The Effects of Vitamin D Supplementation During Pregnancy on Maternal, Neonatal, and Infant Health: A Systematic Review and Meta-analysis

Abstract

Context: Previous research linked vitamin D deficiency in pregnancy to adverse pregnancy outcomes.

Objective: Update a 2017 systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of vitamin D supplementation during pregnancy, identify sources of heterogeneity between trials, and describe evidence gaps precluding a clinical recommendation.

Data sources: The MEDLINE, PubMed, Europe PMC, Scopus, Cochrane Database of Systematic Reviews, Web of Science, and CINAHL databases were searched. Articles were included that reported on RCTs that included pregnant women given vitamin D supplements as compared with placebo, no intervention, or active control (≤600 IU d-1). Risk ratios (RRs) and mean differences were pooled for 38 maternal, birth, and infant outcomes, using random effects models. Subgroup analyses examined effect heterogeneity. The Cochrane risk of bias tool was used.

Data extraction: Included articles reported on a total of 66 trials (n = 17 276 participants).

Data analysis: The median vitamin D supplementation dose was 2000 IU d-1 (range: 400-60 000); 37 trials used placebo. Antenatal vitamin D supplementation had no effect on the risk of preeclampsia (RR, 0.81 [95% CI, 0.43-1.53]; n = 6 trials and 1483 participants), potentially protected against gestational diabetes mellitus (RR, 0.65 [95% CI, 0.49-0.86; n = 12 trials and 1992 participants), and increased infant birth weight by 53 g (95% CI, 16-90; n = 40 trials and 9954 participants). No effect of vitamin D on the risk of preterm birth, small-for-gestational age, or low birth weight infants was found. A total of 25 trials had at least 1 domain at high risk of bias.

Conclusion: Additional studies among the general pregnant population are not needed, given the many existing trials. Instead, high-quality RCTs among populations with low vitamin D status or at greater risk of key outcomes are needed. Benefits of supplementation in pregnancy remain uncertain because current evidence has high heterogeneity, including variation in study context, baseline and achieved end-line 25-hydroxyvitamin D level, and studies with high risk of bias.

Systematic review registration: PROSPERO registration no. CRD42022350057.

Keywords: maternal and child health; meta-analysis; micronutrient supplementation; pregnancy; systematic review; vitamin D.

Figure 1.

PRISMA diagram. ^aTwo articles were retracted by journals: Asemi et al (2013a) and Asemi et al (2013b); the article by Karamali et al (2015) was manually removed because Asemi was the corresponding author of Karamali et al (2015). ^bData from the Etemadifar et al (2015) and Zhang et al (2016) articles were ineligible for meta-analysis because they did not contribute to the analysis for any outcome of interest. ^c(1) The Roth et al (2018) and Morris et al (2021) reports are from the same Maternal Vitamin D for Infant Growth trial (merged into Roth et al (2018)); (2) the Enkhmaa et al (2019) and Nasantogtokh et al (2023) report on the same trial (merged into Enkhmaa et al (2019)); (3) the Jefferson et al (2019), Powell et al (2019), and Khatiwada et al (2021) articles report data from the Kellogg trial (merged into Jefferson et al (2019)); (4) Brustad et al (2020), Sass et al (2020), and Brustad et al (2023) data are from the same trial (merged into Brustad et al (2020)); and (5) Corcoy et al (2020) and Harreiter et al (2022) data are from the same trial (merged into Corcoy et al (2020)). ^dThe Jamilian et al (2017) and Razavi et al (2017) articles were manually removed because they were from the research group that published articles that subsequently were retracted. ^eThe Bhowmik et al (2021) article was ineligible for meta-analysis because it did not contribute to the analysis for any outcome of interest. ^f(1) The El-Heis et al (2022) and Moon et al (2023) data were merged with those of Cooper et al (2016) (MAVIDOS [Maternal Vitamin D Osteoporosis Study]), which were included in Roth et al review; (2) the Brustad et al (2020) study data were merged with those of Chewas et al (2016) (COPSAC2010 [Copenhagen Prospective Studies on Asthma in Childhood] trial), which was also included in the Roth et al review.