Association between maternal vitamin D levels and risk of adverse pregnancy outcomes: a systematic review and dose-response meta-analysis

Epidemiological studies have investigated the associations between vitamin D and the risk of adverse pregnancy outcomes; however, the results are conflicting and dose-response relationships remain to be confirmed. This study aimed to summarize previous studies on the associations of vitamin D levels with the risk of gestational diabetes mellitus (GDM), pre-eclampsia (PE), gestational hypertension (GH), and caesarean section (C-section), and to clarify the dose-response trends. PubMed, Embase, Scopus, and Web of Science were searched to identify eligible articles. A total of 69 prospective observational studies including cohort studies, case-cohort studies, or nested case-control studies were included in the current systematic review, of which 68 studies were available for meta-analysis. Compared with the lowest level, the highest level of 25(OH)D was significantly associated with a lower risk of GDM (RR: 0.76; 95% CI: 0.66-0.87), PE (RR: 0.74; 95% CI: 0.60-0.90;), and GH (RR: 0.87; 95% CI: 0.79-0.97); however, no significant relationship was found for C-section (RR: 1.00; 95% CI: 0.90-1.12). There was significant between-study heterogeneity for GDM (I-2 = 69.2%; P-heterogeneity < 0.001), PE (I-2 = 52.0%; P-heterogeneity = 0.001), and C-section (I-2 = 59.1%; P-heterogeneity < 0.001), while no heterogeneity was found for GH (I-2 = 0.0%; P-heterogeneity = 0.676). For each 25 nmol L-1 increase in 25(OH)D, the pooled RR was 0.92 (95% CI: 0.86-0.97) for GDM and 0.89 (95% CI: 0.84-0.94) for PE, respectively. Notably, the dose-response analysis showed a non-linear relationship between maternal 25(OH)D levels and the risk of PE (Pnon-linearity = 0.009). Our meta-analysis provides further scientific evidence of the inverse association between 25(OH)D levels and the risk of GDM, PE, and GH, which may be useful for the prevention of pregnancy complications. However, more evidence from prospective studies is needed regarding the dietary intake of vitamin D during pregnancy.