Defying birth defects through diet?

The risk of certain birth defects can be modified by maternal diet. A high-fat maternal mouse diet has recently been reported to substantially increase the penetrance of birth defects known to be associated with a deficiency of transcription factor Cited2 as well as induce cleft palate. These effects were associated with a more than twofold reduction in embryonic expression of Pitx2c. This investigation suggests the need to further explore this provocative gene-diet interaction in human studies

Folic Acid Food Fortification—Its History, Effect, Concerns, and Future Directions

Periconceptional intake of folic acid is known to reduce a woman’s risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004

The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age

Factors affecting maternal participation in the genetic component of the National Birth Defects Prevention Study—United States, 1997–2007

As epidemiological studies expand to examine gene–environment interaction effects, it is important to identify factors associated with participation in genetic studies. The National Birth Defects Prevention Study is a multisite case–control study designed to investigate environmental and genetic risk factors for major birth defects. The National Birth Defects Prevention Study includes maternal telephone interviews and mailed buccal cell self-collection kits. Because subjects can participate in the interview, independent of buccal cell collection, detailed analysis of factors associated with participation in buccal cell collection was possible

Epigenome-wide association studies of prenatal maternal mental health and infant epigenetic profiles: a systematic review

Abstract Prenatal stress and poor maternal mental health are associated with adverse offspring outcomes; however, the biological mechanisms are unknown. Epigenetic modification has linked maternal health with offspring development. Epigenome-wide association studies (EWAS) have examined offspring DNA methylation profiles for association with prenatal maternal mental health to elucidate mechanisms of these complex relationships. The objective of this study is to provide a comprehensive, systematic review of EWASs of infant epigenetic profiles and prenatal maternal anxiety, depression, or depression treatment. We conducted a systematic literature search following PRISMA guidelines for EWAS studies between prenatal maternal mental health and infant epigenetics through May 22, 2023. Of 645 identified articles, 20 fulfilled inclusion criteria. We assessed replication of CpG sites among studies, conducted gene enrichment analysis, and evaluated the articles for quality and risk of bias. We found one repeated CpG site among the maternal depression studies; however, nine pairs of overlapping differentially methylatd regions were reported in at least two maternal depression studies. Gene enrichment analysis found significant pathways for maternal depression but not for any other maternal mental health category. We found evidence that these EWAS present a medium to high risk of bias. Exposure to prenatal maternal depression and anxiety or treatment for such was not consistently associated with epigenetic changes in infants in this systematic review and meta-analysis. Small sample size, potential bias due to exposure misclassification and statistical challenges are critical to address in future efforts to explore epigenetic modification as a potential mechanism by which prenatal exposure to maternal mental health disorders leads to adverse infant outcomes

Folate-related gene variants in Irish families affected by neural tube defects

Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (risk genotypes) and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p=0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms

Impact of Voluntary Folic Acid Fortification of Corn Masa Flour on RBC Folate Concentrations in the U.S. (NHANES 2011–2018)

Surveillance data have highlighted continued disparities in neural tube defects (NTDs) by race-ethnicity in the United States. Starting in 2016, the Food and Drug Administration (FDA) authorized voluntary folic acid fortification of corn masa flour to reduce the risk of neural tube defects (NTDs) among infants of Hispanic women of reproductive age. To assess the impact of voluntary corn masa fortification, cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018 for Hispanic women of reproductive age with available red blood cell (RBC) folate concentrations were analyzed, with additional analyses conducted among Hispanic women whose sole source of folic acid intake was fortified foods (enriched cereal grain products (ECGP) only), excluding ready-to-eat cereals and supplements. RBC folate concentration (adjusted geometric mean) among Hispanic women of reproductive age did not differ between 2011–2016 and 2017–2018, though RBC folate concentration increased significantly among lesser acculturated Hispanic women consuming ECGP only. Concentrations of RBC folate for those born outside the U.S and residing in the U.S <15 years increased from 894 nmol/L (95% CI: 844–946) in 2011–2016 to 1018 nmol/L (95% CI: 982–1162; p < 0.001) in 2017–2018. Primarily Spanish-speaking Hispanic women of reproductive age who only consumed ECGP saw an increase from 941 nmol/L (95% CI: 895–990) in 2011–2016 to 1034 nmol/L (95% CI: 966–1107; p = 0.03) in 2017–2018. By subpopulation, we observed no significant changes in the proportion at risk of NTDs (<748 nmol/L) and no changes in the model-based estimated NTD rates following voluntary corn masa fortification. This analysis suggests that there is a remaining risk among Hispanics for folate sensitive NTDs, though continued monitoring of folate status in future NHANES data cycles will help inform the long-term efficacy of voluntary fortification of corn masa flour