Background 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. Objectives 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. Search methods 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. Selection criteria 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. Data collection and analysis 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. Main results We included 30 trials (7033 women), excluded 60 trials, identified six as ongoing/unpublished trials and two trials are awaiting assessments.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. Authors' conclusions 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.

Vitamin D deficiency is highly prevalent during pregnancy. It has been suggested that vitamin D supplementation during pregnancy may reduce the risk of adverse gestational outcomes. To update a previous meta-analysis on the effects of oral vitamin D supplementation (alone or in combination with other vitamins and minerals) during pregnancy on maternal 25(OH)D levels and risk of developing pre-eclampsia, gestational diabetes, preterm birth, impaired glucose tolerance, caesarean section, gestational hypertension and other adverse conditions. We searched for randomized and quasi-randomized trials through the Cochrane Pregnancy and Childbirth Group's Trials Register, the International Clinical Trials Registry Platform, the Networked Digital Library of Theses and Dissertations, and direct communications with relevant organizations. Assessments of inclusion criteria, extraction of data from included studies, and risk of bias' assessments of the included studies were done independently by two review authors. We included 15 trials, excluded 27 trials and 23 trials are still ongoing/unpublished. Data from seven trials with 868 women suggest that pregnant women supplemented with vitamin D had significantly higher 25(OH)D levels compared to controls (mean difference: 54.7nmol/L; 95% CI 36.6, 72.9). Two trials found a lower risk of preeclampsia (8.9% versus 15.5%; average risk ratio 0.52; 95% CI 0.25, 1.05) and two other trials found no difference in the risk of gestational diabetes with vitamin D supplementation. Also, three trials found that supplementation with vitamin D plus calcium reduced the risk of pre-eclampsia (5% versus 9%; average risk ratio 0.51; 95% CI 0.32, 0.80). Supplementing pregnant women with vitamin D led to significantly higher levels of 25(OH)D at term compared to placebo/control but results were inconsistent. Vitamin D supplementation, with or without calcium, may be related to lower risk of preeclampsia but more studies are needed to confirm this.

Calcium intake remains inadequate in many low‐ and middle‐income countries, especially in Africa and South Asia, where average intakes can be below 400 mg/day. Given the vital role of calcium in bone health, metabolism, and cell signaling, countries with low calcium intake may want to consider food‐based approaches to improve calcium consumption and bioavailability within their population. This is especially true for those with low calcium intake who would benefit the most, including pregnant women (by reducing the risk of preeclampsia) and children (by reducing calcium‐deficiency rickets). Specifically, some animal‐source foods that are naturally high in bioavailable calcium and plant foods that can contribute to calcium intake could be promoted either through policies or educational materials. Some food processing techniques can improve the calcium content in food or increase calcium bioavailability. Staple‐food fortification with calcium can also be a cost‐effective method to increase intake with minimal behavior change required. Lastly, biofortification is currently being investigated to improve calcium content, either through genetic screening and breeding of high‐calcium varieties or through the application of calcium‐rich fertilizers. These mechanisms can be used alone or in combination based on the local context to improve calcium intake within a population.

Most low‐ and middle‐income countries present suboptimal intakes of calcium during pregnancy and high rates of mortality due to maternal hypertensive disorders. Calcium supplementation during pregnancy is known to reduce the risk of these disorders and associated complications, including preeclampsia, maternal morbidity, and preterm birth, and is, therefore, a recommended intervention for pregnant women in populations with low dietary calcium intake (e.g., where ≥25% of individuals in the population have intakes less than 800 mg calcium/day). However, this intervention is not widely implemented in part due to cost and logistical issues related to the large dose and burdensome dosing schedule (three to four 500‐mg doses/day). WHO recommends 1.5–2 g/day but limited evidence suggests that less than 1 g/day may be sufficient and ongoing trials with low‐dose calcium supplementation (500 mg/day) may point a path toward simplifying supplementation regimens. Calcium carbonate is likely to be the most cost‐effective choice, and it is not necessary to counsel women to take calcium supplements separately from iron‐containing supplements. In populations at highest risk for preeclampsia, a combination of calcium supplementation and food‐based approaches, such as food fortification with calcium, may be required to improve calcium intakes before pregnancy and in early gestation.

Low calcium intake is common worldwide and can result in nutritional rickets in children and osteomalacia in adults. Calcium‐fortified foods could improve calcium intake. However, there is limited calcium fortification experience, with technical and practical issues that may hamper its adoption. The objective of this landscape review is to summarize these issues to help policymakers guide the planning and design of calcium fortification as a public health strategy. One challenge is the low bioavailability of calcium salts (∼20–40%); thus, large amounts need to be added to food to have a meaningful impact. Solubility is important when fortifying liquids and acidic foods. Calcium salts could change the flavor, color, and appearance of the food and may account for 70–90% of the total fortification cost. Safety is key to avoid exceeding the recommended intake; so the amount of added calcium should be based on the target calcium intake and the gap between inadequate and adequate levels. Monitoring includes the quality of the fortified food and population calcium intake using dietary assessment methods. Calcium fortification should follow regulations, implemented in an intersectorial way, and be informed by the right to health and equity. This information may help guide and plan this public health strategy.