Important exposure, important outcome

Recently, clinical and experimental models have identified links between vitamin D and an assortment of women’s health issues, including infertility, preterm birth, endometriosis, polycystic ovarian syndrome, preeclampsia, bacterial vaginosis, and GDM. In addition, some reports have shown an association between maternal vitamin D levels and type I diabetes risk in offspring.

The incidence of GDM is approximately 14% of total pregnancies in the United States, and that rate continues to increase despite medical attention. Fetal macrosomia, preterm birth, newborn jaundice, and respiratory distress syndrome are among possible complications; mothers are at increased risk for cesarean section and, as noted, future type II diabetes. If maternal vitamin D status turns out to be a modifiable risk factor in GDM, then vitamin D supplementation would be a potential low-cost preventative and therapeutic agent. As we know, a simple intervention can have a major effect—consider how the addition of 400 mcg of folic acid to the daily diet of women of childbearing age significantly reduces the risk of neural tube defects.

Why might it work?

Mechanistically, in vitro and animal models have shown that vitamin D deficiency affects insulin secretion and the expression of insulin receptors. Vitamin D is also known to have anti-inflammatory properties, and mounting evidence demonstrates that inflammation is intimately related to the development of the metabolic syndrome and diabetes. Low serum vitamin D has been associated with type II diabetes and obesity in a number of clinical studies. A connection between GDM and maternal vitamin D levels has been described before, but the data are confusing due to diversity in study size, timing of maternal vitamin D sampling, and adjustment for potential confounding factors.

Burris and colleagues looked for a relationship between maternal 25-hydroxyvitamin D [25(OH)D] levels in the second trimester and GDM by constructing a case-control study “nested” within a prospective cohort study; specifically, Project Viva, a large epidemiologic prenatal prospective cohort study that is exploring ties between gestational factors and offspring health. For Burris et al, the primary outcomes were development of GDM or impaired glucose tolerance, based on the results of glucose challenge testing.

Multiple models

An interesting aspect of this study was the development of multiple models examining the possible association between maternal vitamin D status and GDM. Model 1 showed the unadjusted odds ratios (ORs) and confidence intervals (CIs). Model 2 adjusted for gestational age, season, maternal age, race/ethnicity, education, marital status, smoking, and parity. Model 3 adjusted for everything in model 2 and also adjusted for prepregnancy body mass index (BMI) and pregnancy weight gain. Model 4 went further, adjusting for everything in model 3 plus physical activity and dietary intake of fish and calcium. Multiple models illustrated the contributions of different confounding factors and delineated the difference in the ORs after adjusting for factors unique to this study. These models helped reveal the impact of each successive adjustment.

The researchers found that 68 women met the criteria for GDM. Compared with women who had 25(OH)D levels of 25 nmol/L or more, those with levels less than 25 nmol/L had “significantly increased odds of GDM.” This remained true in the second model after adjusting for several factors. However, Burris and colleagues noted that in the third model, adjustment for BMI weakened the association, and the CI included the null value. This finding was believed to be the result of confounding. Additional adjustments for diet and exercise in model 4 had minimal effect, leading the group to propose that vitamin D’s interaction with glucose tolerance is independent of dietary sources of the nutrient.

Journal Club members thought the study had major strengths and a couple of weaknesses. While they are not ready to begin routine testing of vitamin D levels in pregnant patients, they do believe the researchers added to the evidence indicating that an association exists between 25(OH)D levels and increased risk for GDM. Further studies are necessary. For example, it would be important to determine the basis for the relationship. Do low 25(OH)D levels actually predict GDM or are both the result of something else, such as obesity? Might this relationship exist in the other trimesters? And of course, it would be important to know whether particular dosages of vitamin D supplementation can really reduce the risk for GDM.