Background:
Maternal vitamin D deficiency has been implicated in adverse cardiometabolic profiles during pregnancy as well as pregnancy outcomes, including gestational diabetes mellitus (GDM). Recent evidence suggests that the relationship between vitamin D and cardiometabolic risk and pregnancy outcomes may be mediated by inflammatory pathways, with growing interest in the potential role of adipokines. However, no previous studies have investigated whether associations between vitamin D and pregnancy-related outcomes may be mediated by underlying adipokine concentrations.

Aims:
We investigated relationships between maternal 25-hydroxyvitamin D (25(OH)D) concentrations and cardiometabolic risk factors during pregnancy and subsequent pregnancy outcomes. We also explored whether the associations between 25(OH)D and cardiometabolic risk factors and pregnancy outcomes may be mediated by circulating adipokine concentrations.

Methods:
In this retrospective cohort study, we used bio-banked samples collected at 12-15 weeks gestation from 102 overweight or obese pregnant women who were classified as being at high risk of GDM based on a validated risk prediction tool. We measured circulating serum 25(OH)D (chemiluminescent immunoassay), serum lipids (total, high-, and low- density cholesterol, and triglycerides) (ELISA), serum inflammatory markers: interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and novel adipokines: omentin-1, visfatin, and high molecular weight (HMW)-adiponectin (ELISA). Fasting, 1-hour, and 2-hour glucose levels were assessed by oral glucose tolerance tests conducted at 20-24 weeks gestation, and pregnancy outcomes were recorded at delivery. Multivariable linear and logistic regression models were performed with adjustment for maternal factors: age, body mass index (BMI), parity, smoking status, and country of birth. 

Results:
Participants were aged 31.9 ± 4.5 years (mean ± SD) with a BMI of 30.6 ± 6.6 kg/m2 and 25(OH)D level of 47.9 ± 16.0 nmol/L. In univariable analyses, serum 25(OH)D concentrations were associated with fasting glucose, 1-hour glucose, total cholesterol, triglycerides, and IL-6, and positively associated with HMW-adiponectin and length of gestation. Higher 25(OH)D concentrations were also associated with reduced risk of GDM. In multiple regression analyses adjusted for maternal factors, 25(OH)D concentrations remained negatively associated with fasting and 1-hour glucose, total cholesterol, and triglycerides, and positively associated with HMW-adiponectin and length of gestation. Higher 25(OH)D concentrations remained associated with reduced risk of GDM after adjustment for maternal factors, and became associated with reduced risk of preterm birth after additional adjustment for caesarean section. However, adding HMW-adiponectin to the multivariable models attenuated all associations, except fasting glucose and length of gestation. 

Discussion:
In a well-characterized cohort of overweight or obese pregnant women at high risk of GDM, we found that lower 25(OH)D concentrations at 12-15 weeks gestation were associated with increased cardiometabolic risk factors, and increased risk of GDM and preterm birth. These associations appeared to be largely mediated by HMW-adiponectin concentrations. Large-scale trials are needed to explore whether vitamin D supplementation improves adiponectin concentrations and subsequent pregnancy-related risk factors and outcomes.

Vitamin D deficiency in early pregnancy is associated with increased cardiometabolic risk and gestational diabetes