Metformin combined with insulin in women with gestational diabetes mellitus: a propensity score-matched study



Metformin use in gestational diabetes (GDM) is a common practice. Although its use in combination with insulin might be advantageous, it was never formally tested. We studied whether combined treatment was associated with better obstetric or neonatal outcomes compared to insulin alone.


This is a retrospective study, using the Portuguese National Registry of GDM (2012–2017), of women treated with insulin ± metformin. Primary endpoints were obstetric and neonatal complications. Secondary endpoints were gestational weight gain (GWG) and insulin dose. A propensity score-matched analysis was performed to balance the distribution of age, BMI, insulin treatment duration, HbA1c, first trimester diagnosis of GDM and previous GDM or macrosomia. Women treated with metformin plus insulin and insulin only were then compared.


A total of 4034 women were treated with insulin or insulin plus metformin (10.2%). After propensity score matching, we studied two groups of 386 patients. Obstetric and neonatal complications were similar. Women treated with metformin plus insulin had 201 (52.1%) obstetric complications versus 184 (47.7%) in insulin-only group, p = 0.22; and 112 (29.0%) neonatal complications versus 96 (24.9%), p = 0.19. Patients treated with metformin plus insulin had similar GWG, excessive weight gain and insulin dose compared to the insulin-only group.


Women with GDM treated with insulin plus metformin had similar obstetric and neonatal complications, weight gained and insulin dose compared to those only treated with insulin.

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  1. 1.

    Xiong X, Saunders L, Wang F, Demianczuk N (2001) Gestational diabetes mellitus: prevalence, risk factors, maternal and infant outcomes. Int J Gynecol Obstet 75(3):221–228

    CAS  Article  Google Scholar 

  2. 2.

    Yogev Y, Xenakis E, Langer O (2004) The association between preeclampsia and the severity of gestational diabetes: the impact of glycemic control. Am J Obstet Gynecol 191(5):1655–1660

    Article  Google Scholar 

  3. 3.

    Metzger BE, Lowe LP, Dyer AR et al (2008) Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358(19):1991–2002

    Article  Google Scholar 

  4. 4.

    Voormolen D, de Wit L, van Rijn B et al (2018) Neonatal hypoglycemia following diet-controlled and insulin-treated gestational diabetes mellitus. Diabetes Care 41(7):1385–1390

    CAS  Article  Google Scholar 

  5. 5.

    Buchanan T, Xiang A, Page K (2012) Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol 8(11):639–649

    CAS  Article  Google Scholar 

  6. 6.

    Pintaudi B, Fresa R, Dalfrà M et al (2018) The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study. Acta Diabetol 55(12):1261–1273

    CAS  Article  Google Scholar 

  7. 7.

    Arafa A, Dong J (2019) Maternal height and risk of gestational diabetes: a systematic review and meta-analysis. Acta Diabetol 56(7):723–728

    Article  Google Scholar 

  8. 8.

    Melchior H, Kurch-Bek D, Mund M (2017). The prevalence of gestational diabetes: a population-based analysis of a nationwide screening program. Deutsches Aerzteblatt Online

  9. 9.

    - Instituto Nacional de Saúde Dr. Ricardo Jorge (2011)Diabetes: Factos E Números

  10. 10.

    Management of Diabetes in Pregnancy (2017) Standards of medical care in diabetes—2018. Diabetes Care 41(1):137–143

    Google Scholar 

  11. 11.

    Refuerzo J (2011) Oral Hypoglycemic agents in pregnancy. Obstet Gynecol Clin N Am 38(2):227–234

    Article  Google Scholar 

  12. 12.

    Song R, Chen L, Chen Y et al (2017) Comparison of glyburide and insulin in the management of gestational diabetes: a meta-analysis. PLoS ONE 12(8):e0182488

    Article  Google Scholar 

  13. 13.

    Bertini A, Silva J, Taborda W et al (2005) Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med 33(6):519–523

    CAS  Article  Google Scholar 

  14. 14.

    Mirzamoradi M, Heidar Z, Faalpoor Z, Naeiji Z, Jamali R (2015) Comparison of glyburide and insulin in women with gestational diabetes mellitus and associated perinatal outcome: a randomized clinical trial. Acta Med Iran 53(2):97–103

    PubMed  Google Scholar 

  15. 15.

    Zeng Y, Li M, Chen Y et al (2014) The use of glyburide in the management of gestational diabetes mellitus: a meta-analysis. Adv Med Sci 59(1):95–101

    Article  Google Scholar 

  16. 16.

    Camelo Castillo W, Boggess K, Stürmer T, Brookhart M, Benjamin D, Jonsson Funk M (2015) Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes. JAMA Pediatr 169(5):452–458

    Article  Google Scholar 

  17. 17.

    Liang H, Ma S, Xiao Y, Tan H (2017) Comparative efficacy and safety of oral antidiabetic drugs and insulin in treating gestational diabetes mellitus. Medicine 96(38):e7939

    CAS  Article  Google Scholar 

  18. 18.

    Huhtala M, Tertti K, Pellonperä O, Rönnemaa T (2018) Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin. Diabetes Res Clin Pract 146:8–17

    CAS  Article  Google Scholar 

  19. 19.

    Girard J (2006) The inhibitory effects of insulin on hepatic glucose production are both direct and indirect. Diabetes 55(2):65–69

    Article  Google Scholar 

  20. 20.

    Berggren E, Boggess K (2013) Oral agents for the management of gestational diabetes. Clin Obstet Gynecol 56(4):827–836

    Article  Google Scholar 

  21. 21.

    Kavitha N, De S, Kanagasabai S (2013) Oral hypoglycemic agents in pregnancy: an update. J Obstet Gynecol India 63(2):82–87

    CAS  Article  Google Scholar 

  22. 22.

    Magon N, Seshiah V (2011) Gestational diabetes mellitus: non-insulin management. Indian J Endocrinol Metab 15(4):284–293

    CAS  Article  Google Scholar 

  23. 23.

    Norman R, Wang J, Hague W (2004) Should we continue or stop insulin sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol 16(3):245–250

    Article  Google Scholar 

  24. 24.

    Jiang Y, Chen X, Ding T, Wang X, Zhu Z, Su S (2015) Comparative efficacy and safety of OADs in management of GDM: network meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 100(5):2071–2080

    CAS  Article  Google Scholar 

  25. 25.

    Lv S, Wang J, Xu Y (2015) Safety of insulin analogs during pregnancy: a meta-analysis. Arch Gynecol Obstet 292(4):749–756

    CAS  Article  Google Scholar 

  26. 26.

    Yogev Y, Langer O (2004) The use of anti-hyperglycaemic and hypoglycaemic agents in pregnancy. Fetal Matern Med Rev 15(2):133–143

    Article  Google Scholar 

  27. 27.

    Brown J, Martis R, Hughes B, Rowan J, Crowther CA (2017) Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 1(1):CD011967

    PubMed  Google Scholar 

  28. 28.

    Feig DS, Murphy K, Asztalos E et al (2016) Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial. BMC Pregnancy Childbirth 16(1):173

    Article  Google Scholar 

  29. 29.

    Metzger BE, Gabbe SG, Persson B, Lowe LP, Dyer Alan R, Oats Jeremy J.N., Thomas A (2010) Buchanan international association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33(3):676–682

    Article  Google Scholar 

  30. 30.

    Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: A World Health Organization Guideline (2014) Diabetes Res Clin Pract 103(3):341–363

  31. 31.

    Almeida M, Dores J, Ruas L et al (2017) Consenso “Diabetes Gestacional”: Atualização 2017. Revista Portuguesa de Diabetes 12(1):24–38

    Google Scholar 

  32. 32.

    Institute of Medicine, National Research Council: weight gain during pregnancy: reexamining the guidelines. National Academies Press (US), Washington (DC) (2009)

  33. 33.

    Fenton T, Kim J (2013) A systematic review and metaanalysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 13:59

    Article  Google Scholar 

  34. 34.

    Pazzagli L, Abdi L, Kieler H, Cesta C (2020) Metformin versus insulin use for treatment of gestational diabetes and delivery by caesarean section: a nationwide Swedish cohort study. Eur J Obst Gynecol Reprod Biol 254:271–276

    CAS  Article  Google Scholar 

  35. 35.

    Rowan J, Hague W, Gao W, Battin M, Moore M (2008) Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 358(19):2003–2015

    CAS  Article  Google Scholar 

  36. 36.

    Guo L, Ma J, Tang J, Hu D, Zhang W, Zhao X (2019) Comparative efficacy and safety of metformin, glyburide, and insulin in treating gestational diabetes mellitus: a meta-analysis. J Diabetes Res 2019:1–29

    Article  Google Scholar 

  37. 37.

    Khin M, Gates S, Saravanan P (2018) Predictors of metformin failure in gestational diabetes mellitus (GDM). Diabetes Metab Syndr Clin Res Rev 12(3):405–410

    Article  Google Scholar 

  38. 38.

    Almalki M, Buhary B, Almohareb O et al (2016) Glycemic control and pregnancy outcomes in patients with diabetes in pregnancy: a retrospective study. Indian J Endocrinol Metab 20(4):481–490

    Article  Google Scholar 

  39. 39.

    Bettencourt-Silva R, Neves J, Ferreira M et al (2019) Metformin in overweight and obese women with gestational diabetes: a propensity score-matched study. Endocrine 66(2):192–200

    CAS  Article  Google Scholar 

  40. 40.

    Dodd J, Louise J, Deussen A, Grivell R, Dekker G, McPhee A, Hague W (2019) Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the GRoW randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 7(1):15–24

    CAS  Article  Google Scholar 

  41. 41.

    Chiswick C, Reynolds R, Denison F et al (2015) Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 3(10):778–786

    CAS  Article  Google Scholar 

  42. 42.

    Gandhi P, Bustani R, Madhuvrata P, Farrell T (2012) Introduction of metformin for gestational diabetes mellitus in clinical practice: has it had an impact? Eur J Obstet Gynecol Reprod Biol 160(2):147–150

    CAS  Article  Google Scholar 

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All authors whose names appear on the submission made substantial contributions to the conception, design of the work; the acquisition, analysis, and interpretation of data; drafted the work or revised it critically for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Catarina Chaves.

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Even though we do not have a formal approval from a Bioethics Committee, this work refers to a retrospective observational study using data from a formal and well-established national gestational diabetes mellitus database. All data were anonymously collected and analysed.

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This article belongs to the topical collection Pregnancy and Diabetes, managed by Antonio Secchi and Marina Scavini

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Chaves, C., Cunha, F., Martinho, M. et al. Metformin combined with insulin in women with gestational diabetes mellitus: a propensity score-matched study. Acta Diabetol (2021).

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  • Gestational diabetes mellitus
  • Metformin
  • Insulin
  • Obstetric complications
  • Neonatal complications