Vitamin D, a fat-soluble steroid hormone, plays crucial roles in calcium and phosphorus homeostasis, bone mineralization, and various extraskeletal functions impacting cardiovascular, metabolic, respiratory, and immune systems. Vitamin D deficiency is a growing concern, particularly among pregnant women due to limited sun exposure, darker skin pigmentation, and increased physiological demands during pregnancy. The prevalence of vitamin D deficiency in pregnancy varies widely (5-90%) globally and has been linked to adverse maternal and fetal outcomes, including hypertensive disorders, GDM, preterm birth, and low birth weight. Numerous meta-analyses have explored these associations and the impact of vitamin D supplementation. This umbrella review, registered in PROSPERO (CRD42022368003), synthesizes the existing evidence from meta-analyses to provide a comprehensive overview for clinicians, researchers, and policymakers.

The authors conducted a thorough search of PubMed, Embase, and the Cochrane Library for relevant systematic reviews and meta-analyses published up to October 2, 2023. The review focused on studies examining the effects of vitamin D intake or levels during pregnancy, comparing outcomes in deficient versus sufficient groups or with and without supplementation. The inclusion criteria were stringent, prioritizing meta-analyses of randomized controlled trials (RCTs) and observational studies, excluding conference abstracts and non-English or Chinese publications. The quality of the included meta-analyses was assessed using AMSTAR 2, and the certainty of evidence was evaluated based on the number of included studies, heterogeneity, and consistency between RCTs and observational studies.

This umbrella review followed a predefined protocol registered in PROSPERO. Three databases (PubMed, Embase, Cochrane Library) were systematically searched for systematic reviews and meta-analyses on vitamin D in pregnancy from inception to October 2, 2023. The search strategy is detailed in supplementary materials. Inclusion criteria were established using a PECOS framework (Population: pregnant women; Exposure: vitamin D intake or levels; Comparison: low vs. high vitamin D or supplementation vs. placebo; Outcomes: all health-related outcomes; Study Design: meta-analyses of RCTs or observational studies). Duplicates were removed using EndNote 20, with title/abstract and full-text screening performed independently by two reviewers. Discrepancies were resolved through discussion or consultation with a third reviewer. Data extraction included first author, publication year, outcome type, study design, number of studies, sample size, and effect sizes (OR, RR, MD, SMD). Two reviewers independently extracted data, resolving disagreements by consensus. Methodological quality was assessed using AMSTAR 2, categorizing meta-analyses into high, moderate, low, and critically low quality based on identified weaknesses. The certainty of evidence for each outcome was graded using a modified approach considering the number of studies, heterogeneity (I²), and differences between RCTs and observational studies, leading to 'convincing', 'probable', 'possible', and 'limited' classifications.

The umbrella review included 16 eligible systematic reviews and meta-analyses encompassing 250,569 women. Observational studies revealed a significant association between vitamin D deficiency (<50 nmol/L) and increased risks of preterm birth (OR = 1.28), miscarriage (OR = 1.60), small-for-gestational-age infants (OR = 1.43), GDM (OR = 1.38), recurrent miscarriage (OR = 4.02), and bacterial vaginosis (OR = 1.54). Higher vitamin D levels were associated with a lower risk of pre-eclampsia (RR = 0.68). In offspring, vitamin D deficiency (<30 nmol/L) was linked to lower birth weight (MD = -87.83 g) and head circumference. Higher vitamin D levels were associated with reduced risks of attention-deficit hyperactivity disorder (OR = 0.59) and autism spectrum disorder (OR = 0.57). RCTs showed that vitamin D supplementation (>400 IU/day) increased birth weight, and reduced risks of maternal pre-eclampsia, miscarriage, fetal/neonatal mortality, and various adverse outcomes in women with GDM (e.g., hyperbilirubinemia, polyhydramnios, macrosomia, fetal distress, neonatal hospitalization). The quality of the meta-analyses varied; all received a critically low AMSTAR 2 rating due to multiple critical flaws.

This umbrella review provides compelling evidence linking vitamin D deficiency during pregnancy with adverse maternal and offspring outcomes. The significant associations found in observational studies highlight the importance of addressing vitamin D deficiency. The findings from RCTs support the beneficial effects of vitamin D supplementation, particularly in reducing the risk of several adverse pregnancy-related complications. While the beneficial effect of vitamin D supplementation on preterm birth is less clear cut, it shows promising results in reducing the risk for women with GDM. The heterogeneous findings concerning the impact of vitamin D supplementation on preterm birth and other outcomes may be attributed to factors such as varying baseline vitamin D levels in study participants, different supplementation dosages and durations, and the inclusion of various subgroups within the studies. More research is needed to clarify these findings. The observed associations are likely multifactorial, with vitamin D potentially playing a role in modulating inflammation, immune function, and other critical processes during pregnancy. However, the consistently low AMSTAR 2 scores for the included meta-analyses point to limitations in methodology. Future research should focus on higher-quality, well-designed RCTs with larger sample sizes to further explore these relationships and to determine the optimal dosage and duration of vitamin D supplementation during pregnancy, while also considering potential ethnic variations in vitamin D metabolism and requirements.

Vitamin D deficiency during pregnancy is associated with increased risks of various adverse maternal and offspring health outcomes. Vitamin D supplementation during pregnancy, particularly at doses above 400 IU/day, shows promise in mitigating some of these risks. However, more rigorous research, especially high-quality RCTs, is needed to confirm these findings and determine optimal supplementation strategies. Regular monitoring of vitamin D status in pregnant women, particularly those at high risk of deficiency, is recommended.

The major limitation of this umbrella review is the low methodological quality of the included meta-analyses, as indicated by the consistently low AMSTAR 2 scores. This limits the strength of the conclusions that can be drawn. The heterogeneity observed across some of the meta-analyses, particularly in observational studies, indicates the need for more standardized study designs and outcome measures to improve comparability. Another limitation is that the assessment of vitamin D status was typically based on a single blood sample, which might not fully reflect the overall vitamin D status over the entire pregnancy period. Finally, the varying dosages and durations of vitamin D supplementation across studies make it challenging to establish a definitive optimal dose.