Periconceptional Folic Acid Supplement Use Research Articles

Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

Periconceptional folic acid supplement use among women of reproductive age and its determinants in central rural Germany: Results from a cross sectional study

Prevalence of neural tube defects (NTD) has not decreased in Germany despite longstanding recommendations for folic acid supplementation. To examine the prevalence of periconceptional folic acid supplement use and associated factors among German women of reproductive age. Cross-sectional survey was conducted in hospital-based maternity units in rural Germany. A sample of 1,004 women of reproductive age, either pregnant or in their early postpartum period, took interviewer/self-administered paper-based survey questionnaire. Prevalence of periconceptional folic acid supplement use was assessed, where periconception was defined as 1 month prior to and 3 months post-conception. Prevalence odds ratios (POR) and 95% confidence intervals (CI) using crude and adjusted logistic regression analysis were estimated to examine determinants of folic acid supplement use. Prevalence of folic acid supplement use was 41.5% (95% CI: 37.7%, 45.7%). Multivariable analysis showed lack of educational qualifications, unplanned pregnancy, later diagnosis of pregnancy, increased parity, and not having an awareness of importance of folic acid for optimal pregnancy outcomes were associated with not taking periconceptional folic acid supplements. Books, doctors, friends, media, were sources of information. Periconceptional folic acid is sub-optimal in rural Germany and thus failing to prevent NTDs. Targeted promotion of folic acid supplement use should be conducted periodically by gynecologists and primary care physicians during annual medical screenings. Mandatory folic acid fortification of staple foods is a complementary approach to overcome limitations of individual behaviors of folic acid supplement intake, and should be considered as it has been proven effective in multiple countries.

Folic Acid Supplement Use and Increased Risk of Gestational Hypertension.

Current results regarding the effect of folic acid (FA) supplement use on gestational hypertension (GH) and preeclampsia are limited and inconsistent. We aimed to investigate whether FA supplement use was associated with GH and preeclampsia. Participants from the Tongji Maternal and Child Health Cohort with information on periconceptional FA supplement use and diagnosis of GH/preeclampsia were included (n=4853). Robust Poisson regression was used to assess the association of FA supplement use and GH and preeclampsia. Among the 4853 participants in this study, 1161 (23.9%) and 161 (3.3%) women were diagnosed with GH and preeclampsia, respectively. The risk ratio of developing GH was higher in women who used ≥800 µg/d FA supplement from prepregnancy through midpregnancy than nonusers (risk ratio, 1.33 [1.08-1.65]). After adjusting for social-demographic, reproductive, lifestyle factors, family history of hypertension, other supplement use, and gestational weight gain, the adverse association remained significant (risk ratio, 1.32 [1.06-1.64]). Restricting the analysis among women with normal weight, without family history of hypertension, and without gestational diabetes mellitus, the positive FA-GH association still existed. We did not find any significant association between FA supplement use and preeclampsia regardless of adjustment. High-dose (≥800 µg/d) FA supplement use from prepregnancy through midpregnancy was associated with increased risk of GH. Attention should be given to avoid the potential risk of GH due to inappropriate FA supplement use in women who are planning or capable of pregnancy.

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero - the Norwegian Mother and Child Cohort Study.

The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8years of mothers with epilepsy. The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999-2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child's language abilities at age 5 and 8years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17-19 and in the umbilical cord were measured. The study population included 346 AED-exposed and 388 AED-unexposed children of mothers with epilepsy, and 113674 children of mothers without epilepsy. Mothers of 117 and 121 AED-exposed children responded to the questionnaires at age 5 and 8years, respectively. For AED-exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1-2.5, P=0.03] at age 5years and 2.0 (CI 1.4-3.0, P<0.001) at age 8years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8years (adjusted odds ratio 3.8, CI 1.6-9.0, P=0.002). Higher maternal valproate concentrations correlated with language impairment at age 5years. Periconceptional folic acid supplement use protected against AED-associated language impairment. Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED-associated language impairment.

Paternal characteristics associated with maternal periconceptional use of folic acid supplementation

BackgroundMaternal predictors of folic acid (FA) supplementation use to reduce offspring risk of neural tube defects are well known, while paternal determinants for maternal FA use are less known. Such knowledge is important to increase women’s compliance to recommended periconceptional FA use.MethodsIn a nation-wide study of 683,785 births registered in the Medical Birth Registry of Norway during 1999–2010, the associations between paternal characteristics (age, education, occupation, country of origin) and maternal FA use were estimated by relative risks (RR) with 95% confidence intervals (CI), using log-binomial regression.ResultsMaternal FA use before and during pregnancy (adequate FA use) was found in 16% of the births. The association between paternal age and adequate FA use was inversely U-shaped; adjusted RRs for adequate FA use were 0.35 (95% CI 0.28–0.43) and 0.72 (95% CI 0.71–0.74) for paternal age < 20 and ≥ 40 years, respectively, comparing age 30–34 years. Compulsory education (1–9 years) among fathers was compared to tertiary education; the RR was 0.69 (95% CI 0.68–0.71) for adequate FA use. The lower risk of adequate FA use for paternal compulsory education was present in all categories of maternal education. Occupation classes other than “Higher professionals” were associated with decreased risk of adequate FA use, compared with the reference “Lower professionals”. RR for adequate FA use was 0.58 (95% CI 0.56–0.60) comparing fathers from “Low/middle-income countries” with fathers born in Norway.ConclusionAdequate FA use in the periconceptional period was lower when fathers were younger or older than 30–34 years, had shorter education, had manual or self-employed occupations, or originated from low/middle-income countries. Partners may contribute to increase women’s use of periconceptional FA supplementation.

Periconceptional Folic Acid Supplementation and Infant Risk of Congenital Heart Defects in Norway 1999–2009

The birth prevalence of congenital heart defects (CHDs) has decreased in Canada and Europe. Recommended intake of folic acid in pregnancy is a suggestive risk-reducing factor for CHDs. We investigated the association between periconceptional intake of folic acid supplements and infant risk of CHDs. Information on maternal intake of folic acid supplements before and during pregnancy in the Medical Birth Registry of Norway 1999-2009 was updated with information on CHD diagnoses from national health registers and the Cardiovascular Diseases in Norway Project. The association between folic acid intake and infant risk of CHD was estimated as relative risk (RR) with binomial log linear regression. Among 517 784 non-chromosomal singleton births, 6200 children were identified with CHD and 1153 with severe CHD. For all births, 18.4% of the mothers initiated folic acid supplements before pregnancy and 31.6% during pregnancy. The adjusted RR for severe CHD was 0.99 [95% confidence interval [CI] 0.86, 1.13] comparing periconceptional intake of folic acid with no intake. Specifically, RR for conotruncal defects was 0.99 [95% CI 0.80, 1.22], atrioventricular septal defects 1.19 [95% CI 0.78, 1.81], left ventricular outflow tract obstructions 1.02 [95% CI 0.78, 1.32], and right ventricular outflow tract obstructions 0.97 [95% CI 0.72, 1.29]. Birth prevalence of septal defects was higher in the group exposed to folic acid supplements with RR 1.19 [95% CI 1.10, 1.30]. Periconceptional folic acid supplement use showed no association with severe CHDs in the newborn. An unexpected association with an increased risk of septal defects warrants further investigation.

No major role for periconceptional folic acid use and its interaction with the MTHFR C677T polymorphism in the etiology of congenital anorectal malformations.

Both genetic and nongenetic factors are suggested to be involved in the etiology of congenital anorectal malformations (ARM). Maternal periconceptional use of folic acid supplements were inconsistently suggested to play a role in the prevention of ARM. Therefore, we investigated independent associations and interactions of maternal periconceptional folic acid supplement use and the infant and maternal MTHFR (methylenetetrahydrofolate reductase) C677T polymorphisms with the risk of ARM and subgroups of ARM. A case-control study was conducted among 371 nonsyndromic ARM cases and 714 population-based controls born between 1990 and 2012 using maternal questionnaires and DNA samples from mother and child. Cases were treated for ARM at departments of Pediatric Surgery of the Radboud university medical center, Sophia Children's Hospital-Erasmus MC Rotterdam, and the University Medical Center Groningen in The Netherlands and hospitals throughout Germany. No association with folic acid use was present (odds ratio = 1.1; 95% confidence interval: 0.8-1.4) for ARM as a group. Infant and maternal MTHFR C677T polymorphisms were weakly associated with isolated ARM in particular. Lack of folic acid supplement use in combination with infants or mothers carrying the MTHFR C677T polymorphism did not seem to increase the risk of ARM or subgroups of ARM. The relative excess risks due to interaction did not clearly indicate interaction on an additive scale either. This first study investigating interactions between periconceptional folic acid supplement use and infant and maternal MTHFR C677T polymorphisms in the etiology of ARM did not provide evidence for a role of this gene-environment interaction.

Epigenetic profiles in children with a neural tube defect; a case-control study in two populations.

Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of −0.33% in cases, P-value = 0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.

Influence of maternal folate status on human fetal growth parameters

Worldwide periconceptional folic acid supplement use is recommended to prevent neural tube defects. This also stimulated research on maternal folate status in association with fetal growth, an important predictor of perinatal and future development and health. We provide an overview of literature on associations between maternal folate status during pregnancy determined by folate biomarker concentrations in blood, folic acid supplement use and dietary folate intake, and fetal growth parameters. Literature was searched in PubMed up to November 2011. Some studies suggest inverse associations between serum folate, folic acid supplement use and dietary folate intake and risk of a low birth weight or small for gestational age infant. The strongest evidence, however, revealed positive associations between birth weight and red blood cell folate, folic acid supplement use and dietary folate intake. Red blood cell folate appeared to be most consistently associated with other fetal growth parameters. These findings contribute to the knowledge of the impact of maternal folate status on fetal growth, and subsequently perinatal health and disease risks in later life. Future research is recommended to examine effects of windows, duration and dose of folic acid supplement use and use of folate-rich dietary patterns in different populations on fetal growth parameters.

Periconceptional folic acid supplementation and anthropometric measures at birth in a cohort of pregnant women in Valencia, Spain

We examined the relationship between dietary folate intake and periconceptional use of folic acid (FA) supplements, and small-for-gestational age for weight (SGA-W) and height (SGA-H). The study is based on 786 Spanish women aged 16 years or above, who attended the first-term prenatal population-based screening programme (10-13 weeks) at the reference hospital 'La Fe', Valencia, with singleton pregnancy. Periconceptional use of FA supplements was categorised as non-users, moderate users (≤1mg/d) and high users (>1mg/d). Babies born to mothers who used high doses of FA supplements had a significant reduction in mean birth height compared with babies of non-users (β=-0·53, 95% CI -0·96, -0·09). As regards weight, mothers using moderate and high doses of FA supplements had lower-birth-weight babies for gestational age than non-users (β=-22·96, 95% CI -101·14, 55·23; β=-89·72, 95% CI -188·64, 9·21, respectively), although these decreases were not significant. Results from the multivariate logistic regression models showed that high FA supplement users had a higher significant risk for SGA-H (OR 5·33, 95% CI 2·08, 13·7), and that users of moderate doses were not associated with a higher risk of either a SGA-W or a SGA-H baby. In contrast, increased quintiles of the dietary intake of folate were associated with a decreased risk of SGA-W (P for trend=0·002), although no association was observed for SGA-H. Our findings suggest that periconceptional use of FA supplements greater than 1mg/d is associated with decreased birth height and may entail a risk of decreased birth weight.

Mandatory Fortification of Flour with Folic Acid to Prevent Neural-Tube Defects

Firm evidence from randomized, controlled trials that maternal periconceptional folic acid reduced the risk of neural-tube defects was published in the early 1990s. Despite promotion of periconceptional folic acid supplement use, no more than 50% of women take them and so mandatory fortification of a staple food has been considered by many countries as an important adjunct to any public-health approach for the prevention of neural-tube defects. Even 15 years after the confirming evidence, some countries have yet to commit to mandatory fortification and, in those that have, there is limited and poorly coordinated monitoring and evaluation of its effectiveness and safety.

Folic acid knowledge and use in a multi‐ethnic pregnancy cohort: the role of language proficiency

To investigate the role of language proficiency as determinant of folic acid knowledge and use in a multi-ethnic pregnancy cohort. Prospective cohort study. Pregnant women from Amsterdam attending obstetric care for their first antenatal visit. Number approached: 12,373 women, response rate: 67% (8266 women aged 14-49 years). Ethnicity was based on the country of birth: the Netherlands, Surinam, Antilles, Turkey, Morocco, Ghana, other non-Western and other Western countries. Knowledge about and use of folic acid supplements in pregnancy as elicited in a multilingual questionnaire, as well as determinants of these in ethnic groups separately. Both periconceptional folic acid use and knowledge were significantly lower among Ghanaian, Moroccan, Turkish, and other non-Western women than among women born in the Netherlands or other Western countries. Language proficiency in Dutch was a major determinant of knowledge in all the ethnic groups with a mother tongue other than Dutch [adjusted odds ratios (OR): Western 3.2, non-Western (all countries combined) 7.5], while educational attainment was of secondary importance. Knowledge in turn was the strongest determinant of use (adjusted OR: Western 17.4, non-Western 27.0). Periconceptional folic acid supplement use among women born in non-Dutch-speaking non-Western countries is low, reflecting a lack of knowledge that is determined by the inability to speak and understand the language of the country of residence. Measures to tackle this problem include the provision of linguistically appropriate information via ethnic health advisors, and language courses integrating health education for immigrants.

The C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene (MTHFR), Maternal Use of Folic Acid Supplements, and Risk of Isolated Clubfoot: A Case-Parent-Triad Analysis

Worldwide, 1-4 per 1,000 births are affected by clubfoot. Clubfoot etiology is unclear, but both genetic and environmental factors are thought to be involved. Low folate status in pregnant women has been implicated in several congenital malformations, and folate metabolism may be affected by polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR). Using a case-parent-triad design, the authors investigated whether the MTHFR C677T polymorphism, and maternal periconceptional folic acid supplement use, influenced risk of isolated clubfoot. Three hundred seventy-five United Kingdom case-parent triads were recruited in 1998-1999. Among the children, there was a significant trend of decreasing clubfoot risk with increasing number of T alleles: relative risk for CT vs. CC = 0.75, 95% confidence interval: 0.57, 0.97; relative risk for TT vs. CC = 0.57, 95% confidence interval: 0.35, 0.91; p trend = 0.006. This association was not modified by maternal folic acid use. Maternal MTHFR genotype did not influence clubfoot risk for the offspring overall, although a possible interaction with folic acid use was found. This is the first known report of a specific genetic polymorphism associated with clubfoot. The direction of the association is intriguing and suggests that DNA synthesis may be relevant in clubfoot development. However, clubfoot mechanisms are poorly understood, and the folate metabolism pathway is complex. Further research is needed to elucidate these relations.

The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia

The birth incidence of neural tube defect (NTD) cases in British Columbia (B.C.), and elsewhere in North America, is reported to be declining. This decline is being attributed to folic acid (FA) supplementation and food fortification, but 2nd trimester prenatal screening of pregnancies for NTDs and other congenital anomalies has increased during this timeframe, as well. This descriptive, population-based study evaluates the impact of prenatal screening of NTD-affected pregnancies on (1) pregnancy outcome and (2) reporting of NTD births to the provincial Health Status Registry (B.C.H.S.R.); and it assesses (3) the use of periconceptional FA supplementation. NTD cases were ascertained from medical records of health centres providing care to families with NTD-affected pregnancies and newborns; and from NTD cases reported to the B.C.H.S.R. In 1997-1999, the B.C.H.S.R. published a NTD incidence of 0.77/1000. In this study, 151 NTD-affected pregnancies were identified, with an incidence of 1.16/1000. Partial Reporting of induced abortions in a NTD incidence 45.5% low than the actual incidence. Medical records were available for review on 144/151 pregnancies. Prenatal screening identified 86.1% (124/144) of NTD-affected pregnancies, with 72.6% (90/124) resulting in pregnancy termination, and 27.4% (34/124) continuing to term. Use of FA supplementation in the periconceptional period was recorded in 36.4% of pregnancies (39/107). Thus in B.C. the decline in the NTD incidence is due predominantly to pregnancy terminations following prenatal diagnosis, which reduces the NTD incidence by 60%, from 1.16/1000 to 0.47/1000. Continued efforts for primary and the option of secondary prevention of NTDs are recommended in order to improve newborn health in B.C. and elsewhere. These interventions need to be monitored, however, for optimal health care planning.

Maternal Nutritional Status and the Risk for Orofacial Cleft Offspring in Humans

Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring. It has been suggested that other nutrients also play a role. We investigated the preconceptional intake of macronutrients (protein, fat, carbohydrate, fiber, and cholesterol), vitamins (vitamin A, retinol, beta-carotene, ascorbic acid, and alpha-tocopherol), minerals (calcium, phosphorus, iron, magnesium, and zinc) and food groups in mothers of OFC children and controls. At approximately 14 mo after the index pregnancy, 206 mothers of a child with a nonsyndromic OFC and 203 control mothers completed a FFQ on current food intake and a general questionnaire. After exclusion of pregnant and lactating mothers, mothers who reported a change in diet compared with the preconceptional period, and those for whom periconceptional folic acid supplement use was unclear, 182 OFC mothers and 173 control mothers were evaluated. Macronutrient, vitamin, mineral, and food group intakes were compared. After adjustment for energy, quintiles of dietary nutrient intake and odds ratios with 95% CI were calculated. The preconceptional intake of all macronutrients, vitamins, minerals, and food groups with the exception of milk (products), potatoes, pies/cookies were lower in OFC mothers than in controls. The energy-adjusted intakes of vegetable protein, fiber, beta-carotene, ascorbic acid, alpha-tocopherol, iron, and magnesium were significantly lower in cases compared with controls. Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk. In conclusion, a higher preconceptional intake of nutrients predominantly present in fruits and vegetables reduces the risk of offspring affected by OFC.