Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials

The BMJ

Nov 2017

DOI: 10.1136/bmj.j5237

Citations:206

Influential Citations:6

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

Systematic review and meta-analysis of randomized controlled trials in pregnant women; 43 trials with 8,406 participants included in meta-analyses.

Intervention

Vitamin D supplementation during pregnancy; regimens included vitamin D2 or D3, any dose, regular dosing (at least three times in a regular/recurrent manner such as daily, weekly or monthly) or bolus dosing (one or two doses), administered orally or intramuscularly, from enrollment through delivery.

Results

Vitamin D supplementation increases maternal and cord 25(OH)D concentrations; dose–response is modest. Maternal outcomes are rarely reported and show no robust benefits. Modest improvements include a mean birth weight increase of 58.33 g (95% CI 18.88 to 97.78 g; 37 comparisons) and a reduced risk of small-for-gestational-age births (RR 0.60; 95% CI 0.40 to 0.90; 7 comparisons). No effect on preterm birth (RR 1.00; 95% CI 0.77 to 1.30; 15 comparisons). Possible reduction in offspring wheeze by age 3 years (RR 0.81; 95% CI 0.67 to 0.98; 2 comparisons). Most outcomes come from a minority of trials; only 8 of 43 trials had low risk of bias. Overall, evidence is insufficient to guide clinical or policy recommendations; future well-powered trials should focus on clinically meaningful outcomes such as maternal conditions (e.g., preeclampsia), infant growth, and respiratory outcomes.

Limitations

Most trials were small and of low methodological quality; substantial heterogeneity and incomplete reporting; many outcomes reported in only a minority of trials; risk of bias present in the majority of studies (only 8/43 low risk).

Abstract

Objectives To estimate the effects of vitamin D supplementation during pregnancy on 11 maternal and 27 neonatal/infant outcomes; to determine frequencies at which trial outcome data were missing, unreported, or inconsistently reported; and to project the potential contributions of registered ongoing or planned trials. Design Systematic review and meta-analysis of randomised controlled trials; systematic review of registered but unpublished trials. Data sources Medline, Embase, PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to September 2017; manual searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials. Eligibility criteria for study selection Trials of prenatal vitamin D supplementation with randomised allocation and control groups administered placebo, no vitamin D, or vitamin D ≤600 IU/day (or its equivalent), and published in a peer reviewed journal. Results 43 trials (8406 participants) were eligible for meta-analyses. Median sample size was 133 participants. Vitamin D increased maternal/cord serum concentration of 25-hydroxyvitamin D, but the dose-response effect was weak. Maternal clinical outcomes were rarely ascertained or reported, but available data did not provide evidence of benefits. Overall, vitamin D increased mean birth weight of 58.33 g (95% confidence interval 18.88 g to 97.78 g; 37 comparisons) and reduced the risk of small for gestational age births (risk ratio 0.60, 95% confidence interval 0.40 to 0.90; seven comparisons), but findings were not robust in sensitivity and subgroup analyses. There was no effect on preterm birth (1.0, 0.77 to 1.30; 15 comparisons). There was strong evidence that prenatal vitamin D reduced the risk of offspring wheeze by age 3 years (0.81, 0.67 to 0.98; two comparisons). For most outcomes, meta-analyses included data from a minority of trials. Only eight of 43 trials (19%) had an overall low risk of bias. Thirty five planned/ongoing randomised controlled trials could contribute 12 530 additional participants to future reviews. Conclusions Most trials on prenatal vitamin D published by September 2017 were small and of low quality. The evidence to date seems insufficient to guide clinical or policy recommendations. Future trials should be designed and powered to examine clinical endpoints, including maternal conditions related to pregnancy (such as pre-eclampsia), infant growth, and respiratory outcomes. Systematic review registration PROSPERO CRD42016051292 show less