Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus

1296 Diabetes Care Volume 37, May 2014 EPIDEMIOLOGY/HEALTH SERVICES RESEARCH Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus Monique M. Hedderson,1 Fei Xu,1 Jeanne A. Darbinian,1 Charles P. Quesenberry,1 Sneha Sridhar,1 Catherine Kim,2,3 Erica P. Gunderson,1 and Assiamira Ferrara1 OBJECTIVE Lower levels of sex hormone–binding globulin (SHBG) have been associated with increased risk of diabetes among postmenopausal women; however, it is unclear whether they are associated with glucose intolerance in younger women. We examined whether SHBG concentrations, measured before pregnancy, are associated with risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up examination (1984–1996) and had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case patients were 256 women in whom GDM developed. Two control subjects were selected for each case patient and were matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies. RESULTS Compared with the highest quartile of SHBG concentrations, the odds of GDM increased with decreasing quartile (odds ratio 1.06 [95% CI 0.44–2.52]; 2.33 [1.07–5.09]; 4.06 [1.90–8.65]; P for trend < 0.001), after adjusting for family history of diabetes, prepregnancy BMI, race/ethnicity, alcohol use, prepregnancy weight changes, and homeostasis model assessment of insulin resistance. Having SHBG levels below the median (<64.5 nmol/L) and a BMI ‡25.0 kg/m2 was associated with fivefold increased odds of GDM compared with normal-weight women with SHBG levels at or above the median (5.34 [3.00–9.49]). 1 Kaiser Permanente Northern California, Division of Research, Oakland, CA 2 Department of Medicine, University of Michigan, Ann Arbor, MI 3 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI CONCLUSIONS This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc13-1965/-/DC1. Low prepregnancy SHBG concentrations were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies. Diabetes Care 2014;37:1296–1303 | DOI: 10.2337/dc13-1965 Corresponding author: Monique M. Hedderson, . Received 20 August 2013 and accepted 28 December 2013. © 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/bync-nd/3.0/ for details. care.diabetesjournals.org Gestational diabetes mellitus (GDM) is glucose intolerance with onset or first diagnosis during pregnancy. Women with a history of GDM have a sevenfold increased risk of developing type 2 diabetes mellitus after delivery (1), and the children of women with GDM are more likely to become obese and develop diabetes (2,3). The underlying etiology of GDM appears to be similar to the physiological abnormalities that characterize diabetes outside of pregnancy and is thought to be due to an inability of the pancreatic b-cell to compensate for the increased insulin resistance (IR) induced by pregnancy (4,5). The established risk factors for GDM are similar to the factors associated with the development of type 2 diabetes (6). However, recognized clinical risk factors for GDM are absent in up to half of affected women identified by universal screening strategies (7). Therefore, much remains to be learned about why pregnancy induces glucose intolerance in some women. Prepregnancy metabolic indices that have been associated with subsequent GDM pregnancy include low HDL cholesterol levels, impaired fasting glucose levels, elevated random glucose levels, and higher fasting insulin levels, independent of obesity (8,9). These same biomarkers predict type 2 diabetes in adults. There is increasing interest in identifying prepregnancy risk factors and biomarkers for GDM to increase our understanding of the underlying etiology. Low levels of sex hormone–binding globulin (SHBG) and high levels of testosterone, indicative of serologic hyperandrogenism, have each been associated with incident type 2 diabetes in women (10–12). Sex hormone levels change during early pregnancy because of the pregnancy-induced rise in levels of estradiol, estriol, and SHBG (13), so it is important to understand whether pregravid levels are associated with GDM to ensure that the possible associations are not a consequence of the pregnancy hormone milieu. The aim of this study is to examine the association between prepregnancy SHBG concentrations and the risk of the development of GDM and to determine whether these associations are independent of known risk factors for GDM. Hedderson and Associates RESEARCH DESIGN AND METHODS Kaiser Permanente Northern California (KPNC) is an integrated health-care delivery system that provides medical care for about one-third of the underlying population in the San Francisco Bay area. KPNC subscribers are representative of the region (14). The source population for this study consisted of female KPNC members who completed a voluntary Multiphasic Health Checkup (MHC) examination at the Kaiser Permanente Oakland Medical Center between 1984 and 1996. KPNC members at this facility were invited to complete a comprehensive health checkup upon study enrollment. The MHC consisted of a clinic visit for the completion of questionnaires and clinical measurements, including blood pressure, weight, and serum glucose and cholesterol levels (measured in serum obtained from a random blood draw). An extra serum sample was collected and stored at 2408C for future use. The goal of the MHC was to provide health maintenance through early diagnosis (15). Among women 15–45 years of age who participated in the MHC from 1984– 1996 (n = 27,743 with clinical and questionnaire data, as well as an extra serum sample), we identified 4,098 women who subsequently delivered an infant by 2010 by searching the KPNC hospitalization database and the Pregnancy Glucose Tolerance and GDM Registry (16), an active surveillance registry that annually identifies all pregnancies resulting in a livebirth or stillbirth among KPNC members. Women with recognized prepregnancy diabetes (17) are excluded from the GDM Registry if clinical screening data are available. The registry also captures the results of all screening and diagnostic tests for GDM from the KPNC electronic laboratory database (data available since 1994). Study Design We conducted a nested case-control study within a cohort of 4,098 women who took part in an MHC examination, had an extra tube of serum stored for future use, and had a subsequent pregnancy at KPNC. All cohort members in whom GDM developed were included as case patients; two control subjects were selected for each case from among women not meeting the GDM case patient definition. GDM (...truncated)