Preconception folate status and reproductive outcomes among a prospective cohort of folate-replete women

Background Most studies of folate metabolism and reproduction have been conducted after pregnancy and in folate-deficient populations. However, measurement of maternal folate status preconceptionally may be most relevant to certain folate-linked early processes preceding a successful pregnancy, and there has been a major increase in folate concentrations in women of childbearing age in high resource settings. Objective To examine associations between preconceptional biomarkers of maternal folate status (folate and homocysteine) and reproductive outcomes in folate-replete women. Study Design Cohort nested within the Effects of Aspirin in Gestation and Reproduction trial, a block-randomized, double-blind, placebo-controlled trial whereby women were randomized to daily low-dose aspirin (81 mg/day) or placebo and all women received folic acid (400 μg/day). In total, 1228 women with 1–2 previous pregnancy losses and no documented infertility were recruited from 4 clinical sites in the United States (2006–2012) and were attempting pregnancy for up to 6 menstrual cycles. Log-binomial regression models were used to estimate relative risks and 95% confidence intervals between preconception serum folate and plasma homocysteine for anovulation, pregnancy, and pregnancy loss. Results Greater plasma homocysteine was nonlinearly associated with greater risks of pregnancy loss only among women with 2 previous losses: a relative risk of 1.43 (95% confidence interval, 1.08–1.89) was found for plasma homocysteine concentrations at the study median of 8.0 μmol/L compared with a US population median of 6.0 μmol/L. No meaningful relationships were found between serum folate and any reproductive outcome or between plasma homocysteine and anovulation or becoming pregnant. Conclusion These data justify further study of the role of folate and homocysteine metabolism in normal and abnormal early pregnancy.