## 5 Vitamin D and GDM: An Overview of Randomised Controlled Trials
### Efficacy of Vitamin D Supplementation for Reducing Incident GDM
Insulin sensitivity using the quantitative insulin sensitivity check index (QUICKI) was assessed in three studies from Iran, all of which found improvements after vitamin D supplementation, despite the different doses used (50,000 IU twice or 200 IU daily from \(\sim\)24 weeks gestation) and different regimens including vitamin D alone [78] or co-supplementing with calcium [84], or with magnesium, zinc and calcium [45; 46]. Conversely, findings for HOMA of beta-cell function (HOMA-\(\beta\)) were inconsistent. One study from China [39] reported a reduction in HOMA-\(\beta\) in 103 women receiving 1000 IU daily cholecystalciferol in fortified yoghurt from 14 weeks gestation for 16 weeks, while two smaller studies (n = 54 and n = 56) from Iran [78; 84] found no significant effect after two doses of 50,000 IU cholecystalciferol from \(\sim\)24 weeks gestation. Hence, in women with GDM, vitamin D appears to have some favourable effects on fasting glucose and insulin resistance, but results tend to vary for most outcomes, likely a reflection of the varied study designs, populations and supplementation regimens. Of the six studies in healthy women, four were conducted in Iran, with one study in the US [43] and one across Europe [44]. The US study reported that 2000 IU of cholecystalciferol daily from 20 weeks gestation had no effect on insulin, HbA1c or fasting, 1-h or 2-h glucose post-OGTT [43]. Similarly, the multi-centre European trial [44] found a small reduction in fasting glucose but no effect on insulin, HOMA-IR, or 1-h or 2-h glucose post-OGTT after supplementation with 1600 IU of cholecalciferol daily from 15 weeks gestation until delivery. It should be noted that in both studies, participants were not vitamin D-deficient at baseline (mean 25(OH)D \(>\) 50 nmol/L). In contrast, all four studies from Iran [37; 38; 79; 81; 82] reported that vitamin D supplementation reduced insulin levels and HOMA-IR. Fasting glucose was reduced in two studies [37; 38; 82] while two reported no effect [79; 81]; and three of the four studies [37; 38; 81; 82] showed a reduction in HOMA-\(\beta\) and an increase in QUICKI (the fourth [79] did not measure these outcomes). Overall, the studies from Iran suggest an improvement in insulin resistance and glycaemic control with vitamin D supplementation, despite having quite different study regimens. For example, [PERSON] et al. [37; 38] provided only 400 IU of cholecystalciferol daily from 25 weeks gestation, while the remaining three studies provided 50,000 IU biweekly from 12 [79] or 20 weeks gestation [81; 82]. The doses in the latter studies average to approximately 3571 IU daily, a dose nine times higher than that provided in the studies by [PERSON] and colleagues [37; 38]. Yet, with the exception of fasting glucose, these studies seem to be in agreement that vitamin D supplementation can improve measures of glycaemic control and insulin resistance in pregnant women without GDM, irrespective of the dose and duration of supplementation. This contrasts with the study by [PERSON] et al. [79] which included three comparison groups (50,000 IU biweekly; 50,000 IU monthly, and 200 IU daily [controls]), and reported that differences in glycaemic measures were only significant when comparing the high dose (biweekly) group with the controls, but not when comparing the lower dose (monthly) group with controls. Whether the effect of vitamin D on these outcomes is influenced by dosage regimens or other factors such as ethnicity, baseline risk profiles includingglycaemic control or vitamin D status, or other study or population characteristics, remains unclear from the available evidence.