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Question: Is it useful to check glutamic acid decarboxylase (GAD) antibodies in gestational diabetes?
Answer: Yes and no. If the question is about a cost-effective means to identify the majority of women who will progress to diabetes following gestational diabetes, the answer is no. Gestational diabetes mellitus (GDM) is present in 6–15% of pregnant women and is associated with an increased risk of later diabetes and impaired glucose tolerance at followup. The form is usually type 2 and its incidence is highest in those women who have the highest body mass index (BMI), the greatest blood glucose concentrations on their glucose tolerance tests, and the need for insulin treatment during pregnancy.1–3
The risk of developing type 1 diabetes is not related to metabolic control during pregnancy and is lower than that seen in first-degree relatives of people with type 1 diabetes.4,5 Should diabetes-related autoantibody measurement be used to identify the few women who may develop type 1 in the future? The answer—still being researched—is only yes in order to increase our knowledge of the pathophysiology and epidemiology of a subpopulation of gestational diabetes.6–8
A major issue regarding the demonstration of autoimmune markers in women with GDM is the potential increased risk for the development of type 1 either at short-term postpartum or after longer follow-up.6-8 In the past, studies of the progression to type 1 in women who have had GDM focused specifically on unequivocal diagnosis with rapid progression and overt clinical manifestations.9,10 The original investigations only studied anti-islet cell antibody (ICA) positivity. In fact, the first investigation of the prevalence of ICA in GDM showed that three out of five ICA-positive gestational diabetic women developed classical type 1 diabetes shortly after pregnancy.9 Other reports only measured antiinsulin antibodies (IA) and found a positivity rate of 2–25%, but some of these reports include women treated with exogenous insulin.10
Assays for GAD antibodies are reported to be the screening tests of choice in GDM.11 GAD is the biosynthesizing enzyme of gammaaminobutyric acid. GAD exists in two isoforms, GAD65 and GAD67 kdaltons.12 The major antigenic determinant in autoimmune diabetes (type 1A) is the middle and C-terminal region of the molecule.12 Prevalence rate of GAD antibodies in GDM is 0–38%, depending on genetic, ethnic, environmental, and methodological issues. Most reports concur that detecting diabetes-related autoantibodies during pregnancy increases the risk of maternal glucose intolerance/diabetes.3,13,14 Therefore, some have proposed using multiple antibody assays (ICA, IA, and GAD)—and assessment of genetic markers—to predict future diabetes risk in women with GDM. Although this strategy may identify women at risk for future type 1, it is not cost-effective.
In recent 11-year follow-up studies of women diagnosed with GDM, the cumulative risk for diabetes was 13.8% in women with prior GDM and 0% in control women without a history of GDM (P=0.02). Five women presented with type 1 (11.4% of all diabetes cases). The cumulative incidence of type 1 at 11 years was only 0.7%. Surprisingly, autoantibody positivity was not a type 1 predictor.4
Although GAD antibodies have been shown to reliably predict development of type 1, the prevalence of positivity is so low in GDM women that there is no merit in using GAD antibody screening in this population.6,7 However, autoimmune GDM may be a distinct entity and may be worth identification even if this type of diabetes does not predict future type 1.15 GDM women with autoimmune markers present with few classical risk factors for the development of GDM (prepregnancy BMI <25, age <35 years, absence of a first-degree relative with type 2) may comprise up to 10% of all Caucasian women with the diagnosis of GDM.14 In this respect, screening women for potential immune intervention using GAD antibodies of women with GDM does have merit.
In the absence of effective means to prevent development of type 1, measuring GAD antibodies should only be considered an important tool for studying the natural history of type 1.
So is it useful to check GAD antibodies in gestational diabetes? Yes and
no, depending on the reason for asking the question. 
Footnotes
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Editor's note: The references are available on the Web version of this article.
References
2. Baekkeskov S, Aanstoot HJ, Christgau S, et al.: Identification of the 64 autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347: 151–156, 1990.[Medline]
3. Kaufman DL, Erlander MG, Clare-Salzler M, et al.: Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. J Clin Invest 92:1608–1616, 1992.
4. Steel JM, Irvine WJ, Clarke BF: The significance of pancreatic islet cell antibody and abnormal glucose tolerance during pregnancy. J Clin Lab Immunol 4:83–85, 1980.[Medline]
5. Ginsberg-Fellner F, Mark EM, Nechemias C, et al.: Islet cell antibodies in gestational diabetics. Lancet ii: 362–363, 1980.
6. Catalano PM, Tyzbir ED, Sims EA: Incidence and significance of islet cell antibodies in women with previous gestational diabetes. Diabetes Care 13:478–482, 1990.[Abstract]
7. Damm P, Kuhl C, Buschard K, et al.: Prevalence and predictive value of islet cell antibodies and insulin autoantibodies in women with gestational diabetes. Diabet Med 11:558–563, 1994.[Medline]
8. Dozio N, Beretta A, Belloni C, et al.: Low prevalence of islet autoantibodies in patients with gestational diabetes mellitus. Diabetes Care 20:81–83, 1997.[Abstract]
9. Mauricio D, Balsells M, Morales J, et al.: Islet cell autoimmunity in women with gestational diabetes and risk of progression to insulin-dependent diabetes mellitus. Diabetes Metab Rev 2:275–285, 1996.
10. Lapolla A, Fedele D, Pedeni B, et al.: Low frequency of
autoantibodies to islet cell, glutamic acid decarboxylase, and second-islet
antigen in patients with gestational diabetes mellitus: A follow-up study.
Ann N Y Acad Sci 958:263–266, 2002.
11. Bartha JL, Martínez del Fresno P, Comino-Delgado R: Postpartum metabolism and autoantibody markers in women with gestational diabetes mellitus diagnosed in early pregnancy. Am J Obstet Gynecol 184:965–970, 2001.[Medline]
12. Bo S, Menato G, Pinach S, et al.: Clinical characteristics and outcome of pregnancy in women with gestational hyperglycemia with and without antibodies to beta-cell antigens. Diabet Med 20: 64–68, 2003.[Medline]
13. Mitchell ML, Hermos RJ, Larson CA, et al.: Prevalence of GAD
autoantibodies in women with gestational diabetes mellitus.
Diabetes Care 23:1705–1706, 2000.
14. Füchtenbusch M, Bonifacio E, Lampasona V, et al.: Immune responses to glutamic acid decarboxylase and insulin in patients with gestational diabetes. Clin Exp Immunol 135: 318–321, 2004.[Medline]
15. Mauricio D, de Leiva A: Autoimmune gestational diabetes mellitus: A distinct clinical entity? Diabetes Metab Res Rev 17: 422–428, 2001.[Medline]
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