Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials

Maternal–child health benefits of optimizing vitamin d status during pregnancy may include a reduced risk of pre-eclampsia, improved fetal growth and beneficial effects on infant immune function. these hypotheses require evaluation by randomized controlled antenatal vitamin d supplementation trials using doses that are high enough to elevate serum 25-hydroxyvitamin d concentrations into the range believed to be associated with improved health outcomes. such doses may be considerably higher than the current recommended dietary allowance (600 iu day–1) or standard prenatal supplement dose (400 iu day–1), and may even be higher than the tolerable upper intake level (4000 iu day–1) advised by the institute of medicine (2010). a critical review of the published literature yielded limited data regarding the safety of antenatal vitamin d regimens. there have been no published reports of the teratogenic effects of vitamin d on humans. some animal studies have suggested the potential for dose-dependent fetal toxicities (for example, growth impairment, skeletal malformations and cardiovascular anomalies), but the relevance of these observations to humans is unknown. antenatal vitamin d supplementation trials should incorporate a range of methods for objectively establishing maternal and fetal safety, and aim to identify the lowest doses of vitamin d required to achieve target outcomes.