Respiratory syncytial virus vaccination during pregnancy for improving infant outcomes.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTIs) in infants. Maternal RSV vaccination is a preventive strategy of great interest, as it could have a substantial impact on infant RSV disease burden. In recent years, the clinical development of maternal RSV vaccines has advanced rapidly. OBJECTIVES: To assess the efficacy and safety of maternal respiratory syncytial virus (RSV) vaccination for preventing RSV disease in infants. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register and two other trials registries on 21 October 2022. We updated the search on 27 July 2023, when we searched MEDLINE, Embase, CENTRAL, CINAHL, and two trials registries. Additionally, we searched the reference lists of retrieved studies and conference proceedings. There were no language restrictions on our searches. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing maternal RSV vaccination with placebo or no intervention in pregnant women of any age. The primary outcomes were hospitalisation with clinically confirmed or laboratory-confirmed RSV disease in infants. The secondary outcomes covered adverse pregnancy outcomes (intrauterine growth restriction, stillbirth, and maternal death) and adverse infant outcomes (preterm birth, congenital abnormalities, and infant death). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (25 study reports) involving 17,991 pregnant women. The intervention was an RSV pre-F protein vaccine in four studies, and an RSV F protein nanoparticle vaccine in two studies. In all studies, the comparator was a placebo (saline, formulation buffer, or sterile water). We judged four studies at overall low risk of bias and two studies at overall high risk (mainly due to selection bias). All studies were funded by pharmaceutical companies. Maternal RSV vaccination compared with placebo reduces infant hospitalisation with laboratory-confirmed RSV disease (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.31 to 0.82; 4 RCTs, 12,216 infants; high-certainty evidence). Based on an absolute risk with placebo of 22 hospitalisations per 1000 infants, our results represent 11 fewer hospitalisations per 1000 infants from vaccinated pregnant women (15 fewer to 4 fewer). No studies reported infant hospitalisation with clinically confirmed RSV disease. Maternal RSV vaccination compared with placebo has little or no effect on the risk of congenital abnormalities (RR 0.96, 95% CI 0.88 to 1.04; 140 per 1000 with placebo, 5 fewer per 1000 with RSV vaccination (17 fewer to 6 more); 4 RCTs, 12,304 infants; high-certainty evidence). Maternal RSV vaccination likely has little or no effect on the risk of intrauterine growth restriction (RR 1.32, 95% CI 0.75 to 2.33; 3 per 1000 with placebo, 1 more per 1000 with RSV vaccination (1 fewer to 4 more); 4 RCTs, 12,545 pregnant women; moderate-certainty evidence). Maternal RSV vaccination may have little or no effect on the risk of stillbirth (RR 0.81, 95% CI 0.38 to 1.72; 3 per 1000 with placebo, no difference with RSV vaccination (2 fewer to 3 more); 5 RCTs, 12,652 pregnant women). There may be a safety signal warranting further investigation related to preterm birth. This outcome may be more likely with maternal RSV vaccination, although the 95% CI includes no effect, and the evidence is very uncertain (RR 1.16, 95% CI 0.99 to 1.36; 6 RCTs, 17,560 infants; very low-certainty evidence). Based on an absolute risk of 51 preterm births per 1000 infants from pregnant women who received placebo, there may be 8 more per 1000 infants from pregnant women with RSV vaccination (1 fewer to 18 more). There was one maternal death in the RSV vaccination group and none in the placebo group. Our meta-analysis suggests that RSV vaccination compared with placebo may have little or no effect on the risk of maternal death (RR 3.00, 95% CI 0.12 to 73.50; 3 RCTs, 7977 pregnant women; low-certainty evidence). The effect of maternal RSV vaccination on the risk of infant death is very uncertain (RR 0.81, 95% CI 0.36 to 1.81; 6 RCTs, 17,589 infants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The findings of this review suggest that maternal RSV vaccination reduces laboratory-confirmed RSV hospitalisations in infants. There are no safety concerns about intrauterine growth restriction and congenital abnormalities. We must be careful in drawing conclusions about other safety outcomes owing to the low and very low certainty of the evidence. The evidence available to date suggests RSV vaccination may have little or no effect on stillbirth, maternal death, and infant death (although the evidence for infant death is very uncertain). However, there may be a safety signal warranting further investigation related to preterm birth. This is driven by data from one trial, which is not fully published yet. The evidence base would be much improved by more RCTs with substantial sample sizes and well-designed observational studies with long-term follow-up for assessment of safety outcomes. Future studies should aim to use standard outcome measures, collect data on concomitant vaccines, and stratify data by timing of vaccination, gestational age at birth, race, and geographical setting.

Action against birth defects: if not now, when?

BACKGROUND: More children are surviving through interventions to address the infectious causes of under-5 mortality; subsequently, the proportion of deaths caused by birth defects is increasing. Prevention, diagnosis, treatment and care interventions for birth defects are available but are needed where the burden is highest, low-and-middle-income countries. OBJECTIVES: A selection of birth defect focused publications, conferences, and World Health Assembly resolutions from 2000 to 2017 show that global efforts were made to raise the profile of birth defects in global public health. However, recent donor support and national government interest has waned. Without concerted global action to improve primary prevention and care for children born with birth defects, the Sustainable Development Goal targets for child survival will not be met. RESULTS: Birth defects make up 8% and 10% of global under-5 and neonatal deaths respectively, making them significant contributors to preventable loss of life for children. Survivors face long-term morbidity and lifelong disability which compounds the health and economic woes of individuals, families, communities and society as a whole. Demographic changes in sub-Saharan Africa portend a growing number of births with 1.6 billion projected from 2021 to 2050. More births and better survival without effective prevention and treatment for birth defects translates into more mortality and disability from birth defects. CONCLUSIONS: We recommend interventions for prevention of birth defects. These are evidenced-based and affordable, but require low- and middle-income countries to strengthened their health systems. Action against birth defects now will prevent premature deaths and long-term disability, and lead to stronger, more resilient health systems.

Ethical guidelines for birth defect prevention recommended by experts. / 出生缺陷预防的伦理指导原则专家建议.

China's maternal and child health work is still facing many challenges, such as unbalanced development and inadequate services. Since the adjustment of the family planning policy, the proportion of older and more productive sub-parturient women have increased, the risk for birth defects has increased, the demand for newborn safety has further increased, and the work of maternal and child health is facing new challenges. The experts from the medicine, medical ethics, sociology, and other fields put forward the principle of ethical guidance for birth defect prevention after full discussion and continuous revision based on expert proposals, which include the principle of life dignity, love, scientific principle, fair principle, respect for autonomy principle, the principle of beneficence and the principle of good privacy protection. The guideline can serve the birth defect prevention clinical practice, be better to respect and safeguard the legitimate rights and interests of people at childbearing age, eliminate ethics cognition pitfalls of birth defect prevention, and regulate the behavior of birth defect prevention-related ethics.

Cardiopatia congênita afeta cerca de 30 mil crianças por ano no Brasil

As cardiopatias congênitas são um conjunto de malformações na estrutura ou na função do coração que surgem durante o desenvolvimento fetal.

Surco perineal: un viejo poco conocido / Perineal groove: a little-known old man

Introducción: El surco perineal es una malformación infrecuente dela línea media. Se trata de un surco húmedo, mucoso y no queratinizado localizado en la línea media del periné desde la horquilla vulvar hastael borde anal anterior. Es una malformación infrecuente, usualmente asintomática y de resolución espontánea en la mayoría de los casos. Esta anomalía es frecuentemente confundida con otras malformaciones por lo que su reconocimiento es fundamental para evitar yatrogenia. Caso clínico: Se presenta el caso de una recién nacida con una lesión asintomática en la línea media del periné sospechosa de malformación anorrectal. Tras valoración por el Servicio de Cirugía Pediátrica se diagnosticó de surco perineal. Comentarios: Debido a la infrecuencia y escasa documentación bibliográfica del surco perineal, esta malformación es desconocida paramuchos sanitarios. Este caso expone la importancia de tener presente estaanomalía para evitar diagnósticos erróneos, tratamientos innecesarios y estrés familiar.(AU)

Introduction: Perineal groove is an infrequent midline malformation. It is a humid, mucosal, non keratinized groove located at theperineal midline, extending from the vulvar fourchette to the anterioranal border. It is rare and usually asymptomatic, and it heals spontane-ously in most cases. It is frequently mistaken for other malformations,which means correctly identifying it is essential to avoid iatrogenesis. Clinical case: We present the case of a female newborn with anasymptomatic lesion at the perineal midline consistent with anorectal malformation. Following assessment by the Pediatric Surgery Department, she was diagnosed with perineal groove. Discussion: Perineal groove is a little known malformation amonghealthcare professionals as it is infrequent and there are not many publications in the literature about it. This case demonstrates how importantit is to keep this abnormality in mind to avoid erroneous diagnoses, unnecessary treatments, and family stress.(AU)

Efficacy of 4.0 mg versus 0.4 mg Folic Acid Supplementation on the Reproductive Outcomes: A Randomized Controlled Trial.

Folic acid (FA) supplementation prevents neural tube defects (NTDs), but the effects on other reproductive outcomes are unclear. While common recommendation is 0.4 mg/day in addition to regular nutrition, the most appropriate dose of FA is still under debate. We investigated the effects of a higher dose of periconception FA on reducing adverse reproductive outcomes. In this multicenter double-blind randomized controlled trial (RCT), 1060 women (aged 18-44 years and planning a pregnancy) were randomly assigned to receive 4.0 mg or 0.4 mg of FA daily. The primary outcome was the occurrence of congenital malformations (CMs). A composite outcome including one or more adverse pregnancy outcomes was also evaluated. A total of 431 women had a natural conception within 1 year. The primary outcome occurred in 8/227 (3.5%) women receiving 4.0 mg FA and 9/204 (4.4%) women receiving 0.4 mg FA (RR 0.80; 95%CI 0.31 to 2.03). The composite outcome occurred in 43/227 (18.9%) women receiving 4.0 mg FA and 75/204 (36.8%) women receiving 0.4 mg FA (RR 0.51; 95%CI 0.40 to 0.68). FA 4.0 mg supplementation was not associated with different occurrence of CMs, compared to FA 0.4 mg supplementation. However, FA 4.0 mg supplementation was associated with lower occurrence of other adverse pregnancy outcomes.

An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity.

To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures.

Pregnancy and viral infections: Mechanisms of fetal damage, diagnosis and prevention of neonatal adverse outcomes from cytomegalovirus to SARS-CoV-2 and Zika virus.

Some maternal infections, contracted before or during pregnancy, can be transmitted to the fetus, during gestation (congenital infection), during labor and childbirth (perinatal infection) and through breastfeeding (postnatal infection). The agents responsible for these infections can be viruses, bacteria, protozoa, fungi. Among the viruses most frequently responsible for congenital infections are Cytomegalovirus (CMV), Herpes simplex 1-2, Herpes virus 6, Varicella zoster. Moreover Hepatitis B and C virus, HIV, Parvovirus B19 and non-polio Enteroviruses when contracted during pregnancy may involve the fetus or newborn at birth. Recently, new viruses have emerged, SARS-Cov-2 and Zika virus, of which we do not yet fully know the characteristics and pathogenic power when contracted during pregnancy. Viral infections in pregnancy can damage the fetus (spontaneous abortion, fetal death, intrauterine growth retardation) or the newborn (congenital anomalies, organ diseases with sequelae of different severity). Some risk factors specifically influence the incidence of transmission to the fetus: the timing of the infection in pregnancy, the order of the infection, primary or reinfection or chronic, the duration of membrane rupture, type of delivery, socio-economic conditions and breastfeeding. Frequently infected neonates, symptomatic at birth, have worse outcomes than asymptomatic. Many asymptomatic babies develop long term neurosensory outcomes. The way in which the virus interacts with the maternal immune system, the maternal-fetal interface and the placenta explain these results and also the differences that are observed from time to time in the fetal­neonatal outcomes of maternal infections. The maternal immune system undergoes functional adaptation during pregnancy, once thought as physiological immunosuppression. This adaptation, crucial for generating a balance between maternal immunity and fetus, is necessary to promote and support the pregnancy itself and the growth of the fetus. When this adaptation is upset by the viral infection, the balance is broken, and the infection can spread and lead to the adverse outcomes previously described. In this review we will describe the main viral harmful infections in pregnancy and the potential mechanisms of the damages on the fetus and newborn.

Reducing the Burden of Anemia and Neural Tube Defects in Low- and Middle-Income Countries: An Analysis to Identify Countries with an Immediate Potential to Benefit from Large-Scale Mandatory Fortification of Wheat Flour and Rice.

Using a predetermined set of criteria, including burden of anemia and neural tube defects (NTDs) and an enabling environment for large-scale fortification, this paper identifies 18 low- and middle-income countries with the highest and most immediate potential for large-scale wheat flour and/or rice fortification in terms of health impact and economic benefit. Adequately fortified staples, delivered at estimated coverage rates in these countries, have the potential to avert 72.1 million cases of anemia among non-pregnant women of reproductive age; 51,636 live births associated with folic acid-preventable NTDs (i.e., spina bifida, anencephaly); and 46,378 child deaths associated with NTDs annually. This equates to a 34% reduction in the number of cases of anemia and 38% reduction in the number of NTDs in the 18 countries identified. An estimated 5.4 million disability-adjusted life years (DALYs) could be averted annually, and an economic value of 31.8 billion United States dollars (USD) generated from 1 year of fortification at scale in women and children beneficiaries. This paper presents a missed opportunity and warrants an urgent call to action for the countries identified to potentially avert a significant number of preventable birth defects, anemia, and under-five child mortality and move closer to achieving health equity by 2030 for the Sustainable Development Goals.

Prevalência e fatores associados às malformações congênitas em nascidos vivos / Prevalencia y factores asociados a las malformaciones congénitas en nacidos vivos / Prevalence and factors associated with congenital malformations in live births

Resumo Objetivo: Estimar a prevalência de malformações congênitas e identificar os fatores associados em nascidos vivos. Métodos: Estudo transversal, de base populacional, com dados do Sistema de Informações sobre nascidos vivos. Procedeu-se a uma análise estatística bivariada (teste Qui-quadrado) e multivariada (regressão logística múltipla) para avaliar a associação entre as variáveis e o desfecho (nascidos vivos que possuem ou não malformações congênitas). Resultados: Registraram-se 346.874 nascidos vivos, desses 3.473 apresentaram algum tipo de malformação congênita, com prevalência média de 1,0%. Na análise múltipla os fatores, positivamente associados à prevalência foram: duração da gestação menor que 37 semanas (OR= 1,17), idade materna entre 20 e 29 anos (OR= 0,893), tipo de gravidez única (OR= 1,775), tipo de parto (OR= 0,827) e consultas de pré-natal inferior a seis (OR= 1,214). Conclusão: As variáveis apontadas no estudo integraram um modelo preditivo que pode auxiliar no planejamento dos serviços de saúde, sugerir hipóteses sobre os fatores etiológicos, e subsidiar as ações do pré-natal com atenção para os fatores identificados.

Resumen Objetivo: Estimar la prevalencia de malformaciones congénitas e identificar los factores asociados en nacidos vivos. Métodos: Estudio transversal, de base poblacional, con datos del Sistema de Información sobre nacidos vivos. Se procedió a un análisis estadístico bivariado (prueba χ2 de Pearson) y multivariado (regresión logística múltiple) para evaluar la relación entre las variables y el resultado (nacidos vivos que tienen o no tienen malformaciones congénitas). Resultados: Se registraron 346.874 nacidos vivos, de los cuales 3.473 presentaron algún tipo de malformación congénita, con prevalencia promedio de 1,0 %. En el análisis múltiple, los factores asociados de forma positiva a la prevalencia fueron: duración de la gestación menor a 37 semanas (OR= 1,17), edad materna entre 20 y 29 años (OR= 0,893), tipo de gestación única (OR= 1,775), tipo de parto (OR= 0,827) y consultas de atención prenatal inferiores a seis (OR= 1,214). Conclusión: Las variables observadas en el estudio integran un modelo predictivo que puede ayudar a la planificación de los servicios de salud, sugerir hipótesis sobre los factores etiológicos y respaldar las acciones de la atención prenatal con énfasis en los factores identificados.

Abstract Objective: To estimate the prevalence of congenital malformations and to identify associated factors in live births. Methods: Cross-sectional study, population-based, with data from the Live Births Information System. A bivariate statistical analysis (Chi-square test) and a multivariate statistical analysis (multiple logistic regression) were performed to evaluate the association between the variables and the outcome (live-births with or without congenital malformations). Results: A total of 346,874 live births were registered, of which 3,473 presented some type of congenital malformation, with an average prevalence of 1.0%. In the multiple analysis, the factors positively associated with prevalence were: duration of pregnancy less than 37 weeks (OR = 1.17), maternal age between 20 and 29 years (OR = 0.893), singleton pregnancy (OR = 1.775), type of delivery (OR - 0.827), and number of prenatal consultations inferior to six (OR = 1.214). Conclusion: The variables pointed out in the study integrated a predictive model that can help in the planning of health services, suggest hypotheses regarding etiological factors, and finance prenatal care actions with attention to the identified factors.

The Reproductive Journey in the Genomic Era: From Preconception to Childhood.

It is estimated that around 10-15% of the population have problems achieving a pregnancy. Assisted reproduction techniques implemented and enforced by personalized genomic medicine have paved the way for millions of infertile patients to become parents. Nevertheless, having a baby is just the first challenge to overcome in the reproductive journey, the most important is to obtain a healthy baby free of any genetic condition that can be prevented. Prevention of congenital anomalies throughout the lifespan of the patient must be a global health priority. Congenital disorders can be defined as structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth, or sometimes may only be detected later during childhood. It is considered a frequent group of disorders, affecting 3-6% of the population, and one of the leading causes of morbidity and mortality. Congenital anomalies can represent up to 30-50% of infant mortality in developed countries. Genetics plays a substantial role in the pathogenesis of congenital anomalies. This becomes especially important in some ethnic communities or populations where the incidence and levels of consanguinity are higher. The impact of genetic disorders during childhood is high, representing 20-30% of all infant deaths and 11.1% of pediatric hospital admissions. With these data, obtaining a precise genetic diagnosis is one of the main aspects of a preventive medicine approach in developed countries. The field of reproductive health has changed dramatically from traditional non-molecular visual microscope-based techniques (i.e., fluorescence in situ hybridization (FISH) or G-banding karyotype), to the latest molecular high-throughput techniques such as next-generation sequencing (NGS). Genome-wide technologies are applied along the different stages of the reproductive health lifecycle from preconception carrier screening and pre-implantation genetic testing, to prenatal and postnatal testing. The aim of this paper is to assess the new horizon opened by technologies such as next-generation sequencing (NGS), in new strategies, as a genomic precision diagnostic tool to understand the mechanisms underlying genetic conditions during the "reproductive journey".

Association of Improved Periconception Hemoglobin A1c With Pregnancy Outcomes in Women With Diabetes.

Importance: Prepregnancy diabetes is associated with higher perinatal and maternal morbidity, especially if periconception glycemic control is suboptimal. It is not known whether improved glycemic control from preconception to early pregnancy and midpregnancy periods can reduce the risk of adverse perinatal and maternal outcomes. Objective: To determine whether a net decline in glycated hemoglobin A1c (HbA1c) from preconception to the first half of pregnancy is associated with a lower risk of adverse outcomes for mother and child. Design, Setting, and Participants: This population-based cohort study was completed in all of Ontario, Canada, from 2007 to 2018. Included were births among women with prepregnancy diabetes whose HbA1c was measured within 90 days preconception and again from conception through 21 weeks completed gestation (early pregnancy to midpregnancy). Statistical analysis was performed from July to September 2020. Exposures: Net decrease in HbA1c from preconception to early pregnancy and midpregnancy. Main Outcomes and Measures: The main outcome was a congenital anomaly from birth to age 1 year. Other outcomes included preterm birth or perinatal mortality among offspring as well as severe maternal morbidity (SMM) or death among mothers. Adjusted relative risks (aRRs) were calculated per 0.5% absolute net decline in HbA1c from preconception up to early pregnancy and midpregnancy, adjusting for maternal age at conception, preconception HbA1c and hemoglobin concentration, and gestational age at HbA1c measurement. Results: A total of 3459 births were included, with a mean (SD) maternal age of 32.6 (5.0) years at conception. Overall, the mean (SD) HbA1c decreased from 7.2% (1.6%) preconception to 6.4% (1.1%) in early pregnancy to midpregnancy. There were 497 pregnancies (14.4%) with a congenital anomaly, with an aRR of 0.94 (95% CI, 0.89-0.98) per 0.5% net decrease in HbA1c, including for cardiac anomalies (237 infants; aRR, 0.89; 95% CI, 0.84-0.95). The risk was also reduced for preterm birth (847 events; aRR, 0.89; 95% CI, 0.86-0.91). SMM or death occurred among 191 women (5.5%), with an aRR of 0.90 (95% CI, 0.84-0.96) per 0.5% net decrease in HbA1c. Conclusions and Relevance: These findings suggest that women with prepregnancy diabetes who achieve a reduction in HbA1c may have improved perinatal and maternal outcomes. Further study is recommended to determine the best combination of factors, such as lifestyle changes and/or glucose-lowering medications, that can influence periconception HbA1c reduction.

Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial.

BACKGROUND: Birth defects are the main cause of fetal death, infant mortality and morbidity worldwide. However, the etiology of birth defects remains largely unknown. Maternal folate status during periconception plays an important role in organogenesis and folic acid supplement reduces the risk of neural tube defects, congenital heart diseases, and several other birth defects. This trial seeks to evaluate the effectiveness of folate-oriented tertiary interventions during periconception on the incidence of fetus and birth defects. METHODS: This is a single-blind, two-arm cluster randomized controlled trial in Shanghai, China. Eligible women from 22 clusters are recruited at pre-pregnancy physical examinations clinical settings. Compared to the routine perinatal care group (control arm), folate-oriented tertiary interventions will be provided to the intervention arm. The core interventions consist of assessments of folate status and metabolism, folate intake guidance, and re-evaluation of folate status to ensure red blood cell folate level above 400 ng/ml (906 nmol/L) before pregnancy. Screening and consulting of fetus and birth defects, and treatments of birth defects during pregnancy and afterward will be provided to both arms. The primary outcome is a composite incidence of fetus defects, stillbirth, and neonatal birth defects identified from the confirmation of pregnancy to 28 days after birth. Secondary outcomes include maternal and offspring adverse complications and cost-effectiveness of folate-oriented tertiary interventions. This protocol adheres to the SPIRIT Checklist. DISCUSSION: To achieve the recommended folate status before or during pregnancy is still a challenge worldwide. This community-based cluster-randomized controlled intervention trial will evaluate the effectiveness of a package of interventions aiming at achieving recommended maternal folate status covering pre- and during pregnancy in reducing fetus and birth defects. Our study has the potential to improve the community-based practice of reducing modifiable risk factors of disease and improving primary prevention of the defects in China. The procedures would formulate the policy on folic acid supplementation during periconception against birth defects in primary care settings. TRIAL REGISTRATION: Clinical Trial Registry, NCT03725878 . Prospectively registered on 31 October 2018.

Mechanisms of oocyte aneuploidy associated with advanced maternal age.

It is well established that maternal age is associated with a rapid decline in the production of healthy and high-quality oocytes resulting in reduced fertility in women older than 35 years of age. In particular, chromosome segregation errors during meiotic divisions are increasingly common and lead to the production of oocytes with an incorrect number of chromosomes, a condition known as aneuploidy. When an aneuploid oocyte is fertilized by a sperm it gives rise to an aneuploid embryo that, except in rare situations, will result in a spontaneous abortion. As females advance in age, they are at higher risk of infertility, miscarriage, or having a pregnancy affected by congenital birth defects such as Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Turner syndrome (monosomy X). Here, we review the potential molecular mechanisms associated with increased chromosome segregation errors during meiosis as a function of maternal age. Our review shows that multiple exogenous and endogenous factors contribute to the age-related increase in oocyte aneuploidy. Specifically, the weight of evidence indicates that recombination failure, cohesin deterioration, spindle assembly checkpoint (SAC) disregulation, abnormalities in post-translational modification of histones and tubulin, and mitochondrial dysfunction are the leading causes of oocyte aneuploidy associated with maternal aging. There is also growing evidence that dietary and other bioactive interventions may mitigate the effect of maternal aging on oocyte quality and oocyte aneuploidy, thereby improving fertility outcomes. Maternal age is a major concern for aneuploidy and genetic disorders in the offspring in the context of an increasing proportion of mothers having children at increasingly older ages. A better understanding of the mechanisms associated with maternal aging leading to aneuploidy and of intervention strategies that may mitigate these detrimental effects and reduce its occurrence are essential for preventing abnormal reproductive outcomes in the human population.

The effect of the National Birth Defects Intervention Project on the prevention of congenital disabilities among children in China: a natural experiment.

Most childhood disabilities are caused by congenital factors such as birth defects. The present study aims to evaluate the effect of periconceptional nutrition intervention on the prevention of congenital disability among Chinese children using the National Birth Defects Intervention Project as a natural experiment. We obtained individual-level data from the Second National Sample Survey on Disability, a nationally representative survey, and 110 365 children born between September 1999 and August 2003 were included for analysis. Difference-in-differences estimates of the project effects on congenital disability were captured by exploiting temporal variation in the timing of project exposure across four birth cohorts along with geographical variation in project category at the province level. The findings contribute to an emerging body of evidence showing that prenatal micronutrient intervention before and during early pregnancy could substantially reduce the risk of congenital disability in childhood (OR 0·73; 95 % CI 0·57, 0·94). The National Birth Defects Intervention Project improved the awareness of reproductive health and disability prevention in the population. It highlights the need for a potential policy change focusing on early-life health investment in China.

Maternal use of folic acid and multivitamin supplements and infant risk of birth defects in Norway, 1999-2013.

The association between folic acid supplementation and birth defects other than neural tube defects (NTD) remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999-2013. We used the European Surveillance of Congenital Anomalies (EUROCAT) classification system to define eleven organ-specific major birth defect groups (nervous system, eye, ear-face-neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999-2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared with infants of non-users, the adjusted relative risk (aRR) was 0·94 (95 % CI 0·91, 0·98) for total birth defects (n 18 382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0·58; 95 % CI 0·42, 0·80, n 377), genital organ defects (aRR 0·81; 95 % CI 0·72, 0·91, n 2299) and limb defects (aRR 0·81; 95 % CI 0·74, 0·90, n 3409). Protective associations were also suggested for NTD, respiratory system defects and digestive system defects although CI included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear-face-neck, heart or oral clefts were not observed.

A importância do metilfolato na prevenção dos defeitos abertos do tubo neural / The importance of methylfolate in the prevention of open neural tube defects

A suplementação periconcepcional com vitamina B9 ou folato é considerada medida efetiva para diminuir a ocorrência e a recorrência de defeitos do tubo neural (DTNs). É recomendada para todas as mulheres que planejam gravidez ou que possam engravidar. O ácido fólico necessita passar por processos enzimáticos necessários à metabolização para a sua forma ativa L-5-metiltetrahidrofolato (L-metilfolato, 5-MTHF) envolvida nos processos biológicos e que circula no plasma. A enzima metilenotetrahidrofolato redutase (MTHFR) é de fundamental importância para fornecer 5-MTHF, forma biologicamente ativa. A presença de polimorfismo do gene da MTHF-redutase promove menor atividade enzimática e menor produção de L-metilfolato.(AU)