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Oral Agents Revised 2006:Use of oral agents for glycemic controlduring pregnancy complicated by GDM Over the past few years, oral agents have been reintroduced in themanagement of diabetes during pregnancy.30 There are several reviews ofsulfonylureas, biguanides, and glucosidase inhibitors used primarily inpregnancies complicated by gestational diabetes.9, 14, 32, 36, 39, 40 Oral agentswere once thought to be associated with an increased incidence ofcongenital malformations.8, 21, 33, 36 However, the issue of malformationsmay be more related to hyperglycemia. Hyperglycemia is a knownteratogen. Inadequate blood glucose control using oral agents prior topregnancy usually continues into the first trimester of pregnancy.24, 38 Forthose women on oral agents with inadequate blood glucose control priorto conception, it is the hyperglycemia that is thought to be the teratogen.
A meta-analysis of the safety of oral agents in the first trimester supportsthis contention.19 Human insulin and insulin analogs (with the exceptionof glargine) do not appear to be teratogens in human pregnancies 4 andthus, continue to be recommended by ACOG and the ADA as the onlypharmacologic antihyperglycemic agent for use during pregnancy.1, 2 Firm recommendations for oral agent use in pregnancy are limited by thepaucity of level 1 evidence. Some providers do not believe these agentscan achieve adequate glycemic control.25, 35 As beta cell destructionincreases, oral agents lose their ability to maintain euglycemia. Onlyglyburide has been studied in a prospective randomized control trial30demonstrating that it did produce comparable maternal and neonataloutcomes to insulin in about 200 patients. Placental transfer of glyburidehas been shown to be insignificant.11, 12 Metformin has widespread use among infertility specialists as a treatmentfor insulin resistance associated with the infertility experienced by womenwith polycystic ovarian syndrome (PCOS). When metformin is continuedthrough the first trimester to avoid miscarriage, no increase inmalformation rates have been reported.16, 22 Women using metformin forfertility are generally insulin resistant but may not be hyperglycemic earlyin pregnancy thus eliminating the concern for glucose-mediatedteratogenicity. Metformin is thought to cross the placenta but does notalter placental metabolism of glucose.13 Several other studies ofmetformin use throughout pregnancy in women with PCOS imply areduced rate of GDM and preeclampsia without adverse effects on thefetus and newborn, up to 4 years of age.17 Breastfeeding with metforminappears to be safe with no difference between infants breastfed by womenwithout metformin.3, 20 In 2000, there was a 0% utilization of oral agents reported by theCalifornia Diabetes and Pregnancy Program affiliates. Data summaries CALIFORNIA DIABETES & PREGNANCY PROGRAM from 2003 reveal a 5% utilization of oral agents. The long-term effectsof these medications are not fully known. CDAPP continues to trackthe use of oral agents during pregnancy and has begun to link outcomeswith certain agents. (2005 CDAPP data base) During the recent 5th International Gestational Diabetes Workshop,
glyburide was included as an option for treating gestational diabetes.
It may be prudent to keep in mind that:
Most of the published data concern utilization of oral agentsin pregnancy is in the GDM population. Oral agents alonemay be effective in women with type 2 if the degree of betacell impairment is minimal.
No randomized control trials have been published concerningoutcomes with glyburide use for type 2 women duringpregnancy.
If glyburide is used, consider the following: 1. Discuss and document risks and benefits of the agent's use 2. Establish and maintain diet and exercise therapy. 3. Comply with recommended SMBG schedule. 4. Conduct fetal surveillance as recommended for patients utilizing Be aware that hypoglycemia can occur Adhere to MNT meal and snack regimen to avoidhypoglycemiaEnsure that the woman can recognize and treathypoglycemiaMonitor weight and assess for appropriate weight gain Recommendations regarding the use of metformin in pregnancy arereserved until outcomes of the metformin in GDM (MIG) study areavailable in 2006.5 CALIFORNIA DIABETES & PREGNANCY PROGRAM REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin: Gestational Diabetes. Washington DC: ACOG; 2001.
2. American Diabetes Association: Clinical Practice Recommendations 2002. Diabetes Care. 2002; 25:S1-S140.
3. Briggs GG, Ambrose PJ, Nageotte MP, Padilla G, Wan S. Excretion of metformin into breast milk and the effect on nursing infants.
Obstet Gynecol 2005; 105:1437-1441.
4. Briggs GG, Freeman RK, Yaffe, SJ. Drugs in Pregnancy and Lactation (5th edition). Philadelphia: Williams & Wilkins; 1998.
5. Brown FM, Wyckoff J, Rowan JA, Jovanovic L, Sacks, DA, Briggs GG. Metformin in Pregnancy: It’s time has not yet come(letter to the editor). Diabetes Care 2006; 29(2): 485-486.
6. Cefalo RC. A comparison of glyburide and insulin in women with gestational diabetes mellitus. Obstetrical and Gynecological Survey.
2001; 56: 126-127.
7. Chmait R, Dinise T, Daneshmand S, Kim M, Moore T. Prospective cohort study to establish predictors of glyburide success ingestational diabetes mellitus. American Journal of Obstetrics andGynecology. 2001; 185: S197.
8. Coetzee EJ, Jackson WP. Oral hypoglycaemics in the first trimester and fetal outcome. South African Medical Journal. 1984; 65:635-637.
9. Coustan DR. Oral hypoglycemic agents for the ob/gyn.
10. Dornhorst A. A comparison of glyburide and insulin in women with gestational diabetes mellitus. Diabetic Medicine. 2001; 18:12-14.
11. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. AmericanJournal of Obstetrics and Gynecology. 1991; 165:807-812.
12. Elliott BD, Schenker S, Langer O, Johnson R, Prihoda T.
Comparative placental transport of oral hypoglycemic agents inhumans: A model of human placental drug transfer. AmericanJournal of Obstetrics and Gynecology. 1994; 171:653-660.
13. Elliott BS, Langer O, Schuessling F. Human placental glucose uptake and transport are not altered by the oral antihyperglycemicagent metformin. American Journal of Obstetrics and Gynecology.
1997; 176:527-530.
CALIFORNIA DIABETES & PREGNANCY PROGRAM REFERENCES
14. El-Sayed YY, Lyell DJ. New therapies for the pregnant patient with Continued
diabetes. Diabetes Technol Ther. 2001 Winter; 3(4):635-40.
15. Gavin F. Jacobson, MD, Gladys A. Ramos, MD, Jenny Y. Ching, RN, Russell S. Kirby,PhD, MS, Assiamira Ferrara, MD, PhD, D.
Robin Field, MD. A Comparison of glyburide and insulin for themanagement of gestational diabetes in a large managed careorganization. Am J Obstet Gynecol, 2005.
16 Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P.
Continuing metformin throughout pregnancy in women withpolycystic ovary syndrome appears to safely reduce first-trimesterspontaneous abortion: a pilot study. Fertility and Sterility. 2001;75:46-52.
17. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L and Wang, P. Height, weight, and motor & social development duringthe first 18 months of life in 126 infants born to 109 mothers withpolycystic ovary syndrome who conceived on and continuedmetformin through pregnancy. Human Reproduction Vol.19, No.6pp. 1323 - 1330, 2004 18. Greene MF. Oral hypoglycemic drugs for gestational diabetes (editorial). The New England Journal of Medicine. 2000; 343:1178-1179.
19. Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G. The safety of oral hypoglycemic agents in the first trimester of pregnancy: ameta-analysis. Can J Clin Pharmacol. 2003 Winter; 10(4):179-8.
20. Hale TW, Kristensen JH, Hackett LP, Kohan R, Ilett KF. Transfer of metformin into human milk. Diabetologia (2002) 45:1509-1514 21. Harris EL. Adverse reactions to oral antidiabetic agents. British 22. Jakubowicz DJ, Iurono MJ, Jakubowicz S, Roberts KA, Nestler JE.
Effects of metformin on early pregnancy loss in the polycysticovary syndrome. The Journal of Clinical Endocrinology &Metabolism. 2002; 87; 524-529.
23. Kemball ML, McIver C, Milner RD, Nourse CH, Schiff D, Tiernan JR. Neonatal hypoglycaemia in infants of diabetic mothers givensulphonylurea drugs in pregnancy. Archives of Disease inChildhood. 1970; 45:696-701.
24. Kitzmiller J. Limited efficacy of glyburide for glycemic control.
American Journal of Obstetrics and Gynecology. 2001; 185:S198.
CALIFORNIA DIABETES & PREGNANCY PROGRAM REFERENCES
25. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy Continued
improves ovulatory rates, cervical scores, and pregnancy rates inclomiphene citrate-resistant women with polycystic ovarysyndrome. Fertility and Sterility. 2002; 77:101-106.
26. Koren G. The use of glyburide in gestational diabetes - an ideal example of "bench to bedside". Pediatric Research. 2001; 49:734.
27. Kremer CJ, Duff P. Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol 2004;190:1438-9 28. Langer O et al. Glyburide Therapy: The relationship Between Dosage and level of GDM Severity. Amer J Obstet Gynecol, Vol189, No.6 December Suppl 2003.
29. Langer O, Conway D, Berkus M, Xenakis E. There is no association between oral hypoglycemic use and fetal anomalies.
American Journal of Obstetrics and Gynecology. 1999; 180:38S.
30. Langer O, Conway DL, Berkus MD, Xenakis M, Gonzales O. A comparison of glyburide and insulin in women with gestationaldiabetes mellitus. The New England Journal of Medicine. 2000;343:1134-1138.
31. Langer O. Oral hypoglycemic agents and the pregnant diabetic: "from bench to bedside". Semin Perinatol. 2002 Jun; 26(3):215-24. 32. Merlob P, Levitt O, Stahl B. Oral antihyperglycemic agents during pregnancy and lactation: a review. Pediatr Drugs. 2002; 4(11):755-60.
33. Notelovitz MB. Sulphonylurea therapy in the treatment of the pregnant diabetic. South African Medical Journal. 1971; 45:226-229.
34. Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. The Lancet. 1991;338:866-869.
35. Preece R, Jovanovic L. New and future diabetes therapies: are they safe during pregnancy? J Matern Fetal Neonatal Med. 2002Dec;12(6):365-75 36. Slocum JM, Sosa ME. Use of antidiabetes agents in pregnancy: current practice and controversy. J Perinat Neonatal Nurs. 2002Sep;16(2):40-53; CALIFORNIA DIABETES & PREGNANCY PROGRAM REFERENCES
37. Sutherland HW, Bewsher PD, Cormack JD, Hughes CR, Reid A, Continued
Russell G, and Stowers JM. Effect of moderate dosage ofchlorpropamide in pregnancy on fetal outcome. Archives ofDisease in Childhood. 1974; 49:283-291.
38. Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, Mestman JH, Buchanan TA. Congenital malformations in pregnanciescomplicated by NIDDM. Diabetes Care. 1995; 18:1446-1451.
39. Tran, Nam D. MD, PhD; Hunter, Stephen K. MD, PhD; Yankowitz, Jerome MD Oral Hypoglycemic Agents in Pregnancy. Obstetrical &Gynecological Survey. 59(6):456-463, June 2004.
40. Zarate A, Ochoa R, Hernandez M, Basurto L. Effectiveness of acarbose in the control of glucose tolerance worsening inpregnancy. Ginecologia y Obstetricia de Mexico. 2000; 68:42-45. CALIFORNIA DIABETES & PREGNANCY PROGRAM

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