Increased Iron Levels Linked to Gestational Diabetes

Findings from a new study, published in Diabetologia, have raised questions about routine recommendations regarding iron supplementation in pregnancy.

“Iron is regarded as a double-edged sword in living systems, as both iron deficiency and overload can be harmful. Pregnant women are particularly vulnerable to iron deficiency and related adverse pregnancy outcomes,” the researchers wrote, noting that guidelines from several groups recommend routine iron supplementation in pregnancy. However, they also explained that new findings “have raised critical concerns about significant links between larger iron stores and disturbances in glucose metabolism, including an increased risk of type 2 diabetes among non-pregnant individuals.” The link between larger iron stores in pregnancy and gestational diabetes, though, remains unclear.

The researchers conducted a case-control study of 107 women with gestational diabetes and 214 controls who were matched by age, race/ethnicity, and gestational week of blood collection within the prospective multiracial Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort (2009-2013). Biomarkers of iron status, including plasma hepcidin, ferritin, and soluble transferring receptor (sTfR), were measured. These data were then used to calculate the sTfR-to-ferritin ratio twice before gestational diabetes diagnosis (gestational weeks 10 to 14 and weeks 15 to 26) and at weeks 23 to 31 and weeks 33 to 39. The researchers identified gestational diabetes diagnosis via medical records based on oral glucose tolerance tests.

According to study results, women with gestational diabetes had 16% higher hepcidin concentrations than controls during weeks 15 to 26 (median: 6.4 vs 5.5 ng/mL; P =.02). Hepcidin levels also appeared to be positively associated with gestational diabetes risk. The adjusted odds ratio [OR] for women in the highest vs lowest quartile was 2.61 (95% confidence interval [CI], 1.07-6.36).

Similarly, ferritin levels were positively associated with risk for gestational diabetes. Adjusted ORs for ferritin levels in the highest vs lowest quartile were 2.43 (95% CI, 1.12-5.28) at weeks 10 to 14 and 3.95 (95% CI, 1.38-11.30) at weeks 15 to 26.

The researchers reported that the ratio of sTfR to ferritin was inversely related to risk for gestational diabetes, with adjusted ORs for women in the highest vs lowest quartile being 0.33 (95% CI, 0.14-0.80) at weeks 10 to 14 and 0.15 (95% CI, 0.05-0.48) at weeks 15 to 26.

The researchers cited several possible reasons for their findings, including potential mechanisms through which iron may play a role in the development of gestational diabetes.

“As a strong pro-oxidant, free iron can catalyze several cellular reactions that generate reactive oxygen species and increase the level of oxidative stress. Oxidative stress induced from excess iron accumulation can cause beta cell damage and apoptosis and, consequently, contribute to impaired insulin synthesis and secretion,” they wrote.

The researchers also noted that high iron stores in the liver could lead to insulin resistance due to impaired insulin signaling and attenuated capacity of the liver to extract insulin.

“In summary, findings from this longitudinal and prospective study among multiracial, relatively healthy pregnant women without major pre-pregnancy chronic diseases, suggest that higher maternal iron stores may play a role in the development of [gestational diabetes] starting as early as the first trimester,” the researchers concluded. “These findings are of clinical and public health importance as they extend the observation of an association between high body iron stores and elevated risk of glucose intolerance among no-pregnant individuals to pregnancy, and raise potential concerns about the recommendations of routine iron supplementation among pregnant women who already have sufficient iron.”

Disclosures: The researchers report no relevant financial disclosures.

Reference

1. Rawal S, Hinkle SN, Bao W, et al. A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort. Diabetologia. 2016 Nov 10. doi:10.1007/s00125-016-4149-3 [Epub ahead of print].