Risk of Excess Maternal Folic Acid Supplementation in Offspring.

Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.

Update on the impact of voluntary folic acid fortification of corn masa flour on red blood cell folate concentrations-National Health and Nutrition Examination Survey, 2011-March 2020.

BACKGROUND: Folic acid is a micronutrient that is effective at preventing neural tube defects (NTDs). In 2016, the FDA authorized the voluntary fortification of corn masa flour (CMF) with folic acid to reduce disparities in NTDs among infants of women who do not regularly consume other fortified cereal grains, in particular Hispanic women of reproductive age (WRA). METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020 assessing the impact of voluntary fortification of CMF on the folate status of Hispanic WRA. We analyzed folic acid usual intake and red blood cell (RBC) folate concentrations among non-pregnant, non-lactating Hispanic WRA, comparing pre-fortification (2011-2016) to post-fortification (2017-March 2020) data. RBC folate concentrations were used to create model-based estimation of NTD rates. RESULTS: The proportion of Hispanic WRA with folic acid usual intakes <400 µg/d did not change (2011-2016: 86.1% [95% Confidence Interval, CI: 83.7-88.5]; 2017-March 2020: 87.8% [95% CI: 84.8-90.7]; p = .38) nor did the proportion of Hispanic WRA with RBC folate below optimal concentrations (<748 nmol/L, 2011-2016: 16.0% [95% CI: 13.7-18.2]; 2017-March 2020: 18.1% [95% CI: 12.1-24.0]; p = 0.49). Model-based estimates of NTD rates suggest further improvements in the folate status of Hispanic WRA might prevent an additional 157 (95% Uncertainty Interval: 0, 288) NTDs/year. CONCLUSIONS: Voluntary fortification of CMF with folic acid has yet to have a significant impact on the folate status of WRA. Continued monitoring and further research into factors such as fortified product availability, community knowledge, and awareness of folic acid benefits would inform and improve future public health interventions.

Preconception folic acid supplementation for the prevention of birth defects: a prospective, population-based cohort study in mainland China.

BACKGROUND: Folic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting. METHODS: This prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses. RESULTS: Complete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66-0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39-0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease. CONCLUSION: This retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.

Periconceptional folic acid usage and its associated factors in eastern Sudan: A cross-sectional study.

BACKGROUND: Several countries poorly adhere to the World Health Organization's recommendation of folic acid supplementation in the periconceptional period, especially in limited-resource settings. OBJECTIVE: The objective of this study was to investigate the prevalence of and the factors associated with folic acid usage in the periconceptional period among pregnant women at Gadarif Maternity Hospital in eastern Sudan. STUDY DESIGN: This is a cross-sectional study. METHODS: This study was conducted in eastern Sudan from April to September 2022. A total of 720 pregnant women in their first trimester were enrolled. The sociodemographic characteristics and clinical and obstetrical data of pregnant women in their first trimester were assessed using a face-to-face questionnaire. In addition, multivariate regression analysis was performed. RESULTS: In this study, the median (interquartile range) of the age and gravidity of the enrolled women was 26.3 (24.14-29.52) years and 2 (1-4), respectively. Of these 720 women, 423 (58.8%) used folic acid during the periconceptional period, while 27 (3.7%) women used folic acid in the preconceptional period. None of the investigated factors (age, residence, education, employment, body mass index, or gravidity) were associated with periconceptional use of folic acid. CONCLUSION: The study revealed a low prevalence of folic acid usage in preconceptional period among pregnant women in eastern Sudan. Additional efforts are needed to promote folic acid usage in the preconceptional period as well as in the first trimester.

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study.

OBJECTIVES: To determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000-2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour to be monitored. DESIGN: Population-based, observational study using congenital anomaly (CA) registration data for England curated by the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). SETTING: Regions of England with active registration in the time period. PARTICIPANTS: Babies that were liveborn or stillborn and pregnancies that resulted in a termination of pregnancy or a late miscarriage (20-23 weeks' gestation) with an NTD. MAIN OUTCOME MEASURES: Total birth prevalence of anencephaly, spina bifida and all NTDs in England. Poisson regression analysis was used to evaluate time trends with regional register as a random effect. The progress of national registration across England was assessed. RESULTS: There were 4541 NTD pregnancies out of 3 637 842 births in England; 1982 anencephaly and 2127 spina bifida. NTD prevalence was 12.5 (95% CI 12.1 to 12.9) per 10 000 total births. NTD prevalence per 10 000 total births was significantly higher in 2015-2019 (13.6, 95% CI 12.9 to 14.4) compared with 2010-2014 (12.1, 95% CI 11.7 to 12.5). An increasing trend in NTDs overall was detected (incidence rate ratio (IRR) 1.01, 1.00 to 1.02), although further analysis determined this effect was confined to 2015-2019 (compared against 2000-2004, IRR 1.14, 1.04 to 1.24). The birth prevalence of anencephaly reflected this pattern. The prevalence of spina bifida remained relatively stable over time. CONCLUSIONS: Baseline NTD prevalence for England has been established. National and standardised CA registration is in place, facilitating the systematic and consistent monitoring of pre-fortification and post-fortification NTD trends and evaluating the impact of fortification on NTD prevalence.

Scientific impact of the National Birth Defects Prevention Network multistate collaborative publications.

BACKGROUND: Given the lack of a national, population-based birth defects surveillance program in the United States, the National Birth Defects Prevention Network (NBDPN) has facilitated important studies on surveillance, research, and prevention of major birth defects. We sought to summarize NBDPN peer-reviewed publications and their impact. METHODS: We obtained and reviewed a curated list of 49 NBDPN multistate collaborative publications during 2000-2022, as of December 31, 2022. Each publication was reviewed and classified by type (e.g., risk factor association analysis). Key characteristics of study populations and analytic approaches used, along with publication impact (e.g., number of citations), were tabulated. RESULTS: NBDPN publications focused on prevalence estimates (N = 17), surveillance methods (N = 11), risk factor associations (N = 10), mortality and other outcomes among affected individuals (N = 6), and descriptive epidemiology of various birth defects (N = 5). The most cited publications were those that reported on prevalence estimates for a spectrum of defects and those that assessed changes in neural tube defects (NTD) prevalence following mandatory folic acid fortification in the United States. CONCLUSIONS: Results from multistate NBDPN publications have provided critical information not available through other sources, including US prevalence estimates of major birth defects, folic acid fortification and NTD prevention, and improved understanding of defect trends and surveillance efforts. Until a national birth defects surveillance program is established in the United States, NBDPN collaborative publications remain an important resource for investigating birth defects and informing decisions related to health services planning of secondary disabilities prevention and care.

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress.

Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure, primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates Src/PI3K/ERK signaling, thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.

Analysis of Gut Characteristics and Microbiota Changes with Maternal Supplementation in a Neural Tube Defect Mouse Model.

Adequate nutrient supply is crucial for the proper development of the embryo. Although nutrient supply is determined by maternal diet, the gut microbiota also influences nutrient availability. While currently there is no cure for neural tube defects (NTDs), their prevention is largely amenable to maternal folic acid and inositol supplementation. The gut microbiota also contributes to the production of these nutrients, which are absorbed by the host, but its role in this context remains largely unexplored. In this study, we performed a functional and morphological analysis of the intestinal tract of loop-tail mice (Vangl2 mutants), a mouse model of folate/inositol-resistant NTDs. In addition, we investigated the changes in gut microbiota using 16S rRNA gene sequencing regarding (1) the host genotype; (2) the sample source for metagenomics analysis; (3) the pregnancy status in the gestational window of neural tube closure; (4) folic acid and (5) D-chiro-inositol supplementation. We observed that Vangl2+/Lp mice showed no apparent changes in gastrointestinal transit time or fecal output, yet exhibited increased intestinal length and cecal weight and gut dysbiosis. Moreover, our results showed that the mice supplemented with folic acid and D-chiro-inositol had significant changes in their microbiota composition, which are changes that could have implications for nutrient absorption.

Determinants of neural tube defects among women who gave birth in hospitals in Eastern Ethiopia: evidence from a matched case control study.

INTRODUCTION: Neural tube defects (NTDs) are severe birth defects caused by nutritional, genetic or environmental factors. Because NTDs continue to have a significant health and economic impact on children and community at large, it is crucial to investigate potential risk factors in order to develop novel approaches to NTDs prevention. Determinants for the development of NTDs differ by country, region as well as within the country. The objective of this study was to identify the determinants of NTDs among newborns delivered in three hospitals found in eastern Ethiopia. METHODS: A hospital-based matched case-control study was conducted among 138 cases and 138 control women who delivered in three teaching hospitals in Eastern Ethiopia in 2021. Data were collected using a structured and pre-tested interviewer-administered questionnaire. Cases were mothers who delivered a neonate with any type of NTDs regardless of gestational age or fetal viability, whereas controls were mothers who delivered an apparently healthy newborn. Chi-square was used to assess the significant difference between the two groups. Conditional logistic regression model was used to generate adjusted odds ratio with its corresponding 95% confidence intervals and compare the two groups. RESULTS: Anencephaly (51.4%) and spinal bifida (34.1%) were the most frequently observed NTDs. None of study participants took preconception folic acid supplementation. Being a non-formal mothers (AOR = 0.34, 95% CI: 0.12-0.92, P = 0.034), rural residence, (AOR = 3.4, 95% CI: 1.18-9.78, P = 0.023), history of spontaneous abortion (AOR = 2.95, 95% CI: 1.15-7.55, P = 0.023), having severe anemia (AOR = 3.4, 95% CI: 1.17-9.87, P = 0.024), history of fever or cold (AOR = 2.75; 95% CI: 1.05-7.15, P = 0.038), and an exposure to various agro-chemicals (AOR = 3.39, 95% CI: 1.11-10.3, P = 0.032) were independent determinants of NTDs. CONCLUSION AND RECOMMENDATION: In this study, NTDs were associated to several determinant factors in the area, including residential area, history of spontaneous abortion, severe anemia, fever/cold, antibiotic use before or during early pregnancy, and exposure to agrochemicals. Addressing the identified determinants is critical in averting the incidence of NTDs in the study area. Moreover, more research is needed to investigate women's dietary practices as well as the practice of preconception folic acid supplementation for pregnant women in Ethiopia's current health care system.

Inequities in pre-pregnancy folic acid use in Central and South Auckland: secondary analysis from a postpartum contraception survey.

Introduction In Aotearoa New Zealand (NZ), there is inequity in rates of neural tube defects (NTDs). Among Maaori, NTD occur in 4.58/10 000 live births, and for Pacific peoples, it is 4.09/10 000 live births; this is compared to 2.81/10 000 live births for non-Maaori, non-Pacific peoples. Aim To describe self-reported pre-pregnancy folic acid supplementation and to determine the association between pregnancy intendedness, ethnicity, parity, maternal age, care provider and pre-pregnancy folic acid supplementation. Methods Secondary analysis of postpartum survey data collected at Te Whatu Ora Te Toka Tumai and Counties Manukau birthing facilities in 2020 was conducted. Descriptive analyses explored pregnancy intendedness and self-reported folic acid use by demographic variables. Multivariable logistic regression explored independent associations between demographic variables and folic acid use among intended pregnancies. Results In total, 398 participants completed the survey. The response rate was (140/149) 94% at Counties Manukau and (258/315) 82% at Te Toka Tumai. Pre-pregnancy supplementation was reported by 182 of 398 participants (46%). Use was higher among those who intended their pregnancy (151/262, 58%) compared to those who were 'pregnancy ambivalent' (9/33, 27%) or did not intend to become pregnant (22/103, 21%). Factors independently associated with supplementation among intended pregnancies included: 'Other ethnicity' (European, Middle Eastern, Latin American, African) compared to Maaori (aOR 5.3 (95% CI 1.3, 21.8)), age ≥30 years compared to Discussion Low rates of pre-pregnancy folic acid supplementation exist in Auckland with significant ethnic disparity. Mandatory fortification of non-organic wheat is important, but supplementation is still recommended to maximally reduce risk.

Birth prevalence and risk factors of neural tube defects in Ethiopia: a systematic review and meta-analysis.

OBJECTIVE: This study aims to estimate the prevalence of neural tube defects (NTDs) and to identify potential risk factors in the Ethiopian context. STUDY DESIGN: Systematic review and meta-analysis. STUDY PARTICIPANTS: A total of 611 064 participants were included in the review obtained from 42 studies. METHODS: PubMed (Medline), Embase and Cochrane Library databases in combination with other potential sources of literature were systematically searched, whereby studies conducted between January 2010 and December 2022 were targeted in the review process. All observational studies were included and heterogeneity between studies was verified using Cochrane Q test statistics and I2 test statistics. Small study effects were checked using Egger's statistical test at a 5% significance level. RESULT: The pooled prevalence of all NTDs per 10 000 births in Ethiopia was 71.48 (95% CI 57.80 to 86.58). The between-study heterogeneity was high (I2= 97.49%, p<0.0001). Birth prevalence of spina bifida (33.99 per 10 000) was higher than anencephaly (23.70 per 10 000), and encephalocele (4.22 per 10 000). Unbooked antenatal care (AOR 2.26, 95% CI (1.30 to 3.94)), preconception intake of folic acid (AOR 0.41, 95% CI (0.26 to 0.66)), having chronic medical illness (AOR 2.06, 95% CI (1.42 to 2.99)), drinking alcohol (AOR 2.70, 95% CI (1.89 to 3.85)), smoking cigarette (AOR 2.49, 95% CI (1.51 to 4.11)), chewing khat (AOR 3.30, 95% CI (1.88 to 5.80)), exposure to pesticides (AOR 3.87, 95% CI (2.63 to 5.71)), maternal age ≥35 (AOR 1.90, 95% CI (1.13 to 3.25)), maternal low educational status (AOR 1.60, 95% CI (1.13 to 2.24)), residing in urban areas (AOR 0.75, 95% CI (0.58 to 0.97))and family history of NTDs (AOR 2.51, 95% CI (1.36 to 4.62)) were associated with NTD cases. CONCLUSION: The prevalence of NTDs in Ethiopia is seven times as high as in other Western countries where prevention measures are put in place. Heredity, maternal and environmental factors are associated with a high prevalence of NTDs. Mandatory fortification of staple food with folic acid should be taken as a priority intervention to curb the burden of NTDs. To smoothen and overlook the pace of implementation of mass fortification, screening, and monitoring surveillance systems should be in place along with awareness-raising measures. PROSPERO REGISTRATION NUMBER: CRD42023413490.

[Top 4 Research Studies of the month for Italian Primary Care Physicians: November 2023.] / La Top 4 di novembre 2023. Gli studi clinici che vale la pena conoscere se lavori nelle cure primarie in Italia.

This monthly article provides a collection of summaries of the most relevant studies identified as POEMs (patient-oriented evidence that matters) for Italian primary care physicians. 1) Based on efficacy, safety, and cost, a regimen of terbinafine 250 mg once daily for 12 weeks, followed by a 12-week period of no therapy, and then a 4-week booster of terbinafine 250 mg is preferred for onychomycosis in adults for the outcome of complete cure at 1 year. 2) A high-quality randomized trial found that standard-course antibiotic therapy for children with uncomplicated urinary tract infection was superior to short-course therapy. However, the number needed to treat of 28 suggests that offering short-course therapy is not unreasonable, especially if there is good follow-up in the subsequent weeks. 3) An updated guideline of the American College of Physicians on screening of colorectal cancer adds 2 new recommendations. One is to consider not screening patients aged 45 to 49 years. The other recommendation is against screening using stool Dna, computed tomography colonography, capsule endoscopy, urine, or serum screening tests for colorectal cancer. 4) The US Preventive Services Task Force found additional evidence on the benefit of folic acid supplementation for preventing neural tube defects. Since the critical period starts at least 1 month before conception, the task force recommends a daily supplement of 0.4 mg to 0.8 mg folic acid for all women who plan to or could become pregnant.

Maternal folic acid supplementation and the risk of ankyloglossia (tongue-tie) in infants; a systematic review.

BACKGROUND: Maternal folic acid supplementation is protective against the development of neural tube defects (NTDs) in babies. However, recent public-facing communications have raised concerns about a causal relationship between folic acid supplementation, particularly after the first trimester, and ankyloglossia (tongue-tie) in infants. Non-evidence-based communications are potentially harmful because they could adversely affect adherence to folic acid supplementation, increasing NTD occurrence. This study aimed to review evidence on the relationships between maternal folic acid supplementation during preconception and/or pregnancy and the risk of ankyloglossia in infants. METHODS: We searched the databases MEDLINE, EMBASE, Cochrane CENTRAL, and Scopus. We searched for observational, and interventional studies, and systematic reviews investigating the effect of maternal folic acid supplementation during preconception or pregnancy on the occurrence of ankyloglossia in offspring. The search was registered on PROSPERO on 01/12/2022, ID: CRD42022375862. RESULTS: The database searches yielded 93 articles. After removing duplicates and screening titles and abstracts, 26 remained. One article was judged relevant for inclusion in analyses; a case-control study that directly mentions the relationship between folic acid supplementation and ankyloglossia. This study reported that regular intake of folic acid supplements was higher in women with infants with ankyloglossia. However, this study has limitations regarding design, selection bias, and confounding, calling the findings into question. CONCLUSIONS: Insufficient evidence exists for a relationship between folic acid supplementation and ankyloglossia. Currently, the benefits of folic acid supplementation far outweigh the risks. This must be clearly communicated to patients by their clinicians during preconception and antenatal care.

National Diet and Nutrition Survey data reveal a decline in folate status in the United Kingdom population between 2008 and 2019.

BACKGROUND: Folate is essential for healthy growth and development. Fortification of foods with folic acid can improve folate status and reduce risk of neural tube defects (NTD). Following concern around folate status in the United Kingdom, the United Kingdom government announced in 2021 the intention to introduce mandatory folic acid fortification. OBJECTIVE: This study aimed to describe folate status in the United Kingdom population prior to the implementation of mandatory folic acid fortification of non-whole wheat (non-wholemeal) flour and to assess trends in folate status, including in females of reproductive age (FRA). METHODS: Data were from the United Kingdom National Diet and Nutrition Survey Rolling Program (2008-2019), a cross-sectional, nationally representative survey of children and adults aged 1.5+ (n = 5792 with folate result). Serum folate concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and red blood cell (RBC) folate concentration by microbiological assay. Concentration data were compared against method-specific cut-offs and thresholds, and relationships were explored against demographic and lifestyle characteristics. RESULTS: RBC and serum folate concentration significantly decreased by ∼3 percentage points per year between 2008 and 2019 in all age/sex groups. Prevalence of deficiency (RBC folate < 305 nmol/L) was highest in children aged 11 to 18 y (17% in 2016-2019). The proportion of FRA below the cut-off for increased risk of NTD (RBC folate < 748 nmol/L) increased from 69% to 89% between 2008 and 2019. Ethnicity, smoking status, and income were significant determinants of RBC and serum folate concentrations. CONCLUSIONS: These data reveal a decline in population folate status in the United Kingdom between 2008 and 2019 and a high prevalence of folate deficiency. A high proportion of FRA had RBC folate concentrations below the cut-off for increased risk of NTD. These data provide information on folate status in a population not currently exposed to mandatory folic acid fortification and are essential to model and assess its impact.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations.

BACKGROUND: Neural tube defects (NTDs) still occur among some women who consume 400 µg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. OBJECTIVES: To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. METHODS: Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 µg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. RESULTS: NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. CONCLUSIONS: Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

"Prevalence and secular trend of neural tube defects in fetal deaths in Argentina, 1994-2019".

BACKGROUND: Fetal deaths are a major source of information on the epidemiology of neural tube defects (NTDs; anencephaly and myelomeningocele). We analyzed NTDs prevalence and secular trend using fetal death records between 1994 and 2019 in Argentina. MATERIALS AND METHODS: Data were obtained from the Department of Statistics and Information of the Ministry of Health (DEIS). Using the number of fetal deaths due to anencephaly and myelomeningocele, we estimated the proportion of all fetal deaths due to anencephaly, myelomeningocele, and NTDs (anencephaly + myelomeningocele) during pre- and post-fortification period in Argentina. We also estimated the ratio of fetal deaths due to anencephaly, myelomeningocele, and NTDs (anencephaly + myelomeningocele) to 10,000 live births. Secular trend in the outcomes was analyzed using a Poisson model and Joinpoint regression analysis. RESULTS: In the entire period analyzed, the NTD proportion on fetal deaths was 1.32. In 1994, NTDs accounted for 34.7% of congenital malformations fetal deaths (CM) and 1.7% of all fetal deaths, whereas in 2019, these percentages were 9.4% and 0.5%, respectively. NTDs present a negative secular trend (p < .05). The risk of fetal death due to anencephaly and myelomeningocele decreases between 2005 and 2019 by 67% and 51% respectively (p < .05) in comparison to the period between 1994 and 2004 before the effective fortification of wheat flour used in the food industry destined for the domestic market. DISCUSSION AND CONCLUSION: We found a significant decrease in the risk of all fetal deaths due to NTDs, particularly anencephaly, in Argentina over the study period, with most reduction observed during the mandatory flour fortification era (introduced in Argentina in 2002). The inclusion of fetal deaths in NTD surveillance, coupled or uncoupled with other pregnancy outcomes, is essential for monitoring preventive supplementation measures.

Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement.

Importance: Neural tube defects are among the most common congenital malformations in the US, with an estimated 3000 pregnancies affected each year. Many of these neural tube defects are caused by low folate levels in the body. Objective: The US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on the benefits and harms of folic acid supplementation. Population: Persons who are planning to or could become pregnant. Evidence Assessment: The USPSTF concludes that, for persons who are planning to or could become pregnant, there is high certainty that folic acid supplementation has a substantial net benefit to prevent neural tube defects in their offspring. Recommendation: The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. (A recommendation).

Folic Acid Supplementation to Prevent Neural Tube Defects: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Neural tube defects are among the most common birth defects in the US. Objective: To review new evidence on the benefits and harms of folic acid supplementation for the prevention of neural tube defects to inform the US Preventive Services Task Force. Evidence Review: Sources included PubMed, Cochrane Library, Embase, and trial registries from July 1, 2015, through July 2, 2021; references; and experts, with surveillance through February 10, 2023. Two investigators independently reviewed English-language randomized studies and nonrandomized cohort studies in very highly developed countries that focused on the use of folic acid supplementation for the prevention of neural tube defect-affected pregnancies; methodological quality was dually and independently assessed. Findings: Twelve observational studies (reported in 13 publications) were eligible for this limited update (N = 1 244 072). Of these, 3 studies (n = 990 372) reported on the effect of folic acid supplementation on neural tube defects. For harms, 9 studies were eligible: 1 randomized clinical trial (n = 431) reported on variations in twin delivery, 7 observational studies (n = 761 125) reported on the incidence of autism spectrum disorder, and 1 observational study (n = 429 004) reported on maternal cancer. Two cohort studies and 1 case-control study newly identified in this update reported on the association between folic acid supplementation and neural tube defects (n = 990 372). One cohort study reported a statistically significant reduced risk of neural tube defects associated with folic acid supplementation taken before pregnancy (adjusted relative risk [aRR], 0.54 [95% CI, 0.31-0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39-0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83]), but this association occurred for only the later of 2 periods studied (2006-2013 and not 1999-2005). No other statistically significant benefits were reported overall. No study reported statistically significant harms (multiple gestation, autism, and maternal cancer) associated with pregnancy-related folic acid exposure. Conclusions and Relevance: New evidence from observational studies provided additional evidence of the benefit of folic acid supplementation for preventing neural tube defects and no evidence of harms related to multiple gestation, autism, or maternal cancer. The new evidence was consistent with previously reviewed evidence on benefits and harms.

Folic Acid to Prevent Neural Tube Defects.

This JAMA Patient Page describes the pros and cons of folic acid supplementation during pregnancy to lower risk of fetal neural tube defects.