History of infertility, risk of type 2 diabetes and HbA1c levels in the Nurses’ Health Study II

Abstract Aims/hypothesis The aim of the study was to investigate the relationship between infertility history, the risk of type 2 diabetes and HbA 1c levels. Methods Among the participants in the Nurses’ Health Study II ( n =116,429), those who reported infertility (>12 months of trying to conceive), both overall and by infertility diagnosis, were compared with gravid women with no history of infertility. We used Cox proportional hazard models to estimate the HR and 95% CI of type 2 diabetes and adjusted for a priori potential confounding variables. Person-time was stratified a priori by age (≤50 and >50 years); in secondary analyses, we restricted the sample to those with a BMI of <25 kg/m 2 at 18 years of age. We used linear regression models to assess the prospective association between the history of infertility and log-transformed blood HbA 1c concentrations measured on average at age 44, among a subset of participants with this measure ( n =2399). Results The association between a history of infertility and the risk of type 2 diabetes differed before and after the age of 50 ( p value, test for interaction: 0.0004). Up to 50 years of age, infertility history was associated with a 32% greater risk of type 2 diabetes (95% CI 1.22, 1.43); for specific infertility diagnoses, ovulatory disorders were associated with a 67% greater risk (95% CI 1.48, 1.89), whereas tubal blockage (HR 1.29 [95% CI 1.01, 1.64]), male factor infertility (HR 1.30 [95% CI 1.08, 1.57]) and ‘cause not found’ (HR 1.26 [95% CI 1.05, 1.51]) were all associated with a ~30% greater risk of type 2 diabetes. After the age of 50, the association between overall infertility and type 2 diabetes attenuated (HR 1.12 [95% CI 1.06, 1.19]), as did associations between ovulatory disorders and type 2 diabetes (HR 1.18 [95% CI 1.05, 1.32]). The association between tubal blockage and the risk of type 2 diabetes remained similar after the age of 50 (HR 1.26 [95% CI 1.05, 1.51]). The overall association between infertility and the risk of type 2 diabetes remained elevated among women with a BMI of <25 kg/m 2 at the age of 18 (≤50 years, HR 1.32 [95% CI 1.20, 1.44]; >50 years, HR 1.11 [95% CI 1.04, 1.19]). Women with a history of infertility also had slightly higher mean HbA 1c levels than women without a history of infertility (relative difference: 0.7% [95% CI 0.04, 1.32]), reflecting a minimal absolute difference in HbA 1c . Conclusions/interpretation Women with a history of infertility had a greater risk of developing type 2 diabetes, particularly prior to the age of 51 years. Specific reasons for infertility were associated with an elevated type 2 diabetes risk, including ovulatory disorders and tubal factors. These associations were independent of BMI.