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

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.