Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: A combined analysis

Two randomized, double-blind trials of vitamin D3 during pregnancy. NICHD trial: single-center; TRF trial: two-center. Participants were pregnant women aged 16+ with singleton pregnancies enrolled at 12-16 weeks gestation and planning ongoing prenatal care. Exclusions included pre-existing calcium or parathyroid disorders or chronic diuretic or cardiac therapy; active thyroid disease; identical data collection methods and questionnaires used; outcomes included maternal baseline and delivery 25(OH)D, neonatal 25(OH)D, and comorbidities of pregnancy.

Vitamin D3 supplementation with daily total doses of 400, 2000, or 4000 IU, starting at 12-16 weeks gestation and continuing until delivery. In NICHD, 400 IU/day came from prenatal vitamins and 1600 or 3600 IU/day from vitamin D tablets to reach total dose of 2000 or 4000 IU/day. In TRF, after an initial 1-month run-in of 2000 IU/day, total daily dose for the remainder was 2000 or 4000 IU/day, delivered via vitamin D tablets matching placebo in appearance; prenatal vitamins provided 400 IU/day.

Combined analysis showed higher final maternal and cord blood 25(OH)D and higher rates of vitamin D sufficiency in higher-dose groups (p<0.0001). Differences persisted after adjusting for race and study. There were no significant differences in maternal adverse events, but trends toward lower gestational diabetes, infection, hypertensive disorders, and bacterial vaginosis with higher dose, most pronounced in the 4000 IU/day group. Each 10 ng/mL increase in final maternal 25(OH)D at delivery was associated with lower odds of infection and preterm birth without preeclampsia; for four major comorbidities combined, OR 0.84 per 10 ng/mL increase (p=0.006). Achieving vitamin D sufficiency during pregnancy appears linked to better maternal-fetal health, and adherence to supplementation is crucial. Larger trials are needed to confirm mechanisms.

Nonadherence to vitamin D supplementation in >1/3 of participants likely diluted effects; TRF trial lacked a no-treatment control arm; adherence assessed by self-report and pill counts, which may be inaccurate; pooling data from two trials with different designs may introduce heterogeneity.