Treatments in Endocrinology

, Volume 3, Issue 3, pp 133–139 | Cite as

Is There a Role for Oral Antihyperglycemics in Gestational Diabetes and Type 2 Diabetes during Pregnancy?

  • Carol J. Homko
  • Eyal Sivan
  • Albert E. Reece
Current Opinion


Diabetes mellitus is a heterogeneous disorder of glucose intolerance that is generally classified into the following categories: type 1 and type 2 diabetes and gestational diabetes (GDM). Currently, the number of pregnancies complicated by type 2 diabetes and GDM exceed those affected by type 1 diabetes. Numerous studies have established a direct relationship between maternal glycemic control and neonatal outcomes for all types of diabetes. Therefore, modern treatment protocols during pregnancy emphasize strict glycemic control by a combination of diet and medication. Traditionally, insulin therapy has been considered the gold standard for management because of its efficacy in achieving tight glucose control and the fact that it does not cross the placenta. Since GDM and type 2 diabetes are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral antihyperglycemic agents that target these defects is of potential interest. However, because of concerns regarding transplacental passage and, therefore, the possibility of fetal teratogenesis and prolonged neonatal hypoglycemia, these agents are not currently recommended in pregnancy.

There are no randomized controlled trials on which to draw conclusions regarding the teratogenicity of these oral agents. However, most retrospective studies and the published clinical experience have not demonstrated an increased risk of malformed infants among women treated with oral antihyperglycemic agents. Rather, the data indicate that the increased risk for major congenital anomalies appears to be related to maternal glycemic control prior to and during conception. These studies and currently available data on the use of both metformin and sulfonylureas in pregnancy have also failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities. To date, there has only been one randomized controlled trial to test the effectiveness and safety of sulfonylurea therapy (glyburide [glibenclamide]) in the management of women with GDM. Both the insulin- and glyburide-treated women were able to achieve satisfactory glucose control and had similar perinatal outcomes. Glyburide was not detected in the cord serum of any infant in the glyburide group.

In summary, based on the currently available data, it appears that glyburide could be safely and effectively utilized in the management of GDM. However, more intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary. It is important to emphasize that it is the level of metabolic control achieved and not the mode of therapy that is crucial to improving outcomes in these pregnancies.


Metformin Acarbose Oral Agent Glyburide Chlorpropamide 
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This work was supported by a grant from the General Clinical Research Center branch of the National Center for Research Resources (2M01-RR-349). The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Sepe SJ, Connell FA, Geiss LS, et al. Gestational diabetes: incidence, maternal characteristics and perinatal outcome. Diabetes 1985; 34: 13–6PubMedGoogle Scholar
  2. 2.
    Hadden DR. Geographic, ethnic, and racial variations in the incidence of gestational diabetes mellitus. Diabetes 1985; 34 Suppl. 2: 8–12Google Scholar
  3. 3.
    King H. Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age. Diabetes Care 1998; 21 Suppl. 2: B9–13Google Scholar
  4. 4.
    Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop Conference on GDM. Diabetes Care 1998; 21 Suppl. 2: B161–7Google Scholar
  5. 5.
    Engelgau MM, Herman WH, Smith PJ, et al. The epidemiology of diabetes and pregnancy in the US, 1988. Diabetes Care 1995; 18: 1029–33PubMedCrossRefGoogle Scholar
  6. 6.
    Dornhorst A, Paterson CM, Nicholls JSD, et al. High prevalence of gestational diabetes in women from ethnic minority groups. Diabet Med 1992; 9: 820–5PubMedCrossRefGoogle Scholar
  7. 7.
    Berkowitz RS, Lapinski RH, Lee D. Race/ethnicity and other risk factors for gestational diabetes. Am J Epidemiol 1992; 135: 965–73PubMedGoogle Scholar
  8. 8.
    Langer O. Management of gestational diabetes. Clin Obstet Gynecol 2000; 43: 106–15PubMedCrossRefGoogle Scholar
  9. 9.
    Hagay ZJ. Diabetic ketoacidosis in pregnancy: etiology, pathophysiology, and management. Clin Obstet Gynecol 1994; 37: 39–49PubMedCrossRefGoogle Scholar
  10. 10.
    Kimmerle R, Heinemann L, Delecki A, et al. Severe hypoglycemia incidence and predisposing factors in 85 pregnancies of type 1 diabetic women. Diabetes Care 1992; 15: 1034–7PubMedCrossRefGoogle Scholar
  11. 11.
    Persson B, Hanson U. Neonatal morbidities in gestational diabetes mellitus. Diabetes 1998; 21 Suppl. 2: 79–84Google Scholar
  12. 12.
    Langer O, Rodriquez DA, Xenakis EM-J, et al. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994; 170: 1036–42PubMedGoogle Scholar
  13. 13.
    Tyrala EE. The infant of the diabetic mother. Obstet Gynecol Clin North Am 1996; 23: 221–41PubMedCrossRefGoogle Scholar
  14. 14.
    Sivan E, Feldman B, Dolitzki M, et al. Glyburide crosses the placenta in vivo in pregnant rats. Diabetologia 1995; 38: 753–6PubMedCrossRefGoogle Scholar
  15. 15.
    Adam PAJ, Schwartz R. Diagnosis and treatment: should oral hypoglycemic agents be used in pediatric and pregnant patients? Pediatrics 1968; 42: 819–23PubMedGoogle Scholar
  16. 16.
    Kembell ML, McIver C, Milner RDG, et al. Neonatal hypoglycemia in infants of diabetic mothers given sulphonylurea drugs in pregnancy. Arch Dis Child 1970; 45: 696–701CrossRefGoogle Scholar
  17. 17.
    Becerra JE, Khoury MJ, Cordero JF, et al. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based-case-control study. Pediatrics 1990; 85: 1–9PubMedGoogle Scholar
  18. 18.
    Miodovnik M, Mimouni F, Dignam PSJ, et al. Major malformations in infants of IDDM women. Diabetes Care 1998; 11: 713–9CrossRefGoogle Scholar
  19. 19.
    Horton Jr WE, Sadler TW. Effects of maternal diabetes on early embryogenesis: alterations in morphogenesis produced by the ketone body, β-hydroxybutyrate. Diabetes 1983; 32: 610–6PubMedCrossRefGoogle Scholar
  20. 20.
    Rosenn B, Miodovnik M, Combs CA, et al. Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol 1994; 84: 515–20PubMedGoogle Scholar
  21. 21.
    Freinkel N, Cockroft DL, Lewis NJ, et al. The 1986 McCollum Award Lecture: fuel-mediated teratogenesis during early organogenesis. Am J Clin Nutr 1986; 44: 986–95PubMedGoogle Scholar
  22. 22.
    Eriksson UJ, Hakan-Borg LA, Forsberg H, et al. Diabetic embryopathy: studies with animal and in vitro models. Diabetes 1991; 40 Suppl. 2: 94–8Google Scholar
  23. 23.
    Styrud J, Eriksson UJ. Development of rat embryos in culture media containing different concentrations of normal and diabetic rat serum. Teratology 1992; 46: 473–83PubMedCrossRefGoogle Scholar
  24. 24.
    Kitzmiller JL, Gavin LA, Gin GD, et al. Preconception management of diabetes continued through early pregnancy prevents the excess frequency of major congenital anomalies in infants of diabetic mothers. JAMA 1991; 265: 731–6PubMedCrossRefGoogle Scholar
  25. 25.
    Kitzmiller JL, Buchanan TA, Kjos S, et al. Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 1996; 19: 525–41Google Scholar
  26. 26.
    Wilhoite MB, Benvert HW, Palomaki GE, et al. The impact of preconception counseling on pregnancy outcomes: the experience of the Maine diabetes in pregnancy program. Diabetes Care 1993; 16: 340–55CrossRefGoogle Scholar
  27. 27.
    Smithberg M, Runner MN. Teratogenic effects of hypoglycemic treatments in inbred strains of mice. Am J Anat 1963; 113: 479–89PubMedCrossRefGoogle Scholar
  28. 28.
    Smoak IW. Teratogenic effects of chlorpropamide in mouse embryos in vitro [abstract]. Teratology 1992; 45: 474Google Scholar
  29. 29.
    Denno KM, Sadler TW. Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis. Teratology 1994; 49: 260–6PubMedCrossRefGoogle Scholar
  30. 30.
    Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycemic drugs. Lancet 1991; 338: 866–9PubMedCrossRefGoogle Scholar
  31. 31.
    Coetzee EJ, Jackson WPU. Metformin in management of pregnant insulin-dependent diabetics. Diabetologia 1979; 16: 241–5PubMedCrossRefGoogle Scholar
  32. 32.
    Coetzee EJ, Jackson WP. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 1984; 65: 635–7PubMedGoogle Scholar
  33. 33.
    Coetzee EJ, Jackson WP. The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract 1986; 1: 281–7CrossRefGoogle Scholar
  34. 34.
    Coetzee EJ, Jackson WP. Pregnancy in established non-insulin-dependent diabetics: a five-and-a-half year study at Groote Schuur Hospital. S Afr Med J 1980; 58: 795–802PubMedGoogle Scholar
  35. 35.
    Coetzee EJ, Jackson WP. Diabetes newly diagnosed during pregnancy: a 4-year study at Groote Schuur Hospital. S Afr Med J 1979; 56: 467–75PubMedGoogle Scholar
  36. 36.
    Hod M, Shafrir E. Oral hypoglycemic agents as an alternative therapy for gestational diabetes. Isr J Med Sci 1995; 31: 640–3PubMedGoogle Scholar
  37. 37.
    Langer O. Oral hypoglycemic agents and the pregnant diabetic: ‘from bench to bedside’. Semin Perinatal 2002; 26: 215–24CrossRefGoogle Scholar
  38. 38.
    Towner D, Kjos S, Leung B, et al. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 1995; 18: 1446–61PubMedCrossRefGoogle Scholar
  39. 39.
    Glueck CJ, Philips H, Cameron D, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75: 46–52PubMedCrossRefGoogle Scholar
  40. 40.
    Glueck CJ, Ping W, Suichi K, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 2002; 77: 520–5PubMedCrossRefGoogle Scholar
  41. 41.
    Hellmuth E, Damm P, Molsted-Pedersen L. Congenital malformations in offspring of diabetic women treated with oral hypoglycemic agents during embryogenesis. Diabetic Med 1994; 11: 471–4PubMedCrossRefGoogle Scholar
  42. 42.
    Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal chlorpropamide therapy. Pediatrics 1968; 42: 824–5PubMedGoogle Scholar
  43. 43.
    Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343: 1134–8PubMedCrossRefGoogle Scholar
  44. 44.
    Elliott BD, Langer O, Schenker S, et al. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 1991; 165: 807–12PubMedGoogle Scholar
  45. 45.
    Zarate A, Ochoa R, Hernandez M, et al. Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy [in Spanish]. Ginecol Obstet Mex 2000; 68: 42–5PubMedGoogle Scholar
  46. 46.
    Medical Economics staff, editor. Physicians’ desk reference 2003. 57th ed. Montvale (NJ): Medical Economics, 2003Google Scholar
  47. 47.
    Elliott BD, Schenker S, Langer O, et al. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol 1994; 171: 653–60PubMedGoogle Scholar
  48. 48.
    Elliott BD, Langer O, Schuessling F. Human placental glucose uptake and transport are not altered by the oral antihyperglycemic agent metformin. Am J Obstet Gynecol 1997; 176: 527–30PubMedCrossRefGoogle Scholar
  49. 49.
    Buchanan T, Xiang A, Peters R, et al. Prevention of type 2 diabetes by treatment of insulin resistance: comparison of early vs. late intervention in the TRIPOD study. Diabetes 2002 Jun; 51 Suppl. 2: 35CrossRefGoogle Scholar
  50. 50.
    Buchanan TA, Xiang AH, Peters RK, et al. Protection from type 2 diabetes persists in the TRIPOD cohort eight months after stopping troglitazone. Diabetes 2001 Jun; 50 Suppl. 2: 81Google Scholar
  51. 51.
    Buchanan TA. Pancreatic β-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 989–93PubMedCrossRefGoogle Scholar
  52. 52.
    Xiang A, Peters R, Kjos S, et al. Continued protection from diabetes during treatment of the TRIPOD cohort with pioglitazone [abstract]. Diabetes 2003 Jun; 52 Suppl. 1:75Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Carol J. Homko
    • 1
    • 2
  • Eyal Sivan
    • 3
  • Albert E. Reece
    • 4
  1. 1.General Clinical Research CenterTemple University School of Medicine, 4 WestPhiladelphiaUSA
  2. 2.The Department of Obstetrics, Gynecology and Reproductive SciencesTemple University School of MedicinePhiladelphiaUSA
  3. 3.Department of Obstetrics and GynecologySheba Medical CenterTel-HashomerIsrael
  4. 4.Office of the DeanUniversity of Arkansas College of MedicineLittle RockUSA

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