Prediction of Type 1 Diabetes Postpartum in Patients With Gestational Diabetes Mellitus by Combined Islet Cell Autoantibody Screening: A Prospective Multicenter Study

Abstract

Women with gestational diabetes mellitus (GDM) have a considerable risk of developing diabetes later in life. To determine the predictive value of autoantibody markers in gestational diabetic pregnancy for the development of type 1 diabetes postpartum, we tested 437 patients with GDM (289 women treated with diet only [GDM-A] and 148 requiring insulin treatment during pregnancy [GDM-B]) for antibodies to islet cells (ICAs), GAD (GADAs), and tyrosine phosphatase ICA512/IA-2 (IA2As). We prospectively followed them with repeated oral glucose tolerance tests and antibody determinations for up to 7 years postpartum (mean, 1.6 years; range, 0-7.2 years). The cumulative risk of diabetes up to 5 years postpartum was 17% (95% CI 12-22%). The risk of type 1 diabetes was 3% (2-5%) by 9 months and 7% (4-9%) 2 years after delivery. At delivery, 8.5% of all patients were ICA+, 9.5% were GADA+, 6.2% were IA2A+, and 18.1% were positive for at least one antibody (12.6% for GDM-A vs. 30.4% for GDM-B, P < 0.0001). During follow-up, GADAs persisted in 75%, ICAs in 35%, and IA2As in 30% of the subjects positive for the respective marker at delivery. By 2 years postpartum, 29% (19-39%) of patients positive for at least one antibody developed type 1 diabetes, compared with 2% (1-4%) of antibody-negative patients (P < 0.0001). Thereby, the risk for type 1 diabetes 2 years postpartum increased with the number of antibodies present at delivery from 17% (6-28%) for one antibody, to 61% (30-91%) for two antibodies, and to 84% (55-100%) for 3 antibodies. Risk of progression to type 1 diabetes postpartum was also associated with the status of parity. Women with one or more pregnancies before the index pregnancy had a higher risk for type 1 diabetes 2 years after delivery (14.7% [4.9.-24.5%]) than women having their first (i.e., index) pregnancy (5% [2.9-7.1%]) (P < 0.006). A comparison of different prediction strategies showed that single antibody screening with GADA yielded the highest sensitivity of 63% (45-75%), compared with ICA (48% [31-65%]) and IA2A (34% [13-47%]). Combined screening with two autoantibodies increased sensitivity to 74% (58-90%) and 75% (60-92%) when using GADA plus ICA or GADA plus IA2A, respectively. Screening with all three markers improved sensitivity further to 82% (67-100%). Beta-cell autoantibodies determined at delivery in women with GDM are highly predictive for the development of type 1 diabetes postpartum. Autoantibody screening in pregnant women with GDM from populations at high risk for type 1 diabetes should therefore be considered to allow early diagnosis and appropriate therapy.

Genotypic and phenotypic differences between Arabian and Scandinavian women with gestational diabetes mellitus

“…The frequency of GAD65Ab has been shown to vary between different populations. In Maine (USA), about 6% of the women with GDM were positive for GAD65Ab [41], whereas the frequency in GDM women from Germany was as high as 9.5% [23]. In Italy, the frequency of GAD65Ab varied from 0 to 3.6% in GDM women [42,43].…”

“…Increased frequencies of HLA-risk antigens and high prevalence of ICA, insulinoma-associated antigen 2 (IA-2) and GAD antibodies have also been reported in women with GDM [22,23].…”

Diabetes epidemiology as a tool to trigger diabetes research and care

“…Therefore, in this situation, use of the anti-GAD assay could be both health and cost effective. Similarly, the identification of a subgroup of patients with GDM who are positive for anti-GAD has the same implications [53,54]. These women would be the subset most likely to develop Type I diabetes at a later time [54].…”

“…Similarly, the identification of a subgroup of patients with GDM who are positive for anti-GAD has the same implications [53,54]. These women would be the subset most likely to develop Type I diabetes at a later time [54]. In addition, they are probably the group most likely to require and benefit from insulin therapy during pregnancy.…”

“…The evidence has, however, mounted from a host of studies that anti-GAD has a clear role in diagnosing slow-onset Type I diabetes in adults [40,42,43, 47±51] and, indeed, in predicting future insulin dependency [33, 50±52]. Other workers have recommended, as we have [53], that all women with gestational diabetes mellitus (GDM) should have an anti-GAD test [54]. Only the widespread lack of inexpensive commercial anti-GAD assays has hindered the more general use in clinical practice for classification of diabetes in adults but this is likely to change as the assay becomes more widely available.…”