NTD-affected Pregnancies Research Articles

From Awareness to Action: Addressing Folic Acid Supplementation in Western India Among Women of Reproductive Age.

Background Folate, a vitamin B9, can be sourced naturally in the diet or the form of supplements. Studies highlight the prevention of neural tube abnormalities in women of reproductive age. To prevent these, low daily doses of FA (400-800 μg) are recommended for all women planning pregnancy, with higher doses for those with previous NTD-affected pregnancies. Folic acid supplementation lowers the risk of NTDs, other birth defects, and obstetrical complications. Methods The study explored awareness of and knowledge of folic acid supplements among women of childbearing age in Pune City, western Maharashtra, India. The cross-sectional survey was carried out at Symbiosis University Hospital and Research Centre (SUHRC), involving 300 female participants aged 16-44 years. The study utilized a structured questionnaire to evaluate participants' knowledge of folic acid supplements, their benefits, and usage patterns. Results Use as well as awareness of folic acid supplements was strongly associated with educational attainment. The awareness was low or none in participants who never attended school, and highest among the university graduates. The study included 300 women aged 16-45. About 43% of the study participants were between the ages of 23 and 29 years old; 57.7% were single, and 59.3% among them were university graduates. 59.7% of the study participants knew about folic acid supplements, but only 20% took them regularly. Knowledge about ideal timing and benefits was limited among them. 38% correctly identified prepregnancy as the ideal time to start. Only 18% knew it prevents neural tube defects, and 27% knew it could be obtained naturally. Conclusion The study highlights a lack of detailed knowledge about folic acid supplements among the study participants. Recommendations to enhance the supplement's intake include public health campaigns, enhanced healthcare provider education, easy-to-read informational materials, and strengthening government supplement programs to improve awareness and food fortification. Further research on consumption barriers for the supplement needs to be carried out.

The concept of folic acid supplementation and its role in prevention of neural tube defect among pregnant women: PRISMA.

Folic acid is the synthetic form of vitamin B9, found in supplements and fortified foods, while folate occurs naturally in foods. Folic acid and its derivatives are extremely important in the synthesis of nucleic acids (DNA and ribose nucleic acid [RNA]) and different proteins. It acts as a coenzyme for the transfer of 1 carbon in the biosynthesis of purine, pyrimidine, and amino acids. Folic acid is critically important in rapidly proliferating tissues, including fetus and trophoblastic tissue to prevent neural tube defect (NTD). The main objective of this review is to identify the role of folic acid to prevent NTD among pregnancy mothers. Electronic databases including Web of Science, Google Scholar, MEDLINE, Scopus, and Cochrane library used to systematically search without limitation of publication date and status. In pregnancy, the first trimester is a significant time for neural tube closure. Decreased blood folic acid levels inhibit DNA replication, repair, RNA synthesis, histone and DNA methylation, methionine production, and homocysteine remethylation reactions that cause NTDs in pregnancy. Therefore, folic acid supplementation is critically important for childbearing mothers before conception and in the first trimester pregnancy. As a result, women are recommended to take 400 microgram FA/day from preconception until the end of the first trimester to prevent NTD-affected pregnancies. This allows the developing neural tissue to acquire critical mass and provides the preferred rostrocaudal orientation so that these divisions contribute to the elongation of the developing neural tube in embryos.

Polymorphisms in Maternal Selected Folate Metabolism-Related Genes in Neural Tube Defect-Affected Pregnancy.

Neural tube defects (NTDs) are abnormalities of the brain and spinal cord, which occur as a result of failure in neural tube closure during embryogenesis. Causes of NTDs are complex and multiple, with hereditary, lifestyle, and environmental factors appearing to play a role. In spite of their impact on public health, the role genetics play on NTDs in Ethiopia is lacking. In this study, the role of polymorphisms in MTHFR 677C > T (rs1801133), MTHFR 1298A > C (rs1801131), MTRR 66A > G (rs1801394), RFC1 80A > G (rs1051266), and TCN2 776C > G (rs1801198) on the risk of having NTD-affected pregnancy was investigated. One hundred women with NTD-affected pregnancy and 100 women with normal pregnancy were included in the study. DNA was extracted from saliva and genotyping for five polymorphisms in four genes was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The departure of the genotype's distribution from Hardy-Weinberg equilibrium (HWE) was evaluated using the x2 goodness-of-fit test. Frequencies of genotypes and alleles in case and control mothers were determined and differences between relative frequencies were evaluated by the x2 or the Fisher's exact test. The statistically significant difference was absent in the genotype and allele frequencies for all the analyzed polymorphisms between cases and controls (P > 0.05). MTHFR 677C > T, MTHFR 1298A > C, MTRR 66A > G, RFC1 80A > G, and TCN2 776C > G polymorphisms lack association with the risk of having a pregnancy affected by NTD. The role of other genes or environmental factors in NTD etiology needs to be investigated.

Folate Deficiency Is Spatially Dependent and Associated with Local Farming Systems among Women in Ethiopia

ABSTRACTBackgroundFolate is essential for the synthesis and integrity of DNA, normal cell formation, and body growth. Folate deficiency among women of reproductive age (WRA) increases the risk of poor birth outcomes including neural tube defect (NTD)-affected pregnancies. Folate status is largely dependent on dietary intakes.ObjectivesWe aimed to explore the spatial distribution of biomarkers of folate status and their association with farming systems among nonpregnant WRA in Ethiopia.MethodsSerum and RBC folate concentration data were derived from the Ethiopia National Micronutrient Survey of 2015. The spatial dependencies of folate concentration of WRA were investigated and its relation with the dominant local farming system was explored.ResultsThe median serum folate and RBC folate concentrations were 12.3 nmol/L and 567.3 nmol/L, respectively. The national prevalence of folate deficiency using homocysteine concentration as a metabolic indicator based on serum and RBC folate concentration was 11.6% and 5.7%, respectively. The majority of women (77.9%) had low RBC folate concentrations consistent with increased risk of NTD-affected pregnancies. Folate nutrition was spatially dependent at distances of ≤ 300 km. A marked variability in folate concentration was observed between farming systems: greater RBC folate concentration (median: 1036 nmol/L) was found among women from the Lake Tana fish-based system, whereas the lowest RBC folate concentration (median: 386.7 nmol/L) was observed in the highland sorghum chat mixed system.ConclusionsThe majority (78%) of WRA in Ethiopia had low folate status potentially increasing the risk of NTD-affected pregnancies. These findings may help national and subnational nutrition intervention strategies to target the most affected areas in the country.

Folate, Vitamin B12, and Homocysteine Levels in Women With Neural Tube Defect-Affected Pregnancy in Addis Ababa, Ethiopia.

BackgroundNeural tube defects (NTDs) are prevalent congenital defects associated with pre-pregnancy diet with low levels of maternal folate. They are linked to severe morbidity, disability, and mortality, as well as psychological and economic burdens.ObjectiveThe goal of this study was to determine the levels of folate, vitamin B12, and homocysteine in the blood of women who had a pregnancy impacted by NTDs.Subjects and MethodsA hospital-based case–control study was undertaken between September 2019 and August 2020. The study comprised a total of 100 cases and 167 controls. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of folate, vitamin B12, and homocysteine in the serum.ResultsOnly 39% of the cases and 54.5% of control mothers reported periconceptional use of folic acid/multivitamin, which indicated a statistically significant difference (p = 0.014). Logistic regression indicated that periconceptional use of folic acid/multivitamin was associated with NTDs (p = 0.015, OR = 1.873, 95% CI: 1.131–3.101). We found that 57% of the cases and 33.5% of controls, as well as 43% of cases and 20.4% of controls had serum folate and vitamin B12 levels below the cut-off value, respectively. Twenty-seven percent of the cases and 6.6% of controls had hyperhomocysteinemia (HHcy). The median concentrations of folate, vitamin B12, and homocysteine in cases and controls were 4.78 and 8.86 ng/ml; 266.23 and 455 pg/ml; 13.43 and 9.7 μmol/l, respectively. The median concentration of folate (p < 0.001) and vitamin B12 (p < 0.001) were significantly lower in the cases than controls, while the homocysteine concentration (p < 0.001) was significantly lower in the controls than cases. Folate [OR (95% CI) = 1.652 (1.226–2.225; p = 0.001)], vitamin B12 [OR (95% CI) = 1.890 (1.393–2.565; p < 0.001], and homocysteine [OR (95% CI) = 0.191 (0.09–0.405; p < 0.001)] levels were associated with NTDs.ConclusionFolate and vitamin B12 are deficient in both cases and control mothers. The lower levels of folate and vitamin B12 with an elevated homocysteine level in NTD-affected pregnancy may be an indication that these biochemical variables were risk factors for NTDs. Folate/multivitamin supplementation and/or food fortification should be promoted.

Placental concentrations of alkali metals and their associations with neural tube defects in offspring.

The role of alkali metals in the development of neural tube defects (NTDs) is little known. We examined the associations between placental concentrations of lithium (Li), sodium (Na), potassium (K), rubidium (Rb), and cesium (Cs), and the occurrence of NTDs in fetuses. 408 women who had NTD-affected pregnancies and 593 women who delivered healthy infants were included. Logistic regression, weight quantile sum regression (WQSR), and Bayesian kernel machine regression (BKMR) were applied to assess whether these metals are associated with the occurrence of NTDs. Cs showed an inverse association with the odds of NTDs [adjusted odds ratio (aOR): 0.58, 95% confidence interval (CI): 0.36-0.91] in single-metal logistic model. Estimates did not change much in the multiple-metal logistic model. In WQSR, the WQS index was inversely associated with the odds of NTDs (aOR: 0.62, 95%CI: 0.51-0.75), in which Cs (weighted 0.45) had the highest weight. In BKMR, the odds of NTDs decreased with the levels of the five-metal mixtures. Cs was associated with decreased odds of NTDs when the remaining four metals were fixed at their 25th and 50th percentiles, while Na was associated with increased odds of NTDs when setting other metals at the 25th, 50th, or 75th percentile. A high concentration of Cs and Na in placental tissue was respectively associated with decreased and increased odds of NTDs. In addition, the occurrence of NTDs decreased with the levels of the five-metal mixtures.

Maternal Obesity and the Risk of Selected Foetal Abnormalities (Neural Tube Defects and Orofacial Clefts) In Malaysia: A Retrospective Observational Study

Objective: To evaluate the association between maternal obesity and the risk of selected foetal abnormalities (neural tube defects and orofacial clefts) in Malaysia. Materials and Methods: We conducted a single-centre retrospective observational study on all women who delivered at Hospital Sultanah Aminah Johor Bahru, Malaysia from 1st January 2017 to 31st December 2018. The presence of neural tube defects (NTD) and orofacial clefts (OC) were identified from medical records, including all live births, stillbirths and terminations of pregnancy. All deliveries during the study period were reviewed to collect data on maternal weight, height and demographics. We performed multiple logistic regression to estimate factors contributing to selected anomalies. Results: A total of 28,228 pregnancies were included. There were 57 NTD-affected pregnancies and 34 OCaffected pregnancies identified during the two-year study period. There was no statistically significant association found between maternal obesity and the occurrence of NTDs or OCs. Pre-gestational diabetes had a significant association with NTD-affected pregnancies (aOR 3.454, 95% CI [1.017, 11.725], p=0.091). The highest incidence rate of NTDs was among Malaysian Indians (2.540 per 1,000 deliveries). Malaysian Chinese and Malaysians of other ethnicities were found to have a significantly higher risk of having OC-affected pregnancies with aOR of 2.371 (95% CI [1.035-5.428], p=0.024) and 4.910 (95% CI [1.454-16.579], p=0.024) respectively. Conclusion: Our study showed no significant association between maternal obesity and selected foetal abnormalities (NTD and OC), and that pre-gestational diabetes is a significant risk factor for NTD in Malaysia.

Single and mixed effects of metallic elements in maternal serum during pregnancy on risk for fetal neural tube defects: A Bayesian kernel regression approach

Studies of the association between prenatal exposure to metal elements and risk for neural tube defects (NTDs) have produced inconsistent results. Little research has examined the joint effects and interactions of multiple elements. This study examined 273 women with NTD-affected pregnancies and 477 controls. Cadmium, cobalt, chromium, copper, iron, mercury, manganese, molybdenum, lead, and zinc were quantified in maternal serum. Single and mixed effects of these elements on NTD risk were evaluated with Bayesian kernel machine regression, and the effects of individual elements were validated using logistic regression. As a result, NTD risk increased with the concentration of the mixture of the 10 elements. NTD risk rose as the levels of the five toxic elements increased, with effect sizes larger than the overall analyses, but they decreased, albeit non-significantly, as the levels of the five essential elements increased. Lead and manganese showed risk effects on NTDs, with odds ratios (ORs) of 1.94 (1.76–2.13) and 1.25 (1.14–1.38), respectively, with the remaining nine elements remaining at their median. Molybdenum showed a protective effect against NTDs with an OR 0.87 (0.90–0.94). The single-element results were validated using logistic regression. In conclusion, NTD risk increased with concentrations of the five toxic elements, with lead and manganese being the major contributors. Essential elements showed protective effects against NTD risk.

Maternal ethnicity and the prevalence of British pregnancies affected by neural tube defects.

BackgroundFew data are available on the prevalence of neural tube defects (NTDs) within different ethnic communities of the UK. This study aimed to calculate prevalence estimates for NTD-affected pregnancies, classified by maternal ethnicity, and to explore why variations in prevalence might exist.MethodsA cross-sectional study was performed with data from regional congenital anomaly registers in England and Wales, for NTD-affected pregnancies between 2006 and 2011. Using binomial regression models, we examined NTD-affected pregnancy prevalence estimates and rate ratios (PRRs), by maternal ethnicity.ResultsThe prevalence of NTDs was 12.14 per 10,000 births, with no differences between study years. Anencephaly, encephalocele and spina bifida occurred at 4.98, 1.37 and 5.80 per 10,000 births respectively. Mothers of Indian ethnicity were 1.84 times more likely (95% CI: 1.24, 2.73) and Bangladeshi mothers 2.86 times more likely (95% CI: 1.48, 5.53) than White mothers to have an NTD-affected pregnancy, after adjusting for maternal deprivation and maternal age. The excess prevalence in Indian mothers was specifically for anencephaly (PRR 2.57; 95% CI: 1.52, 4.34), and in Bangladeshi mothers the trend was for increased spina bifida (PRR 3.86; 95% CI: 0.72, 8.69). Anencephaly in Indian mothers was especially associated with other congenital anomalies (non-isolated NTDs).ConclusionsDifferent British ethnic groups vary in NTD prevalence. The excess prevalence of anencephaly as a non-isolated NTD in pregnancies of Indian mothers could indicate involvement of genetic or other unmeasured behavioral factors. Future work is needed to seek etiological explanations for the ethnicity differences and to develop improved methods for primary prevention.

Prenatal exposure to organochlorine pesticides is associated with increased risk for neural tube defects

Neural tube defects (NTDs) are among the most common and disabling fetal congenital defects. Organochlorine pesticides (OCPs) are ubiquitous in the environment. In this study, 119 women who had NTD-affected pregnancies (cases) and 119 women who delivered healthy neonates (controls) were recruited in a rural area of Northern China. We used concentrations of OCPs in umbilical cord tissue as markers of prenatal exposure to investigate the association between in utero exposure to OCPs and NTD risk. Concentrations of 20 OCPs were quantified by gas chromatography–mass spectrometry, and 16 of the 20 OCPs were included in the analyses. Odds ratios and 95% confidence intervals (95% CIs) for the associations between levels of individual OCPs and NTD risk were estimated separately with logistic regression adjusting for potential confounders. The combined effects of exposure to the 16 OCPs as a mixture were analyzed with Bayesian kernel machine regression (BKMR). Logistic regression showed that the risk for NTDs increased 5.44-fold (95% CI, 2.21–13.41) for β-hexachlorocyclohexane, 2.51-fold (95% CI, 1.07–5.86) for endosulfan I, 3.78-fold (95% CI, 1.60–8.89) for endosulfan II, 3.42-fold (95% CI, 1.44–8.12) for ο,ρ'-dichlorodiphenyldichloroethane, and 2.89-fold (95% CI, 1.22–6.86) for ρ,ρ'-dichlorodiphenyltrichloroethane when the concentration of each of these OCPs was above its median (exposed) compared to below its median (non-exposed). Other OCPs were not associated with NTD risk in multivariate models. In BKMR, NTD risk increased almost linearly with concentrations of the 16 OCPs as a mixture, which suggests joint effects on NTD risk. Exposure to α-hexachlorocyclohexane, β-hexachlorocyclohexane, endosulfan II, ο,ρ'-dichlorodiphenyldichloroethane, and ρ,ρ'-dichlorodiphenyldichloroethane was associated with an increased risk for NTDs when levels of the remaining 15 OCPs were taken into account. Taken together, these findings show that prenatal exposure to OCPs is associated with increased risk for NTDs.

Prenatal exposure to barium and the occurrence of neural tube defects in offspring

Neural tube defects (NTDs) have a complex etiology. Few studies have assessed alkaline earth metals exposures and occurrence of NTDs. We examined the association between prenatal exposure to magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba) and risk for NTDs in a case-control study, and assessed the teratogenic effects of Ba on mice. Placentas were collected from 408 women with NTD-affected pregnancies and 593 women who delivered healthy infants, and concentrations of these metals were determined as prenatal exposure markers. The single effect of individual exposure and joint effect of coexposure to these metals were evaluated with logistic regression and Bayesian kernel machine regression (BKMR), respectively. Barium chloride (BaCl2) was intragastrically administered to pregnant ICR mice and fetal mice were examined for NTDs. Median concentrations of Mg and Ba were higher in NTD cases than in controls (Pall < 0.001). In logistic regression, higher levels of Ba were associated with 1.6-fold increased risk for NTDs (95% confidence interval: 1.06–2.43). In BKMR, the joint effect of the four-metal mixture on NTD risk increased steadily with the levels of the mixture. A change in Ba concentration from the 25th to 75th percentile displayed a risk effect when the other three metals were fixed at the 25th, 50th or 75th percentile, while such a change in Ca concentration showed a protective effect when the other metals were held at the 25th or 50th percentile. No interactions among metals were found. In the mouse experiment, dams treated with 200 mg/kg BaCl2 showed 16.8% of NTDs in fetal mice, compared to 2.6% in the untreated control group (P < 0.01). Taken together, higher mixture levels of the four alkaline earth metals were associated with increased risk for NTDs, with Ba being the major contributor for the joint effect. Intragastric administration of Ba can induce NTDs in mice.

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.

The Fallacy of Using Administrative Data in Assessing the Effectiveness of Food Fortification. Comment on: "Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset. Nutrients 2020, 12, 247".

Our objective in this comment is to highlight several limitations in an ecological research study that was published in Nutrients by Murphy and Westmark (2020) in January 2020. The study used data from the Food Fortification Initiative (FFI) website, and applying an ecological study design, made an error of “ecologic fallacy” in concluding that “national fortification with folic acid is not associated with a significant decrease in the prevalence of neural tube defects (NTDs) at the population level”. We list study limitations that led to their erroneous conclusions, stemming from incorrect considerations regarding NTD prevalence, the average grain availability for a country, the fortification coverage in a country, the population reach of fortified foods within a country, and the absence of the consideration of fortification type (voluntary vs. mandatory), country-specific policies on elective terminations for NTD-affected pregnancies, stillbirth proportions among those with NTDs, and fortification implementation. FFI data are derived from many sources and intended for fortification advocacy, not for hypothesis testing. The flawed study by Murphy & Westmark (2020) in Nutrients promotes a confusing and incorrect message to stakeholders, misguides policy makers, and hinders progress in global NTD prevention through a cost-effective, safe, and effective intervention: the mandatory large-scale folic acid fortification of staple foods.

Lower rates of neural tube defects in Israel following folic acid supplementation policy

Neural tube defects (NTDs) are common and disabling congenital malformations that remain a public health challenge despite prevention efforts. In 2000, The Israeli Ministry of Health published recommendations on daily folic acid (FA) supplementation for women of reproductive age and established a national NTD registry. This study aims to evaluate the long-term impact of the FA supplementation policy on NTD rates in Israel and the need for further intervention.In this descriptive report, we present the rate of NTD-affected pregnancies recorded in the registry between 2000 and 2012, their subtype (anencephaly, spina bifida or other), outcome (live birth, stillbirth or pregnancy termination), ethnic group (Jewish, Bedouin and non-Bedouin Muslim) and years of maternal education.The final analysis included 2374 NTD cases reported between 2000 and 2012, compared with 1,668,073 live births. During this period NTD rates decreased from 20.3 to 11.2 cases per 10,000 live births, a 45% reduction. Reductions were seen in rates of spina bifida, anencephaly and encephalocele. NTD rates decreased in all pregnancy outcomes and in all ethnic groups, though rates among Bedouins remain high. Women with higher levels of education tended to have lower NTD rates, and were more prone to choose termination of an affected pregnancy.Following the institution of FA supplementation in Israel, a substantial reduction was seen in NTD rates. Nonetheless, Israeli NTD rates remain higher than in other developed countries. FA interventions should continue to be vigorously implemented, especially in vulnerable populations. The global success of mandatory fortification of grain strongly advocates its consideration in Israel.

Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia

IntroductionFolic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may...

Oxidative–Antioxidative Markers in Pregnant Women with Fetal Neural Tube Defects

Objective We compared markers of oxidative stress (OS) in mothers with and without fetal neural tube defects (NTDs). Methods: Pregnant mothers in the second trimester with NTD-affected fetuses and age, gestational age, and body mass index-matched control mothers with unaffected fetuses were included. Maternal serum thiol-disulfide homeostasis parameters and ischemia-modified albumin (IMA) were measured. Results: In 30 affected mothers compared to 31 controls, disulfide levels, disulfide/native thiol, and disulfide/total thiol ratios were higher; native and total thiol levels and native thiol/total thiol ratios were lower (p < 0.001). Mothers with NTD-affected fetuses had higher levels of IMA than controls (p = 0.025). Conclusion: The thiol-disulfide homeostasis balance was shifted in favor of disulfide, suggesting increased thiol oxidation and OS in the second trimester of NTD-affected pregnancies. Maternal levels of IMA, an oxidatively altered form of albumin, thus a measure of OS, were higher in NTD-affected second trimester pregnancies compared to controls.

Modelling the impact of mandatory folic acid fortification of bread or flour in Ireland on the risk of occurrence of NTD-affected pregnancies in women of childbearing age and on risk of masking vitamin B12 deficiency in older adults

The rate of neural tube defects (NTDs) in Europe has remained similar since the 1990s despite folic acid supplement recommendations (400µg/day) for women of childbearing age. Mandatory folic acid fortification of staple foods has proved effective for reducing the prevalence of NTDs in over 80 countries. This study estimated the impact of addition of folic acid to bread or flour in the Republic of Ireland on reducing the risk of occurrence of NTD-affected pregnancies and the possible risk of masking (undiagnosed) vitamin B12 deficiency in older adults. Analyses were based on the Irish National Adult Nutrition Survey (2008-2010). Folic acid fortification was modelled using DaDiet© software. Estimates were made of the increase in average daily folic acid intake in women (18-50years) and the risk of exceeding the tolerable upper intake level (UL) of 1000µg for folic acid in adults over 50years of age. The fortification scenarios examined would reduce the risk of NTD-affected pregnancies by 8-32%, corresponding to an increase of 39-152μg in the mean daily folic acid intake of WCBA. The risk of masking anaemia associated with vitamin B12 deficiency in older adults would be negligible as the probability of exceeding the UL for folic acid, even by a small amount, is very low (≤ 0.2%). These levels of addition of folic acid to bread or flour would effectively reduce the risk of NTDs while allowing safe consumption of folic acid at current levels from other fortified foods and supplements.

Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies

Women with a previous neural tube defect (NTD)-affected pregnancy are recommended to consume 4,000 μg daily folic acid (FA) for prevention (10 times the general-population recommendation). Protection from doses between 400 and 4,000 μg for this and other higher risk groups is unclear. In the case-control Slone Birth Defects Study (1988-2015), we examined the associations between periconceptional FA doses and NTDs among four higher risk groups: NTD family history, periconceptional antiepileptic drug exposure (AED), pregestational diabetes, and prepregnancy obesity. Mothers completed standardized interviews about pregnancy events and exposures. FA categorizations were based on (a) supplements only and (b) supplements and diet ("total folate"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) (adjusted for age and study center) using logistic regression. Cases and controls included: 45 and 119 with family history, 25 and 108 with AED exposure, 12 and 63 with pregestational diabetes, 111 and 1,243 with obesity. Daily FA supplementation was associated with lower NTD risk compared to no supplementation (adjusted ORs were 0.33 [95% CI 0.13, 0.76] for family history, 0.31 [0.09, 0.95] for AED exposure, 0.25 [0.04, 1.05] for pregestational diabetes, 0.65 [0.40, 1.04] for obesity). Though estimates were imprecise, as total folate increased stronger point estimates were observed, notably among family history. No mothers with a prior NTD-affected pregnancy supplemented with 4,000 μg. Our findings reinforce that all women of childbearing potential should consume at least 400 μg FA/day to protect against NTDs. Higher risk groups may benefit from higher doses.

One-Carbon Cofactor Intake and Risk of Neural Tube Defects Among Women Who Meet Folic Acid Recommendations: A Multicenter Case-Control Study.

We aimed to investigate associations between individual and concurrent (≥2) intakes of one-carbon cofactors vitamins B6 and B12, choline, betaine, and methionine and neural tube defect (NTD) outcomes among mothers meeting the folic acid recommendations. In the Slone Birth Defects Study (case-control design; North America, 1998-2015), mothers of 164 NTD cases and 2,831 nonmalformed controls completed food frequency questionnaires and structured interviews. Estimated intakes of one-carbon cofactors were dichotomized (high vs. low) for all except betaine (low or middle vs. high). We used logistic regression models to estimate odds ratios and 95% confidence intervals adjusted for center, age, and race. The analysis was restricted to mothers with estimated daily total folate intake of ≥400 μg during periconception. Fewer cases, compared with controls, had high intakes for each one-carbon cofactor except betaine, where the starkest contrast occurred in the middle group. Women with concurrent high intakes of B6, B12, choline, and methionine and moderate intake of betaine had approximately half the risk of an NTD-affected pregnancy (odds ratio = 0.49, 95% confidence interval: 0.23, 1.08). These findings suggest that, in the presence of folic acid, one-carbon cofactors-notably when consumed together-might reduce NTD risk. Additional research should inform any changes to clinical recommendations.

Women's periconceptional lowered carbohydrate intake and NTD-affected pregnancy risk in the era of prefortification with folic acid.

A recent study observed women's restricted carbohydrate diet in the year before conception was associated with increased risk of neural tube defect (NTD)-affected pregnancies. That study corresponded to the era of postfortification of folic acid. Because folic acid and carbohydrate measures would derive from similar foods, investigators of that study could not determine whether the increased risk with restricted carbohydrate intake was a consequence of lower folate intake. We extend their novel observation by examining rigorous NTD data prior to folic acid fortification. Data were derived from a population-based case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 449 NTD cases and with mothers of 458 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess macro- and micronutrient intakes based on reported intakes 3 months before conception. Case mothers were twice as likely to have consumed a low carbohydrate (≤5th percentile intake among controls) diet with a crude odds ratio of 2.0 (95% confidence interval, 1.2-3.4). Adjustment for race/ethnicity, education, alcohol intake, and folic acid use made very little difference on the odds ratio. Adjustment for total energy intake appeared to be the only factor to slightly attenuate the odds ratio. Our findings indicate that the association between low carbohydrate intake and NTD risk may not be wholly a function of low folic acid in the postfortification era. Such a finding offers new clues to pursue for the seemingly folate-insensitive NTDs that continue to occur.