OBSTETRICS OBSTETRICS Prenatal Multivitamin Supplementation and Rates of Congenital Anomalies: A Meta-Analysis

Department of Pharmaceutical Sciences, University of Toronto, and The Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 09/2006; 28(8):680-9.
Source: PubMed


Background: The use of folic acid-fortified multivitamin supplements has long been associated with decreasing the risk of neural tube defects. Several studies have also proposed the effectiveness of these supplements in preventing other birth defects; however, such effects have never been systematically examined. Objective: We conducted a systematic review and meta-analysis to evaluate the protective effect of folic acid-fortified multivitamin supplements on other congenital anomalies. Methods: We searched Medline, PubMed, EMBASE, Toxline, Healthstar, and Cochrane databases for studies describing the outcome of pregnancies in women using multivitamin supplements that were published in all languages from January 1966 to July 2005. The references from all collected articles were reviewed for additional articles. Two independent reviewers who were blinded to

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    • "However, the Hungarian RCT [30] and some observational studies [34-37] suggest that FA may reduce the risk of CMs overall, or the risk of a specific and selected group of them [38], namely oral clefts [39-42], cardiac defects [43-46], urinary tract anomalies except hypospadias [47], limb reduction defects [48], omphalocele [49], anal atresia [50]. "
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    ABSTRACT: BackgroundIn 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae.Methods/DesignThis project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis.DiscussionThe rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes.Trial registrationItalian trial: Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161.
    BMC Pregnancy and Childbirth 05/2014; 14(1):166. DOI:10.1186/1471-2393-14-166 · 2.19 Impact Factor
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    • "In the present study 19.8% of mothers with affected offspring did not take folic acid during the first pregnancy, with OR (0.017) showing significant association between absence of folic acid intake during the first trimester and LRDs. Goh et al. (2006) revealed that the use of multivitamin supplements provided consistent protection against limb defects (OR 0.48, 95% CI 0.30–0.76, in case–control studies; OR 0.57, 95% CI 0.38–0.85, in cohort and randomized controlled studies). The Atlanta population-based case–control study also found a significant risk reduction for all birth defects (OR 0.80, 95% CI 0.69–0.93) "
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    ABSTRACT: Background Limb reduction defects (LRDs) refer to absence of either parts of a limb or entire limbs. They represent one of the most common visible phenotypic effects of several etiologies. The major causes of LRDs are abnormal genetic problems and intrauterine disruption. Many environmental risk factors have been implicated, such as teratogens. Objective The aim of the study was to identify environmental risk factors that may predispose to isolated LRDs. Patients and methods Forty-one Egyptian patients with isolated LRDs were studied. In addition to medical examination a detailed history was taken for each case, including parental exposure to different teratogens as a result of residence, occupation, special habits, or pregnancy history of the mother, including nutrition and maternal stress during pregnancy. Results Most studied cases were sporadic, without a positive family history for LRD. The results showed significant risk impact on LRD with maternal exposure to environmental hazards (pesticides, insecticides, radiation) (P=0.00) and maternal history of drug intake in the form of hormones and NSAIDs (P=0.001); the risk increased among mothers who did not take folic acid supplement during the first trimester (P=0.017). Finally, early maternal trauma played a role as a risk factor for LRD, with a P value of 0.005. Conclusion Delineation of the environmental risk factors could be the first approach to preventing isolated LRDs.
    01/2014; 3(2):53-64. DOI:10.1097/01.MXE.0000449828.39449.fa
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    • "Identification of the protective effect of periconceptional folic acid supplementation against neural tube defects in neonates led to the mandated fortification of flours and other grain products in several countries [1-4]. In addition to the prevention of neural tube defects, folic acid supplementation has been associated with decreased risk of other congenital malformations, such as heart defects and oral clefts [5-8]. Despite these benefits, concern has been raised to possible adverse effects. "
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    ABSTRACT: Investigation of the biological mechanism by which folate acts to affect fetal development can inform appraisal of expected benefits and risk management. This research is ethically imperative given the ubiquity of folic acid fortified products in the US. Considering that folate is an essential component in the one-carbon metabolism pathway that provides methyl groups for DNA methylation, epigenetic modifications provide a putative molecular mechanism mediating the effect of folic acid supplementation on neonatal and pediatric outcomes. In this study we use a Mendelian Randomization (Mendelian Randomization) approach to assess the effect of red blood cell (RBC) folate on genome-wide DNA methylation in cord blood. Site-specific CpG methylation within the proximal promoter regions of approximately 14,500 genes was analyzed using the Illumina Infinium Human Methylation27 Bead Chip for 50 infants from the Epigenetic Birth Cohort at Brigham and Women's Hospital in Boston. Using methylenetetrahydrofolate reductase genotype as the instrument, the Mendelian Randomization approach identified 7 CpG loci with a significant (mostly positive) association between RBC folate and methylation level. Among the genes in closest proximity to this significant subset of CpG loci, several enriched biologic processes were involved in nucleic acid transport and metabolic processing. Compared to the standard ordinary least squares regression method, our estimates were demonstrated to be more robust to unmeasured confounding. To the authors' knowledge, this is the largest genome-wide analysis of the effects of folate on methylation pattern, and the first to employ Mendelian Randomization to assess the effects of an exposure on epigenetic modifications. These results can help guide future analyses of the causal effects of periconceptional folate levels on candidate pathways.
    BMC Bioinformatics 12/2013; 14(1):353. DOI:10.1186/1471-2105-14-353 · 2.58 Impact Factor
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