Periconceptional Folic Acid Supplementation and Risks of Small and Large for Gestational Age at Birth: The Mediation Effects of Maternal Homocysteine Level during Pregnancy

Background: Periconceptional folic acid supplementation (FAS) is widely recommended. However, the role of periconceptional FAS on neonatal birth weight remains unclear. Objectives: This study aimed to explore the independent effects of periconceptional FAS on risks of small for gestational age (SGA) and large for gestational age (LGA) and to test the potential mediation role of maternal homocysteine (Hcy) during pregnancy on the above significant associations. Methods: A large-scale prospective birth cohort was conducted in the Tongzhou Maternal and Child Health Hospital, Beijing, China, from June 2018 to August 2019. Periconceptional FAS was evaluated by a self-administered questionnaire on the day of recruitment in early pregnancy (<14th wk of gestation). FAS was defined as participants who had taken folic acid (FA) supplements, FA-containing multivitamins, or other FA-containing nutritional supplements. Neonatal birth weight was measured at delivery. Maternal serum Hcy concentrations were measured in early and late pregnancy, respectively. Logistic regression analyses were performed to assess the associations between FAS during preconception and/or early pregnancy and the occurrence of SGA or LGA. Mediation models were constructed to determine the role of maternal Hcy concentrations on the above associations. Results: FAS before pregnancy [risk ratios (RR), 0.814; 95% confidence interval (CI): 0.667, 0.993], during early pregnancy (RR, 0.625; 95% CI: 0.453, 0.862), and from prepregnancy to early pregnancy (RR, 0.565; 95% CI: 0.371, 0.859) were associated with a lower risk of LGA. However, no significant association was found between periconceptional FAS and SGA birth. Maternal Hcy concentration in late pregnancy mediated the independent effects of maternal FAS during preconception, early pregnancy, and both pre- and early pregnancy stages on risks of LGA birth (P < 0.05). Conclusions: Periconceptional FAS was associated with a lower risk of LGA, which may be mediated by the reduced serum Hcy concentration in late pregnancy. The current recommendation of periconceptional FAS should be complied with to reduce risks of LGA.