Gestational diabetes mellitus (GDM) is carbohydrate intolerance, short of overt diabetes, diagnosed during pregnancy. GDM is associated with adverse pregnancy outcomes, such as fetal macrosomia with its attendant risks of birth injury during vaginal delivery, neonatal hypoglycemia, plethora and hyperbilirubinemia, excess fetal/neonatal fat deposition, childhood obesity, and disordered carbohydrate metabolism. Maternal problems include an increased risk of cesarean delivery and hypertensive disorders of pregnancy. Many of these adverse outcomes can be prevented or ameliorated by efforts to maintain maternal euglycemia. Various professional organizations recommend lifestyle modification including diet and exercise with self-glucose monitoring.1,2 If goals for glucose control are not met, an antidiabetic medication should be prescribed. The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) network randomized controlled trials (RCTs) demonstrated that identification and treatment of mild GDM reduces adverse outcomes.3,4 (In ACHOIS, the 2-hour 75-g glucose tolerance test [GTT] value had to be 140-199 mg/dL, while in the MFMU study the fasting value on the 100-g GTT had to be < 95 mg/dL.) Medication was needed in 8% to 20% of subjects. A higher proportion of patients with GDM require antidiabetic medications when the spectrum is not limited to “mild” GDM.
Both the American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) recommend insulin as the first-line medication for treating GDM uncontrolled by lifestyle modification (Table 1).1,2 The Society for Maternal-Fetal Medicine (SMFM) considers insulin and metformin to be reasonable and safe first-line alternatives.5 None of these professional organizations recommend glyburide as first-line therapy. A review of pharmacy dispensing in over 437,000 pregnancies during the second and third trimesters between 2001 and 2007 reported that 70% of patients prescribed an antidiabetic drug received only insulin and 3% received only metformin, while 21% received another oral agent, mostly a sulfonylurea such as glyburide. An additional 5% received multiple agents.6 Another review comparing pharmacy data for glyburide and insulin to treat GDM reported that by 2011, glyburide was prescribed twice as frequently as insulin.7 Both of these publications were prior to the systematic reviews described below. A survey of MFM specialists published in 2017 reported that 57% use glyburide as their first-line treatment for GDM, 36% use insulin and 4% use metformin.8 This article will address these three medications for GDM: insulin, glyburide and metformin (Table 2).
Insulin of various types is the longstanding first-line treatment when GDM glycemic goals are not met with lifestyle modification. There is minimal passage of insulin across the placenta, which is the primary reason why it is preferred for GDM. The major drawbacks of the drug include the requirement for subcutaneous injection and risk of hypoglycemia, which is unusual in GDM unless a meal is missed after an insulin injection. In addition, people with diabetes with significant glycosuria may gain weight when insulin treatment prevents loss of calories in urine. A description of various types of insulin and dosing paradigms is beyond the scope of this article and may be found elsewhere.9
- American College of Obstetricians and Gynecologists. Gestational Diabetes Mellitus. ACOG Practice Bulletin No. 190. Obstet Gynecol. 2018;131:e49-64.
- American Diabetes Association. Management of Diabetes in Pregnancy: Chapter 14 in Standards of Medical Care in Diabetes—2019. 2019;42(Supplement 1): S165-S172.
- Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005 Jun 16;352(24):2477-2486. Epub 2005 Jun 12.
- Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009; 361:1339-1348.
- Society of Maternal-Fetal Medicine Publications Committee: SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;218(5):B2-B4.
- Lawrence JM, Andrade SE, Avalos LA, Beaton SJ, et al for the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) Study Group. Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007. Obstet Gynecol. 2013;212(1):106-114.
- Castillo WC, Boggess K, Stürmer T, Brookhart A, et al. Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000-2011. Obstet Gynecol. 2014;123(6):1177-1184.
- Bimson BE, Rosenn BM, Morris SA, Sasso EB, Schwartz RA, Brustman LE. Current trends in the diagnosis and management of gestational diabetes mellitus in the United States. J Matern Fetal Neonatal Med. 2017;30(21):2607-2612.
- Durnwald C. Gestational diabetes mellitus: Glycemic control and maternal prognosis. UpToDate: https://www.uptodate.com/contents/gestational-diabetes-mellitus-glycemic-control-and-maternal-prognosis?search=gestational%20diabetes%20and%20treatment&source=search_result&selectedTitle=1~85&usage_type=default&display_rank=1 Accessed 27 Dec 2018.
- Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000 Oct 19;343(16):1134-1138.
- Hebert MF, Ma X, Naraharisetti SB, Krudys KM, et al. Are we optimizing gestational diabetes treatment with glyburide? Clin Pharmacol Therap. 2009;85(6):607-614.
- Schwartz RA, Rosenn B, Aleksa K, Koren G. Glyburide transport across the human placenta. Obstet Gynecol. 2015;125(3):583-588.
- Balsells M, Garcia-Patterson A, Solà I, et al. Glybenclamide, metformin and insulin for treatment of gestational diabetes: a systematic review and meta-analysis. BMJ. 2015;350:h102.
- Farrar D, Simmonds M, Bryant M, et al. Treatment for gestational diabetes: a systematic review and meta-analysis. BMJ Open. 2017;7: e015557.
- Brown J, Grzeskowiak L, Williamson K et al. Insulin for the treatment of women with gestational diabetes. Cochrane Database Syst Rev. 2017;(5 Nov 17): DOI: 10.1002/14651858.CD012037.pub2.
- Caritis SN, Hebert MF. A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol. 2013;121(6):1309-1312.
- Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83:1575-1578.
- Hague, WM, Davoren PM, McIntyre D, et al: Metformin crosses the placenta: a modulator for fetal insulin resistance? BMJ 4 Dec 2003; rapid response to editorial from BMJ. 2003;327:880-88. Published online.
- Rowan JA, Haghue WM, Gao W, Bazttin MR, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003-2015.
- Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donowan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med. 2017;34(1):27-36.
- Romero R, Erez O, Hüttemann M, Maymon E, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(1):282-302.
- Barbour LA, Sciffres C, Valent AM, Friedman JE, et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;219(4):367.e1-367.e7.
- Rowan JA, Rush EC, Obolonkin V, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care. 2011;34(10):2279-2284.
- Rowan JA, Rush EC, Plank LD, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7-9 years of age. BMJ Open Diabetes Res Care. 2018;6(1):e000456.
- Ro TB, Ludvigsen HV, Carlsen SM, Vanky E. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest. 2012;72(7):570-575.
- Engen Hanem LG, Stridsklev S, Juliusson PB, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age; follow-up of two RCTs. J Clin Endocrinol Metab. 2018;103(4):1612-1621.
- Legro RS, Barnhart HX, Schlaff WD, et al for the Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
- Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: A randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95:E448-E455.