ABSTRACT: Because fetal development requires energy and micronutrients, periconceptional use of multivitamins may be beneficial. Supplementation with folate has been recommended before and early in pregnancy to decrease the risk for neural tube defects, but the use of periconceptional multivitamins is controversial. Data from the Danish National Birth Cohort were used to examine the association between periconceptional multivitamin or folate-only use and risk for early and late fetal death.
The Danish National Birth Cohort maintains data on 100,419 pregnancies in 92,374 women recruited in 1996 to 2002. The final study cohort comprised 35,914 pregnancies in 35,172 women. Women reported on supplement use by type and frequency during a 12-week periconceptional period, divided into a 6-week preconception and a 6-week postconception period and categorized as weeks 1 to 2, 3 to 4, and 5 to 6 relative to the two 6-week periods. Different patterns of multivitamin use were based on no, partial (1–3 weeks), or regular use (4–6 weeks) in either 6-week period. The associations between periconceptional multivitamin or folate use and early (<20 weeks) and late (≥20 weeks) fetal death were estimated by hazard ratios (HRs) with 95% confidence intervals (CIs). Comparisons were made between supplement use or not at any time during the periconceptional period.
Multivitamin use was reported in 22,285 pregnancies (62.1%); folate-only supplementation, in 2236 pregnancies (6.2%); and no use of any supplementation, in 11,393 pregnancies (31.7%). A total of 1346 fetal deaths occurred at less than 20 weeks; and 206, at 20 weeks or later. Rates of fetal death decreased across gestation from 49.8 per 10,000 weeks in weeks 8 to 11, 22.9 in weeks 12 to 19, 3.3 in weeks 20 to 27, and 2.8 at 28 weeks or later. Multivitamin use was associated with a 12% increased crude risk for fetal death, restricted to losses at less than 20 weeks of gestation (HR, 1.18; 95% CI, 1.05–1.33) compared with losses thereafter (HR, 0.82; 95% CI, 0.62–1.10; P for interaction = 0.02). The folate-only users had no excess risk at any time. Compared with the non-users and the women with 1 to 2 weeks of preconception multivitamin use, risk for early fetal death increased slightly with longer preconception use (crude HRs, 1.23 and 1.32; 95% CI, 0.93–1.61 and 1.09–1.60, for 3–4 and 5–6 weeks, respectively; P for trend = 0.002). For postconception multivitamin use, risk for early fetal death was increased in the women with 3 to 4 weeks of use compared with the nonusers (crude HR, 1.28; 95% CI, 1.08–1.51) but not in the women with either lesser or more use. For late fetal death, a decrease in risk occurred for 3 to 4 and 5 to 6 weeks of postconception use (crude HRs, 0.73 and 0.57; 95% CIs, 0.46–1.15 and 0.34–0.96, respectively) but not for 1 to 2 weeks of use (crude HR, 1.18; 95% CI, 0.78–1.80; P for trend = 0.02). Compared with the women with no use, only regular use throughout the periconceptional period was associated with increased risk for early fetal death (crude HR, 1.29; 95% CI, 1.12–1.48). For late fetal death, especially the women for whom regular multivitamin use was initiated after conception, the risk was reduced by ∼35% to 60%.
A small but consistent increased risk for early fetal death was found in the multivitamin users, especially those with regular preconceptional intake. For late fetal death, a beneficial effect was noted for multivitamin use in the women with regular postconception use. Although folate-only use was not associated with fetal death, this study could not provide evidence against use of folate supplements to reduce the risk for neural tube defects, and it was insufficient to alter recommendations regarding multivitamins containing folate. Randomized trials and large observational studies are needed to formulate recommendations.
Research Unit of Gynaecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark (E.A.N.); Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark (E.A.N., J.O., B.H.B.); Department of Epidemiology, Graduate School of Public Health (L.M.B., J.M.C.), and Department of Obstetrics, Gynecology & Reproductive Sciences (L.M.B., J.M.C.), University of Pittsburgh, Pittsburgh, PA; and Department of Epidemiology, Statens Serum Institut, Copenhagen S, Denmark (S.F.O.)