Folic Acid Intake, Fetal Brain Growth, and Maternal Smoking in Pregnancy: A Randomized Controlled Trial

Abstract

Background Folic acid supplementation during pregnancy plays an important role in fetal growth and development. To our knowledge, no experimental study has examined the effect of folic acid on fetal brain growth in women who smoke cigarettes during pregnancy. Objectives The aim of this study was to investigate the efficacy of higher-dose compared with standard-dose folic acid supplementation on prenatal fetal brain growth, measured by head circumference, brain weight, and brain-body weight ratio (BBR). Design In this randomly assigned, double-blind, controlled clinical trial, we recruited 345 smoking pregnant women attending a community health center in Tampa, FL between 2010 and 2014. Participants were randomly assigned in a 1:1 ratio to receive either 0.8 mg folic acid/d (standard of care at the study center) or 4 mg folic acid/d (higher strength). Participants were also enrolled in a smoking cessation program. A 2-level linear growth model was used to assess treatment effect and factors that predict intrauterine growth in head circumference over time. Multiple linear regression analyses were conducted to estimate the effect of higher-strength folic acid on head circumference at birth, fetal brain weight, and fetal BBRs. Results Mothers who received the higher dose of folic acid had infants with a 1.18 mm larger mean head circumference compared with infants born to mothers who received the standard dose, but this difference was not statistically significant ( P = 0.2762). Higher-dose folic acid also had no significant effect on brain weight. The BBR of infants of mothers who received higher-dose folic acid was, however, 0.33 percentage points lower than that for infants of mothers who received the standard dose of folic acid ( P = 0.044). Conclusions Infants of smokers in pregnancy may benefit from higher-strength maternal folic acid supplementation. We noted a decrease in the proportion of infants with impaired BBR among those on higher-dose folic acid. This trial was registered at clinicaltrials.gov as NCT01248260.

A Female Newborn With Occipital Encephalocele and a Hypoplastic Right Ventricle Secondary to Tricuspid and Pulmonary Atresia: A Case Report

“…The current US Preventive Services Task Force (USPSTF) recommendation is that all persons planning to become pregnant should take a daily supplement containing 0.4 to 0.8 mg of folic acid [ 10 ]. It has been shown that higher doses of folic acid (4mg) prevent reduction in fetal body size [ 11 ] and optimize brain growth [ 12 ] among infants of women who smoke tobacco during pregnancy [ 11 ]. Further research is needed to explore the effects of high-dose folic acid in specific populations, such as smokers and individuals with diabetes to reduce the risk of CHDs.…”

Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review

“…Preconception folic acid supplement use increased foetal head size and cerebellar growth in three studies [34,36,45], but not in two other studies [46,48]. Folic acid supplement use at other time points had no effect on neonatal head size [37,43,44,47]. The majority of studies that assessed maternal folic acid supplementation disclosed that supplementation and food fortification, even after conception, ameliorated offspring neurodevelopment and reduced the risk of psychosis from infancy to childhood [78][79][80][81][82].…”

“…Preconception, early and mid-trimester folic acid supplement use were not associated with neonatal HC in two studies [37,46]. An RCT by Yusuf et al reported that even high dose folic acid use (4 mg/day) during the first trimester among smokers had no significant effect on neonatal HC or brain weight at birth when compared to those who received the standard dosage (0.8 mg/day) [44]. However, folic acid supplement use in combination with iron from preconception onwards significantly increased HC at birth by 0.16 cm (B = 0.16, 95% CI −0.03; 0.34, P = 0.012) [45].…”

Risk of Excess Maternal Folic Acid Supplementation in Offspring

“…Eryilmaz et al showed that the prenatal exposure of folic acid was associated with a cortical thickness increase in the bilateral, frontal, and temporal regions, as well as delayed age-associated cortical thinning in the temporal and parietal regions [ 34 ]. A randomized controlled trial (RCT) was performed to assess the effect of folic acid on fetal brain growth among pregnant women who smoke [ 35 ]. The results indicated that infants born to mothers who received high dose folic acid (4 mg/day) showed no difference in brain weight, but were 0.33 percentage points lower in brain/body weight ratio compared to those in the standard dose group (0.8 mg/day) [ 35 ].…”

“…A randomized controlled trial (RCT) was performed to assess the effect of folic acid on fetal brain growth among pregnant women who smoke [ 35 ]. The results indicated that infants born to mothers who received high dose folic acid (4 mg/day) showed no difference in brain weight, but were 0.33 percentage points lower in brain/body weight ratio compared to those in the standard dose group (0.8 mg/day) [ 35 ].…”