Background: Pregnant women are advised to take folic acid supplements before conception and during the first three months of pregnancy. Many women continue folic acid supplementation throughout pregnancy, and concerns have been raised about associations between excess folic acid intake and adverse child health outcomes. Unmetabolized folic acid (UMFA) is found in serum at higher folic acid intakes and has been proposed as a biomarker for excess folic acid intake. Objective: To determine if removing folic acid from prenatal multivitamin and mineral supplements after 12 weeks of pregnancy reduces concentrations of serum UMFA at 36 weeks′ gestation. Design: A double-blind, parallel-group, randomized controlled trial. Women with a singleton pregnancy 12-16-weeks′ gestation were randomly assigned to a multi-micronutrient supplement containing no folic acid (intervention) or 800 μg folic acid/day (control) from enrolment until 36 weeks′ gestation. Maternal serum was analyzed for UMFA and secondary outcomes of red blood cell and serum folate at 36 weeks′ gestation. Results: UMFA was detected in most of the 103 randomized women (86% >limit of detection). However, only 12% (n=11/90) of serum samples were above the limit of quantification (0.55 nmol/L), preventing analysis of UMFA concentrations. Fewer women had detectable UMFA in the no folic acid group compared to the 800 μg folic acid group (72% [n=33/46] vs. 98% [n=43/44]; p = 0.001). Maternal serum and red blood cell folate concentrations were lower in the no folic acid intervention group compared to the control group (median 23.2 vs. 49.3 nmol/L, 1335 vs. 1914 nmol/L, respectively; p< 0.,001) and no woman was classified as folate deficient. Conclusions: Removing folic acid from prenatal multivitamin and mineral supplements reduced the number of women with detectable UMFA at 36 weeks′ gestation, however, differences in UMFA concentration between treatment groups were not quantifiable.

SW serves as a consultant at InovoBiologic Inc, AB, Canada. All other authors declare no conflict of interest.

ACTRN12619001511123

https://bmjopen.bmj.com/content/10/11/e040416

This study was supported by grants from The Adelaide Women's and Children's Hospital Foundation and a SAHMRI Early Career Researcher Seed Grant. MS is supported by an Ella McKnight Scholarship from the Royal Australian and New Zealand College of Obstetricians and Gynecologists. KPB is supported by a Women's and Children's Hospital Foundation MS McLeod Postdoctoral Research Fellowship. DCS is supported by the Australian Government Research Training Program Scholarship from The University of Adelaide. TRS is supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leadership Investigator Grant. DJP is supported by an NHMRC, Medical Research Futures Fund (MRFF) Career Development Fellowship. MM is supported by NHMRC Principal Research Fellowship.

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