Maternal 25(OH)D attenuates the relationship between ambient air pollution during pregnancy and fetal hyperinsulinism

Inflammatory responses have been demonstrated to link air pollution with insulin resistance and type 2 diabetes in adults. However, few studies have focused on the relationship between prenatal air pollution and fetal β-cell function and the mediating effect of systematic inflammation remains elusive. Whether the anti-inflammatory effect of vitamin D could attenuate the β-cell dysfunction in early life warrants further investigations. We aimed to determine whether maternal blood 25(OH)D attenuates the associations of ambient air pollution during pregnancy with fetal hyperinsulinism mediated by maternal inflammatory response. A total of 8250 mother-newborn pairs were included between 2015 and 2021 in the Maternal & Infants Health in Hefei study. Weekly mean air pollution exposure to fine particles (PM_2.5 and PM₁₀), SO₂, and CO was estimated across pregnancy. Maternal serum samples in the third trimester were used to measure the high-sensitivity c-reactive protein (hs-CRP) and 25(OH)D. Cord blood samples at delivery were collected for the measurement of C-peptide. Fetal hyperinsulinism was based on cord C-peptide >90th centile. An increased fetal hyperinsulinism risk was associated with per 10 μg/m³ increase in PM_2.5 [odds ratios (OR): 1.45 (95% confidence interval (CI):1.32, 1.59)], per 10 μg/m³ increase in PM₁₀ [OR = 1.49 (95% CI:1.37, 1.63)], per 5 μg/m³ increase in SO₂ [OR = 1.91 (95% CI: 1.70, 2.15)], and per 0.1 mg/m³ increase in CO [OR = 1.48 (95% CI:1.37, 1.61)] across pregnancy. Mediation analysis showed a 16.3% contribution of maternal hsCRP to the relationship between air pollution throughout pregnancy and fetal hyperinsulinism. Air pollution-associated higher levels of hsCRP and risk of fetal hyperinsulinism could be attenuated by higher maternal 25(OH)D levels. Prenatal ambient air pollution exposures were associated with an increased fetal hyperinsulinism risk mediated by maternal serum hsCRP. Higher antenatal 25(OH)D levels could attenuate air pollution-induced inflammatory responses and hyperinsulinism risk.