No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Maternal Periconceptional Use of Multivitamins and Reduced Risk for Conotruncal Heart Defects and Limb Deficiencies Among Offspring
Abstract
We investigated whether a woman's periconceptional use of a multivitamin containing folic acid was associated with a reduced risk for delivering offspring with a conotruncal heart defect or a limb deficiency. Data were derived from a population-based case-control study of fetuses and liveborn infants with conotruncal or limb defects among a 1987-88 cohort of births in California. Telephone interviews were conducted with mothers of 207 (87.0% of eligible) conotruncal cases, 178 (82.0%) limb defect cases, and of 481 (76.2%) randomly selected liveborn nonmalformed control infants. Reduced risks were observed for maternal use of multivitamins containing folic acid from one month before until two months after conception. Odds ratios and 95% confidence intervals for any compared to no multivitamin use were 0.70 (0.46-1.1) for conotruncal defects and 0.64 (0.41-1.0) for limb defects. Controlling for maternal race/ethnicity, age, education, gravidity, alcohol use, and cigarette use resulted in a further reduction to the odds ratio for conotruncal defects, 0.53 (0.34-0.85), but not for limb defects. Among non-vitamin using women, consumption of cereal containing folic acid was also associated with reduced risk for both defects. Women who take multivitamins have 30-35% lower risk of delivering offspring with either conotruncal or limb defects. This association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin components, or some unknown behaviors that highly correlate with regular use of a multivitamin. However, should the association prove causal, it offers an important opportunity for preventing thousands of serious birth defects.
... Out of 37 included studies, almost 50% were conducted in the United States and Hungary. Specifically, 9 studies were obtained from the United States, [13][14][15][16][17][18][19][20][21] and another 9 studies were from Hungary. [22][23][24][25][26][27][28][29][30] The remaining 7 studies were from China; 31-37 3 studies from Netherlands; 38-40 2 studies from the United States and Canada; 41,42 2 studies from Norway; 43,44 1 study from Denmark and Norway; 45 1 study from Russia; 46 1 study from Northern Ireland; 47 1 study from Australia 48 and 1 study from India. ...
... are case-control studies. [13][14][15][16][17][18][19][20][21][22][23][24][25]28,29,31,[33][34][35][38][39][40][41][42][46][47][48] The remaining 8 are cohort studies 27,32,36,37,[43][44][45]49 and 2 randomized controlled trial (RCT) studies. 26,30 The sample size of included studies ranged from 407 with the use of case-control study design in the United States and Canada to 894,927 participants with the use of cohort study design in Norway. ...
Introduction
Various trial and epidemiological studies consistently documented the association between maternal folic acid supplementations and neural tube defects. However, existing literatures revealed inconclusive findings about maternal periconceptional folic acid supplementations and the risk of congenital heart defects. Thus, the current systematic review and meta-analysis was aimed to estimate the pooled association between maternal periconceptional folic acid supplementations and congenital heart defects.
Methods
Electronic searches of PubMed, Web of Science/Scopus, Cochrane library and Google Scholar databases were conducted to access the required studies published up to March 2021. Predetermined eligibility criteria were used for study selections. Data extraction were independently done on excel. STATA version 14 software was used to calculate the pooled effect size with 95% confidence intervals (95% CI) of maternal periconceptional folic acid supplementations on congenital heart defects using the DerSimonian and Laird random effects meta-analysis (random effects model). Statistical heterogeneity was checked using the Cochran Q test (chi-squared statistic), I ² statistic, and by visual inspection of the funnel plot.
Results
A total of 37 studies of case–control, cohort and randomized controlled trial in nature were included in the review. The finding of the present systematic review and meta-analysis indicated that periconceptional folic acid supplementation significantly decreases the risk of congenital heart defects (risk ratio (RR), 0.79; CI, 0.71, 0.89). Both Cochrane Q test statistic (χ ² = 19.33, p = 0.962) and I ² test statistic (I ² = 0.0%, p = 0.962) did not reveal statistically significant heterogeneity among included studies. In this meta-analysis, traditional funnel plot, Begg’s funnel plot, Egger’s weighted regression (p = 0.13) as well as Begg’s rank correlation statistic (p = 0.676) revealed no evidence of publication bias.
Conclusion
The present systematic review and meta-analysis found that maternal periconception folic acid supplementation was significantly associated with the risk of congenital heart defects. The risk of congenital heart defects was significantly reduced by 21% among those children of mothers who use periconceptional folic acid supplementations in high-income countries. We recommend that a large prospective study be conducted to investigate the association between maternal periconceptional folic acid supplementation and occurrence of congenital heart defect of various types, especially in the developing countries.
... 13,14 Folic acid supplementation and multivitamins containing folic acid have also been reported to show protective effects to prevent congenital limb deficiencies. 15,16 Some reports also show higher risks of limb deficiencies in relation to maternal thyroid problems, 8 preeclampsia, 8 influenza, 17 goiter, 17 and rheumatoid arthritis. 17 Some studies have reported an association between pregestational diabetes and congenital limb deficiencies 8,18-25 but not others. ...
... Time period effects are unlikely because maternity care and the guidelines on drug use during pregnancy were similar after 2008. In this study, we did not have information on maternal folic acid or multivitamin supplementation, which may influence the results.15,16 Overall, over 70% of pregnant mothers in Finland use dietary supplements.37 ...
Background
Risk factors for congenital limb deficiencies are poorly understood.
Objective
To investigate risk factors for congenital limb deficiencies.
Methods
We conducted a nationwide population‐based case–control (1:5) study in Finland, using national registers on congenital anomalies, births, and induced abortions, cross‐linked with data on maternal prescription medicine use obtained from the registers on Reimbursed Drug Purchases and Medical Special Reimbursements. Five hundred and four children with limb deficiencies (241 isolated, 181 syndromic, and 82 other associated anomalies) were identified, and 2,520 controls were matched to cases on residence and year of pregnancy. Non‐syndromic cases (n = 323) were subdivided into longitudinal (n = 120), transverse (n = 123), intercalary (n = 24), mixed (n = 18), and unknown (n = 38) deficiencies.
Results
Pregestational diabetes was associated with all limb deficiencies (adjusted odds ratio [OR] 12.71, 95% confidence interval [CI] 2.37, 68.25) and with isolated (OR 11.42, 95% CI 2.00, 64.60) deficiencies. Primiparity was associated with increased risk of congenital limb deficiencies among all cases (OR 1.49, 95% CI 1.15, 1.93), isolated cases (OR 1.46, 95% CI 1.09, 1.96), and among cases with longitudinal (OR 1.90, 95% CI 1.24, 2.90) and transverse deficiencies (OR 1.75, 95% CI 1.13, 2.70). Young maternal age (<25 years) was associated with all congenital limb deficiencies (OR 1.40, 95% CI 1.02, 1.90) and transverse deficiencies (OR 1.76, 95% CI 1.05, 2.96). Advanced maternal age (≥35 years) was associated with syndromic (OR 1.82, 95% CI 1.19, 2.78) and transverse deficiencies (OR 1.94, 95% CI 1.06, 3.57). Maternal antiepileptic medication was associated with all (OR 5.77, 95% CI 1.75, 19.04) and with isolated cases (OR 3.83, 95% CI 1.02, 14.34).
Conclusions
It is important that pregnant women taking medications, especially antiepileptics, or women with pregestational diabetes are carefully monitored with regard to the occurrence and risk of limb deficiencies in the fetus.
... respectively). This is close to what Shaw et al found in a small case-control study from 1995, where the odds ratio was 0.64 (0.41-1.0) [32]. Canfield et al studied whether grain fortification with folic acid had affected rates of several birth defects, including LRD, using data from 23 state member programs in the National Birth Defects Prevention Network (NBDPN) to analyse prevalence rates before and after grain fortification was implemented [33]. ...
... They found a small, but statistically significant reduced prevalence of upper LRD when comparing post-versus pre-fortification rates. Other studies that have found preventive effects of folate or multivitamin supplements containing folate include the Hungarian double blind placebo controlled trial [34], an American case control study on multivitamin supplementation and risk of several birth defects where 31 LRD cases were included [35], and a study using data from the population based Atlanta Birth defects Case Control study where effects were found mainly for transverse limb defects [32]. A systematic review and meta analysis from 2017 summed up studies on multivitamin use and adverse birth outcomes and found a summary relative risk for limb deficiencies at 0.68 (95% CI, 0.52-0.89) ...
Background:
Following the Thalidomide disaster, the Medical Birth Registry of Norway (MBRN) was established in 1967, with epidemiological surveillance of congenital anomalies as one main aim. Limb reduction defects (LRD) constitute a rare and heterogeneous anomaly group, where correct registration and classification is important for surveillance and research. We aimed at reviewing and recoding LRD cases in the MBRN using the same classification system for all years, and evaluate time trends, characteristics and risk factors, 1970-2016.
Methods:
After reviewing and recoding LRD cases using International Classification of Diseases (ICD), 10th version, for all years, time trends, association with major anomalies, risk factors and infant outcomes were calculated. Generalized linear models for the binomial family with log link gave relative risks (RR) with 95% confidence intervals (CI). Classification of LRD as suggested by European surveillance of congenital anomalies (EUROCAT) was attempted.
Results:
Overall LRD prevalence, 1970-2016, was 4.4 per 10 000, slightly increasing during 1970-1981, followed by relatively stable rates. There were more defects in upper than lower limbs. Defects in hands/fingers were most common, but unspecific descriptions prevented classification of LRD according to EUROCAT. A majority of cases had associated anomalies, the most common being other limb defects, followed by cardiac defects and anomalies in the nervous and digestive systems. From 1999, 26% of LRD cases were terminated, more than 90% of these had associated major anomalies. Stillbirth, neonatal and infant mortality were higher among infants with LRD, also related to associated anomalies. Pre-gestational diabetes was associated with a more than three times increased risk of offspring total LRD, while no association with maternal epilepsy was found. Taking folate/multivitamin supplements before and/or during pregnancy was associated with lower risk of offspring LRD (adjusted RR 0.7; 95% CI 0.6-0.9), while daily smoking did not significantly increase the risk.
Conclusion:
The MBRN now has information on LRD coded by ICD-10 from 1970, but information is not specific enough to use other recommended classification systems. Collecting radiographic descriptions and/or more details from hospital records would improve the quality of the registry data. Taking folate supplements before/during pregnancy may reduce the risk of offspring LRD.
... 9 An analysis of data on the prevalence of limb reduction defects in births before and after fortification of food with FA in Chile, Brazil and Argentina showed no significant change in prevalence before and after the fortification of food. 13 It is possible that differences in folate concentrations between populations and/or changes in folate concentrations over time due to the fortification of food with FA explain the apparent discrepancy between the findings of studies published before 2003, 6,[22][23][24] and also the later case-control study in the USA, 9 and the evaluation of fortification of food with FA. 13 Robataille et al. 9 specifically suggested that higher FA intake among women associated with fortification of food during their study period (1997)(1998)(1999)(2000)(2001)(2002)(2003) might have reduced the protective effect of FA through supplementation. They pointed out that no association between periconceptional use of a vitamin supplement or dietary folate intake and a decreased risk for neural tube defects was observed in a case-control study of births in the USA during the period 1998-2003 after the fortification of food with FA. 25 Because nearly all studies conducted to date have examined multivitamin supplements, little is known about the roles of specific micronutrients. ...
... Associations of specific subtypes of limb reduction defects have been inconsistent, potentially because of small numbers of cases and different methods of classifying cases. 22,23 The current study found a significant preventive effect of FA on upper limb reduction defects in China. No preventive effect of FA on lower limb reduction defects was observed, maybe because of the limited sample size (only four cases). ...
Background:
Folic acid (FA) supplementation prevents neural tube defects, but there are mixed results for its ability to prevent limb reduction defects. We examined whether a preventive effect of FA supplementation exists for congenital limb reduction defects in a large population in China.
Methods:
Data from a large population-based cohort study in China were used to evaluate the effects of FA supplementation on birth defects. All births at 20 complete gestational weeks, including live births, stillbirths and pregnancy terminations, and all structural congenital anomalies, regardless of gestational week, were recorded. A total of 247 831 singleton live births delivered at gestational ages of 20-42 weeks to women from northern and southern China with full information on FA intake were included. Limb reduction defects were classified by subtype and maternal FA supplementation.
Results:
The prevalence of limb reduction defects was 2.7 per 10 000 births among women who took FA compared with 9.7 per 10 000 births among those who did not take FA in northern China; the prevalence was 4.5 and 3.8 per 10 000 births, respectively, in southern China. In both unadjusted and adjusted analyses, the estimated relative risk for upper limb reduction defects [odds ratio (OR) = 0.17, 95% confidence interval (CI): 0.04, 0.63] and total limb reduction defects (OR = 0.24, 95% CI: 0.08, 0.70) in northern China, but not for lower limb reduction defects ,was significantly decreased in association with FA supplementation in northern China. There was no association between FA supplementation and either an increased or decreased risk for limb reduction defects in southern China.
Conclusions:
FA supplementation successfully reduces the prevalence of limb reduction defects in northern China, whose population has low folate concentrations.
... This is in accordance with other studies that have shown higher prevalence of various birth defects, especially congenital neural tube and heart defects, 17,18 linked to folate deficiency and variations in folate pathway genes. Various observational studies [19][20][21][22][23][24][25][26][27][28] have shown the association between peri-conceptional use of folic acid/multi- vitamins and a reduction of birth defects including neural tube defects and CHDs. Folic acid has been recognized as a key factor in cardiovascular development and folic acid antagonists have been shown to increase the risk of CHD. ...
... Adverse pregnancy outcomes, including preeclampsia, recurrent early pregnancy losses, neural tube defect, orofacial clefts, Trisomy 21 and CHD have been reported with high homocysteine levels. 21,23 Further, homocysteine, S-ade- nosyl homocysteine and methionine have been reported as the most important biomarkers to predict CHD in the offspring. 29 It has been suggested that abnormal differentiation of neural crest cells in the presence of high homocysteine concentrations may lead to the development of neural tube and cono-truncal heart defects. ...
Background/objectives:
The objective of the study was to assess the role of variations in serum folate, vitamin B12, homocysteine and the presence of genetic polymorphisms as risk factors for congenital heart disease (CHD) in children.
Subjects/methods:
A total of 32 children with CHD, and their mothers and 32 normal children and their mothers formed the study and control groups, respectively. Serum folate, vitamin B12 and homocysteine as well as genetic polymorphisms MTHFR C677→︀T, MTHFR A1298→︀C, MTR A2756→︀G and MTRR A66→︀G were assessed.
Results:
Low serum folate and genetic polymorphisms MTHFR C677→︀T and MTRR A66→︀G among children and their mothers and high homocysteine among mothers were noted as risk factors for CHD (P<0.05). Vitamin B12 levels were normal and showed no association. Presence of MTHFR C677→︀T and MTRR A66→︀G, both concurrently among children as well as mothers and simultaneously among mother-child pairs, showed several fold increase in the risk for CHD. On multivariate analysis, the risk factors noted for CHD were presence of MTHFR C677→︀T among children and their mothers and MTRR A66→︀G among mothers. Analyses for nutrient-gene interaction revealed significant associations between low serum folate and high serum homocysteine levels, and the presence of selected genetic polymorphisms.
Conclusions:
Low serum folate, high homocysteine and presence of selected genetic polymorphisms among children and their mothers were noted as risk factors for CHD. Nutrient-gene interaction being a modifiable risk factor, the study recommends the use of peri-conceptional folate supplementation with vitamin B12 sufficiency for primary prevention of CHD.European Journal of Clinical Nutrition advance online publication, 6 September 2017; doi:10.1038/ejcn.2017.135.
... Several Studies (Shaw et al., 1995;Czeizel 1996;McBride e al., 2004) reported an association between matenal folate level and congenital heart defects in infants. They showed a significant reduced risk of congenital heart defects among fetuses whose their mother receive folic acid supplementations. ...
Adequate folic acid intake is essential throughout gestation to ensure normal fetal growth anddevelopment. Although the causal relationship between the deficiency of folic acid (Plasma totalhomocysteine"tHcy" level is elevated) and risk of neural tube defects are well proved, the relationbetween folic acid deficiency and other pregnancy complications is still un clear. The present study aimsto review the data published about the relationship between serum folate and pregnancy complications.By reviewing 57 studies, this study concludes that folic acid deficiency leads to elevate plasmahomocysteine, which increased risk of serious complications of pregnancy and delivery. So, it isrecommended for women to take 400 microgram of folic acid supplements daily, before pregnancy toprevent those complications.
... También a partir de estudios que investigan los efectos de la suplementación vitamínica con ácido fólico, se observa relación entre CC, anomalías por reducción de miembros y DCTN y así es que se comprueba disminución de riesgo para defectos cardíacos conotruncales, defectos de miembros y DCTN en madres suplementadas con ácido fólico desde un mes antes del embarazo y hasta completar el segundo mes de gestación. En las mujeres que no reciben suplemento vitamínico, el consumo de cereal fortificado también se asocia con una disminución del riesgo del 30 al 35% para estos defectos (559). ...
... There is strong evidence that periconceptional folic acid intake decreases the risk of conotruncal heart defects [20][21][22][23][24][25][26][27]. Folate-related genes, such as MTHRF, are known to influence the risk of heart defects via interactions with maternal folic acid intake [28]. ...
Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (ORmeta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (ORmeta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (ORmeta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (ORmeta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.
... This result is statistically significant (p = 0.01), which might be one factor for the occurrence of NTDs in the case groups. Previous studies indicated the evidence of reduced NTD occurrence ranging between 35 and 75%, related with the consumption of multivitamins containing folic acid and food with high folate content (20)(21)(22)(23). We found that 57% of the cases and 33.5% of the controls had serum folate levels below 6 ng/ml, which is a folate deficiency state. ...
Background
Neural 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.
Objective
The 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 Methods
A 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.
Results
Only 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.
Conclusion
Folate 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.
... The characteristics of all studies are summarized in Supplemental Table 1. Of them, more than half of the studies (61.9%) were published after 2010, and 5 studies performed in the United States [17][18][19][20][21], 9 studies in Europe [22][23][24][25][26][27][28][29][30], 4 studies in China [31][32][33][34], 2 studies in Canada [35,36], and 1 study in Australia [37]. Figure 2 represents the results of the association between maternal FA supplementation and the risk of CHD in this study. The overall results of this meta-analysis showed the decreased risk of CHD with maternal FA supplementation (OR = 0.82, 95% CI: 0.72-0.94; ...
Background
Folic acid (FA), as a synthetic form of folate, has been widely used for dietary supplementation in pregnant women. The preventive effect of FA supplementation on the occurrence and recurrence of fetal neural tube defects (NTD) has been confirmed. Incidence of congenital heart diseases (CHD), however, has been parallelly increasing worldwide. The present study aimed to evaluate whether FA supplementation is associated with a decreased risk of CHD.
Methods
We searched the literature using PubMed, Web of Science and Google Scholar, for the peer-reviewed studies which reported CHD and FA and followed with a meta-analysis. The study-specific relative risks were used as summary statistics for the association between maternal FA supplementation and CHD risk. Cochran's Q and I² statistics were used to test for the heterogeneity.
Results
Maternal FA supplementation was found to be associated with a decreased risk of CHD (OR = 0.82, 95% CI: 0.72–0.94). However, the heterogeneity of the association was high (P < 0.001, I² = 92.7%). FA supplementation within 1 month before and after pregnancy correlated positively with CHD (OR 1.10, 95%CI 0.99–1.23), and high-dose FA intake is positively associated with atrial septal defect (OR 1.23, 95%CI 0.64–2.34). Pregnant women with irrational FA use may be at increased risk for CHD.
Conclusions
Data from the present study indicate that the heterogeneity of the association between maternal FA supplementation and CHD is high and suggest that the real relationship between maternal FA supplementation and CHD may need to be further investigated with well-designed clinical studies and biological experiments.
... Although the association between maternal FAS and CHD appeared plausible considering the significance of folate in human metabolisms, the findings of epidemiologic studies conducted in different regions (e.g., the United States [33], Norway [13,29] and Hungary [34,35]) were contradictory due to discrepancies in design, bias, or confounding; they could also be explained by regional differences in dietary vitamin insufficiency. An analysis of data from the China Nutrition and Health Surveillance, 2015-2017, found that folate status among pregnant Chinese women is still suboptimal, and that taking FAS would result in adequate serum folate concentrations [36]. ...
Objectives
It was the first time to examine the role of maternal polymorphisms of FOLR1 gene and FOLR2 gene, as well as their interactions with maternal folic acid supplementation (FAS), in the risk of ventricular septal defect (VSD).
Methods
A case-control study was conducted with 385 mothers of VSD infants and 652 controls. The exposures of interest were FAS and FOLR1 gene and FOLR2 gene polymorphisms. The logistic regression model was used for accessing the strength of association.
Results
After controlling for the potential confounders, women who did not utilize folic acid had a substantially higher risk of VSD (aOR = 2.25; 95% CI: 1.48 to 3.43), compared to those who did. We also observed genetic polymorphisms of FOLR1 gene at rs2071010 (GA vs. GG: aOR = 0.63, 95%CI: 0.45 to 0.88) and rs11235462 (AA vs. TT: aOR = 0.53, 95%CI: 0.33 to 0.84), as well as FOLR2 gene at rs651646 (AA vs. TT: aOR = 0.46, 95%CI: 0.30 to 0.70), rs2298444 (CC vs. TT: aOR = 0.58, 95%CI: 0.36 to 0.91) and rs514933 (TC vs. TT: aOR = 0.57, 95%CI: 0.41 to 0.78) were associated with a lower risk of VSD. Furthermore, there was a statistically significant interaction between maternal FAS and genetic polymorphisms at rs514933 on the risk of VSD (FDR_P = 0.015).
Conclusions
The maternal genetic polymorphisms of the FOLR1 gene and FOLR2 gene, as well as FAS and their interactions, were shown to be significantly associated with the risk of VSD in offspring.
... While it is recognized that folic acid during pregnancy can decreases the incidence of NTDs in newborns 12,13 . Its connotation with less incidence of CHDs is only expressive 14,15 . The exact action of folic acid on morphogenesis of cardiac tissues still vague, it may help in the cardiac neural cells migration that subsidize to the progress of the embryonic heart 16,17 . ...
... CHD is considered a folic acid-sensitive birth defect because women who take folic acid-containing multivitamins early in pregnancy have a 30-40% lower risk of having offspring with these heart defects [7,8]. Folic acid is an essential B vitamin that the human body cannot synthesize; it can only be obtained from the diet. ...
Background
We performed the present study to better elucidate the correlation of reduced folate carrier-1 (RFC1) A80G (rs1051266) polymorphism with the risk of congenital heart disease (CHD).
Material/Methods
According to the designed search strategy, a systematic literature search was performed through the PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, VIP, and Wan Fang databases to collect published case-control studies on the correlation between RFC1 A80G polymorphism and CHD. All relevant studies up to October 1, 2019 were identified. The odds ratio (OR) and 95% confidence interval (CI) of the genotype distribution were used as the effect indicators.
Results
A total of 6 eligible studies was finally included in our meta-analysis, including 724 children with CHD, 760 healthy children, 258 mothers of the children with CHD, and 334 mothers of healthy control children. The meta-analysis revealed that for fetal analysis, only in the heterozygous model (GA vs GG, OR=1.36, 95% CI [1.06, 1.75], P=0.02) was RFC1 A80G polymorphism associated with risk of CHD. In maternal analysis, 3 genetic models of RFC1 A80G polymorphism increased the risk of CHD: the allelic model (A vs G, OR=1.36, 95% CI [1.07, 1.71], P=0.01), the homozygote model (AA vs GG, OR=2.99, 95%CI [1.06, 8.41], P=0.04), and the dominance model (GA+AA vs GG, OR=1.53, 95%CI [1.08, 2.16], P=0.02).
Conclusions
The maternal RFC1 A80G polymorphism has a strong correlation with CHD. Compared with the G allele, the A allele increases the risk of CHD by 0.36-fold.
... Чаще всего для таких целей используются эпидемиологические исследования случай-контроль, при которых сравниваются частоты конкретных генетических вариантов (полиморфизмов) среди пораженных и здоровых индивидов. Например, в ряду эпидемиологических исследований было продемонстрировано, что периконцепционное употребление фолиевой кислоты женщинами репродуктивного возраста снижало вероятность развития дефектов нервной трубки, а также врожденных пороков сердца, расщелины губы/нёба и редукционных пороков конечностей [4]. При изучении причин этого эмпирически полученного факта было показано, что полиморфный вариант гена метилентетрагидрофолатредуктазы (MTHFR 677C>T) кодирует термолабильный фермент с пониженной активностью, что может приводить к снижению концентрации фолата и повышению гомоцистеина в сыворотке носителей такого полиморфизма, а это и является фактором риска возникновения дефектов нервной трубки и конотрункальных пороков сердца [5]. ...
Congenital malformations are the main cause of infant and child morbidity and mortality worldwide. Most congenital malformations are represented by non-syndromic forms, their etiology has not yet been studied. However, the latest genetic technologies have opened up new possibilities in the study of congenital malformations. The article presents latest achievements in the genetics of non-syndromic forms of congenital malformations. Genome-wide association study (GWAS) is an effective method for identifying gene variants associated with a predisposition to the congenital malformations; this method helps to identify correlations between single nucleotide polymorphism (SNP) and certain malformations. Numerous studies demonstrate that in addition to SNP the copy number variations (CNV) play an important role in the etiology of some birth defects (for example, congenital heart defects). It has been established that 5—10% of isolated congenital heart defects can be associated with rare CNV. Next-generation sequencing (NGS) is expected to play important role in the identification of birth defect etiology. The authors have obtained the first data on the genes involved in the development of malformations such as congenital heart defects, neural tube defects, facial clefts.
... The efficacy of periconceptional folic acid intake in reducing NTDs is well established (7). Some reports indicate association also with reduced risk of other mid-line defects, such as cono-truncal heart malformations, ventricular septal defect and atrial septal defect (8,9), gastroschisis (10), and hypospadias (11). For oro-facial clefts, there are inconsistent reports on the association with periconceptional folic acid. ...
Background: There is an increasing awareness to ankyloglossia (tongue-tie) in infants, with marked increase in its report in the medical literature. Some reports indicate increase in prevalence. Whether the increase ankyloglossia rate is a real phenomenon or merely reflects
increased awareness and reports has to be determined. One explanation for the increasing ankyloglossia rates is the growing trend of breast feeding initiation, often impaired by ankyloglossia, which brings it to medical attention. We propose an alternative hypothetical
explanation based on increasing utilization of periconceptional folic acid supplementation for the prevention of neural tube defects (NTDs). Inadequate folic acid supply during organogenesis
impairs cell division, and the mid-line structures are at the highest risk. We postulated that higher folic acid supply during organogenesis might enhance tissue synthesis with tighter closure of
mid-line structures including the lingual frenulum, resulting in ankyloglossia. Methods: To assess this hypothesis, we undertook an observational case control study comparing folic acid utilization before pregnancy in mothers of infants with and without ankyloglossia. Infants with ankyloglossia (n=85) were compared to a control group without ankyloglossia (n=140). Results: There was a slight, insignificant elevated frequency of reported utilization of folic acid (“any intake”) among mothers of infants with ankyloglossia compared with controls (74.1% and 66.4%, respectively). This difference was slightly higher, yet insignificant when folic acid intake
“in most days” was considered (65.9% and 53.6%, respectively, OR=1.67, 95%CI=0.93-3.05, P = 0.07). In contrast, the reported intake of pre-conceptional folic acid “on a regular basis” was
significantly higher among mothers of infants with ankyloglossia compared with controls (54.1% and 25.7%, respectively, OR=3.41, 95%CI=1.85-6.27, p < 0.0001). Interpretation: The reported association between higher frequency of regular pre-conceptional folic acid intake and ankyloglossia, supports the hypothesis for this association. More studies are required to test this hypothesis.
... Maternal vitamin consumption, especially folic acid supplementation during pregnancy, has consistently been shown to reduce the risk of neural tube defects [7,8]. It may also reduce the risk of other congenital malformations such as cardiovascular defects [9,10], oral clefts [11,12], urinary tract defects [13,14] and limb-reduction defects [10,12]. Folic acid is the fully oxidized monoglutamyl form of folate, a water-soluble B vitamin [15]. ...
Objectives:
Maternal folic acid supplementation is considered mandatory in almost every country in the world to prevent congenital malformations. However, little is known about the association of maternal folic acid intake with the occurrence of childhood cancer. Hence, this study aimed to determine the effects of maternal folic acid consumption on the risk of childhood cancer.
Methods:
A total of 158 related articles were obtained from PubMed, Google Scholar, Scopus, and ProQuest using standardized keywords, of which 17 were included in the final review.
Results:
Eleven of the 17 articles showed a significant protective association between maternal folic acid supplementation and childhood cancer. Using a random-effects model, pooled odds ratios (ORs) showed a protective association between maternal folic acid supplementation and childhood acute lymphoblastic leukaemia (OR, 0.75; 95% confidence interval [CI], 0.66 to 0.86). However, there was no significant association between maternal folic acid supplementation and acute myeloid leukaemia (OR, 0.70; 95% CI, 0.46 to 1.06) or childhood brain tumours (OR, 1.02; 95% CI, 0.88 to 1.19).
Conclusions:
Maternal folic acid supplementation was found to have a protective effect against childhood acute lymphoblastic leukaemia. Thus, healthcare professionals are recommended to provide regular health education and health promotion to the community on the benefits of folic acid supplementation during pregnancy.
... Deficiencies in folate and Cbl are fetal development risk factors for pathogenic conditions, including neural tube, limb, cardiac, and jaw defects [35][36][37][38]. Cbl, required for folate dependent homocysteine metabolism, is often deficient in pregnant women [39]. ...
Purpose
Vitamin B12 (cobalamin, Cbl) plays a role in the recycling of folate, which is important in pregnancy. Transcobalamin II (TCN2) and transcobalamin receptor (TCblR) proteins are involved in the cellular uptake of Cbl. TCN2 binds Cbl in the plasma, and TCblR binds TCN2-Cbl at the cell surface. Therefore, we investigated the potential association between polymorphisms in Cbl transport proteins, TCN2 and TCblR, and recurrent implantation failure (RIF) susceptibility.
Methods
The genotypes of TCN2 67A>G, TCN2 776C>G, and TCblR 1104C>T were determined for RIF patients and healthy controls using a polymerase chain reaction restriction fragment length polymorphism assay. Additionally, statistical analysis was performed to compare the genotype frequencies between RIF patients and controls.
Results
The TCN2 67 polymorphism AG type was associated with RIF risk. Some allele combinations that contained the TCN2 67 polymorphism G allele were associated with increased RIF risk, whereas other allele combinations that contained the TCblR 1104 polymorphism T alleles were associated with decreased RIF risk. In genotype combination analysis, two combinations containing the TCN2 67 polymorphism AG type were associated with RIF risk.
Conclusion
Our study showed that the polymorphisms of TCN2 and TCblR are associated with RIF and are potential genetic predisposing factors for RIF among Korean women. Additionally, our findings support a potential role for TCN2 and TCblR in RIF among Korean women. However, further studies are required to investigate the role of the polymorphisms in those proteins and RIF because the roles of the TCN2 and TCblR polymorphisms in RIF are not clear.
... Presumptive neural tissue has an unusually high requirement for folates. The most telling evidence that neural crest cells have a high demand for folates is, unlike most other embryonic tissue, neural crest cells express very high levels of the message for folate receptors [11][12][13][14][15]. It has been clearly demonstrated that mRNA for Folr1, the murine ortholog of the human FRα (described later in this chapter), is expressed in neuroepithelial cells of both the neural plate and contiguous areas that would include presumptive cranial neural crest cells [12,13,15]. ...
Birth defects are a global problem that affect approximately 6% of all births [1]. In the United States, birth defects are the leading cause of hospitalizations [2], medical expenditures [3], and death in the fi rst year of life [4]. Worldwide, at least 3.3 million children under the age of 5 years die each year because of a serious birth defect [1]. Indeed, birth defects are one, if not the leading, health care concern for the youngest members of our societies.
... This CHD subgroup involves cardiac structures that are partially derived from cell lineages [5], and includes malformations such as tetralogy of Fallot (TOF), pulmonary atresia with ventricular septal defect (PA/VSD), double outlet of right ventricle (DORV), transposition of the great arteries (TGA), persistent truncus arteriosus (PTA), and interrupted aortic arch (IAA). CTD was considered to be a folate-sensitive birth defect because women who take multivitamins containing folic acid early in pregnancy are at approximately a 30-40% reduced risk of delivering offspring with these heart defects [6,7]. Although the protective mechanism of folic acid is unclear, evidence has been reported that genetic variations that alter the activity of key enzymes in the folate pathway could influence the risk of such heart defects [8][9][10]. ...
Background:
Conotruncal heart defects (CTDs) are a subgroup of congenital heart defects that are considered to be the most common type of birth defect worldwide. Genetic disturbances in folate metabolism may increase the risk of CTDs.
Methods:
We evaluated five single-nucleotide polymorphisms (SNPs) in genes related to folic acid metabolism: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), solute carrier family 19, member 1 (SLC19A1 G80A), methionine synthase (MTR A2576G), and methionine synthase reductase (MTRR A66G), as risk factors for CTDs including various types of malformation, in a total of 193 mothers with CTD-affected offspring and 234 healthy controls in a Chinese population.
Results:
Logistic regression analyses revealed that subjects carrying the TT genotype of MTHFR C677T, the C allele of MTHFR A1298C, and the AA genotype of SLC19A1 G80A had significant 2.47-fold (TT vs. CC, OR [95% CI] = 2.47 [1.42-4.32], p = 0.009), 2.05-2.20-fold (AC vs. AA, 2.05 [1.28-3.21], p = 0.0023; CC vs AA, 2.20 [1.38-3.58], p = 0.0011), and 1.68-fold (AA vs. GG, 1.68 [1.02-2.70], p = 0.0371) increased risk of CTDs, respectively. Subjects carrying both variant genotypes of MTHFR A1298C and SLC19A1 G80A had a higher (3.23 [1.71-6.02], p = 0.0002) increased risk for CTDs. Moreover, the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.
Conclusions:
Our data suggest that maternal folate-related SNPs might be associated with the risk of CTDs in offspring.
... Folate deficiency during human embryonic development leads to severe congenital defects in the neural tube (spina bifida) and neural crest development, such as defects in the peripheral nervous system, orofacial clefts and heart defects (Antony and Hansen, 2000;Beaudin and Stover, 2007;Blom et al., 2006;Li et al., 2011;Pitkin, 2007;Shaw et al., 1995;Tolarova, 1982). These defects raise the question of why the developing neural tube and the neural crest are more vulnerable to folate deficiency than other tissues. ...
Folate deficiency has been known to contribute to neural tube and neural crest defects, but why these tissues are particularly affected, and which are the molecular mechanisms involved in those abnormalities are important human health questions that remain unanswered. Here we study the function of two of the main folate transporters, FolR1 and Rfc1, which are robustly expressed in these tissues. Folate is the precursor of S-adenosylmethionine, which is the main donor for DNA, protein and RNA methylation. Our results show that knockdown of FolR1 and/or Rfc1 reduced the abundance of histone H3 lysine and DNA methylation, two epigenetic modifications that play an important role during neural and neural crest development. Additionally, by knocking down folate transporter or pharmacologically inhibiting folate transport and metabolism, we observed ectopic Sox2 expression at the expense of neural crest markers in the dorsal neural tube. This is correlated with neural crest associated defects, with particular impact on orofacial formation. By using bisulfite sequencing, we show that this phenotype is consequence of reduced DNA methylation on the Sox2 locus at the dorsal neural tube, which can be rescued by the addition of folinic acid. Taken together, our in vivo results reveal the importance of folate as a source of the methyl groups necessary for the establishment of the correct epigenetic marks during neural and neural crest fate-restriction.
... The prevalence of TGA is higher in infants of diabetic mothers [169,170] as well as in cases of in vitro fertilization [171]. On the other hand, the periconceptional use of folic acid reduces the risk of CHDs, including TGA, and its intake is recommended as a protective factor against a large spectrum of congenital malformations [172]. ...
Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left–right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects.
... Based on the evident reduction of NTDs after periconceptional folic acid fortification (FAF) [9][10][11][12], three countries in South America have implemented national fortification policies: Chile in January 2000 [13], Argentina in December 2003 [14], and Brazil in July 2004 [15]. While Chile and Argentina have fortified wheat flour with 2.2 mg/kg to provide an estimated average of 400 μg/day of folic acid as recommended by the Centre for Disease Control [16]; Brazil has fortified wheat and corn flour at a lower dose (1.5mg/kg) [15,17]. ...
Background
Historically, neural tube defects (NTDs) have predominated in female infants but the reasons remain unclear. In South America, the pre- folic acid fortification (FAF) rates of NTDs were around 18/10,000 births for females and 12/10,000 births for males, with an estimated sex ratio (male/female) of 0.67. During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial. To date and to our knowledge, however, no studies specifically focusing on these changes to test this hypothesis directly have been undertaken. The aim of this study was to analyze changes in the sex ratio of infants with NTDs after FAF in South American countries.
Materials and methods
With a descriptive cross-sectional study design, 2,597 infants with isolated NTDs born between 1990 and 2013 in 3 countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network were included: (Chile N = 521 and Argentina N = 1,619 [with FAF policies]; Venezuela N = 457 [without FAF policies; used as control]; total births = 2,229,561). The differences-in-differences method and Poisson regressions were used to evaluate the sex ratio shift from female to male before vs. after FAF, and to assess whether these differences were related to the fortification.
Results and conclusions
In Chile and Argentina the prevalence of NTDs, particularly anencephaly and cervico-thoracic spina bifida, showed a greater reduction rate in females than in males after FAF, resulting in a change of the sex ratio of infants with NTDs. Some mechanisms possibly involved in this differential reduction are proposed which might be useful to identify the pathogenesis of NTDs as a whole and specifically of those susceptible to the protective effect of folic acid.
... Randomized trials have shown that folic acid supplementation before pregnancy can reduce the risk of having a baby with a neural tube defect (1,2). Further follow-up of the Hungarian randomized trial (3) and reports from observational studies also suggested a role of vitamin supplementation in preventing other congenital malformations (4)(5)(6)(7)(8). Additionally, prenatal vitamin supplementation was linked to decreased risks of preterm delivery, low birth weight (9,10), and fetal death (10). ...
Background: Total homocysteine (tHcy) measured in serum or plasma is a marker of folate status and a risk factor for cardiovascular disease.
Objective: Our objective was to investigate associations between tHcy and complications and adverse outcomes of pregnancy.
Design: Plasma tHcy values measured in 1992–1993 in 5883 women aged 40–42 y were compared with outcomes and complications of 14492 pregnancies in the same women that were reported to the Medical Birth Registry of Norway from 1967 to 1996.
Results: When we compared the upper with the lower quartile of plasma tHcy, the adjusted risk for preeclampsia was 32% higher [odds ratio (OR): 1.32; 95% CI: 0.98, 1.77; P for trend = 0.02], that for prematurity was 38% higher (OR: 1.38; 95% CI: 1.09, 1.75; P for trend = 0.005), and that for very low birth weight was 101% higher (OR: 2.01; 95% CI: 1.23, 3.27; P for trend = 0.003). These associations were stronger during the years closest to the tHcy determination (1980–1996), when there was also a significant relation between tHcy concentration and stillbirth (OR: 2.03; 95% CI: 0.98, 4.21; P for trend = 0.02). Neural tube defects and clubfoot had significant associations with plasma tHcy. Placental abruption had no relation with tHcy quartile, but the adjusted OR when tHcy concentrations >15 μmol/L were compared with lower values was 3.13 (95% CI: 1.63, 6.03; P = 0.001).
Conclusion: Elevated tHcy concentration is associated with common pregnancy complications and adverse pregnancy outcomes.
... Multiple studies have suggested that multivitamins containing folic acid may reduce the risk of CHDs (5)(6)(7)(8). Efforts to elucidate the mechanism by which folic acid exerts a protective effect have evaluated the metabolism of 3 folate-dependent pathways-DNA nucleotide synthesis pathway, homocysteine-methionine pathway, and glutathione-transsulfuration pathway (Figure 1). ...
Background: Women who have had pregnancies that were affected by nonsyndromic congenital heart defects have alterations in the homocysteine-methionine pathway that may indicate increased exposure to oxidative stress or reduced antioxidant defense or both.
Objective: Our goal was to establish a maternal metabolic risk profile for nonsyndromic congenital heart defects that would enhance current preventive strategies.
Design: Using a case-control design, we measured biomarkers of the transsulfuration pathway in a population-based sample of women whose pregnancies were affected by congenital heart defects (331 cases) and in a control group of women (125 controls). Plasma concentrations of reduced and oxidized glutathione, vitamin B-6, homocysteine, cysteine, cysteinylglycine (CysGly), and glutamylcysteine (GluCys) were compared between cases and controls after adjustment for lifestyle and sociodemographic variables.
Results: After covariate adjustment, cases had significantly lower mean plasma concentrations of reduced glutathione (P < 0.0001), GluCys (P < 0.0001), and vitamin B-6 (P = 0.0023) and significantly higher mean concentrations of homocysteine (P < 0.0001) and oxidized glutathione (P < 0.0001) than did controls.
Conclusions: Biomarkers of oxidative stress involved in the transsulfuration pathway were significantly higher in women with pregnancies affected by congenital heart defects than in women without such a history. Further analysis of relevant biomarkers of oxidative stress and genetic and environmental factors is required to define the basis for the observed alterations. Identifying the nature and extent of alterations in biomarkers of oxidative stress may suggest primary intervention strategies and provide clues to a greater understanding of the pathogenesis of congenital heart defects.
... However, the results of these studies are not consistent. [1][2][3][4][5] Some studies have shown a decrease in the rates of one or more defects, whereas others have not confirmed these findings. [6][7][8][9][10] It has been suggested that maternal/placental microenvironment before conception has influenced the development of the fetal organs and that cardiac defects can be explained by abnormalities of the microenvironment of the fetus. ...
Objective
It is suggested that folic acid and/or multivitamins, taken periconceptionally, have a role in the prevention of many congenital anomalies. The aim of this study was to determine the serum micronutrient levels in mother–infant pairs with CHD compared with those with healthy newborns and their mothers.
Methods
Serum levels of folic acid, homocysteine, zinc, vitamin A, vitamin D, and vitamin B 12 were measured from 108 newborns with CHD (study group) and 103 healthy newborns (control group). The mothers’ micronutrient levels were also measured simultaneously.
Results
When compared with healthy newborns, for both maternal and neonatal data, homocysteine and zinc levels were higher and vitamin D levels were lower in the study group. In multivariate analysis, only maternal high zinc levels were associated with CHD in the newborns (p=0.02, OR: 0.9, 95% CI 0.8–0.9). The results did not change when analysed for truncal anomalies including truncus arteriosus, tetralogy of Fallot, and d-transposition of great arteries. There were positive correlations between maternal and neonatal levels of micronutrients, except vitamin B 12 .
Conclusion
We thought that high homocysteine and zinc levels and low vitamin D levels in mother–infant pairs might have a role in the aetiopathogenesis of CHD. Large-scale, prospective studies are needed to clarify the role of micronutrients in CHDs.
... Randomized and cohort studies conducted in the 1980s and 1990s show that folic acid supplementation significantly reduces the risk of neural tube defects [5][6][7][8][9][10][11][12]. The follow--up observations also indicate that folate supplementation reduces the occurrence of heart defects, urinary tract defects, limb defects, cleft lip and palate and preeclampsia [3,4,[13][14][15]. ...
... Epidemiological studies that investigated the association between folic acid intake and the risk of CHDs have reached conflicting results. Twelve studies found that folic acid supplementation before and/or during pregnancy reduced the risk of CHDs [8][9][10][11][12][13][14][15][16][17][18][19], six studies reported no association between folic acid supplements and CHD risk [20][21][22][23][24][25], while one study found a significantly increased risk of CHDs associated with folic acid supplement use [26]. Three studies investigated dietary folate intake and risk of CHDs and found no association [27][28][29]. ...
It has been reported that folic acid supplementation before and/or during pregnancy could reduce the risk of congenital heart defects (CHDs). However, the results from limited epidemiologic studies have been inconclusive. We investigated the associations between maternal folic acid supplementation, dietary folate intake, and the risk of CHDs.A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. After exclusion of stillbirths and multiple births, a total of 94 births were identified with congenital heart defects, and 9,993 births without any birth defects. Unconditional logistic regression was used to estimate the associations.Compared to non-users, folic acid supplement users before pregnancy had a reduced risk of overall CHDs (OR: 0.42, 95% CI: 0.21-0.86, Ptrend = 0.025) after adjusted for potential confounders. A protective effect was observed for certain subtypes of CHDs (OR: 0.37, 95% CI: 0.16-0.85 for malformation of great arteries; 0.26, 0.10-0.68 for malformation of cardiac septa; 0.34, 0.13-0.93 for Atrial septal defect). A similar protective effect was also seen for multiple CHDs (OR: 0.49, 95% CI: 0.26-0.93, Ptrend = 0.004). Compared with the middle quartiles of dietary folate intake, lower dietary folate intake (
... Previous epidemiological studies showed that periconceptional use of multivitamins containing folic acid reduces the risk of having a child with CHD [11,12]. Shaw et al., [13] were the first to show that the maternal use of these vitamins during the sensitive period of heart development reduced the risk of conotruncal heart defects in particular. Hernandez-Diaz et al., [14] also suggested that folate is a key factor in cardiovascular development by showing an increased risk of CHD after maternal exposure to folate antagonists during the first trimester of pregnancy. ...
Background
Recent advances in genetic technology have had a significant impact on the practice of clinical genetics and the diagnosis of genetic syndromes associated with cardiac malformations.
Aim
The present study was aimed to determine whether biomarkers of the folic acid pathway, including homocysteine and methionine metabolism are altered among non pregnant women who have had a previous pregnancy affected by congenital heart defects.
Subjects and methods
The study was conducted on 50 women attending the Medical Genetics center and the Pediatric Cardiology Clinic, Faculty of Medicine, Ain Shams University for follow up. Mothers were subdivided into: Group 1 (Cases): 25 mothers with a history of congenital heart defects in previous children. Group 2 (Controls): 25 mothers and their children didn’t have any birth defects including congenital heart defects. In both groups women will be excluded: If they were pregnant or taking folate antagonist medications (antiepileptic drugs) or vitamin supplementations at the time of the study. Measurement of plasma concentration of: Vitamin B-12, folic acid, Homocysteine, Methionine, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), by using Radio immunoassay kit was done.
Results
There is a significant difference between cases and controls as regards history of early neonatal deaths (28%) in cases versus (4%) in controls (P < 0.05). The study also revealed that the most frequent congenital cardiovascular malformation is VSD (32%) followed by ASD (20%).As regards biomarker concentrations all, were significantly different between case and control subjects except for methionine.
Conclusion
An elevated levels of maternal homocysteine is an independent risk factor for congenital heart defects. Finally: There is an increasing need for professionals to apply and interpret genetic testing in a clinically meaningful way for prevention of congenital heart defects.
Background
Although many studies shown that the risk of congenital heart disease (CHD) was closely related to genetic and environmental factors, the exact mechanism was still unclear. This study was to assess the association of maternal folic acid supplementation (FAS), the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene polymorphisms in offspring and their interactions with the risk of CHD and its subtypes.
Methods
A case-control study was conducted on 595 children with CHD and 605 healthy child controls. The multivariate logistic regression model was used to assess the association of maternal FAS, offspring MTRR gene polymorphisms and their interactions with CHD and its subtypes.
Results
This study shown that maternal FAS was significantly associated with a reduced risk of CHD (OR = 0.55, 95%CI: 0.36–0.83) and its subtypes including ASD (OR = 0.25, 95%CI: 0.14–0.45), VSD (OR = 0.42, 95%CI: 0.27–0.64), and CTD (OR = 0.23, 95%CI: 0.09–0.59) in offspring. Offspring MTRR gene polymorphisms at rs162048 (GG vs AA: OR = 2.05, 95%CI: 1.35–3.13), rs1802059 (AA vs GG: OR = 5.13, 95%CI: 2.15–12.23; GA vs GG: OR = 1.81, 95%CI: 1.35–2.43), rs10380 (TT vs CC: OR = 2.27, 95%CI: 1.20–4.31) and rs1801394 (GG vs AA: OR = 1.58, 95%CI: 1.02–2.42) were significantly associated with the risk of CHD, and similar results were also found for three subtypes of CHD. Additionally, a statistically significant interaction between maternal FAS and offspring MTRR gene polymorphism at rs1802059 was observed (OR = 0.38, 95%CI: 0.15–0.94). Among children who had a variant genotype at rs1802059, the risk of CHD was significantly decreased when their mother used folate for this pregnancy compared with mothers not using folate.
Conclusions
In those of Chinese descent, maternal FAS and offspring MTRR gene polymorphisms are significantly associated with the risk of CHD and its three subtypes. Furthermore, maternal FAS may help to offset some of risks of CHD due to offspring MTRR genetic variants. However, more studies with prospective designs and larger samples are needed to confirm our findings.
Trial registration
Registration number: ChiCTR1800016635; Registration time: 14/06/2018.
As the development of modern medicine continues to improve the survival rate of infants at birth, there is an increasing demand for rehabilitation. The causes of several common diseases in pediatric rehabilitation can be traced back to the pregnancy and perinatal period. Common diseases originated in utero and requiring rehabilitation in childhood include cerebral palsy, congenital muscular torticollis, congenital heart disease, congenital talipes equinovarus, and congenital scoliosis. Cerebral palsy (CP), also known as brain paralysis, describes a group of permanent disorders in the development of posture and central motor function accompanied by activity limitation. It results from nonprogressive damage to the brain of the developing fetus in utero or infants after birth. Congenital muscular torticollis (CMT) is caused by the unilateral thickening or shortening of the sternocleidomastoid muscle, which is associated with the in utero development of sternocleidomastoid muscle and intrauterine fetal posture. Preoperative and postoperative rehabilitation of congenital heart disease plays an important role in improving prognosis and promoting normal physical and mental development in children. Congenital talipes equinovarus may be attributed to the genetic or chromosomal abnormalities or compression in utero. Congenital scoliosis is usually caused by abnormal formation and segmentation of the spine and ribs in utero. Most children with these conditions can manifest as growth retardation, immature brain development, poor physical fitness, susceptibility to infection, and motor, cognitive, speech, and social development disorders, which require early rehabilitation to promote recovery, improve function, facilitate motor, cognitive and speech development, prevent complications, and eventually improve their long-term quality of life as far as possible. The rehabilitation and follow-up process should continue throughout the infancy or even to the early childhood.
The failure to repress transcription of repetitive genomic elements can lead to catastrophic genome instability and is associated with various human diseases. As such, multiple parallel mechanisms cooperate to ensure repression and heterochromatinization of these elements, especially during germline development and early embryogenesis. A vital question in the field is how specificity in establishing heterochromatin at repetitive elements is achieved. Apart from trans-acting protein factors, recent evidence points to a role of different RNA species in targeting repressive histone marks and DNA methylation to these sites in mammals. Here, we review recent discoveries on this topic and predominantly focus on the role of RNA methylation, piRNAs, and other localized satellite RNAs.
Retrotransposons, including LINE‐1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy‐paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double‐strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi‐layered regulatory processes to prevent the dangerous effects of their expression. In recent years significant progress was made in revealing how retrotransposon biology intertwines with general post‐transcriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post‐transcriptional factors in the biology of retrotransposons, focusing on LINE‐1. I emphasize general RNA metabolism such as methylation of adenine (m6A), RNA 3’ end polyadenylation and uridylation, RNA decay, and translation regulation. I discuss effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles. Retrotransposons, such as LINE‐1 (here drawn as a dangerous snake), are part of genomes and are strictly controlled by various mechanisms, including post‐transcriptional regulation (here represented by the primitive human). This might either suppress them, or activate them. Retrotransposon activation leads to their propagation and a mutual co‐existence with the host genome, potentially creating new regulatory circuits.
Transposable elements (TEs) are active in neuronal cells raising the question whether TE insertions contribute to risk of neuropsychiatric disease. While genome-wide association studies (GWAS) serve as a tool to discover genetic loci associated with neuropsychiatric diseases, unfortunately GWAS do not directly detect structural variants such as TEs. To examine the role of TEs in psychiatric and neurologic disease, we evaluated 17,000 polymorphic TEs and find 76 are in linkage disequilibrium with disease haplotypes (P < 10-6 ) defined by GWAS. From these 76 polymorphic TEs, we identify potentially causal candidates based on having insertions in genomic regions of regulatory chromatin and on having associations with altered gene expression in brain tissues. We show that lead candidate insertions have regulatory effects on gene expression in human neural stem cells altering the activity of a minimal promoter. Taken together, we identify 10 polymorphic TE insertions that are potential candidates on par with other variants for having a causal role in neurologic and psychiatric disorders.
Objective
Congenital heart disease (CHD) is the most common type of congenital birth defect, but little is known about possible modifiable behavioral risk factors. The study aimed to assess whether intake of periconceptional or postconceptional multivitamin was associated with a decreased risk of CHD in the offspring.
Study Design: The study population comprised 15,567 women from the Copenhagen Pregnancy Cohort with complete data on multivitamin intake before and during pregnancy, who gave birth to live-born singletons from October 2012 to October 2016. Main outcome measure was CHD defined according to the International Classification of Diseases (ICD), 10th revision. Cases of CHD were classified into five subgroups based on the clinical phenotype: 1) Conotruncal defects, 2) Left ventricular outflow tract obstruction, 3) Right ventricular outflow tract obstruction, 4) Septal defects, and 5) Other CHD. Multivariate logistic regression analyses were performed with adjustment for maternal age, chronic disease, assisted reproductive technology, smoking status, and alcohol consumption.
Results
Of the 15,567 included women, 31.9% reported a daily multivitamin intake in the periconceptional period, 53.7% in the postconceptional period, and 14.4% women did not report a daily multivitamin intake. The prevalence of CHD in the population was 0.7% (n=112). Periconceptional and postconceptional multivitamin intake was not associated with risk of overall CHD in offspring: Adjusted OR was 0.64 (95% CI 0.36-1.13) and 0.77 (95% CI 0.47-1.30), respectively.
Conclusion
The current large cohort study did not show a preventive effect of multivitamin intake in the periconceptional or postconceptional period on the risk of CHD in the offspring.
Epidemiological approaches to the study of cardiovascular malformations (CVMs) face challenges of disease definition, nomenclature, changing diagnostic methodologies, the rarity of the disease in the general population, and the incorporation of current knowledge on genetics and morphogenesis into designing studies to investigate risk factors and implement preventive strategies. Previous studies, especially the population-based Baltimore-Washington Infant Study, have documented variability in the prevalence of specific types of CVM by time, place, and personal characteristics and have highlighted the potential prevention of diabetes-associated heart malformations through timely medical management of pre-conception diabetes. Left-sided obstructive heart defects have been identified as targets for new studies of genetic risk factors. Potential environmental risk factors for CVMs also have been identified, such as organic solvents and pesticides, coincident with the emergence of new strategies to study genetic susceptibility and gene-environment interactions. Increased collaborative, multicenter research on these and other factors, such as nutritional factors in early pregnancy, offers new hope for potentially reducing the burden of CVM in the population. Am. J. Med. Genet. (Semin. Med. Genet.) 97:319–325, 2000. © 2001 Wiley-Liss, Inc.
Congenital heart disease (CHD) is one of the major debilitating birth defects resulting in significant impact on neonatal and child mortality globally. The etiology of CHD is complex and multifactorial. Many causative genes responsible for CHDs have been identified from the familial forms previously. Still, the non-Mendelian inheritance and predominant sporadic cases have stimulated research to understand the epigenetic basis and environmental impact on the incidence of CHD. The fetal epigenetic programming affecting cardiac development is susceptible to the availability of key dietary factors during the crucial periconceptional period. This article highlights the need and importance of in-depth research in the new emerging area of maternal nutritional epigenetics and CHD. It summarizes the current research and underlines the limitations in these types of studies. This review will benefit the future research on nutrition as a modifiable environmental factor to decrease the incidence of CHD.
Background:
Maternal folic acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study.
Methods:
We assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of ≥400 mcg as a potential effect modifier.
Results:
We analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake ≥400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null.
Conclusions:
Similar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake ≥400 mcg, with some associations somewhat stronger in this group.
The association between folic acid supplementation and birth defects other than neural tube defects remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999-2013. We used the EUROCAT classification system to define 11 organ-specific major birth defect groups (nervous system, eye, ear-face-neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs, and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999-2013, 888,294 (99.0%) live born infants, 6,633 (0.7%) stillborn infants, and 2,135 (0.2%) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared to infants of non-users, the adjusted relative risk (aRR) was 0.94 (95% confidence intervals (CIs) 0.91-0.98) for total birth defects (n=18,382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0.58; 0.42-0.80, n=377), genital organ defects (aRR 0.81; 0.72-0.91, n=2,299), and limb defects (aRR 0.81; 0.74-0.90, n=3,409). Protective associations were also suggested for neural tube defects, respiratory system defects, and digestive system defects although CIs included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear-face-neck, heart or oral clefts were not observed.
Women planning a pregnancy and pregnant women in the first trimester are recommended to use folate-containing supplements in order to prevent neural tube defects. The prevention of many cases of neural tube defects with folic acid is evident from meta-analysis, randomized controlled trials (RCTs), observational studies in humans and experimental evidence in animals. However, folate supplementation in pregnant women or a higher maternal folate status has been shown to be protective against other adverse birth outcomes such as congenital heart defects, low birth weight, and preterm birth. Additionally, infants and children with congenital heart defects often show disorders in folate metabolism (low folate, higher homocysteine, or low vitamin B12). Maternal genotype for several folate metabolizing genes has shown associations with the risk of having a child with congenital heart defect. There is some evidence that folate supplementation could have differential effects on sub-types of congenital heart defects, but it is not clear whether the prevention time window is the same as for neural tube defects. Some studies proposed a high dose of folic acid (in mg/d) to prevent congenital heart defects in women with a high global risk (such as those with diabetes or obesity). There are currently no RCTs to support that doses of folic acid in mg range are more effective than the currently recommended 400-800 µg/d taken at least 2-3 months before conception until the end of the first trimester.
Objective: To investigate the effectiveness of the metabolic markers homocysteine, vitamin B12, folate, and B-type natriuretic peptide in maternal and cord blood for detecting congenital heart disease.
Methods: Homocysteine, vitamin B12, folate, and B-type natriuretic peptide concentrations in maternal and cord blood samples at term were measured in the case (n = 42) and control (n = 43) groups with and without fetal congenital heart disease, respectively. Additionally, newborns with congenital heart disease were divided into two subgroups: those with (n = 30) and without (n = 8) 6-month infant survival. The case and control groups and case subgroups were compared with each other with respect to maternal age, gravidity, parity, gestational age at delivery, birth weight, maternal and cord blood levels of homocysteine, vitamin B12, folate, and B-type natriuretic peptide, and arterial cord blood pH and base excess values. Statistical analyses were performed using SPSS for Windows, version 22.0. The Student’s t-test, the Mann–Whitney U test, and the χ² test were used where appropriate. A p value of < .05 was considered statistically significant.
Results: Mean maternal age, birth weight and median gravidity, parity and gestational age at delivery were not significantly different between the case and control groups, as well as between the case subgroups (all p > .05). Concentrations of metabolic markers in maternal blood were not significantly different between the two groups (p > .05). Homocysteine and B-type natriuretic peptide levels in cord blood samples were significantly higher, whereas folate levels were significantly lower in the case group compared with the control group (all p < .05). Cord blood B-type natriuretic peptide levels were significantly higher (p < .05) and arterial cord blood pH values were significantly lower (p < .05) in the case subgroup without 6-month infant survival compared with the case subgroup with 6-month infant survival.
Conclusion: High cord blood B-type natriuretic peptide and homocysteine levels and low cord blood folate levels at term may be useful for predicting congenital heart disease in the neonate. Neonates with congenital heart disease who have high cord blood B-type natriuretic peptide and low pH values may have adverse outcomes.
Data S1. A detailed discussion on previous findings from studies of the association between folic acid and congenital heart defects.
Table S1. The Classification System for Congenital Heart Defect Phenotypes
Table S2. Relative Risk of Congenital Heart Defect* (Overall), Severe Heart Defect†, Conotruncal Defect‡, and Septal Defect§ by Maternal Intake of Folic Acid Supplements in the Periconceptional Period Among 94 228 Births the DNBC (Danish National Birth Cohort), Denmark, 1996–2003
Table S3. Relative Risk of congenital Heart Defect* (Overall), Severe Heart Defect†, Conotruncal Defect‡, and Septal Defect§ by Maternal Intake of Folic Acid Supplements in the Periconceptional Period Among 102 985 Births in MoBa (Norwegian Mother and Child Cohort Study), Norway, 1999–2009
Table S4. Relative risks of Congenital Heart Defect* (Overall), Severe Heart Defect†, Conotruncal Defect‡, and Septal Defect§ by Maternal Intake of Folic Acid Supplements, Adjusting for Covariates Using 3 Models, Combining 94 228 Births∥ in the DNBC (Danish National Birth Cohort), Denmark, 1996–2003, and 102 985 Births∥ in MoBa (Norwegian Mother and Child Cohort Study), Norway, 1999–2009
Table S5. Relative Risk of Congenital Heart Defects* (Overall), by Maternal Intake of Folic Acid Supplements in the Periconceptional Period, in Sensitivity Analyses With Restrictions to Live Births, Singleton Births, Mother Without Heart Defect, or Planned Pregnancies, Combining 94 228 Births in the DNBC (Danish National Birth Cohort), Denmark, 1996–2003, and 102 985 Births in MoBa (Norwegian Mother and Child Cohort Study), Norway, 1999–2009
Background
Evidence 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 Results
Women 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.
Conclusions
Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.
The primary aim of preconception and interconception care is to improve maternal health and birth outcome for mother, infant and family through prevention and interventions. Preconception care is defined by interventions that aim to identify and modify biomedical, behavioral, and social risks to a woman's health through prevention and management. These interventions focus on risk factors that can be modified and/or eliminated prior to conception or in early pregnancy in order to impact overall pregnancy health and birth outcome. There is strong evidence for daily consumption of adequate amounts of folic acid prior to conception and the first trimester of pregnancy in reducing the risk for neural tube defect (NTDs). The incidence of chronic medical disorders such as diabetes, hypertension, and obesity has steadily increased over the past several decades in reproductive age women. Women on angiotensin‐converting enzyme (ACE) inhibitors should discontinue the medication prior to pregnancy because of the teratogenicity associated with the drug.
Conotruncal heart defects are considered to be one of the most common types of birth defect worldwide. Genetic disturbances in folate metabolism such as Thymidylate synthase may increase risk for conotruncal heart defects. We evaluated two common Thymidylate synthase polymorphisms, including the 28 bp tandem repeat in the promoter enhancer region of the 5′-untranslated region and the 6 bp deletion in the 3′-untranslated region, as risk factors of conotruncal heart defects including various subtypes of malformations, in a total of 193 mothers with conotruncal heart defect in offspring and 234 healthy controls in the Chinese population. Logistic regression analyses revealed that mothers who were homozygotes with deletion (−/−) had a 1.8-fold (odds ratio: 1.8; 95% confidence interval: 1.0–3.0, p = 0.040) increased risk for conotruncal heart defect in offspring, respectively, when compared with mothers carrying the wild type (+/+) genotype. Consistently, individuals carrying the genotype −/− of the Thymidylate synthase 6 bp deletion also had higher plasma homocysteine levels compared to the mothers carrying the genotype +/+ in the control and conotruncal heart defect groups (p = 0.006 and p = 0.004, respectively). However, our results showed that Thymidylate synthase 28 bp tandem repeat polymorphism was not associated with risk for conotruncal heart defect and plasma homocysteine level. In conclusion, our data suggest that the maternal Thymidylate synthase 6 bp deletion polymorphism might be associated with plasma homocysteine level and risk for conotruncal heart defect in offspring.
Heart disease and machine learning are the two different words where one is related to medical field and another one to artificial intelligence. In medical filed most of them are facing the problems with the heart disease and machine learning is developing area in computer science. Heart disease is general called cardiac disease where it gives the more data or information, it is to be collected to give the reports for the patients and the machine learning also requires the data for predicting and to solve the problems. Machine learning techniques are used in prediction of heart diseases where it gives the faster prediction with less computation time and better accuracy to progress their health. Heart disease prediction requires lot of data for predicting and in cloud computing also we have more data and the data available in cloud it is difficult to analyze. So we use machine learning algorithms or techniques to predict the heart disease and the in the similar way we can apply these algorithms or techniques to predict or analyze the data that is available in cloud. In this paper we are going to use machine learning algorithms called Backpropagation Algorithm and later we use optimization algorithm later. Backpropagation algorithm deals with the artificial neural networks. Backpropagation is a method used to calculate the error contribution of each neuron after a batch of data (in image recognition, multiple images) is processed. This is used by an enveloping optimization algorithm to adjust the weight of each neuron, completing the learning process for that case. Machine learning algorithms and techniques are used for recognize the intensity of risk issues in humans and it helps the patients to take safety measures in well advances to save the patient's life.
Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition. It has therefore been suggested that increased LINE-1 activity may be the cause of aberrant innate immune activation in AGS Here, we establish that, contrary to expectations, RNase H2 is required for efficient LINE-1 retrotransposition. As RNase H1 overexpression partially rescues the defect in RNase H2 null cells, we propose a model in which RNase H2 degrades the LINE-1 RNA after reverse transcription, allowing retrotransposition to be completed. This also explains how LINE-1 elements can retrotranspose efficiently without their own RNase H activity. Our findings appear to be at odds with LINE-1-derived nucleic acids driving autoinflammation in AGS.
Retrotransposable elements are stretches of DNA that encode proteins with the inherent ability to insert their own RNA or another RNA by reverse transcriptase as DNA into a new genomic location. In humans, the only autonomous retrotransposable elements are members of the Long INterspersed Element‐1 (LINE‐1) family. LINE‐1s may cause gene inactivation and human disease. We present a brief summary of the published knowledge about LINE‐1s in humans and the RNAs that these elements can transpose, and we focus on the effect of LINE‐1‐mediated retrotransposition on human neutrophil function.
Retrotransposons can cause genetic disease by two primary mechanisms: 1) insertional mutagenesis and 2) non‐allelic homologous recombination. The only known neutrophil function affected by retrotransposition is that of NADPH oxidase activity. Four patients with chronic granulomatous disease (CGD) are known with LINE‐1‐mediated insertional inactivation of CYBB, the gene that encodes the gp91phox component of the phagocyte NADPH oxidase. In addition, five CGD patients had a large deletion in the NCF2 gene, encoding the p67phox component, and two CGD patients had a similar deletion in NCF1, encoding p47phox. These deletions were caused by non‐allelic homologous recombination between two Alu elements at the borders of each deletion. Alu elements have spread throughout the human genome by LINE‐1 retrotransposition.
Probably, the occurrence of LINE‐1‐mediated insertions causing autosomal CGD has been underestimated. It might be worthwhile to reinvestigate the DNA from autosomal CGD patients with missplice mutations and large deletions for indications of LINE‐1‐mediated insertions.
This article is protected by copyright. All rights reserved.
Background: Genetic or nutritional disturbances in folate metabolism may affect embryonic development because of the critical role of folate in nucleotide synthesis and methylation reactions. The possible role of a mild deficiency in methylenetetrahydrofolate reductase (MTHFR) and low dietary folate in pregnancy outcomes and heart morphogenesis requires further investigation.
Objective: We investigated the effect of mild MTHFR deficiency, low dietary folate, or both on resorption rates, on length and weight, and on the incidence of heart malformations in murine embryos.
Design: Female Mthfr +/+ and +/− mice were fed a control diet (CD) or a folic acid–deficient diet (FADD) before mating with male Mthfr +/− mice. On gestational day 14.5, implantation and resorption sites were recorded and viable embryos were examined for gross malformations, growth delay, and congenital heart defects.
Results: Plasma homocysteine in Mthfr +/− dams and in FADD-treated dams was significantly higher than that in Mthfr +/+ dams and CD-treated dams, respectively. A significantly higher rate of resorption and greater developmental delay were observed in hyperhomocysteinemic mice than in CD-treated +/+ dams. Heart defects were identified in 4 of 11, 5 of 10, and 4 of 10 litters from CD-treated +/−, FADD-treated +/+, and FADD-treated +/− dams, respectively, but not in any of those from CD-treated +/+ dams (0/11 litters).
Conclusion: Our findings suggest that mild MTHFR deficiency, low dietary folate, or both in the dams increase the incidence of fetal loss, intrauterine growth retardation, and heart defects. These data support the benefit of folic acid supplementation in pregnant women, particularly in those with MTHFR deficiency.
The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing such during the periconceptional period. The extent to which folic acid supplementation can reduce the first occurrence of defects is not known.
We conducted a randomized, controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects. Women planning a pregnancy (in most cases their first) were randomly assigned to receive a single tablet of a vitamin supplement (containing 12 vitamins, including 0.8 mg of folic acid; 4 minerals; and 3 trace elements) or a trace-element supplement (containing copper, manganese, zinc, and a very low dose of vitamin C) daily for at least one month before conception and until the date of the second missed menstrual period or later.
Pregnancy was confirmed in 4753 women. The outcome of the pregnancy (whether the fetus or infant had a neural-tube defect or congenital malformation) was known in 2104 women who received the vitamin supplement and in 2052 who received the trace-element supplement. Congenital malformations were significantly more prevalent in the group receiving the trace-element supplement than in the vitamin-supplement group (22.9 per 1000 vs. 13.3 per 1000, P = 0.02). There were six cases of neural-tube defects in the group receiving the trace-element supplement, as compared with none in the vitamin-supplement group (P = 0.029). The prevalence of cleft lip with or without cleft palate was not reduced by periconceptional vitamin supplementation.
Periconceptional vitamin use decreases the incidence of a first occurrence of neural-tube defects.
A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A, D, B1, B2, B-6, C, and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups - namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid.
We studied the association between multivitamin use during the periconceptional period and the occurrence of neural tube defects using data from the Atlanta Birth Defects Case-Control Study. There were 347 babies with neural tube defects who were live born or stillborn to residents of metropolitan Atlanta from 1968 through 1980. The 2829 control-babies born without birth defects were randomly selected through birth certificates. Periconceptional multivitamin use was defined as reported use for each of the three months before conception through the first three months of pregnancy. Mothers who reported not using multivitamins any time during the six-month period were defined as nonusers. Fourteen percent of mothers reported periconceptional multivitamin use and 40% reported nonuse. Multivitamin users were different from nonusers in a number of demographic, health-related, and life-style characteristics. We found an overall apparent protective effect of periconceptional multivitamin use on the occurrence of neural tube defects, with a crude estimated relative risk of 0.40 (95% confidence interval, 0.25 to 0.63). At this time, it is not possible to determine whether this apparently lower risk is the direct result of multivitamin use or the result of other characteristics of women who use multivitamins.
(JAMA 1988;260:3141-3145)
We examined the relation of multivitamin intake in general, and folic acid in particular, to the risk of neural tube defects in a cohort of 23 491 women undergoing maternal serum α-fetoprotein screening or amniocentesis around 16 weeks of gestation. Complete questionnaires and subsequent pregnancy outcome information was obtained in 22 776 pregnancies, 49 of which ended in a neural tube defect. The prevalence of neural tube defect was 3.5 per 1000 among women who never used multivitamins before or after conception or who used multivitamins before conception only. The prevalence of neural tube defects for women who used folic acid-containing multivitamins during the first 6 weeks of pregnancy was substantially lower—0.9 per 1000 (prevalence ratio, 0.27; 95% confidence interval, 0.12 to 0.59 compared with never users). For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the nonusers and the prevalence ratios were close to 1.0.
(JAMA. 1989;262:2847-2852)
A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups--namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid.
Multiple congenital abnormalities have been produced in the rat by an extremely short and transitory deficiency of pteroylglutamic acid instituted during the early part of pregnancy, the “critical” period of differentiation and organogenesis. A deficiency period of only 48 hours during this period, after implantation on day 7 and before day 12, resulted in 70 to 100% abnormal young or fetal death. In contrast a 24-hour period of deficiency after implantation had practically no effect on fetal development nor did a 72-hour deficiency period before implantation. The earlier phases of embryonic development were more severely affected by the same length of deficiency than the later phases. Throughout the experiments the mothers receiving the PGA-deficient diet gained weight and were in good condition, regardless of death or abnormality of the fetuses.
The abnormalities produced included multiple types of defects of the nervous, ocular, skeletal, respiratory, cardiovascular, and urogenital systems; the diaphragm and body walls were also affected. The type of anomaly and the incidence varied both with the duration and with the time of instituting the deficiency.
The California Birth Defects Monitoring Program maintains a population-based birth defects registry of structural congenital malformations, monitoring over 600000 resident births annually. Cases are actively ascertained from hospitals and genetic centres throughout California and from selected facilities in adjacent states. Field staff identify presumptive cases from careful review of medical records. Diagnostic and demographic information is collected from in-patient and genetic centre medical charts for children diagnosed with major structural malformations between conception and 1 year of age. The application of these data to epidemiological investigations of birth defects is described in the context of prevalence studies, aetiological studies and evaluative studies, and the strengths and limitations of the registry data are discussed.
The pioneering studies of Smithells et al. showed the reduction of recurrent neural-tube defects (NTD) after periconceptional folic acid-containing multivitamin supplementation. The Hungarian Periconceptional Service was established in 1984, and this primary health care system offered a chance to organize a randomized controlled trial to check whether the supplementation of a multivitamin containing 0.8 mg of folic acid during the periconceptional period is appropriate for the reduction of a first occurrence of NTD in the family. This found a reduction of approximately 90% of primary NTD. An unexpected finding was a significant reduction in the rate of congenital abnormalities overall: 20.6 per 1000 in the 'multivitamin' group, and 40.6 per 1000 in the 'trace-element-like' placebo group (RR = 0.53, 95% CI: 0.35-0.70). When the 6 cases of NTD were excluded, this difference in the rates of major congenital abnormalities between the two study-groups remained very highly significant (p < 0.0001). Cardiovascular malformations and urinary tract defects were particularly affected. These findings were confirmed in the Hungarian cohort-controlled trial and by observational studies in other countries. Two questions remain to be answered. Is folic acid better alone or with multivitamins? What is the optimal dose of folic acid? Overall, the Hungarian experiences of periconceptional care have shown not only primary prevention of several severe congenital abnormalities but also a good cost-benefit balance.
The classification for congenital limb malformations adopted by the American Society for Surgery of the Hand, the International Federation of Societies for Surgery of the Hand, and the International Society of Prosthetics and Orthotics is presented. This method groups similar patterns of deficiencies according to the parts that have been primarily affected by certain embryological failures, whether the insult involves a total part (skeletal and soft tissue) or only the dermomyofascial structures. The main categories of this classification are (I) failure of formation of parts. (II) failure of differentiation (separation) of parts, (III) duplication, (IV) overgrowth, (V) undergrowth, (VI) congenital constriction band syndrome, and (VII) generalized skeletal abnormalities. The rationale and method of use of the classification are discussed. This method has been tested and used in a variety of centers and has been found to be properly conceived and practical.
In a population-based case-control study of dietary folate and neural tube defects, information was collected by interview and self-administered questionnaires from the mothers of cases with only neural tube defects, from the mothers of matched control infants with defects other than neural tube defects, and from the mothers of matched live-born infants with no birth defects. The association of midline birth defects (excluding neural tube defects) with dietary folate intake in the first 6 weeks of pregnancy was assessed by restricting the analysis to the 59 mothers of infants with midline defects in the first control group and comparing them with their matched control infants in the second control group. The crude and adjusted odds ratios for dietary folate and for folic acid supplementation were close to one, and all confidence intervals embraced unity. These data do not provide evidence of an association between midline birth defects (excluding neural tube defects) and either dietary folate or folic acid supplementation.
The California Birth Defects Monitoring Program maintains a population-based birth defects registry of structural congenital malformations, monitoring over 600,000 resident births annually. Cases are actively ascertained from hospitals and genetic centres throughout California and from selected facilities in adjacent states. Field staff identify presumptive cases from careful review of medical records. Diagnostic and demographic information is collected from in-patient and genetic centre medical charts for children diagnosed with major structural malformations between conception and 1 year of age. The application of these data to epidemiological investigations of birth defects is described in the context of prevalence studies, aetiological studies and evaluative studies, and the strengths and limitations of the registry data are discussed.
We examined the relation of multivitamin intake in general, and folic acid in particular, to the risk of neural tube defects in a cohort of 23,491 women undergoing maternal serum alpha-fetoprotein screening or amniocentesis around 16 weeks of gestation. Complete questionnaires and subsequent pregnancy outcome information was obtained in 22,776 pregnancies, 49 of which ended in a neural tube defect. The prevalence of neural tube defect was 3.5 per 1000 among women who never used multivitamins before or after conception or who used multivitamins before conception only. The prevalence of neural tube defects for women who used folic acid-containing multivitamins during the first 6 weeks of pregnancy was substantially lower--0.9 per 1000 (prevalence ratio, 0.27; 95% confidence interval, 0.12 to 0.59 compared with never users). For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the nonusers and the prevalence ratios were close to 1.0.
A population-based case-control study was conducted to test the hypothesis that the risk of the occurrence of neural-tube defects in infants with no other birth defects (isolated neural-tube defects) is associated inversely with the maternal dietary intake of free and/or total folate in early pregnancy. Information was collected from the mothers of 77 case subjects with isolated neural-tube defects who were born in Western Australia from 1982 to 1984, from the mothers of 77 control subjects with birth defects other than neural-tube defects (control group 1) and from the mothers of 154 control subjects with no birth defects (control group 2). The case and control subjects were matched individually by the date of the mother's last menstrual period. Odds ratios were adjusted for a number of potentially-confounding variables, such as the country of birth of the parents, paternal social class, previous pregnancy outcome, interval between index and previous pregnancy and pregnancy order. Crude and adjusted odds ratios showed a protective effect of an increasing intake of free folate in the first six weeks of pregnancy. Adjusted odds ratios, with reference to the lowest quartile of intake, (and their 95% confidence intervals) were 0.72 (0.25-2.08), 0.37 (0.11-1.23) and 0.31 (0.10-0.97) for quartiles 2-4 when control group 1 was used, and 0.44 (0.17-1.13), 0.34 (0.13-0.90) and 0.16 (0.06-0.49) when control group 2 was used. Similar, but weaker, trends were seen when total folate intake was the exposure variable. These findings support the hypothesis that the dietary intake of folate in early pregnancy protects against the occurrence of isolated neural-tube defects in infants. Measures of postpartum dietary folate and of postpartum serum and red-cell folate levels showed no association with the occurrence of neural-tube defects in infants.
Because the causes of conotruncal cardiac defects are poorly understood, a case-control study was conducted to investigate maternal risk factors for conotruncal cardiac defects. Eligible cases included all infants who were born from 1976 through 1980 to residents of the five county metropolitan Atlanta area and diagnosed with truncus arteriosus, transposition of the great arteries or tetralogy of Fallot. Eligible control infants were a sample of comparable infants without birth defects. Maternal interviews were conducted for 73% (83 of 114) of eligible cases and 72% (1,303 of 1,804) of eligible control infants. The results showed increased risks associated with maternal diabetes (odds ratio 5.6; 90% confidence interval 2.5 to 15.6), maternal stress related to job loss, divorce, separation or death of a close friend or relative (odds ratio 2.4; 90% confidence interval 1.4 to 4.2) and a history of a sibling with a cardiac defect (odds ratio 4.8; 90% confidence interval 2.2 to 10.5). The statistical power of the data was adequate to rule out threefold or greater increases in risk for a wide variety of other exposures, including maternal illnesses other than diabetes, contraceptive use, nonmedicinal drugs (for example, coffee, tea, alcohol, cigarettes, street drugs), employment and education. This population-based study offers no clues that could explain either the high rate of transposition of the great arteries or the temporal trend of an increasing rate of tetralogy of Fallot in Atlanta.
We studied the association between multivitamin use during the periconceptional period and the occurrence of neural tube defects using data from the Atlanta Birth Defects Case-Control Study. There were 347 babies with neural tube defects who were live born or stillborn to residents of metropolitan Atlanta from 1968 through 1980. The 2829 control-babies born without birth defects were randomly selected through birth certificates. Periconceptional multivitamin use was defined as reported use for each of the three months before conception through the first three months of pregnancy. Mothers who reported not using multivitamins any time during the six-month period were defined as nonusers. Fourteen percent of mothers reported periconceptional multivitamin use and 40% reported nonuse. Multivitamin users were different from nonusers in a number of demographic, health-related, and life-style characteristics. We found an overall apparent protective effect of periconceptional multivitamin use on the occurrence of neural tube defects, with a crude estimated relative risk of 0.40 (95% confidence interval, 0.25 to 0.63). At this time, it is not possible to determine whether this apparently lower risk is the direct result of multivitamin use or the result of other characteristics of women who use multivitamins.
In accordance with a previous protocol, a second cohort of 254 mothers with a history of previous neural tube defect (NTD) births was before a subsequent conception and continued until the time of the second missed menstrual period. There were 2 NTD recurrences (0.9% of 234 infants/fetuses examined), which is significantly fewer than the 11 NTD recurrences (5.1% of 215 infants/fetuses examined) born to 219 unsupplemented (US) mothers in the same centres over the same period. When the data for the two cohorts were combined, the overall recurrence rates were 0.7% for 454 fully supplemented (FS) mothers and 4.7% for 519 US mothers. The recurrence rates after 1 previous NTD were 0.5% for FS and 4.2% for US mothers: after 2 or more previous NTDs, 2.3% for FS and 9.6% for US. There were no recurrences among the offspring of a further 114 mothers whose duration of supplementation fell short of the full regimen (partially supplemented, PS).
A randomized controlled double-blind trial was undertaken in south Wales to prevent the recurrence of neural-tube defects in women who had had one child with a neural-tube defect. Sixty women were allocated before conception to take 4 mg of folic acid a day before and during early pregnancy and 44 complied with these instructions. Fifty-one women were allocated to placebo treatment. There were no recurrences among the compliant mothers but two among the non-compliers and four among the women in the placebo group. Thus there were no recurrences among those who received supplementation and six among those who did not; this difference is significant (p = 0.04). It is concluded that folic acid supplementation might be a cheap, safe, and effective method of primary prevention of neural-tube defects but that this must be confirmed in a large, multicentre trial.
With a case-control study, we investigated whether periconceptional intake of supplemental or dietary folate reduced the risk of having a neural tube defect (NTD)-affected pregnancy. Mothers of 549 (88% of eligible) cases and 540 (88%) controls were interviewed in person about vitamin supplements used in either the 3 months before or the 3 months after conception and also about usual diet in the 3 months before conception. Women with any use of a folic acid-containing vitamin in the 3 months before conception had a lower risk of having an NTD-affected pregnancy [odds ratio (OR) = 0.65; 95% confidence interval (CI) = 0.45-0.94]. ORs were similar for 3 levels (< 0.4, 0.4-0.9, and > 0.9 mg per day) of average daily intake of folic acid. Any level of use in the first 3 months after conception resulted in a lowered risk as well (OR = 0.60; 95% CI = 0.46-0.79). Reduced risks were less marked for Hispanics and were not observed among women who graduated from college. Modest reduced risks were noted among non-vitamin users whose estimated daily dietary intake of folate was more than 0.227 mg. We observed decreasing risk with increasing folate intake from combined dietary sources and vitamin supplements. A reduction in NTD risk associated with folate intake is consistent with other studies; however, the reduced risk may be particular to subsets of the population, primarily non-Hispanic women and women whose education does not exceed high school.
Women are advised to take folic acid before they conceive as a precaution against neural-tube defects. However, the use of folic acid in preventing orofacial clefts is unknown. We investigated whether a woman's periconceptional use of multivitamins containing folic acid was associated with a reduced risk of orofacial clefts. We derived data from a population-based case-control study of fetuses and liveborn infants with orofacial anomalies among a 1987-89 cohort of births in California. We interviewed 731 (84.7%) of eligible mothers with orofacial cleft case infants and 734 (78.2%) mothers with non-malformed control infants. We found a reduced risk of orofacial clefts if the mother had used multivitamins containing folic acid during the period from one month before through two months after conception. The odds ratios ranged from 0.50-0.73 depending on cleft phenotype. Controlling for the potential influence of other variables did not substantially alter the results. Maternal daily consumption of cereal containing folic acid was also associated with a reduced risk of orofacial clefts. Women who used multivitamins containing folic acid periconceptionally had a 25-50% reduction in risk for offspring with orofacial clefts compared to women who did not use such vitamins. However, this association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin supplement components, or behaviours, that are highly correlated with the use of multivitamins containing folic acid.
Birth defects now are the leading cause of infant mortality and a major contributor to heightened morbidity in the United States. Considerable medical and nonmedical resources are devoted to treating persons with birth defects. Yet, little is known about birth defects' economic burden to society and the profile of component direct and indirect costs over the lifespan of those born with specific birth defects. Using an incidence approach, we made the most comprehensive estimates to date of the cost of 18 of the most clinically significant birth defects in the United States. Our analysis provides the basis for assessing competing strategies for research and prevention.
To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities.
Randomised controlled trial of supplementation with multivitamins and trace elements.
Hungarian family planning programme.
4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life.
A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception.
Number of major and mild congenital abnormalities.
The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference cannot be explained totally by the significant reduction of neural tube defects. The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group; relative risk 1.85 (95% confidence interval 1.02 to 3.38); difference, 7.6/1000. The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group; relative risk 1.95 (1.23 to 3.09); difference, 13.6/1000. The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant.
Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities. Further studies are needed to differentiate the chance effect and vitamin dependent effect.
A recent controlled trial has established that use of a 4-mg folic acid supplement before and during early pregnancy reduces the risk of recurrent neural tube defects (NTDs) by 72%. The present study was designed to determine whether folic acid also reduces the risk of first (occurrent) NTDs.
Case-control study.
Tertiary and birth hospitals in metropolitan areas of Boston, Mass, Philadelphia, Pa, and Toronto, Ontario.
Mothers of 436 occurrent cases with NTDs and mothers of 2615 controls with other major malformations.
The prevalence of use of multivitamins containing folic acid was compared between mothers of cases and controls.
The mothers of 17% of cases and 3% of controls reported knowledge of the folic acid-NTD hypothesis and were excluded from further analysis. For daily use of a multivitamins containing folic acid in the periconceptional period (28 days before through 28 days after the last menstrual period), the relative risk (RR) (and 95% confidence interval) was 0.4 (0.2 to 0.6). The most commonly used dose of folic acid was 0.4 mg, and the RR estimate was 0.3 (95% confidence interval, 0.1 to 0.6). For dietary folate, there was a dose-related decline in risk according to the quintile of intake (P for trend = .02).
These findings suggest that daily periconceptional intake of 0.4 mg of folic acid (the dose most commonly contained in over-the-counter multivitamin preparations) reduces the risk of occurrent NTDs by approximately 60%. A relatively high dietary intake of folate may also reduce the risk.
Limb reduction defects (LRD), reported to the Congenital Malformations Registry in upstate New York between 1983-1987, were investigated in terms of LRD classification, parental demographics, and LRD characteristics. After excluding LRD with chromosome abnormalities, we followed guidelines developed by the European Congenital Anomaly Surveillance Consortium (EUROCAT) to classify 271 LRD into six groups based on similar patterns of embryological failure. The descriptive analysis indicated a prevalence of 0.45 per 1,000 births (stable over 5 years) for LRD diagnosed during the first 2 years of life. Among 271 LRD cases, 95 were classified as terminal transverse (35.1%), 71 as split limbs (26.2%), 36 as preaxial (13.3%), 32 as postaxial (11.8%), 26 as intercalary (9.6%), and 11 as multiple types (4.1%). In cases with multiple limb involvement (28.4%), two thirds had the same type of LRD in each limb. The multiple types and preaxial groups showed the most distinctive characteristics: they had the highest frequency of suspected syndromes, other birth defects, and syndactyly compared to the other LRD. There were no significant differences in the distribution of demographic variables among different LRD types. Consideration of the incidence and characteristics of LRD by classifying them into these distinct subgroups may be useful for evaluating possible mechanisms of malformation.
Congenital cardiovascular anomalies were observed in the offspring when rats were placed on a dietary regimen deficient in pteroylglutamic ("folic") acid during gestation. These cardiovascular malformations occurred only when the mothers were given this diet for specific periods, as short as two or three days, in early pregnancy, at a time when the heart and aortic arches were in the initial stages of development.
Little effect on fetal development was observed when stock female rats of the Long-Evans strain were given riboflavin-deficient diets for the period of gestation. However, when the vitamin deficiency was accentuated by the addition of the antimetabolite, galactoflavin, to the deficient diet for the entire gestation period or for only 4 to 6 days early in gestation, a high incidence of fetal death or congenital abnormalities resulted. The abnormalities observed included those of the skeleton, the cardiovascular and urogenital systems, the cerebrum and the eyes; herniations of the diaphragm and body walls were also observed. Skeletal defects predominated when the antimetabolite was given throughout gestation. Both skeletal and cardiovascular anomalies were prevalent when the antimetabolite was given from days 7 to 13 followed by vitamin supplementation for the remainder of gestation. Cardiovascular defects were the only anomalies resulting from the transitory deficiency induced by galactoflavin ingestion from days 7 to 11. When diets containing the highest level of the antimetabolite were supplemented with riboflavin throughout gestation, fetal development was normal.
Nutritional deficiency has been shown by many workers to be teratogenic to the animal embryo. Vitamins of the B group especially appear to be essential for normal organogenesis. This is consistent with the known general functions of the B vitamins, which, acting as intracellular enzymes, promote rapid cell growth, for example, in the adult hæmatopoietic and gastro‐intestinal systems.
In this study an attempt has been made to detect deficiencies in the diets of 99 mothers who bore malformed children. When their estimated diets were compared with those of a matched control series, some small differences were found in several groups of malformation, especially congenital heart disease and talipes. The most usual differences were in iron and the B group vitamins, thiamine and niacin ; but whether these differences are biologically important cannot be stated. No differences were found in mongolism and spina bifida.
Fetal, Neonatal and Infant Cardiac Disease
- Clark EB
Dietary factors and birth defects. Association for the Advancement of Science
- Rp Sharma
Sharma RP (1993): Dietary factors and
birth defects. Association for the
Advancement of Science. California
Academy of Sciences.
Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects
- S Lin
- E G Marshall
- G K Davidson
- G B Roth
- C M Druschel
- H Jick
- S S Jick
- C L Bruell
- D S Macclaughlin
- K J Rothman
- W Willet
Lin S, Marshall EG, Davidson GK, Roth
GB, Druschel CM (1993): Evaluation
of congenital limb reduction defects
in upstate New York. Teratology
Milunsky A, Jick H, Jick SS, Bruell
CL, MacClaughlin DS, Rothman KJ,
Willet W(1989):Multivitamin/folic
acid supplementation in early
pregnancy reduces the prevalence of
neural tube defects. JAMA
47:127-135.
262:2847-2852.
Dietary Department of Health and Human of Health, National Cancer Institute. Health habits and history questionnaire: Dietary history and other factors: Personal computer system packet
- Cw Asling
- Mm Nelson
- Hv Wright
- Evans Bower
- C Stanley
Asling CW, Nelson MM, Wright HV, Evans
Bower C, Stanley FJ (1989) : Dietary
Department of Health and Human
of Health, National Cancer
Institute. Health habits and history
questionnaire: Dietary history and
other factors: Personal computer
system packet. Version 2.3,
Bethesda, MD.
Congenital cardiovascular anomalies induced by pteroylglutamic acid deficiency during gestation in the rat folate as a risk factor for neural-tube defects: Evidence from a case-control study in Western Australia
- Cdc Baird
- Mm Nelson
- Iw Monie
- Hm Evans
Baird CDC, Nelson MM, Monie IW, Evans
HM (1954) : Congenital cardiovascular
anomalies induced by pteroylglutamic
acid deficiency during gestation in
the rat. Circ Res 2:544-554.
folate as a risk factor for
neural-tube defects: Evidence from a
case-control study in Western
Australia. Med J Aust 150:613-619.
Statistics and Epidemiology Research Corporation
EGRET (1991): Statistics and
Epidemiology Research Corporation,
Seattle, Washington.
Congenital skeletal abnormalities in fetal rats resulting from maternal pteroylglutamic acid deficiency during gestation
HM (1955): Congenital skeletal
abnormalities in fetal rats
resulting from maternal
pteroylglutamic acid deficiency
during gestation. Anat Rec 121:775-800.
Dietary Department of Health and Human of Health, National Cancer Institute. Health habits and history questionnaire: Dietary history and other factors: Personal computer system packet
- C Bower
- F J Stanley
Bower C, Stanley FJ (1989) : Dietary
Department of Health and Human
of Health, National Cancer
Institute. Health habits and history
questionnaire: Dietary history and
other factors: Personal computer
system packet. Version 2.3,
Bethesda, MD.
Association for the Advancement of Science. California Academy of Sciences
- R P Sharma
Sharma RP (1993): Dietary factors and
birth defects. Association for the
Advancement of Science. California
Academy of Sciences.
JAMA 260:3141-3145.
Congenital Limb and Heart Anomalies and Maternal Vitamin Use 545
- D B Pitt
- P E Samson
Pitt DB, Samson PE (1961): Congenital
Limb and Heart Anomalies and Maternal Vitamin Use 545
- Czeizel
National Institutes of Health National Cancer Institute. Health habits and history questionnaire: Dietary history and other factors: Personal computer system packet
- Human Department Of Health
- Services
- Werler