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.

Preventing Hypothermia in Newborns With Congenital Anomalies in the Delivery Room.

BACKGROUND: Thermoregulation interventions in the delivery room have historically focused on preterm infants and studies often exclude term infants or those infants with known congenital anomalies. PURPOSE: The purpose of this quality improvement project was to reduce the rate of admission hypothermia in neonates of all gestational ages born with congenital anomalies and admitted to the intensive care unit (ICU). METHODS: Utilizing the Institute for Healthcare Improvement model for improvement, implementation of plan, do study, act cycles focused on standardizing temperatures of the delivery room and resuscitation bed, recommendations for temperature monitoring, trialing polyethylene lined hats, and implementing a delivery room thermoregulation checklist. RESULTS: Overall, the mean rate of neonates admitted to the ICU hypothermic (<36.5°C) decreased from 27% to 9% over an 8-month period. IMPLICATIONS FOR PRACTICE AND RESEARCH: The interventions significantly reduced the number of neonates admitted to the ICU with hypothermia. Implementation of thermoregulation bundles should apply to all neonates with congenital anomalies to decrease risks associated with hypothermia.

[Call for attention to the prevention of perinatal death attributed to birth defect].

Birth defect and perinatal death are major public issues threatening the health of women and children in China. However, perinatal death attributed to birth defects has not yet received sufficient attention. To minimize the occurrence of perinatal death caused by birth defects, this review article deeply analyzed the current status of epidemiology, clinical, and basic research on perinatal death attributed to birth defects both domestically and internationally, and proposed to encourage the conduct of national research on perinatal causes. We should also pay attention to the application of the perinatal cause of death classification system, and focus on accurate diagnosis and the three-level prevention and control of perinatal death attributed to birth defect.

[Prenatal screening and prenatal diagnosis clinical laboratory diagnostic pathway].

Congenital defects and genetic diseases in the fetus are the focus of prenatal screening and prenatal diagnosis. Obstetrics and gynecology, pediatrics, medical imaging (ultrasound and magnetic resonance imaging), clinical laboratory, pathology, and other disciplines are mostly involved in this multidisciplinary work on maternal and infant health care, which aims to prevent birth defects in strict accordance with laws, regulations, and pertinent industry standards, such as the Notice of the National Health Commission on Issuing the Basic Standards for Prenatal Screening Technical Medical Institutions and the Basic Standards for Prenatal Diagnosis Technical Medical Institutions (Guowei Maternal and Child Letter [2019] No. 297). To further support the implementation of prenatal screening and diagnosis work and streamline workflow, this study has compiled the timing, inspection, and testing procedures of various projects in each link from the standpoint of the disease clinical laboratory diagnostic pathway. This approach improves communication amongst various disciplines in prenatal screening and diagnosis work and offers clinical service quality, and it also helps improve the standard of the birth population and prevent and controll severe birth defects.

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.

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.

NAD Deficiency, Congenital Malformations, and Niacin Supplementation.

BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system. RESULTS: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).

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.

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.

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.

The rise of the genetic counseling profession in China.

The rapid development of genetic and genomic technologies has greatly boosted medical genetic researches and clinical services worldwide. Since last century, genetic counseling in the United States has helped individuals and families understand, accept, and cope with their genetic issues. This fledging profession, which is in essence a branch of social work, emerged in China relatively late but has rapidly grown over the last few years. We believe that genetic counseling will continue to play a pivotal role in building communication channels between medical doctors and their patients, the government and the general public, and social organizations and their customers in China. The growth of genetic counseling aims to enable patients and family members to make informed decision which in turn will lead to the reduction of the birth prevalence of severe congenital anomalies and genetic disorders.

Congenital anomalies in the offspring of occupationally exposed mothers: a systematic review and meta-analysis of studies using expert assessment for occupational exposures.

STUDY QUESTION: Is there an association between maternal occupational exposure to solvents, pesticides and metals as assessed by expert-based assessment and congenital anomalies in the offspring? SUMMARY ANSWER: There is an association between maternal occupational exposure to solvents and congenital anomalies in the offspring, including neural tube defects, congenital heart defects and orofacial clefts. WHAT IS KNOWN ALREADY: One important environmental risk factor for development of congenital anomalies is maternal occupational exposure to chemicals in the workplace prior to and during pregnancy. A number of studies have assessed the association with often conflicting results, possibly due to different occupational exposure assessing methods. STUDY DESIGN, SIZE, DURATION: For this systematic review with meta-analysis, the search terms included maternal occupation, exposure, congenital anomalies and offspring. Electronic databases MEDLINE and EMBASE were searched for English studies up to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two reviewers independently screened all citations identified by the search. Case-control studies and cohort studies were included if (I) they reported on the association between maternal occupational exposure to solvents, pesticides or metals and congenital anomalies, and (II) assessment of occupational exposure was performed by experts. Data on study characteristics, confounders and odds ratios (ORs) were extracted from the included studies for four subgroups of congenital anomalies. Methodological quality was assessed using the Newcastle-Ottawa Scale. In the meta-analysis, random effects models were used to pool estimates. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 2806 titles and abstracts and 176 full text papers were screened. Finally, 28 studies met the selection criteria, and 27 studies could be included in the meta-analysis. Our meta-analysis showed that maternal occupational exposure to solvents was associated with neural tube defects (OR: 1.51, 95%CI: 1.09-2.09) and congenital heart defects (OR: 1.31, 95%CI:1.06-1.63) in the offspring. Also maternal occupational exposure to glycol ethers, a subgroup of solvents, was associated with neural tube defects (OR: 1.93, 95%CI: 1.17-3.18) and orofacial clefts (OR: 1.95, 95%CI: 1.38-2.75) in the offspring. Only one study investigated the association between maternal occupational exposure to solvents and hypospadias and found an association (OR: 3.63, 95%CI: 1.94-7.17). Results of the included studies were consistent. In our meta-analysis, we found no associations between occupational exposure to pesticides or metals and congenital anomalies in the offspring. LIMITATIONS, REASONS FOR CAUTION: A limited number of studies was included, which made it impossible to calculate pooled estimates for all congenital anomalies, analyse individual chemicals or calculate exposure-response relations. Bias could have been introduced because not all included studies corrected for potentially confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Employers and female employees should be aware of the possible teratogenic effects of solvent exposure at the workplace. Therefore, is it important that clinicians and occupational health specialist provide women with preconception advice on occupational solvent exposure, to reduce the congenital anomaly risk. STUDY FUNDING/COMPETING INTEREST(S): NSp was paid by the Graduate School of Medical Sciences (MD/PhD program), UMCG, Groningen, the Netherlands. EUROCAT Northern Netherlands is funded by the Dutch Ministry of Health, Welfare and Sports. There are no competing interests. REGISTRATION NUMBER: CRD42017053943.

Moderate maternal folic acid supplementation ameliorates adverse embryonic and epigenetic outcomes associated with assisted reproduction in a mouse model.

STUDY QUESTION: Could clinically-relevant moderate and/or high dose maternal folic acid supplementation prevent aberrant developmental and epigenetic outcomes associated with assisted reproductive technologies (ART)? SUMMARY ANSWER: Our results demonstrate dose-dependent and sex-specific effects of folic acid supplementation in ART and provide evidence that moderate dose supplements may be optimal for both sexes. WHAT IS KNOWN ALREADY: Children conceived using ART are at an increased risk for growth and genomic imprinting disorders, often associated with DNA methylation defects. Folic acid supplementation is recommended during pregnancy to prevent adverse offspring outcomes; however, the effects of folic acid supplementation in ART remain unclear. STUDY DESIGN, SIZE, DURATION: Outbred female mice were fed three folic acid-supplemented diets, control (rodent daily recommended intake or DRI; CD), moderate (4-fold DRI; 4FASD) or high (10-fold DRI; 10FASD) dose, for six weeks prior to ART and throughout gestation. Mouse ART involved a combination of superovulation, in vitro fertilisation, embryo culture and embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: Midgestation embryos and placentas (n = 74-99/group) were collected; embryos were assessed for developmental delay and gross morphological abnormalities and embryos and placentas were examined for epigenetic defects. We assessed methylation at four imprinted genes (Snrpn, Kcnq1ot1, Peg1 and H19) in matched midgestation embryos and placentas (n = 31-32/group) using bisulfite pyrosequencing. In addition, we examined genome-wide DNA methylation patterns in placentas (n = 6 normal placentas per sex/group) and embryos (n = 6 normal female embryos/group; n = 3 delayed female embryos/group) using reduced representation bisulfite sequencing (RRBS). MAIN RESULTS AND THE ROLE OF CHANCE: Moderate, but not high dose supplementation, was associated with a decrease in the proportion of developmentally delayed embryos. Although moderate dose folic acid supplementation reduced DNA methylation variance at certain imprinted genes in embryonic and placental tissues, high dose supplementation exacerbated the negative effects of ART at imprinted loci. Furthermore, folic acid supplements resolved female-biased aberrant imprinted gene methylation. Supplementation was more effective at correcting ART-induced genome-wide methylation defects in male versus female placentas; however, folic acid supplementation also led to additional methylation perturbations which were more pronounced in males. LARGE-SCALE DATA: The RRBS data from this study have been submitted to the NCBI Gene Expression Omnibus under the accession number GSE123143. LIMITATIONS REASONS FOR CAUTION: Although the combination of mouse ART utilised in this study consisted of techniques commonly used in human fertility clinics, there may be species differences. Therefore, human studies, designed to determine the optimal levels of folic acid supplementation for ART pregnancies, and taking into account foetal sex, are warranted. WIDER IMPLICATIONS OF THE FINDINGS: Taken together, our findings support moderation in the dose of folic acid supplements taken during ART. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Canadian Institutes of Health Research (FDN-148425). The authors declare no conflict of interest.

Building New York State Centers of Excellence in Children's Environmental Health: A Replicable Model in a Time of Uncertainty.

Public health programs may be seriously affected in periods of federal retrenchment. During these times, state-based strategies provide an alternate pathway for advancing public health.A 12-year campaign to secure state support for a network of Centers of Excellence in Children's Environmental Health (CEH) promoting health of children across New York State is described. It was driven by rising rates of asthma, birth defects, developmental disorders, and other noncommunicable diseases in children; growing evidence associating hazardous environmental exposures with these conditions; and recognition that federal resources in CEH are insufficient.Critical campaign elements were (1) formation of a statewide coalition of academic health centers, health care providers, public health officials, community advocates, and other stakeholders; (2) bipartisan collaborations with legislative champions and government leaders; (3) assessment of the burden of developmental disorders and noncommunicable diseases associated with environmental exposures among children; (4) maps documenting the presence of environmental hazards in every county statewide; (5) iterative charting of a changing political landscape; and (6) persistence. The 2017 award of a 5-year, $10 million contract to establish Centers of Excellence in CEH demonstrates the value of this statewide strategy.

Maternal exposure to outdoor air pollution and congenital limb deficiencies in the National Birth Defects Prevention Study.

BACKGROUND: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor. AIM: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs. METHODS: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter <2.5 µm [PM2.5], particulate matter <10 µm [PM10], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], and ozone [O3]) were averaged over gestational weeks 2-8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor. RESULTS: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM10, PM2.5, and O3. However, weekly averages of the daily average NO2 and SO2, and daily max NO2, SO2, and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO2 and O3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02-1.30); but aORs for SO2 and NO2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use. CONCLUSION: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO2, and NO2, though replication through further epidemiologic research is warranted.

Fish consumption prior to pregnancy and pregnancy outcomes in the National Birth Defects Prevention Study, 1997-2011.

OBJECTIVE: To evaluate the relationships between maternal fish consumption and pregnancy outcomes in a large, population-based sample of women in the USA. DESIGN: We collected average fish consumption prior to pregnancy using a modified version of the semi-quantitative Willett FFQ. We estimated adjusted OR (aOR) and 95 % CI for associations between different levels of fish consumption and preterm birth (<37 weeks), early preterm birth (<32 and <35 weeks) and small-for-gestational-age infants (SGA; <10th percentile). SETTING: The National Birth Defects Prevention Study (NBDPS). SUBJECTS: Control mother-infant pairs with estimated delivery dates between 1997 and 2011 (n 10 919). RESULTS: No significant associations were observed between fish consumption and preterm birth or early preterm birth (aOR = 0·7-1·0 and 0·7-0·9, respectively). The odds of having an SGA infant were elevated (aOR = 2·1; 95 % CI 1·2, 3·4) among women with daily fish consumption compared with women consuming fish less than once per month. No associations were observed between other levels of fish consumption and SGA (aOR = 0·8-1·0). CONCLUSIONS: High intake of fish was associated with twofold higher odds of having an SGA infant, while moderate fish consumption prior to pregnancy was not associated with preterm or SGA. Our study, like many other studies in this area, lacked information regarding preparation methods and the specific types of fish consumed. Future studies should incorporate information on nutrient and contaminant contents, preparation methods and biomarkers to assess these relationships.

Progress in Development of Interventions to Prevent Birth Defects in Diabetic Pregnancies.

Diabetic embryopathy is a diabetic complication, in which maternal hyperglycemia in early pregnancy causes birth defects in newborn infants. Under maternal diabetic conditions, hyperglycemia disturbs intracellular molecular activities and organelles functions. These include protein misfolding in the endoplasmic reticulum (ER), overproduction of reactive oxygen species (ROS) in mitochondria, and high levels of nitric oxide (NO). The resultant ER, oxidative, and nitrosative stresses activate apoptotic machinery to cause cell death in the embryo, ultimately resulting in developmental malformations. Based on the basic research data, efforts have been made to develop interventional strategies to alleviate the stress conditions and to reduce embryonic malformations. One of the challenges in birth defect prevention is to identify effective and safe agents to be used in pregnancy. One approach is to search and characterize naturally occurring phytochemicals, including flavonoids, curcuminoids and stilbenoids, for use in prevention of diabetic embryopathy.

Development of an integrated, district-wide approach to pre-pregnancy management for women with pre-existing diabetes in a multi-ethnic population.

BACKGROUND: Poor diabetes management prior to conception, results in increased rates of fetal malformations and other adverse pregnancy outcomes. We describe the development of an integrated, pre-pregnancy management strategy to improve pregnancy outcomes among women of reproductive age with diabetes in a multi-ethnic district. METHODS: The strategy included (i) a narrative literature review of contraception and pre-pregnancy interventions for women with diabetes and development of a draft plan; (ii) a chart review of pregnancy outcomes (e.g. congenital malformations, neonatal hypoglycaemia and caesarean sections) among women with type 1 diabetes (T1D) (n = 53) and type 2 diabetes (T2D) (n = 46) between 2010 and 2015 (iii) interview surveys of women with T1D and T2D (n = 15), and local health care professionals (n = 13); (iv) two focus groups (n = 4) and one-to-one interviews with women with T1D and T2D from an Australian background (n = 5), women with T2D from cultural and linguistically diverse (CALD) (n = 7) and indigenous backgrounds (n = 1) and partners of CALD women (n = 3); and (v) two group meetings, one comprising predominantly primary care, and another comprising district-wide multidisciplinary inter-sectoral professionals, where components of the intervention strategy were finalised using a Delphi approach for development of the final plan. RESULTS: Our literature review showed that a range of interventions, particularly multifaceted educational programs for women and healthcare professionals, significantly increased contraception uptake, and reduced adverse outcomes of pregnancy (e.g. malformations and stillbirth). Our chart-review showed that local rates of adverse pregnancy outcomes were similarly poor among women with both T1D and T2D (e.g. major congenital malformations [9.1% vs 8.9%] and macrosomia [34.7% vs 24.4%]). Challenges included lack of knowledge among women and healthcare professionals relating to diabetes management and limited access to specialist pre-pregnancy care. Group meetings led to a consensus to develop a district-wide approach including healthcare professional and patient education and a structured approach to identification and optimisation of self-management, including contraception, in women of reproductive age with diabetes. CONCLUSIONS: Sufficient evidence exists for consensus on a district-wide strategy to improve pre-pregnancy management among women with pre-existing diabetes.

47-Fold rise of diabetes in childbearing age Chilean women: Markov model and cost-effectiveness of prevention of birth defects.

AIM: Prevalence of type 2 diabetes mellitus (T2DM) during childbearing age in Chile had a 47-fold rise in 7 years, reaching 120 844 women, half of which are unaware of their condition. We aimed to project pregnancies and births among Chilean women of childbearing age (WCBA) with T2DM and report the incidence of birth defects and the associated years of life lost and lifetime costs. METHODS: Markov model of cohort of WCBA with T2DM (WCBA-DM) with a 20-year time horizon (2018-2037), using data from previous studies. Two scenarios were assessed: scenario A: no universal detection of T2DM and scenario B: universal screening of T2DM using glycosylated hemoglobin levels. Both lifetime costs and disability-adjusted life years (DALY) were calculated with a 5% discount rate (US$ of 2017). RESULTS: In scenario A, 12 163 infants with birth defects could be born among the analyzed cohort, resulting in 243 260 years of life lost, 296 652 DALY and in lifetime costs of US$ 1 957 657 966. In scenario B, the first three figures could be reduced by 70.4% to 3599 infants with birth defects, 71 980 years of life lost and 87 794 DALY. Due to the addition of diabetes screening and new patient costs to scenario B, there would be a lesser reduction (67.3%) in total lifetime costs, to US$ 640 669 296. CONCLUSION: Screening of diabetes in WCBA would yield a 20-year reduction of 70.4% in the number of infants with birth defects, years of life lost and DALY. Total lifetime costs could be reduced by 67.3%.