Folic acid fortification and congenital heart disease.

Background: Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. Methods and Findings: In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p= 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p= 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p= 0.031 and 0.53, 0.28–0.99, p= 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (,1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p= 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics. Conclusions: Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy. Please see later in the article for the Editors’ Summary. Citation: Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, et al. (2009) Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study. PLoS Med 6(5): e1000061. doi:10.1371/journal.pmed.1000061 Academic Editor: Nicholas M. Fisk, University of Queensland Centre for Clinical Research, Australia Received September 8, 2008; Accepted March 3, 2009; Published May 12, 2009 Copyright: ! 2009 Bukowski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The FASTER trial was supported by grant from National Institutes of Health and National Institute of Child Health and Human Development (RO1 HD 38625).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Mary D’Alton has acted as a consultant for Artemis Health. Abbreviations: BMI, body mass index; CI, confidence interval; HR, hazard ratio, IQR, interquartile range; OR, odds ratio; PPROM, preterm premature rupture of the membranes. * E-mail: [email protected] PLoS Medicine | www.plosmedicine.org 1 May 2009 | Volume 6 | Issue 5 | e1000061