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

Abstract

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.