place in therapy. Thus, tioconazole is an effective and well tolerated treatment for vaginal candidiasis and superficial fungal infections of the skin.

Erol TAVMERGENa, Ferruh ACETa, Cüneyt Eftal TANERb, Fatih DURMUŞOĞLUc, Yaprak ÜSTÜNd, Berna DİLBAZd, Fatma Feriha ÇİLLİe The Efficacy and Safety of Gynomax® XL Vaginal Ovule in the Treatment of Common Vaginal Infections: A Single-Arm Clinical Trial, Gyno-Türk

ABSTRACT Objective: The objective of this study was to evaluate the efficacy, safety, and tolerability of Gynomax® XL vaginal ovule in the treatment of bacterial vaginosis (BV), candidal vulvovaginitis (CVV), trichomonal vaginitis (TV), and mixed vaginal infections (MVI). Material and Methods: A total of 98 women diagnosed clinically with BV, CVV, TV, or MVI have completed this study. Patients were given Gynomax® XL for 3 consecutive days, and approximately 10 (+/-5) days after the treatment, a follow-up visit was conducted. In addition to the clinical examinations, vaginal swab samples were collected in both visits for microbiological tests. Results: Based on the clinical diagnosis of the investigators, most of the patients had MVIs (54.1%), followed by BV (24.5%) and CVV (20.4%) at the baseline visit. One (1.0%) patient was diagnosed as having TV. According to the microbiologic examination results, 44 (44.9%) patients had BV, 20 (20.4%) had CVV, and 13 (13.3%) had MVIs. According to the clinical findings, overall complete recovery (CR) was observed in 76.5% of the patients and according to the microbiologic findings, overall CR was observed in 85.7% of the patients. Microbiologic results evaluated by each diagnostic criterion showed that CR was detected in 93.2%, 85.0%, and 61.5% of the patients with BV, CVV, and MVIs, respectively. There were no serious or non-serious adverse events leading to patient withdrawal or treatment discontinuation during this study. Conclusion: Gynomax® XL vaginal ovules administered once daily for three consecutive days provide effective and safe treatment in patients with BV, CVV, and MVIs.

Paladine HL, Desai UA. Vaginitis: Diagnosis and Treatment

Vaginitis is defined as any condition with symptoms of abnormal vaginal discharge, odor, irritation, itching, or burning. The most common causes of vaginitis are bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis. Bacterial vaginosis is implicated in 40% to 50% of cases when a cause is identified, with vulvovaginal candidiasis accounting for 20% to 25% and trichomoniasis for 15% to 20% of cases. Noninfectious causes, including atrophic, irritant, allergic, and inflammatory vaginitis, are less common and account for 5% to 10% of vaginitis cases. Diagnosis is made using a combination of symptoms, physical examination findings, and office-based or laboratory testing. Bacterial vaginosis is traditionally diagnosed with Amsel criteria, although Gram stain is the diagnostic standard. Newer laboratory tests that detect Gardnerella vaginalis DNA or vaginal fluid sialidase activity have similar sensitivity and specificity to Gram stain. Bacterial vaginosis is treated with oral metronidazole, intravaginal metronidazole, or intravaginal clindamycin. The diagnosis of vulvovaginal candidiasis is made using a combination of clinical signs and symptoms with potassium hydroxide microscopy; DNA probe testing is also available. Culture can be helpful for the diagnosis of complicated vulvovaginal candidiasis by identifying nonalbicans strains of Candida. Treatment of vulvovaginal candidiasis involves oral fluconazole or topical azoles, although only topical azoles are recommended during pregnancy. The Centers for Disease Control and Prevention recommends nucleic acid amplification testing for the diagnosis of trichomoniasis in symptomatic or high-risk women. Trichomoniasis is treated with oral metronidazole or tinidazole, and patients' sex partners should be treated as well. Treatment of noninfectious vaginitis should be directed at the underlying cause. Atrophic vaginitis is treated with hormonal and nonhormonal therapies. Inflammatory vaginitis may improve with topical clindamycin as well as steroid application.

Schwebke JR, Gaydos CA, Nyirjesy P, Paradis S, Kodsi S, Cooper CK.  Diagnostic Performance of a Molecular Test versus Clinician Assessment of Vaginitis; Liviaxan; Infeción de vías urinarias

Vaginitis is a common complaint, diagnosed either empirically or using Amsel's criteria and wet mount microscopy. This study sought to determine characteristics of an investigational test (a molecular test for vaginitis), compared to reference, for detection of bacterial vaginosis, Candida spp., and Trichomonas vaginalis Vaginal specimens from a cross-sectional study were obtained from 1,740 women (≥18 years old), with vaginitis symptoms, during routine clinic visits (across 10 sites in the United States). Specimens were analyzed using a commercial PCR/fluorogenic probe-based investigational test that detects bacterial vaginosis, Candida spp., and Trichomonas vaginalis Clinician diagnosis and in-clinic testing (Amsel's test, potassium hydroxide preparation, and wet mount) were also employed to detect the three vaginitis causes. All testing methods were compared to the respective reference methods (Nugent Gram stain for bacterial vaginosis, detection of the Candida gene its2, and Trichomonas vaginalis culture). The investigational test, clinician diagnosis, and in-clinic testing were compared to reference methods for bacterial vaginosis, Candida spp., and Trichomonas vaginalis The investigational test resulted in significantly higher sensitivity and negative predictive value than clinician diagnosis or in-clinic testing. In addition, the investigational test showed a statistically higher overall percent agreement with each of the three reference methods than did clinician diagnosis or in-clinic testing. The investigational test showed significantly higher sensitivity for detecting vaginitis, involving more than one cause, than did clinician diagnosis. Taken together, these results suggest that a molecular investigational test can facilitate accurate detection of vaginitis.

Martell B, Kushner H, Richardson E, Mize A, Mayer P. Pharmacokinetics of Lidocaine and Its Metabolites Following Vaginal Administration of Lidocaine Gel to Healthy Female Subjects

Lidocaine vaginal bioadhesive gel is being developed as a local anesthetic for use in minimally invasive outpatient gynecological procedures and was investigated in single-dose and multiple-dose studies in healthy young adult women. Lidocaine doses of 2.5%, 5%, and 10% (w/w) were administered, and parent drug and metabolites monoethylglycinexylidide and glycinexylidide were measured in plasma. Lidocaine was absorbed through vaginal tissue and into the systemic circulation in a dose-proportional manner, and there was little systemic accumulation. Plasma concentrations were 10- to 20-fold lower than concentrations obtained after administration of intravenous lidocaine used to treat arrhythmic activity, thus demonstrating a wide safety margin for a vaginal lidocaine product.

Raja IM, Basavareddy A, Mukherjee D, Meher BR. Randomized, double-blind, comparative study of oral metronidazole and tinidazole in treatment of bacterial vaginosis

Objective: To compare the efficacy and tolerability of oral metronidazole and tinidazole in patients with bacterial vaginosis (BV) using Amsel's criteria. Patients and methods: This was a randomized double-blind study, conducted by the Departments of Pharmacology and Gynecology of a tertiary care teaching hospital. Patients diagnosed with BV received either tablet metronidazole 500 mg twice daily for 5 days or tablet tinidazole 500 mg once daily + one placebo for 5 days and instructed to come for follow-up at the 1st week and 4th week. They were categorized as cured, partially cured, and not cured based on Amsel's criteria at the end of the study and compared between two groups using Chi-square test. Results: A total 120 women were enrolled in the study, of which 114 completed the study. The treatment arms were comparable. The cure rate with low-dose tinidazole was significantly more compared to metronidazole at 4th week (P = 0.0013), but not at 1st week (P = 0.242). The adverse drug reactions were less with tinidazole compared to metronidazole. Conclusion: Tinidazole at lower dose offers a better efficacy than metronidazole in long-term cure rates and in preventing relapses with better side effect profile.

Workowski KA, Bolan GA; Sexually transmitted diseases treatment guidelines, 2015

These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs

Z Abbaspoor Efficacy and safety of oral tinidazole and metronidazole in treatment of bacterial vaginosis: a randomized control trial

Aims: Oral metronidazole 500 mg twice a day for one week is currently the treatment of choice for bacterial vaginosis (BV). Complete treatment by this regimen takes time and occurs less often. This drug has significant side effects too. Using a drug in the shortest treatment course may increases the success of treatment. To evaluate the effectiveness and safety of oral tinidazole compare to metronidazole in treatment of BV. Methods: In this randomized, controlled, double-blind, comparative, clinical trial, 110 non-pregnant women aged between 15-45 years with confirmed diagnosis of BV by Amsels criteria were randomly assigned to receive either 2 g tinidazole tablet once daily for 2 days (n=55) or 500 mg metronidazole table twice daily for 7 days (n=55).The cure and recurrence rate were evaluated in both groups after 2 and 4 weeks follow up visits. For statistical analysis t-test, test, fisher's exact test and Mann-Whitney test were used. Results: The results showed that cure rate after 2 weeks in tinidazole tablet group was 84.6 and in metronidazole group was 85.4 (p=0.9), and after 4 weeks recurrence rate in tinidazole and metronidazole groups was 6.9 and 12.1 respectively (P=0.3). Conclusions: Tinidazole table 2 g once daily for 2 days is as effective as metronidazole tablet 500 mg twice a day for 7 days in treatment of BV.

Thulkar J, Kriplani A, Agarwal N. A comparative study of oral single dose of metronidazole, tinidazole, secnidazole and ornidazole in bacterial vaginosis

Objective: To compare the cure rates of oral single dose of metronidazole (2 g), tinidazole (2 g), secnidazole (2 g), and ornidazole (1.5 g) in cases of bacterial vaginosis. Materials and methods: This was a prospective, comparative, randomized clinical trial on 344 Indian women (86 women in each group) who attended a gynecology outpatient department with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Gynecological examination but they did not complaint of it. For diagnosis and cure rate of bacterial vaginosis, Amsel's criteria were used. Statistical analysis was done by Chi-square test of proportions. The cure rate was compared considering metronidazole cure rate as gold standard. Results: At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs. Conclusion: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis.

Clark SM, Costantine MM, Hankins GD. Review of NVP and HG and Early Pharmacotherapeutic Intervention

NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures. ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective pharmacotherapies available to treat NVP are lacking.

Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG.  Hyperemesis gravidarum, a literature review

Hyperemesis gravidarum (HG) is a condition causing severe nausea and vomiting in early pregnancy often resulting in hospital admission. The incidence of HG is approximately 0.5% of live births, said to be higher in multiple pregnancies, hydatidiform mole and other conditions associated with increased pregnancy hormone levels. Both the aetiology and pathogenesis of HG remain unknown. We conducted a literature review (1966-now) to summarize the current evidence on the aetiology and pathogenesis of HG. The potential role of pregnancy-related hormones such as progesterone, estrogen and HCG has been widely studied; however, various other hormones such as leptin, placental growth hormone, prolactin, thyroid and adrenal cortical hormones have been implicated in the aetiology of HG. In addition to endocrinological hypotheses, the rationale and evidence considering infectious, immunological, psychological, metabolic and anatomical causes for HG have been analysed here. Many studies suffer from the low number of patients included, the variable definition used for HG and varying assay methodology used in studies of hormone measurement. This review highlights the need for more extensive studies addressing the pathogenesis and aetiology of HG.

Jueckstock JK, Kaestner R, Mylonas I. Managing hyperemesis gravidarum: a multimodal challenge

Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect.In most cases, the condition is self limiting and subsides by around 20 weeks gestation. More severe forms require medical intervention once other organic causes of nausea and vomiting have been excluded. In addition, a psychosomatic approach is often helpful.In view of its potential complexity, general practitioners and obstetricians should be well informed about HG and therapy should be multimodal.

Kutcher JS, Engle A, Firth J, Lamm SH. Bendectin and birth defects. II: Ecological analyses

Background: Bendectin was the primary pharmaceutical treatment of nausea and vomiting of pregnancy (NVP) in the United States until the early 1980s. Its manufacture was then discontinued after public allegations that it was causing birth defects. Subsequently, meta-analyses of the many epidemiological cohort and case/control studies used to examine that hypothesis have demonstrated the absence of a detectable teratogenic effect. This study presents an ecological analysis of the same hypothesis that examines specific malformations. Methods: Annual birth defect prevalence data for the 1970s to the 1990s have been obtained for specific birth defects from the Center for Disease Control's nationwide Birth Defect Monitoring Program. These data for the US have been compared graphically to the annual US Bendectin sales for the treatment of NVP. Data have also been obtained for annual US rates for hospitalization for NVP. The three data sets have been temporally compared in graphic analysis.Results: The temporal trends in prevalence rates for specific birth defects examined from 1970 through 1992 did not show changes that reflected the cessation of Bendectin use over the 1980-84 period. Further, the NVP hospitalization rate doubled when Bendectin use ceased. Conclusions: The population results of the ecological analyses complement the person-specific results of the epidemiological analyses in finding no evidence of a teratogenic effect from the use of Bendectin.

Koren G, Clark S, Hankins GD, Caritis SN, Umans JG, Miodovnik M, Mattison DR, Matok I. Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy

Background: Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (Diclegis®) for NVP, based in part, on the results of a phase III randomized trial demonstrating the efficacy of this drug combination [study drug marketed under the trade name Diclectin® in Canada and Diclegis® in the United States] compared to placebo in pregnant women. Study drug dosing occurred for 14 days, which is substantially longer than what has been performed in similar studies. The objective of this study was to evaluate, through secondary analysis, whether the primary measure of efficacy can be demonstrated after five days of treatment. Methods: Women suffering from NVP were randomized to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from two to four tablets a day, based on a pre-specified titration protocol. The primary efficacy endpoint was the change in the validated Pregnancy-Unique Quantification of Emesis (PUQE) score at baseline versus Day 15 between Diclegis®-treated and placebo-treated women. For the present study, the change in PUQE score between baseline and Day 15 (end of the study) was compared to the changes observed for Days 3, 4, and 5. Results: The use of delayed-release doxylamine succinate and pyridoxine hydrochloride tablets show improved NVP symptom control as compared to placebo on Days 3,4 and 5, with sustained efficacy until the end of the trial. Conclusion: A four day study drug dosing trial with Diclegis® is sufficient to document efficacy, as the results are similar to those achieved after 14 study drug dosing days. The benefit seen at the earlier time validates drug efficacy and minimizes the natural course of improvement.

Scorza K, Williams A, Phillips JD, Shaw J. Evaluation of nausea and vomiting

A comprehensive history and physical examination can often reveal the cause of nausea and vomiting, making further evaluation unnecessary. Acute symptoms generally are the result of infectious, inflammatory, or iatrogenic causes. Most infections are self-limiting and require minimal intervention; iatrogenic causes can be resolved by removing the offending agent. Chronic symptoms are usually a pathologic response to any of a variety of conditions. Gastrointestinal etiologies include obstruction, functional disorders, and organic diseases. Central nervous system etiologies are primarily related to conditions that increase intracranial pressure, and typically cause other neurologic signs. Pregnancy is the most common endocrinologic cause of nausea and must be considered in any woman of childbearing age. Numerous metabolic abnormalities and psychiatric diagnoses also may cause nausea and vomiting. Evaluation should first focus on detecting any emergencies or complications that require hospitalization. Attention should then turn to identifying the underlying cause and providing specific therapies. When the cause cannot be determined, empiric therapy with an antiemetic is appropriate. Initial diagnostic testing should generally be limited to basic laboratory tests and plain radiography. Further testing, such as upper endoscopy or computed tomography of the abdomen, should be determined by clinical suspicion based on a complete history and physical examination.

London V, Grube S, Sherer DM, Abulafia O. Hyperemesis Gravidarum: A Review of Recent Literature

Background: In the United States, hyperemesis gravidarum is the most common cause of hospitalization during the first half of pregnancy and is second only to preterm labor for hospitalizations in pregnancy overall. In approximately 0.3-3% of pregnancies, hyperemesis gravidarum is prevalent and this percentage varies on account of different diagnostic criteria and ethnic variation in study populations. Despite extensive research in this field, the mechanism of the disease is largely unknown. Although cases of mortality are rare, hyperemesis gravidarum has been associated with both maternal and fetal morbidity. The current mainstay of treatment relies heavily on supportive measures until improvement of symptoms as part of the natural course of hyperemesis gravidarum, which occurs with progression of gestational age. However, studies have reported that severe, refractory disease manifestations have led to serious adverse outcomes and to termination of pregnancies. Summary: Despite extensive research in the field, the pathogenesis of hyperemesis gravidarum remains unknown. Recent literature points to a genetic predisposition in addition to previously studied factors such as infectious, psychiatric, and hormonal contributions. Maternal morbidity is common and includes psychological effects, financial burden, clinical complications from nutritional deficiencies, gastrointestinal trauma, and in rare cases, neurological damage. The effect of hyperemesis gravidarum on neonatal health is still debated in literature with conflicting results regarding outcomes of birth weight and prematurity. Available therapy options remain largely unchanged in the past several decades and focus on parenteral antiemetic medications, electrolyte repletion, and nutritional support. Most studies of therapeutic options do not consist of randomized control studies and cross-study analysis is difficult due to considerable variation of diagnostic criteria. Key Messages: Hyperemesis gravidarum carries a significant burden on maternal health and US health care. Most published research on pathogenesis is observational and suggests multifactorial associations with hyperemesis gravidarum. Precise, strictly defined criteria for clinical diagnosis are likely to benefit meta-analyses of further research studies regarding pathogenesis as well as therapeutic options.

Maltepe C, Koren G. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum--a 2013 update

Nausea and vomiting of pregnancy (NVP) affects up to 85% of all pregnancies, yet many physicians are uncertain as to how to best treat their patients in the presence of controversial data on fetal risks. This review provides an update on the management of NVP, including pharmacological and non pharmacological approaches Due to a high rate of recurrent symptoms, it is important for women to receive early treatment to reduce the severity of symptoms with the aim of preventing hospitalization and improving quality of life.

Clark SM, Costantine MM, Hankins GD. Review of NVP and HG and Early Pharmacotherapeutic Intervention

NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures. ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective pharmacotherapies available to treat NVP are lacking.

Koren G, Clark S, Hankins GD, Caritis SN, Umans JG, Miodovnik M, Mattison DR, Matok I. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial

Background: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. Methods: We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Results: Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Conclusions: Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy.

O'Donnell A, McParlin C, Robson SC, Beyer F, Moloney E, Bryant A, Bradley J, Muirhead C, Nelson-Piercy C, Newbury-Birch D, Norman J, Simpson E, Swallow B, Yates L, Vale L. Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review and economic assessment

Background: Nausea and vomiting in pregnancy (NVP) affects up to 85% of all women during pregnancy, but for the majority self-management suffices. For the remainder, symptoms are more severe and the most severe form of NVP - hyperemesis gravidarum (HG) - affects 0.3-1.0% of pregnant women. There is no widely accepted point at which NVP becomes HG. Objectives: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of treatments for NVP and HG. Data sources: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, PsycINFO, Commonwealth Agricultural Bureaux (CAB) Abstracts, Latin American and Caribbean Health Sciences Literature, Allied and Complementary Medicine Database, British Nursing Index, Science Citation Index, Social Sciences Citation Index, Scopus, Conference Proceedings Index, NHS Economic Evaluation Database, Health Economic Evaluations Database, China National Knowledge Infrastructure, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from inception to September 2014. References from studies and literature reviews identified were also examined. Obstetric Medicine was hand-searched, as were websites of relevant organisations. Costs came from NHS sources. Review methods: A systematic review of randomised and non-randomised controlled trials (RCTs) for effectiveness, and population-based case series for adverse events and fetal outcomes. Treatments: vitamins B6 and B12, ginger, acupressure/acupuncture, hypnotherapy, antiemetics, dopamine antagonists, 5-hydroxytryptamine receptor antagonists, intravenous (i.v.) fluids, corticosteroids, enteral and parenteral feeding or other novel treatment. Two reviewers extracted data and quality assessed studies. Results were narratively synthesised; planned meta-analysis was not possible due to heterogeneity and incomplete reporting. A simple economic evaluation considered the implied values of treatments. Results: Seventy-three studies (75 reports) met the inclusion criteria. For RCTs, 33 and 11 studies had a low and high risk of bias respectively. For the remainder (n = 20) it was unclear. The non-randomised studies (n = 9) were low quality. There were 33 separate comparators. The most common were acupressure versus placebo (n = 12); steroid versus usual treatment (n = 7); ginger versus placebo (n = 6); ginger versus vitamin B6 (n = 6); and vitamin B6 versus placebo (n = 4). There was evidence that ginger, antihistamines, metoclopramide (mild disease) and vitamin B6 (mild to severe disease) are better than placebo. Diclectin® [Duchesnay Inc.; doxylamine succinate (10 mg) plus pyridoxine hydrochloride (10 mg) slow release tablet] is more effective than placebo and ondansetron is more effective at reducing nausea than pyridoxine plus doxylamine. Diclectin before symptoms of NVP begin for women at high risk of severe NVP recurrence reduces risk of moderate/severe NVP compared with taking Diclectin once symptoms begin. Promethazine is as, and ondansetron is more, effective than metoclopramide for severe NVP/HG. I.v. fluids help correct dehydration and improve symptoms. Dextrose saline may be more effective at reducing nausea than normal saline. Transdermal clonidine patches may be effective for severe HG. Enteral feeding is effective but extreme method treatment for very severe symptoms. Day case management for moderate/severe symptoms is feasible, acceptable and as effective as inpatient care. For all other interventions and comparisons, evidence is unclear. The economic analysis was limited by lack of effectiveness data, but comparison of costs between treatments highlights the implications of different choices. Limitations: The main limitations were the quantity and quality of the data available. Conclusion: There was evidence of some improvement in symptoms for some treatments, but these data may not be transferable across disease severities. Methodologically sound and larger trials of the main therapies considered within the UK NHS are needed.

Abou Chacra L, Fenollar F, Diop K. Bacterial Vaginosis: What Do We Currently Know?

The vaginal microbiome is a well-defined compartment of the human microbiome. It has unique conditions, characterized by the dominance of one bacterial species, the Lactobacilli. This microbiota manifests itself by a low degree of diversity and by a strong dynamic of change in its composition under the influence of various exogenous and endogenous factors. The increase in diversity may paradoxically be associated with dysbiosis, such as bacterial vaginosis (BV). BV is the result of a disturbance in the vaginal ecosystem; i.e., a sudden replacement of Lactobacilli by anaerobic bacteria such as Gardnerella vaginalis, Atopobium vaginae, Ureaplasma urealyticum, Mycoplasma hominis, and others. It is the most common cause of vaginal discharge in women of childbearing age, approximately 30% of all causes. The etiology of this dysbiosis remains unknown, but its health consequences are significant, including obstetrical complications, increased risk of sexually transmitted infections and urogenital infections. Its diagnosis is based on Amsel's clinical criteria and/or a gram stain based on the Nugent score. While both of these methods have been widely applied worldwide for approximately three decades, Nugent score are still considered the "gold standard" of BV diagnostic tools. Given the limitations of these tools, methods based on molecular biology have been developed as alternative rational strategies for the diagnosis of BV. The treatment of BV aims at restoring the balance of the vaginal flora to stop the proliferation of harmful microorganisms. Prescription of antibiotics such as metronidazole, clindamycin, etc. is recommended. Faced with the considerable uncertainty about the cause of BV, the high rate of recurrence, the unacceptable treatment options, and clinical management which is often insensitive and inconsistent, research on this topic is intensifying. Knowledge of its composition and its associated variations represents the key element in improving the therapeutic management of patients with the most suitable treatments possible.

PA Regidor, M Sailer. Open Prospective Study to Evaluate the Efficacy of a New Vaginal Pessary Containing 300mg Tinidazole, 200mg Tioconazole and 100mg Lidocaine with a 3-day Regime (GynomaxXL®) in the Treatment of Vaginal Infections due to Bacterial Vaginosis, Candidiasis and Mixed Infections

Introduction: The management of infections of the vulva and vagina depend on the selection and administration of effective specific therapies that allow a fast treatment, enhancing the compliance of the patients. Objective: The efficacy and safety of a new medicinal product containing 300mg tinidazole/200mg tioconazole/100mg lidocaine for the treatment against vaginal candida albicans, bacterial vaginosis and combined infections was evaluated upon 69 patients. Clinical controls, pH, 10% KOH probe, microscopical and microbiological analysis were performed at day 1, day 4, day 10 and at day 30 of the study. Success was defined as follows: 0 points = no symptoms, 1 point = mild symptoms, 2 points = moderate symptoms, 3 points = severe symptoms. Results: A complete clinical recovery at day 10 was observed in 54 (80.6%) patients. A clinical improvement in 12 (17.9%) and a failure in 1 patient (1,5 %). At day 30 a clinical complete recovery was observed in 58 (86.6%) patients, a clinical improvement in 7 (10.4%) and a failure in 2 patients (3 %). Conclusion: This formulation (GynomaxXL), a vaginal suppository given at 3 consecutive days, is a highly effective and safe combination in the therapy of vulvovaginal candidiasis and bacterial vaginosis. Clinical trial registration number: GМXL-03-01.

Fajfr M, Balik M, Cermakova E, Bostik P.  Effective Treatment for Uncomplicated Urinary Tract Infections with Oral Fosfomycin, Single Center Four Year Retrospective Study

Abstract: Fosfomycin represents a relatively old antibiotic, but it is experiencing a comeback in recent years. According to some studies, the increasing therapeutic use of this drug led to a rapid increase in the levels of resistance in bacteria causing urinary tract infection. In the presented study, levels of resistance to fosfomycin in more than 3500 bacterial isolates before and after fosfomycin introduction into therapeutic use in the Czech Republic and the clinical efficacy of treatment in 300 patients using this drug were assessed. The results show that the resistance levels to fosfomycin in Escherichia coli isolates before and after the drug registration were not significantly different (3.4% and 4.4%, respectively). In some other Gram-negative rods, such as otherwise susceptible Enterobacter, resistance to fosfomycin increased significantly from 45.6% to 76.6%. Fosfomycin treatment of urinary tract infections showed an excellent seven-day clinical efficacy (79.7%). However, when used to treat recurrent or complicated urinary tract infections, fosfomycin treatment was associated with high levels of infection relapse, leading to relapse in a total of 20.4% of patients during the first two months. This indicates that fosfomycin exhibits good efficacy only for the treatment of uncomplicated urinary tract infections

Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin

The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, the in vitro activity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

Zamudio-Chávez O, Méndez-Tovar S, Apodaca-Tomas K, et al. Estudio de sensibilidad de fosfomicina en enterobacterias y microorganismos multidrogorresistentes de muestras de pacientes del Hospital General «Dr. Gaudencio González Garza» del CMN «La Raza»

Introducción: El aumento constante de la resistencia microbiana es actualmente un problema a nivel mundial y ha llevado a muchos países a elaborar planes nacionales de control y a investigadores a diseñar nuevas estrategias terapéuticas para las infecciones. Objetivos: Conocer la sensibilidad a fosfomicina de las enterobacterias y microorganismos multidrogorresistentes aislados de diferentes especímenes de laboratorio. Material y métodos: Se realizó un estudio descriptivo analítico en donde se recolectaron 100 cepas, especialmente de la familia Enterobacteriaceae y otras multidrogorresistentes, aisladas de pacientes hospitalizados y de terapia ambulatoria; fueron identificadas por el sistema automatizado MALDI-TOF (bioMérieux) y VITEK 2XL; se sometieron a un reto de sensibilidad contra fosfomicina por el método de Kirby-Bauer. Resultados: Se identificaron 98% de cepas sensibles y 2% resistentes a este antibiótico. Conclusión: La fosfomicina puede considerarse como una opción terapéutica adecuada para enterobacterias y cepas multidrogorresistentes con base en la sensibilidad estudiada.

van Nimwegen JF, van der Tuuk K, Liefers SC, Verstappen GM, Visser A, Wijnsma RF, Vissink A, Hollema H, Mourits MJE, Bootsma H, Kroese FGM. Vaginal dryness in primary Sjögren’s syndrome: a histopathological case–control study

Objective: The aim was to study clinical, histopathological and immunological changes in the vagina and cervix of women with primary SS, which might explain vaginal dryness. Methods: We included 10 pre-menopausal female primary SS patients with vaginal dryness and 10 pre-menopausal controls undergoing a laparoscopic procedure. The vaginal health index was recorded. Multiplex immunoassays and flow cytometry were performed on endocervical swab and cervicovaginal lavage samples to evaluate cellular and soluble immune markers. Mid-vaginal and endocervical biopsies were taken and stained for various leucocyte markers, caldesmon (smooth muscle cells), avian V-ets erythroblastosis virus E26 oncogene homologue (ERG; endothelial cells) and anti-podoplanin (lymphatic endothelium). The number of positive pixels per square micrometre was calculated. Results: One patient was excluded because of Clamydia trachomatis, and two controls were excluded because of endometriosis observed during their laparoscopy. Vaginal health was impaired in primary SS. CD45+ cells were increased in vaginal biopsies of women with primary SS compared with controls. Infiltrates were predominantly located in the peri-epithelial region, and mostly consisted of CD3+ lymphocytes. In the endocervix, CD45+ infiltrates were present in patients and in controls, but a higher number of B lymphocytes was seen in primary SS. Vascular smooth muscle cells were decreased in the vagina of primary SS patients. No differences were found in leucocyte subsets in the vaginal and endocervical lumen. CXCL10 was increased in endocervical swab samples of primary SS patients. Conclusion: Women with primary SS show impaired vaginal health and increased lymphocytic infiltration in the vagina compared with controls. Vaginal dryness in primary SS might be caused by vascular dysfunction, possibly induced by IFN-mediated pathways.

Bilardi J, Walker S, McNair R, Mooney-Somers J, Temple-Smith M, Bellhouse C, Fairley C, Chen M, Bradshaw C. Women's Management of Recurrent Bacterial Vaginosis and Experiences of Clinical Care: A Qualitative Study

Background: Few data are available on how women manage recurring bacterial vaginosis (BV) and their experiences of the clinical care of this condition. This study aimed to explore women's recurrent BV management approaches and clinical care experiences, with a view to informing and improving the clinical management of BV. Methods: A descriptive, social constructionist approach was chosen as the framework for the study. Thirty-five women of varying sexual orientation who had experienced recurrent BV in the past 5 years took part in semi-structured interviews. Results: The majority of women reported frustration and dissatisfaction with current treatment regimens and low levels of satisfaction with the clinical management of BV. Overall, women disliked taking antibiotics regularly, commonly experienced adverse side effects from treatment and felt frustrated at having symptoms recur quite quickly after treatment. Issues in clinical care included inconsistency in advice, misdiagnosis and inappropriate diagnostic approaches and insensitive or dismissive attitudes. Women were more inclined to report positive clinical experiences with sexual health physicians than primary care providers. Women's frustrations led most to try their own self-help remedies and lifestyle modifications in an attempt to treat symptoms and prevent recurrences, including well-known risk practices such as douching. Conclusion: In the face of considerable uncertainty about the cause of BV, high rates of recurrence, unacceptable treatment options and often insensitive and inconsistent clinical management, women are trying their own self-help remedies and lifestyle modifications to prevent recurrences, often with little effect. Clinical management of BV could be improved through the use of standardised diagnostic approaches, increased sensitivity and understanding of the impact of BV, and the provision of evidence based advice about known BV related risk factors.

Morán, Carlos El papel de los inositoles para tratar el síndrome de ovario poliquístico

Después de más de 80 años de la descripción inicial por Stein y Leventhal del síndrome de ovario poliquístico, sigue considerándose una entidad idiopática compleja y, no obstante una exploración amplia de los fármacos que pudieran modificar su curso o aliviar los síntomas, son escasos los que se han encontrado exitosos clínicamente para tratar los trastornos fisiopatológicos de fondo, como la resistencia a la insulina y la disociación neuroendocrina de las gonadotropinas.

Buitrón-García FR, Bailón-Uriza R, Santoyo-Haro S, Díaz-Sánchez V. Evidencias en indicaciones de la progesterona

la progesterona es una hormona esteroide con participación en la ovulación, implantación, embarazo y regulación de la función uterina durante el ciclo menstrual y de otros órganos, como la glándula mamaria. Por su mecanismo de acción, la progesterona está indicada en distintos padecimientos ginecológicos y obstétricos: síndrome premenstrual, amenaza de aborto, parto pretérmino, hemorragia uterina disfuncional y mastalgia relacionada con el ciclo menstrual.

Meléndez-González CV, Saldaña-Solórzano CF, González-Habib R, Tirán-Saucedo J. Relación entre el índice de masa corporal bajo previo al embarazo y el riesgo de parto prematuro

identificar si existe relación entre el índice de masa corporal bajo previo a la concepción y el riesgo de parto pretérmino y de ruptura prematura de membranas pretérmino. Se analizaron los datos de 120 pacientes y la regresión lineal generalizada mostró una relación estadísticamente significativa entre el índice de masa corporal previo al embarazo y el riesgo de parto pretérmino (r2 = 0.016, p = < 0.001). El IMC bajo, previo al embarazo, se relaciona con aumento poco importante del riesgo de parto pretérmino; el riesgo de ruptura prematura de membranas se incrementa discretamente en pacientes con antecedente de amenaza de aborto y ruptura prematura de membranas pretérmino.

Flores-Venegas Sandra Rocío, Germes-Piña Fernando, Levario-Carrillo Margarita. Complicaciones obstétricas y perinatales en pacientes con anemia

Determinar la relación entre complicaciones obstétricas y perinatales con la anemia durante el embarazo. Se estudiaron 1051 pacientes divididas en dos grupos: con anemia (n = 172) y sin anemia (n = 879). Se consideró anemia a la hemoglobina menor de 11 g/dL o hematocrito menor de 33%. Se clasificaron de acuerdo con la OMS como: anemia leve 10-10.9 g/dL, moderada 7-9.9 g/dL y severa menos de 7.0 g/dL. La prevalencia de anemia fue de 16%. La anemia leve se identificó con mayor frecuencia 10% (n = 111), anemia moderada y severa 6% (n = 61). Las complicaciones maternas y neonatales no mostraron asociación con la anemia materna durante el embarazo. La hemotransfusión fue mayor en pacientes con anemia (9 vs 1%).

Valdés-Bango M, Castelo-Branco C. Anticoncepción con solo progestina

La anticoncepción con solo progestinas representa una de las opciones anticonceptivas más prescrita en la actualidad. Incluye una amplia variedad de posibilidades, ya sea en formas de presentación, vías de administración y composición, como la píldora de desogestrel, los implantes subdérmicos de levonorgestrel o etonorgestrel, el inyectable de acetato de medroxiprogesterona o el sistema intrauterino de liberación de levonorgestrel. Todas comparten un componente hormonal único de la familia de las progestinas, que confiere la eficacia anticonceptiva y evita los efectos secundarios atribuibles a los estrógenos. La anticoncepción con solo progestinas es uno de los métodos con eficacia más elevada y su mecanismo de acción se basa, principalmente, en el efecto del progestágeno a nivel central (retrocontrol negativo en el eje hipotálamo-hipofisario) y periférico (atrofia endometrial, alteración de la motilidad tubárica y transformación del moco cervical). Los anticonceptivos con solo progestina pueden indicarse a cualquier mujer que demande anticoncepción, pues son métodos, en cualquiera de sus vías de administración, muy eficaces. Estarán especialmente indicados en mujeres que, de forma temporal, como en la lactancia, o de forma permanente, como las fumadoras de más de 35 años o con otros factores de riesgo de trombosis venosa profunda, no puedan utilizar métodos que contengan estrógenos. También pueden prescribirse para disminuir el sangrado menstrual o la dismenorrea.

Durand-Carbajal MM. Anticoncepción de emergencia en la práctica clínica.

La anticoncepción de emergencia, poscoito o píldora del día siguiente se refiere al consumo de ciertos anticonceptivos hormonales orales o la colocación de un dispositivo de cobre (DIU-TCu) posterior al coito como medida de emergencia para impedir un embarazo no deseado. La anticoncepción de emergencia es un método de respaldo ocasional y no para uso rutinario o continuo. La anticoncepción hormonal de emergencia, en cualquiera de sus presentaciones y compuestos, debe administrarse lo antes posible después del coito sin protección, en un plazo no mayor a 120 horas. Sin embargo, debe informársele a la mujer que la eficacia se reduce cuanto más se prolongue el intervalo entre el coito y la ingesta del anticonceptivo. La mayor eficacia se registra cuando se toma en las primeras 24 a 72 horas. No existen situaciones en que los riesgos de la anticoncepción de emergencia (en combinación o solo con progestina) superen las ventajas de la prevención del embarazo. Las mujeres con embarazo ectópico previo, que estén amamantando, con enfermedades cardiovasculares, migrañas y enfermedad hepática pueden recibir anticoncepción de emergencia. Es importante que el personal de salud prescriba correctamente los métodos anticonceptivos, incluida la anticoncepción de emergencia

Celis-González C, Palacios S, Durand-Carbajal M, et al. Anticoncepción oral libre de estrógenos.

Antecedentes: Las píldoras de solo progestágeno, tradicionalmente se han asociado con un control del ciclo insuficiente, reglas estrictas para la ingesta y con indicación exclusiva para las mujeres con contraindicaciones para los estrógenos. Objetivo: Revisar la evolución de los anticonceptivos de solo progestágeno en relación con su formulación, limitaciones e indicaciones. Método: Búsqueda en las bases de PubMed de artículos originales publicados entre 1980 y 2019 con los MeSH: Estrogen-free oral hormonal contraception; Progestogenonly contraceptives; antimineralocorticoide estrogen; Drospirenone. Resultados: Se encontraron 65 artículos y se descartaron 34 por limitaciones en la metodología, poblaciones de estudio limitadas, o no representativas.

Garza-Garza Mario Alberto, Aguilar-Melgar Ashanti Edith, Dávila-Garza Sergio Alberto, Galache-Vega Pedro, Santos-Haliscak Roberto. Correlación de los valores de vitamina D con los de hormona antimülleriana en mujeres con infertilidad

Evaluar la asociación entre las concentraciones séricas de 25-hidroxivitamina D y las de hormona antimülleriana en pacientes mexicanas con infertilidad. Estudio retrospectivo, transversal, de análisis relacional de pacientes que acudieron a consulta al Centro de Fertilidad-IECH entre los meses de mayo de 2019 y mayo de 2020. Se utilizó la prueba de normalidad de Kolmogorov-Smirnov, con medias y desviaciones estándar para valores normales; medianas y rangos intercuartiles (RIQ) para valores no paramétricos. Para mostrar diferencias entre los grupos se aplicó la prueba t pareada y de Mann-Whitney dependiendo, respectivamente, de la normalidad de los datos y del coeficiente de correlación de Spearman para calcular la dependencia entre las variables no paramétricas. Se usó el programa GraphPad Prism (v 8), el valor de p < 0.05 se consideró con significación estadística. Se analizaron 106 expedientes de pacientes con diagnóstico de infertilidad con media de 35 ± 4.97 años y mediana de 19.90 ng/mL (RIQ 57.06) de 25-hidroxivitamina D. La deficiencia de vitamina D (menos de 20 ng/mL) no se asoció con los valores de hormona antimülleriana (p = 0.0525); se encontró diferencia entre las concentraciones de vitamina D para pacientes menores y mayores de 35 años (p = 0.0423) y una correlación entre vitamina D y hormona antimülleriana (rho de Spearman: -0.210, IC95%: -0.41 a -0.005, p = 0.0495).

Soria-Gonzales Lalescka Araceli, Moquillaza-Alcántara Victor Hugo. ́ndice de masa corporal pregestacional y ganancia de peso gestacional relacionados con el peso al nacer

Evaluar la relación entre el índice de masa corporal previo al embarazo, la ganancia de peso y el peso del recién nacido. Estudio analítico y transversal mediante muestreo probabilístico efectuado en pacientes que concluyeron su embarazo en el Hospital San Juan de Lurigancho, Perú, durante el año 2018. Parámetros de estudio: índice de masa corporal previo al embarazo: bajo peso, normal, sobrepeso y obesidad; ganancia de peso: insuficiente, adecuada y excesiva; peso del recién nacido en gramos. La variación del peso al nacer según el índice de masa corporal previo al embarazo y la ganancia de peso se evaluaron con pruebas H de Kruskal-Wallis y ANOVA, respectivamente. También se utilizó un modelo de regresión lineal múltiple con IC95%. Se estudiaron 197 pacientes que iniciaron el embarazo siendo obesas o con bajo peso que tuvieron neonatos con mayor peso al nacer (3516.9 ± 480.7 g y 3564 ± 148.5 g, respectivamente). Se determinó que no existe asociación entre el índice de masa corporal previo al embarazo y el peso del recién nacido (p = 0.753). Sin embargo, el peso al nacer fue mayor en los hijos de madres con excesiva ganancia de peso (3582.9 ± 442.1 g) y menor en quienes tuvieron insuficiente ganancia de peso (3278.9 ± 447.9 g). Esto demuestra asociación significativa entre la ganancia de peso durante el embarazo y el peso al nacer (p < 0.001). El índice de masa corporal previo al embarazo, de forma independiente, no se relacionó con el peso al nacer. Sin embargo, junto con la ganancia de peso durante el embarazo sí se relacionó positivamente con el peso del recién nacido.

Ayala-Yáñez R, Martínez-Ruíz M, Alonso-de Mendieta M, et al. Metformina interacciones moleculares, celulares y su repercusión en la Obstetricia

Objetivo: Identificar los mecanismos celulares más reconocidos de la metformina y su relación con patologías en Obstetricia y determinar las moléculas y vías involucradas con potencial terapéutico. Estudio retrospectivo efectuado con base en la búsqueda de artículos registrados en Pubmed y Cochrane publicados en inglés entre los años 2000 a 2019 que contuvieran las palabras clave (MeSH): 'Metformin'; 'Celular mechanisms'; 'AMPK'; 'LKB1'; 'Gestational diabetes', 'Abortion' y 'Preeclampsia'.  Se encontraron 1750 artículos que contenían las palabras clave de búsqueda; al final solo se analizaron 57. En estos se concluye que la intervención con este fármaco inhibe el complejo I de la cadena respiratoria mitocondrial, con repercusión en varios procesos celulares. La diabetes gestacional, el aborto y la preeclampsia se consideraron por su incidencia y relevancia obstétrica, y por la indicación de la metformina en su tratamiento. Se identificaron los mecanismos involucrados en el efecto colateral gastrointestinal y la asociación con los mecanismos celulares influidos por la metformina. En los padecimientos obstétricos se identificaron los procesos metabólicos para tratamiento común, la diabetes gestacional fue la más identificada por la experiencia en diabetes mellitus. Si bien la metformina tiene una indicación clara en pacientes con diabetes gestacional, los resultados son insuficientes para aborto; en preeclampsia los mecanismos intervenidos pueden tener mayor potencial terapéutico y preventivo.

Vega-Gonzáles Emilio Oswaldo, Arnao-Degollar Verónica, García-Cajaleón Judith. Complicaciones en embarazadas con diagnóstico positivo de COVID-19

Comparar las complicaciones en embarazadas con diagnóstico positivo de COVID-19 aguda y pasada atendidas en dos establecimientos de salud de Lima Metropolitana, Perú. Estudio descriptivo, analítico y retrospectivo efectuado en pacientes embarazadas atendidas en dos centros materno infantiles de Lima Metropolitana de junio a diciembre de 2020 en quienes se aplicó la prueba de anticuerpos para COVID-19. Los datos recolectados se trasladaron a una matriz del programa SPSS 25 y se analizaron con prueba exacta de Fisher, cálculo de razón de momios e IC95%. Se analizaron 177 embarazadas con reporte positivo a una prueba rápida One Step test for Novel Coronavirus (2019-nCov) IgM/IgG Antibody (Coloidal Gold). La mayoría tuvo infección pasada, con solo IgG (50.0%), seguidas de infección aguda con IgM e IgG (43.2%). Solo el 6.8% tuvo infección en su etapa inicial, identificada solo con IgM. La única complicación con diferencia significativa entre las embarazadas con COVID-19 positiva, con infección aguda e infección pasada, fue la ruptura prematura de membranas, con un valor de p = 0.019 con la prueba exacta de Fisher. La complicación materna más frecuente fue la ruptura prematura de membranas con 16.4% y la culminación del parto fue mediante cesárea en el 27.7%. Solo se encontró una asociación significativa entre la infección aguda y la ruptura prematura de membranas (p = 0.019; OR = 2.563 IC95%: 1.115-5.892).

Reyes-Hernández MU, Bermúdez-Rentería LG, Cifuentes-Fernández EF, et al. Desenlaces perinatales adversos en fetos con diagnóstico prenatal de cardiopatía congénita

Determinar la prevalencia de desenlaces perinatales adversos en fetos con diagnóstico prenatal de cardiopatía congénita en una unidad de tercer nivel de la Ciudad de México Estudio observacional, retrospectivo, transversal y descriptivo efectuado en la Clínica de Cardiología Fetal de la Unidad Médica de Alta Especialidad del Hospital de Ginecoobstetricia 3, Centro Médico Nacional La Raza, en fetos con diagnóstico prenatal de cardiopatía congénita confirmada al nacimiento, evaluados entre enero de 2018 y junio 2019. Parámetros de estudio: variables demográficas maternas, tipo de cardiopatía y desenlaces perinatales. Se utilizó estadística descriptiva y el paquete estadístico SPSS versión 24. Se analizaron 87 fetos que arrojaron una prevalencia de cardiopatías congénitas de 1.2% de los 6979 nacimientos registrados durante el periodo de estudio. Las cardiopatías más frecuentes fueron: arritmias (17 de 87), lesiones cardiacas derechas (17 de 87), anomalías complejas (16 de 87) y lesiones cardiacas izquierdas (14 de 87). Hubo desenlaces perinatales adversos en 62 de los 87 fetos; muertes perinatales en 17 de los 87 (óbitos 4 de 87 y muertes neonatales 13 de 87), ingresaron a cuidados intensivos 35 de 87 y tuvieron parto pretérmino 27 de 87. El grupo de fetos con diagnóstico prenatal de cardiopatías congénitas tuvo una elevada prevalencia de desenlaces perinatales adversos.

Aguilar-Mor María Elena, Treviño-Báez Joaquín Darío, Castañeda-Díaz Marisela, Martínez-Gaytán Victoria, O-Pérez Luis Oswaldo de la. Efecto y tolerancia gastrointestinal de mioinositol vs metformina en el control metabólico y hormonal de pacientes con síndrome de ovario poliquístico

Evaluar el efecto de las cápsulas de soft-gel de mioinositol en la reducción del índice de HOMA, el control metabólico y hormonal en pacientes con síndrome de ovario poliquístico versus metformina y la tolerabilidad gastrointestinal de ambos. Estudio clínico prospectivo, de etiqueta abierta, controlado no aleatorizado vs activo de referencia, con diseño de grupos paralelos efectuado en el servicio de Biología de la Reproducción Humana de la Unidad Médica de Alta Especialidad 23, IMSS, Monterrey NL, de agosto 2019 a octubre 2020, en pacientes con resistencia a la insulina asociada con síndrome de ovario poliquístico e infertilidad. Se estudiaron 83 pacientes: 33 que recibieron 600 mg de mioinositol en cápsulas soft-gel por vía oral cada 12 h y 50 que tomaron 850 mg de metformina cada 12 h durante 12 semanas. Completaron el estudio 75 pacientes. El grupo tratado con mioinositol tuvo una reducción del índice de HOMA de 1.49 ± 1.05 (con valor delta de cambio) versus el grupo tratado con metformina de 0.42 ± 0.40 (con igual valor delta de cambio). La diferencia entre ambos grupos fue estadísticamente significativa. Otros parámetros metabólicos y hormonales también tuvieron desenlaces favorables en ambos grupos, pero con una tendencia superior en el grupo de mioinositol. Se demostró la ventaja del tratamiento con mioinositol en la reducción del índice de HOMA y otros parámetros metabólicos y hormonales en pacientes con resistencia a la insulina asociada con síndrome de ovario poliquístico e infertilidad, con buena tolerabilidad gastrointestinal.

Panduro-Barón J Guadalupe, Barrios-Prieto Ernesto, Pérez-Molina J Jesús, Panduro-Moore Elizabeth Guadalupe, Rosas-Gómez Elvira Sarahí Michelle, Quezada-Figueroa Norma Argelia. Obesidad y sus complicaciones maternas y perinatales

Describir las complicaciones maternas y perinatales más frecuentes en mujeres embarazadas y con obesidad.Se comparó un grupo de pacientes embarazadas con índice de masa corporal (IMC) mayor de 30 kg/m2, con feto único, con más de 29 semanas de embarazo versus un grupo control de igual cantidad de embarazadas con feto único y con más de 29 semanas de gestación e IMC normal (20.1 a 24.9 kg/m2). A los resultados se les aplicaron las pruebas χ2, exacta de Fisher y razón de momios. Se compararon 380 mujeres embarazadas con obesidad con igual cantidad de pacientes con IMC normal. El grupo de embarazadas con obesidad fue de mayor edad (media de 27.9 vs 21.9 años), trabajaban más fuera de su casa (146 vs 62 mujeres), hubo más multigestas (92 vs 55) y en el embarazo tuvieron más problemas de amenaza de aborto (91 vs 47), diabetes (70 vs 21), hipertensión (68 vs 17) y desprendimiento prematuro de placenta normoinserta (8 vs 2), fue más frecuente la cesárea (242 vs 162), desenlaces que tuvieron diferencia estadística significativa. Los neonatos tuvieron Apgar más bajo (Apgar ≤ 7 al minuto: hubo 61 vs 30) y más macrosomía (47 vs 18) con una diferencia estadística significativa, no así las malformaciones (14 vs 7) y mayor cantidad de ingresos a cuidados intensivos neonatales (44 vs 29) que, aunque fueron más frecuentes, no tuvieron diferencia estadística.

Garcés-Burbano YL, Bastidas-Sánchez BE, Ijají-Piamba JÉ, et al. Predicción de complicaciones maternas en trastornos hipertensivos del embarazo

Determinar los factores sociodemográficos, clínicos y paraclínicos que pudieran predecir complicaciones maternas en las embarazadas con trastornos hipertensivos. Estudio prospectivo, descriptivo y comparativo de serie de casos efectuado en las pacientes atendidas para la finalización del embarazo entre el 15 de junio de 2019 y el 15 de junio de 2020 en el servicio de Ginecoobstetricia del Hospital San José de Popayán. Criterio de inclusión: tener 20 o más semanas de embarazo y diagnóstico de trastorno hipertensivo. Se analizaron las variables sociodemográficas, clínicas y paraclínicas. Se reunieron 198 pacientes y se excluyeron 2 por no cumplir con los criterios de inclusión. El promedio de edad fue 26.7 (DE ± 7.9) años. La presión arterial al ingreso y la máxima fueron significativamente mayores en el grupo con complicaciones. El área bajo la curva para la aspartato aminotransferasa fue 0.78 (EE = 0.036; IC95%: 0.71-0.86), para lactato deshidrogenasa 0.73 (EE = 0.040; IC95%: 0.65-0.80) y para proteínas en orina espontánea 0.60 (EE = 0.043; IC95%: 0.52-0.69), estos reportes paraclínicos tuvieron significación estadística para el grupo con complicaciones (p ‹ 0.05). Las pruebas de función hepática y las proteínas en orina espontánea fueron las variables que mejor se asociaron con complicaciones en pacientes con trastornos hipertensivos del embarazo. Su identificación permitiría realizar intervenciones y seguimiento y reducir los eventos adversos maternos.

Leyva-Vázquez JI, Martínez-Marín DG, Flores-Bello L, et al. Principales motivos de consulta ginecológica de las adolescentes

Determinar los principales motivos de consulta ginecológica de las adolescentes. Estudio observacional, descriptivo, transversal, retrospectivo, homodémico y unicéntrico efectuado en el Hospital General de Zona 20 del IMSS Puebla en pacientes adolescentes atendidas entre el 1 de enero y el 31 de diciembre 2019. Criterios de inclusión: adolescentes entre 10 y 19 años, con cualquier afección ginecológica, con o sin alguna comorbilidad agregada. Criterios de exclusión: embarazadas o puérperas. Criterios de eliminación: expedientes con información incompleta. Variables de estudio: edad, escolaridad, ocupación, índice de masa corporal y motivos de consulta. Se revisaron 467 expedientes de pacientes adolescentes que recibieron diagnóstico de alguna afección ginecológica pero solo se incluyeron al estudio 450. La primera valoración ginecológica fue, en promedio, a los 18 años (21.8%). Los principales motivos de consulta fueron: sangrado uterino anormal (n = 66), mastopatía fibroquística (n = 63), dismenorrea (n = 55), amenorrea secundaria (n = 45) y síndrome de ovario poliquístico (n = 41). Los cinco principales motivos de consulta ginecológica de las adolescentes fueron: sangrado uterino anormal, mastopatía fibroquística, dismenorrea, amenorrea secundaria y síndrome de ovario poliquístico, al igual que lo reportado en la bibliografía internacional.

Oviedo-Cruz H, Carrasco-Blancas ER, Valenzuela-Muhech YL, et al. Validación de la calculadora de la Fundación de Medicina Fetal para tamiz de preeclampsia adaptada a población mexicana

Validar el rendimiento de la calculadora de la Fundación de Medicina Fetal 4.0 adaptada a población mexicana. Estudio de cohorte efectuado en embarazos con feto único, según el modelo de riesgos en competencia para preeclampsia en un centro de medicina fetal de la Ciudad de México. El riesgo a priori se calculó de acuerdo con la historia clínica. La presión arterial media, el índice de pulsatilidad medio de la arteria uterina y la proteína plasmática A asociada al embarazo se midieron a las 11 a 14 semanas de gestación con metodología estandarizada. El valor de cada marcador se transformó en múltiplos de la mediana adaptados a la población local. Se aplicaron la distribución normal multivariante y el teorema de Bayes para obtener las probabilidades posprueba individuales, que se utilizaron como clasificadores para el área bajo la curva de característica receptor-operador. La incidencia de preeclampsia fue del 5.0% (54/1078). El área bajo la curva de característica receptor-operador fue de 0.784 (0.712; 0.856) para preeclampsia a menos de 37 semanas y de 0.807 (0.762; 0.852) para preeclampsia global. La calculadora FMF 4.0 adaptada a población mexicana resultó válida. Si bien tuvo menor rendimiento al esperado para preeclampsia a menos de 37 semanas, el rendimiento para preeclampsia global fue satisfactorio. Se justifica desarrollar la calculadora local.

Martínez-Lazcano F, Guzmán-López A, Riquelme-Heras H, et al. Asociación entre el hiperparatiroidismo secundario a la deficiencia de vitamina D en el embarazo y la frecuencia de preeclampsia

Establecer si existe asociación entre el hiperparatiroidismo secundario a una deficiencia de vitamina D en el embarazo y la frecuencia de preeclampsia. Estudio de casos y controles, prospectivo y longitudinal efectuado en pacientes con y sin preeclampsia que entre el 1 de enero y el 30 de junio del 2021 acudieron al Hospital Universitario de la Universidad Autónoma de Nuevo León para la atención del parto. Criterios de inclusión: pacientes embarazadas con diagnóstico de preeclampsia en el último trimestre de la gestación con tensión arterial igual o mayor a 140-90 mmHg y proteinuria igual o mayor a 30 mg/dL. Para el grupo control: embarazadas sanas, sin diagnóstico de preeclampsia en el último trimestre de la gestación. Criterios de exclusión: tabaquismo, alcoholismo y drogadicción y quienes no aceptaron entrar al estudio o tuvieran diagnóstico de enfermedades médicas crónicas. Se estudiaron 90 pacientes divididas en dos grupos: con preeclampsia (n = 45) y sin ésta (control, n = 45). Se encontró una relación entre la deficiencia de vitamina D, la hipocalcemia y la preeclampsia; no así entre la paratohormona y la preeclampsia en los rangos internacionales de la primera. La preeclampsia se encontró con mayor frecuencia en pacientes de 12 a 15 años.El hiperparatiroidismo secundario a la deficiencia de vitamina D en el embarazo no se observó en pacientes con preeclampsia, quienes sí la padecieron tuvieron concentraciones de paratohormona en límites normales. Se encontró una relación entre la deficiencia de vitamina D, la hipocalcemia y la preeclampsia.

Ruipérez-Pacheco Estefanía, Carmona-Payán Paola, Blázquez-Barbero Elena, Herráiz-Martínez Miguel Ángel Influencia del sobrepeso y la obesidad pregestacionales en el embarazo y en los desenlaces perinatales

Comparar las diferencias en la vía de nacimiento (cesárea, instrumentado o parto eutócico) entre embarazadas con IMC ≥ 25 y menor de 25. Secundario: comparar las diferentes complicaciones gestacionales y puerperales en embarazadas con IMC ≥ 25 y menor que éste. Estudio analítico, longitudinal, observacional, de cohortes y retrospectivo efectuado en pacientes atendidas entre diciembre de 2010 y diciembre de 2015 en el Hospital Clínico San Carlos, Madrid, España. Parámetros de estudio: concepción natural o asistida, diabetes gestacional, enfermedad hipertensiva e hipotiroidismo gestacionales, peso del feto y semanas de embarazo al momento de su finalización, inducción y sus causas, vía del parto y complicaciones puerperales. Se estudiaron 642 embarazadas con límites de edad de 13 y 45 años, con media de 32 años. El riesgo de cesárea fue 1.6 veces superior en embarazadas con IMC ≥ 25. Este grupo tuvo dos veces más diabetes gestacional y fetos macrosómicos y tres veces más hipertensión gestacional que las embarazadas con IMC normal. Las inducciones del parto y las complicaciones del puerperio tuvieron una tendencia mayor en IMC más elevados, sin diferencias estadísticamente significativas.

Perichart-Perera O, Rodríguez-Cano AM. Suplementación de micronutrientes durante el embarazo revisión narrativa de revisiones sistemáticas y metanálisis

Describir los efectos de la suplementación con vitamina B12, vitamina D, calcio, magnesio, zinc y múltiples micronutrientes asociados con complicaciones perinatales. Estudio retrospectivo, basado en la búsqueda bibliográfica de revisiones sistemáticas y metanálisis en la base de datos de Medline-PubMed, acerca de la suplementación con Vitamina B12, vitamina D, calcio, magnesio y zinc, además de la suplementación con múltiples micronutrientes en mujeres con embarazo único, sanas y con alteraciones metabólicas, de artículos publicados entre 2012 y 2022. Se incluyeron 51 revisiones y metanálisis. De acuerdo con los estudios, la suplementación con vitamina D reduce el riesgo de diabetes gestacional y preeclampsia, y posiblemente el riesgo de bajo peso al nacimiento y de pequeño para la edad gestacional. La suplementación con calcio disminuye el riesgo de hipertensión gestacional y preeclampsia en mujeres con alto riesgo y con bajo consumo de calcio. La suplementación con múltiples micronutrientes demostró un efecto en la reducción del bajo peso al nacimiento, pequeño para la edad gestacional, óbito y, posiblemente, parto pretérmino. Pocos estudios reportan que la suplementación con magnesio disminuye la hospitalización materna y mejora el control glucémico en mujeres con diabetes gestacional. Se requieren más estudios de suplementación con vitamina B12, zinc y magnesio

Leopoldo Santiago-Sanabria, Pamela María Ibarra-Gussi, Mario Enrique Rendón-Macías, Paulina Treviño-Villarreal, David Islas-Tezpa, Gina Daniela Porras-Ibarra, Ximena van Tienhoven Depresión posparto: prevalencia y factores de riesgo asociados en una muestra de población mexicana

Determinar la prevalencia de depresión posparto en una muestra de población mexicana por medio de la Escala de Edimburgo y los factores de riesgo asociados con su inicio. Estudio observacional, transversal, relacional y analítico efectuado en una muestra de población mexicana atendida entre los meses de marzo a julio del 2022 en cuatro hospitales de segundo y tercer nivel de cuatro entidades de la República Mexican. De una muestra de 717 pacientes a quienes se aplicó la Escala de Edimburgo, 106 resultaron positivas a depresión posparto, lo que da una prevalencia del 14.9%. La edad promedio de las pacientes fue de 26 años (límites de 12 y 46). El estado civil soltera resultó un factor protector de depresión posparto y, en su contraparte, quienes estaban casadas tuvieron cierta predisposición a la depresión posparto. A mayor grado de escolaridad menor predisposición a la depresión posparto.

Herández-Ruíz S, Solano-Ceh A, Villarreal-Ríos E, Curiel-Pérez MO, Galicia-Rodríguez L, Elizarrarás-Rivas J, Jiménez-Reyes OH. Prevalencia de diabetes e hipertensión gestacional en embarazadas con obesidad pregestacional

Describir la prevalencia de diabetes gestacional e hipertensión arterial en pacientes embarazadas con obesidad pregestacional. Estudio retrospectivo, transversal y descriptivo llevado a cabo en mujeres embarazadas con diagnóstico previo de obesidad (índice de masa corporal superior a 29.99) y con control prenatal. Parámetros evaluados: estilo de vida (alimentación, actividad física, consumo de alcohol, tabaco o alguna toxicomanía) y características físicas, clínicas y bioquímicas durante el embarazo actual por trimestre (índice de masa corporal, glucosa, presión arterial sistólica y diastólica). El diagnóstico de diabetes gestacional se estableció mediante una prueba de tolerancia a la glucosa entre las semanas 24 y 28 de embarazo. La hipertensión gestacional se diagnosticó por cifras de presión arterial mayores e iguales a 140-90 mmHg a partir de la semana 20 de embarazo y en ausencia de proteinuria. El análisis estadístico incluyó porcentajes, promedios e intervalos de confianza. La prevalencia de diabetes gestacional en embarazadas con obesidad fue 13.7% (IC95%: 9.6 a 17.9) y la de hipertensión gestacional en embarazadas con obesidad 7.4% (IC95%: 4.3 a 10.6). La obesidad es un factor conocido de riesgos, en particular de diabetes e hipertensión en el embarazo. Su alta prevalencia hace necesario implementar campañas de prevención que favorezcan su reducción.

Espitia, F. Indicaciones de la drospirenona más allá de la anticoncepción

Introducción: la drospirenona es una progestina de tercera generación, derivada de la espironolactona; la cual goza de actividad anti-mineralocorticoide y anti-androgénica, además de una alta eficacia anticonceptiva. El objetivo de esta revisión consistió en evaluar la efectividad y seguridad de la drospirenona, más allá de sus efectos anticonceptivos. Métodos: se hizo una revisión sistemática de la literatura en las bases de datos electrónicas (Medline vía PubMed, Central, CINAHL, Cochrane Database of Systematic Reviews (plataforma Wiley), entre otras), a través de términos de búsqueda libres y estandarizados. Los desenlaces evaluados incluyeron tratamiento de la endometriosis, síndrome de ovario poliquístico, sangrado uterino disfuncional, síndrome premenstrual y terapia de reemplazo hormonal, así como los efectos adversos. La búsqueda se limitó a artículos y revisiones bibliográficas publicadas a partir de 1990 hasta el 2020, en inglés y español. Resultados: se incluyeron 48 publicaciones. La drospirenona demostró ser eficaz y segura en el tratamiento de condiciones ginecológicas frecuentes como: la endometriosis, síndrome de ovario poliquístico (SOP), sangrado uterino disfuncional, síndrome premenstrual y en la terapia de reemplazo hormonal. Se observó una baja frecuencia de efectos adversos. Conclusiones: la drospirenona es eficaz y segura para el tratamiento de algunas afecciones ginecológicas de frecuente consulta en la práctica diaria, con ventajas adicionales en su régimen 24/4, además de escasa presencia de efectos adversos. Se requiere mayor evidencia más allá de la anticoncepción, para promover su recomendación e indicaciones en la práctica clínica.

Gallego Vélez L. Nuevas perspectivas hormonales en anticoncepción

Existen múltiples métodos anticonceptivos modernos disponibles en el mercado, las mujeres que requieren anticoncepción deberán elegir el que consideren más apropiado luego de una adecuada asesoría. Para facilitar las decisiones informadas, las mujeres durante las asesorías en salud sexual y reproductiva por parte de los profesionales de la salud, deben recibir información basada en la evidencia, culturalmente apropiada y adaptada a sus necesidades, valores y creencias individuales, y su decisión final deberá ser respetada.

Palacios S, Regidor PA, Colli E, Skouby SO, Apter D, Roemer T, Egarter C, Nappi RE, Skřivánek A, Jakimiuk AJ, Weyers S, Ács N, Elia D, Gemzell Danielsson K, Bitzer J. Oestrogen-free oral contraception with a 4 mg drospirenone-only pill: new data and a review of the literature

Purpose: The contraceptive pill is an effective and safe method of preventing pregnancy. The progestins used for contraception either are components of a combined hormonal contraceptive (tablets, patches or vaginal rings) or are used alone in progestin-only formulations. Progestin-only contraceptives are available as daily oral preparations, subcutaneous or intramuscular injectables (every 1-3 months), subdermal implants (every 3-5 years) and intrauterine systems (every 3-5 years). Long-acting progestins are highly effective in typical use and have a very low risk profile and few contraindications.Material and Methods: A new progestin-only, oestrogen-free contraceptive, drospirenone, in a dosage of 4 mg/day in a 24/4 regimen, has received regulatory approval in the USA and the EU. The molecule has antigonadotropic, antimineralocorticoid, antiestrogenic and antiandrogenic properties.Results: The regimen was chosen to improve the bleeding profile; maintain plasma oestradiol levels at those of the early follicular phase, to avoid hypoestrogenism; and preserve efficacy even with a missed pill, as drospirenone has a half-life of 30-34 h.Conclusions: Clinical studies have shown good efficacy, very low cardiovascular side effects and a favourable bleeding pattern, as well as maintenance of ovulation inhibition after scheduled 24 h delays in pill intake.

Palacios S, Colli E, Regidor PA Bleeding profile of women using a drospirenone-only pill 4 mg over nine cycles in comparison with desogestrel 0.075 mg

Progestin-only pills are associated with irregular bleeding pattern including amenorrhea. Desogestrel 75mcg even being a pill that inhibits ovulation shows a poor cycle control that limits a more common use. A drospirenone (DRSP)-only pill was developed to improve the bleeding profile. Methods A phase III study in healthy women aged 18 to 45 years was performed to compare the bleeding profile and safety of women taking a DRSP only pill in a regime of 24 days of 4 mg of DRSP tablets followed by 4 days of placebo versus desogestrel 0.075 mg per day continuously over 9 cycles. A total of 858 women with 6691 drospirenone and 332 women with 2487 desogestrel treatment cycles were analyzed. The primary endpoint was the proportion of women with bleeding/spotting days in each cycle from cycles 2 to 9 and cumulative in cycles 2 to 4 and cycles 7 to 9 including and excluding those with amenorrhea. Findings In each cycle, up to cycle 7, the proportion of women with unscheduled bleeding including those which did not bleed was statistically significantly lower in the DRSP group than in the DSG group (p = 0.0001, chi-square test). The mean [SD] number of unscheduled bleeding and spotting days during cycles 2–9 was statistically significantly lower in the DRSP group than in the DSG group (21.5 [22.86] days vs. 34.7 [33.73] days, p = 0.0003, Wilcoxon-ranksum-test). Excluding amenorrhoeic women following results were obtained: In the cycles 2–6, the proportion of women with unscheduled bleeding was statistically significantly lower in the DRSP group than in the DSG group (p = 0.0001, chi-square test). The mean [SD] number of bleeding days was 8.6 [8.52] days vs. 12.9 [16.47] days, p = 0.0233.

Palacios S, Colli E, Regidor PA. Metabolic and laboratory effects of a progestin-only pill containing drospirenone 4 mg in comparison to desogestrel 75 µg: a double-blind, double-dummy, prospective, randomised study.

Mainly, ethinyloestradiol (EE) in combined hormonal contraceptives (CHC) is a potent inducer of hepatic coagulation factors, has an impact on cholesterol and triglyceride levels and glucose tolerance. Progestins in CHC modify the oestrogen effects in different ways, depending on their pharmacologic properties. The metabolic impact of progestin-only contraceptives is generally considered low.Methods: The influence of novel drospirenone (DRSP)-only pill (4 mg DRSP in 24/4 intake) on a variety of lipid-, carbohydrate- and bone metabolic parameters and on haemostatic variables including clotting factors and D-Dimer level was evaluated in comparison to 0.075 mg desogestrel (DSG) during a multicentric, prospective, double-blind, double-dummy clinical trial with 1190 participants over nine treatment cycles.Results: For both DRSP and DSG, there was a decrease in cholesterol (total, HDL, and LDL) and triglyceride levels. No relevant influence on glucose, insulin, and c-peptide levels or bone remodelling markers were detected in both treatment groups. Considering the coagulatory parameters, there was no impact on hemostasis.Conclusions: The results confirm the beneficial properties of the drospirenone-only pill.

Palacios S, Colli E, Regidor PA. Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime

A new estrogen-free contraceptive has been approved by both the FDA and more than 15 European authorities. It is composed of drospirenone (DRSP) at a dosage of 4 mg in a regimen 24/4. The molecule is known to have anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. The purpose of these clinical trials with a new estrogen-free contraceptive was to introduce a contraceptive method with high efficacy and showing a profile with low cardiovascular risks. No single case of VTE was documented, no changes in hemastosiological parameters were observed, a small decrease in RR in patients with pretreatment values between 130 and 140 and/or 85 to 90 mm HG and no influence on ECG parameters were observed.

Regidor PA, Colli E. Drospirenone 4 mg in a 24/4 regimen maintains inhibition of ovulation even after a 24-h delay pill intake - Pharmacological aspects and comparison to other progestin-only pills

This review focuses on the pharmacological and inhibition of the ovulation of progestin-only, estrogen-free contraceptive containing drospirenone in a dosage of 4 mg in a regimen 24/4. The USA and European regulatory authorities have approved it. The molecule has anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. This regime improves the bleeding profile, maintains the plasma E2 levels comparable to the menstrual cycle's early follicular phase, avoids hypoestrogenism, and preserves efficacy despite forgetting the tablet intake as drospirenone has a half lifetime of 30-34 hours. Clinical studies have shown good efficacy, very low cardiovascular side effects, and high acceptability and maintenance of ovulation inhibition after scheduled 24-h delays in pill intake. The molecule is compared to other POP like levonorgestrel or desogestrel.

Regidor PA, Colli E. The progestin-only pills drospirenone 4 mg and desogestrel 0.075 mg as an option for the management of dysmenorrhea and mastodynia

Introduction: Dysmenorrhea and mastodynia are the most common gynecologic pain causes in women of all ages and races during their reproductive life. The following study aimed to show the influence of two POP´s in the development of dysmenorrhea and mastodynia after nine months of use. Material and methods: A total of 858 women with 6691 drospirenone (DRSP) cycles and 332 women with 2487 desogestrel (DSG) cycles were analyzed. Women included in this study were all child-bearing potentials, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study medication treatment, aged 18 to 45. Results: At screening, 168 (19.6%) of the 858 patients using DRSP and 64 (19,3%) of the DSG patients reported that they had suffered from dysmenorrhea within six cycles prior to the first visit before starting with the medication. 20,2% of the DRSP and 10,9% of the DSG group had a sever dysmenorrhea. After 9 cycles this was reduced to 0,6% and 3,1% respectively. In total, 96 women (11.2%) in the DRSP and 49 (14,8%) experienced mastodynia within six cycles before the screening. Of these 91.6% in the DRSP group and 91,8% in the DSG group had no or mild mastodynoa at follow-up. Discussion: The progestins 4 mg and desogestrel 0,075 mg showed a marked effect in the non-contraceptive aspects of dysmenorrhea and mastodynia so that new possibilities are opened for these two benign gynecological diseases. Future studies must reaffirm these first data.

Kubba A, Gemzell-Danielsson K, Palacios S, Wiegratz I, Grandi G, Colli E, Regidor PA. The drospirenone (DRSP)-only pill: clinical implications in the daily use

Objectives: Progestins used in contraception are either components of combined hormonal contraceptives or are used as a single active ingredient. Progestins are highly effective in long-term contraception and have a very good safety profile with very few contraindications. Methods: An oestrogen-free ovulation inhibitor POP has been authorised in the USA and the EU. It contains 4 mg of drospirenone (DRSP). The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular- phase levels, preventing oestrogen deficiency. Results: Clinical trials have demonstrated high contraceptive effectiveness, a very low risk of cardiovascular risk events and a favourable bleeding pattern. Due to the long half-life of DRSP (30-34 h), the effectiveness is maintained even in case of a forgotten pill on a single occasion. Studies involving deliberate 4 days in one cycle 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Conclusions: This review article will describe the clinical impact in the daily use of the 4 mg DRSP only pill and the resulting data on the effectiveness and safety of this hormonal contraceptive.

Melka D, Kask K, Colli E, Regidor PA. A A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

after daily administration of an oral test preparation containing 4 mg of drospirenone at the steady state. The secondary objective of the trial was to assess safety based on clinical and laboratory measurements and reporting of adverse events and/or adverse drug reactions. Patients and methods: This was an open label, non-comparative single-center study. Drospirenone 4 mg per day was the first postpartum contraceptive for the study participants who were no longer breastfeeding yet were still lactating. It was administered for 7 days to achieve steady-state concentration. All participants were volunteers who planned to use oral contraceptives as their family planning method in the future. Results: Twelve volunteers completed the trial according to the protocol, and the samples of all 12 study completers were analyzed. The average concentration-time curve of drospirenone in plasma 24 h after the administration of the last dose (area under the curve (0-24 h)) was 635.33 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0-120 h)) was 1180.57 ng h/mL, respectively. The average Cmax was 48.64 ng/mL.The average concentration-time curve of drospirenone in milk 24 h after the administration of the last dose (area under the curve (0-24 h)) was 134.35 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0-120 h)) was 227.17 ng h/mL, respectively. The average Cmax was 10.34 ng/mL. Conclusion: On average, 18.13% of plasma drospirenone made it to breast milk and the highest concentration of drospirenone in breast milk was 17.55% of that in plasma. The total quantity of drospirenone passing to breast milk is on average 4478 ng during a 24-h period representing 0.11% of the maternal daily dose. Thus, at the recommended doses, no effects on breastfed newborns/infants are anticipated with drospirenone 4 mg.

Römer T, Bitzer J, Egarter C, Hadji P, Kiechle M, Kramer H, Oppelt PG, Peters K, Stute P, Schaudig K, Wiegratz I, Regidor PA. Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 – 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive.

Regidor PA, Mueller A, Mayr M. Pharmacological and metabolic effects of drospirenone as a progestin-only pill compared to combined formulations with estrogen

oral contraceptives. Formulations with 17-β-estradiol are used to treat climacteric symptoms. A drospirenone-only formulation has been introduced for contraception. Here, the pharmacological properties of drospirenone, the impact of the different formulations on metabolic and laboratory parameters, and the resulting clinical implications are reviewed. Ethinylestradiol, an inhibitor of CYP metabolic enzymes, changes the pharmacokinetics of drospirenone, leading to a higher drospirenone exposure with ethinylestradiol/drospirenone compared to the drospirenone-only preparation. In addition, several metabolic alterations have been described. The impact of estetrol is less pronounced, and for 17-β-estradiol/drospirenone and drospirenone-only, decreased triglyceride and cholesterol levels were observed. Ethinylestradiol induces various pro-coagulatory factors, leading to hypercoagulability. The effect is significantly reduced with estetrol, and no influence was observed with the drospirenone-only preparation. The anti-mineralocorticoid activity of drospirenone seems to positively counteract the renin-angiotensin-aldosterone-system-activating action of ethinylestradiol. There is no influence on blood pressure with ethinylestradiol/drospirenone and estetrol/drospirenone formulations, while in clinical trials, a reduction has been observed with 17-β-estradiol/drospirenone and drospirenone-only. Anti-aldosterone activity via non-renal mineralocorticoid receptors is associated with cardiovascular health, while interactions with parathyroid hormone signaling impact bone structure and vascular calcification. Though the clinical relevance is unclear for drospirenone, data in this context are reviewed. To sum up, the advantages of drospirenone in hormonal contraception and treatment of menopausal symptoms have been demonstrated for all the formulations described here. Combination with estrogen confers benefits and risks, which must be considered.

Regidor PA, Richter WH, Koytchev R, Kirkov V, Colli E. Evaluation of the food effect on a drospirenone only contraceptive containing 4 mg administered with and without high-fat breakfast in a randomised trial

f an oral test preparation containing 4 mg drospirenone (DRSP) under fasting conditions compared to PK upon food intake after single dose administration. Methods: Open label, single centre, two-treatment, two-sequence, crossover study in 24 healthy female volunteers, with duration of 1 day per sequence and with a real wash-out period of 14 days to investigate the relative bioavailability of DRSP with both forms of administration. The 90% confidence intervals (CI) were calculated for the intra-individual ratio (test with food vs. without food) of the PK endpoints Area under the curve; 0-72 h [AUC(0-72 h)] and maximal plasma concentration [Cmax] of DRSP. Results: The 90% CI calculated by analysis of variance using logistic transformation (ANOVA-log) for the endpoint, intra-individual ratio (Test 'A' = with food intake) vs. Test 'B' = without food intake) of AUC(0-72 h) of drospirenone was between 104.72 and 111.36%. The 90% CI calculated by means of ANOVA- log for the endpoint intra-individual ratio (Test 'A' vs. Test 'B') of Cmax of DRSP was between 118.58 and 141.10%. The mean relative bioavailability of the test with food 'A' compared to the Test without food 'B' after single dose administration based on the endpoints AUC(0-72 h) was 107.99%; for the endpoint Cmax it was 129.35%. Conclusions: The rate of absorption, based on the endpoint Cmax of DRSP was increased by about 30% under fed conditions. With respect to consumer habits, this may represent a relevant benefit for contraceptive safety, as the time span between food consumption and pill intake does not play a role. Implications: Our results suggest that the food intake has no impact on the absorption of 4 mg DRSP in the management of contraception. This increases the contraceptive efficacy as no interference with food is expected when consuming the oral formulation under real life conditions.

Palacios C, Trak-Fellermeier MA, Martinez RX, Lopez-Perez L, Lips P, Salisi JA, John JC, Peña-Rosas JP. Regimens of vitamin D supplementation for women during pregnancy

Background: Vitamin D deficiency during pregnancy increases the risk of pre-eclampsia, gestational diabetes, preterm birth, and low birthweight. In a previous Cochrane Review we found that supplementing pregnant women with vitamin D alone compared to no vitamin D supplementation may reduce the risk of pre-eclampsia, gestational diabetes, and low birthweight and may increase the risk of preterm births if it is combined with calcium. However the effects of different vitamin D regimens are not yet clear. Objectives: To assess the effects and safety of different regimens of vitamin D supplementation alone or in combination with calcium or other vitamins, minerals or nutrients during pregnancy, specifically doses of 601 international units per day (IU/d) or more versus 600 IU/d or less; and 4000 IU/d or more versus 3999 IU/d or less. Search methods: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (12 July 2018), and the reference lists of retrieved studies.Selection criteria: Randomised trials evaluating the effect of different vitamin D regimens (dose, frequency, duration, and time of commencement of supplementation during pregnancy), alone or in combination with other nutrients on pregnancy and neonatal health outcomes. We only included trials that compared 601 IU/d or more versus 600 IU/d or less and 4000 IU/d or more versus 3999 IU/d or less. We did not include in the analysis groups that received no vitamin D, as that comparison is assessed in another Cochrane Review. Data collection and analysis: Two review authors independently: i) assessed the eligibility of studies against the inclusion criteria; ii) extracted data from included studies, and iii) assessed the risk of bias of the included studies. Our primary maternal outcomes were: pre-eclampsia, gestational diabetes, and any adverse effects; our primary infant outcomes were preterm birth and low birthweight. Data were checked for accuracy. The certainty of the evidence was assessed using the GRADE approach. Main results: In this review, we included data from 30 trials involving 7289 women. We excluded 11 trials, identified 16 ongoing/unpublished trials and two trials are awaiting classification. Overall risk of bias for the trials was mixed.Comparison 1. 601 IU/d or more versus 600 IU/d or less of vitamin D alone or with any other nutrient (19 trials; 5214 participants)Supplementation with 601 IU/d or more of vitamin D during pregnancy may make little or no difference to the risk of pre-eclampsia (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.42); 5 trials; 1553 participants,low-certainty evidence), may reduce the risk of gestational diabetes (RR 0.54, 95% CI 0.34 to 0.86; 5 trials; 1846 participants; moderate-certainty evidence), may make little or no difference to the risk of preterm birth (RR 1.25, 95% CI 0.92 to 1.69; 4 trials; 2294 participants; low-certainty evidence); and may make little or no difference to the risk of low birthweight (RR 0.90, 95% CI 0.66 to 1.24; 4 trials; 1550 participants; very low-certainty evidence) compared to women receiving 600 IU/d or less.Comparison 2. 4000 IU or more versus 3999 IU or less of vitamin D alone (15 trials; 4763 participants)Supplementation with 4000 IU/d or more of vitamin D during pregnancy may make little or no difference to the risk of: pre-eclampsia (RR 0.87, 95% CI 0.62 to 1.22; 4 trials, 1903 participants, low-certainty evidence); gestational diabetes (RR 0.89, 95% CI 0.56 to 1.42; 5 trials, 2276 participants; low-certainty evidence); preterm birth (RR 0.85, 95% CI 0.64 to 1.12; 6 trials, 2948 participants, low-certainty evidence); and low birthweight (RR 0.92, 95% CI 0.49 to 1.70; 2 trials; 1099 participants; low-certainty evidence) compared to women receiving 3999 IU/d or less.Adverse events (such as hypercalcaemia, hypocalcaemia, hypercalciuria, and hypovitaminosis D) were reported differently in most trials; however, in general, there was little to no side effects reported or similar cases between groups.

Kamenov Z, Gateva A. Inositols in PCOS

Background: Myoinositol (MI) and D-chiro-inositol (DCI) are involved in a number of biochemical pathways within oocytes having a role in oocyte maturation, fertilization, implantation, and post-implantation development. Both inositols have a role in insulin signaling and hormonal synthesis in the ovaries. (2) Methods: Literature search (with key words: inositols, myo-inositol, d-chiro-inositol, PCOS) was done in PubMed until Sept. 2020 and 197 articles were identified, of which 47 were of clinical trials (35 randomized controlled trials). (3) Results: Many studies have demonstrated that in patients with polycystic ovarian syndrome (PCOS) MI treatment improved ovarian function and fertility, decreased the severity of hyperandrogenism including acne and hirsutism, positively affected metabolic aspects, and modulated various hormonal parameters deeply involved in the reproductive axis function and ovulation. Thus treating with MI has become a novel method to ameliorate PCOS symptoms, improve spontaneous ovulation, or induce ovulation. The current review is focused on the effects of MI and DCI alone or in combination with other agents on the pathological features of PCOS with focus on insulin resistance and adverse metabolic outcomes. (4) Conclusions: The available clinical data suggest that MI, DCI, and their combination in physiological ratio 40:1 with or without other compound could be beneficial for improving metabolic, hormonal, and reproductive aspects of PCOS.

Roseff S, Montenegro M. Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary.

The aim of this paper is to critically analyze the composition of many inositol-based products currently used to treat Polycystic Ovary Syndrome (PCOS). Several different combinations of myo-inositol and D-chiro-inositol, with and without additional compounds such as micro- and macroelements, vitamins, and alpha-lipoic acid, have been formulated over the years. Such therapeutic proposals do not take various features of inositol stereoisomers into consideration. As an example, it is important to know that D-chiro-inositol treatment may be beneficial when administered in low doses, yet the progressive increase of its dosage results in the loss of its advantageous effects on the reproductive performance of women and a deterioration in the quality of blastocysts created via in vitro fertilization (IVF). In addition, we have to consider that the intestinal absorption of myo-inositol is reduced by the simultaneous administration of D-chiro-inositol since the two stereoisomers compete with each other for the same transporter that has similar affinity for each of them. A decrease in myo-inositol absorption is also found when it is coadministered with inhibitors of sugar intestinal absorption and/or types of sugars such as sorbitol, maltodextrin, and sucralose. The combination of these may require higher amounts of myo-inositol in order to reach a therapeutic dosage compared to inositol administration alone, a particularly important fact when physicians strive to obtain a specific plasma level of the stereoisomer. Finally, we must point out that D-chiro-inositol was found to be an aromatase inhibitor which increases androgens and may have harmful consequences for women. Therefore, the inositol supplements used in PCOS treatment must be carefully defined. Clinical evidence has demonstrated that the 40 : 1 ratio between myo-inositol and D-chiro-inositol is the optimal combination to restore ovulation in PCOS women. Therefore, it is quite surprising to find that inositol-based treatments for PCOS seem to be randomly chosen and are often combined with useless or even counterproductive molecules, all of which can weaken myo-inositol's efficacy. Such treatments clearly lack therapeutic rationale.

Nordio M, Basciani S, Camajani E. The 40:1 myo-inositol/D-chiro-inositol plasma ratio is able to restore ovulation in PCOS patients: comparison with other ratios.

Objective: The aim of this clinical trial was to evaluate the efficacy of seven different ratios between two inositols stereoisomers, myo-inositol (MI) and D-chiro-inositol (DCI), in the therapy of polycystic ovary syndrome (PCOS). Patients and methods: fifty-six PCOS patients (8 for each group) were treated by oral route using the following formulations: DCI alone, and 1:3.5; 2.5:1; 5:1; 20:1; 40:1, 80:1 MI/DCI ratio. They received 2 g of inositols twice a day for 3 months. The primary outcome was ovulation, the secondary outcome included the improvement of FSH, LH, Sex Hormone Binding Globulin (SHBG), 17-beta-Estradiol (E2), free testosterone, basal and postprandial insulin levels, as well as HOMA index, BMI and menses. Results: We found that the 40:1 MI/DCI ratio is the best for PCOS therapy aimed at restoring ovulation and normalizing important parameters in these patients. The other formulations were less effective. In particular, a decreased activity was observed when the 40:1 ratio was modified in favour of DCI. Conclusions: Our data demonstrated that DCI activity is beneficial mainly at a specific ratio with MI, whereas the increase of DCI causes the loss of the beneficial effects at reproductive level. These results in humans validate a previous preclinical study with different MI/DCI ratios carried out in an experimental model of PCOS mice.

Bevilacqua A, Bizzarri M. Inositols in Insulin Signaling and Glucose Metabolism

In the past decades, both the importance of inositol for human health and the complex interaction between glucose and inositol have been the subject of increasing consideration. Glucose has been shown to interfere with cellular transmembrane transport of inositol, inhibiting, among others, its intestinal absorption. Moreover, intracellular glucose is required for de novo biosynthesis of inositol through the inositol-3-phosphate synthase 1 pathway, while a few glucose-related metabolites, like sorbitol, reduce intracellular levels of inositol. Furthermore, inositol, via its major isomers myo-inositol and D-chiro-inositol, and probably some of its phosphate intermediate metabolites and correlated enzymes (like inositol hexakisphosphate kinase) participate in both insulin signaling and glucose metabolism by influencing distinct pathways. Indeed, clinical data support the beneficial effects exerted by inositol by reducing glycaemia levels and hyperinsulinemia and buffering negative effects of sustained insulin stimulation upon the adipose tissue and the endocrine system. Due to these multiple effects, myoIns has become a reliable treatment option, as opposed to hormonal stimulation, for insulin-resistant PCOS patients.

Devarshi PP, Grant RW, Ikonte CJ, Hazels Mitmesser S. Maternal Omega-3 Nutrition, Placental Transfer and Fetal Brain Development in Gestational Diabetes and Preeclampsia.

Omega-3 fatty acids, particularly docosahexaenoic fatty acid (DHA), are widely recognized to impact fetal and infant neurodevelopment. The impact of DHA on brain development, and its inefficient synthesis from the essential alpha-linolenic acid (ALA), has led to recommended DHA intakes of 250-375 mg eicosapentaenoic acid + DHA/day for pregnant and lactating women by the Dietary Guidelines for Americans. Despite these recommendations, the intake of omega-3s in women of child-bearing age in the US remains very low. The low maternal status of DHA prior to pregnancy could impair fetal neurodevelopment. This review focuses on maternal omega-3 status in conditions of gestational diabetes mellitus (GDM) and preeclampsia, and the subsequent impact on placental transfer and cord blood concentration of omega-3s. Both GDM and preeclampsia are associated with altered maternal omega-3 status, altered placental omega-3 metabolism, reduced cord blood omega-3 levels and have an impact on neurodevelopment in the infant and on brain health later in life. These findings indicate lower DHA exposure of the developing baby may be driven by lower placental transfer in both conditions. Thus, determining approaches which facilitate increased delivery of DHA during pregnancy and early development might positively impact brain development in infants born to mothers with these diseases.

Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst Rev.

Background: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. Objectives: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. Selection criteria: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. Data collection and analysis: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. Main results: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega-3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. Authors' conclusions: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3.

G. Vitrano, G. Mocera, M. Guardino, V. Giallombardo, R. Venezia Oral plus vaginal alpha-lipoic acid in women at risk for preterm delivery

OBJECTIVE: The etiology of preterm labor is multifactorial. An inflamma- tory response is always involved with the acti- vation of NF-kB that determines synthesis and release of inflammatory molecules, implicated in fetal membrane activation, cervical mod- ifications, abdominal pain and spontaneous uterine contractions. There is a close rela- tionship between preterm birth and cervical shortening in the second quarter of pregnan- cy. We evaluated the benefits of alpha-lipoic acid administration on women considered at risk of preterm delivery due to the presence of symptoms (pelvic pain and uterine contrac- tions) or reduced cervical length. PATIENTS AND METHODS: This prospec- tive observational study was carried out at the Gynecology and Obstetrics Unit of Paler- mo University Hospital (Palermo, Italy), from October 2015 to April 2016. The inclusion criteria were: women aged 18-35, with ges- tational age between 24 and 33 weeks of amenorrhea, pregnancy at risk of preterm de- livery due to cervical length between 35-25 mm (in presence of symptoms) or < 30 and > 15 mm (if asymptomatic), intact membranes and negative for vaginosis. Patients were treateddailywithalphalipoicacidorally(300 mg, twice a day for 30 days) and vaginally (10 mg, once a day for 10 days), or untreat- ed (controls). Patients were evaluated at the baseline (T 0), after 7 days, after 30 days, and at 34 weeks of gestation considering: maternal characteristics, symptomology and cervical length. RESULTS: Among 60 analyzed women, 50 were treated orally and vaginally with al- pha-lipoic acid, whereas 10 did not undergo any therapy. In the treated group, 10 patients were asymptomatic and 40 symptomatic. The symptoms disappeared in 37 patients. In the untreated group, 4 women were symptomatic and 6 asymptomatic. At the end all wom- en were symptomatic. Mean cervical length showed a reduction in the untreated group compared to the treated group. CONCLUSIONS: The vaginal/oral-combined administration with alpha-lipoic acid showed effectiveness in reducing symptoms and preventing cervical shortening in our set of patients. No adverse effects were detected during the treatment.

Petca A, Bot M, Maru N, Calo IG, Borislavschi A, Dumitrascu MC, Petca RC, Sandru F, Zvanca ME. Benefits of α-lipoic acid in high-risk pregnancies (Review).

α-Lipoic acid (ALA) is a natural molecule that is inconsistently synthesized by the human body and must be provided from exogenous sources, such as food and dietary supplements. Once absorbed, the oxidized form of ALA is transformed into its reduced form, dihydrolipoic acid (DHLA). ALA/DHLA exert direct and indirect antioxidant, anti-inflammatory and fine immunomodulatory effects. ALA/DHLA reduce the levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-17), while increasing the secretion of anti-inflammatory cytokines (IL-10). They also inhibit cyclooxygenase 2, thereby decreasing the secretion of prostaglandin E2 and nitrogen oxide, and reducing the risk of miscarriage in the first trimester of pregnancy. In patients at risk of abortion, administration of ALA from the first trimester has shown efficacy by accelerating subchorionic hematoma resorption, with a significant decrease in the accompanying abdominal pain. ALA has been proven to be efficient in maintaining the length of the cervix and keeping it closed following one episode of premature labor. Preeclampsia is a dysfunction caused by abnormal placentation and an excessive maternal inflammatory response, leading to extreme hypoxia in the placental bed and exaggerated oxidative stress, with release of oxygen free radicals. Oxidative stress plays a key role in the development of preeclampsia and intrauterine growth restriction. The hypothesis of antioxidant supplementation may play an essential part in disease prevention and fetal neuroprotection.

Eligio Parente, Giulia Colannino, Pasquale Ferrara Efficacy of Magnesium and Alpha Lipoic Acid Supplementation in Reducing Premature Uterine Contractions

Objective: Premature uterine contractions represent one of the major symptoms related to pre- term labor. So far, primary prevention of preterm labor is based on the early identification of symptoms and on pharmacological treatments which are prone of several secondary effects. In this double-blinded, randomized, placebo-controlled trial, the efficacy of a supplementation of magnesium and alpha-lipoic acid has been evaluated. Methods: Three hundred pregnant women at 14 - 34 weeks of gestation were enrolled and randomly divided to receive a daily single tablet containing a supplement of magnesium and alpha-lipoic acid (DAV®LoLiPharmasrl, Rome-Italy) or placebo until delivery. The incidence of episodes of preterm uterine contraction, associated or not with pain, as well as maternal need of hospitalization was evaluated. Results: Magnesium and li- poic acid supplementation was effective to significantly reduce the incidence of preterm uterine contractions compared to placebo. In particular, 52% of women who received the supplementa- tion reported no symptoms of preterm uterine contractions throughout pregnancy, and persistent episodes of uterine contractions were significantly reduced compared to placebo (20% vs 60%, respectively). Furthermore, only 20% of subjects who received the supplementation required hospitalization, while it has been necessary for 40% of women who received placebo. Conclusions: Our findings suggest that supplementation with magnesium and lipoic acid is effective in reducing the incidence of premature uterine contraction and related episodes of hospitalization, compared to placebo. Nevertheless, further studies based on larger cohorts of patients are necessary to con- firm the efficacy of these preliminary results.

Behjat Sasan S, Zandvakili F, Soufizadeh N, Baybordi E. The Effects of Vitamin D Supplement on Prevention of Recurrence of Preeclampsia in Pregnant Women with a History of Preeclampsia

Introduction: Preeclampsia is a pregnancy-specific syndrome. One of the hypotheses concerning the etiology of preeclampsia is vitamin D deficiency during pregnancy. Method and materials: The present study is a randomized controlled clinical trial which aims to determine the effect of vitamin D supplement on reducing the probability of recurrent preeclampsia. 72 patients were placed in control group while 70 patients were randomized to the intervention group. The intervention group received a 50000 IU pearl vitamin D3 once every two weeks. The control group was administered placebo. Vitamin D or placebo was given until the 36th week of pregnancy. Results: The patients in intervention group have significantly lower (P value = 0.036) probability of preeclampsia than patients in the control group. The risk of preeclampsia for the control group was 1.94 times higher than that for the intervention group (95% CI 1.02, 3.71). Conclusion: The intended intervention (i.e., prescription of vitamin D) has a protective effect against recurrent preeclampsia. Vitamin D supplementation therapy in pregnancy could help in reducing the incidence of gestational hypertension/preeclampsia.

Rivera-Paredez B, Macías N, Martínez-Aguilar MM, Hidalgo-Bravo A, Flores M, Quezada-Sánchez AD, Denova-Gutiérrez E, Cid M, Martínez-Hernández A, Orozco L, Quiterio M, Flores YN, Salmerón J, Velázquez-Cruz R. Association between Vitamin D Deficiency and Single Nucleotide Polymorphisms in the Vitamin D Receptor and GC Genes and Analysis of Their Distribution in Mexican Postmenopausal Women

Genome-wide association studies in people with European ancestry suggest that polymorphisms in genes involved in vitamin D (VD) metabolism have an effect on serum concentrations of 25-hydroxyvitamin D. However, nothing is known about these polymorphisms in populations with Amerindian ancestry. Our aim was to evaluate the association between genetic variants on the vitamin D receptor (VDR) and the vitamin D binding protein (GC) genes, involved in the VD pathway, and VD deficiency in 689 unrelated Mexican postmenopausal women. We also described the frequencies of these variants in 355 postmenopausal women from different ethnic groups. Based on our preliminary results of 400 unrelated Mexican postmenopausal women, three single nucleotide polymorphisms (SNPs) were selected for genotyping. The SNPs rs4516035 in VDR and rs2282679 in GC were associated with VD deficiency. Additionally, women who carried three risk alleles had a 3.67 times higher risk of suffering VD deficiency, compared to women with no risk alleles (p = 0.002). The rs4516035-C allele frequency in the Amerindian population was enriched in the South East region of Mexico. In contrast, the highest frequency of the rs2298850-C allele, a proxy for the tag SNP rs2282679, was observed in the South region. Our results indicate that genetic variants in VDR and GC genes are associated with VD deficiency in Mexican postmenopausal women. Moreover, an association was observed for the variants rs3794060 and rs4944957 of the DHCR7/NADSYN1 gene with osteopenia/osteoporosis.

Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease

Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40-60 ng/mL (100-150 nmol/L) to achieve the optimal overall health benefits of vitamin D.

Cuartas Silvina, Pérez Torre María. Metabolismo e importancia de los ácidos grasos poliinsaturados en la gestación y lactancia

Introducción: Los ácidos grasos polinsaturados de cadena larga son esenciales en la nutrición del feto y del recién nacido. Objetivo: Examinar la importancia de los ácidos grasos poliinsaturados durante el embarazo y la lactancia, para destacar los requerimientos, las recomendaciones y fuentes alimentarias. Métodos: Se realizó una revisión sistemática de la literatura internacional de los últimos 15 años en bases de datos, en español y en inglés. Se utilizaron las siguientes palabras clave: embarazo, lactancia, ácidos grasos poliinsaturados, omega 3/6, fuentes y requerimientos. Se identificaron los aspectos más relevantes y controversiales. Resultados: El ácido araquidónico y docosahexaenoico influyen sobre el perfil lipídico, la sensibilidad a la insulina, la proliferación y diferenciación de los preadipocitos. Sus concentraciones durante la gestación resultan uno de los principales factores responsables de la programación fetal, que son las adaptaciones metabólicas que condicionan la evolución de la salud futura. Concentraciones óptimas de ácidos grasos omega 3 y 6 son vitales para el desarrollo neurológico del feto y del recién nacido. La funcionalidad de la placenta puede afectar la adiposidad y los niveles fetales de nutrientes clave, como los ácidos grasos poliinsaturados de cadena larga. Conclusiones: La dieta es uno de los principales factores ambientales durante la gestación. La lactancia materna es la mejor alternativa nutricional durante el primer año de vida, por eso es fundamental promocionarla. Es importante ofrecer una asistencia adecuada y generar estrategias que estimulen el consumo de ácidos omega-3 como una herramienta de prevención a largo plazo.

Dominguez LJ, Farruggia M, Veronese N, Barbagallo M. Vitamin D sources, metabolism, and deficiency: available compounds and guidelines for its treatment

Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D's role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs and systems in the human body. This growing interest is mostly due to the evidence that modest-to-severe vitamin D deficiency is widely prevalent around the world. There is broad agreement that optimal vitamin D status is necessary for bones, muscles, and one's general health, as well as for the efficacy of antiresorptive and anabolic bone-forming treatments. Food supplementation with vitamin D, or the use of vitamin D supplements, are current strategies to improve vitamin D levels and treat deficiency. This article reviews consolidated and emerging concepts about vitamin D/hormone D metabolism, food sources, deficiency, as well as the different vitamin D supplements available, and current recommendations on the proper use of these compounds.

Martínez-Zavala N, López-Sánchez GN, Vergara-Lopez A, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Vitamin D deficiency in Mexicans have a high prevalence: a cross-sectional analysis of the patients from the Centro Médico Nacional 20 de Noviembre

Disorders of vitamin D concentration (deficiency or insufficiency) are a global health problem, which are associated with various chronic diseases. In Latin America, alterations in vitamin D prevalence are different from those shown in previous studies and may be due to differences in geographic location, skin color, and diet type.Purpose: To know the prevalence of vitamin D insufficiency (21-29 ng/mL) and deficiency (< 20 ng/mL) in Mexican patients; although it is a risk factor for developing multiple complex diseases, its prevalence in the population is still unknown.Methods: Cross-sectional study carried out at the endocrinology service of the highly specialized national center November 20. Data on cardiovascular risk factors were obtained and 25-hydroxy vitamin D was measured by chemiluminescence. Prevalence was calculated, and the results were analyzed to categorize the patients according to 25-hydroxy vitamin D deficient or insufficient levels.Results: The mean value of the serum vitamin D concentration was 18.37 ng/mL. Of the 117 patients, 93.2% (n = 109) have decreased vitamin D values; 62.4% (n = 73) of the patients had vitamin D deficiency and 30.8% (n = 36) vitamin D insufficiency. The prevalence of vitamin D deficiency was 62.4% and 30.8% for vitamin D insufficiency. The total prevalence of alterations in vitamin D levels in this population was 93.2%. Conclusions: This study reports a prevalence of vitamin D deficiency and insufficiency much higher than those described by previous studies, which is of utmost importance for the population due to the morbidities associated with these alterations.

Ganguly A, Tamblyn JA, Finn-Sell S, Chan SY, Westwood M, Gupta J, Kilby MD, Gross SR, Hewison M.  Vitamin D, the placenta and early pregnancy: effects on trophoblast function

Pregnancy is associated with significant changes in vitamin D metabolism, notably increased maternal serum levels of active vitamin D, 1,25-dihydroxyvitamin (1,25(OH)2D). This appears to be due primarily to increased renal activity of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) that catalyzes synthesis of 1,25(OH)2D, but CYP27B1 expression is also prominent in both the maternal decidua and fetal trophoblast components of the placenta. The precise function of placental synthesis of 1,25(OH)2D remains unclear, but is likely to involve localized tissue-specific responses with both decidua and trophoblast also expressing the vitamin D receptor (VDR) for 1,25(OH)2D. We have previously described immunomodulatory responses to 1,25(OH)2D by diverse populations of VDR-expressing cells within the decidua. The aim of the current review is to detail the role of vitamin D in pregnancy from a trophoblast perspective, with particular emphasis on the potential role of 1,25(OH)2D as a regulator of trophoblast invasion in early pregnancy. Vitamin D deficiency is common in pregnant women, and a wide range of studies have linked low vitamin D status to adverse events in pregnancy. To date, most of these studies have focused on adverse events later in pregnancy, but the current review will explore the potential impact of vitamin D on early pregnancy, and how this may influence implantation and miscarriage

Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Jones G. Vitamin D Toxicity-A Clinical Perspective

Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally. Although VDT is rare, the health effects can be serious if it is not promptly identified. Many forms of exogenous (iatrogenic) and endogenous VDT exist. Exogenous VDT is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of VDT due to vitamin D overdosing. Endogenous VDT may develop from excessive production of an active vitamin D metabolite - 1,25(OH)2D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous VDT may also develop from an excessive production of 25(OH)D and 1,25(OH)2D in congenital disorders, such as Williams-Beuren syndrome. Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism. Researchers have proposed many processes to explain VDT. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. Increased public awareness of vitamin D-related health benefits might increase the risk of VDT due to self-administration of vitamin D in doses higher then recommended for age and body weight or even higher than the established upper limit intake values. Consequently, the incidence of hypercalcemia due to hypervitaminosis D might increase.

Mojibian M, Soheilykhah S, Fallah Zadeh MA, Jannati Moghadam M. The effects of vitamin D supplementation on maternal and neonatal outcome: A randomized clinical trial

Background: Vitamin D supplementation during pregnancy has been supposed to defend against adverse gestational outcomes. Objective: This randomized clinical trial study was conducted to assess the effects of 50,000 IU of vitamin D every two weeks supplementation on the incidence of gestational diabetes (GDM), gestational hypertension, preeclampsia and preterm labor, vitamin D status at term and neonatal outcomes contrasted with pregnant women that received 400 IU vitamin D daily. Materials and methods: 500 women with gestational age 12-16 weeks and serum 25 hydroxy vitamin D (25 (OH) D ) less than 30 ng/ml randomly categorized in two groups. Group A received 400 IU vitamin D daily and group B 50,000 IU vitamin D every 2 weeks orally until delivery. Maternal and Neonatal outcomes were assessed in two groups. Results: The incidence of GDM in group B was significantly lower than group A (6.7% versus 13.4%) and odds ratio (95% Confidence interval) was 0.46 (0.24-0.87) (P=0.01). The mean ± SD level of 25 (OH) D at the time of delivery in mothers in group B was significantly higher than A (37.9 ± 19.8 versus 27.2 ± 18.8 ng/ml, respectively) (P=0.001). There were no differences in the incidence of preeclampsia, gestational hypertension, preterm labor, and low birth weight between two groups. The mean level of 25 (OH) D in cord blood of group B was significantly higher than group A (37.9 ± 18 versus 29.7 ± 19ng/ml, respectively). Anthropometric measures between neonates were not significantly different. Conclusion: Our study showed 50,000 IU vitamin D every 2 weeks decreased the incidence of GDM.

Guillot M, Robitaille CA, Turner L, Pronovost E, Caouette G, Matte-Gagné C, Olivier F, Bartholomew J, Massé É, Morin A, Mohamed I, Marc I. Effects of maternal docosahexaenoic acid supplementation on brain development and neurodevelopmental

Introduction: Docosahexaenoic acid (DHA), an omega-3 fatty acid, is important for brain development with possible implications in neurodevelopmental outcomes. In the two-arm, randomised, double-blind, placebo-controlled Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants trial, very preterm infants (<29 weeks' gestation) were supplemented in high doses of DHA or placebo until they reached 36 weeks' postmenstrual age. We propose a long-term neurodevelopmental follow-up of these children. This protocol details the follow-up at 5 years of age, which aims to (1) confirm our long-term recruitment capacity and (2) determine the spectrum of neurodevelopmental outcomes at preschool age following neonatal DHA supplementation. Methods and analysis: This long-term follow-up involves children (n=194) born to mothers (n=170) randomised to DHA (n=85) or placebo (n=85) from the five sites in Quebec when they will be 5 years' corrected age. The primary outcome measure is related to the long-term recruitment capacity, which we determined as successful if 75% (±10%, 95% CI) of the eligible children consent to the 5-year follow-up study. Interviews with mothers will be conducted to assess various aspects of neurodevelopment at preschool age (executive functions, behavioural problems, global development and health-related quality of life), evaluated with standardised neurodevelopmental questionnaires. In addition, a semistructured interview conducted in a subset of the mothers will be used to determine their acceptability and identify barriers and enablers to their eventual participation to the next phase of the trial. This follow-up study will require approximately 22 months to be completed. Ethics and dissemination: This study was approved by the CHU de Québec-Université Laval Research Ethics Board (MP-20-2022-5926). Mothers will provide informed consent before participating in this study. Findings will be disseminated through peer-reviewed publications and conference presentations.

Mosha D, Liu E, Hertzmark E, Chan G, Sudfeld C, Masanja H, Fawzi W. outcomes of breastfed preterm neonates: protocol for a follow-up at preschool age of a randomised clinical trial (MOBYDIckPS)

Objective: Prematurity, stillbirth and other adverse birth outcomes remain major concerns in resource-limited settings. Poor dietary intake of micronutrients during pregnancy has been associated with increased risk of adverse outcomes. We determined the relationships between dietary Fe and Ca intakes during pregnancy and risks of adverse birth outcomes among HIV-negative women. Design: Women's diet was assessed through repeated 24 h diet recalls in pregnancy. Mean intakes of total Fe, Fe from animal sources and Ca during pregnancy were examined in relation to adverse birth outcomes and neonatal mortality. Women were prescribed daily Fe supplements as per standard perinatal care. Setting: Dar es Salaam, Tanzania. Subjects: A cohort of 7634 pregnant women. Results: Median (interquartile range) daily dietary intake of total Fe, animal Fe and Ca was 11·9 (9·3-14·7), 0·5 (0-1·1) and 383·9 (187·4-741·2) mg, respectively. Total Fe intake was significantly associated with reduced risk of stillbirth (trend over quartiles, P=0·010). Animal Fe intake was significantly associated with reduced risk of preterm birth and extreme preterm birth. Animal Fe intake was inversely related to neonatal mortality risk; compared with women in the lowest intake quartile, those in the top quartile were 0·51 times as likely to have neonatal death (95 % CI 0·33, 0·77). Higher Ca intake was associated with reduced risk of preterm birth (relative risk; 95 % CI: 0·76; 0·65, 0·88) and extreme preterm birth (0·63; 0·47, 0·86). Women in the highest Ca intake quartile had reduced risk of neonatal mortality (0·59; 0·37, 0·92).Conclusions: Daily dietary Fe and Ca intakes among pregnant women are very low. Improvement of women's diet quality during gestation is likely to improve the risks of adverse birth outcomes.

Zhao J, Zhao Y, Binns CW, Lee AH. Increased Calcium Supplementation Postpartum Is Associated with Breastfeeding among Chinese Mothers: Finding from Two Prospective Cohort Studies

The calcium supplementation status during the postpartum period among Chinese lactating women is still unclear. The objective of this study is to utilize data from two population-based prospective cohort studies to examine the calcium supplementation status and to identify whether breastfeeding is associated with increased calcium supplementation among Chinese mothers after child birth. Information from 1540 mothers on breastfeeding and calcium supplementation measured at discharge, 1, 3, and 6 months postpartum were extracted to evaluate the association between breastfeeding and calcium supplementation postpartum. A generalized linear mixed model was applied to each study initially to account for the inherent correlation among repeated measurements, adjusting for socio-demographic, obstetric factors and calcium supplementation during pregnancy. In addition, breastfeeding status measured at different follow-up time points was treated as a time dependent variable in the longitudinal analysis. Furthermore, the effect sizes of the two cohort studies were pooled using fixed effect model. Based on the two cohort studies, the pooled likelihood of taking calcium supplementation postpartum among breastfeeding mothers was 4.02 times (95% confidence interval (2.30, 7.03)) higher than that of their non-breastfeeding counterparts. Dietary supplementation intervention programs targeting different subgroups should be promoted in Chinese women, given c

Khaing W, Vallibhakara SA, Tantrakul V, Vallibhakara O, Rattanasiri S, McEvoy M, Attia J, Thakkinstian A. Calcium and Vitamin D Supplementation for Prevention of Preeclampsia: A Systematic Review and Network Meta-Analysis

Vitamin D supplementation effects with or without calcium in pregnancy for reducing risk of preeclampsia and gestational or pregnancy induced hypertension are controversial. Literature was systematically searched in Medline, Scopus and Cochrane databases from inception to July 2017. Only randomized controlled trials (RCTs) in English were selected if they had any pair of interventions (calcium, vitamin D, both, or placebo). Systematic review with two-step network-meta-analysis was used to indirectly estimate supplementary effects. Twenty-seven RCTs with 28,000 women were eligible. A direct meta-analysis suggested that calcium, vitamin D, and calcium plus vitamin D could lower risk of preeclampsia when compared to placebo with the pooled risk ratios (RRs) of 0.54 (0.41, 0.70), 0.47 (0.24, 0.89) and 0.50 (0.32, 0.78), respectively. Results of network meta-analysis were similar with the corresponding RRs of 0.49 (0.35, 0.69), 0.43 (0.17, 1.11), and 0.57 (0.30, 1.10), respectively. None of the controls were significant. Efficacy of supplementation, which was ranked by surface under cumulative ranking probabilities, were: vitamin D (47.4%), calcium (31.6%) and calcium plus vitamin D (19.6%), respectively. Calcium supplementation may be used for prevention for preeclampsia. Vitamin D might also worked well but further large scale RCTs are warranted to confirm our findings.

Lo TH, Wu TY, Li PC, Ding DC. Effect of Vitamin D supplementation during pregnancy on maternal and perinatal outcomes

Vitamin D deficiency is common globally with a higher prevalence in women, especially during pregnancy. Among the pregnant women, Vitamin D deficiency was reported up to 80% in the Asian group. Vitamin D deficiency was related to a higher risk of maternal complications including preeclampsia, impaired glucose tolerance, and cesarean section rate, and neonatal complications including low birthweight, neonatal hypocalcemia seizure, and impaired skeletal, lung and immune development. There were no data supporting Vitamin D deficiency screening routinely in pregnancy regarding cost-effectiveness or health benefits. The measurement of Vitamin D in the high-risk group of women is necessary. Subsequent supplement with Vitamin D with and without calcium supplement during pregnancy had been statistically significantly reported to decrease the risk of preeclampsia, preterm birth, and low birth body weight. However, due to a lack of studies, the strategies of dietary and nutritional supplement for fetal growth restriction prevention are not statistically effective and are not yet recommended. The present review is to provide an overview of the clinical and the experimental evidence of Vitamin D deficiency-related complication and review of available options for the prevention and management of these complications.

Mousa A, Naqash A, Lim S. Macronutrient and Micronutrient Intake during Pregnancy: An Overview of Recent Evidence

Nutritional status during pregnancy can have a significant impact on maternal and neonatal health outcomes. Requirements for macronutrients such as energy and protein increase during pregnancy to maintain maternal homeostasis while supporting foetal growth. Energy restriction can limit gestational weight gain in women with obesity; however, there is insufficient evidence to support energy restriction during pregnancy. In undernourished women, balanced energy/protein supplementation may increase birthweight whereas high protein supplementation could have adverse effects on foetal growth. Modulating carbohydrate intake via a reduced glycaemic index or glycaemic load diet may prevent gestational diabetes and large-for-gestational-age infants. Certain micronutrients are also vital for improving pregnancy outcomes, including folic acid to prevent neural tube defects and iodine to prevent cretinism. Newly published studies support the use of calcium supplementation to prevent hypertensive disorders of pregnancy, particularly in women at high risk or with low dietary calcium intake. Although gaps in knowledge remain, research linking nutrition during pregnancy to maternofoetal outcomes has made dramatic advances over the last few years. In this review, we provide an overview of the most recent evidence pertaining to macronutrient and micronutrient requirements during pregnancy, the risks and consequences of deficiencies and the effects of supplementation on pregnancy outcomes

Hofmeyr GJ, Manyame S, Medley N, Williams MJ. Calcium supplementation commencing before or early in pregnancy, for preventing hypertensive disorders of pregnancy

Background: The hypertensive disorders of pregnancy include pre-eclampsia, gestational hypertension, chronic hypertension, and undefined hypertension. Pre-eclampsia is considerably more prevalent in low-income than in high-income countries. Objectives: To determine the effect of calcium supplementation, given before or early in pregnancy and for at least the first half of pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, and fetal and neonatal outcomes. Search methods: We searched the Cochrane Pregnancy and Childbirth Trials Register (31 July 2018), PubMed (13 July 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP; 31 July 2018), and reference lists of retrieved studies. Main results: Calcium versus placeboWe included one study (1355 women), which took place across multiple hospital sites in Argentina, South Africa, and Zimbabwe. Most analyses were conducted only on 633 women from this group who were known to have conceived, or on 579 who reached 20 weeks' gestation; the trial was at moderate risk of bias due to high attrition rates pre-conception. Non-pregnant women with previous pre-eclampsia received either calcium 500 mg daily or placebo, from enrolment until 20 weeks' gestation. All participants received calcium 1.5 g daily from 20 weeks until birth.Primary outcomes: calcium supplementation commencing before conception may make little or no difference to the risk of pre-eclampsia (69/296 versus 82/283, risk ratio (RR) 0.80, 95% confidence interval (CI) 0.61 to 1.06; low-quality evidence). For pre-eclampsia or pregnancy loss or stillbirth (or both) at any gestational age, calcium may slightly reduce the risk of this composite outcome, however the 95% CI met the line of no effect (RR 0.82, 95% CI 0.66 to 1.00; low-quality evidence). Supplementation may make little or no difference to the severe maternal morbidity and mortality index (RR 0.93, 95% CI 0.68 to 1.26; low-quality evidence), pregnancy loss or stillbirth at any gestational age (RR 0.83, 95% CI 0.61 to 1,14; low-quality evidence), or caesarean section (RR 1.11, 95% CI 0.96 to 1,28; low-quality evidence).Authors' conclusions: The single included study suggested that calcium supplementation before and early in pregnancy may reduce the risk of women experiencing the composite outcome pre-eclampsia or pregnancy loss at any gestational age, but the results are inconclusive for all other outcomes for women and babies. Therefore, current evidence neither supports nor refutes the routine use of calcium supplementation before conception and in early pregnancy.To determine the overall benefit of calcium supplementation commenced before or in early pregnancy, the effects found in the study of calcium supplementation limited to the first half of pregnancy need to be added to the known benefits of calcium supplementation in the second half of pregnancy.Further research is needed to confirm whether initiating calcium supplementation pre- or in early pregnancy is associated with a reduction in adverse pregnancy outcomes for mother and baby. Research could also address the acceptability of the intervention to women, which was not covered by this review update.

Rajwar E, Parsekar SS, Venkatesh BT, Sharma Z. Effect of vitamin A, calcium and vitamin D fortification and supplementation on nutritional status of women: an overview of systematic reviews

Background: Micronutrient deficiency affects the health and development of vulnerable population such as children and pregnant women. Measures such as fortification of food and supplementation have been implemented to prevent or control deficiencies related to micronutrients. Objective: To assess the effect of vitamin A, vitamin D, and calcium fortification and supplementation on nutritional status of women in reproductive age group. To assess the toxicities and adverse events related to intervention. Methodology: Systematic reviews including RCTs on women of reproductive age group provided with vitamin A, vitamin D, and calcium supplementation or fortified food were included, to report all malnutrition-related outcomes due to deficiency of the abovementioned micronutrients. The Cochrane Database of Systematic Reviews, EPPI Centre, Campbell Collaboration, PubMed, Web of Science, and Scopus were searched electronically for English language publications, until 31 March 2018. Hand searching of the articles was done from the Journal of Food Science and Technology. Two independent reviewers selected the systematic reviews, extracted data, and assessed for the quality. Results: A total of 16 systematic reviews were included in narrative synthesis. Supplementation of vitamin A was reported to result in increased maternal serum retinol concentrations and increased breast milk retinol concentration. It reduced the risk of anemia (Hb < 11 g/dL) and reduced maternal clinical infection. Vitamin D supplementation increased 25-hydroxy vitamin D levels. There was insufficient evidence for the effect on bone mineral density and serum calcium levels. Calcium supplementation did not have any significant effect on body weight, weight gain, and body mass index of the participants.

Perichart-Perera O, Rodríguez-Cano AM, Gutiérrez-Castrellón P. Importancia de la suplementación en el embarazo: papel de la suplementación con hierro, ácido fólico, calcio, vitamina D y multivitamínicos

La promoción de la salud y la prevención de enfermedades son componentes esenciales de la atención prenatal. Las insuficiencias de nutrimentos afectan negativamente la morbimortalidad del binomio madre-hijo, así como a la salud de las siguientes generaciones. Aunque una alimentación saludable generalmente es suficiente para cubrir las necesidades aumentadas de micronutrimentos, la suplementación es parte del cuidado habitual para garantizar un embarazo saludable y el desarrollo óptimo del producto. Actualmente la suplementación de hierro y ácido fólico es la única recomendación mundialmente aceptada para todas las mujeres embarazadas. Por otro lado, existen grupos de mujeres vulnerables que podrían beneficiarse de esquemas de suplementación individualizados complementarios. Recientemente se ha publicado información relevante relacionada con la suplementación de distintos micronutrimentos de forma individual y múltiple con efectos importantes en la salud materno-fetal, lo cual podría tener implicaciones en la práctica clínica de los profesionales de la salud. Esta revisión presenta la evidencia científica y las recomendaciones de distintos organismos sobre la suplementación de hierro, ácido fólico, calcio, vitamina D y suplementación múltiple de vitaminas y minerales durante el embarazo.

Fogacci S, Fogacci F, Cicero AFG. Nutraceuticals and Hypertensive Disorders in Pregnancy: The Available Clinical Evidence

The aim of the present critical review is to summarize the available clinical evidence supporting the use of some dietary supplements that have been shown to lower blood pressure in hypertensive pregnant women. A systematic search strategy was carried out to identify trials in MEDLINE (National Library of Medicine, Bethesda, Maryland, MD, USA; January 1980 to September 2019) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). The terms 'nutraceuticals', 'dietary supplements', 'pregnancy', 'pre-eclampsia', 'clinical trial', and 'human' were incorporated into an electronic search strategy. The references of the identified studies and review articles were reviewed to look for additional studies of interest. We preferably selected papers that reported recent comprehensive reviews or meta-analysis, or original clinical trials of substances with blood pressure-lowering or vascular protective effect in pregnancy. There is a relative body of evidence that supports the use of calcium, vitamin D, folic acid, and resveratrol in preventing the development of hypertensive disorders in pregnancy, and evidence supporting drug treatment too. Further clinical research is advisable to identify the dosage and timing of the supplementation, the group of women that might benefit the most from this approach, and the nutraceuticals with the best cost-effectiveness and risk-benefit ratio for widespread use in clinical practice.

Winter EM, Ireland A, Butterfield NC, Haffner-Luntzer M, Horcajada MN, Veldhuis-Vlug AG, Oei L, Colaianni G, Bonnet N. Pregnancy and lactation, a challenge for the skeleton

In this review we discuss skeletal adaptations to the demanding situation of pregnancy and lactation. Calcium demands are increased during pregnancy and lactation, and this is effectuated by a complex series of hormonal changes. The changes in bone structure at the tissue and whole bone level observed during pregnancy and lactation appear to largely recover over time. The magnitude of the changes observed during lactation may relate to the volume and duration of breastfeeding and return to regular menses. Studies examining long-term consequences of pregnancy and lactation suggest that there are small, site-specific benefits to bone density and that bone geometry may also be affected. Pregnancy- and lactation-induced osteoporosis (PLO) is a rare disease for which the pathophysiological mechanism is as yet incompletely known; here, we discuss and speculate on the possible roles of genetics, oxytocin, sympathetic tone and bone marrow fat. Finally, we discuss fracture healing during pregnancy and lactation and the effects of estrogen on this process.

Hofmeyr GJ, Seuc A, Betrán AP, Cormick G, Singata M, Fawcus S, Mose S, Frank K, Hall D, Belizán J, Roberts JM, Magee LA, von Dadelszen P; The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: A randomized placebo-controlled study

Background: Low dietary calcium is associated with the hypertensive disorders of pregnancy, and evidence suggests that the risks associated with pre-eclampsia are reduced by calcium supplementation. In the general (non-pregnant) population, low dietary calcium intake is associated with hypertension with inconsistent evidence that calcium supplementation may reduce blood pressure. Women with pre-eclampsia are also at risk of hypertension later in life. An exploratory sub-study among early participants enrolled in the WHO long-term calcium supplementation in women at high risk of pre-eclampsia (CAP) study reported a trend to more blood pressure reduction with calcium in non-pregnant women with previous severe as opposed to non-severe pre-eclampsia. The current study reports the effects of low-dose calcium supplementation in non-pregnant women in the complete trial cohort. Methods: The CAP Study was a multi-country randomized, double-blind placebo-controlled clinical trial to test the hypothesis that calcium deficiency may play a role in the genesis of pre-eclampsia in early pregnancy. From 2011 to 2016, non-pregnant women who had pre-eclampsia or eclampsia in their most recent pregnancy were randomized to receive either 500 mg/day elemental calcium or placebo. In this sub-study we compared the change in blood pressure from baseline to the 12-week visit between participants receiving calcium versus placebo for those not pregnant at the 12-week visit. Results: Of 1355 women randomized, 810 attended a 12-week visit without being pregnant, of whom 791 had blood pressure measurements available for both baseline and 12-week visits. There was a greater reduction in blood pressure in the calcium group compared with the placebo group for systolic pressure (difference 3.1 mmHg, 95% CI 0.8 to 5.4) and mean arterial pressure (MAP) (difference 2.0 mmHg, 95% CI 0.1 to 3.8). The difference in diastolic blood pressure reduction (1.4 mmHg, 95% CI -0.5 to 3.3) was not statistically significant (p = 0.140). For women with previous pre-eclampsia with severe features (n = 447), there was significantly greater reduction in blood pressure in the calcium than the placebo group (difference for systolic 4.0, 95% CI 0.7 to 7.3; diastolic 3.0, 95% CI 0.5 to 5.5 and mean arterial pressure 3.3, 95% CI 0.8 to 5.9 mmHg). For women with previous pre-eclampsia without severe features (n = 344), there were no significant differences between calcium and placebo groups. ANOVA analysis found no statistically significant interaction between previous pre-eclampsia severity and treatment, for systolic (p = 0.372), diastolic (p = 0.063) or mean blood pressure (p = 0.103).Conclusions: Low-dose calcium supplementation significantly reduced systolic and mean arterial pressure in non-pregnant women with previous pre-eclampsia. We did not confirm a greater calcium effect in women with previous pre-eclampsia with severe versus non-severe features. The effect of low-dose calcium is of importance since even modest blood pressure reductions at a population level may have important benefits in terms of reduced major complications of hypertension. This study adds to the mounting evidence of health benefits which could be achieved for populations with low dietary calcium through strategies to increase calcium intake, particularly among women at high risk due to previous pre-eclampsia.

Oh C, Keats EC, Bhutta ZA. Vitamin and Mineral Supplementation During Pregnancy on Maternal, Birth, Child Health and Development Outcomes in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

Almost two billion people are deficient in key vitamins and minerals, mostly women and children in low- and middle-income countries (LMICs). Deficiencies worsen during pregnancy due to increased energy and nutritional demands, causing adverse outcomes in mother and child, but could be mitigated by interventions like micronutrient supplementation. To our knowledge, this is the first systematic review that aimed to compile evidence from both efficacy and effectiveness trials, evaluating different supplementation interventions on maternal, birth, child health, and developmental outcomes. We evaluated randomized controlled trials and quasi-experimental studies published since 1995 in peer-reviewed and grey literature that assessed the effects of calcium, vitamin A, iron, vitamin D, and zinc supplementation compared to placebo/no treatment; iron-folic (IFA) supplementation compared to folic acid only; multiple micronutrient (MMN) supplementation compared to IFA; and lipid-based nutrient supplementation (LNS) compared to MMN supplementation. Seventy-two studies, which collectively involved 314 papers (451,723 women), were included. Meta-analyses showed improvement in several key birth outcomes, such as preterm birth, small-for-gestational age (SGA) and low birthweight with MMN supplementation, compared to IFA. MMN also improved child outcomes, including diarrhea incidence and retinol concentration, which are findings not previously reported. Across all comparisons, micronutrient supplementation had little to no effect on mortality (maternal, neonatal, perinatal, and infant) outcomes, which is consistent with other systematic reviews. IFA supplementation showed notable improvement in maternal anemia and the reduction in low birthweight, whereas LNS supplementation had no apparent effect on outcomes; further research that compares LNS and MMN supplementation could help understand differences with these commodities. For single micronutrient supplementation, improvements were noted in only a few outcomes, mainly pre-eclampsia/eclampsia (calcium), maternal anemia (iron), preterm births (vitamin D), and maternal serum zinc concentration (zinc). These findings highlight that micronutrient-specific supplementation should be tailored to specific groups or needs for maximum benefit. In addition, they further contribute to the ongoing discourse of choosing antenatal MMN over IFA as the standard of care in LMICs.

World Health Organization WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications

In 2019, the Executive Guideline Steering Group (GSG) on WHO maternal and perinatal health recommendations prioritized the development of a new WHO recommendation on calcium supplementation before and/or early in pregnancy for preventing hypertensive disorders of pregnancy, in response to the publication of a multi-country trial evaluating the use of pre-pregnancy calcium supplementation.

Santander Ballestín S, Giménez Campos MI, Ballestín Ballestín J, Luesma Bartolomé MJ. Is Supplementation with Micronutrients Still Necessary during Pregnancy? A Review

Introduction: Proper nutrition during pregnancy is important to prevent nutritional imbalances that interfere with pregnancy. Micronutrients play critical roles in embryogenesis, fetal growth, and maternal health, as energy, protein, vitamin, and mineral needs can increase during pregnancy. Increased needs can be met by increasing the intake of dietary micronutrients. Severe micronutrient deficiency or excess during pregnancy can have negative effects on fetal growth (intrauterine growth retardation, low birth weight, or congenital malformations) and pregnancy development (pre-eclampsia or gestational diabetes). We investigate whether it is necessary to continue micronutrient supplementation during pregnancy to improve women's health in this stage and whether this supplementation could prevent and control pathologies associated with pregnancy. Aim: The present review aims to summarize evidence on the effects of nutritional deficiencies on maternal and newborn morbidity. Methods: This aim is addressed by critically reviewing results from published studies on supplementation with different nutrients during pregnancy. For this, major scientific databases, scientific texts, and official webpages have been consulted. PubMed searches using the terms "pregnancy" OR "maternal-fetal health" AND "vitamins" OR "minerals" OR "supplementation" AND "requirement" OR "deficiency nutrients" were performed. Results: There are accepted interventions during pregnancy, such as folic acid supplementation to prevent congenital neural tube defects, potassium iodide supplementation to correct neurodevelopment, and oral iron supplementation during the second half of pregnancy to reduce the risk of maternal anemia and iron deficiency. A number of micronutrients have also been associated with pre-eclampsia, gestational diabetes mellitus, and nausea and vomiting in pregnancy. In general, experimental studies are necessary to demonstrate the benefits of supplementation with different micronutrients and to adjust the recommended daily doses and the recommended periconceptional nutrition for mothers. Conclusions: Presently, there is evidence of the benefits of micronutrient supplementation in perinatal results, but indiscriminate use is discouraged due to the fact that the side effects of excessive doses are not known. Evidence supports the idea that micronutrient deficiencies negatively affect maternal health and the outcome of pregnancy. No single micronutrient is responsible for the adverse effects; thus, supplementing or correcting one deficiency will not be very effective while other deficiencies exist.

Tihtonen K, Korhonen P, Isojärvi J, Ojala R, Ashorn U, Ashorn P, Tammela O. Calcium supplementation during pregnancy and maternal and offspring bone health: a systematic review and meta-analysis

Insufficient calcium intake during pregnancy may lead to maternal bone resorption and lower bone density of offspring. We evaluated the impact of supplementary calcium with or without vitamin D during pregnancy on maternal and offspring bone mineral density (BMD) and teeth firmness of the offspring. Randomized controlled trials (RCTs) were searched systematically in 11 databases. Two researchers independently screened the titles and abstracts of 3555 records and the full texts of 31 records to examine eligibility. The search yielded seven RCTs (11 reports, n = 1566). No advantage of calcium supplementation was found on maternal BMD after delivery or during breastfeeding, or on offspring BMD, even when dietary calcium intake was low. The results were neither modified by the dose of calcium nor concomitant vitamin D administration. A suspicion of some long-term harm of the intervention on maternal BMD and growth of female offspring was raised based on the data. One study suggested some benefit of high-dose calcium supplementation on offspring teeth firmness at 12 years old. A low number of the studies and abundant missing data reduced the quality of the findings. The impact of calcium supplementation on maternal and offspring bone health was deemed unknown because of inconclusive research results.

von Schacky C Importance of EPA and DHA Blood Levels in Brain Structure and Function

Brain structure and function depend on a constant and sufficient supply with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by blood. Blood levels of EPA and DHA reflect dietary intake and other variables and are preferably assessed as percentage in erythrocytes with a well-documented and standardized analytical method (HS-Omega-3 Index®). Every human being has an Omega-3 Index between 2 and 20%, with an optimum of 8-11%. Compared to an optimal Omega-3 Index, a lower Omega-3 Index was associated with increased risk for total mortality and ischemic stroke, reduced brain volume, impaired cognition, accelerated progression to dementia, psychiatric diseases, compromises of complex brain functions, and other brain issues in epidemiologic studies. Most intervention trials, and their meta-analyses considered EPA and DHA as drugs with good bioavailability, a design tending to produce meaningful results in populations characterized by low baseline blood levels (e.g., in major depression), but otherwise responsible for many neutral results and substantial confusion. When trial results were evaluated using blood levels of EPA and DHA measured, effects were larger than comparing EPA and DHA to placebo groups, and paralleled epidemiologic findings. This indicates future trial design, and suggests a targeted use EPA and DHA, based on the Omega-3 Index.

Thurfah JN, Christine, Bagaskhara PP, Alfian SD, Puspitasari IM. Dietary Supplementations and Depression

Depression is a mood disturbance condition that occurs for more than two weeks in a row, leading to suicide. Due to adverse effects of depression, antidepressants and adjunctive therapies, such as dietary supplementation, are used for treatment. Therefore, this review explored and summarized dietary supplements' types, dosages, and effectiveness in preventing and treating depression. A literature search of the PubMed database was conducted in August 2021 to identify studies assessing depression, after which scale measurements based on dietary supplements were identified. From the obtained 221 studies, we selected 63 papers. Results showed PUFA (EPA and DHA combination), vitamin D, and probiotics as the most common supplementation used in clinical studies to reduce depressive symptoms. We also observed that although the total daily PUFA dosage that exhibited beneficial effects was in the range of 0.7-2 g EPA and 0.4-0.8 g DHA daily, with an administration period of three weeks to four months, positive vitamin D-based supplementation effects were observed after administering doses of 2000 IU/day or 50,000 IU/week between 8 weeks and 24 months. Alternatively, microbes from the genus Lactobacillus and Bifidobacterium in the probiotic group with a minimum dose of 108 CFU in various dose forms effectively treated depression. Besides, a depression scale was helpful to assess the effect of an intervention on depression. Hence, PUFA, vitamin D, and probiotics were proposed as adjunctive therapies for depression treatment based on the results from this study.

Ghnaimawi S, Zhang S, Baum JI, Huang Y. The Effects of Maternal Intake of EPA and DHA Enriched Diet During Pregnancy and Lactation on Offspring's Muscle Development and Energy Homeostasis

EPA and DHA are n-3 long-chain polyunsaturated fatty acids with a diversity of health benefits on offspring. The objective of this study was to test the in vivo effect of maternal ingestion of EPA and DHA on fetal and offspring muscle development and energy balance. Two groups of female C57BL/6 mice were fed EPA and DHA enriched diet (FA) and diet devoid of EPA and DHA (CON) respectively throughout the entire period of gestation and lactation. Embryos at E13 and offspring at age of D1 and D21 were selected for sample collection and processing. No change in birth number and body weight were observed between groups at D1 and D21. Transient increase in the expression levels of myogenesis regulating genes was detected at D1 (p < 0.05) in FA group. Most of the expression of muscle protein synthesis regulating genes were comparable (p > 0.05) between FA and CON groups at D1 and D21. The significant increase in MHC4, and IGF-1 was not linked to increased muscle mass. A persistent increase in ISR expression (p < 0.05) but not in GLUT-4 (p > 0.05) was detected in offspring. Up-regulation of adipogenesis regulating genes was accompanied by increasing intramuscular fat accumulation in the offspring of FA group. Considerable increase in transcripts of genes regulating lipid catabolism and thermogenesis in liver (p < 0.05) was noticed in FA group at D21; whereas, only the levels of carnitine palmitoyl transferase 1A (Cpt1α) and Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (Ehhadh) increased at D1. Similarly, genes regulating lipolysis were highly expressed at D21 in FA group. EPA and DHA treatment promoted BAT development and activity by increasing the expression of BAT signature genes (p < 0.05). Also, maternal intake of EPA and DHA enriched diet enhanced browning of sWAT. Taken together, maternal ingestion of EPA/DHA may be suggested as a therapeutic option to improve body composition and counteract childhood obesity- related metabolic disorders and confer lifelong positive metabolic impact on offspring.

Petca A, Bot M, Maru N, Calo IG, Borislavschi A, Dumitrascu MC, Petca RC, Sandru F, Zvanca ME. Benefits of α-lipoic acid in high-risk pregnancies (Review)

α-Lipoic acid (ALA) is a natural molecule that is inconsistently synthesized by the human body and must be provided from exogenous sources, such as food and dietary supplements. Once absorbed, the oxidized form of ALA is transformed into its reduced form, dihydrolipoic acid (DHLA). ALA/DHLA exert direct and indirect antioxidant, anti-inflammatory and fine immunomodulatory effects. ALA/DHLA reduce the levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-17), while increasing the secretion of anti-inflammatory cytokines (IL-10). They also inhibit cyclooxygenase 2, thereby decreasing the secretion of prostaglandin E2 and nitrogen oxide, and reducing the risk of miscarriage in the first trimester of pregnancy. In patients at risk of abortion, administration of ALA from the first trimester has shown efficacy by accelerating subchorionic hematoma resorption, with a significant decrease in the accompanying abdominal pain. ALA has been proven to be efficient in maintaining the length of the cervix and keeping it closed following one episode of premature labor. Preeclampsia is a dysfunction caused by abnormal placentation and an excessive maternal inflammatory response, leading to extreme hypoxia in the placental bed and exaggerated oxidative stress, with release of oxygen free radicals. Oxidative stress plays a key role in the development of preeclampsia and intrauterine growth restriction. The hypothesis of antioxidant supplementation may play an essential part in disease prevention and fetal neuroprotection.

Menichini D, Imbrogno MG, Basile L, Monari F, Ferrari F, Neri I. Oral supplementation of α-lipoic acid (ALA), magnesium, vitamin B6 and vitamin D stabilizes cervical changes in women presenting risk factors for preterm birth

Objective: Recently, the PTB risk has been related to the objective measurement of cervical length (CL), since a CL of less than 25 mm is an accurate predictor of increased risk of PTB. Primary prevention of preterm labor is based on the early identification of symptoms and on pharmacological treatments with tocolytic drugs for inhibition of uterine contractions that are associated with a shortening of the cervix. Unfortunately, most of these drugs have important side effects. Patients and methods: This study aimed to evaluate whether the administration of a combination of oral α-lipoic acid (ALA), magnesium, vitamin B6 and vitamin D to pregnant women presenting risk factors for PTB could reduce the rate of cervical shortening at 19-22 weeks of gestational age. Results: A total of 122 women attending the first-trimester aneuploidy screening at 11-14 weeks of pregnancy and presenting risk factors for PTB were included in the study. Cervical length significantly decreased in the control group compared with the treatment group (-3.86 ± 1.97 vs. 1.50 ± 1.26; p=0.02). Although the rate of preterm birth did not significantly decrease (9.5% vs. 5.1%), admission for threatened PTB was statistically reduced in the treatment group compared with the control group (3.4% vs. 14.3%). Conclusions: Oral supplementation of ALA, magnesium, vitamin B6 and vitamin D significantly counteracted cervix shortening in pregnant women presenting risk factors for PTB.

Wagh GN, Kundavi Shankar KM, Bachani S A review of conventional and sustained-release formulations of oral natural micronized progesterone in obstetric indications

Background: Exogenous progesterone is a treatment option for obstetric indications associated with reduced progesterone activity. Oral natural micronized progesterone (NMP) is effective, although it requires multiple daily doses and may cause adverse events due to its active metabolites. A sustained-release formulation of NMP (NMP-SR) has been developed to overcome the limitations of conventional oral NMP. Methods: This narrative review examines the available evidence for oral NMP and NMP-SR in several obstetric indications of interest. Results: Literature searches identified 17 studies of oral NMP (luteal phase support during assisted reproduction, prevention of threatened miscarriage, prevention of preterm delivery), and clinical studies supporting use of NMP-SR (luteal phase support during intrauterine insemination, maintenance of high-risk pregnancy). Oral NMP was effective for luteal phase support during in vitro fertilization and intrauterine insemination, prevention of threatened miscarriage, and prevention of preterm delivery. NMP-SR was comparable to dydrogesterone for luteal phase support during intrauterine insemination and effectively maintained high-risk pregnancies. Oral NMP-SR was well tolerated. Conclusions: By releasing progesterone gradually and circumventing first-pass metabolism, NMP-SR elicits the desired therapeutic effect with benefits over conventional oral NMP in terms of bioavailability, once-daily dosing and improved tolerability. Oral NMP-SR appears to be a valuable option for treating obstetric conditions associated with insufficient progesterone exposure.

Di Renzo GC, Tosto V, Tsibizova V, Fonseca E. Prevention of Preterm Birth with Progesterone

Gestational age at birth is a critical factor for perinatal and adulthood outcomes, and even for transgenerational conditions' effects. Preterm birth (PTB) (prematurity) is still the main determinant for infant mortality and morbidity leading cause of infant morbidity and mortality. Unfortunately, preterm birth (PTB) is a relevant public health issue worldwide and the global PTB rate is around 11%. The premature activation of labor is underlined by complex mechanisms, with a multifactorial origin influenced by numerous known and probably unknown triggers. The possible mechanisms involved in a too early labor activation have been partially explained, and involve chemokines, receptors, and imbalanced inflammatory paths. Strategies for the early detection and prevention of this obstetric condition were proposed in clinical settings with interesting results. Progesterone has been demonstrated to have a key role in PTB prevention, showing several positive effects, such as lower prostaglandin synthesis, the inhibition of cervical stromal degradation, modulating the inflammatory response, reducing gap junction formation, and decreasing myometrial activation. The available scientific knowledge, data and recommendations address multiple current areas of debate regarding the use of progesterone in multifetal gestation, including different formulations, doses and routes of administration and its safety profile in pregnancy.

Alan Rigoberto Carvajal-Sepúlveda, Fred Morgan-Ortiz, Everardo Quevedo-Castro, Guadalupe López-Manjarrez, Fred Valentín Morgan-Ruiz, Perla Yareli Gutiérrez-Arzapalo. Deficiencia de vitamina D en pacientes con preeclampsia severa y embarazo único a término

La preeclampsia es una de las principales causas de morbimortalidad materna, es una enfermedad específica del embarazo caracterizado por trastornos hipertensivos que pueden estar asociados a diferentes grados de proteinuria, con posibilidad de evolucionar a diferentes espectros clínicos de severidad. En presencia de alguna de las características marcadas como “severas”, los pacientes pueden clasificarse automáticamente. La forma activa de la vitamina D juega un papel regulador en el proceso de placentación, la cual se une a su receptor de vitamina D (VDR), que se expresa en altas cantidades en el trofoblasto y tejido decidual en función de la carga genética y la síntesis de vitamina D endógena. Cuando hay una disminución en la carga de VDR, el trofoblasto comienza a crecer e invadir de manera desorganizada, la invasión no llega a ser funcional, porque la desorganización hace que los espacios lagunares no sean alcanzados correctamente, comprometiendo el suministro de oxígeno de la unidad fetoplacentaria. Debido a estos eventos ocurre una disminución del factor de crecimiento tipo 3 (TGFB3), encargado de inducir el crecimiento placentario, neovascu-larización y aporte nutrimental al trofoblasto invasor, contribuyendo a la patogenia de la preeclampsia. En general, resultados de distintos estudios sugieren que los niveles disminuidos de 25(OH) D en el embarazo pueden estar asocia-dos con la preeclampsia en subgrupos específicos de la población.

Parveen R, Khakwani M, Tabassum S, Masood S. Oral versus Vaginal Micronized Progesterone for the Treatment of Threatened Miscarriage

This study was planned with an aim to find out the effectiveness of oral versus vaginal micronized progesterone for the treatment of threatened miscarriage. This randomized controlled trial was conducted at The Department of Obstetrics and Gynaecology, Nishtar Hospital Multan, from August 2019 to January 2020. A total of 136 pregnant women, aged 18 to 45 years having vaginal bleeding were included and divided into two groups (68 women in each group). Participants in the Group-A were given oral micronized progesterone as 200mg twice a day while Group-B participants were given vaginal progesterone suppository 400mg once a day. All women were followed up until 20th week of their pregnancy. Outcome was labeled as prevention of miscarriage if woman had no bleeding per vagina and pregnancy went beyond 20th weeks of gestation. In a total of 136 women enrolled, mean age was noted to be 30.85+3.34 years. Overall, mean gestational age was noted to be 9.3+2.7 weeks. A total of 98 women (49 in each group) completed the follow up and were included in the final analysis regarding outcome. Among Groups-A, 45 (91.8) had prevention of miscarriage while 4 (9.2%) had miscarriage in comparison to 36 (73.5%) in Group-B had prevention of miscarriage whereas 13 (26.5%) had miscarriage and this difference was statistically significant in between the both study groups as women in Group-A had significantly better outcome in terms of prevention of miscarriage. (P value = 0.0164). The use of oral micronized progesterone was found to be significantly more effective than vaginal progesterone in women with threatened miscarriage.

Nagy B, Szekeres-Barthó J, Kovács GL, Sulyok E, Farkas B, Várnagy Á, Vértes V, Kovács K, Bódis J Key to Life: Physiological Role and Clinical Implications of Progesterone.

The most recent studies of progesterone research provide remarkable insights into the physiological role and clinical importance of this hormone. Although the name progesterone itself means “promoting gestation”, this steroid hormone is far more than a gestational agent. Progesterone is recognized as a key physiological component of not only the menstrual cycle and pregnancy but also as an essential steroidogenic precursor of other gonadal and non-gonadal hormones such as aldosterone, cortisol, estradiol, and testosterone. Based on current findings, progesterone and novel progesterone-based drugs have many important functions, including contraception, treatment of dysfunctional uterine bleeding, immune response, and prevention of cancer. Considering the above, reproduction and life are not possible without progesterone; thus, a better understanding of this essential molecule could enable safe and effective use of this hormone in many clinical conditions.

Benjamin Brown, Ciara Wright, Safety and efficacy of supplements in pregnancy

Pregnancy is a time where expectant mothers often focus on their diet to improve their own health and to preserve the future health of their children. There is much conflicting information in the public domain about the safety and/or efficacy of nutritional supplements during pregnancy. Despite this, the market for supplements is growing. This review discusses the roles of critical nutrients in pregnancy and the available evidence on the use of supplements to reduce risks and improve maternal and fetal outcomes. Recommendations are made for pregnant women, taking into account safety data and tolerable upper intakes set for pregnant women. It is important for dieticians, nutritionists, physicians, and other healthcare providers to be able to offer accurate and evidence-based advice on supplement use in pregnancy. Routine supplementation may not be necessary for all, but individuals at risk are identified.

Chen Z, Chen J. The Efficacy of Calcium Carbonate-Vitamin D3 in Pregnant Women for the Prevention of Hypertensive Disorders in Pregnancy

Objective. To evaluate the efficacy of calcium carbonate-vitamin D3 in pregnant women for the prevention of hypertensive disorders in pregnancy. Methods. Between April 2020 and June 2021, 60 pregnant women undergoing prenatal examinations in our hospital were recruited and assigned via the random number table method at a ratio of 1 : 1 to receive conventional pregnancy care (observation group) or conventional pregnancy care plus calcium carbonate-vitamin D3 administration (experimental group). Outcome measures included blood pressure, blood calcium, the occurrence of hypertensive disorders, and adverse events. Results. The diastolic blood pressure (DBP) and systolic blood pressure (SBP) levels at delivery in the experimental group were significantly lower than those in the observation group (). Pregnant women in the experimental group had significantly higher blood calcium levels at labor than those in the observation group (). The administration of calcium carbonate-vitamin D3 resulted in a significantly lower incidence of hypertensive disorders and adverse events versus conventional pregnancy care (). Conclusion. The effect of calcium carbonate-vitamin D3 administration during pregnancy for the prevention of hypertensive disorders is significant, which effectively improves the blood calcium level of pregnant women and reduces the occurrence of adverse events, so it is worthy of clinical promotion and application.

Y Chai, P Ning, UY Peng  Recent Advance in Understanding Vitamin D in Postpartum Depression

Postpartum Depression (PPD) is a prevalent mental disorder that affects approximately 20% women after giving birth worldwide. The common PPD symptoms include loss of appetite, suicidal thoughts, withdrawal from loved ones and babies. PPD not only affects mothers’ mental health but also results in mother-infant attachment and bonding problems. Though the exact PPD etiology remains poorly understood, cumulative studies have demonstrated that vitamin D deficiency during pregnancy is associated with PPD, and vitamin D3 supplementation during pregnancy greatly reduces PPD. This article specifically reviews the recent studies in the relationship between vitamin D3 deficiency and PPD, vitamin D3 treatment for PPD prevention, and the potential mechanisms by which vitamin D3 deficiency results in PPD

Fallah M, Askari G, Asemi Z. Is Vitamin D Status Associated with Depression, Anxiety and Sleep Quality in Pregnancy: A Systematic Review

Women's mental health is a significant health issue for pregnant women during and after pregnancy. Postpartum depression (PPD) is defined as the presence of depression in the 1st year after delivery. This study reviews the relationship between Vitamin D levels, anxiety and poor sleep quality related to pregnancy. Search yielded 14 eligible studies. Quality of most included studies was medium to high. Nine studies reported that Vitamin D deficiency was directly associated to the incidence of PPD and sleep disorders. One study reported an indirect association, and three researches did not observe any association between Vitamin D status, sleep disorders and PPD. One study reported a direct association to anxiety but did not have any relation to PPD.

Yilmaz B, Li H. Gut Microbiota and Iron: The Crucial Actors in Health and Disease. 

Iron (Fe) is a highly ample metal on planet earth (~35% of the Earth's mass) and is particularly essential for most life forms, including from bacteria to mammals. Nonetheless, iron deficiency is highly prevalent in developing countries, and oral administration of this metal is so far the most effective treatment for human beings. Notably, the excessive amount of unabsorbed iron leave unappreciated side effects at the highly interactive host⁻microbe interface of the human gastrointestinal tract. Recent advances in elucidating the molecular basis of interactions between iron and gut microbiota shed new light(s) on the health and pathogenesis of intestinal inflammatory diseases. We here aim to present the dynamic modulation of intestinal microbiota by iron availability, and conversely, the influence on dietary iron absorption in the gut. The central part of this review is intended to summarize our current understanding about the effects of luminal iron on host⁻microbe interactions in the context of human health and disease.

Luis Izquierdo. Efficacy and Tolerability of Oral Iron Protein Succinylate in the Treatment of Iron Deficiency Anemia in Adults with Gastrointestinal Diseases

Iron deficiency anemia (IDA) is commonly associated with several pathological gastrointestinal (GI) conditions in adults, being induced through different mechanisms, such as chronic bleeding, chronic inflammation, malabsorption, autoimmune re-actions, or, quite frequently, as a combination of different mechanisms. All patients must be treated with iron supplementation with the aim of restoring normal hemoglobin levels and iron status. Oral iron compounds are the first line treatment options for ID clinical conditions, according to International Guidelines, as they have proven to be efficacious, safe, and relatively inexpensive. However, ferric salts are scarcely absorbed, and ferrous compounds present a poor GI tolerability. Iron-protein succinylate (IPS), an iron complex that keeps ferric iron bonded to the protein content of a succinylated casein shell at acid pH values, has been shown to release gradually iron into the intestinal lumen, protecting the gastrointestinal mucosa from eventual damage, an ensuring an optimal intestinal iron absorption. This review focuses on IPS in the treatment of IDA associated to a variety of GI medical conditions in adults. Results from diverse studies including IDA due to acute and chronic GI conditions, as well as IDA associated to gastric surgery, confirm a consistent improvement in hematologic parameters and clinical symptoms, and an optimal tolerability profile.

Martínez Sánchez, Lina María, Jaramillo Jaramillo, Laura Isabel, Villegas Álzate, Juan Diego, Álvarez Hernández, Luis Felipe, & Ruiz Mejía, Camilo. La anemia fisiológica frente a la patológica en el embarazo

Introducción: Algunos de los cambios fisiológicos del embarazo, implican el riesgo de sufrir diferentes trastornos, entre ellos la anemia, la cual está altamente asociada a mortalidad materno-fetal. La Organización Mundial de la Salud estima que aproximadamente 42 % de las gestantes sufren de anemia en algún momento del embarazo. Los tipos de anemia más frecuentes son la ferropénica, megaloblástica y de células falciformes. La anemia por deficiencia de hierro es la de mayor incidencia durante el embarazo. Objetivo: Actualizar la información existente en la literatura científica internacional acerca de la anemia fisiológica y patológica en el embarazo, con énfasis en el diagnóstico y tratamiento. Métodos: Se realizó una búsqueda exhaustiva de la literatura mediante los MeSH: anemia, embarazo, deficiencia de hierro, vitamina B12, ácido fólico y fisiología en inglés y en español. Para la búsqueda, se usaron las bases de datos PubMed, MedLine, SciELO y Google Académico. Resultados: Se hallaron más de 18 321 artículos, de los cuales 40 cumplieron los criterios de inclusión para ser seleccionados. Conclusiones: Si bien un número considerable de cuadros de anemia gestacional corresponden a anemias dilucionales fisiológicas sin ningún tipo de repercusión clínica, es de fundamental importancia el reconocimiento de cuadros patológicos, por la asociación que estos tienen a desenlaces maternos y perinatales adversos.

Martínez-Villegas O, Baptista-González HA Anemia por deficiencia de hierro en niños: un problema de salud nacional

La deficiencia de hierro y la anemia por deficiencia de hierro se manifiestan en todas las etapas de la vida, los grupos más vulnerables son niños, adolescentes y mujeres en edad reproductiva con gran repercusión médica y social; ambos trastornos deben ser entendidos dentro del continuo de la vida del ser humano porque una etapa previa resulta fundamental para explicar las variaciones en edades posteriores. Diferentes condiciones fisiológicas y patológicas favorecen la anemia por deficiencia de hierro; en México, sin duda, la ingesta alta de fitatos en niños de uno a cuatro años es un factor de riesgo. Las manifestaciones clínicas dependen de la gravedad de la anemia, edad, comorbilidades, cronicidad y velocidad de inicio. La ferritina sérica es la prueba más específica que refleja las reservas de hierro en el organismo. La deficiencia de hierro y la anemia no se alivian con el tratamiento farmacológico a base de los diferentes componentes con hierro, es importante entender los problemas que aquejan al grupo etario particular y los antecedentes de ese grupo. En México la deficiencia de hierro y la anemia por deficiencia de hierro continúan siendo un problema de salud pública, existen diferentes estrategias que se han implementado para prevenirlas; sin embargo, en los últimos años ha disminuido su interés a tal grado de no aparecer ya en las Encuestas Nacionales de Salud y Nutrición, hecho que limita la evaluación de la efectividad de las intervenciones para atacarla.

Rosas-González EA, Álvarez-Altamirano K, Bejarano-Rosales MP, Fuchs-Tarlovsky V, Santoyo-Sánchez A, Ramos-Peñafiel CO La travesía del hierro en el embarazo: una vía para su deficiencia

El hierro es uno de los elementos más abundantes en la tierra, en el ser humano participa en muchos procesos biológicos. En el embarazo el requerimiento de hierro aumenta y es por medio de la placenta que la madre abastece al feto. En todo el mundo 40% de las mujeres embarazadas padecen anemia, por lo que su metabolismo materno-fetal juega una parte importante en el entendimiento de la fisiopatología de la enfermedad y posible terapéutica. La baja ingesta, predisposición y la inadecuada administración complementaria son factores que intervienen en la alta prevalencia de anemia y deficiencia de hierro en esta etapa de la vida. En este artículo de revisión se describe la epidemiologia, metabolismo y principales mecanismos por los que se conduce a la deficiencia del metal más importante de los sistemas biológicos: el hierro.

Al Wattar BH, Fisher M, Bevington L, Talaulikar V, Davies M, Conway G, Yasmin E. Clinical Practice Guidelines on the Diagnosis and Management of Polycystic Ovary Syndrome: A Systematic Review and Quality Assessment Study

Context: Clinical practice guidelines (CPGs) are key instruments to implement the practice of evidence-based medicine. We aimed to evaluate the methodological quality and variations in CPGs recommendations on the diagnosis and management of polycystic ovary syndrome (PCOS). Evidence acquisition: We searched MEDLINE, EMBASE, and CENTRAL until December 2020 for all evidence-based CPGs and consensus statements on PCOS. We extracted data in duplicate to map clinical recommendations across prespecified disease domains and assessed CPGs methodological quality of using the Appraisal of Guidelines, Research & Evaluation II tool. Evidence synthesis: We included 13 PCOS CPGs published between 2007 and 2018. CPGs recommendations were mostly focused on screening for and managing metabolic disease (12/13, 92%), followed by cardiovascular risk assessment (10/13, 77%). Mental health (8/13, 62%) and diagnosis in adolescents (7/13, 54%) were the least reported domains. Most CPGs had a high quality for scope and purpose description (12/13, 92%) while stakeholder's involvement and applicability of recommendations to clinical practice were appropriate in only 2 CPGs (2/13, 15%). We identified inconsistency in recommendations on PCOS diagnosis in adolescents, optimal lifestyle interventions, hirsutism and acne treatments, interventions to reduce the risk of ovarian hyperstimulation syndrome, the frequency and screening criteria for metabolic and cardiovascular disease, and optimal screening tools for mental health illness in women with PCOS. Cnclusion: Current CPGs on the diagnosis and management of PCOS vary in their scope and methodological quality, which may hinder evidence translation into clinical practice. We identified disease domains with existing evidence gap to guide future research and guideline updates.

Maladkar, M. , Sankar, S. and Yadav, A A Novel Approach for Iron Deficiency Anaemia with Liposomal Iron: Concept to Clinic

Iron deficiency anaemia is the most common nutritional deficiency disorder, contributing to 50 percent of all the anaemias in the world. Dietary changes alone are insufficient for the correction and management of iron deficiency anaemia. Hence, iron supplementation is necessary. Conventional oral iron therapy is limited in many patients because of dose dependent side effects, insufficient absorption, lack of compliance and limitation in various inflammatory conditions. Liposomal iron is a technologically designed, innovative form of iron which due to its differential delivery system ensures higher absorption and bioavailability, greater tolerability and least gastro-intestinal side effects unlike conventional oral iron preparations. This review provides a critical discussion and a comprehensive view based on the author’s review of the medical literature concerning the technology of liposomal iron preparation, mechanism of its absorption, its advantage over conventional iron preparations and clinical evidence on its usage in iron deficient states in pregnancy and certain inflammatory conditions

Pastore P, Roverso M, Tedesco E, Micheletto M, Mantovan E, Zanella M, Benetti F. Comparative Evaluation of Intestinal Absorption and Functional Value of Iron Dietary Supplements and Drug with Different Delivery Systems

Iron is a fundament micronutrient, whose homeostasis is strictly regulated. Iron deficiency anemia is among the most widespread nutritional deficiencies and its therapy, based on dietary supplement and drugs, may lead to severe side effects. With the aim of improving iron bioavailability while reducing iron oral therapy side effects, novel dietary supplements based on innovative technologies-microencapsulation, liposomes, sucrosomes-have been produced and marketed. In the present work, six iron dietary supplements for different therapeutic targets were compared in terms of bioaccessibility, bioavailability, and safety by using an integrated in vitro approach. For general-purpose iron supplements, ME + VitC (microencapsulated) showed a fast, burst intestinal iron absorption kinetic, which maintained iron bioavailability and ferritin expression constant over time. SS + VitC (sucrosomes), on the other side, showed a slower, time-dependent iron absorption and ferritin expression trend. ME + Folate (microencapsulated) showed a behavior similar to that of ME + VitC, albeit with a lower bioavailability. Among pediatric iron supplements, a time-dependent bioavailability increase was observed for LS (liposome), while PIC (polydextrose-iron complex) bioavailability is severely limited by its poor bioaccessibility. Finally, except for SS + VitC, no adverse effects on intestinal mucosa vitality and barrier integrity were observed. Considering obtained results and the different therapeutic targets, microencapsulation-based formulations are endowed with better performance compared to the other formulations. Furthermore, performances of microencapsulated products were obtained with a lower iron daily dose, limiting the potential onset of side effects.

Garzon S, Cacciato PM, Certelli C, Salvaggio C, Magliarditi M, Rizzo G. Iron Deficiency Anemia in Pregnancy: Novel Approaches for an Old Problem

Iron needs increase exponentially during pregnancy to meet the increased demands of the fetoplacental unit, to expand maternal erythrocyte mass, and to compensate for iron loss at delivery. In more than 80% of countries in the world, the prevalence of anemia in pregnancy is > 20% and could be considered a major public health problem. The global prevalence of anemia in pregnancy is estimated to be approximately 41.8%. Undiagnosed and untreated iron deficiency anemia (IDA) can have a great impact on maternal and fetal health. Indeed, chronic iron deficiency can affect the general wellbeing of the mother and leads to fatigue and reduced working capacity. Given the significant adverse impact on maternal-fetal outcomes, early recognition and treatment of this clinical condition is fundamental. Therefore, the laboratory assays are recommended from the first trimester to evaluate the iron status. Oral iron supplementation is the first line of treatment in cases of mild anemia. However, considering the numerous gastrointestinal side effects that often lead to poor compliance, other therapeutic strategies should be evaluated. This review aims to provide an overview of the current evidence about the management of IDA in pregnancy and available treatment options.

Piskin E, Cianciosi D, Gulec S, Tomas M, Capanoglu E Iron Absorption: Factors, Limitations, and Improvement Methods

Iron is an essential element for human life since it participates in many functions in the human body, including oxygen transport, immunity, cell division and differentiation, and energy metabolism. Iron homeostasis is mainly controlled by intestinal absorption because iron does not have active excretory mechanisms for humans. Thus, efficient intestinal iron bioavailability is essential to reduce the risk of iron deficiency anemia. There are two forms of iron, heme and nonheme, found in foods. The average daily dietary iron intake is 10 to 15 mg in humans since only 1 to 2 mg is absorbed through the intestinal system. Nutrient-nutrient interactions may play a role in dietary intestinal iron absorption. Dietary inhibitors such as calcium, phytates, polyphenols and enhancers such as ascorbic acid and proteins mainly influence iron bioavailability. Numerous studies have been carried out for years to enhance iron bioavailability and combat iron deficiency. In addition to traditional methods, innovative techniques are being developed day by day to enhance iron bioavailability. This review will provide information about iron bioavailability, factors affecting absorption, iron deficiency, and recent studies on improving iron bioavailability.

D'Anna R, Corrado F, Loddo S, Gullo G, Giunta L, Di Benedetto A. Myoinositol plus α-lactalbumin supplementation, insulin resistance and birth outcomes in women with gestational diabetes mellitus: a randomized, controlled study.

To verify whether myo-inositol plus α-lactalbumin may reduce insulin resistance and excessive fetal growth in women with gestational diabetes mellitus. In a 12-month period, 120 women with a diagnosis of gestational diabetes mellitus were consecutively enrolled with an allocation of 1:1 in each group and randomly treated with myo-inositol plus α-lactalbumin plus folic acid (treated group) or folic acid (control group) for 2 months. Primary outcome was the variation of insulin resistance through the study evaluated by HOMA-IR. Secondary outcome was the evaluation, through the study, of fetal growth by ultrasound measurements of abdominal circumference centiles and estimated fat thickness. Some clinical outcomes were also considered. After 2 months, in the treated group, a significant reduction in insulin resistance (HOMA values 3.1 ± 1.4 vs 6.1 ± 3.4, p = 0.0002) and fetal growth was shown (Abdominal circumference centiles 54.9 ± 23.5 vs 67.5 ± 22.6, P = 0.006). Among clinical outcomes, a significant decrease in the rate of women who needed insulin (6.7% vs 20.3%, p = 0.03) and of pre-term birth (0 vs 15.2%, p = 0.007) was evidenced. A combination of myo-inositol and α-lactalbumin may reduce insulin resistance and excessive fetal growth.

Unfer V, Dinicola S, Laganà AS, Bizzarri M. Altered Ovarian Inositol Ratios May Account for Pathological Steroidogenesis in PCOS.

The presence of abnormal ovarian ratios of myo-inositol (MI) to D-chiro-inositol (DCI) is a recurrent feature in PCOS. Available evidence suggests that MI and DCI may modulate steroid biosynthesis, likely in an opposite manner. Specifically, MI seems to induce estrogen production, while DCI has a role in the synthesis of androgens. Elevated insulin levels, generally associated with PCOS, alter the physiological MI/DCI ratio, increasing MI-to-DCI conversion through activation of a specific epimerase enzyme. DCI directly increases testosterone biosynthesis in thecal cells and reduces its conversion to estradiol by downregulating aromatase enzyme in granulosa cells. This manuscript reviews the literature that supports the connection between altered MI/DCI ratios and pathological steroidogenesis observed in PCOS women. Furthermore, it discusses the application of inositol-based treatment protocols in managing PCOS symptoms and improving the quality of patients' life.

Várbíró S, Takács I, Tűű L, Nas K, Sziva RE, Hetthéssy JR, Török M. Effects of Vitamin D on Fertility, Pregnancy and Polycystic Ovary

Polycystic ovary syndrome (PCOS) is one of the most common endocrine reproductive disorders in women. Vitamin D deficiency is also quite common in this condition. The degree of vitamin D deficiency correlates with the severity of PCOS. Both male and female vitamin D levels play a role in fertility and affect the outcomes of in vitro fertilization (IVF). Moreover, fertility and IVF indicators are improved by vitamin D not only in healthy women but in those diagnosed with PCOS. Both vitamin D deficiency and PCOS increase pregnancy-related complications. Vitamin D supplementation and optimal vitamin D levels decrease both maternal and fetal risk for complications and adverse events. Furthermore, vitamin D supplementation may ameliorate or even prevent pregnancy-related reversible bone loss in mothers. This review emphasizes the roles of vitamin D deficiency and vitamin D supplementation and their correlation with PCOS regarding reproductive health.

Lerchbaum E, Theiler-Schwetz V, Kollmann M, Wölfler M, Pilz S, Obermayer-Pietsch B, Trummer C. Effects of Vitamin D Supplementation on Surrogate Markers of Fertility in PCOS Women: A Randomized Controlled Trial.

Vitamin D (VD) might play an important role in polycystic ovary syndrome (PCOS) and female fertility. However, evidence from randomized controlled trials (RCT) is sparse. We examined VD effects on anti-Müllerian hormone (AMH) and other endocrine markers in PCOS and non-PCOS women. This is a post hoc analysis of a single-center, double-blind RCT conducted between December 2011 and October 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. We included 180 PCOS women and 150 non-PCOS women with serum 25-hydroxyvitamin D (25(OH)D) concentrations <75 nmol/L in the trial. We randomized subjects to receive 20,000 IU of VD3/week (119 PCOS, 99 non-PCOS women) or placebo (61 PCOS, 51 non-PCOS women) for 24 weeks. Outcome measures were AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, dehydroepiandrosterone sulfate, and androstenedione. In PCOS women, we observed a significant treatment effect on FSH (mean treatment effect 0.94, 95% confidence interval [CI] 0.087 to 1.799, p = 0.031) and LH/FSH ratio (mean treatment effect -0.335, 95% CI -0.621 to 0.050, p = 0.022), whereas no significant effect was observed in non-PCOS women. In PCOS women, VD treatment for 24 weeks had a significant effect on FSH and LH/FSH ratio but no effect on AMH levels.

Muscogiuri G, Altieri B, de Angelis C, Palomba S, Pivonello R, Colao A, Orio F. Shedding new light on female fertility: The role of vitamin D

In the last decades several studies suggested that vitamin D is involved in the modulation of the reproductive process in women due to the expression of VDR and 1α-hydroxylase in reproductive tissues such as ovary, uterus, placenta, pituitary and hypothalamus. Vitamin D has also a role in the regulation of sex hormone steroidogenesis. Increasing evidence suggests that vitamin D might have a regulatory role in polycystic ovary syndrome (PCOS)-associated symptoms, including ovulatory dysfunction, insulin resistance and hyperandrogenism. Vitamin D deficiency also has been reported to contribute to the pathogenesis of endometriosis due to its immunomodulatory and anti-inflammatory properties. Although most of the studies supported a role of vitamin D in the onset of these diseases, randomized controlled trials to assess the efficacy of vitamin D supplementation have never been performed. In this review we critically discuss the role of vitamin D in female fertility, starting from in vitro and in vivo studies, focusing our attention on the two most frequent causes of female infertility: PCOS and endometriosis.

Bosdou JK, Konstantinidou E, Anagnostis P, Kolibianakis EM, Goulis DG. Vitamin D and Obesity: Two Interacting Players in the Field of Infertility. 

Obesity plays an important role in human fertility in both genders. The same is true for vitamin D, for which accumulating evidence from observational human studies suggests a key role for both male and female fertility. In the latter case, however, robust data from relevant interventional studies are currently lacking. It is also not clear whether obesity and vitamin D deficiency, besides their independent effect on human infertility, act in synergy. Several pathogenetic mechanisms may be proposed as a linkage between vitamin D deficiency and obesity, with respect to infertility. In any case, the independent contribution of vitamin D deficiency in obese infertile states needs to be proven in interventional studies focusing on either vitamin D supplementation in obese or weight loss strategies in vitamin D-deficient infertile patients.

Gambioli R, Forte G, Buzzaccarini G, Unfer V, Laganà AS. Myo-Inositol as a Key Supporter of Fertility and Physiological Gestation

Pregnancy is a complex process, featuring several necessary changes in women's physiology. Most women undergo healthy pregnancies; even so, several women experience reduced fertility or pathologies related to the pregnancy. In the last years, researchers investigated several molecules as promoters of fertility. Among all, myo-inositol (myo-ins) represents a safe compound that proved useful in issues related to fertility and pregnancy. In fact, myo-ins participates in several signaling processes, including the pathways of insulin and gonadotropins, and, therefore, it is likely to positively affect fertility. In particular, several clinical trials demonstrate that its administration can have therapeutic effects in infertile women, and that it can also be useful as a preventive treatment during pregnancy. Particularly, myo-ins could prevent the onset of neural tube defects and the occurrence of gestational diabetes mellitus, promoting a trouble-free gestation. Due to the safety and efficiency of myo-ins, such a treatment may also substitute several pharmaceuticals, which are contraindicated in pregnancy.

Chan SY, Barton SJ, Loy SL, Chang HF, Titcombe P, Wong JT, Ebreo M, Ong J, Tan KM, Nield H, El-Heis S, Kenealy T, Chong YS, Baker PN, Cutfield WS, Godfrey KM; NiPPeR Study Group. Time-to-conception and clinical pregnancy rate with a myo-inositol, probiotics, and micronutrient supplement: secondary outcomes of the NiPPeR randomized trial

Objective: To determine whether a combined myo-inositol, probiotics and micronutrient nutritional supplement impacts time-to-natural-conception and clinical pregnancy rates. Results: Of 1729 women randomized, 1437 (83%; intervention, n=736; control, n=701) provided data. Kaplan-Meier curves of conception were similar between intervention and control groups; the time at which 20% achieved natural conception was 90.5 days (95% confidence interval: 80.7, 103.5) in the intervention group compared with 92.0 days (76.0, 105.1) in the control group. Cox's proportional hazard ratios (HRs) comparing intervention against control for cumulative achievement of pregnancy (adjusted for site, ethnicity, age, body mass index, and gravidity) were similar at 3, 6, and 12 months. Among both study groups combined, overall time-to-conception lengthened with higher preconception body mass index, and was longer in non-White than in White women. Among women who were overweight the intervention shortened time-to-conception compared with control regardless of ethnicity (12-month HR=1.47 [1.07, 2.02], P=.016; 20% conceived by 84.5 vs. 117.0 days) and improved it to that comparable to nonoverweight/nonobese women (20% conceived by 82.1 days). In contrast, among women with obesity, time-to-conception was lengthened with intervention compared with control (12-month HR=0.69 [0.47, 1.00]; P=.053; 20% conceived by 132.7 vs. 108.5 days); an effect predominantly observed in non-White women with obesity. Conclusions: Time-to-natural-conception and clinical pregnancy rates within a year were overall similar in women receiving the intervention supplement compared with control. Overweight women had a longer time-to-conception but there was suggestion that the supplement may shorten their time-to-conception to that comparable to the nonoverweight/nonobese women. Further studies are required to confirm this.

Kamenov, Z.; Gateva, A.; Dinicola, S.; Unfer, V. Comparing the Efficacy of Myo-Inositol Plus α-Lactalbumin vs. Myo-Inositol Alone on Reproductive and Metabolic Disturbances of Polycystic Ovary Syndrome

Despite the beneficial effect of myo-inositol on metabolic, hormonal, and reproductive parameters of polycystic ovary syndrome (PCOS) patients, 28% to 38% could be resistant to this treatment. The combination with the milk protein α-lactalbumin can be a useful therapeutic approach to overcome inositol resistance and achieve ovulation in these women. This open-label prospective study aimed to compare the effects of supplementing myo-inositol plus α-lactalbumin vs myo-inositol alone on reproductive and metabolic abnormalities in PCOS. A total of 50 anovulatory women with a PCOS diagnosis were randomly assigned to receive myo-inositol alone or a combination of myo-inositol and α-lactalbumin for three months. Anthropometric measures, hormonal levels, and menstrual cycle duration were collected at baseline and after treatment. The therapy with myo-inositol plus α-lactalbumin improved both ovulation rate and menstrual cycle duration more than myo-inositol alone. The body weight was significantly reduced in women receiving myo-inositol plus α-lactalbumin, while patients in the myo-inositol group experienced no change. In addition, the improvement of hyperandrogenism was more prominent in patients treated with myo-inositol plus α-lactalbumin. The benefits of associating myo-inositol and α-lactalbumin clearly make this combination a true edge in the management of PCOS.

Aslfalah H, Jamilian M, Ansarihadipour H, Abdollahi M, Khosrowbeygi A.  Effect of alpha-lipoic acid supplementation on the lipid profile and lipid ratios in women with gestational diabetes mellitus: A clinical trial study.

Background: Evidence suggests that Oxidative stress has been shown to plays an important role in gestational diabetes mellitus (GDM) etiology. On the other hand, women with GDM are at an increased risk for complications such as endothelial dysfunction and cardiovascular diseases. Objective: To investigate the effects of alpha-lipoic acid (ALA) on the maternal circulating values of lipid profile and lipid ratios in women with GDM. Materials and methods: Sixty women with GDM were participated in the present study. The ALA group (n = 30) received ALA (100 mg/day) and the placebo group (n = 30) received cellulose acetate (100 mg/day) for eight wk. The maternal circulating values of hemoglobin A1C, triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglyceride-glucose (TyG) index, atherogenic index of plasma (AIP), non-HDL-C, and lipid ratios were assessed before and after the intervention. P-value < 0.05 was considered as statistically significant. Results: The values of TyG index (p <0.001), TG (p = 0.006), TG/HDL-C (p = 0.003), and AIP (p = 0.005) decreased significantly in the ALA group after the intervention. Conclusion: Maternal circulating values of TyG index, TG, TG/HDL, AIP decreased after eight wk of ALA supplementation in women with GDM.

Watkins OC, Selvam P, Pillai RA, Cracknell-Hazra VKB, Yong HEJ, Sharma N, Cazenave-Gassiot A, Bendt AK, Godfrey KM, Lewis RM, Wenk MR, Chan SY. Myo-inositol moderates maternal BMI and glycemia related variations in in-vitro placental 13C-DHA-metabolism, altering their relationships with birthweight

Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with 13C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized 13C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most 13C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased 13C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased 13C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.

Insights on the Use of α-Lipoic Acid for Therapeutic Purposes Insights on the Use of α-Lipoic Acid for Therapeutic Purposes

α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.

Aslfalah H, Jamilian M, Ansarihadipour H, Abdollahi M, Khosrowbeygi A. Effect of alpha-lipoic acid supplementation on the lipid profile and lipid ratios in women with gestational diabetes mellitus: A clinical trial study

Background: Evidence suggests that Oxidative stress has been shown to plays an important role in gestational diabetes mellitus (GDM) etiology. On the other hand, women with GDM are at an increased risk for complications such as endothelial dysfunction and cardiovascular diseases. Objective: To investigate the effects of alpha-lipoic acid (ALA) on the maternal circulating values of lipid profile and lipid ratios in women with GDM. Materials and methods: Sixty women with GDM were participated in the present study. The ALA group (n = 30) received ALA (100 mg/day) and the placebo group (n = 30) received cellulose acetate (100 mg/day) for eight wk. The maternal circulating values of hemoglobin A1C, triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglyceride-glucose (TyG) index, atherogenic index of plasma (AIP), non-HDL-C, and lipid ratios were assessed before and after the intervention. P-value <0.05 was considered as statistically significant. Results: The values of TyG index (p <0.001), TG (p = 0.006), TG/HDL-C (p = 0.003), and AIP (p = 0.005) decreased significantly in the ALA group after the intervention. Conclusion: Maternal circulating values of TyG index, TG, TG/HDL, AIP decreased after eight wk of ALA supplementation in women with GDM.

Griffith RJ, Alsweiler J, Moore AE, Brown S, Middleton P, Shepherd E, Crowther CA. Interventions to prevent women from developing gestational diabetes mellitus: an overview of Cochrane Reviews

Background: The prevalence of gestational diabetes mellitus (GDM) is increasing, with approximately 15% of pregnant women affected worldwide, varying by country, ethnicity and diagnostic thresholds. There are associated short- and long-term health risks for women and their babies.Objectives: We aimed to summarise the evidence from Cochrane systematic reviews on the effects of interventions for preventing GDM.Methods: We searched the Cochrane Database of Systematic Reviews (6 August 2019) with key words 'gestational diabetes' OR 'GDM' to identify reviews pre-specifying GDM as an outcome. We included reviews of interventions in women who were pregnant or planning a pregnancy, irrespective of their GDM risk status. Two overview authors independently assessed eligibility, extracted data and assessed quality of evidence using ROBIS and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm (GRADE moderate- or high-quality evidence with a confidence interval (CI) that did not cross the line of no effect); clear evidence of no effect or equivalence (GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect); possible benefit or harm (low-quality evidence with a CI that did not cross the line of no effect or GRADE moderate- or high-quality evidence with a wide CI); or unknown benefit or harm (GRADE low-quality evidence with a wide CI or very low-quality evidence). Main results: We included 11 Cochrane Reviews (71 trials, 23,154 women) with data on GDM. Nine additional reviews pre-specified GDM as an outcome, but did not identify GDM data in included trials. Ten of the 11 reviews were judged to be at low risk of bias and one review at unclear risk of bias. Interventions assessed included diet, exercise, a combination of diet and exercise, dietary supplements, pharmaceuticals, and management of other health problems in pregnancy. The quality of evidence ranged from high to very low. Diet Unknown benefit or harm: there was unknown benefit or harm of dietary advice versus standard care, on the risk of GDM: risk ratio (RR) 0.60, 95% CI 0.35 to 1.04; 5 trials; 1279 women; very low-quality evidence. There was unknown benefit or harm of a low glycaemic index diet versus a moderate-high glycaemic index diet on the risk of GDM: RR 0.91, 95% CI 0.63 to 1.31; 4 trials; 912 women; low-quality evidence. Exercise Unknown benefit or harm: there was unknown benefit or harm for exercise interventions versus standard antenatal care on the risk of GDM: RR 1.10, 95% CI 0.66 to 1.84; 3 trials; 826 women; low-quality evidence. Diet and exercise combined Possible benefit: combined diet and exercise interventions during pregnancy versus standard care possibly reduced the risk of GDM: RR 0.85, 95% CI 0.71 to 1.01; 19 trials; 6633 women; moderate-quality evidence. Dietary supplements Clear evidence of no effect: omega-3 fatty acid supplementation versus none in pregnancy had no effect on the risk of GDM: RR 1.02, 95% CI 0.83 to 1.26; 12 trials; 5235 women; high-quality evidence. Possible benefit: myo-inositol supplementation during pregnancy versus control possibly reduced the risk of GDM: RR 0.43, 95% CI 0.29 to 0.64; 3 trials; 502 women; low-quality evidence. Possible benefit: vitamin D supplementation versus placebo or control in pregnancy possibly reduced the risk of GDM: RR 0.51, 95% CI 0.27 to 0.97; 4 trials; 446 women; low-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of probiotic with dietary intervention versus placebo with dietary intervention (RR 0.37, 95% CI 0.15 to 0.89; 1 trial; 114 women; very low-quality evidence), or probiotic with dietary intervention versus control (RR 0.38, 95% CI 0.16 to 0.92; 1 trial; 111 women; very low-quality evidence) on the risk of GDM. There was unknown benefit or harm of vitamin D + calcium supplementation versus placebo (RR 0.33, 95% CI 0.01 to 7.84; 1 trial; 54 women; very low-quality evidence) or vitamin D + calcium + other minerals versus calcium + other minerals (RR 0.42, 95% CI 0.10 to 1.73; 1 trial; 1298 women; very low-quality evidence) on the risk of GDM. Pharmaceutical Possible benefit: metformin versus placebo given to obese pregnant women possibly reduced the risk of GDM: RR 0.85, 95% CI 0.61 to 1.19; 3 trials; 892 women; moderate-quality evidence. Unknown benefit or harm:eight small trials with low- to very low-quality evidence showed unknown benefit or harm for heparin, aspirin, leukocyte immunisation or IgG given to women with a previous stillbirth on the risk of GDM. Management of other health issues Clear evidence of no effect: universal versus risk based screening of pregnant women for thyroid dysfunction had no effect on the risk of GDM: RR 0.93, 95% CI 0.70 to 1.25; 1 trial; 4516 women; moderate-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of using fractional exhaled nitrogen oxide versus a clinical algorithm to adjust asthma therapy on the risk of GDM: RR 0.74, 95% CI 0.31 to 1.77; 1 trial; 210 women; low-quality evidence. There was unknown benefit or harm of pharmacist led multidisciplinary approach to management of maternal asthma versus standard care on the risk of GDM: RR 5.00, 95% CI 0.25 to 99.82; 1 trial; 58 women; low-quality evidence.Authors' conclusions: No interventions to prevent GDM in 11 systematic reviews were of clear benefit or harm. A combination of exercise and diet, supplementation with myo-inositol, supplementation with vitamin D and metformin were of possible benefit in reducing the risk of GDM, but further high-quality evidence is needed. Omega-3-fatty acid supplementation and universal screening for thyroid dysfunction did not alter the risk of GDM. There was insufficient high-quality evidence to establish the effect on the risk of GDM of diet or exercise alone, probiotics, vitamin D with calcium or other vitamins and minerals, interventions in pregnancy after a previous stillbirth, and different asthma management strategies in pregnancy. There is a lack of trials investigating the effect of interventions prior to or between pregnancies on risk of GDM.

Limanaqi F, Biagioni F, Busceti CL, Polzella M, Fabrizi C, Fornai F. Potential Antidepressant Effects of Scutellaria baicalensis, Hericium erinaceus and Rhodiola rosea

Recent studies focused on the pharmacology and feasibility of herbal compounds as a potential strategy to target a variety of human diseases ranging from metabolic to brain disorders. Accordingly, bioactive ingredients which are found within a variety of herbal compounds are reported to produce both neuroprotective and psychotropic activities which may help to combat mental disorders such as depression, anxiety, sleep disturbances and cognitive alterations. In the present manuscript, we focus on three herbs which appear effective in mitigating anxiety or depression with favourable risk-benefit profiles, namely Scutellaria baicalensis (S. baicalensis), Hericium erinaceus (H. erinaceus) and Rhodiola rosea (R. rosea). These three traditional folk medicinal herbs target the main biochemical events that are implicated in mental disorders, mimicking, to some extent, the mechanisms of action of conventional antidepressants and mood stabilizers with a wide margin of tolerability. In detail, they rescue alterations in neurotransmitter and neuro-endocrine systems, stimulate neurogenesis and the synthesis of neurotrophic factors, and they counteract oxidative stress, mitochondrial dysfunction and inflammation. Albeit the encouraging results that emerge from both experimental and clinical evidence, further studies are needed to confirm and better understand the mental-health promoting, and specifically, the antidepressant effects of these herbs.

Rivera Dommarco JA, Colchero MA , Fuentes ML, González de Cosío Martínez T, Aguilar Salinas CA, Hernández Licona G, Barquera S (eds.). La obesidad en México. Estado de la política pública y recomendaciones para su prevención y control.

La obesidad en México. Estado de la política pública y recomendaciones para su prevención y control es un claro ejemplo de cómo puede y debe abordarse el gran reto que tenemos por delante. Cuenta con la participación de más de 75 científicos, entre autores y revisores, y está dividido en dos secciones: en la primera se presenta un documento de postura; es decir, un análisis sucinto del problema de la obesidad en México y sus múltiples causales, así como recomendaciones puntuales que permitirán a la administración federal prevenir y controlar el problema; en la segunda sección, el libro compila 10 capítulos que pormenorizan y dan sustento a cada una de las recomendaciones previamente señaladas.

GA Turan, T Delibasi Gestational Diabetes and Infertility

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications which affect the mother and offspring. In addition to adverse perinatal outcomes, it may lead to permanent health problems for the mother, such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), while increasing the risk of future obesity, CVD, T2DM and GDM in the child. Approximately 15% of women seek fertility treatment. Over the last decade, it has come to attention that patients with an infertility history are more prone to having GDM during their pregnancies, and this review examines the relationship between GDM and infertility. The elevated estrogen, progesterone, leptin, placental lactogen and growth hormone are the main reasons for increased insulin resistance during pregnancy. Despite some confounding factors in the mechanism of GDM in patients with an infertility history, infertility treatment increases the risk, according to numerous studies. The obesity epidemic and associated disorders have become a significant public health concern worldwide. Lifestyle modification for weight loss before pregnancy is encouraged, but there is no strong evidence for improvement in perinatal results. GDM, infertility and infertility treatment have a potential risk of alteration in the embryo’s environment and cause epigenetic reprogramming, which may be inherited to the next generation. The fertility treatment impacts the patient’s and offspring’s health. Patients should be informed about the risks so that they consent and get involved in the decision. Infertility treatment may be accepted as a reason for high-risk pregnancy, and patients can be screened for GDM in early pregnancy.

Arefhosseini S, Roshanravan N, Tutunchi H, Rostami S, Khoshbaten M, Ebrahimi-Mameghani M. Myo-inositol supplementation improves cardiometabolic factors, anthropometric measures, and liver function in obese patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of metabolic syndrome is closely associated with type 2 diabetes mellitus. Myo-inositol (MI)—a 6-C sugar alcohol—with insulin-mimetic, anti-diabetic, lipid-lowering, and anti-inflammatory properties has exerted favorable effects on insulin resistance-related disorders and metabolic disease, while recent animal studies revealed its positive effects on liver function. This study aimed to investigate the effects of MI supplementation on cardiometabolic factors, anthropometric measures, and liver function in obese patients with NAFLD. Anthropometric measures decreased significantly in both groups, while the reduction in weight (p = 0.049) and systolic blood pressure (p = 0.006) in the MI group was significantly greater than in the placebo group after adjusting for baseline values and energy intake. Although energy and macronutrient intakes decreased significantly in both groups, between-group differences were not significant after adjusting for the potential confounders. MI supplementation led to a significant reduction in serum fasting insulin (p = 0.008) and HOMA-IR (p = 0.046). There were significant improvements in lipid profile, liver enzymes, and aspartate aminotransferase/alanine aminotransferase ratio as well as serum ferritin level in the MI group, compared to the placebo group at the endpoint. By MI supplementation for eight weeks, 1 in 3 patients reduced one- grade in the severity of NAFLD.

Blasi I, Daolio J, Pugni V, Comitini G, Morciano M, Grassi G, Todros T, Gargano G, Aguzzoli L. Correlations between parameters of glycaemic variability and foetal growth, neonatal hypoglycaemia and hyperbilirubinemia in women with gestational diabetes

The diagnosis of gestational diabetes mellitus (GDM) is important to prevent maternal and neonatal complications. This study aimed to investigate the feasibility of parameters of glycaemic variability to predict neonatal complications in women with GDM. A retrospective study was conducted on pregnant women tested positive at the oral glucose tolerance test (OGTT) during 16-18 or 24-28 weeks of gestation. Glycaemic measures were extracted from patients' glucometers and expanded to obtain parameters of glycaemic variability. Data on pregnancy outcomes were obtained from clinical folders. Descriptive group-level analysis was used to assess trends in glycaemic measures and foetal outcomes. Twelve patients were included and analysed, accounting for 111 weeks of observations. The analysis of trends in parameters of glycaemic variability showed spikes of glycaemic mean, high blood glucose index and J-index at 30-31 weeks of gestation for cases with foetal macrosomia, defined as foetal growth >90° percentile, neonatal hypoglycaemia and hyperbilirubinemia. Specific trends in parameters of glycaemic variability observed at third trimester correlate with foetal outcomes. Further research is awaited to provide evidence that monitoring of glycaemic variability trends could be more clinically informative and useful than standard glycaemic checks to manage women with GDM at delivery.

Bertrand A, Gallot D, Pereira B, Delabaere A Myoinositol supplementation for the prevention of gestational diabetes in at-risk patients. Systematic review and meta-analysis

Background: Gestational diabetes (GD) is associated with an increase in maternal and fetal morbidity. The risk factors involved have been clearly identified but no prevention strategies have yet provided robust evidence of their efficacy. Myoinositol has insulin sensitization properties and is of potential interest in the treatment of the disorder. Aim: The aim of this work was to assess the efficacy of myoinositol supplementation during pregnancy to prevent GD in patients with known risk factors. Method: A systematic literature review was performed on studies comparing the effects of myoinositol supplementation and placebo on the occurrence of GD in at-risk pregnant women. The main judgement criterion was diagnosis of GD between 24 and 28 gestational weeks by an oral glucose tolerance test. The secondary judgement criteria were the occurrence of maternal fetal complications and the need to initiate insulin treatment to manage GD. Results: Nine studies were included in the meta-analysis. The results showed a significantly higher risk of GD in patients on placebo than in those receiving myoinositol (RR ​= ​2.58, CI 95%: 1.68 to 3.97, p ​< ​0.0001) but wide variations between studies (I2 ​= ​71.94%, p ​< ​0.001). And the risk of prematurity was significantly greater in the children of mothers on placebo (RR: 2.15, IC 95%: 1.32 to 3.20, p ​= ​0.002). Conclusion: Myoinositol supplementation taken from the beginning of pregnancy reduces the incidence of GD and could be of interest at a dose of 4 ​g/day as a prevention strategy for patients with identified risk factors.

Wei J, Yan J, Yang H. Inositol Nutritional Supplementation for the Prevention of Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

This study was aimed at assessing the efficacy and safety of inositol nutritional supplementation during pregnancy for the prevention of GDM. PubMed, Embase, MEDLINE, and Cochrane library were systematically searched for randomized controlled trails (RCTs) in this field until May 2022. Primary outcomes were the incidence for GDM and plasma glucose levels by oral glucose tolerance test (OGTT). Pooled results were expressed as relative risk (RR) or mean difference (MD) with a 95% confidence interval (95% CI). Seven RCTs with 1321 participants were included in this study. Compared with the control group, 4 g myo-inositol (MI) supplementation per day significantly decreased the incidence of GDM (RR = 0.30, 95% CI (0.18, 0.49), p < 0.00001). It significantly decreased the plasma glucose levels of OGTT regarding fasting-glucose OGTT (MD = −4.20, 95% CI (−5.87, −2.54), p < 0.00001), 1-h OGTT (MD = −8.75, 95% CI (−12.42, −5.08), p < 0.00001), and 2-h OGTT (MD = −8.59, 95% CI (−11.81, −5.83), p < 0.00001). It also decreased the need of insulin treatment, and reduced the incidence of preterm delivery and neonatal hypoglycemia. However, no difference was observed between 1.1 g MI per day plus 27.6 mg D-chiro-inositol (DCI) per day and the control group regarding all evaluated results. In conclusion, 4 g MI nutritional supplementation per day during early pregnancy may reduce GDM incidence and severity, therefore may be a practical and safe approach for the prevention of GDM.

Mashayekh-Amiri S, Mohammad-Alizadeh-Charandabi S, Abdolalipour S, Mirghafourvand M. Myo-inositol supplementation for prevention of gestational diabetes mellitus in overweight and obese pregnant women: a systematic review and meta-analysis

Background: The prevalence of gestational diabetes mellitus [GDM] and of its most important predisposing factor, i.e. overweight and obesity, have increased dramatically over the past 20 years. Therefore, the aim of this study was to systematically review the articles on the effect of myo-inositol supplementation on the prevention of GDM in pregnant women with overweight and obesity. Methods: We conducted a systematic literature search in electronic database (MEDLINE, Cochrane Library, ClinicalTrials.gov, Embase, ProQuest, PubMed, Google scholar, Scopus, Web of science and forward and backward citations) to identify all randomized controlled trials (RCTs) published until 21 December 2021. Finally, Among the 118 identified records, four studies were eligible and were included in this systematic review. The meta-analysis results were reported in the form of odds ratio (OR) to compare the incidence of GDM and pregnancy outcomes. They were also presented in the form of mean difference (MD) to compare fasting glucose (FG), 1-h and 2-h oral glucose tolerance test (OGTT) levels between the two groups. This study was registered on PROSPERO, number CRD42021290570. Results: The results showed that the incidence of GDM was significantly lower in the myo-inositol group (OR 0.32, 95% CI 0.21 to 0.48; P < 0.001; I2 = 0%; Moderate certainty evidence). Moreover, FG-OGTT (MD - 2.64 mg/dl, 95% CI - 4.12 to - 1.17; P < 0.001; I2 = 0%; Moderate certainty evidence), 1-h-OGTT (MD - 7.47 mg/dl, 95% CI - 12.24 to - 2.31; P = 0.005; I2 = 27%; Low certainty evidence) and 2-h-OGTT levels (MD - 10.51 mg/dl, 95% CI - 16.88 to - 4.14; P = 0.001; I2 = 59%; Low certainty evidence) in the myo-inositol group were significantly lower than in the control group. Regarding the pregnancy outcomes, the incidence of gestational hypertension and preterm delivery was significantly lower in the myo-inositol group. However, no between-group difference was observed in the other outcomes.

Guarnotta V, Cuva G, Imbergamo MP, Giordano C. Myoinositol supplementation in the treatment of gestational diabetes mellitus: effects on glycaemic control and maternal-foetal outcomes

Background: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset during pregnancy. It is characterized by high risk of adverse outcomes for the mother and the foetus, if not adequately controlled. The aim of the study was to evaluate the effects of 4000 mg of myoinositol supplementation in women with GDM on maternal-foetal outcomes, compared to controls.Methods: A cohort of 330 women with GDM, 150 supplemented with myoinositol and 180 controls were enrolled. Clinical and metabolic parameters and the prevalence of maternal and foetal complications were assessed.Results: The same number of women in the two groups started insulin as additional therapy. Women treated with myoinositol more frequently had a long-acting insulin scheme of treatment than those untreated (p<0.001), while women untreated with myoinositol more frequently had a basal-bolus insulin regimen (p<0.001) compared to women on myoinositol. Patients treated with myoinositol had significantly lower fasting plasma glucose (p=0.032), post-prandial dinner glucose (p=0.014), insulin requirement both in the 2nd and in the 3rd trimesters (p=0.001 and p<0.001, respectively), than those not treated with myoinositol. With regard to maternal/foetal outcomes, lower birth weight (p=0.043) and frequency of hypoglycaemic events (p=0.001) were observed in women treated with myoinositol compared to controls. Conclusions: Women with GDM treated with myoinositol showed an improved glycaemic control in the 3rd trimester of pregnancy and a lower insulin requirement, when insulin was added to the treatment, compared to controls. In addition, they showed lower preterm birth weight and neonatal hypoglycaemia, compared to women not supplemented with myoinositol.

Amaefule CE, Drymoussi Z, Gonzalez Carreras FJ, et al. Myo-inositol nutritional supplement for prevention of gestational diabetes (EMmY): a randomised, placebo-controlled, double-blind pilot trial with nested qualitative study

Objectives: To determine the feasibility and acceptability of conducting a randomised trial on the effects of myo-inositol in preventing gestational diabetes in high-risk pregnant women. Design: A multicentre, double-blind, placebo-controlled, pilot randomised trial with nested qualitative evaluation. Interventions: 2 g of myo-inositol or placebo, both included 200 µg folic acid, twice daily until delivery. Primary outcome measures: Rates of recruitment, randomisation, adherence and follow-up. Secondary outcome measures: Glycaemic indices (including homoeostatic model assessment-insulin resistance HOMA-IR), gestational diabetes (diagnosed using oral glucose tolerance test at 28 weeks and by delivery), maternal, perinatal outcomes, acceptability of intervention and costs. Results: Of the 1326 women screened, 58% (773/1326) were potentially eligible, and 27% (205/773) were recruited. We randomised 97% (198/205) of all recruited women (99 each in intervention and placebo arms) and ascertained outcomes in 90% of women (178/198) by delivery. The mean adherence was 52% (SD 44) at 28 weeks' and 34% (SD 41) at 36 weeks' gestation. HOMA-IR and serum insulin levels were lower in the myo-inositol vs placebo arm (mean difference -0.6, 95% CI -1.2 to 0.0 and -2.69, 95% CI -5.26 to -0.18, respectively). The study procedures were acceptable to women and healthcare professionals. Women who perceived themselves at high risk of gestational diabetes were more likely to participate and adhere to the intervention. The powder form of myo-inositol and placebo, along with nausea in pregnancy were key barriers to adherence.

DiNicolantonio JJ, H O'Keefe J. Myo-inositol for insulin resistance, metabolic syndrome, polycystic ovary syndrome and gestational diabetes

Myo-inositol, also known as inositol (cyclohexanehexol), is a cyclic carbohydrate with six hydroxyl groups.1 For a long time, it was considered a B vitamin (vitamin B8). However, it is not considered an essential nutrient because it is formed from glucose. Each kidney makes around 2 g of myo-inositol per day, and the average dietary intake is 0.5–1.0g/day.2 3 The liver and brain also synthesise myo-inositol, although at much lower amounts compared with the kidneys. Importantly, however, in the brain, myoinositol levels reach concentrations 10-fold to 15-fold greater than that of blood, and there is limited uptake of myo-inositol from systemic circulation.3

Ibrahim I, Abdullahi H, Fagier Y, Ortashi O, Terrangera A, Okunoye G. Effect of antenatal dietary myo-inositol supplementation on the incidence of gestational diabetes mellitus and fetal outcome: protocol for a double-blind randomised controlled trial

Introduction: Gestational diabetes mellitus (GDM) affects 23.6% of Qatari women and is associated with maternal and perinatal morbidity and long-term risk of developing type 2 diabetes. A number of challenges exist with current interventions, including non-compliance with dietary advice, the reluctance of mothers to ingest metformin tablets or use insulin injections. These challenges highlight the importance of pursuing evidence-based prevention strategies. Myo-inositol is readily available as an US Food and Drug Administration-approved food supplement with emerging but limited evidence suggesting it may be beneficial in reducing the incidence of GDM. Further studies, such as this one, from different ethnic contexts and with differing risk factors, are urgently needed to assess myo-inositol effects on maternal and neonatal outcomes.

Baldassarre MPA, Di Tomo P, Centorame G, Pandolfi A, Di Pietro N, Consoli A, Formoso G Myoinositol Reduces Inflammation and Oxidative Stress in Human Endothelial Cells Exposed In Vivo to Chronic Hyperglycemia

Myo-inositol (Myo) improves insulin resistance, glucose metabolism, and helps gestational diabetes (GDM) management. GDM is associated with a pro-inflammatory state and increased oxidative stress, which are both involved in vascular damage in diabetes. Our aim was to study Myo anti-inflammatory/antioxidant potential effects on an in vitro model of human umbilical vein endothelial cells (HUVECs). To this end, monocyte cell adhesion to HUVECs, adhesion molecule membrane exposure, and oxidative stress levels were determined in cells from control (C-) and GDM women treated during pregnancy either with diet only (GD-) or with diet plus Myo (GD+Myo). To deeply study the vascular effects of Myo, the same evaluations were performed in C- and GD-HUVECs following 48 h in vitro stimulation with Myo. Notably, we first observed that GD-HUVECs obtained from women assuming Myo supplementation exhibited a significantly decreased number of monocytes that adhered to endothelial cells, less adhesion molecule exposure, and lower intracellular reactive oxygen species (ROS) levels in the basal state as compared to GD-HUVECs obtained from women treated by diet only. This Myo anti-inflammatory/antioxidant effect was confirmed by 48 h in vitro stimulation of GD-HUVECs as compared to controls. Altogether, these results strongly suggest that Myo may exert protective actions against chronic inflammation induced by endothelial dysfunction in diabetes.

Wang L, Cheng H, Wang X, Zheng L. Effectiveness and acceptability of myoinositol in prevention of gestational diabetes mellitus

Background:: The existing meta-analyses and randomized studies on myoinositol are of poor quality, with small sample sizes, and involve a homogeneous population. The general applicability of these findings to the National Health Service is unclear. We thus conduct this new high-quality systematic review and meta-analysis to assess the efficacy and safety of myoinositol in pregnant woman. Methods:: The study protocol will be developed and executed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. All of the following inclusion criteria in the PICOS order will be met by the studies included in our meta-analysis: 1. population: pregnant woman without gestational diabetes mellitus (GDM); 2. intervention: group with myoinositol; 3.comparison intervention: group without myoinositol; 4.outcome measures: at least one of the following outcome measures should to be reported: rate of GDM, offspring birthweight, fasting glucose, oral glucose tolerance test, and the side effects associated with the myoinositol; and 5. study design: English randomized trials. The following electronic databases will be searched: PubMed, Scopus, EMBASE, and Cochrane Library databases. The Cochrane risk of bias tool will be used to evaluate the risk of bias of the included randomized trials by 2 independent reviewers. Results:: We will perform a meta-analysis using standard techniques for the outcomes. Conclusions:: It was hypothesized that myoinositol supplementation could increase the action of endogenous insulin and prevent GDM and its complications.

Iervolino M, Lepore E, Forte G, Laganà AS, Buzzaccarini G, Unfer V Natural Molecules in the Management of Polycystic Ovary Syndrome (PCOS): An Analytical Review

Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by chronic ovulation dysfunction and hyperandrogenism. It is considered the most common endocrinological disorder, affecting up to 25% of women of reproductive age, and associated with long-term metabolic abnormalities predisposing to cardiovascular risk, such as insulin resistance (IR), dyslipidemia, endothelial dysfunction, and systemic inflammation. PCOS is also characterized by elevated serum levels of luteinizing hormone (LH), causing a condition of hyperandrogenism and a consequent altered ratio between LH and the follicle stimulating hormone (FSH). Over the years, several different approaches have been proposed to alleviate PCOS symptoms. Supplementation with natural molecules such as inositols, resveratrol, flavonoids and flavones, vitamin C, vitamin E and vitamin D, and omega-3 fatty acids may contribute to overcoming PCOS pathological features, including the presence of immature oocyte, IR, hyperandrogenism, oxidative stress and inflammation. This review provides a comprehensive overview of the current knowledge about the efficacy of natural molecule supplementation in the management of PCOS.

Sadeghi HM, Adeli I, Calina D, Docea AO, Mousavi T, Daniali M, Nikfar S, Tsatsakis A, Abdollahi M. Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing.

Polycystic ovary syndrome (PCOS) is an endocrine-gynecology disorder affecting many women of childbearing age. Although a part of the involved mechanism in PCOS occurrence is discovered, the exact etiology and pathophysiology are not comprehensively understood yet. We searched PubMed for PCOS pathogenesis and management in this article and ClinicalTrials.gov for information on repurposed medications. All responsible factors behind PCOS were thoroughly evaluated. Furthermore, the complete information on PCOS commonly prescribed and repurposed medications is summarized through tables. Epigenetics, environmental toxicants, stress, diet as external factors, insulin resistance, hyperandrogenism, inflammation, oxidative stress, and obesity as internal factors were investigated. Lifestyle modifications and complementary and alternative medicines are preferred first-line therapy in many cases. Medications, including 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents, and some supplements have supporting data for being repurposed in PCOS. Since there are few completed clinical trials with a low population and mostly without results on PCOS repurposed medications, it would be helpful to do further research and run well-designed clinical trials on this subject. Moreover, understanding more about PCOS would be beneficial to find new medications implying the effect via the novel discovered routes.

Cardinale V, Lepore E, Basciani S, Artale S, Nordio M, Bizzarri M, Unfer V. Positive Effects of α-Lactalbumin in the Management of Symptoms of Polycystic Ovary Syndrome

To date, the involvement of α-Lactalbumin (α-LA) in the management of polycystic ovary syndrome (PCOS) refers to its ability to improve intestinal absorption of natural molecules like inositols, overcoming the inositol resistance. However, due to its own aminoacidic building blocks, α-LA is involved in various biological processes that can open new additional applications. A great portion of women with PCOS exhibit gastrointestinal dysbiosis, which is in turn one of the triggering mechanisms of the syndrome. Due to its prebiotic effect, α-LA can recover dysbiosis, also improving the insulin resistance, obesity and intestinal inflammation frequently associated with PCOS. Further observations suggest that altered gut microbiota negatively influence mental wellbeing. Depressive mood and low serotonin levels are indeed common features of women with PCOS. Thanks to its content of tryptophan, which is the precursor of serotonin, and considering the strict link between gut and brain, using α-LA contributes to preserving mental well-being by maintaining high levels of serotonin. In addition, considering women with PCOS seeking pregnancy, both altered microbiota and serotonin levels can induce later consequences in the offspring. Therefore, a deeper knowledge of potential applications of α-LA is required to transition to preclinical and clinical studies extending its therapeutic advantages in PCOS.

Rajani Shrivastava, Veena Agrawal Study of Efficacy of Combination of Cyproterone Acetate and Ethenyl Estradiol in Androgenic Symptom

Introduction: Androgenic disorders are the most common endocrinopathies of women. The present study was done to study the eficacy and side effects of cyproterone acetate and ethinylestradiol combination for the management of symptoms of hyperandrogenism in females. Material and Methods: The present study was done on 20 females in the Department of Obstetrics and Gynaecology, GRMC, Gwalior. All patients were given combination of cyproterone acetate (2mg) and ethinylestradiol (0.35 μg) from day 1 of menstrual cycle till day 21. Follow up was done 6 months to 1 year for improvement in their presenting complaints of acne, hirsutism and menstrual irregularities. Results: In present study, most (80%) of the female were married, most (65%) of them were having age between 21- 30 years. Seventy percent were having acne, 60% had menstrual irregularity and 45% had hirsutism. After 3 cycle, 40% showed disappearance of papules, 71% had improvement in hirsutism in mild cases and 75% patients showed improvement in regular menstrual cycle and normal blood loss during menses whereas, after 6 cycles all patients showed complete disappearance of papules and hirsutism. Only one patient reported severe headache and nausea with the therapy. Conclusion: The combination of cyproterone acetate and ethinylestradiol was effective in reducing the symptoms of hyperandrogenesim in females. Effect of drug combination over androgenic symptoms was noted with earliest effect seen over menstrual irregularities which were earliest to normalise within3 cycles.With the exception of nausea and breast tension in the short term and chloasma with long-term treatment, the therapy was well tolerated.

Al Wattar BH, Fisher M, Bevington L, Talaulikar V, Davies M, Conway G, Yasmin E. Clinical Practice Guidelines on the Diagnosis and Management of Polycystic Ovary Syndrome: A Systematic Review and Quality Assessment Study

Context: Clinical practice guidelines (CPGs) are key instruments to implement the practice of evidence-based medicine. We aimed to evaluate the methodological quality and variations in CPGs recommendations on the diagnosis and management of polycystic ovary syndrome (PCOS). Evidence acquisition: We searched MEDLINE, EMBASE, and CENTRAL until December 2020 for all evidence-based CPGs and consensus statements on PCOS. We extracted data in duplicate to map clinical recommendations across prespecified disease domains and assessed CPGs methodological quality of using the Appraisal of Guidelines, Research & Evaluation II tool. Evidence synthesis: We included 13 PCOS CPGs published between 2007 and 2018. CPGs recommendations were mostly focused on screening for and managing metabolic disease (12/13, 92%), followed by cardiovascular risk assessment (10/13, 77%). Mental health (8/13, 62%) and diagnosis in adolescents (7/13, 54%) were the least reported domains. Most CPGs had a high quality for scope and purpose description (12/13, 92%) while stakeholder's involvement and applicability of recommendations to clinical practice were appropriate in only 2 CPGs (2/13, 15%). We identified inconsistency in recommendations on PCOS diagnosis in adolescents, optimal lifestyle interventions, hirsutism and acne treatments, interventions to reduce the risk of ovarian hyperstimulation syndrome, the frequency and screening criteria for metabolic and cardiovascular disease, and optimal screening tools for mental health illness in women with PCOS. Cnclusion: Current CPGs on the diagnosis and management of PCOS vary in their scope and methodological quality, which may hinder evidence translation into clinical practice. We identified disease domains with existing evidence gap to guide future research and guideline updates.

Fonseka S, Wijeyaratne CN, Gawarammana IB, Kalupahana NS, Rosairo S, Ratnatunga N, Kumarasiri R. Effectiveness of Low-dose Ethinylestradiol/Cyproterone Acetate and Ethinylestradiol/Desogestrel with and without Metformin on Hirsutism in Polycystic Ovary Syndrome: A Randomized, Double-blind, Triple-dummy Study.

The effectiveness of different combined oral contraceptive pills and metformin in reducing hirsutism in patients with polycystic ovary syndrome (PCOS) remains unclear. We sought to determine the effects of ethinylestradiol (35μg)/cyproterone acetate (2mg) (EE/CPA) and ethinylestradiol (20μg)/desogestrel (0.15mg) (EE/DES), alone or with metformin, on hirsutism in PCOS. METHODS: A randomized, double-blind, triple-dummy study was conducted on women with PCOS and hirsutism (N=107) who received one of four drug combinations (Arm A: EE/ CPA; Arm B: EE/DES; Arm C: EE/CPA plus metformin; or Arm D: EE/DES plus metformin). Hirsutism was assessed at baseline, six months, and 12 months by using five outcomes variables. RESULTS: No outcomes variable showed a significant difference between the four arms at 12 months. There was a significant reduction in both hair density and modified Ferriman-Gallwey score (mFGS) in Arm A, mFGS in Arm B, hair density in Arm C, and diameter of sideburn hair in Arm D, respectively. Separately, there was a significant increase noted in the hair growth rate of chin and an improvement in patients’ perceptions of hirsutism in all four study arms. CONCLUSION: EE/CPA and EE/DES were equally effective in improving hirsutism in PCOS, with no added benefit from low-dose metformin.

Guarnieri, G.; Iervolino, M.; Cavallone, S.; Unfer, V.; Vianello, A. The “Asthma-Polycystic Ovary Overlap Syndrome” and the Therapeutic Role of Myo-Inositol.

Asthma is a heterogeneous inflammatory disease characterized by abnormalities in immune response. Due to the inherent complexity of the disease and the presence of comorbidities, asthma control is often difficult to obtain. In asthmatic patients, an increased prevalence of irregular menstrual cycles, infertility, obesity, and insulin resistance has been reported. Given that these conditions are also common in patients with polycystic ovary syndrome (PCOS), we propose the definition of “asthma-PCOS overlap syndrome” to indicate a medical condition which shares characteristics of both diseases. The aim of this review is to analyze the links between asthma and PCOS and evaluate the therapeutic role of myo-inositol, a natural compound currently utilized in patients with PCOS, in the management of asthma patients.

Unfer, V.; Dinicola, S.; Russo, M. A. A PCOS Paradox: Does Inositol Therapy Find a Rationale in All the Different Phenotypes?

A recent evaluation of the published data regarding the PCOS topic has highlighted a paradox in the definition of this condition. Even though the name of the syndrome refers to ovarian dysfunction, it seems that patients diagnosed with PCOS are more likely affected by an endocrine and metabolic issue. The term PCOS might not be appropriate to indicate the phenotypes described by the Rotterdam criteria, since the only phenotype with a gynecological issue alone is PCOS phenotype D. This novel perspective regarding how PCOS is currently defined leads the way to a reinterpretation of the entire pathological context and the treatment prescribed, such as inositols. A new point of view on the etiopathogenesis of the disease completely changes the current meaning of PCOS and consequently the therapeutic rationale evaluated to date.

Dausset C, Bornes S, Miquel S, Kondjoyan N, Angenieux M, Nakusi L, Veisseire P, Alaterre E, Bermúdez-Humarán LG, Langella P, Engel E, Forestier C, Nivoliez A. Identification of sulfur components enhancing the anti-Candida effect of Lactobacillus rhamnosus Lcr35.

GYNOPHILUS (Lcr REGENERANS) is a live biotherapeutic product (LBP) aimed at restoring the vaginal microbiome and contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35. In this study, the LBP formulation and manufacturing process significantly enhanced the anti-Candida activity of L. rhamnosus Lcr35, with a complete loss of viability of the yeast after 48 h of coincubation. Sodium thiosulfate (STS), one excipient of the product, was used as a potentiator of the anti-Candida spp. activity of Lactobacilli. This contact-independent phenomenon induced fungal cell disturbances, as observed by electron microscopy observations. Nonverbal sensory experiments showed clear odor dissimilarities between cocultures of L. rhamnosus Lcr35 and C. albicans in the presence and absence of STS, suggesting an impact of odor-active metabolites. A volatolomic approach allowed the identification of six odor-active compounds, including one sulfur compound that was identified as S-methyl thioacetate (MTA). MTA was associated with the antifungal effect of Lcr35, and its functional link was established in vitro. We show for the first time that the LBP GYNOPHILUS, which is a highly active product in the reduction of vulvovaginal candidiasis, requires the presence of a sulfur compound to fully achieve its antifungal effect.

Santiago Palacios, Ma Jesús Cancelo Hidalgo, Silvia P. González, Montserrat Manubens, Rafael Sánchez-Borrego Síndrome genitourinario de la menopausia: recomendaciones de la Sociedad Española de Ginecología y Obstetricia

El síndrome genitourinario de la menopausia (SGM) se definió para sustituir al término "atrofia vulvovaginal" como el conjunto de signos y síntomas genitourinarios asociados a la disminución de estrógenos. La primera línea de tratamiento para las manifestaciones vaginales del SGM son los hidratantes (evidencia IA) y lubricantes vaginales (evidencia IIB). Cuando estas medidas no son suficientes, o en casos moderados o intensos, el tratamiento de elección son los estrógenos locales (evidencia IA). Si coexisten síntomas vasomotores que afectan la calidad de vida, la indicación es el tratamiento hormonal sistémico (evidencia IA). Actualmente, se dispone de ospemifeno (evidencia IA), un modulador selectivo de los receptores vaginales de estrógenos (SERM), aprobado en Europa para el tratamiento de los síntomas moderados o graves en mujeres postmenopáusicas que no cumplen los requisitos para recibir estrógenos vaginales. Otros posibles tratamientos del SGM son el láser y la radiofrecuencia. No hay evidencia para indicar el uso de terapias alternativas y complementarias

Loranca-Moreno P, Vázquez-Gallardo G, Brito-Gavilanes MB, Hernández-Sánchez JB, Vieyra-Lobato I, Chávez-León AY Efecto de la administración complementaria de vitamina D en pacientes con osteoporosis posmenopáusica sin respuesta a tratamiento con antirresortivos

Antecedentes: La osteoporosis es una enfermedad ósea sistémica en la que existe baja masa ósea y alto riesgo de fractura que deterioran la calidad de vida de las pacientes en la posmenopausia, la terapia antirresortiva, el calcio y la vitamina D es la principal terapia. Objetivo: Evaluar la eficacia de la administración complementaria de vitamina D a dosis de 4000 UI al día (Histofil®) adicionada a la terapia antirresortiva (bisfosfonatos vs denosumab) y carbonato de calcio 1.2 g al día en pacientes con osteoporosis posmenopáusica del Hospital Regional 1° de Octubre, ISSSTE, Ciudad de México. Materiales y Métodos: Estudio experimental longitudinal y analítico efectuado de enero de 2018 a julio de 2019 en pacientes con osteoporosis posmenopáusica y terapia antirresortiva (bisfosfonatos, denosumab o ambos), carbonato de calcio más vitamina D (Caltrate +D) al menos durante 12 meses, el 97.2% tenía hipovitaminosis D (concentraciones menores de 30 ng/dL) se adicionó vitamina D 4000 UI (Histofil®) durante 12 meses. Resultados: Se incluyeron 105 pacientes. Los resultados de la densidad mineral ósea fueron en la cadera antes de la suplementación y después, respectivamente: puntuación T -1.90 ± 0.86 vs -1.50 ± 0.92; p = 0.003, mientras que en la columna fue de: puntuación T -2.70 ± 0.67 vs puntuación T -2.20 ± 1.55; p ≤ 0.001. Conclusiones: La administración y la medición sérica de la vitamina D (25-hidroxicolecalciferol) son sumamente relevantes para valorar la adecuada respuesta al tratamiento contra la osteoporosis posmenopáusica.

Tronina T, Popłoński J, Bartmańska A. Flavonoids as Phytoestrogenic Components of Hops and Beer

The value of hops (Humulus lupulus L.) in beer production has been undisputed for centuries. Hops is rich in humulones and lupulones which gives the characteristic aroma and bitter taste, and preserves this golden drink against growing bacteria and molds. Besides α- and β-acids, the lupulin glands of hop cones excrete prenylated flavonoids, which exhibit a broad spectrum of biological activities and therefore has therapeutic potential in humans. Recently, interest in hops was raised due to hop prenylated flavanones which show extraordinary estrogen activities. The strongest known phytoestrogen so far is 8-prenylnaringenin (8-PN), which along with 6-prenylanaringenin (6-PN), 6,8-diprenylnaringenin (6,8-DPN) and 8-geranylnaringenin (8-GN) are fundamental for the potent estrogen activity of hops. This review provides insight into the unusual hop phytoestrogens and shows numerous health benefits associated with their wide spectrum of biological activities including estrogenic, anticancer, neuropreventive, antinflamatory, and antimicrobial properties, which were intensively studied, and potential applications of these compounds such as, as an alternative to hormone replacement therapy (HRT).

Villa P, Amar ID, Bottoni C, Cipolla C, Dinoi G, Moruzzi MC, Scambia G, Lanzone A. The impact of combined nutraceutical supplementation on quality of life and metabolic changes during the menopausal transition: a pilot randomized trial

Purpose: The aim of this study was to assess the efficacy of a combined nutraceutical supplement on symptoms and early metabolic alterations during the menopausal transition. This pilot randomized study was conducted at the service for menopause disorders of the Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy. Methods: Ninety women in menopausal transition who attended our service with menopausal symptoms were enrolled in the study. Sixty patients, randomly assigned to the treatment group, were prescribed one daily tablet of a combined nutraceutical compound with phytoestrogen substances, vitamins, micronutrients and passion flower herbal medicine for 6 months. Thirty patients did not receive any treatment and comprised the control group. The intensity of perimenopausal symptoms was assessed by the modified Kuppermann Index (KI) at enrollment and at 3 and 6 months of treatment. At baseline and at the end of the study, patients underwent a clinical evaluation, a pelvic ultrasound and analysis of blood samples. Results: In the nutraceutical supplemented group, a significant reduction in menopausal symptoms was demonstrated according to the KI after 3 and 6 months of supplementation (p < 0.01). The within-group analysis of different KI parameters in the treated group showed a significant improvement in hot flushes (p < 0.001), insomnia (p < 0.01), fatigue (p < 0.01) and irritability (p < 0.01). Metabolic parameters did not change significantly in the nutraceutical supplemented group. In the control group, total cholesterol level showed a significant increase (p < 0.05). Conclusions: Combined nutraceutical supplementation provides an effective and safe solution for early symptoms occurring during menopausal transition.

Li Y, Pham V, Bui M, Song L, Wu C, Walia A, Uchio E, Smith-Liu F, Zi X. Rhodiola rosea L.: an herb with anti-stress, anti-aging, and immunostimulating properties for cancer chemoprevention

Purpose of review: Rhodiola rosea extracts have been used as a dietary supplement in healthy populations, including athletes, to non-specifically enhance the natural resistance of the body to both physical and behavior stresses for fighting fatigue and depression. We summarize the information with respect to the new pharmacological activities of Rhodiola rosea extracts and its underlying molecular mechanisms in this review article.Recent findings: In addition to its multiplex stress-protective activity, Rhodiola rosea extracts have recently demonstrated its anti-aging, anti-inflammation, immunostimulating, DNA repair and anti-cancer effects in different model systems. Molecular mechanisms of Rhodiola rosea extracts's action have been studied mainly along with one of its bioactive compounds, salidroside. Both Rhodiola rosea extracts and salidroside have contrast molecular mechanisms on cancer and normal physiological functions. For cancer, Rhodiola rosea extracts and salidroside inhibit the mTOR pathway and reduce angiogenesis through down-regulation of the expression of HIF-1α/HIF-2α. For normal physiological functions, Rhodiola rosea extracts and salidroside activate the mTOR pathway, stimulate paracrine function and promote neovascularization by inhibiting PHD3 and stabilizing HIF-1α proteins in skeletal muscles. In contrast to many natural compounds, salidroside is water-soluble and highly bioavailable via oral administration and concentrated in urine by kidney excretion.Summary: Rhodiola rosea extracts and salidroside can impose cellular and systemic benefits similar to the effect of positive lifestyle interventions to normal physiological functions and for anti-cancer. The unique pharmacological properties of Rhodiola rosea extracts or salidroside deserve further investigation for cancer chemoprevention, in particular for human urinary bladder cancer.

Kasper S, Dienel A. Multicenter, open-label, exploratory clinical trial with Rhodiola rosea extract in patients suffering from burnout symptoms

Purpose: This study is the first clinical trial aiming to explore the clinical outcomes in burnout patients treated with Rhodiola rosea. The reported capacity of R. rosea to strengthen the organism against stress and its good tolerability offer a promising approach in the treatment of stress-related burnout. The aim of the treatment was to increase stress resistance, thus addressing the source rather than the symptoms of the syndrome and preventing subsequent diseases associated with a history of burnout. The objective of the trial was to provide the exploratory data required for planning future randomized trials in burnout patients in order to investigate the clinical outcomes of treatment with R. rosea dry extract in this target group.Methods: The study was planned as an exploratory, open-label, multicenter, single-arm trial. A wide range of rating scales were assessed and evaluated in an exploratory data analysis to generate hypotheses regarding clinical courses and to provide a basis for the planning of subsequent studies. A total of 118 outpatients were enrolled. A daily dose of 400 mg R. rosea extract (WS® 1375, Rosalin) was administered over 12 weeks. Clinical outcomes were assessed by the German version of the Maslach Burnout Inventory, Burnout Screening Scales I and II, Sheehan Disability Scale, Perceived Stress Questionnaire, Number Connection Test, Multidimensional Mood State Questionnaire, Numerical Analogue Scales for different stress symptoms and impairment of sexual life, Patient Sexual Function Questionnaire, and the Clinical Global Impression Scales. Results: The majority of the outcome measures showed clear improvement over time. Several parameters had already improved after 1 week of treatment and continued to improve further up to the end of the study. The incidence of adverse events was low with 0.015 events per observation day.Discussion: The trial reported here was the first to investigate clinical outcomes in patients suffering from burnout symptoms when treated with R. rosea. During administration of the study drug over the course of 12 weeks, a wide range of outcome measures associated with the syndrome clearly improved.Conclusion: The results presented provide an encouraging basis for clinical trials further investigating the clinical outcomes of R. rosea extract in patients with the burnout syndrome.

Ma GP, Zheng Q, Xu MB, Zhou XL, Lu L, Li ZX, Zheng GQ. Rhodiola rosea L. Improves Learning and Memory Function: Preclinical Evidence and Possible Mechanisms

Rhodiola rosea L. (R. rosea L.) is widely used to stimulate the nervous system, extenuate anxiety, enhance work performance, relieve fatigue, and prevent high altitude sickness. Previous studies reported that R. rosea L. improves learning and memory function in animal models. Here, we conducted a systematic review and meta-analysis for preclinical studies to assess the current evidence for R. rosea L. effect on learning and memory function. Ultimately, 36 studies involving 836 animals were identified by searching 6 databases from inception to May 2018. The primary outcome measures included the escape latency in Morris water maze (MWM) test on behalf of learning ability, the frequency and the length of time spent on the target quadrant in MWM test representing memory function, and the number of errors in step down test, dark avoidance test and Y maze test on behalf of memory function. The secondary outcome measures were mechanisms of R. rosea L. for learning and/or memory function. Compared with control, the pooled results of 28 studies showed significant effects of R. rosea L. for reducing the escape latency (P < 0.05); 23 studies for increasing the frequency and the length of time spent on the target quadrant (P < 0.05); and 6 studies for decreasing the number of errors (P < 0.01). The possible mechanisms of R. rosea L. are largely through antioxidant, cholinergic regulation, anti-apoptosis activities, anti-inflammatory, improving coronary blood flow, and cerebral metabolism. In conclusion, the findings suggested that R. rosea L. can improve learning and memory function.

Bangratz M, Ait Abdellah S, Berlin A, Blondeau C, Guilbot A, Dubourdeaux M, Lemoine P. A preliminary assessment of a combination of rhodiola and saffron in the management of mild-moderate depression

Objective: The medicinal plants Rhodiola rosea L. (rhodiola, golden root) and Crocus sativus L. (saffron) have been shown separately to induce significant effects in depression. The objective of this study was to assess a fixed combination of rhodiola and saffron in mild-moderate depression. Methods: In this observational study conducted with general practitioners (GPs), 45 adults (aged 18-85 years) suffering from mild or moderate depression (International Statistical Classification of Diseases and Related Health Problems 10th Revision definition) and reaching a score on the Hamilton Rating Scale for Depression of 8-18 were supplemented with a combination of rhodiola and saffron extracts (one tablet, 154 mg of rhodiola and 15 mg of saffron; recommended dose two tablets per day for 6 weeks).Results: After 6 weeks (D42) of supplementation, Hamilton Rating Scale for Depression scores (primary outcome) decreased significantly by 58%±28.5% (from 13.6±2.3 at D0 to 5.6±3.8 at D42, P<0.0001; n=41). Score improvement was reported in 85.4% of patients. A significant drop in both Hospital Anxiety and Depression Scale anxiety and depression scores was also observed at D42, the decrease being significant from 2 weeks of supplementation. At the end of the study, both GPs and patients deemed there was a significant improvement in depression (Clinical Global Impression - improvement and Patient Global Impression of Change). Safety was excellent, and no serious adverse effects were recorded. Conclusion: Results of this observational study performed in primary care suggest that the combination of rhodiola and saffron tested could be useful for the management of mild-moderate depression and improve depressive and anxiety symptoms. A double-blind placebo-controlled study is needed to confirm these results.

Zhuang W, Yue L, Dang X, Chen F, Gong Y, Lin X, Luo Y. Rosenroot ( Rhodiola): Potential Applications in Aging-related Diseases

Aging is a progressive accumulation of changes in the body, which increases the susceptibility to diseases such as Alzheimer's disease, Parkinson's disease, cerebrovascular disease, diabetes, and cardiovascular disease. Recently, Chinese medicinal herbs have been investigated for their therapeutic efficacy in the treatment of some aging-related diseases. Rhodiola, known as 'Hongjingtian' in Chinese, has been reported to have anti-aging activity. Here, we provide a comprehensive review about its origin, chemical constituents, and effects on aging-related diseases.

Zhang Z, Deng T, Wu M, Zhu A, Zhu G. Botanicals as modulators of depression and mechanisms involved

Depression is the most disastrous mood disorder affecting the health of individuals. Conventional treatments with chemical compounds for depression have limitations, while herbal medicine has unique therapeutic effects. This paper introduces the pharmacological basis and biological mechanisms underlying the botanical antidepressants over the past 5 years. Based upon the specific therapeutic targets or mechanisms, we analyzed the pathological roles of monoamine neurotransmitters, the hypothalamic-pituitary-adrenal axis, inflammation, oxidative stress, synaptic plasticity performed in antidepressant of the botanicals. In addition, gut flora and neurogenesis were also preferentially discussed as treatment approaches. Based on the complex pathogenesis of depression, we suggested that mixed use of botanicals, namely prescription would be more suitable for treatment of depression. In addition, neural circuit affected by botanicals or active components should also attract attention as the botanicals have potential to be developed into fast-acting antidepressants. Finally, gut flora might be a new systemic target for the treatment of depression by botanicals. This review would strength botanical medicine as the antidepressant and also provides an overview of the potential mechanisms involved.

Mejia-Montilla J, Reyna-Villasmil E, Albán-Andrade M, Meza-Lozada M, Cevallos-Rodríguez M, Manzano-Solís A. Suplementación de vitamina D en embarazadas y en mujeres con patologías ginecológicas

Aparte de los efectos de la vitamina D en el mantenimiento de la homeostasis del calcio y promoción de la mineralización ósea, existen pruebas que sugieren que modula procesos reproductivos. Cerca del 70 % de los adultos tienen deficiencias de vitamina D y existe una brecha entre la ingesta dietética recomendada y el suministro deficiente en la población general. Estudios observacionales muestran que la deficiencia de vitamina D es un marcador de riesgo para la reducción de la fertilidad y resultante adversa del embarazo. La evidencia sugiere que podría tener efectos benéficos sobre los parámetros metabólicos, hormonales y celulares del síndrome de ovarios poliquísticos, miomatosis uterina y endometriosis y parece estar asociada con mejoras de los resultados de la fertilización in vitro. El objetivo de esta revisión fue evaluar el papel de la suplementación de vitamina D en embarazadas y en mujeres con patologías ginecológicas.

Ko SH, Kim HS. Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women. Nutrients

Menopause is clinically diagnosed as a condition when a woman has not menstruated for one year. During the menopausal transition period, there is an emergence of various lipid metabolic disorders due to hormonal changes, such as decreased levels of estrogens and increased levels of circulating androgens; these may lead to the development of metabolic syndromes including cardiovascular diseases and type 2 diabetes. Dysregulation of lipid metabolism affects the body fat mass, fat-free mass, fatty acid metabolism, and various aspects of energy metabolism, such as basal metabolic ratio, adiposity, and obesity. Moreover, menopause is also associated with alterations in the levels of various lipids circulating in the blood, such as lipoproteins, apolipoproteins, low-density lipoproteins (LDLs), high-density lipoproteins (HDL) and triacylglycerol (TG). Alterations in lipid metabolism and excessive adipose tissue play a key role in the synthesis of excess fatty acids, adipocytokines, proinflammatory cytokines, and reactive oxygen species, which cause lipid peroxidation and result in the development of insulin resistance, abdominal adiposity, and dyslipidemia. This review discusses dietary recommendations and beneficial compounds, such as vitamin D, omega-3 fatty acids, antioxidants, phytochemicals-and their food sources-to aid the management of abnormal lipid metabolism in postmenopausal women.

Barańska A, Kanadys W, Bogdan M, Stępień E, Barczyński B, Kłak A, Augustynowicz A, Szajnik M, Religioni U. The Role of Soy Isoflavones in the Prevention of Bone Loss in Postmenopausal Women: A Systematic Review with Meta-Analysis of Randomized Controlled Trials

The aim of the report was to determine the effects of soy isoflavones on lumbar spine, femoral neck, and total hip bone mineral density (BMD) in menopausal women. MEDLINE (PubMed), EMBASE, and Cochrane Library databases were searched for articles published in English during 1995–2019. Studies were identified and reviewed for inclusion and exclusion eligibility. Weighted mean differences (WMD) were calculated for each study and were pooled by using the random effects model. Eighteen randomized controlled trials were selected for meta-analysis. Different types of soy phytoestrogens, i.e., genistein extracts, soy isoflavones extracts, soy protein isolate, and foods containing diverse amounts of isoflavones were used in the studies. The analysis showed that daily intake of 106 (range, 40–300) mg of isoflavones for 6–24 months moderately but statistically significantly positively affects BMD, compared with controls: lumbar spine WMD = 1.63 (95% CI: 0.51 to 2.75)%, p = 0004; femoral neck WMD = 1.87 (95% CI: 0.14 to 3.60)%, p = 0.034; and total hip WMD = 0.39 (95% CI: 0.08 to 0.69)%, p = 0.013. Subgroups analyses indicated that the varying effects of isoflavones on BMD across the trials might be associated with intervention duration, racial diversity (Caucasian, Asian), time after menopause, form of supplements (especially genistein), and dose of isoflavones. Our review and meta-analysis suggest that soy isoflavones are effective in slowing down bone loss after menopause.

Stewart S, Newson L, Briggs TA, Grammatopoulos D, Young L, Gill P. Long COVID risk - a signal to address sex hormones and women's health

The COVID-19 pandemic has brought health inequalities into sharp focus on an international scale. Vulnerability to and mortality from acute COVID-19 infection is higher in men [1], whereas, Long COVID disproportionately affects women [2]. Why?

Witt WP, Harlaar N, Palmer A The Impact of COVID-19 on Pregnant Women and Children: Recommendations for Health Promotion

COVID-19 continues to have severe repercussions on children and pregnant women. The repercussions include not only the direct impact of COVID-19 (ie, children getting infected by COVID-19) but also indirect impacts (eg, safeguarding from child maltreatment, obesogenic behaviors, language and socioemotional development, educational consequences [eg, interrupted learning]; social isolation; mental health; behavioral health [eg, increased substance use in adolescence]; health and economic impact of COVID-19 on caregivers and family relationships. It has also shed light on long-standing structural and socioeconomic issues, including equity in nutrition and food security, housing, childcare, and internet access. Using a socioecological, life course, and population health approach, we discuss the implications for pregnant women and children's health and well-being and give recommendations for mitigating the short and long-term deleterious impact COVID- 19 on women, children, and their families.

Kahankova R, Barnova K, Jaros R, Pavlicek J, Snasel V, Martinek R. Pregnancy in the time of COVID-19: towards Fetal monitoring 4.0

On the outbreak of the global COVID-19 pandemic, high-risk and vulnerable groups in the population were at particular risk of severe disease progression. Pregnant women were one of these groups. The infectious disease endangered not only the physical health of pregnant women, but also their mental well-being. Improving the mental health of pregnant women and reducing their risk of an infectious disease could be achieved by using remote home monitoring solutions. These would allow the health of the mother and fetus to be monitored from the comfort of their home, a reduction in the number of physical visits to the doctor and thereby eliminate the need for the mother to venture into high-risk public places. The most commonly used technique in clinical practice, cardiotocography, suffers from low specificity and requires skilled personnel for the examination. For that and due to the intermittent and active nature of its measurements, it is inappropriate for continuous home monitoring. The pandemic has demonstrated that the future lies in accurate remote monitoring and it is therefore vital to search for an option for fetal monitoring based on state-of-the-art technology that would provide a safe, accurate, and reliable information regarding fetal and maternal health state. In this paper, we thus provide a technical and critical review of the latest literature and on this topic to provide the readers the insights to the applications and future directions in fetal monitoring. We extensively discuss the remaining challenges and obstacles in future research and in developing the fetal monitoring in the new era of Fetal monitoring 4.0, based on the pillars of Healthcare 4.0.

Bikdeli B, Khairani CD, Krishnathasan D, Bejjani A, Armero A, Tristani A, Davies J, Porio N, Assi AA, Nauffal V, Campia U, et, al. Major cardiovascular events after COVID-19, event rates post-vaccination, antiviral or anti-inflammatory therapy, and temporal trends: Rationale and methodology of the CORONA-VTE-Network study

Background: Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied. The CORONA-VTE-Network study will share contemporary information related to rates of cardiovascular and thrombotic events in patients with COVID-19 overall, as well as within key subgroups, including by time of inclusion, vaccination status, patients undergoing hemodialysis, the elderly, and sex-informed analyses such as comparison of women and men, or among pregnant and breastfeeding women.

Monti P, Solazzo G, Accurti V, Gambitta B, Iodice S, Boito S, Cantone L, Manenti A, Dioni L, Montomoli E, Persico N, Bollati V. Pyroptosis: A Promising Mechanism Linking SARS-CoV-2 Infection to Adverse Pregnancy Outcomes

Pregnancy is characterized by a delicate immune balance; therefore, infectious diseases might increase the risk of adverse pregnancy outcomes (APOs). Here, we hypothesize that pyroptosis, a unique cell death pathway mediated by the NLRP3 inflammasome, could link SARS-CoV-2 infection, inflammation, and APOs. Two blood samples were collected from 231 pregnant women at 11-13 weeks of gestation and in the perinatal period. At each time point, SARS-CoV-2 antibodies and neutralizing antibody titers were measured by ELISA and microneutralization (MN) assays, respectively. Plasmatic NLRP3 was determined by ELISA. Fourteen miRNAs selected for their role in inflammation and/or pregnancy were quantified by qPCR and further investigated by miRNA-gene target analysis. NLRP3 levels were positively associated with nine circulating miRNAs, of which miR-195-5p was increased only in MN+ women (p-value = 0.017). Pre-eclampsia was associated with a decrease in miR-106a-5p (p-value = 0.050). miR-106a-5p (p-value = 0.026) and miR-210-3p (p-value = 0.035) were increased in women with gestational diabetes. Women giving birth to small for gestational age babies had lower miR-106a-5p and miR-21-5p (p-values = 0.001 and 0.036, respectively), and higher miR-155-5p levels (p-value = 0.008). We also observed that neutralizing antibodies and NLRP3 concentrations could affect the association between APOs and miRNAs. Our findings suggest for the first time a possible link between COVID-19, NLRP3-mediated pyroptosis, inflammation, and APOs. Circulating miRNAs might be suitable candidates to gain a comprehensive view of this complex interplay.

Martínez-Zamora MÁ, Feixas G, Gracia M, Rius M, Quintas L, de Guirior C, Carmona F Evaluation of menstrual symptoms after Coronavirus disease 2019 vaccination in women with endometriosis

Objectives: We aimed to investigate the impact of mRNA-based SARS-CoV-2 vaccines on menstrual cycle-related symptoms in women with endometriosis and assess the effect of hormonal therapy on potential SARS-CoV-2 vaccination-induced menstrual changes. Design: A total of 848 women who received at least two doses of mRNA-based COVID-19 vaccines were prospectively recruited: 407 with endometriosis (endometriosis group) and 441 healthy controls (non-endometriosis group). Methods: Data regarding demographics, clinical characteristics, hormonal treatment, and menstrual-associated symptoms in the first and second cycle after vaccination were collected through an online survey. Results: A similar percentage of patients in both the endometriosis and the non-endometriosis group self-reported menstrual-associated changes the first (52.6% versus 48.8%, respectively) and second cycle after vaccination (29.0% versus 28.1%, respectively). Although the total symptoms recorded were not different between the two groups, several specific symptoms were statistically more frequent in the endometriosis group. These were pain disorders and fatigue in the first cycle after vaccination and pain disorders, menstrual headache and fatigue in the second cycle after vaccination. Bleeding frequency/regularity disorders were found to be more frequent in the non-endometriosis group in the first cycle after vaccination. Patients under hormonal treatment reported fewer changes in menstrual symptoms in the first and second cycle after vaccination compared with those not receiving this treatment. Similarly, patients in the endometriosis group receiving hormonal treatment reported fewer changes in menstrual-associated symptoms compared with those not following any hormonal treatment in the first and second menstrual cycle after the last vaccination

Digby AM, Dahan MH. Obstetrical and gynecologic implications of COVID-19: what have we learned over the first two years of the pandemic

The rapidly evolving nature of the coronavirus disease 2019 (COVID-19) pandemic has resulted in the publication of a breadth of information in the field of Obstetrics and Gynecology. This article is an examination of the impacts of COVID-19 on women's health, specifically on pregnancy, fertility, and delays to care. We review, in brief, the clinical presentation, transmission, and definitions of post-COVID conditions. Additionally, this article explores the reassuring evidence published regarding the use of mRNA vaccines in preconception and fertility treatments.

Juliá-Burchés C, Martínez-Varea A. An Update on COVID-19 Vaccination and Pregnancy

Pregnant women are more prone to experience severe COVID-19 disease, including intensive care unit (ICU) admission, use of invasive ventilation, extracorporeal membrane oxygenation (ECMO), and mortality compared to non-pregnant individuals. Additionally, research suggests that SARS-CoV-2 infection during pregnancy is linked to adverse pregnancy outcomes, such as preterm birth, preeclampsia, and stillbirth, as well as adverse neonatal outcomes, including hospitalization and admission to the neonatal intensive care unit. This review assessed the available literature from November 2021 to 19 March 2023, concerning the safety and effectiveness of COVID-19 vaccination during pregnancy. COVID-19 vaccination administered during pregnancy is not linked to significant adverse events related to the vaccine or negative obstetric, fetal, or neonatal outcomes. Moreover, the vaccine has the same effectiveness in preventing severe COVID-19 disease in pregnant individuals as in the general population. Additionally, COVID-19 vaccination is the safest and most effective method for pregnant women to protect themselves and their newborns from severe COVID-19 disease, hospitalization, and ICU admission. Thus, vaccination should be recommended for pregnant patients. While the immunogenicity of vaccination in pregnancy appears to be similar to that in the general population, more research is needed to determine the optimal timing of vaccination during pregnancy for the benefit of the neonate.

Akinosoglou K, Schinas G, Rigopoulos EA, Polyzou E, Tzouvelekis A, Adonakis G, Gogos C COVID-19 Pharmacotherapy in Pregnancy: A Literature Review of Current Therapeutic Choices

The clinical management of COVID-19 in pregnant women, who are considered a vulnerable population, remains uncertain even as the pandemic subsides. SARS-CoV-2 affects pregnant individuals in multiple ways and has been associated with severe maternal morbidity and mortality, as well as neonatal complications. The unique anatomy and physiology of gestation make managing COVID-19 in this population a complex and challenging task, emphasizing the importance of spreading knowledge and expertise in this area. Therapeutic interventions require distinct clinical consideration, taking into account differences in pharmacokinetics, vertical transmission, drug toxicities, and postnatal care. Currently, there is limited data on antiviral and immunomodulating COVID-19 pharmacotherapy in pregnancy. Some medication has been shown to be safe and well tolerated among pregnant women with COVID-19; however, the lack of randomized clinical trials and studies in this patient population is evident. Available vaccines are considered safe and effective, with no evidence of harm to the fetus, embryo development, or short-term postnatal development. Pregnant women should be counseled about the risks of SARS-CoV-2 infection and informed of available ways to protect themselves and their families. Effective treatments for COVID-19 should not be withheld from pregnant individuals, and more research is needed to ensure the best outcomes.

Kontovazainitis CG, Katsaras GN, Gialamprinou D, Mitsiakos G. Covid-19 vaccination and pregnancy: a systematic review of maternal and neonatal outcomes

Objectives: Although the vaccination against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS Cov-2) is considered safe during pregnancy, vaccine hesitancy among pregnant women is high. The results of published observational studies addressing the issue of Covid-19 vaccination's efficacy and safety during pregnancy need to be summarized. Content: This systematic review compares the incidence of major maternal and neonatal outcomes between SARS Cov-2 vaccinated and unvaccinated pregnant women. The included studies enrolled pregnant women of any age and any trimester. Medline-Pubmed, Scopus, Cochrane Library, and grey literature were searched until the 28th of May 2022, and 2,947 studies were found. Summary: Seven observational cohort studies, enrolling 67,274 pregnant women, were selected. When comparing vaccinated and unvaccinated pregnant women, SARS Cov-2 vaccines were not associated with major maternal and neonatal adverse events. The rate of SARS Cov-2 infections among vaccinated pregnant women compared to unvaccinated is significantly reduced by 43%. Outlook: SARS Cov-2 vaccination in pregnant women is effective and safe. The results are promising, but caution is advised due to some limitations: only observational studies addressing this issue were found. Parallelly, the enrolled populations and the intervention (vaccination type and the number of doses) were not homogeneous.

Gislaine Casanova, Poli Mara Spritzer Effects of micronized progesterone added to non-oral estradiol on lipids and cardiovascular risk factors in early postmenopause: a clinical trial

Much attention has been drawn to the deleterious effects of adding progestins to estrogen as hormone therapy (HT) in postmenopausal women. Some widely prescribed progestins have been shown to partially oppose the beneficial effects of estrogens on surrogate markers of cardiovascular disease (CVD) risk. Progestins with higher androgenic activity may interfere with lipid profile and glucose tolerance, and could affect mechanisms of estrogen-induced C-reactive protein (CRP) stimulation. Recent data have shown that norpregnane derivatives, but not micronized progesterone, increase the risk of venous thromboembolism among transdermal estrogens users. The aim of the present study was to assess the effects of combining micronized progesterone with non-oral estrogen therapy on lipid profile and cardiovascular risk factors in a sample of early postmenopausal women. Methods: Clinical trial including 40 women receiving intranasal 17β estradiol 3 mg/day for two months and 46 women receiving percutaneous 17β estradiol gel 1.5 mg/day for three months (E2). Both groups received an additional 200 mg/day of micronized progesterone by vaginal route 14 days/month (E2+P). Outcome measures included body weight, waist circumference, body mass index (BMI), lipid profile and ultra-sensitive C-reactive protein (usCRP) at baseline and during the E2 or E2+P portions of treatment. Results: Mean age was 51±3 years. Mean time since menopause was 22.2±10 months. Most participants were overweight; HT did not change BMI. E2 and E2+P did not affect waist circumference and weight. Menopausal symptoms improved after HT. The effects of intranasal and percutaneous estradiol were similar, regardless of the addition of progesterone. Similarly, for the overall group of 86 women, micronized progesterone did not alter the response to E2. Blood pressure, glucose, insulin, HDL-c, triglycerides, and usCRP remained constant with or without micronized progesterone. Total cholesterol decreased after E2, and progesterone maintained this reduction. LDL-c levels were similar at baseline and with E2, and lower during E2+P in relation to baseline.Conclusions: Cyclic, short term exposure to vaginal micronized progesterone did not alter the metabolic and cardiovascular effects of non-oral E2 in early, apparently healthy, postmenopausal women.

Jarosław von Mach-Szczypiński , Stanisław Stanosz, Jakub Kościuszkiewicz, Krzysztof Safranow New aspects of postmenopausal osteoporosis treatment with micronized estradiol and progesterone

Objectives: The aim of the study was to assess the effectiveness of postmenopausal osteoporosis treatment with natural sex hormones. Material and methods: The single-blind study included 210 women, randomly allocated to three different groups, with various methods of treatment: Group I (70 controls) received transcutaneous placebo for the course of one year, Group II (70 females, aged 52.2 ± 3.1 years) used oral hormone supplementary therapy (HST), and Group III (70 females, aged 51.9 ± 3.5 years) received transcutaneous modified hormone replacement therapy (MHRT), supplemented with intravaginal lutein, dietary minerals, and 1000 IU of vitamin D3/day. Results: No increase in bone mineral density was observed in the control group. However, mineral density of the vertebral bodies was significantly higher after 3 and 5 years in the HST group (p < 0.05), and after 1 year in the MHRT group (p < 0.01). This increase was even more significant (p < 0.001) after 3 and 5 years in the MHRT group. Conclusions: Transcutaneous hormone therapy with micronized estradiol and progesterone is the treatment of choice in postmenopausal osteoporosis, as evidenced by bone mineral density and biochemical markers.

Louise R Newson , Amir Lass Effectiveness of transdermal oestradiol and natural micronised progesterone for menopausal symptoms

This article discusses the role of hormone replacement therapy (HRT) in the management of menopausal symptoms, and specifically considers the advantages of different types and preparations of HRT, based on the current medical evidence. The menopause is a normal life event for women, not an illness or a medical condition. However, the effects of the menopause often have a negative impact on women’s wellbeing and quality of life. Furthermore, the low oestrogen levels and other biological changes that occur in these women are also associated with an increased risk of cardiovascular disease, osteoporosis, diabetes, and dementia. In addition to hot flushes and sweats, symptoms include mood changes, memory loss, urogenital atrophy, reduced libido, sleep disturbances, joint pains, and muscle stiffness.1 These symptoms can be non-existent, or can last for a few years or even decades.

Jennifer L Gordon, David R Rubinow, Tory A Eisenlohr-Mou, Kai Xia, Peter J Schmidt, Susan S Girdler Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial

The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms. To examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects.Results: Of 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects.

Jennifer L Gordon, David R Rubinow, Lana Watkins, Alan L Hinderliter, Melissa C Caughey, Susan S Girdler The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease

The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. Methods: Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12.Results: Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing.Conclusions: TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

Newson LR, Lass A. Effectiveness of transdermal oestradiol and natural micronised progesterone for menopausal symptoms

This article discusses the role of hormone replacement therapy (HRT) in the management of menopausal symptoms, and specifically considers the advantages of different types and preparations of HRT, based on the current medical evidence. The menopause is a normal life event for women, not an illness or a medical condition. However, the effects of the menopause often have a negative impact on women’s wellbeing and quality of life. Furthermore, the low oestrogen levels and other biological changes that occur in these women are also associated with an increased risk of cardiovascular disease, osteoporosis, diabetes, and dementia.

Safdari F, Motaghi Dastenaei B, Kheiri S, Karimiankakolaki Z. Effect of Evening Primrose Oil on Postmenopausal Psychological Symptoms: A Triple-Blind Randomized Clinical Trial

Objectives: Psychological symptoms of menopause may impose a negative effect on the quality of life of menopausal women. Thus, the management of these symptoms can improve the quality of life and psychological health of such woman. The present study aimed to determine the effect of evening primrose on psychological symptoms in menopausal women. Methods: In this triple-blind randomized clinical trial, the effect of the evening primrose oil on postmenopausal psychological symptoms was investigated. The subjects were 100 menopausal women, referred to a healthcare center in Dastena city (Chaharmahal and Bakhtiari Province, Iran), who were randomly assigned to two groups. The intervention group used two 1 g pearls of evening primrose oil daily. The study instruments included a sub-scale of Menopause Rating Scale (MRS). Menopause data were analyzed using an independent t -test and Friedman test by the SPSS software. P values < 0.05 were considered statistically significant. Results: The two groups were balanced in demographic characteristics and psychological disorder severity before the intervention. The median (interquartile range) MRS score in the intervention group before the intervention and 2 and 4 weeks after the intervention were 11 (10–12), 6 (5–7), and 3 (2–4), respectively, and in the placebo, they were 11 (9–11), 10 (9–11), and 11 (10–12). A significant reduction was observed in the intervention group compared with the placebo group 2 and 4 weeks post-intervention. Conclusions: The use of evening primrose oil can decrease postmenopausal psychological symptoms.

Chen Q, Wang H, Wang G, Zhao J, Chen H, Lu X, Chen W. Lactic Acid Bacteria: A Promising Tool for Menopausal Health Management in Women

Menopause is a period during which women undergo dramatic hormonal changes. These changes lead to physical and mental discomfort, are greatly afflictive, and critically affect women’s lives. However, the current safe and effective management measures for women undergoing menopause are insufficient. Several probiotic functions of lactic acid bacteria (LAB) have been recognized, including alleviation of lactose intolerance, protection of digestive tract health, activation of the immune system, protection against infections, improvement of nutrient uptake, and improvement of the microbiota. In this review, we highlight the currently available knowledge of the potential protective effects of LAB on preventing or mitigating menopausal symptoms, particularly in terms of maintaining balance in the vaginal microbiota, reducing bone loss, and regulating the nervous system and lipid metabolism. Given the increasing number of women entering menopause and the emphasis on the management of menopausal symptoms, LAB are likely to soon become an indispensable part of clinical/daily care for menopausal women. Herein, we do not intend to provide a comprehensive analysis of each menopausal disorder or to specifically judge the reliability and safety of complementary therapies; rather, we aim to highlight the potential roles of LAB in individualized treatment strategies for the clinical management of menopause.

Abou Chacra L, Fenollar F, Diop K. Bacterial Vaginosis: What Do We Currently Know?

The vaginal microbiome is a well-defined compartment of the human microbiome. It has unique conditions, characterized by the dominance of one bacterial species, the Lactobacilli. This microbiota manifests itself by a low degree of diversity and by a strong dynamic of change in its composition under the influence of various exogenous and endogenous factors. The increase in diversity may paradoxically be associated with dysbiosis, such as bacterial vaginosis (BV). BV is the result of a disturbance in the vaginal ecosystem; i.e., a sudden replacement of Lactobacilli by anaerobic bacteria such as Gardnerella vaginalis, Atopobium vaginae, Ureaplasma urealyticum, Mycoplasma hominis, and others. It is the most common cause of vaginal discharge in women of childbearing age, approximately 30% of all causes. The etiology of this dysbiosis remains unknown, but its health consequences are significant, including obstetrical complications, increased risk of sexually transmitted infections and urogenital infections. Its diagnosis is based on Amsel's clinical criteria and/or a gram stain based on the Nugent score. While both of these methods have been widely applied worldwide for approximately three decades, Nugent score are still considered the "gold standard" of BV diagnostic tools. Given the limitations of these tools, methods based on molecular biology have been developed as alternative rational strategies for the diagnosis of BV. The treatment of BV aims at restoring the balance of the vaginal flora to stop the proliferation of harmful microorganisms. Prescription of antibiotics such as metronidazole, clindamycin, etc. is recommended. Faced with the considerable uncertainty about the cause of BV, the high rate of recurrence, the unacceptable treatment options, and clinical management which is often insensitive and inconsistent, research on this topic is intensifying. Knowledge of its composition and its associated variations represents the key element in improving the therapeutic management of patients with the most suitable treatments possible.

Razavi BM, Fazly Bazzaz BS. A review and new insights to antimicrobial action of local anesthetics

Local anesthetics (LAs) are medications which can provide analgesia in distinct body regions through the blockade of voltage-gated sodium channels. Besides pain management, the supplemental role of LAs as antimicrobial agents has been documented in several studies. Different databases including PubMed, Scopus, and Web of Science with the name of different local anesthetics and related names for antimicrobial keywords were searched without time limitation. This review summarized different in vitro and in vivo studies regarding antimicrobial effects of different LAs with focuses on antimicrobial applications of most studied LAs, interaction with different agents which combined with LAs, and mechanisms of action and structural dependence of LAs antibacterial effects. Among different LAs, lidocaine is the most studied preparation. Reduction of the incidence of endophthalmitis after intravitreal injection, prophylaxis for surgical wound infections, prevention of the incidence of catheter-associated infections, oral biofilm reduction on the buccal mucosa, and prevention against bacteria that produced nosocomial infection are some examples of lidocaine antimicrobial application. Studies showed that different factors including structure, concentration, duration of exposure, type of microorganism tested, and temperature affect the degree of LA antimicrobial activity. In addition, various agents such as antibiotics, preservatives, opioids, epinephrine, and propofol can combine with LAs and affect their antimicrobial properties through synergistic or antagonistic action. Due to antibacterial activities, LAs could be applied in a clinic for prophylaxis of surgical site infection. In the application of LAs prior to diagnostic procedures caution should be needed; otherwise, when culturing the specimen, they could lead to false negative results

Farinati A, Semeshchenko D, Marqués M, Martin S. Impact of in vitro clindamycin on the combination of clindamycin and ketoconazole on exopolymer of candida spp biofilms of urogenital original.

Introduction: The vaginal mucosa has been widely used for administering antimicrobial agents to treat endogenous infections of the lower genital tract in pregnant and non-pregnant women. Candida spp. elaborates biofilms, and its formation is a complex process requiring that fungal cells establish multiple interactions with the medium. Biofilms are surrounded by an exopolymer matrix that can restrict the activity of antibodies, the diffusion of substances, and be associated with antimicrobials, therefore limiting its actions. General antimicrobials and particular anti-mycotic agents can face difficulties to access the cells within the exopolymer matrix. Many formulas used for empirical treatment have improper combinations with limited or null activity on the biofilms. The presence of molecules that cause its inhibition, thus eliminating the exopolymer matrix inducers, or by other mechanism, will allow the specific antimicrobial activity.

Candel FJ, Matesanz David M, Barberán J. New perspectives for reassessing fosfomycin: applicability in current clinical practice

Fosfomycin is the treatment of choice for cystitis in immunocompetent patients, patients with transplants, pregnant women and in pediatric settings. The drug is especially useful due to its microbiological activity and oral posology in cystitis caused by ESBL bacteria. Administer intravenously at high doses and combined with other antimicrobial agents. Fosfomycin has been useful in treating infections by multiresistant Gram-negative bacteria, such as Enterobacteriaceae, carbapenemase carriers and P. aeruginosa, extensively resistant or panresistant in urinary infections and in skin and soft tissue. Fosfomycin has also been shown active in combination with daptomycin or imipenem in osteoarticular infections by methicillin-resistant Staphylococcus aureus. Fosfomycin is an old antibiotic that still has much to reveal.

Hernández-Hernández D, Ortega-González Y, Padilla-Fernández B, Gutiérrez-Hernández PR, Castro-Díaz DM. Management of Acute Cystitis in the Era of COVID-19

Purpose of Review No specific guidelines have been developed for acute cystitis management during the COVID-19 pandemic. This review aims to provide up-to-date information about treatment and follow-up in patients with symptoms suggesting lower urinary tract infection. Recent Findings Uncomplicated cystitis does not need microbiological confirmation; thus, clinical diagnosis via telephone interview or questionnaires may be done. When complicated infections are suspected, in-person evaluation or close followup is mandatory. Antibiotic treatment is still the gold standard for treatment, although non-pharmacological strategies have also been suggested and further investigations are warranted. Summary Urinary tract infections are still a frequent reason for consultation that needs to be addressed in both primary care and specialized levels. Their management during the pandemic is similar than in precedent years, but telehealth options have emerged which can facilitate diagnosis and treatment.

Bitton A. Cystitis in Women: Focus

Urinary tract infections are one of the most common conditions in medical practice, especially in general medicine. Whether it is uncomplicated adolescent cystitis after first sexual intercourse, postmenopausal infection or recurrent cystitis at any age, lower urinary tract infection disrupts the quality of life for many women. Despite the often multifactorial origin, each woman has a very specific reason for developing cystitis and it is necessary to look for the trigger (s) [1]. The reason for consultation is most often simple dysuria (difficulty voiding), but can also present in 2 to 5% of cases in the form of urgency voiding or pollakiuria [2]. The prevalence figures for acute uncomplicated urinary tract infection range from 30 to 50 per thousand in adult women [3]. The urinary tract infections constitute one of the most frequent diseases in medical practice, especially in general medicine. Whether it is the simple cystitis of the teenager after sexual intercourse, the infection in the middle-age woman after menopausis or the recurrent cystitis at any age, the infection of the low urinary tract unsettles the quality of life of numerous women. In spite of often multifactorial origin, every woman has a very particular reason to develop a cystitis and it is necessary to search one or several factors.

Radwan, M., Hagras, A., Nagla, S. et al. The efficacy of fosfomycin trometamol in prevention of postoperative urinary tract infection in pregnant women after endoscopic procedures: open clinical trial.

Fosfomycin tromethamine is recommended (category B) for the treatment of urinary tract infections in pregnant women. We aimed to evaluate the efficacy of single-dose preoperative fosfomycin tromethamine in the prevention of urinary tract infection in pregnant women who underwent lower urinary tract endoscopic surgeries. The subjects of this study were pregnant women who underwent lower urinary tract endoscopic procedures. All patients received Fosfomycin tromethamine1 packet (3 g) dissolved in water the day before surgery. Routine pre- and postoperative urine analysis and urine cultures were performed when needed. Patients were monitored for urinary tract infections and the side effects of the drug. Moreover, maternal and fetal complications were monitored. The study was conducted on 31 pregnant women with a mean age of 24.48 ± 5.35 years. The endoscopic procedures were as follows: 28 (90.3%) DJ ureteric insertions for hydronephrosis, 2 (6.5%) urinary bladder stones, and cystoscopy (3.2%) for gross hematuria. Two (6.5%) patients had postoperative asymptomatic bacteriuria that resolved with oral antibiotic therapy. Fosfomycin tromethamine is safe in preventing urinary tract infection and decreases the need for postoperative parenteral antibiotics in pregnant women who require lower urinary tract endoscopic procedures.

Nazia Hakeem, Warsha Brij Lal, Sanam Imtiaz, Sadia Mushtaq, Saira Almas Efficacy of Fosfomycin in Urinary Tract Infections Occurring During Pregnancy

Objective: To determine efficacy of fosfomycin in urinary tract infections occurring during pregnancy. Descriptive study.Total 147 pregnant women presented with urinary tract infections were enrolled. Detailed demographics were recorded after taking informed written consent.Participants were given fosfomycin sachet 3gm stat dose after confirmation of UTI symptoms and they were followed for about 13 days and advised to proceed for Urine C/S. Participants were assessed on the basis of persistent symptoms of UTI and identification of bacteria in urine C/S. Data was analyzed by SPSS 20.0.Results:The mean age of the patients was 29.41±4.71 years. Mean BMI recorded was 28.65±3.21 kg/m2. According to the efficacy of drug (fosfomycin ), UTI was cured in 89 (60.5%) patients. The efficacy of fosfomycin in urinary tract infections occurring during pregnancy in our study was 60.5%

Biliavska, L.; Pankivska, Y.; Povnitsa, O.; Zagorodnya, S. The Role of Lactic Acid in the Management of Bacterial Vaginosis: A Systematic Literature Review

Background and objectives: The use of antagonistic probiotic microorganisms and their byproducts represents a promising approach for the treatment of viral diseases. In the current work, the effect of exopolysaccharides (EPSs) produced by lactic acid bacteria from different genera on the structural and functional characteristics of cells and the development of adenoviral infection in vitro was studied. Materials and Methods: Cytotoxicity of six EPSs of lactic acid bacteria of the genera Lactobacillus, Leuconostoc and Pediococcus was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The influence of the EPSs on the infectivity of human adenovirus type 5 (HAdV-5) and on the cell cycle under a condition of adenovirus infection was studied using plaque reduction assay and flow cytometric analysis, respectively. Results: It was shown that exopolysaccharides were non-toxic to Madin-Darby bovine kidney cells (MDBK) as they reduced their viability by 3–17%. A change in the distribution of the cell cycle phases in the non-infected cell population treated with EPSs was observed. The analysis demonstrated an increase in the number of cells in the S phase by 47% when using EPSs 15a and a decrease in the number of cells in the G1 phase by 20–27% when treated with the EPSs 15a, 33a, and 19s. The use of EPSs did not led to the normalization of the life cycle of HAdV-5 infected cells to the level of non-infected cells. The EPSs showed low virucidal activity and reduced the HAdV-5 infectivity to 85%. Among the studied exopolysaccharides, anti-adenovirus activity was found for EPS 26a that is produced by Lactobacillus spp. strain. The treatment of cells with the EPS following virus adsorption completely (100%) suppressed the formation and release of HAdV-5 infectious. Conclusions: EPS 26a possessed distinct anti-HAdV-5 activity and the obtained data demonstrate the potential of using exopolysaccharides as anti-adenoviral agents.

Sun K, Luo J, Jing X, Guo J, Yao X, Hao X, Ye Y, Liang S, Lin J, Wang G, Guo F.  Astaxanthin protects against osteoarthritis via Nrf2: a guardian of cartilage homeostasis

Scope: Osteoarthritis (OA) is a progressive disease characterized by cartilage degradation. Astaxanthin (Ast), a natural compound with remarkable antioxidant activity and multiple medical applications due to its activation of Nrf2 signaling, has been studied for application to various degenerative diseases. Currently, however, little is known about its efficacy in treating OA. This study reports the effects of Ast on cartilage homeostasis in OA progression. Methods: IL-1β, TNF-α, and tert-butyl hydroperoxide (TBHP) were used to impair cartilage homeostasis. Modulating effects of Ast on the Nrf2 signaling pathway, and damage-associated events including extracellular matrix (ECM) degradation, inflammation, oxidative stress, chondrocyte apoptosis, and in vivo cartilage degradation were examined. Results: Ast attenuated ECM degradation of OA chondrocytes through the Nrf2 signaling, and ameliorated the IL-1β-induced inflammatory response and ECM degradation via blockade of MAPK signaling. Additionally, Ast alleviated TNF-α-induced ECM degradation and chondrocyte apoptosis by inhibiting the NF-κB signaling, suppressed TBHP-induced oxidative stress, and subsequently reduced chondrocyte apoptosis. In vitro results were finally corroborated in vivo by demonstrating that Ast attenuates the severity of cartilage destruction in a mouse model of OA. Conclusions: Ast could protect against osteoarthritis via the Nrf2 signaling, suggesting Ast might be a potential therapeutic supplement for OA treatment.

Sadigursky D, Magnavita VFS, Sá CKC, Monteiro HS, Braghiroli OFM, Matos MAA.  UNDENATURED COLLAGEN TYPE II FOR THE TREATMENT OF OSTEOARTHRITIS OF THE KNEE.

Objective: To test the hypothesis that undenatured type II collagen (UC-II) relieves pain, quality of life, and joint function in women aged from 60 to 80 years with knee osteoarthritis. Methods: 53 patients in the UC-II treatment group (for 90 days) and 52 in the control group (without UC-II) were evaluated at 1, 30, and 90 days regarding health-related quality of life, pain, and function with questionnaires, anthropometric data, alignment, range of motion, and radiographic analysis. Results: Quality of life increased significantly in the Physical domain in the treatment vs control group. Also, there was a difference between the first and the last evaluation on the pain visual analog scale (-3.8 ± 1.8 versus -1.3 ± 2.0) and on the WOMAC score (-9.5 ± 11.9 versus -1.3 ± 11.1). No variation in the temporal evolution of the Mental domain was found. Conclusion: Pain, joint stiffness, and quality of life (Physical domain) improved with the inclusion of UC-II for 90 days to the therapeutic toolbox for knee osteoarthritis in individuals aged 60 to 80 years. Level of evidence II, Comparative Prospective Study.

Ram Prabhoo; Gauri Billa Undenatured collagen type II for the treatment of osteoarthritis: a review

Osteoarthritis is a prevalent musculoskeletal condition worldwide with rising rates in elderly people. Both mechanical and immunological factors are implicated in the pathogenesis of osteoarthritis resulting in destruction of the articular cartilage. Non-steroidal anti-inflammatory drugs (NSAIDs) commonly used for the treatment of osteoarthritis, are associated with several adverse events and also do not affect the underlying disease process. Clinicians and patients both seek options which are safe and effective in the treatment of osteoarthritis. Collagen derivatives represent a suitable option in such cases. Collagen is the most abundant component of the cartilage. Collage derivatives have shown to have disease modifying action in osteoarthritis. Depending on the degree of hydrolysis and molecular weight, collage derivatives are classified into undenaured collagen, gelatin and collage hydrolysate. Collagen derivatives are well tolerated without major safety concerns. Undenatured type II collagen has shown to provide significant improvement in patients with osteoarthritis. In this article we discuss, the pathophysiology of osteoarthritis with focus on immunological factors and evidence for the use of undenatured collagen type II in osteoarthritis.

Thomas S, Browne H, Mobasheri A, Rayman MP. What is the evidence for a role for diet and nutrition in osteoarthritis?

As current treatment options in OA are very limited, OA patients would benefit greatly from some ability to self-manage their condition. Since diet may potentially affect OA, we reviewed the literature on the relationship between nutrition and OA risk or progression, aiming to provide guidance for clinicians. For overweight/obese patients, weight reduction, ideally incorporating exercise, is paramount. The association between metabolic syndrome, type-2 diabetes and OA risk or progression may partly explain the apparent benefit of dietary-lipid modification resulting from increased consumption of long-chain omega-3 fatty-acids from oily fish/fish oil supplements. A strong association between OA and raised serum cholesterol together with clinical effects in statin users suggests a potential benefit of reduction of cholesterol by dietary means. Patients should ensure that they meet the recommended intakes for micronutrients such as vitamin K, which has a role in bone/cartilage mineralization. Evidence for a role of vitamin D supplementation in OA is unconvincing.

Loeser RF. The Role of Aging in the Development of Osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis and a significant cause of pain and disability in older adults. Among the risk factors for OA, age is the most prominent. This review will discuss the relationship between aging and the development of OA, with a particular focus on mechanisms relevant to cartilage degeneration and the role of excessive levels of reactive oxygen species. Rather than just causing random oxidative damage, an increase in reactive oxygen species that leads to oxidative stress disrupts specific cell signaling pathways. This disruption in cell signaling affects the ability to maintain the cartilage extracellular matrix and eventually causes cell death. By understanding the specific cell signaling pathways that lead to OA through altered redox signaling, novel targets will be discovered that will be an advance over the current non-targeted anti-oxidant approach that has not been successful in treating chronic diseases of aging such as OA.

Mathieu S, Soubrier M, Peirs C, Monfoulet LE, Boirie Y, Tournadre A. A Meta-Analysis of the Impact of Nutritional Supplementation on Osteoarthritis Symptoms

Conflicting evidence exists concerning the effects of nutrient intake in osteoarthritis (OA). A systematic literature review and meta-analysis were performed using PubMed, EMBASE, and Cochrane Library up to November 2021 to assess the effects of nutrients on pain, stiffness, function, quality of life, and inflammation markers. We obtained 52 references including 50 on knee OA. Twelve studies compared 724 curcumin patients and 714 controls. Using the standardized mean difference, improvement was significant with regard to pain and function in the curcumin group compared to placebo, but not with active treatment (i.e., nonsteroidal anti-inflammatory drugs, chondroitin, or paracetamol). Three studies assessed the effects of ginger on OA symptoms in 166 patients compared to 164 placebo controls. Pain was the only clinical parameter that significantly decreased. Vitamin D supplementation caused a significant decrease in pain and function. Omega-3 and vitamin E caused no changes in OA parameters. Herbal formulations effects were significant only for stiffness compared to placebo, but not with active treatment. A significant decrease in inflammatory markers was found, especially with ginger. Thus, curcumin and ginger supplementation can have a favorable impact on knee OA symptoms. Other studies are needed to better assess the effects of omega-3 and vitamin D.

Cordingley DM, Cornish SM. Omega-3 Fatty Acids for the Management of Osteoarthritis: A Narrative Review

Osteoarthritis (OA) is a disease which results in degeneration of cartilage within joints and affects approximately 13.6% of adults over 20 years of age in Canada and the United States of America. OA is characterized by a state of low-grade inflammation which leads to a greater state of cellular catabolism disrupting the homeostasis of cartilage synthesis and degradation. Omega-3 polyunsaturated fatty acids (PUFAs) have been postulated as a potential therapeutic treatment option for individuals with OA. Omega-3 PUFAs are recognized for their anti-inflammatory properties, which could be beneficial in the context of OA to moderate pro-inflammatory markers and cartilage loss. The purpose of this narrative review is to outline recent pre-clinical and clinical evidence for the use of omega-3 in the management of OA.

Oppedisano F, Bulotta RM, Maiuolo J, Gliozzi M, Musolino V, Carresi C, Ilari S, Serra M, Muscoli C, Gratteri S, Palma E, Mollace V. The Role of Nutraceuticals in Osteoarthritis Prevention and Treatment: Focus on n-3 PUFAs

Osteoarthritis (OA) is a disease caused by joint degeneration with massive cartilage loss, and obesity is among the risk factors for its onset, though the pathophysiological mechanisms underlying the disease and better therapeutic approach still remain to be assessed. In recent years, several nutraceutical interventions have been investigated in order to define better solutions for preventing and treating OA. Among them, polyunsaturated fatty acids (n-3 PUFAs) appear to represent potential candidates in counteracting OA and its consequences, due to their anti-inflammatory, antioxidant, and chondroinductive effects. PUFAs have been found to counteract the onset and progression of OA by reducing bone and cartilage destruction, inhibiting proinflammatory cytokine release, reactive oxygen species (ROS) generation, and the NF-κB pathway's activation. Moreover, a diet rich in n-3 PUFAs and their derivatives (maresins and resolvins) demonstrates beneficial effects on associated pain reduction. Finally, it has been shown that together with the anti-inflammatory and antioxidant properties of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, their antiapoptotic and antiangiogenic effects contribute in reducing OA development. The present review is aimed at assessing evidence suggesting the potential benefit of nutraceutical supplementation with PUFAs in OA management according to their efficacy in targeting relevant pathophysiological mechanisms responsible for inflammation and joint destruction processes, and this may represent a novel and potentially useful approach in OA prevention and treatment. For that purpose, a PubMed literature survey was conducted with a focus on some in vitro and in vivo studies and clinical trials from 2015 to 2020.

María Elena Aguilar-Mora, Joaquín Darío Treviño-Báez,Marisela Castañeda-Díaz,Victoria Martínez-Gaytán, Luis Oswaldo de la O-Pérez Efecto y tolerancia gastrointestinal de mioinositol vs metformina en el control metabólico y hormonal

OBJETIVO: Evaluar el efecto de las cápsulas de soft-gel de mioinositol en la reducción del índice de HOMA, el control metabólico y hormonal en pacientes con síndrome de ovario poliquístico versus metformina y la tolerabilidad gastrointestinal de ambos. MATERIALES Y MÉTODOS: Estudio clínico prospectivo, de etiqueta abierta, controlado no aleatorizado vs activo de referencia, con diseño de grupos paralelos efectuado en el servicio de Biología de la Reproducción Humana de la Unidad Médica de Alta Especialidad 23, IMSS, Monterrey NL, de agosto 2019 a octubre 2020, en pacientes con resistencia a la insulina asociada con síndrome de ovario poliquístico e infertilidad. RESULTADOS: Se estudiaron 83 pacientes: 33 que recibieron 600 mg de mioinositol en cápsulas soft-gel por vía oral cada 12 h y 50 que tomaron 850 mg de metformina cada 12 h durante 12 semanas. Completaron el estudio 75 pacientes. El grupo tratado con mioinositol tuvo una reducción del índice de HOMA de 1.49 ± 1.05 (con valor delta de cambio) versus el grupo tratado con metformina de 0.42 ± 0.40 (con igual valor delta de cambio). La diferencia entre ambos grupos fue estadísticamente significativa. Otros parámetros metabólicos y hormonales también tuvieron desenlaces favorables en ambos grupos, pero con una tendencia superior en el grupo de mioinositol. CONCLUSIONES:Se demostró la ventaja del tratamiento con mioinositol en la reducción del índice de HOMA y otros parámetros metabólicos y hormonales en pacientes con resistencia a la insulina asociada con síndrome de ovario poliquístico e infertilidad, con buena tolerabilidad gastrointestinal.

Elisa Lepore, Rosa Lauretta, Marta Bianchini, Marilda Mormando, Cherubino Di Lorenzo, Vittorio Unfer, et al. Inositols depletion and resistance: Principal mechanisms and therapeutic strategies

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.

Simona Dinicola, Vittorio Unfer, Fabio Facchinetti, Christophe O Soulage, et al. Inositols: From Established Knowledge to Novel Approaches

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

Weixuan Chen, Yanli Pang Metabolic Syndrome and PCOS: Pathogenesis and the Role of Metabolites

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases among women of reproductive age and is associated with many metabolic manifestations, such as obesity, insulin resistance (IR) and hyperandrogenism. The underlying pathogenesis of these metabolic symptoms has not yet been fully elucidated. With the application of metabolomics techniques, a variety of metabolite changes have been observed in the serum and follicular fluid (FF) of PCOS patients and animal models. Changes in metabolites result from the daily diet and occur during uncommon physiological routines. However, some of these metabolite changes may provide evidence to explain possible mechanisms and new approaches for prevention and therapy. This article reviews the pathogenesis of PCOS metabolic symptoms and the relationship between metabolites and the pathophysiology of PCOS. Furthermore, the potential clinical application of some specific metabolites will be discussed.

Giovanni Monastra, Ivana Vucenik, Abdel Halim Harrath, Saleh H Alwasel, Zdravko A Kamenov, Antonio Simone Laganà, Noemi Monti 6, Valeria Fedeli, Mariano Bizzarri  PCOS and Inositols: Controversial Results and Necessary Clarifications. Basic Differences Between D-Chiro and Myo-Inositol

Myo-Inositol (myo-Ins) and its phosphate derivatives—including inositol phosphates (InsPs), inositol pyrophosphates (IPPs) and phosphatidyl-inositol phosphate (PtdIns)—are credited to act as second messengers, which accumulate rapidly and transiently in response to external or endocrine signals, a phenomenon that allows signaling to be discrete and regulated (1, 2). Noticeably, inositol is involved in the transduction of several endocrine signals, including insulin (3, 4), thyroid hormones (5), gonadotropins (6), lipids with hormone-like activity (as prostaglandins) (7), and many other endocrine systems (8). Namely, in the last decade, a growing body of clinical and experimental research provided robust evidence about the efficiency of inositol in reversing a few clinical, metabolic, and endocrine features of the Polycystic Ovary Syndrome (PCOS). Myo-inositol, alone or in combination with its isomer D-Chiro-Inositol (DChiro-Ins), showed to exert a variable—albeit significant—effect in improving both symptoms and outcome in PCOS patients (9). Experimental and pilot clinical studies pointed out that a combination of both isomers could provide a reliable rationale for establishing a proper treatment strategy, as first suggested by Beemster’s seminal study (10, 11).

Andrea R. Genazzani, Lourdes Ibáñez, Andrzej Milewicz, Duru Shah Impact Of Polycystic Ovary Metabolic Syndrome and Obesity on Women Health

This volume comprehensively focuses on polycystic ovary, metabolic syndrome and obesity and their impact on women’s health, reproduction and quality of life from adolescence to old age. PCOS is analyzed form the early origins - highlighting the importance of diagnosis, management and treatment starting from the high-risk period of adolescence - throughout infertility PCOS-related issues, pregnancy and menopause transition. All aspects of this syndrome are covered also in relation with endocrine and metabolic features that affects women’s health.This book is a very useful tool for gynecologists, endocrinologists, obstetricians, reproductive medicine and general practitioners and is an important resource for all physicians involved in women’s health.

Carmona-Ruiz IO, Saucedo-de-la-Llata E, Moraga-Sánchez MR,3Romeu- Sarrió A Mioinositol en combinación con D-chiro-inositol: resultados preliminares en el tratamiento de primera línea de pacientes con síndrome de ovario poliquístico

OBJETIVO: evaluar el efecto de la combinación de mioinositol y D-chiro-inositol en el perfil metabólico y endocrino de mujeres con síndrome de ovario poliquístico. MATERIALES Y MÉTODOS: estudio experimental, prospectivo y longitudinal efectuado en pacientes con diagnóstico de síndrome de ovario poliquístico (criterios de Rotterdam) sin tratamiento o intervención previa. Diariamente se administraron, por vía oral, 2000mg de mioinositol y 400 mg de D-chiro-inositol, durante 90 días. Se evalúan y comparan el perfil clínico y metabólico de cada paciente antes y después de la intervención. RESULTADOS: se estudiaron 61 pacientes con síndrome de ovario poliquístico, con una diferencia estadísticamente significativa en los valores de la escala Ferriman-Gallwey (6.06 ± 2.0 y 5.57 ± 1.1; p = 0.003 pre y postratamiento, respectivamente); volumen ovárico izquierdo (7.76 ± 3.2 y 7.18 ± 2.3; p = 0.005, pre y postratamiento, respectivamente). La cuenta de folículos antrales del ovario izquierdo fue de 10.65 ± 6.4 y 10.20 ± 5.7; p=0.029 pre y postratamiento, respectivamente. La cuenta de folículos antrales del ovario derecho fue: 12.11 ± 6.5 y 11.75 ± 6.1; p=0.048 pre y postratamiento, respectivamente. Hubo mejoría en los valores del HOMA (1.85 ± 1.0 y 1.67 ± 0.7; p=0.015 pre y postratamiento, respectivamente. En la proporción LH-FSH: 1.13 ± 0.8 y 0.99 ± 0.6; p=0.018 pre y postratamiento, respectivamente. CONCLUSIÓN: los resultados del estudio muestran un efecto positivo de la administración combinada de mioinositol y D-chiro-inositol en el perfil clínico y metabólico de pacientes con síndrome de ovario poliquístico. La mejora en las concentraciones séricas de andrógenos, de la proporción LH-FSH y la regularización de los ciclos menstruales puede contribuir al aumento de la fertilidad en pacientes con síndrome de ovario poliquístico y factor ovárico.

De Diego MV, Gómez-Pardo O, Groar JK, López-Escobar A, Martín-Estal I, Castilla-Cortázar I, Rodríguez-Zambrano MÁ. Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study

Purpose: To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). Methods: This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). Results: Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. Conclusions: Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.

Soldat-Stanković V, Popović-Pejičić S, Stanković S, Prtina A, Malešević G, Bjekić-Macut J, Livadas S, Ognjanović S, Mastorakos G, Micić D, Macut D. The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial

Purpose: To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). Methods: In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. Results: After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). Conclusion: Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women.

Minisha Sood, Susan B. Zweig, Marsha C. Tolentino, Marina Strizhevsky, and Leonid Poretsky Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting approximately 5–10 % of reproductive-age women. PCOS is

Minisha Sood, Susan B. Zweig, Marsha C. Tolentino, Marina Strizhevsky, and Leonid Poretsky PCOS Therapy

considered the most common cause of anovulatory infertility. PCOS is widely accepted as a combination of ovulatory dysfunction, androgen excess, and polycystic ovaries with the exclusion of specific disorders that may lead to similar phenotypes. Genetic variants have also been identified which result in PCOS. PCOS is associated with insulin resistance, type 2 diabetes mellitus, dyslipidemia, and visceral obesity. The treatment of PCOS is multifaceted, including the use of oral contraceptives, insulin sensitizers, antiandrogen agents, and other medications; PCOS therapy is tailored to patient-specific physiological conditions and treatment goals

Zeng L, Yang K. Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis

Purpose: To assess the effectiveness and safety of myoinositol for patients with PCOS. Methods: In this meta-analysis, data from randomized controlled trials are obtained to assess the effects of myoinositol vs. placebo or western medicine in women with PCOS. The study's registration number is CRD42017064563. The primary outcomes included total testosterone, estradiol (E2) and the homeostatic model assessment (HOMA) of insulin resistance. Result: Ten trials involving 573 patients were included. The meta-analysis results show that: compared with the control group, myoinositol may improve HOMA index (WMD -0.65; 95% CI -1.02, -0.28; P = 0. 0005) and increase the E2 level (WMD 16.16; 95% CI 2.01, 30.31; P = 0. 03); while there is no enough strong evidence that the myoinositol has an effect on the total testosterone level (WMD -16.11; 95% CI -46.08, 13.86; P = 0. 29). Conclusion: Based on current evidence, myoinositol may be recommended for the treatment of PCOS with insulin resistance, as well as for improving symptoms caused by decreased estrogen in PCOS.

Xu Y, Wu Y, Huang Q.  Comparison of the effect between pioglitazone and metformin in treating patients with PCOS:a meta-analysis

Background: Pioglitazone was used to treat patients of PCOS in many researches, but the treatment has not been recognized by public or recommended by all the guidelines. Method: We conducted a meta-analysis of the related literatures to objectively evaluate the clinical effectiveness and safety by comparing pioglitazone with metformin administrated by PCOS patients. Searches were performed in Cochrane Library, EMBASE and PubMed (last updated December 2016). Results: Eleven studies among 486 related articles were identified through searches. Fixed effects and random effects models were used to calculate the overall risk estimates. The results of the meta-analysis suggest that improvement of the menstrual cycle and ovulation in pioglitazone treatment group was better than metformin group [OR = 2.31, 95% CI (1.37, 3.91), P < 0.001, I 2 = 41.8%]. Improvement of the F-G scores in metformin treatment group was better than pioglitazone group [SMD = 0.29, 95% CI (0.0, 0.59), P = 0.048, I 2 = 0.0%]. BMI was more elevated in pioglitazone group than in metformin group [SMD = 0.83, 95% CI (0.24, 1.41), P = 0.006, I 2 = 82.8%]. There were no significant differences of the other data between the two groups. Conclusions: This meta-analysis indicated that pioglitazone ameliorated menstrual cycle and ovulation better than metformin and metformin ameliorated BMI and F-G scores better than pioglitazone in treating patients with PCOS. Pioglitazone might be a good choice for the patients with PCOS who were intolerant or invalid to metformin for the treatment.

Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, Ling Y, Fu H, Dong W, Shen J, Reeves A, Greenberg AS, Zhao L, Peng Y, Ding X. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain-gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3-V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain-gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes.

National Institutes of Health Datos sobre la vitamina D

La vitamina D es un nutriente necesario para la salud. Ayuda al cuerpo a absorber el calcio, una de las principales sustancias necesarias para tener huesos fuertes. Junto con el calcio, la vitamina D contribuye a prevenir la osteoporosis, una enfermedad que hace que los huesos se vuelvan más delgados y débiles y sean más propensos a fracturas. Además, al cuerpo le hace falta la vitamina D para otras funciones. Los músculos la necesitan para el movimiento y los nervios para transmitir mensajes entre el cerebro y otras partes del cuerpo. La vitamina D es indispensable para que el sistema inmunitario pueda combatir las bacterias y los virus que lo atacan.

Carranza-Lira, Sebastián, López-Chávez, Melissa, Díaz de León-de Luna, Alejandra, Rosales-Ortiz, Sergio, & Méndez-González, Guadalupe J. Relación de la concentración de vitamina D en sangre con la masa muscular y la función cognitiva en mujeres posmenopáusicas

Introducción: Las concentraciones bajas de vitamina D se han asociado con la pérdida de masa muscular y la alteración de la función cognitiva. Objetivo: Conocer la relación de la concentración sanguínea de vitamina D con la masa muscular y la función cognitiva en mujeres posmenopáusicas. Materiales y métodos: Se estudiaron 99 mujeres posmenopáusicas ≥ 50 años. Se midió la circunferencia de la pantorrilla, los pliegues cutáneos tricipital, bicipital, subescapular y suprailíaco. Se calcularon: el área muscular del brazo, el área muscular libre de hueso y la masa muscular total. Se realizó la prueba corta de desempeño físico (PCDF), se aplicó el cuestionario de diagnóstico rápido de sarcopenia (SARC-F) y el Mini Examen del Estado Mental (MMSE). Se tomó una muestra de sangre para medir la concentración de vitamina D en sangre. Para el análisis estadístico se utilizó la prueba U de Mann-Whitney y análisis de correlación de Spearman. Resultados: Se encontró que a mayor edad hubieron mayores concentraciones de vitamina D y mayor puntaje SARC-F. Las concentraciones de vitamina D se correlacionaron negativamente con la fuerza de agarre, la PCDF y la puntuación total del MMSE. Conclusiones: La vitamina D no tuvo una influencia positiva sobre la masa muscular. Se observó un mejor desempeño en el MMSE en aquellas con concentraciones más bajas de vitamina D.

Štulíková K, Karabín M, Nešpor J, Dostálek P. Therapeutic Perspectives of 8-Prenylnaringenin, a Potent Phytoestrogen from Hops

Hop (Humulus lupulus L.), as a key ingredient for beer brewing, is also a source of many biologically active molecules. A notable compound, 8-prenylnaringenin (8-PN), structurally belonging to the group of prenylated flavonoids, was shown to be a potent phytoestrogen, and thus, became the topic of active research. Here, we overview the pharmacological properties of 8-PN and its therapeutic opportunities. Due to its estrogenic effects, administration of 8-PN represents a novel therapeutic approach to the treatment of menopausal and post-menopausal symptoms that occur as a consequence of a progressive decline in hormone levels in women. Application of 8-PN in the treatment of menopause has been clinically examined with promising results. Other activities that have already been assessed include the potential to prevent bone-resorption or inhibition of tumor growth. On the other hand, the use of phytoestrogens is frequently questioned regarding possible adverse effects associated with long-term consumption. In conclusion, we emphasize the implications of using 8-PN in future treatments of menopausal and post-menopausal symptoms, including the need for precise evidence and further investigations to define the safety risks related to its therapeutic use.

Abdi F, Mobedi H, Roozbeh N. Hops for Menopausal Vasomotor Symptoms: Mechanisms of Action

Menopause is a critical stage of women's life associated with various complaints and distresses. Vasomotor symptoms (VMS), such as hot flushes, night sweats, sleep disturbances, and fatigue, are the most common menopause symptoms affecting about 50% to 80% of middle-aged women. Obviously, these symptoms, resulting from estrogen deficiency during menopause, can exert negative effects on women's health and quality of life and thus require to be managed through approaches such as hormone replacement therapy (HRT). Many herbal treatments for menopause symptoms contain and its components such as 8-prenylnaringenin, 6-PN, isoxanthohumol and xanthohumol. Recent in-vivo studies have highlighted the ability of 8-prenylnaringenin to reduce serum-luteinizing hormone (LH) and follicle-stimulating hormone (FSH), to increase serum prolactin levels and uterine weight, and to induce vaginal hyperplastic epithelium. Previous research has shown that hops extract can strongly bind to both estrogen receptors, stimulate alkaline phosphatase activity in Ishikawa cells, and upregulate presenelin-2 and progesterone receptor mRNA in Ishikawa cells. Numerous clinical trials have documented significant reductions in the frequency of hot flushes following the administration of hop-containing preparations. Nevertheless, further clinical trials with larger sample size and longer follow-up are warranted to confirm such benefits.

Gaudard AM, Silva de Souza S, Puga ME, Marjoribanks J, da Silva EM, Torloni MR. Bioidentical hormones for women with vasomotor symptoms

Review question This Cochrane review evaluates the effectiveness and safety of bioidentical hormone treatment (BHT) compared to no treatment or non- bioidentical hormone treatment (HT) for vasomotor symptoms experienced during the menopausal transition period. Background Various hormone therapies (HT) are available to treat menopausal vasomotor symptoms. Bioidentical hormones are chemically identical to those produced by the human body, and several types are well-tested and available on prescription. Many women have opted for bioidentical hormone therapy (BHT) on the assumption that it would be safer than other forms of HT. However, as it is unclear whether BHT is better or safer than other forms of HT, we evaluated the evidence. Study characteristics This review includes 23 randomised controlled trials conducted up to July 2015. These studies included a total of 5779 women who were in the menopausal transition period and suffered from hot flushes. Most of the studies (20/23) included only women with moderate to severe hot flushes. None of the studies reported night sweats as a separate outcome. Key results There is low to moderate quality evidence that BHT in various forms and doses is more effective than placebo in decreasing the frequency of moderate to severe hot flushes in women in the menopausal transition period. There was low to moderate quality evidence of higher rates of adverse effects such as headache, vaginal bleeding, breast tenderness and skin reactions in the BHT group. There is some evidence to suggest that higher doses of BHT are associated with more effectiveness but also higher risk of adverse effects. No data are yet available about the safety of BHT with regard to long-term outcomes such as heart attack, stroke and breast cancer. All women with a uterus who are taking any form of estrogen require co-administration of a progestogen, as unopposed estrogen is associated with endometrial hyperplasia. There is no good evidence of a difference in effectiveness between BHT and CEE, and findings with regard to adverse effects are inconsistent. The quality of the evidence is too low to reach any firm conclusions for this comparison. Quality of the evidence The main limitations in the quality of the evidence were study risk of bias (mainly due to poor reporting of methods), imprecision and lack of data suitable for analysis.

Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis; Terapia de remplaso hormonal

The serotonergic system forms a diffuse network within the central nervous system and plays a significant role in the regulation of mood and cognition. Manipulation of tryptophan levels, acutely or chronically, by depletion or supplementation, is an experimental procedure for modifying peripheral and central serotonin levels. These studies have allowed us to establish the role of serotonin in higher order brain function in both preclinical and clinical situations and have precipitated the finding that low brain serotonin levels are associated with poor memory and depressed mood. The gut-brain axis is a bi-directional system between the brain and gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral functioning of the digestive tract. An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to tryptophan and serotonin, producing a possibility that alterations in the gut may be important in the pathophysiology of human central nervous system disorders. In this review we will discuss the effect of manipulating tryptophan on mood and cognition, and discuss a possible influence of the gut-brain axis.

Hajirahimkhan A, Simmler C, Yuan Y, Anderson JR, Chen SN, Nikolić D, Dietz BM, Pauli GF, van Breemen RB, Bolton JL. Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms

The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERβ selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical supplements. Although hops shows strong estrogenic properties via ERα, licorice might have different estrogenic activities due to its ERβ selectivity, partial estrogen agonist activity, and non-enzymatic conversion of isoliquiritigenin to liquiritigenin.

Zavatta A, Parisi F, Mandò C, Scaccabarozzi C, Savasi VM, Cetin I. Role of Inflammaging on the Reproductive Function and Pregnancy

During female lifetime and pregnancy, inflammation and cellular senescence are implicated in physiological processes, from ovulation and menstruation, to placental homeostasis and delivery. Several lifestyles, nutritional, and environmental insults, as well as long-lasting pregestational inflammatory diseases may lead to detrimental effects in promoting and sustaining a chronic excessive inflammatory response and inflammaging, which finally contribute to the decay of fertility and pregnancy outcome, with a negative effect on placental function, fetal development, and future health risk profile in the offspring. Maladaptation to pregnancy and obstetric disease may in turn increase maternal inflammaging in a feedback loop, speeding up aging processes and outbreak of chronic diseases. Maternal inflammaging may also impact, through transgenerational effects, on future adult health. Hence, efficacious interventions should be implemented by physicians and healthcare professionals involved in prevention activities to reduce the modifiable factors contributing to the inflammaging process in order to improve public health.

Vanhees K, Vonhögen IG, van Schooten FJ, Godschalk RW. You are what you eat, and so are your children: the impact of micronutrients on the epigenetic programming of offspring

The research field of fetal programming has developed tremendously over the years and increasing knowledge suggests that both maternal and paternal unbalanced diet can have long-lasting effects on the health of offspring. Studies implicate that macronutrients play an important role in fetal programming, although the importance of micronutrients is also becoming increasingly apparent. Folic acid and vitamins B2, B6 and B12 are essential for one-carbon metabolism and are involved in DNA methylation. They can therefore influence the programming of the offspring's epigenome. Also, other micronutrients such as vitamins A and C, iron, chromium, zinc and flavonoids play a role in fetal programming. Since it is estimated that approximately 78 % of pregnant women in the US take vitamin supplements during pregnancy, more attention should be given to the long-term effects of these supplements on offspring. In this review we address several different studies which illustrate that an unbalanced diet prior and during pregnancy, regarding the intake of micronutrients of both mother and father, can have long-lasting effects on the health of adult offspring.

Saunders, C., dos Santos, K. Nutritional Aspects of Gestation and Puerperium

This chapter is organized into two major sections that address issues about the nutritional aspects of (1) gestation and (2) puerperium, based on the best scientific evidence. The recommended tools and methods for nutritional assessment and weight management followed by nutritional requirements during pregnancy and lactation are presented at each section. Adequacy of gestational weight gain and interventions to reduce postpartum weight retention are opportunely contextualized in the present obesity scenario. Recommendations for common situations in prenatal or postnatal care such as digestive symptoms, nutritional deficiencies, pica, hypertensive disorders of pregnancy, diabetes mellitus, and prescription of nutritional supplements are critically discussed. The main nutritional guidelines for adult and adolescent pregnant or lactating women are summarized for use by health professionals in clinical practice. Current topics emerging in the field of maternal and child nutrition are introduced in this chapter: chrononutrition, vegetarianism, DASH diet, e-Health, and early life programming.

Oakes, J.L., Ideraabdullah, F.Y. Maternal Nutrition and Epigenetic Perturbation: Modeling Trends to Translation

Maternal nutrition plays an essential role in offspring health and development. Critical stages include: (1) preconception, affecting oocyte development and uterine environment preparation; (2) gestation, affecting uterine environment and placental nutrient transfer and (3) postnatal, through lactation. It remains debatable which stage is most important, but arguably, the most complex cellular events occur during gestation. During this time, embryo development requires a well orchestrated and tightly regulated cascade of genetic, molecular and biochemical events. Among these are epigenetic events necessary for gene expression regulation. These produce heritable yet often reversible states established based on transcriptional needs of the cell. A growing body of research highlights the role of maternal nutrition in determining epigenetic states important for pre- and postnatal development. Here, we discuss recent findings addressing epigenetic response to nutrition with relevance to developmental origins of phenotypic outcome.

Nordgren TM, Lyden E, Anderson-Berry A, Hanson C. Omega-3 Fatty Acid Intake of Pregnant Women and Women of Childbearing Age in the United States: Potential for Deficiency?

Omega-3 fatty acids play critical roles during fetal growth and development with increased intakes associated with improved maternal-fetal outcomes. Omega-3 fatty acid intake in Western diets is low, and the impact of socioeconomic factors on omega-3 fatty acid intake in pregnant women and women of childbearing age has not been reported. We used the National Health and Nutrition Examination Survey (NHANES) cycles 2003-2012 to assess the relationship between omega-3 fatty acid intake and socioeconomic factors in women of childbearing age. Out of 7266 eligible participants, 6478 were women of childbearing age, while 788 were identified as pregnant at the time of the survey. Mean EPA+DHA intake of the population was 89.0 mg with no significant difference between pregnant and non-pregnant women. By univariate and multivariate analyses adjusting for confounders, omega-3 fatty acid intake was significantly associated with poverty-to-income ratio, race, and educational attainment. Our results demonstrate that omega-3 fatty acid intake is a concern in pregnant women and women of childbearing age in the United States, and that socioeconomically disadvantaged populations are more susceptible to potential deficiencies. Strategies to increase omega-3 fatty acid intake in these populations could have the potential to improve maternal and infant health outcomes.

Broś-Konopielko M, Białek A, Johne M, Czajkowski K. Increased LC PUFA Levels in the Serum of Pregnant Women and Their Children as a Result of Dietary Supplementation with ‘Omega’ Fatty Acids

Essential fatty acids (EFA) and long-chain polyunsaturated fatty acids (LC PUFA) are considered the most valuable bioactive fatty acids (FA) of the greatest importance for the mother's and child's health (e.g., placentation process, labor course, development of the central nervous system, visual acuity, cognitive functions), which results in dietary recommendations concerning EFA and LC PUFA intake in the diet of pregnant women. In this study, we aimed to evaluate the frequency of different food products consumption and 'omega' dietary supplements usage in groups of pregnant women. We also measured n-3 and n-6 FA content in serum samples of pregnant women and their children with the GC-FID technique, estimated the efficacy of applied supplementation, and compared the usefulness of different dietary supplements dedicated for pregnant women. 'Omega' dietary supplements effectively increased LC PUFA in the maternal blood (EPA, p = 0.0379; DHA p &lt; 0.0001; n-3 PUFA, p &lt; 0.0001), which penetrated the umbilical cord (EPA, p = 0.0131; DHA, p = 0.0288). If fish and seafood consumption is not enough, dietary supplements of the highest quality may provide sufficient LC PUFA without apprehension of MetHg contamination. 'Omega' dietary supplementation seems the most efficient way of providing an optimal supply of LC PUFA for the developing child from the earliest stages of development, which will bring advantages in the child's future life and its health.

Khanjari Z, Iravani M, Abedi P, Ghanbari S.  Effect of Omega-3 fatty acid supplementation on sexual function of pregnant women: a double blind randomized controlled trial

The aim of this study was to evaluate the effect of omega-3 fatty acid supplementation on female sexual function during pregnancy. The present study was a double-blind randomized controlled clinical trial performed on 124 pregnant women (62 people in each group) at 16-22 weeks of gestation who referred to health centers in Ilam in 2020 to receive prenatal care. The intervention group received 300 mg of omega-3 supplements and the control group received placebo once a day for 8 weeks. Data collection tools in this study included a demographic questionnaire, three 24-h dietary recall (24HR), female sexual function index (FSFI), and Van den Bergh Pregnancy-Related Anxiety Questionnaire (PRAQ). Before intervention, the total score of sexual function in the intervention group and control groups, showed no statistically significant difference (P = 0.123). However, 4 and 8 weeks after intervention, the mean total score of sexual function in the intervention group was significantly higher than that of the control group after intervention (P < 0.0001). Before intervention, the total score of gestational anxiety in the intervention and control groups, showed no statistically significant difference (P = 0.149). However, 4 and 8 weeks after intervention, the mean total score of gestational anxiety in the intervention group was significantly lower than that of the control group (P < 0.0001). Based on three 24-h dietary recall, regardless of daily intake of 300 mg of omega-3 supplement, the percentage of polyunsaturated fatty acid (PUFA) intake from daily energy intake was not statistically significant between the intervention and control groups from baseline to follow-up (P > 0.01). Based on the results of this study, omega-3 supplementation could improve sexual function in pregnant women by preventing increased pregnancy anxiety. However, more studies are needed to prove the effectiveness of omega-3s on female sexual function during pregnancy.

Harris MA, Reece MS, McGregor JA, Wilson JW, Burke SM, Wheeler M, Anderson JE, Auld GW, French JI, Allen KG. The Effect of Omega-3 Docosahexaenoic Acid Supplementation on Gestational Length: Randomized Trial of Supplementation Compared to Nutrition Education for Increasing n-3 Intake from Foods.

Objective: DHA supplementation was compared to nutrition education to increase DHA consumption from fish and DHA fortified foods. Design: This two-part intervention included a randomized double-blind placebo controlled DHA supplementation arm and a nutrition education arm designed to increase intake of DHA from dietary sources by 300 mg per day. Setting: Denver Health Hospitals and Clinics, Denver, Colorado, USA. Population: 871 pregnant women aged 18-40 were recruited between 16 and 20 weeks of gestation of whom 564 completed the study and complete delivery data was available in 505 women and infants. Methods: Subjects received either 300 or 600 mg DHA or olive oil placebo or nutrition education. Main outcome variable: Gestational length. Results: Gestational length was significantly increased by 4.0-4.5 days in women supplemented with 600 mg DHA per day or provided with nutrition education. Each 1% increase in RBC DHA at delivery was associated with a 1.6-day increase in gestational length. No significant effects on birth weight, birth length, or head circumference were demonstrated. The rate of early preterm birth (1.7%) in those supplemented with DHA (combined 300 and 600 mg/day) was significantly lower than in controls. Conclusion: Nutrition education or supplementation with DHA can be effective in increasing gestational length.

Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancy

Background: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. Objectives: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. Selection criteria: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. Data collection and analysis: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. Main results: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega-3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. Authors' conclusions: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3. There was a possibly reduced risk of perinatal death and of neonatal care admission, a reduced risk of LBW babies; and possibly a small increased risk of LGA babies with omega-3 LCPUFA.For our GRADE quality assessments, we assessed most of the important perinatal outcomes as high-quality (e.g. preterm birth) or moderate-quality evidence (e.g. perinatal death). For the other outcome domains (maternal, child/adult and health service outcomes) GRADE ratings ranged from moderate to very low, with over half rated as low. Reasons for downgrading across the domain were mostly due to design limitations and imprecision.Omega-3 LCPUFA supplementation during pregnancy is an effective strategy for reducing the incidence of preterm birth, although it probably increases the incidence of post-term pregnancies. More studies comparing omega-3 LCPUFA and placebo (to establish causality in relation to preterm birth) are not needed at this stage. A further 23 ongoing trials are still to report on over 5000 women, so no more RCTs are needed that compare omega-3 LCPUFA against placebo or no intervention. However, further follow-up of completed trials is needed to assess longer-term outcomes for mother and child, to improve understanding of metabolic, growth and neurodevelopment pathways in particular, and to establish if, and how, outcomes vary by different types of omega-3 LCPUFA, timing and doses; or by characteristics of women.

Nordgren TM, Anderson Berry A, Van Ormer M, Zoucha S, Elliott E, Johnson R, McGinn E, Cave C, Rilett K, Weishaar K, Maddipati SS, Appeah H, Hanson C. Omega-3 Fatty Acid Supplementation, Pro-Resolving Mediators, and Clinical Outcomes in Maternal-Infant Pairs; Salud Materna y Epigenómica

Omega (n)-3 fatty acids are vital to neonatal maturation, and recent investigations reveal n-3 fatty acids serve as substrates for the biosynthesis of specialized pro-resolving lipid mediators (SPM) that have anti-inflammatory and immune-stimulating effects. The role SPM play in the protection against negative maternal-fetal health outcomes is unclear, and there are no current biomarkers of n-3 fatty acid sufficiency. We sought to ascertain the relationships between n-3 fatty acid intake, SPM levels, and maternal-fetal health outcomes. We obtained n-3 fatty acid intake information from 136 mothers admitted for delivery using a food frequency questionnaire and measured docosahexaenoic acid (DHA)-derived SPMs resolvin D1 (RvD1) and RvD2 in maternal and cord plasma. We found significantly elevated SPM in maternal versus cord plasma, and increased SPM levels were associated with at-risk outcomes. We also identified that increased DHA intake was associated with elevated maternal plasma RvD1 (p = 0.03; R² = 0.18) and RvD2 (p = 0.04; R² = 0.20) in the setting of neonatal intensive care unit (NICU) admission. These findings indicate that increased n-3 fatty acid intake may provide increased substrate for the production of SPM during high-risk pregnancy/delivery conditions, and that increased maternal plasma SPM could serve as a biomarker for negative neonatal outcomes.

Miles EA, Calder PC. Can Early Omega-3 Fatty Acid Exposure Reduce Risk of Childhood Allergic Disease?

A causal link between increased intake of omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and increased incidence of allergic disease has been suggested. This is supported by biologically plausible mechanisms, related to the roles of eicosanoid mediators produced from the n-6 PUFA arachidonic acid. Fish and fish oils are sources of long chain omega-3 (n-3) PUFAs. These fatty acids act to oppose the actions of n-6 PUFAs particularly with regard to eicosanoid synthesis. Thus, n-3 PUFAs may protect against allergic sensitisation and allergic manifestations. Epidemiological studies investigating the association between maternal fish intake during pregnancy and allergic outcomes in infants/children of those pregnancies suggest protective associations, but the findings are inconsistent. Fish oil provision to pregnant women is associated with immunologic changes in cord blood. Studies performed to date indicate that provision of fish oil during pregnancy may reduce sensitisation to common food allergens and reduce prevalence and severity of atopic eczema in the first year of life, with a possible persistence until adolescence. A recent study reported that fish oil consumption in pregnancy reduces persistent wheeze and asthma in the offspring at ages 3 to 5 years. Eating oily fish or fish oil supplementation in pregnancy may be a strategy to prevent infant and childhood allergic disease.

Amaral YN, Marano D, Silva LM, Guimarães AC, Moreira ME.  Are There Changes in the Fatty Acid Profile of Breast Milk with Supplementation of Omega-3 Sources? A Systematic Review

Purpose To evaluate the effect of supplementation with omega-3 sources on the fatty acid composition of human milk. Methods The review consisted of the search for articles published in PubMed, Biblioteca Virtual de Saúde (Virtual Health Library[VHL]) and Web of Science databases using the following keywords: fatty acids, omega-3, human milk and supplementation; for this purpose, we have used the program of research to integrate the services for the maintenance of autonomy (PRISMA) checklist. The following selection criteria were used: articles in English, Portuguese, Spanish or Italian, published between 2000 and 2015, and about studies performed in humans. We found 710 articles that met the established criteria; however, only 22 of them were selected to be part of this study. Results All studies found a positive relationship between the consumption of omega-3 sources and their concentration in human milk. The differences in the findings are due to the distinct methods used, such as the specific time of the omega-3 supplementation, the type of omega-3 source offered, as well as the sample size. Conclusion Although the studies were different in several methodological aspects, it was possible to observe the importance of omega-3 supplementation during gestation and/or the puerperium.

Tummala, L.S., Agrawal, A. & Lundberg, G. Management Considerations for Lipid Disorders During Pregnancy

Purpose of review. Dyslipidemias including familial hypercholesterolemia and elevated lipoprotein (a) are not uncommon in young women who may desire pregnancy. In all women, abnormal lipid metabolism has been linked to adverse outcomes during pregnancy, including hypertensive disease of pregnancy, gestational diabetes mellitus, and preterm birth. Optimal management of dyslipidemias in pregnant women remains undefined, as statins are contraindicated in this group. Recent findings. Recent literature questions this traditional avoidance of statins, however, as well as explores their potential benefit in pre-eclampsia specifically. Summary In this review, the arsenal of nutrition, bile acid resins, omega-3 fatty acids, and low-density lipoprotein cholesterol apheresis is explored, as are newer therapies like mipomersen and proprotein convertase subtilisin/kexin type 9 inhibitors, for the management of dyslipidemias during pregnancy.

Guéant, JL., Guéant-Rodriguez, RM Maternal Folate, Methyl Donors, One-Carbon Metabolism, Vitamin B12 and Choline in Foetal Programming.

Experimental and human population studies have established links between the deficit in dietary methyl donors (MDD) of one-carbon metabolism (1-CM) during pregnancy and foetal programming. This review on MDD foetal programming is focused on the mechanisms dissected in animal models and the associations with outcomes of obesity, metabolic syndrome and cognition in population studies. 1-CM plays a central role in the influence of metabolic and nutritional factors on DNA methylation and regulation of gene expression through its role on the synthesis of S-adenosylmethionine (SAM), which is needed for methylation of DNA, RNA and histones, the activation of nuclear receptor pathways and the adaptation to cellular stress. This complex metabolic network is regulated by a number of genes and requires micronutrients such as folate, vitamins B12 and B6 and choline to function properly. Experimental and epidemiological studies have clearly demonstrated an association between dietary and metabolic markers of the 1-CM and birth weight and age-related manifestations of foetal programming, including neurodevelopment and cognition, in which epigenomic mechanisms may play a central role. Some of the MDD foetal programming effects are exerted by altered methylation of differentially methylated region (DMR) and imprinted genes. These associations illustrate the need to perform further integrated analyses associating epigenomic and transcriptomic analyses and metabolic and nutritional factors that influence the outcomes of MDD foetal programming.

Khaire, A., Joshi, S. Maternal Long-chain Polyunsaturated Fatty Acids and Pregnancy Outcome

The mother provides various vital nutrients to the growing fetus during pregnancy. Maternal nutrient levels and fatty acids are critical for normal fetal growth and development. All fatty acids provide energy, but structural and metabolic functions primarily require the long-chain polyunsaturated fatty acids (LCPUFA). The biologically most active LCPUFA are docosahexaenoic acid (22:6, omega-3), eicosapentaenoic acid (20:5, omega-3), and arachidonic acid (AA, 20:4 omega-6) which are synthesized from their essential fatty acid precursors, alpha-linolenic acid (18:3, omega-3), and linoleic acid (18:2, omega-6). LCPUFA and their eicosanoid metabolites such prostaglandins and prostacyclins play a vital role in determining the length of gestation, initiation of labor, and placental growth and development. Storage of LCPUFA in maternal fat depots during early pregnancy serves as a sole source of LCPUFA for the growing fetus as the fetus has a limited capacity to synthesize LCPUFA due to lack of desaturases. Therefore, the amount of LCPUFA transported from the mother to fetus depends on maternal LCPUFA intake, metabolism, and placental uptake/transport of fatty acids. Accretion of maternal LCPUFA during pregnancy may reduce the risk of pregnancy complications such as preterm birth, intrauterine growth restriction, gestational diabetes mellitus, and preeclampsia. Maternal DHA and AA status positively influence fetal growth and brain development and also reduce the risk of developing non-communicable diseases in the offspring in adult life. This chapter describes the role of maternal LCPUFA in reducing the risk of adverse pregnancy outcomes.

Koemel NA, Skilton MR. Epigenetic Aging in Early Life: Role of Maternal and Early Childhood Nutrition

Purpose of review: Early life presents a pivotal period during which nutritional exposures are more likely to cause epigenetic modifications, which may impact an individual's health during adulthood. This article reviews the current evidence regarding maternal and early childhood nutritional exposures and their role in epigenetic aging. Recent findings: Maternal and early life consumption of diets higher in fiber, antioxidants, polyphenols, B vitamins, vitamin D, and ω-3 fatty acids is associated with slower epigenetic aging. Conversely, diets higher in glycemic load, fat, saturated fat, and ω-6 fatty acids demonstrate a positive association with epigenetic aging. Maternal and early life nutrition directly and indirectly influences epigenetic aging via changes in one-carbon metabolism, cardiometabolic health, and the microbiome. Clinical trials are warranted to determine the specific foods, dietary patterns, and dietary supplements that will normalize or lower epigenetic aging across the life course.

McKeating DR, Fisher JJ, MacDonald T, Walker S, Tong S, Bennett WW, Kaitu'u-Lino TJ, Perkins AV. Circulating trace elements for the prediction of preeclampsia and small for gestational age babies

Introduction: Poor gestational outcomes due to placental insufficiency can have lifelong consequences for mother and child. Objective: There is a need for better methods of diagnosis, and elemental metabolomics may provide a means to determine the risk of gestational disorders. Methods: This study used blood plasma samples collected at 36 weeks' gestation from women who later developed preeclampsia (n = 38), or small-for-gestational age babies (n = 91), along with matched controls (n = 193). Multi-element analysis was conducted by inductively coupled plasma mass spectrometer (ICP-MS), allowing simultaneous measurement of 28 elements. Results: Women who later developed PE, exhibited significantly increased concentrations of K, Rb and Ba. For SGA pregnancies, there was a significant increase in Cu and a decrease in As concentrations. Despite significant differences in single elements, the elemental profile of groups indicated no clustering of control, PE, or SGA samples. Positive predicative values correctly identified approximately 60% of SGA and 70% of PE samples. Conclusion: This is the first-time elemental metabolomics has been used to predict SGA and PE at 36 weeks. Though significant changes were identified, routine clinical use may be limited but may contribute to a multi marker test. Future analysis should include other biomarkers, metabolic data or clinical measurements made throughout gestation.

Patel, S., Choksi, A., Pant, R., Alam, A., Chattopadhyay, S. Nutritional Programming of Metabolic Syndrome: Role of Nutrients in Shaping the Epigenetics

Increased prevalence of metabolic syndrome like obesity, heart diseases, and diabetes is an emerging public health problem. Susceptibility to such diseases has always been attributed to environmental and genetic factors which certainly play a pivotal role but cannot be the sole causal factor leading to metabolic syndrome. Epigenetics – a mediator between genetics and environment – is emerging as a potential candidate to explain the increase in the prevalence of such metabolic diseases. Changes in the epigenetic landscape marked by DNA methylation, histone methylation, and acetylation can lead to obesity, insulin resistance, diabetes, and vascular dysfunction in both animals and humans. Nutritional programming during early stages of life can manipulate the metabolism and the physiology of the organism. This is where the importance of optimal maternal nutrition comes into play. Both maternal under- and overnutrition have the potential to adversely affect the etiology of metabolic disorders in the developing fetus by changing the epigenetic marks. Various macronutrients and micronutrients in the maternal diet have also been shown to be exhibiting specific effect on the future health of the offspring. Though the role of epigenetics in fetal programming of metabolic syndrome is constantly being well understood, research on the therapeutic aspect is still in its infancy. Interventions and manipulation of dietary supplementation which potentially can make changes in the epigenetic marks can be the future therapeutic targets for chronic metabolic syndrome.

Saghazadeh, A., Mahmoudi, M., Rezaei, N. Nutriepigenomic Immunity

Epigenetic mechanisms and regulatory factors organize a flexible machinery by means of which multicellular organisms generate a heritable alteration in gene expression with respect to the fluctuating external environment. Epigenetic modifications by clever manipulation of maternal dietary and care can transpire independent of DNA sequences to shape a baby and future adult rich not only in immunity to physical diseases – particularly from chronic non-communicable (metabolic and cardiovascular diseases, cancers, and aging) diseases point of view – but also to brain and behavioral disorders. Therefore, despite the book’s dictum to discuss the link between nutrition and immune system function from different aspects, the present chapter first goes beyond to reach that the maternal diet does not leave indiscriminate marks on the offspring epigenome but does plan to manipulate it in a careful pattern and then ends with a nudge to nutriepigenomic immunity.

Shayganfard M. Are Essential Trace Elements Effective in Modulation of Mental Disorders? Update and Perspectives

The emergence of mental disorders is associated with several risk factors including genetic and environmental susceptibility. A group of nutrients serves an especially important role in a number of essential neurodevelopmental processes through brain areas promoting the high degree of brain metabolism during early life, although almost all nutrients are needed. These include macronutrients and micronutrients (e.g., iron, magnesium, zinc, copper, selenium). Numerous nutritional psychiatry trials have been performed to examine the correlation of many individual nutrients with mental health, such as essential trace elements. The increased accumulation or lack of such components will facilitate an alternative metabolic pathway that can lead to many diseases and conditions of neurodevelopment. Mental functions have biochemical bases, so the impairment of such neurochemical mechanisms due to lack of trace elements can have mental effects. In psychological conditions such as depression, anxiety, schizophrenia, and autism, scientific studies demonstrate the putative role of trace element deficiency. Therefore, given the critical roles played by essential trace elements in the neurodevelopment and mental health, the effect of these elements' intake on the modulation of psychological functioning is reviewed.

Skalny AV, Tinkov AA, Voronina I, Terekhina O, Skalnaya MG, Kovas Y. Hair Trace Element and Electrolyte Content in Women with Natural and In Vitro Fertilization-Induced Pregnancy

The objective of the present study was to perform comparative analysis of hair trace element content in women with natural and in vitro fertilization (IVF)-induced pregnancy. Hair trace element content in 33 women with IVF-induced pregnancy and 99 age- and body mass index-matched control pregnant women (natural pregnancy) was assessed using inductively coupled plasma mass spectrometry. The results demonstrated that IVF-pregnant women are characterized by significantly lower hair levels of Cu, Fe, Si, Zn, Ca, Mg, and Ba at p < 0.05 or lower. Comparison of the individual levels with the national reference values demonstrated higher incidence of Fe and Cu deficiency in IVF-pregnant women in comparison to that of the controls. IVF pregnancy was also associated with higher hair As levels (p < 0.05). Multiple regression analysis revealed a significant interrelation between IVF pregnancy and hair Cu, Fe, Si, and As content. Hair Cu levels were also influenced by vitamin/mineral supplementation and the number of pregnancies, whereas hair Zn content was dependent on prepregnancy anthropometric parameters. In turn, planning of pregnancy had a significant impact on Mg levels in scalp hair. Generally, the obtained data demonstrate an elevated risk of copper, iron, zinc, calcium, and magnesium deficiency and arsenic overload in women with IVF-induced pregnancy. The obtained data indicate the necessity of regular monitoring of micronutrient status in IVF-pregnant women in order to prevent potential deleterious effects of altered mineral homeostasis.

Deswal R, Narwal V, Dang A, Pundir CS. The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review

Background: Polycystic ovary syndrome (PCOS), the major endocrinopathy among reproductive-aged women, is not yet perceived as an important health problem in the world. It affects 4%-20% of women of reproductive age worldwide. The prevalence, diagnosis, etiology, management, clinical practices, psychological issues, and prevention are some of the most confusing aspects associated with PCOS. Aim: The exact prevalence figures regarding PCOS are limited and unclear. The aim of this review is to summarize comprehensively the current knowledge on the prevalence of PCOS. Materials and methods: Literature search was performed through PubMed, ScienceDirect, Cochrane Library, and Google Scholar (up to December 2019). All relevant articles published in English language were identified following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Our analysis yielded 27 surveys with a pooled mean prevalence of 21.27% using different diagnostic criteria. The proportion of women with PCOS also increased in the last decade. Conclusion: The current review summarizes and interprets the results of all published prevalence studies and highlights the burden of the syndrome, thereby supporting early identification and prevention of PCOS in order to reverse the persistent upward trend of prevalence.

Jouanne M, Oddoux S, Noël A, Voisin-Chiret AS. Nutrient Requirements during Pregnancy and Lactation

A woman's nutritional status during pregnancy and breastfeeding is not only critical for her health, but also for that of future generations. Nutritional requirements during pregnancy differ considerably from those of non-pregnant women. Thus, a personalized approach to nutritional advice is recommended. Currently, some countries recommend routine supplementation for all pregnant women, while others recommend supplements only when necessary. Maternal physiological adaptations, as well as nutritional requirements during pregnancy and lactation, will be reviewed in the literature examining the impacts of dietary changes. All of these data have been studied deeply to facilitate a discussion on dietary supplement use and the recommended doses of nutrients during pregnancy and lactation. The aim of this review is to evaluate the knowledge in the scientific literature on the current recommendations for the intake of the most common micronutrients and omega-3 fatty acids during pregnancy and lactation in the United States, Canada, and Europe. Taking into account these considerations, we examine minerals, vitamins, and omega-3 fatty acid requirements. Finally, we conclude by discussing the potential benefits of each form of supplementation.

Politano CA, López-Berroa J. Omega-3 Fatty Acids and Fecundation, Pregnancy and Breastfeeding

Long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as the eicosapentaenoic and docosahexaenoic acids, have been linked to human health in all stages of life, from fetal development to aging. These PUFAs act as precursors for various metabolites involved in the prevention of certain diseases. The recognizable effects of these supplements prior to pregnancy (oocyte maturation), during pregnancy (improvement in the risk of premature delivery, among others) and in the offspring (in terms of cognitive function and the approach to neurodevelopmental disorders) are described in the present narrative review. We concluded that the diffusion of these supplements may improve the prognosis of these patients in a simple, effective way, and with high safety rates.

Joo EH, Kim YR, Kim N, Jung JE, Han SH, Cho HY. Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.

Salehi B, Berkay Yılmaz Y, Antika G, Boyunegmez Tumer T, Fawzi Mahomoodally M, Lobine D, Akram M, Riaz M, Capanoglu E, Sharopov F, Martins N, Cho WC, Sharifi-Rad J. Insights on the Use of α-Lipoic Acid for Therapeutic Purposes

α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.

Schatz F, Guzeloglu-Kayisli O, Arlier S, Kayisli UA, Lockwood CJ.  The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding

Background: Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the decidualized endometrium, modification of spiral arteries and post-partum processes. However, decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Methods: We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. Results: Progestin-induced decidualization of estradiol-primed human endometrial stromal cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. Conclusion: Perivascular decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.

Giakoumelou S, Wheelhouse N, Cuschieri K, Entrican G, Howie SE, Horne AW. The role of infection in miscarriage

Background: Miscarriage is the spontaneous loss of a pregnancy before 12 weeks (early miscarriage) or from 12 to 24 weeks (late miscarriage) of gestation. Miscarriage occurs in one in five pregnancies and can have considerable physiological and psychological implications for the patient. It is also associated with significant health care costs. There is evidence that potentially preventable infections may account for up to 15% of early miscarriages and up to 66% of late miscarriages. However, the provision of associated screening and management algorithms is inconsistent for newly pregnant women. Here, we review recent population-based studies on infections that have been shown to be associated with miscarriage. Methods: Our aim was to examine where the current scientific focus lies with regards to the role of infection in miscarriage. Papers dating from June 2009 with key words 'miscarriage' and 'infection' or 'infections' were identified in PubMed (292 and 327 papers, respectively, on 2 June 2014). Relevant human studies (meta-analyses, case-control studies, cohort studies or case series) were included. Single case reports were excluded. The studies were scored based on the Newcastle - Ottawa Quality Assessment Scale. Results: The association of systemic infections with malaria, brucellosis, cytomegalovirus and human immunodeficiency virus, dengue fever, influenza virus and of vaginal infection with bacterial vaginosis, with increased risk of miscarriage has been demonstrated. Q fever, adeno-associated virus, Bocavirus, Hepatitis C and Mycoplasma genitalium infections do not appear to affect pregnancy outcome. The effects of Chlamydia trachomatis, Toxoplasma gondii, human papillomavirus, herpes simplex virus, parvovirus B19, Hepatitis B and polyomavirus BK infections remain controversial, as some studies indicate increased miscarriage risk and others show no increased risk. The latest data on rubella and syphilis indicate increased antenatal screening worldwide and a decrease in the frequency of their reported associations with pregnancy failure. Though various pathogens have been associated with miscarriage, the mechanism(s) of infection-induced miscarriage are not yet fully elucidated. Conclusions: Further research is required to clarify whether certain infections do increase miscarriage risk and whether screening of newly pregnant women for treatable infections would improve reproductive outcomes.

Porcaro G, Brillo E, Giardina I, Di Iorio R. Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: preliminary clinical results; PazOB; Salud Materna y Epigenómica

Objective: The clinic use of alpha Lipoic Acid (ALA) is linked to its capability to exert antioxidant effects and, more interestingly, to counteract the pathologic changes of complex networks of cytokines, chemokines and growth factors, restoring their physiological state. The aim of this randomized controlled clinical trial was to test the contribution of oral supplementation of ALA to the standard treatment with Progesterone vaginal suppositories, in healing subchorionic hematomas in patients with threatened miscarriage. Controls were administered only Progesterone suppositories. Patients and methods: Nineteen pregnant women in the first trimester of gestation, with threatened miscarriage and ultrasound evidence of subchorionic hematoma, were included in the trial and randomly divided in two groups: controls, treated with 400 mg Progesterone (200 mg 2 times per day), given by vaginal suppositories, and case study treated with the same Progesterone dosage, plus ALA, given orally at the dose of 600 mg (300 mg 2 times per day, DAV®, Lo.Li. Pharma srl, Italy). Sixteen patients completed the trial. Treatment was performed until complete resolution of the clinical picture. Results: In both groups, the subjects improved significantly but, in general, a better and faster evolution in the major signs of threatened miscarriage was observed in the subjects treated with ALA and Progesterone. In these patients, the speed of resorption of subchorionic hematoma was significantly (p ≤ 0.05) superior compared to controls. The ALA and Progesterone group showed a faster decrease or disappearance of all symptoms than that observed in the control group, however the difference was not significant. Conclusions: These preliminary results suggest that ALA supplementation significantly contributes to speed up the process of restoration of physiological conditions in threatened miscarriage and ameliorates the medical conditions of both the mothers and the foetus, probably modulating the networks of cytokines, growth factors and other molecules.

North RA, McCowan LM, Dekker GA, Poston L, Chan EH, Stewart AW, Black MA, Taylor RS, Walker JJ, Baker PN, Kenny LC. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort

Objectives: To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Design: Prospective multicentre cohort. Setting: Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. Participants: 3572 "healthy" nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Main outcome measure: Pre-eclampsia defined as ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks' gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37(+0) weeks' gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Results: Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks' gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. Conclusions: The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added.

Clark SM, Costantine MM, Hankins GD. Review of NVP and HG and Early Pharmacotherapeutic Intervention

NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures. ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective pharmacotherapies available to treat NVP are lacking.

Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG.  Hyperemesis gravidarum, a literature review

Hyperemesis gravidarum (HG) is a condition causing severe nausea and vomiting in early pregnancy often resulting in hospital admission. The incidence of HG is approximately 0.5% of live births, said to be higher in multiple pregnancies, hydatidiform mole and other conditions associated with increased pregnancy hormone levels. Both the aetiology and pathogenesis of HG remain unknown. We conducted a literature review (1966-now) to summarize the current evidence on the aetiology and pathogenesis of HG. The potential role of pregnancy-related hormones such as progesterone, estrogen and HCG has been widely studied; however, various other hormones such as leptin, placental growth hormone, prolactin, thyroid and adrenal cortical hormones have been implicated in the aetiology of HG. In addition to endocrinological hypotheses, the rationale and evidence considering infectious, immunological, psychological, metabolic and anatomical causes for HG have been analysed here. Many studies suffer from the low number of patients included, the variable definition used for HG and varying assay methodology used in studies of hormone measurement. This review highlights the need for more extensive studies addressing the pathogenesis and aetiology of HG.

Jueckstock JK, Kaestner R, Mylonas I. Managing hyperemesis gravidarum: a multimodal challenge

Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect.In most cases, the condition is self limiting and subsides by around 20 weeks gestation. More severe forms require medical intervention once other organic causes of nausea and vomiting have been excluded. In addition, a psychosomatic approach is often helpful.In view of its potential complexity, general practitioners and obstetricians should be well informed about HG and therapy should be multimodal.

Kutcher JS, Engle A, Firth J, Lamm SH. Bendectin and birth defects. II: Ecological analyses

Background: Bendectin was the primary pharmaceutical treatment of nausea and vomiting of pregnancy (NVP) in the United States until the early 1980s. Its manufacture was then discontinued after public allegations that it was causing birth defects. Subsequently, meta-analyses of the many epidemiological cohort and case/control studies used to examine that hypothesis have demonstrated the absence of a detectable teratogenic effect. This study presents an ecological analysis of the same hypothesis that examines specific malformations. Methods: Annual birth defect prevalence data for the 1970s to the 1990s have been obtained for specific birth defects from the Center for Disease Control's nationwide Birth Defect Monitoring Program. These data for the US have been compared graphically to the annual US Bendectin sales for the treatment of NVP. Data have also been obtained for annual US rates for hospitalization for NVP. The three data sets have been temporally compared in graphic analysis.Results: The temporal trends in prevalence rates for specific birth defects examined from 1970 through 1992 did not show changes that reflected the cessation of Bendectin use over the 1980-84 period. Further, the NVP hospitalization rate doubled when Bendectin use ceased. Conclusions: The population results of the ecological analyses complement the person-specific results of the epidemiological analyses in finding no evidence of a teratogenic effect from the use of Bendectin.

Koren G, Clark S, Hankins GD, Caritis SN, Umans JG, Miodovnik M, Mattison DR, Matok I. Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy

Background: Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (Diclegis®) for NVP, based in part, on the results of a phase III randomized trial demonstrating the efficacy of this drug combination [study drug marketed under the trade name Diclectin® in Canada and Diclegis® in the United States] compared to placebo in pregnant women. Study drug dosing occurred for 14 days, which is substantially longer than what has been performed in similar studies. The objective of this study was to evaluate, through secondary analysis, whether the primary measure of efficacy can be demonstrated after five days of treatment. Methods: Women suffering from NVP were randomized to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from two to four tablets a day, based on a pre-specified titration protocol. The primary efficacy endpoint was the change in the validated Pregnancy-Unique Quantification of Emesis (PUQE) score at baseline versus Day 15 between Diclegis®-treated and placebo-treated women. For the present study, the change in PUQE score between baseline and Day 15 (end of the study) was compared to the changes observed for Days 3, 4, and 5. Results: The use of delayed-release doxylamine succinate and pyridoxine hydrochloride tablets show improved NVP symptom control as compared to placebo on Days 3,4 and 5, with sustained efficacy until the end of the trial. Conclusion: A four day study drug dosing trial with Diclegis® is sufficient to document efficacy, as the results are similar to those achieved after 14 study drug dosing days. The benefit seen at the earlier time validates drug efficacy and minimizes the natural course of improvement.

Scorza K, Williams A, Phillips JD, Shaw J. Evaluation of nausea and vomiting

A comprehensive history and physical examination can often reveal the cause of nausea and vomiting, making further evaluation unnecessary. Acute symptoms generally are the result of infectious, inflammatory, or iatrogenic causes. Most infections are self-limiting and require minimal intervention; iatrogenic causes can be resolved by removing the offending agent. Chronic symptoms are usually a pathologic response to any of a variety of conditions. Gastrointestinal etiologies include obstruction, functional disorders, and organic diseases. Central nervous system etiologies are primarily related to conditions that increase intracranial pressure, and typically cause other neurologic signs. Pregnancy is the most common endocrinologic cause of nausea and must be considered in any woman of childbearing age. Numerous metabolic abnormalities and psychiatric diagnoses also may cause nausea and vomiting. Evaluation should first focus on detecting any emergencies or complications that require hospitalization. Attention should then turn to identifying the underlying cause and providing specific therapies. When the cause cannot be determined, empiric therapy with an antiemetic is appropriate. Initial diagnostic testing should generally be limited to basic laboratory tests and plain radiography. Further testing, such as upper endoscopy or computed tomography of the abdomen, should be determined by clinical suspicion based on a complete history and physical examination.

London V, Grube S, Sherer DM, Abulafia O. Hyperemesis Gravidarum: A Review of Recent Literature

Background: In the United States, hyperemesis gravidarum is the most common cause of hospitalization during the first half of pregnancy and is second only to preterm labor for hospitalizations in pregnancy overall. In approximately 0.3-3% of pregnancies, hyperemesis gravidarum is prevalent and this percentage varies on account of different diagnostic criteria and ethnic variation in study populations. Despite extensive research in this field, the mechanism of the disease is largely unknown. Although cases of mortality are rare, hyperemesis gravidarum has been associated with both maternal and fetal morbidity. The current mainstay of treatment relies heavily on supportive measures until improvement of symptoms as part of the natural course of hyperemesis gravidarum, which occurs with progression of gestational age. However, studies have reported that severe, refractory disease manifestations have led to serious adverse outcomes and to termination of pregnancies. Summary: Despite extensive research in the field, the pathogenesis of hyperemesis gravidarum remains unknown. Recent literature points to a genetic predisposition in addition to previously studied factors such as infectious, psychiatric, and hormonal contributions. Maternal morbidity is common and includes psychological effects, financial burden, clinical complications from nutritional deficiencies, gastrointestinal trauma, and in rare cases, neurological damage. The effect of hyperemesis gravidarum on neonatal health is still debated in literature with conflicting results regarding outcomes of birth weight and prematurity. Available therapy options remain largely unchanged in the past several decades and focus on parenteral antiemetic medications, electrolyte repletion, and nutritional support. Most studies of therapeutic options do not consist of randomized control studies and cross-study analysis is difficult due to considerable variation of diagnostic criteria. Key Messages: Hyperemesis gravidarum carries a significant burden on maternal health and US health care. Most published research on pathogenesis is observational and suggests multifactorial associations with hyperemesis gravidarum. Precise, strictly defined criteria for clinical diagnosis are likely to benefit meta-analyses of further research studies regarding pathogenesis as well as therapeutic options.

Maltepe C, Koren G. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum--a 2013 update

Nausea and vomiting of pregnancy (NVP) affects up to 85% of all pregnancies, yet many physicians are uncertain as to how to best treat their patients in the presence of controversial data on fetal risks. This review provides an update on the management of NVP, including pharmacological and non pharmacological approaches Due to a high rate of recurrent symptoms, it is important for women to receive early treatment to reduce the severity of symptoms with the aim of preventing hospitalization and improving quality of life.

Clark SM, Costantine MM, Hankins GD. Review of NVP and HG and Early Pharmacotherapeutic Intervention

NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures. ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective pharmacotherapies available to treat NVP are lacking.

Koren G, Clark S, Hankins GD, Caritis SN, Umans JG, Miodovnik M, Mattison DR, Matok I. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial

Background: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. Methods: We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Results: Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Conclusions: Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy.

L Pkhaladze, M Russo, V Unfer, M Nordio, S Basciani, A Khomasuridze Treatment of lean PCOS teenagers: a follow-up comparison between Myo-Inositol and oral contraceptives

Objective: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder widely diffused and diagnosed in women of reproductive age. The pathology exhibits alteration of the reproductive functions, including conditions as hyperandrogenism, menstrual cycle irregularity, type 2 diabetes. These conditions are visible in the patients through phenotypical manifestations as hirsutism, acne, and obesity. Even if the syndrome is characterized by common features among both adult and adolescent women, the diagnostic criteria are different for the two age categories and to date still controversial. We investigated different treatments in PCOS adolescents with non-severe metabolic conditions, to evaluate which could be the appropriate therapeutical approach for these patients. Patients and methods: We enrolled lean teenagers with PCOS, and we divided the patients in two age ranges: 13-16 years old and 17-19 years old. They were treated for 3 months either with oral contraceptive pills (OCP) drospirenone/ethinylestradiol (group A), myo-Inositol (myo-Ins) (group B), or OCP plus myo-Ins (group C). Data were analyzed with a descriptive statistics summarizing quantitative variables including median, 25th and 75th percentiles. Results: We pointed out that the group of 13-16 years old lean teenagers treated with myo-Ins exhibit a significant decrease of weight and body mass index (BMI), and an effective improvement the metabolic and hormonal parameters achieved with a non-pharmacological treatment. In the older teenagers aged 17-19 years, data highlights that myo-Ins treatment in combination with OCP prevents the increases of weight and BMI, improves the metabolic profile of the patients, and strongly ameliorates the hormonal parameters analyzed. Conclusions: The results indicate a different scenario in the two age ranges considered and interestingly suggest an important role of myo-Ins in the PCOS context. A therapy based on this natural compound alone or in combination with OCP seems effective to improve both metabolic and hormonal parameters of PCOS adolescents and thus could represent a novel and valid option to consider for the treatment of this syndrome.

Laganà AS, Vitagliano A, Noventa M, Ambrosini G, D'Anna R. Myo‑inositol supplementation reduces the amount of gonadotropins and length of ovarian stimulation in women undergoing IVF: a systematic review and meta‑analysis of randomized controlled trials

Purpose: To evaluate whether oral myo-inositol supplementation (MI) is able to reduce the amount of gonadotropins (GA) and the length of controlled ovarian hyperstimulation (SL) in both Polycystic Ovarian Syndrome (PCOS) and non-PCOS women undergoing in vitro fertilization (IVF). Methods: We performed a systematic review (PROSPERO ID: CRD42017069439) of randomized controlled trials (RCTs). We searched articles published in English between January 1985 to August 2017, using the combination of the Medical Subject Headings "Inositol" with "Ovulation Induction", "follicle-stimulating hormone, human, with HCG C-terminal peptide", "Reproductive Techniques, Assisted", and "Fertilization in Vitro". We collected data about GA and SL comparing MI to no treatment or D-Chiro-Inositol (DCI) supplementation (controls). A subgroup analysis was performed to evaluate selected outcomes in PCOS and non-PCOS women. Results: We included 8 studies embedding 812 participants. We found a reduction in GA (p < 0.00001) and SL (p = 0.0007) in patients receiving MI with respect to controls. MI was effective in both PCOS (p < 0.00001) and non-PCOS women (p = 0.02) in reducing GA; conversely, MI supplementation decreased the SL only in PCOS women (p < 0.00001). Conclusion: During IVF, MI is effective in both PCOS and non-PCOS women in saving gonadotropins, but reduces efficiently SL only in PCOS women.

Otoya Chaves F, León Quirós S, Rodríguez Morera M. Manejo de infertilidad por anovulación en síndrome de ovario poliquístico

La infertilidad por anovulación es una complicación común asociada al síndrome de ovario poliquístico. La optimización de la salud constituye el primer paso en el abordaje de esta patología, principalmente con cambios en estilo de vida e índice de masa corporal óptimo. En lo referente a farmacoterapia, el citrato de clomifeno es ampliamente utilizado a nivel mundial como primera línea para inducir la ovulación. No obstante, el letrozol y la metformina en combinación con citrato de clomifeno, son terapias con evidencia prometedora que han demostrado ser superiores al citrato de clomifeno en monoterapia, en lo que respecta a fertilidad. Sin embargo, no existe consenso, y se siguen considerando terapias de segunda línea. Las gonadotropinas exógenas y la perforación laparoscópica del ovario son utilizadas cuando hay resistencia a la primera línea. La fertilización in vitro es una opción cuando tanto la primera, como la segunda línea, no son exitosas. Otros medicamentos se encuentran en estudio para determinar su eficacia en esta patología, como los agonistas del receptor del péptido similar al glucagón tipo 1 y esteroisómeros del inositol, empero, aún requieren estudios de mejor calidad.

Tabatabaie M, Amiri S, Golestan Jahromi M, Sene AA, Zandieh Z, Mehdizadeh M, Amjadi F. The effect of Myo-Inositol supplement on molecular regulation of folliculogenesis, steroidogenesis, and assisted reproductive technique outcomes in patients with polycystic ovarian syndrome

Research question: The mechanism of Myo-Inositol, as an adjuvant, on key signaling pathways related to oocyte maturation, fertilization rate, and embryo quality as well as ovarian steroidogenesis in cumulus cells of PCOS patients, is still unclear. Design: Infertile patients who were candidates for ART cycles were divided into three groups (n = 30 in each group), including group 1: PCOS patients only receiving folic acid, group 2: PCOS patients receiving daily Myo-Inositol combined with folic acid, and a control group (group 3): normal ovulatory women without PCOS receiving only folic acid from 1 month prior to IVF cycle until the day of ovum pick up. During the ART procedure, oocytes maturation, fertilization rate, and embryo quality were assessed. The gene expressions of FSHR, LHR, CYP11A1, CYP19A1, 3β-HSD2, and StAR were also analyzed using qRT-PCR. Western blot analysis was performed for the evaluation of AKT, ERK, CREB, and AMPK phosphorylation. Result: Despite equal number of retrieved oocytes, the percentages of MII oocytes, fertilization rate, and embryo quality were found to be significantly higher in group 2 due to the administration of inofolic. The expressions of all the studied genes were significantly higher in the cumulus cells of group 1 compared to the group 2. Higher phosphorylation of ERK1/2 was found in the groups 2 and 3 compared to the group 1. On the other hand, p-Akt has significantly decreased in the group 2 compared to the group 1. Conclusion: Our study provides new insight into the molecular mechanism underlying the positive effect of Myo-Inositol on intrinsic ovarian defects in PCOS, steroidogenesis, oocyte maturation, fertilization rate, and embryo quality.

Hu C, Pang B, Ma Z, Yi H. Immunophenotypic Profiles in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductive-metabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.

Montanino Oliva M, Buonomo G, Calcagno M, Unfer V. Effects of myo-inositol plus alpha-lactalbumin in myo-inositol-resistant PCOS women

Background: Myo-inositol (MI), successfully used in polycystic ovary syndrome (PCOS), was administered with α-LA to exploit its action of favouring the passage of other molecules through biological barriers, and also considering its anti-inflammatory effect. Methods: PCOS patients, according to the Rotterdam ESHRE-ASRM criteria, with anovulation and infertility > 1 year, were included in this open and prospective study. The preliminary phase was aimed at determining a set of MI-resistant PCOS patients. This treatment involved 2 g MI, taken twice per day by oral route, for three months. The Homeostasis Model Assessment (HOMA) index and MI plasma levels were measured. In the main phase, previously selected MI-resistant patients received the same daily amount of MI plus 50 mg α-LA twice a day, for a further three months. Ovulation was assessed using ultrasound examination on days 12, 14 and 20 of the cycle. The HOMA index, lipid, hormone and MI plasma levels were detected at baseline and at the end of this phase. Results: Thirty-seven anovulatory PCOS subjects were included in the study. Following MI treatment, 23 of the 37 women (62%) ovulated, while 14 (38%) were resistant and did not ovulate. In the latter group, MI plasma levels did not increase. These MI-resistant patients underwent treatment in the main phase of the study, receiving MI and α-LA. After this combined treatment, 12 (86%) of them ovulated. Their MI plasma levels were found to be significantly higher than at baseline; also, a hormone and lipid profile improvement was recorded. Conclusion: The combination of MI with α-LA allowed us to obtain significant progress in the treatment of PCOS MI-resistant patients. Therefore, this new formulation was able to re-establish ovulation, greatly increasing the chances of desired pregnancy.

Ravanos K, Monastra G, Pavlidou T, Goudakou M, Prapas N. Can high levels of D-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality?

Objective: It was previously shown that higher concentrations of myo-inositol in human follicular fluid improve oocyte and embryo quality, whereas D-chiro-inositol seems to worsen oocyte quality and ovarian response in polycystic ovary syndrome patients. Our study was the first one aiming to test whether different myo-inositol and D-chiro-inositol concentration in follicular fluids correlate with blastocyst quality in healthy young women. Patients and methods: Eight egg donors and eleven couples undergoing in vitro fertilization, were involved in a prospective observational study. Myo-inositol/D-chiro-inositol ratio was calculated in the follicular fluids and associated with different blastocyst grades. Donors were homogeneous and followed the same standard stimulation protocol. Results: The ratio between myo-inositol and D-chiro-inositol was significantly higher in the specimens rated as good quality blastocysts, compared to those rated as poor-quality blastocysts. In this study, almost all the transferred blastocysts were graded as good quality and were correlated to lower D-chiro-inositol content in the follicular fluid; the implantation rate and pregnancy rate were satisfying. Our data suggest that the reduction of such ratio in follicular fluid seems to play a negative role in follicular development. Conclusions: We found a correlation between myo-inositol/D-chiro-inositol ratio in follicular fluid and blastocyst quality. The value of this ratio may represent a new biomarker for estimating the good features of blastocysts, and a prognostic factor of embryo implantation and pregnancy success. Moreover, the pre-treatment with myo-inositol in women undergoing in vitro fertilization (IVF) may improve oocyte quality and ART outcome.

Clissold SP, Heel RC. Tioconazole. Tioconazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses

Tioconazole is a substituted imidazole antimicrobial agent structurally related to other drugs in this group. It has been shown to have a broad spectrum of activity in vitro against dermatophytes and yeasts, as well as against some chlamydia, trichomonads and Gram-positive bacteria. Both open and controlled clinical trials have clearly demonstrated the efficacy and safety of topical preparations of tioconazole for treating superficial dermatophyte or yeast infections of the skin and vaginal candidiasis. In comparative studies it was at least as effective as alternative imidazole antifungal drugs, and in a few trials significantly greater efficacy has been reported for tioconazole, compared with clotrimazole, miconazole, econazole and syste