Maternal B-vitamin and vitamin D status before, during and after pregnancy, and the influence of supplementation preconception and during pregnancy: NiPPeR double-blind randomized controlled trial

Background Maternal vitamin status preconception and during pregnancy have important consequences for pregnancy outcome and offspring development. Changes in status from preconception to early and late pregnancy and postpartum have been inferred from cross-sectional data, with lower pregnancy concentrations often ascribed to plasma volume expansion, but without truly longitudinal data from preconception through pregnancy and post-delivery, and sparse data on the influence of supplementation. This study characterized longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6-months post-delivery, and determined the influence of supplementation. Methods and Findings Between 2015-2017, 1729 UK, Singapore and New Zealand women aged 18-38 years planning conception were recruited from the community to a double-blind controlled trial and randomized to a standard (control) or an intervention supplement preconception and throughout pregnancy. Vitamins common to both supplements were folic acid and β-carotene, with the intervention additionally including riboflavin, vitamins B6, B12 and D in amounts available in over-the-counter supplements, alongside iron, calcium and iodine (control and intervention) and myo-inositol, probiotics and zinc (intervention only). We measured maternal plasma concentrations of B-vitamins, vitamin D and insufficiency/deficiency markers (homocysteine, hydroxykynurenine-ratio, methylmalonic acid), at recruitment and 1-month after commencing intervention preconception, in early and late pregnancy, and post-delivery (6-months after supplement discontinuation). From all timepoint data, we derived standard deviation scores (SDS) to characterize longitudinal changes in controls and differences between control and intervention participants. At recruitment preconception, significant proportions had marginal or low plasma status for folate (29.2% <13.6 nmol/L), riboflavin (7.5% <5 nmol/L, 82.0% ≤26.5 nmol/L), vitamin B12 (9.1% <221 pmol/L) and vitamin D (48.7% <50 nmol/L). Among controls, plasma concentrations showed differing longitudinal patterns from preconception; riboflavin fell through early/late pregnancy, 25-hydroxyvitamin D was unchanged in early pregnancy, and vitamin B6 and B12 concentrations declined through pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation, with 54.2% developing a low late pregnancy vitamin B6 (pyridoxal 5-phosphate <20 nmol/L). Preconception, the control/intervention groups had similar baseline vitamin concentrations; 1-month after supplement commencement, plasma concentrations became substantially higher in intervention participants; riboflavin by 0.77 SDS (95%CI 0.68-0.87), vitamin B6 1.07 (0.99-1.14), vitamin B12 0.55 (0.46-0.64) and vitamin D 0.51 (0.43-0.60), with the higher levels maintained during pregnancy and marked reduction in insufficiency/deficiency markers (lower homocysteine, hydroxykynurenine-ratio, methylmalonic acid) and the late pregnancy prevalence of vitamin D <50 nmol/L reduced from 35.1% to 8.5%. Plasma vitamin B12 was still higher in the intervention group 6-months post-delivery. Conclusion Significant proportions of preconception women have marginal or low status of folate, riboflavin, vitamin B12 and vitamin D, and many develop markers of vitamin B6 deficiency in late pregnancy. In the absence of supplementation, maternal plasma vitamin concentrations show differing longitudinal patterns from preconception to early and late pregnancy, suggesting plasma volume expansion does not wholly account for lower gestational concentrations. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of deficiency/depletion markers before and during pregnancy, and a higher maternal plasma vitamin B12 was maintained during the recommended lactational period.