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FIGURE. Prevalence of neural tube defects (NTDs) (anencephaly and spina bifida) before and after mandatory folic acid fortification, by maternal race/ethnicity — 19 population-based birth defects surveillance programs,* United States, 1995–2011
Source publication
In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects (NTDs). NTDs are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which can lead to death or varying d...
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Background:
Spina bifida and anencephaly are largely preventable birth defects through mandatory folic acid fortification. Our objective was to estimate the proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented worldwide through mandatory fortification of wheat and/or maize flour with folic acid during the year 2017...
Background:
Maternal emotional stress during pregnancy has previously been associated with congenital neural malformations, but most studies are based on data collected retrospectively. The objective of our study was to investigate associations between antenatal maternal bereavement due to death of a close relative and neural tube defects (NTDs) i...
Background:
The relationship between essential trace metals (ETMs) and the risk of neural tube defects (NTDs) is still unclear. One of the challenges is to evaluate the intake of ETMs of women during their early period of pregnancy. We proposed the hypothesis that an ETM deficiency in women during their early period of pregnancy is associated with...
Neural Tube Defects (NTDs) are congenital structural abnormalities of the brain (anencephaly) and vertebral column (spina bifida) that represented as one of the most common congenital malformations of neonates worldwide. A four-year and eight months () retrospective record review study on prevalence, trend, and associated demographic factors of NTD...
Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid....
Citations
... Infant mortality persists as a global health challenge [1,2] and congenital anomalies, or birth defects, are a leading contributor to infant mortality and disability [2][3][4]. The incidence and burden of congenital anomalies reflects underlying healthcare inequality, nutritional deficiency, and socioeconomic inequalities. ...
... Infant mortality persists as a global health challenge [1,2] and congenital anomalies, or birth defects, are a leading contributor to infant mortality and disability [2][3][4]. The incidence and burden of congenital anomalies reflects underlying healthcare inequality, nutritional deficiency, and socioeconomic inequalities. ...
Congenital anomalies in Sub-Sahara Africa (SSA) are understudied despite the significant pediatric health burden. This retrospective longitudinal hospital-based study evaluated the records of 326 inpatient children under the age of two years with congenital anomalies at Bugando Medical Centre, a tertiary referral hospital in northwestern Tanzania. Classical logistic regression was used in the analysis of congenital malformation of muscles, gastrointestinal malformation, oral facial clefts, neural tube defects, and skeletal malformations. A modified poisson regression was used to model risk factors for Central Nervous System (CNS) hydrocephalus and congenital heart disease (CHD). A majority (78.8%) of children included in the study were less than six months of age. Nearly half (48.8%) were diagnosed with CHD followed by CNS hydrocephalus (10.4%) and congenital malformation of muscles (8.9%). Babies whose mothers missed periconceptual folic acid supplementation had 83% higher risk of hydrocephalus (aPR = 1.83, 95% CI = 1.11–1.96) and 78% higher for CHD (aPR = 1.78, 95% CI = 1.31–1.94). Male children had 1.67 higher odds of muscular congenital malformations (aOR = 1.67, 95% CI = 1.23–1.89). Less than 37 gestational age had a 1.86 higher odds of muscular congenital malformations (aOR = 1.86, 95% CI = 1.53–3.66). Our study highlights the critical need for folic acid supplementation and establishes a need for a registry and the potential for mapping.
... A well-established example is the adequate intake of folate during early development, in the prevention of neural tube defects [4]. While the underlying mechanisms for early 2 of 14 programming are not yet fully elucidated, dietary inputs to the one-carbon metabolic pathway during the periconceptional period may influence adult health-related phenotypes. ...
We aimed to investigate the associations between maternal intake of folate, vitamin B12, B6, B2, methionine, choline, phosphatidylcholine and betaine during the period surrounding pregnancy and offspring weight outcomes from birth to early adulthood. These associations were examined among 2454 mother–child pairs from the Nurses’ Health Study II and Growing Up Today Study. Maternal energy-adjusted nutrient intakes were derived from food frequency questionnaires. Birth weight, body size at age 5 and repeated BMI measurements were considered. Overweight/obesity was defined according to the International Obesity Task Force (<18 years) and World Health Organization guidelines (18+ years). Among other estimands, we report relative risks (RRs) for offspring ever being overweight with corresponding 95% confidence intervals across quintiles of dietary factors, with the lowest quintile as the reference. In multivariate-adjusted models, higher maternal intakes of phosphatidylcholine were associated with a higher risk of offspring ever being overweight (RRQ5vsQ1 = 1.16 [1.01–1.33] p-trend: 0.003). The association was stronger among offspring born to mothers with high red meat intake (high red meat RRQ5vsQ1 = 1.50 [1.14–1.98], p-trend: 0.001; low red meat RRQ5vsQ1 = 1.05 [0.87–1.27], p-trend: 0.46; p-interaction = 0.13). Future studies confirming the association between a higher maternal phosphatidylcholine intake during pregnancy and offspring risk of being overweight or obese are needed.
... The occurrence of NTDs in various populations is affected by genetics, geography, and the maternal diet (Li et al. 2006;Liu et al. 2016). For instance, in Northern China's Shanxi Province in 2003, the frequency of NTDs was 138.7 per 10,000 births, tenfold higher than in the United States and Europe (Li et al. 2006; Morris and Wald 2007;Williams et al. 2015). The diet in this region was shown to be deficient in folate, and the incidence of NTDs in this region was significantly reduced following a campaign to provide folic acid supplementation Meng et al. 2015). ...
Neural tube defects (NTDs) are severe malformations of the central nervous system that arise from failure of neural tube closure. HECTD1 is an E3 ubiquitin ligase required for cranial neural tube closure in mouse models. NTDs in the Hectd1 mutant mouse model are due to the failure of cranial mesenchyme morphogenesis during neural fold elevation. Our earlier research has linked increased extracellular heat shock protein 90 (eHSP90) secretion to aberrant cranial mesenchyme morphogenesis in the Hectd1 model. Furthermore, overexpression of HECTD1 suppresses stress-induced eHSP90 secretion in cell lines. In this study, we report the identification of five rare HECTD1 missense sequence variants in NTD cases. The variants were found through targeted next-generation sequencing in a Chinese cohort of 352 NTD cases and 224 ethnically matched controls. We present data showing that HECTD1 is a highly conserved gene, extremely intolerant to loss-of-function mutations and missense changes. To evaluate the functional consequences of NTD-associated missense variants, functional assays in HEK293T cells were performed to examine protein expression and the ability of HECTD1 sequence variants to suppress eHSP90 secretion. One NTD-associated variant (A1084T) had significantly reduced expression in HEK293T cells. All five NTD-associated variants (p.M392V, p.T801I, p.I906V, p.A1084T, and p.P1835L) reduced regulation of eHSP90 secretion by HECTD1, while a putative benign variant (p.P2474L) did not. These findings are the first association of HECTD1 sequence variation with NTDs in humans.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00439-024-02647-4.
... As such, women of child-bearing age are recommended to consume 400 mg/day of folic acid [6], an oxidized synthetic form of folate. Following nearly 25 years of mandatory folic acid fortification of cereal grains, the incidence of NTDs in the United States decreased by approximately 30% [7] and the rate of folaterelated anemia has decreased by 40% [8]. ...
... Folate deficiency is a known risk factor for NTDs [6,7,24]. The heightened variations of serum folate levels seen in dams under low folate diet leads to more individuals in the range of risk susceptibility [25]. ...
Objectives:
In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy.
Design:
DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet.
Methods:
CD-1 mice were provided diet with normal (3 mg/kg) or low (0.3 mg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects.
Results:
Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions.
Conclusions:
Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.
... Moreover, the US Preventive Service Task Force (USPSTF) recommended all women planning a pregnancy taking a daily dosage of 0.4-0.8 mg folic acid in 2009 [4][5][6]. However, the benefits of folic acid supplementation as a primary care are required to be informed. ...
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.
... 126 Folic acid intervention by flour fortification (wheat or maize flour fortification) has been done in over 80 countries. 114 Periconceptional supplementation to reduce a childbearing age woman's susceptibility to having an infant with a neural tube defect (NTD) 127 can also be performed. The association of NTDs and folate has been one of the most successful public health initiatives in the past 50 to 75 years, 128 with a recommended folic acid dose of 400 lg per day to prevent NTDs. ...
... 144 There are some concerns regarding folic acid fortification, despite the reduced incidence of NTDs discussed above. 127 It can potentially lead to massive consumption levels, which might result in adverse effects. It may be necessary to continue monitoring fortification interventions to quickly identify any emerging concern and investigate it further. ...
Folic acid plays a crucial role in diverse biological processes, notably cell maturation and proliferation. Here, we performed a literature review using articles listed in electronic databases, such as PubMed, Scopus, MEDLINE, and Google Scholar. In this review article, we describe contradictory data regarding the role of folic acid in cancer development and progression. While some studies have confirmed its beneficial effects in diminishing the risk of various cancers, others have reported a potential carcinogenic effect. The current narrative review elucidates these conflicting data by highlighting the possible molecular mechanisms explaining each point of view. Further multicenter molecular and genetic studies, in addition to human randomized clinical trials, are necessary to provide a more comprehensive understanding of the relationship between folic acid and cancer.
... Both within and outside of the US, there are wide variations in the prevalence of NTDs by race and ethnicity. For example, birth prevalence is greater among Latino people compared to White Americans, and lower among Black Americans [22]. Compared to the US, low-and middle-income countries experience higher prevalence of NTDs [23]. ...
... In some areas of Latin America, reports of birth prevalence have reached 96 cases per 10,000 live births, while in certain areas of Africa, estimates approach 75 cases per 10,000 live births [17,24]. Even as Latino people immigrate into the US, they consistently have a higher birth prevalence of NTDs [22]. ...
PURPOSE: The purpose of this project was to establish a pathway for electronic medical record (EMR) customization, utilizing quality improvement methodology, to both identify and address adverse social determinants of health (SDOH) among a diverse spina bifida (SB) population. METHODS: Starting in September 2020, the four fundamental steps were to (1) facilitate an advisory committee to safeguard the standard clinical protocols, (2) characterize barriers to implementation, (3) evaluate workflow to sustain data entry capture, and (4) manage the technology platform for seamless integration. The SB clinic was the first clinic within the enterprise to rollout the use of an adverse SDOH mitigation activity. A Spanish-speaking interpreter was scheduled for all clinics, as many families were limited in English proficiency. RESULTS: The customization of the EMR to support an efficient workflow to address SDOH was feasible in a large and diverse urban medical center. Of the 758 patients served in the clinic, a myelomeningocele diagnosis was present in 86% of individuals. While 52% of participants were female, ethnically 52% of individuals served were Latino. Many of these individuals disclosed being recent immigrants to the United States. Often immigration and asylum related issues were at the forefront of the SDOH issues addressed. CONCLUSION: Given the occurrence of adverse SDOH among individuals with SB, many of whom are new Latin-American immigrants, meaningful clinical efforts are needed to both identify and address the causes of the observed disparities. EMR customization is feasible and can identify and, through social prescriptions, address SDOH to support the provision of safe, high quality, and equitable care for vulnerable and medically complex populations at home and potentially abroad.
... A Brazilian population study presented a 6.3% reduction in spina bifida rates comparing 2001-2004 with 2006-2010 [22]. In the United States, as well, the prevalence of neural tube diseases during the post-fortification period was stable [23]. Similarly, in São Paulo State between 2004 and 2015, neural tube defects had a stationary pattern. ...
Objectives
This study aimed to analyze, in the São Paulo state of Brazil, time trends in prevalence, neonatal mortality, and neonatal lethality of central nervous system congenital malformations (CNS-CM) between 2004 and 2015.
Methods
Population-based study of all live births with gestational age ≥22 weeks and/or birthweight ≥400 g from mothers living in São Paulo State, during 2004–2015. CNS-CM was defined by the presence of International Classification Disease 10th edition codes Q00–Q07 in the death and/or live birth certificates. CNS-CM was classified as isolated (only Q00–Q07 codes), and non-isolated (with congenital anomalies codes nonrelated to CNS-CM). CNS-CM associated neonatal death was defined as death between 0 and 27 days after birth in infants with CNS-CM. CNS-CM prevalence, neonatal mortality, and lethality rates were calculated, and their annual trends were analyzed by Prais-Winsten Model. The annual percent change (APC) with 95% confidence interval (95%CI) was obtained.
Results
7,237,628 live births were included in the study and CNS-CM were reported in 7526 (0.1%). CNS-CM associated neonatal deaths occurred in 2935 (39.0%). Isolated CNS-CM and non-isolated CNS-CM were found respectively in 5475 and 2051 livebirths, with 1525 (28%) and 1410 (69%) neonatal deaths. CNS-CM prevalence and neonatal lethality were stationary, however neonatal mortality decreased (APC −1.66; 95%CI −3.09 to −0.21) during the study. For isolated CNS-CM, prevalence, neonatal mortality, and lethality decreased over the period. For non-isolated CNS-CM, the prevalence increased, neonatal mortality was stationary, and lethality decreased during the period. The median time of CNS-CM associated neonatal deaths was 18 h after birth.
Conclusions
During a 12-year period in São Paulo State, Brazil, neonatal mortality of infants with CNS-CM in general and with isolated CNS-CM showed a decreasing pattern. Nevertheless CNS-CM mortality remained elevated, mostly in the first day after birth.
... It also plays essential roles in redox maintenance by promoting synthesis of glutathione (GSH) and tetrahydrobiopterin (BH4) (via DHFR) 45,46 . Prenatal folate supplementation prevents congenital neurological and heart defects, as well as low birthweight [47][48][49] . We show that post-natal viral infection leads to folic acid malabsorption and demonstrate that folic acid supplementation ameliorates virally associated immune pathology. ...
Background & Aims
Biliary atresia (BA) is an obstructive newborn jaundice disease that leads to liver failure in the majority of affected infants. Viral infection is an important environmental trigger of BA. The aim of the study is to establish how viral infection rewires the cellular and metabolic processes of the digestive systems in at-risk infants and leads to BA development.
Methods
Single cell RNA (scRNA) transcriptomes and V(D)J sequences were generated using small intestine and liver biopsies from BA and control infants. Candidate risk genes were identified by genome-wide association study. Patient specimens, mouse model of experimental biliary atresia, and a myeloid-specific Folr2 knockout mice ( folr2 Mko ) were used to determine immune pathologies that lead to BA development. An open label clinical trial was conducted to determine the therapeutic effect of folic acid on post-Kasai’s outcomes of patients with BA.
Results
Type I interferon (IFN-I) signaling is persistently activated in infants with BA. This promotes expression of hepcidin in hepatic TREM2 ⁺ macrophages and hepatocytes, which impairs SLC40A1-mediated iron excretion from the small intestine, leading to iron accumulation, lipid peroxidation, dysbiosis and folic acid deficiency. By genetic ablation of Folr2, we show that folinate supplementation halts persistent IFN-I activation and suppresses hepcidin expression by TREM2 ⁺ macrophages. In an open label clinical study, folic acid supplementation decreased post-Kasai’s cholangitis incidences and liver transplantation rates by 70%.
Conclusion
Persistent IFN-I signaling plays a critical role in virally induced pathological jaundice in infants, and that folic acid supplementation is an effective therapy for BA.
... Although there is evidence that such strategy is effective, safe, socially equitable and cost-effective in reducing the prevalence and severity of NTDs it has not yet been introduced in Europe, except in Kosovo. The United Kingdom plans however to mandate folic acid fortification in wheat flour and this decision should become effective by 2024 (Rodrigues and Dipietro, 2012;Haggarty, 2021;Williams et al., 2015;Mai et al., 2022;Irvine et al., 2015;Atta et al., 2016;Pardo et al., 2022;Global Fortification Data Exchange, 2023). The number of NTD potentially prevented by flour fortification has been estimated up to 1,000 NTDs per year in Europe (Honein et al., 2001;Morris et al., 2021). ...
Folic acid insufficiency is an important risk factor for congenital neural tube defects. Despite recommendations and national campaigns, the proportion of women taking folic acid in the peri-conceptional period remains insufficient worldwide. We describe in this study the proportion of peri-conceptional folic acid supplementation use and its determinants among a population of hospital workers during the course of a prevention campaign. We performed a single-center cross sectional study in a university hospital in France. Data were collected during 2 months in 2019 by an online questionnaire sent to all professionals. We collected information about folic acid supplementation use, its modalities (form, period, frequency and dosage) and reason for initiating or not supplementation. Response rate was 11.4 % (n = 1,075/9,447). Among the 748 women who reported at least one pregnancy, 72.7 % (95 % CI: 69.4–76.0 %) reported taking folic acid during their last pregnancy. Main reason for initiating supplementation was information given by a health professional (87.8 %), especially by gynaecologists-obstetricians. Principal factors associated with folic acid supplementation use were age between 25 and 35 years, high level of education and recent pregnancy. Folic acid supplementation use is still not systematic before and during pregnancy, even among health professionals. There is a case for mandatory folic acid fortification for the French general population.
