Vitamin D supplementation during pregnancy may be needed to protect against adverse pregnancy outcomes. This is an update of a review that was first published in 2012 and then in 2016. To examine whether vitamin D supplementation alone or in combination with calcium or other vitamins and minerals given to women during pregnancy can safely improve maternal and neonatal outcomes. For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register (12 July 2018), contacted relevant organisations (15 May 2018), reference lists of retrieved trials and registries at clinicaltrials.gov and WHO International Clinical Trials Registry Platform (12 July 2018). Abstracts were included if they had enough information to extract the data. Randomised and quasi‐randomised trials evaluating the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy in comparison to placebo or no intervention. Two review authors independently i) assessed the eligibility of trials against the inclusion criteria, ii) extracted data from included trials, and iii) assessed the risk of bias of the included trials. The certainty of the evidence was assessed using the GRADE approach. We included 30 trials (7033 women), excluded 60 trials, identified six as ongoing/unpublished trials and two trials are awaiting assessments. Supplementation with vitamin D alone versus placebo/no intervention A total of 22 trials involving 3725 pregnant women were included in this comparison; 19 trials were assessed as having low‐to‐moderate risk of bias for most domains and three trials were assessed as having high risk of bias for most domains. Supplementation with vitamin D alone during pregnancy probably reduces the risk of pre‐eclampsia (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.30 to 0.79; 4 trials, 499 women, moderate‐certainty evidence ) and gestational diabetes (RR 0.51, 95% CI 0.27 to 0.97; 4 trials, 446 women, moderate‐certainty evidence ); and probably reduces the risk of having a baby with low birthweight (less than 2500 g) (RR 0.55, 95% CI 0.35 to 0.87; 5 trials, 697 women, moderate‐certainty evidence ) compared to women who received placebo or no intervention. Vitamin D supplementation may make little or no difference in the risk of having a preterm birth < 37 weeks compared to no intervention or placebo (RR 0.66, 95% CI 0.34 to 1.30; 7 trials, 1640 women, low‐certainty evidence ). In terms of maternal adverse events , vitamin D supplementation may reduce the risk of severe postpartum haemorrhage (RR 0.68, 95% CI 0.51 to 0.91; 1 trial, 1134 women, low‐certainty evidence ). There were no cases of hypercalcaemia (1 trial, 1134 women, low‐certainty evidence) , and we are very uncertain as to whether vitamin D increases or decreases the risk of nephritic syndrome (RR 0.17, 95% CI 0.01 to 4.06; 1 trial, 135 women, very low‐certainty evidence ). However, given the scarcity of data in general for maternal adverse events, no firm conclusions can be drawn. Supplementation with vitamin D and calcium versus placebo/no intervention Nine trials involving 1916 pregnant women were included in this comparison; three trials were assessed as having low risk of bias for allocation and blinding, four trials were assessed as having high risk of bias and two had some components having a low risk, high risk, or unclear risk. Supplementation with vitamin D and calcium during pregnancy probably reduces the risk of pre‐eclampsia (RR 0.50, 95% CI 0.32 to 0.78; 4 trials, 1174 women, moderate‐certainty evidence ). The effect of the intervention is uncertain on gestational diabetes (RR 0.33,% CI 0.01 to 7.84; 1 trial, 54 women, very low‐certainty evidence ); and low birthweight (less than 2500 g) (RR 0.68, 95% CI 0.10 to 4.55; 2 trials, 110 women, very low‐certainty evidence ) compared to women who received placebo or no intervention. Supplementation with vitamin D and calcium during pregnancy may increase the risk of preterm birth < 37 weeks in comparison to women who received placebo or no intervention (RR 1.52, 95% CI 1.01 to 2.28; 5 trials, 942 women, low‐certainty evidence ). No trial in this comparison reported on maternal adverse events . Supplementation with vitamin D + calcium + other vitamins and minerals versus calcium + other vitamins and minerals (but no vitamin D) One trial in 1300 participants was included in this comparison; it was assessed as having low risk of bias. Pre‐eclampsia was not assessed. Supplementation with vitamin D + other nutrients may make little or no difference in the risk of preterm birth < 37 weeks (RR 1.04, 95% CI 0.68 to 1.59; 1 trial, 1298 women, low‐certainty evidence ); or low birthweight (less than 2500 g) (RR 1.12, 95% CI 0.82 to 1.51; 1 trial, 1298 women, low‐certainty evidence ). It is unclear whether it makes any difference to the risk of gestational diabetes (RR 0.42, 95% CI 0.10 to 1.73) or maternal adverse events (hypercalcaemia no events; hypercalciuria RR 0.25, 95% CI 0.02 to 3.97; 1 trial, 1298 women,) because the certainty of the evidence for both outcomes was found to be very low. We included 30 trials (7033 women) across three separate comparisons. Our GRADE assessments ranged from moderate to very low, with downgrading decisions based on limitations in study design, imprecision and indirectness. Supplementing pregnant women with vitamin D alone probably reduces the risk of pre‐eclampsia, gestational diabetes, low birthweight and may reduce the risk of severe postpartum haemorrhage. It may make little or no difference in the risk of having a preterm birth < 37 weeks' gestation. Supplementing pregnant women with vitamin D and calcium probably reduces the risk of pre‐eclampsia but may increase the risk of preterm births < 37 weeks (these findings warrant further research). Supplementing pregnant women with vitamin D and other nutrients may make little or no difference in the risk of preterm birth < 37 weeks' gestation or low birthweight (less than 2500 g). Additional rigorous high quality and larger randomised trials are required to evaluate the effects of vitamin D supplementation in pregnancy, particularly in relation to the risk of maternal adverse events. Is vitamin D supplementation beneficial or harmful for women during pregnancy? What is the issue? It is not clear if vitamin D supplementation, alone or in combination with calcium or other vitamins and minerals, during pregnancy have benefits or harms to the mother or her offspring. Why is this important? Vitamin D is essential for human health, particularly bone, muscle contraction, nerve conduction, and general cellular function. Low concentrations of blood vitamin D in pregnant women have been associated with pregnancy complications. It is thought that additional vitamin D through supplementation during pregnancy might be needed to protect against pregnancy complications. What was studied in the review? This is an update of a review that was first published in 2012 and subsequently updated in 2016. This review evaluated the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy in comparison to placebo or no intervention, irrespective of dose, duration or time of commencement of supplementation or type of supplementation (oral or by injection). What evidence did we find? We searched for evidence (July 2018) and found 30 trials (involving 7033 women) for inclusion in this update. Evidence from 22 trials involving 3725 pregnant women suggest that supplementation with vitamin D alone during pregnancy probably reduces the risk of pre‐eclampsia, gestational diabetes, and the risk of having a baby with low birthweight compared to placebo or no intervention and may make little or no difference in the risk of having a preterm birth. It may reduce the risk of maternal adverse events, such as severe postpartum haemorrhage, although it should be noted that this result was unexpected and based on a single trial. Evidence from nine trials involving 1916 pregnant women suggest that supplementation with vitamin D and calcium probably reduces the risk for pre‐eclampsia but may increase the risk of preterm birth. This slight potential harm warrants consideration in women receiving calcium supplementation as part of antenatal care. Evidence from one study involving 1300 pregnant women suggest that supplementation with vitamin D plus other nutrients may make little or no difference in the risk of most outcomes evaluated. Data on maternal adverse events were lacking in most trials. What does this mean? Supplementing pregnant women with vitamin D alone probably reduces the risk of pre‐eclampsia, gestational diabetes, low birthweight and the risk of severe postpartum haemorrhage. It may make little or no difference in the risk of having a preterm birth < 37 weeks' gestation. Supplementing pregnant women with vitamin D and calcium probably reduces the risk of pre‐eclampsia but may increase the risk of preterm births < 37 weeks (these findings warrant further research). Supplementing pregnant women with vitamin D and other nutrients may make little or no difference in the risk of preterm birth or low birthweight (less than 2500 g) and the effects for gestational diabetes and maternal adverse events are unclear. Additional rigorous high quality and larger randomised trials are required to evaluate the effects of vitamin D supplementation in pregnancy, particularly in relation to the risk of maternal adverse events.
