Effects of Vitamin D Supplementation During Pregnancy on Preterm Birth Risk and Maternal-Neonatal Outcomes: A Systematic Review and Meta-Analysis of 38 Randomized Controlled Trials

Abstract

Background and objective: Preterm birth complications are among leading causes of mortality in neonates and children under 5 years of age worldwide. The association between prenatal vitamin D supplementation and risk of preterm birth is controversial based on randomized controlled trials (RCTs). We aimed to determine the effect of vitamin D supplementation during pregnancy on preterm birth and maternal and neonatal secondary outcomes, and to ascertain whether the effects of vitamin D supplementation on preterm birth differed by baseline 25(OH)D status, supplementation dose, and timing of initiation.

Data sources: PubMed, Web of Science, Medline, Cochrane Library, and Embase were searched from inception to April 2023 with no language restrictions.

Study selection: RCTs comparing vitamin D supplementation with placebo, no treatment, or standard low-dose vitamin D (≤ 600 IU/day) in pregnant women were included. The primary outcome was preterm birth (<37 weeks’ gestation) and secondary outcomes included maternal adverse events and neonatal anthropometric indicators.

Results: Thirty-eight RCTs involving 17,392 pregnant women were included. Nineteen RCTs involving 7959 pregnant women reported preterm birth. Vitamin D supplementation was associated with a borderline increase in preterm birth risk in the primary analysis (RR, 1.13; 95% CI, 1.01–1.26; P = 0.04; I² = 0%) but this association was modest and largely driven by one large RCT among women living with HIV. An increased preterm birth signal was noted among participants with a baseline 25(OH)D ≥ 30 nmol/L (OR, 1.25; 95% CI, 1.05–1.48) in exploratory subgroup analyses presented as ORs and this signal was entirely derived from the same HIV trial. No significant subgroup associations were detected in the < 30 nmol/L subgroup or by supplementation dose or initiation timing. No significant effects were noted for maternal or neonatal secondary outcomes.

Limitations: The main study limitations included incomplete reporting of preterm births across trials, reliance on the risk signal on a single population-specific risk signal, dichotomization of baseline 25(OH)D status, and lack of individual participant data for refined subgroup analyses.

Conclusions: Current evidence does not support universal vitamin D supplementation to prevent preterm birth. A possible increased risk of preterm birth among participants with a baseline 25(OH)D ≥ 30 nmol/L should be interpreted cautiously because this finding was driven by a single trial in HIV-positive pregnant women and should not be generalized to healthy pregnant women. Further large-scale RCTs and individual participant data meta-analyses are warranted to clarify whether baseline vitamin D status modifies effects of vitamin D supplementation.

Keywords

Maternal outcomes / neonatal outcomes / pregnancy / preterm birth / randomized controlled trials / vitamin D

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