Background Vitamin D plays a key role in brain development and function; however, evidence in humans has never been systematically reviewed. Hence, we conducted a systematic review, accompanied by meta-analyses where possible, to summarize the existing evidence in humans on the relationship between prenatal 25-hydroxyvitamin D [25(OH)D] circulating levels and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavior, ADHD, and autistic traits.

Methods PubMed, Web of Science and SCOPUS databases were systematically searched using keywords. Study eligibility criteria were: 1) original epidemiologic study performed in humans; 2) available information on circulating concentration of 25(OH)D in maternal or newborn blood as exposure; 3) outcome assessment included information on the offspring’s neurodevelopment evaluated by standardized test scores; and 4) available data on the relevant estimates of effect size and the corresponding 95% confidence intervals (CIs). For all the analyses the lowest category of 25(OH)D concentration was defined as reference. Heterogeneity among studies was evaluated by using the Cochran Q test and quantified by using the I² statistical parameter. Stratified analyses were conducted to assess modification effects by selected factors. Publication bias was examined by using Funnel plot and Egger’s regression asymmetry test. Random-effects meta-analyses were conducted using the metafor package in R

Results Of 260 identified articles, 25 were included in the present review. Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95 (95% CI −0.03, 1.93; p=0.05) for cognition, and 0.88 (95% CI −0.18, 1.93; p=0.10) for psychomotor development. The pooled relative risk for ADHD was 0.72 (95% CI, 0.59, 0.89; p=0.002), and the pooled odds ratio for autism-related traits was 0.42 (95% CI, 0.25, 0.71; p=0.001). Stratified analyses showed stronger associations between 25(OH)D concentrations in early-mid pregnancy and cognition (beta coefficient 1.18, 95% CI -0.16, 2.51; p=0.08), psychomotor performance (beta coefficient 1.43, 95% CI -0.65, 3.52; p=0.18), and risk of autism-related traits (OR 0.28, 95% CI 0.19, 0.42; p<0.01). There was little evidence for protective effects of high prenatal 25(OH)D for language development and behavior difficulties.

Conclusion This meta-analysis provides supporting evidence that increased prenatal exposure to 25(OH)D levels is associated with improved cognitive development and reduced risk of ADHD and autism-related traits later in life. Associations represent a potentially high public health burden given the current prevalence of vitamin D deficiency and insufficiency among childbearing aging and pregnant women.