Periconceptional Folic Acid Intake Research Articles

Huge hydrocephalus: a rare case series with insights into management and outcomes of this neglected cohort.

This study aims to discuss the management challenges of huge hydrocephalus (HH), a severe subset of hydrocephalus, presenting predominantly in underprivileged backgrounds. Insights into the condition's characteristics, factors affecting outcomes, and associated morbidity are discussed. A retrospective review of all operated cases of hydrocephalus with head circumference greater than body length (HC>L) was conducted (January 2019-January 2023). Data on epidemiological parameters, associated cranial abnormalities, cortical mantle thickness, peri-conceptional folic acid intake, surgical interventions, age-appropriate milestones, and complications were collected. Follow-up was conducted for at least 12 months or until expiration. The cohort consisted of 7 males and 5 females with age ranging from 3 to 48 months. 33% of them had associated neurological abnormalities, and 18 surgical interventions were needed for these 12 cases, including ventriculoperitoneal shunt or endoscopic diversion. A 17% wound breakdown rate requiring re-suturing was present, and 33% of cases had postoperative CSF infection, with 33% mortality, with only one case having age-appropriate development seen. The average hospital stay was 11.9 days, six times our center's average. All cases with an Evans index with an average of 0.7 expired within 12 months. None of the 12 mothers took peri-conceptional folic acid, and no case agreed to reduction cranioplasty. Huge hydrocephalus is a rare cohort with significant management challenges and poor prognosis even after treatment. Factors such as delayed intervention and low socioeconomic status contribute to adverse outcomes. Prevention through peri-conceptual folic acid intake and addressing socioeconomic disparities is crucial in reducing disease burden and improving prognosis.

Periconceptional folic acid intake: a one year survey among mothers of patients with myelomeningocele in a regional neurosurgical centre in Northwestern Nigeria

Background: Management of myelomeningocele, the most common neural tube defect in our environment, is quite challenging, and the outcome is usually less pleasing to parents/caregivers. Periconceptional folic acid ingestion reduces the incidence, especially in developed countries with mandated policies for folic acid fortification of staple foods. Awareness of preventive role of folic acid and periconceptional intake has not been studied in our centre. This study aimed to assess the knowledge of the proper intake of folic acid in preventing Myelomeningocele among mothers of patients with myelomeningocele. Methods: This was a prospective cross-sectional study conducted at Usmanu Danfodiyo university teaching hospital (UDUTH) Sokoto state, Nigeria over 12 months period after obtaining ethical clearance and informed consent. Data of mothers of patients with myelomeningocele who presented to the neurosurgical outpatient clinic of our facility was entered into a well-designed proforma. Data was analyzed using simple descriptive statistics, and results were presented in tables and pie chart. Results: Fifty-four mothers were recruited. The most common age range was 20-35 years (70%), with a mean age of 23.8 years±5.49 SD. Nineteen (35%) out of 54 mothers had heard prior information about folic acid, and only 16 (30%) were aware of its appropriate time of intake in preventing myelomeningocele. None of the mothers ingested folic acid in the periconceptional period. Conclusions: There was poor awareness and knowledge of the appropriate timing of folic acid intake in preventing Myelomeningocele in our centre.

Folic acid supplements and perinatal mortality in China.

Periconceptional use of multivitamins containing folic acid prevents external major birth defects, especially neural tube defects. We aimed to explore the effects of maternal folic acid supplementation alone on perinatal mortality with or without external major birth defects plus neural tube defects. From the China-US Collaborative Project for Neural Tube Defects Prevention, we identified 222, 303 singleton pregnancies with detailed information on periconceptional folic acid use, defined as folic acid supplementary before the last menstrual date until to the end of the first trimester. Perinatal mortality included stillbirths after 20 weeks' gestation and early neonatal deaths within 7 days of delivery. Among the fetuses or infants of women who did not take folic acid, the rate of perinatal mortality was 2.99% and 1.62% at least 20 weeks' gestation in the northern and southern regions. Among the fetuses or infants of the women with periconceptional use of folic acid, the rates were 1.85% and 1.39% in the northern and southern region. The estimated relative risk for perinatal mortality [adjusted risk ratio (RR), 0.72; 95% confidence interval (CI), 0.61- 0.85], stillbirth (adjusted RR, 0.78; 95% CI, 0.64-0.96), early neonatal mortality (adjusted RR, 0.61; 95% CI, 0.45-0.82), and neonatal death (adjusted RR, 0.64; 95% CI, 0.49-0.83) in northern China was significantly decreased in association with periconceptional folic acid supplementation. Compared with northern, there was a lesser effect in southern China. Periconceptional intake of 400μg folic acid daily reduces the overall risk perinatal mortality, as well as the risk from external major birth defects and neural tube defects, especially in northern China.

Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls

Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known. We evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study. Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n=189) and controls (n=205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared with periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term. Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n=394). The top differentially methylated region at the promoter region of DUSP22(dual specificity phosphatase 22) demonstrated DNA hypermethylation in ALL cases but not in controls in response to total and food folate intake. We further identified 8 interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and educational level. We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.

A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2020: 30-Year anniversary of gaining knowledge about folic acid's prevention potential for neural tube defects.

Spina bifida and anencephaly are major neural tube defects largely preventable through maternal periconceptional intake of folic acid. We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented through mandatory folic acid fortification of cereal grains, including wheat flour, maize flour, and rice, at the end of year 2020, a time point marking the 30th anniversary of the publication of landmark British Medical Research Council (MRC) study providing unequivocal knowledge on folic acid's FAP SBA prevention potential. The Food Fortification Initiative database was used to identify countries with mandatory fortification policies with folic acid added to cereal grains. We examined the status of FAP SBA prevention assuming mandatory folic acid fortification at 200 mcg/day of folic acid protects against FAP SBA and reduces their prevalence to a minimum achievable rate of 0.5 cases/1000 live births. Our analysis showed that 61,680 FAP SBA cases were prevented in the year 2020 through mandatory folic acid fortification of cereal grains in 58 countries, translating to 22% prevention of total possible FAP SBA prevention globally. Many countries in Africa, Asia, and Europe are yet to implement fortification. In 2020, 30 years after the MRC study was published, 218,270 preventable FAP SBA cases still occurred globally. Global prevention efforts for FAP SBA are inadequate even after three decades of knowledge on their prevention. Universal mandatory fortification of staples should be urgently implemented to prevent thousands of FAP SBA and associated elective terminations, stillbirths, and child mortality.

Association between maternal smoke exposure and congenital heart defects from a case–control study in China

There is a gap in knowledge how maternal exposure to environmental tobacco smoke (ETS) is associated with offspring congenital heart defects (CHDs). In this case–control study, we collected data on 749 fetuses with CHDs and 880 fetuses without any congenital anomalies to examine the association of maternal ETS with fetal CHDs and the potentially moderating effect by maternal hazardous and noxious substances (HNS), periconceptional folate intake and paternal smoking. Maternal exposure to ETS in first trimester was associated with increased risk of CHDs in a dose–response gradient, with the AORs (95% CI) were1.38 (1.00–1.92), 1.60 (1.07–2.41), and 4.94 (2.43–10.05) for ETS < 1 h/day, 1–2 h/day, and ≥ 2 h/day, respectively. With the doubly unexposed group as reference categories, AORs for maternal ETS exposure ≥ 2 h/day in the absence of folate intake, in the presence of HNS exposure or paternal smoking, were 7.21, 11.43, and 8.83, respectively. Significant additive interaction between ETS exposure and maternal folate intake on CHDs was detected. Maternal ETS exposure during first trimester may increase the risk of offspring CHDs in a dose–response shape, and such effect may be modified by maternal folate intake or other potential factors.

Pattern of Congenital Central Nervous System Anomalies Among Newborns at A Regional Special Care Baby Unit (SCBU) in Makurdi, North Central Nigeria

Background: Congenital anomalies of the central nervous system (CNS) are important causes of childhood mortality, chronic illness and disability. They have significant implications for childhood growth and development particularly in resource limited settings. Areview of their occurrence is valuable to instituting preventive and curative health care services.Objective: To document the pattern of congenital CNS anomalies in our practice Subjects and Method: A retrospective study of all neonatal admissions with congenital anomalies of the CNS (Patients) admitted into the Special Care Baby Unit (SCBU) of Benue State University Teaching Hospital (BSUTH) in Makurdi-Nigeria, between June 2013 andJanuary 2016. The anomalies were classified according to the ICD 10 Classification. Other parameters assessed were: age at admission, gestational age at delivery, family history of congenital anomalies, maternal age, social class, history of ante natal care, and admission outcome.Results: A total of 73 (9.3%) out of the admitted 785 neonates had congenital anomalies and majority (28, 38.4%) were of the CNS. The affected patients had a male preponderance (20, 71.4%). Myelomeningocele was the commonest CNS anomaly (20, 71.4 %). Poor antenatal care, lack of periconceptional folic acid (pFA) intake, late folic acid supplementation, low socio economic class, and late presentation were all associated with the incidence of congenital CNS anomalies. The patients had a neonatal mortality rate of 7.1% over the study period of 30 months (2.8% per year).Conclusion: Congenital CNS anomalies were the predominant congenital anomalies, and myelomeningocele was the commonest. The study underscores the need to institute a comprehensive healthcare programme for the prevention and management of congenital anomalies of the CNS in our practice.

Study on the polymorphism of methylenetetrahydrofolate reductase C677T gene as the genetic predisposition of congenital heart disease in North Indian population

Background: The etiology of congenital heart disease (CHD) is still not known properly. The variant alleles in the methylenetetrahydrofolate reductase (MTHFR) C677T gene help in elevating the serum homocysteine level which is an independent predisposing factor for generating CHD. Aims and Objectives: The aim of the present study was to analyze the role of polymorphism of MTHFR C677T gene polymorphisms in CHD patients of Varanasi, Uttar Pradesh, North India. Materials and Methods: The present study included 36 unrelated CHD patients along with their parents. At the same time, 40 healthy control samples were included in the study. MTHFR 677 C&gt;T genotype was identified by polymerase chain reaction followed by restriction digestion restriction fragment length polymorphism mechanism. Results: There was a significant difference observed in MTHFR C677T gene polymorphism between the cases and controls (P&lt;0.001). Among the different etiological factors, increased maternal age, family history, and teratogens are the major ones. Maternal MTHFR C677T genotype and periconceptional folate intake have important ascription toward CHD formation. Conclusion: The results designate that MTHFR C677T polymorphism has a substantial association with the development and progression of CHDs. Folate supplementation might be the probable management strategy for reducing the risk of CHDs as maternal MTHFR C677T polymorphism has an important contribution.

Periconceptional folic acid intake and disturbing factors: A single-center study in Japan.

We investigated folic acid (FA) intake and disturbing factors in pregnant women who visited our center in 2017. Among 1531 pregnant women, 45.1% of women initiated FA supplementation before pregnancy. The risk of failure of supplementation was significantly lower among women of ≥35 (adjusted odds ratio [aOR] 0.43) and 30-34 years of age (aOR: 0.59) in comparison to women of <30 years of age, and among those conceived with timing/artificial insemination of husband (aOR 0.47) and in vitro fertilization/intracytoplasmic sperm injection (aOR 0.32) in comparison to those conceived naturally. The risk among those with 1 (aOR 1.44) or ≥2 previous deliveries (aOR 2.75) was significantly higher in comparison to nulliparous women. Young, multiparous women, and those with natural conception should be targeted to promote preconceptional FA intake.

Detection of Novel mutation in VANGL1 gene indicating genetic association of Myelomeningocele

Aim: To detect the novel mutation in VANGL1 gene indicating genetic association of Myelomeningocele. Methodology: The study design was cross sectional. It comprises of sixty individuals, of them fifty were diagnosed cases of myelomeningocele and ten were healthy individuals taken as controls. The cases were collected from Jinnah Postgraduate Medical Center. The study was carried out in Dow Diagnostic and Research Laboratory (D.D.R.L.). Most of the patients were less than one year of age. The cases were evaluated for various other parameters like site and size of cyst and associated features like presence of hydrocephalus in the individuals. Since folic acid deficiency is the key component in the causation of the disease so mothers were also asked about the consumption of folic acid. Blood was drawn from patients after a written permission from the parents of the concerned patient. It was followed by the conduction of PCR to seek for any mutation in VANGL1 gene. Results: We found a rare mutation in VANGL1 gene revealing substitution of valine to serine at position 239 i.e. V239S. Hydrocephalus being the associated anomaly was present in 32% of the patients. Most of the affected individuals were males. 98% mothers of the sufferers did not take folic acid during pregnancy. In most of the patients, lump was present on the lumbar region. Conclusion: Myelomeningocele is a congenital birth defect with lifelong complications. Its prevalence can be decreased by taking certain measures. Periconceptional intake of folic acid has been established to lessen the risk of the disease. We identified a rare mutation in VANGL1 gene that may result in the causation of myelomeningocele. Keywords: Neural tube defects, mutation, myelomeningocele.

Clinico-epidemiological profile and outcomes of babies with neural tube defects in a tertiary care center in Northern India

Introduction Neural tube defects constitute a major source of disability among children. Proper management requires accurate diagnosis, an assessment of the severity of the lesion, a decision whether intervention is warranted, the nature of the intervention, and educating the family of the need for lifelong medical care. But to do so, reliable data regarding presentation and outcome is very crucial. Aim of the study To discuss the clinical epidemiological profile and outcome of babies admitted with neural tube defects (NTDs). Material and methods Retrospective observational study was done by extracting data from case notes and follow-up files in Department of Neonatology, PGIMER and Dr. RML Hospital, New Delhi over a period from March 2015 to July 2020. Results A total of 25 babies were included in the study. Majority of babies were born to mother at a median age group of 24 (19–36) yrs and nearly one-third of them were illiterate. The history of maternal periconceptional folic acid intake was seen in only five babies (21%). Two third of babies were male (64%) and the median age at admission was at 9 (1–27) days of life. Majority of the cases were open types of NTDs with most common type being meningomyelocele (88%) followed by occipital encephalocele (12%) and there was one case of closed type of neural tube defect having lipomeningomyelocele (4%). The most common associated anomaly was hydrocephalus (76%) followed by Arnold chiari malformation (56%). Motor weakness in form of paraparesis or paraplegia was present in 21 (84%) babies and sensory deficit was present in 44% babies. Bowel and bladder dysfuntion was present in 48% of cases. Ventriculitis was the most common associated morbidity (38%). Meningomyelocele (MMC) repair was the most commonly performed primary surgery (33%) followed by Ventriculo-peritoneal (VP) shunt repair (24%). Twelve babies (48%) were discharged while 2 (8%) expired and 11 (44%) babies left against medical advice Conclusion Neural tube defect is a congenital disorder with significant morbidity. The clinical severity of the NTDs and the uncertainty in their cause makes this a priority for further research. National policies for prevention, in utero diagnosis, and early surgical intervention are required for a better prognosis.

Short interpregnancy intervals and risks for birth defects: support for the nutritional depletion hypothesis

Research suggests short interpregnancy intervals increase risks for adverse perinatal outcomes, including some birth defects. A hypothesized cause is nutritional depletion, including folic acid (FA). We evaluated associations between short interpregnancy intervals, alone and in combination with FA intake, and the occurrence of select malformations. Data were from the National Birth Defects Prevention Study (US case-control, 1997-2011). Participants included multiparous women whose prior pregnancy resulted in live birth. Cases included 8 noncardiac and 6 cardiac defect groups (n=3219); controls were nonmalformed live-borns (n=2508). We categorized interpregnancy interval (<6, 6-11, 12-17, and 18-23 mo) and periconceptional FA intake [no FA supplement use and dietary folate equivalents (DFE) <400 µg/d, no FA supplement use and DFE ≥400 µg/d, or any FA supplement use]. We controlled for age, race/ethnicity, income, pregnancy intention, and study center. ORs <0.8 or >1.2 were considered to represent potentially meaningful associations. ORs for <6 compared with 18-23 mo were >1.2 for 4/8 noncardiac and 3/6 cardiac malformations. Among participants with any FA supplement use, ORs comparing <6 with 6-23 mo were <1.2 for most defects. Conversely, most ORs were >1.2 for <6 mo+no FA supplement use and DFE <400 µg/d compared with 6-23 mo+any FA supplement use. Magnitude and precision varied by defect. Short interpregnancy intervals were associated with a trend of higher risks for several defects, notably in the absence of FA supplement use. To our knowledge, our study is the first to provide preliminary empirical support that these etiologies may be related to shorter interpregnancy intervals and possible nutritional deficiencies. Because FA intake is highly correlated with other nutrients, and because our estimates were generally imprecise, more research with larger sample sizes is needed to better understand the role of FA compared with other nutrients in each defect-specific etiology.

Study on Knowledge and Practice of Periconceptional Intake of Folic Acid among Antenatal Mothers at Saveetha Medical College Hospital, Tamil Nadu

Study on Knowledge and Practice of Periconceptional Intake of Folic Acid among Antenatal Mothers at Saveetha Medical College Hospital, Tamil Nadu

Periconceptional folic acid intake in Northwest Russia: a birth registry study

Abstract Introduction Periconceptional use of folic acid supplementation is an evidence-based measure of birth defects prevention. The study was aimed to assess effect of periconceptual use of folic acid on birth defect prevalence in Arkhangelsk county and to investigate socio-demographic factors, which are associated with adherence to this preventive measure. Methods A registry-based study was conducted with data from the Arkhangelsk County Birth Registry for 2012-2015. The study population included 57084 pregnancies to calculate the proportion of women taking folic acid and 53340 pregnancy outcomes without missing data to analyze related socio-demographic characteristics. Results The proportion of women followed a folic acid supplementation before pregnancy was 1.3% (95% CI: 1.2-1.4), during pregnancy - 55.8% (95%CI: 54.6-56.4). Such women had less risk to deliver a newborn with any birth defects (OR = 0,84, 95%CI: 0,75 - 0,95). Considering birth defects prevalence of 38,6 per 1000 newborns in Arkhangelsk county, number needed to prevent one case of birth defect was 142,9. Based on multivariate analysis, nulliparous married women with higher education, aged 30 or more, had a higher chance to use folic acid before and during pregnancy. The history of spontaneous abortion in the mother's medical history and the first pregnancy were negatively associated with the probability of folic acid intake both before and during pregnancy. Conclusions The compliance to periconceptional intake of folic acid among women in the region was low. A level of compliance was associated with such socio-demographic factors as age, education, marital status, gravidity and parity. The findings have direct applications in improving prenatal care in Arkhangelsk county and establishing targets for prenatal counseling. Key messages A level of compliance to primary prevention of birth defects is associated with such socio-demographic factors as age, education, marital status, gravidity and parity. Prenatal counseling in terms of birth defects prevention should be based on socio-demographic characteristics of pregnant women.

Association between the introduction of a structured form and the quality of diabetes in pregnancy clinic care.

Pregnancy in women with pre-gestational types 1 (T1DM) and 2 (T2DM) diabetes mellitus can be a clinical challenge. This study assessed the association between introducing a structured diabetes in pregnancy proforma, on the quality of medical record documentation and pregnancy outcomes in women with T1DM and T2DM. To evaluate the impact of a proforma on the quality of documenting medical records and pregnancy/neonatal outcomes in women with pre-gestational diabetes. This was a retrospective two-cycle audit: pre- and post-proforma introduction. The documentation quality was assessed based on the rate of missing pre-pregnancy/first trimester haemoglobin A1c (HbA1c), third trimester HbA1c, folate intake and dose, retinopathy and nephropathy progression. Changes in pregnancy outcomes were assessed by mode of delivery, preterm delivery, mean third trimester HbA1c, pre-eclampsia and foetal outcomes. The pre- and post-proforma periods included 91 and 41 pregnancies, respectively. The quality of documentation improved in the post-proforma phase with the rate of missing data declining from 63.4% to 36.6% (P = 0.005) for pre-pregnancy/first trimester HbA1c, 30.8% to 12.2% (P = 0.009) for periconceptional folate intake, 42.9% to 14.6% (P = 0.001) for folate dose, 100% to 31.7% (P < 0.001) for retinopathy progression, 92.3% to 19.5% (P < 0.001) for nephropathy progression and 31.9% to 7.3% (P = 0.016) for third trimester HbA1c. Macrosomia significantly reduced in the second cycle (49% vs 21% P = 0.003). The quality of documentation improved significantly which is likely attributable to the implementation of the proforma. This study supports the use of structured documentation to reduce variation in care and potentially improve pregnancy outcomes.

Male-to-female ratios among NTDs and women's periconceptional intake of folic acid.

About a decade ago, a hypothesis was put forward to explain the preponderance of females among neural tube defect (NTD) fetuses. That hypothesis predicts that a woman's higher levels of early gestational intake of methyl groups, such as folic acid, will be associated with lesser male-to-female ratio differences in NTD-affected births, specifically less preponderance of females. We explored this hypothesis in four distinct studies that investigated human NTDs, obtained information on folic acid, and capitalized on timing of folic acid fortification by investigating data that were collected both prior to and after the 1998 initiation of U.S. mandatory folic acid fortification of grains. We analyzed data from four population-based case control studies conducted in California for birth years spanning 1987-2011. Two studies were conducted before folic acid fortification of the U.S. food supply. Each of the four studies included interviews of women who either had NTD-affected pregnancies (cases) or who did not have a pregnancy affected by a birth defect (controls). In each study, information on periconceptional supplement use was elicited. We explored male-to-female ratios and 95% binomial confidence limits in each data set. Our analyses of two case-control studies performed prior to and two performed post mandatory folate fortification in the United States showed that more NTD-affected fetuses were female in the first two studies. In the studies done before fortification, the frequency of females was even greater among those pregnancies without folic acid supplementation. Our findings suggest folic acid may differentially reduce risk of NTDs among female fetuses.

Maternal Folic Acid Intake and Risk of Nonsyndromic Orofacial Clefts: A Hospital-Based Case-Control Study in Bangalore, India.

Orofacial clefts are the most common congenital anomaly worldwide. Cleft etiology appears to be multifactorial, with genetic and environmental components. Although periconceptional folic acid supplementation has been shown to be protective for neural tube defects, current evidence for its role in cleft prevention is mixed with few studies from low- and middle-income countries. To investigate the association between periconceptional folic acid intake and incidence of nonsyndromic orofacial clefts among infants in Bangalore, India. A hospital-based case-control study (106 cases, 212 controls) utilizing a questionnaire to collect data on prenatal supplements, dietary folate, and potentially confounding factors. Multivariate logistic regression analysis was used to assess relationships between folic acid supplementation and all nonsyndromic clefts, and in separate analyses for cleft lip and/or palate (CL/P) and cleft palate (CP), adjusting for statistically significant variables. A statistically significant protective association was found for separate folic acid supplements (not combined with iron or multivitamins) taken in the periconceptional period and all clefts combined (adjusted odds ratio [OR]: 0.62, 95% confidence interval [CI], 0.45-0.86) and CL/P (adjusted OR: 0.57; 95% CI, 0.38-0.86). Higher levels of dietary folate were found to be associated with a reduced risk for all clefts (adjusted OR: 0.98, 95% CI, 0.96-0.99), CL/P (adjusted OR: 0.98, 95% CI, 0.96-0.99), and CP (adjusted OR: 0.96, 95% CI, 0.93-0.99). This study provides limited evidence for a protective association of periconceptional folic acid supplementation with nonsyndromic orofacial clefts. The low proportion of mothers taking folic acid supplements in the periconceptional period highlights the need for increased education and awareness regarding prenatal nutrition.

Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density.

Periconceptional intake of supplemental folic acid can reduce the incidence of neural tube defects by as much as 70%, but the mechanisms by which folic acid supports cellular processes during neural tube closure are unknown. The mitochondrial 10-formyl-tetrahydrofolate synthetase MTHFD1L catalyzes production of formate, thus generating one-carbon units for cytoplasmic processes. Deletion of Mthfd1l causes embryonic lethality, developmental delay, and neural tube defects in mice. To investigate the role of mitochondrial one-carbon metabolism during cranial neural tube closure, we have analyzed cellular morphology and function in neural tissues in Mthfd1l knockout embryos. The head mesenchyme showed significantly lower cellular density in Mthfd1l nullizygous embryos compared to wildtype embryos during the process of neural tube closure. Apoptosis and neural crest cell specification were not affected by deletion of Mthfd1l. Sections from the cranial region of Mthfd1l knockout embryos exhibited decreased cellular proliferation, but only after completion of neural tube closure. Supplementation of pregnant dams with formate improved mesenchymal density and corrected cell proliferation in the nullizygous embryos. Deletion of Mthfd1l causes decreased density in the cranial mesenchyme and this defect is improved with formate supplementation. This study reveals a mechanistic link between folate-dependent mitochondrially produced formate, head mesenchyme formation and neural tube defects.

Genetic polymorphisms in MTR are associated with non-syndromic congenital heart disease from a family-based case-control study in the Chinese population

Genetic polymorphisms of folate pathway genes have been reported to be associated with congenital heart diseases (CHDs); however, the results remain conflicting. We conducted a family-based case-control study, which included160 CHD case-parent triads and 208 control-parent triads to explore the association of 18 genetic variants of seven folate metabolism-related genes with the risk of CHDs. The MTR C allele of rs1770449 (OR = 1.961, 95%CI: 1.379–2.788) and the MTR A allele of rs1050993 (OR = 1.994, 95%CI: 1.401–2.839) in infants were associated with an increased risk of CHDs. Over-transmission of SNPs rs1770449 and rs1050993 and haplotype CAA (rs1770449-rs1805087-rs1050993) in MTR were detected in total CHDs. The above mentioned associations of MTR with CHDs were also observed in septal defects and conotruncal heart defects subgroups. Without maternal periconceptional folate intake, the risk of CHDs among women carrying the rs1770449 “CT or CC” genotype or the rs1050993 “AG or AA” genotype in MTR was 3.262(95%CI: 1.656–6.429) or 3.263(95%CI: 1.656–6.429) times greater than the aOR in women carrying wild genotype, respectively. Our study suggests that MTR polymorphisms (rs1770449 and rs1050993) may be associated with the risk of CHDs and modify the relation between maternal folate intake and CHDs.

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway.

BackgroundEvidence linking individual‐level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies.Methods and ResultsWomen recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996–2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000–2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non–folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80–1.22), 1.08 (95% CI, 0.93–1.25), and 1.07 (95% CI, 0.97–1.19), respectively. For initiation of folic acid in the preconception period weeks −4 to −1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI, 1.00–1.25), 1.09 (95% CI, 0.95–1.25), 0.98 (95% CI, 0.86–1.12), and 0.97 (95% CI, 0.78–1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results.ConclusionsFolic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.