Abstract
Folic acid (FA) supplementation prevents neural tube defects (NTDs), but the effects on other reproductive outcomes are unclear. While common recommendation is 0.4 mg/day in addition to regular nutrition, the most appropriate dose of FA is still under debate. We investigated the effects of a higher dose of periconception FA on reducing adverse reproductive outcomes. In this multicenter double-blind randomized controlled trial (RCT), 1060 women (aged 18–44 years and planning a pregnancy) were randomly assigned to receive 4.0 mg or 0.4 mg of FA daily. The primary outcome was the occurrence of congenital malformations (CMs). A composite outcome including one or more adverse pregnancy outcomes was also evaluated. A total of 431 women had a natural conception within 1 year. The primary outcome occurred in 8/227 (3.5%) women receiving 4.0 mg FA and 9/204 (4.4%) women receiving 0.4 mg FA (RR 0.80; 95%CI 0.31 to 2.03). The composite outcome occurred in 43/227 (18.9%) women receiving 4.0 mg FA and 75/204 (36.8%) women receiving 0.4 mg FA (RR 0.51; 95%CI 0.40 to 0.68). FA 4.0 mg supplementation was not associated with different occurrence of CMs, compared to FA 0.4 mg supplementation. However, FA 4.0 mg supplementation was associated with lower occurrence of other adverse pregnancy outcomes.
Highlights
IntroductionFolic acid (FA) supplementation before conception and in early pregnancy is recommended to women planning a pregnancy to reduce the risk of neural tube defects (NTDs)
Caution is suggested when evaluating the results, which are of interest. This randomized controlled trial (RCT) failed to show any advantage of Folic acid (FA) 4.0 mg versus 0.4 mg daily supplementation on the occurrence of congenital malformations (CMs)
FA 4.0 mg supplementation started before pregnancy to 12th gestational week was associated with fewer spontaneous abortions, small for gestational age (SGA), preterm births and with a better composite outcome including adverse pregnancy outcomes
Summary
Folic acid (FA) supplementation before conception and in early pregnancy is recommended to women planning a pregnancy to reduce the risk of neural tube defects (NTDs). This protective effect has led to mandatory flour fortification with FA in several countries (such as United States, Canada, Chile, South Africa, and Australia) and to recommendation of daily FA supplement in women planning a pregnancy (such as United States, Canada, Australia, and Europe, including Italy). The available literature offers an uncertain impact of FA supplementation on fertility and prevention of other adverse reproductive outcomes [4,5,6,7,8,9,10,11,12,13,14,15,16]. Observational studies indicated an association between greater level of folate during pregnancy and higher birthweight [6]
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