Abstract
Aim
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.
Methods
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.
Results
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.
Conclusions
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.
Similar content being viewed by others
References
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
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
Metzger BE, Lowe LP, Dyer AR et al (2008) Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358(19):1991–2002
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
Buchanan T, Xiang A, Page K (2012) Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol 8(11):639–649
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
Arafa A, Dong J (2019) Maternal height and risk of gestational diabetes: a systematic review and meta-analysis. Acta Diabetol 56(7):723–728
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
- Instituto Nacional de Saúde Dr. Ricardo Jorge (2011)Diabetes: Factos E Números
Management of Diabetes in Pregnancy (2017) Standards of medical care in diabetes—2018. Diabetes Care 41(1):137–143
Refuerzo J (2011) Oral Hypoglycemic agents in pregnancy. Obstet Gynecol Clin N Am 38(2):227–234
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
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
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
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
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
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
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
Girard J (2006) The inhibitory effects of insulin on hepatic glucose production are both direct and indirect. Diabetes 55(2):65–69
Berggren E, Boggess K (2013) Oral agents for the management of gestational diabetes. Clin Obstet Gynecol 56(4):827–836
Kavitha N, De S, Kanagasabai S (2013) Oral hypoglycemic agents in pregnancy: an update. J Obstet Gynecol India 63(2):82–87
Magon N, Seshiah V (2011) Gestational diabetes mellitus: non-insulin management. Indian J Endocrinol Metab 15(4):284–293
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
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
Lv S, Wang J, Xu Y (2015) Safety of insulin analogs during pregnancy: a meta-analysis. Arch Gynecol Obstet 292(4):749–756
Yogev Y, Langer O (2004) The use of anti-hyperglycaemic and hypoglycaemic agents in pregnancy. Fetal Matern Med Rev 15(2):133–143
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
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
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
Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: A World Health Organization Guideline (2014) Diabetes Res Clin Pract 103(3):341–363
Almeida M, Dores J, Ruas L et al (2017) Consenso “Diabetes Gestacional”: Atualização 2017. Revista Portuguesa de Diabetes 12(1):24–38
Institute of Medicine, National Research Council: weight gain during pregnancy: reexamining the guidelines. National Academies Press (US), Washington (DC) (2009)
Fenton T, Kim J (2013) A systematic review and metaanalysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 13:59
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
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
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
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
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
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
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
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
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
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
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.
Informed Consent
The informed consent in this study was applicable due to the retrospective nature of the study and full anonymization of the data.
Consent to participate
The consent to participate in this study was not necessary due to the retrospective nature of the study and full anonymization of the data.
Consent for publication
The author consents to the publication of this article.
Availability of data and material
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Additional information
This article belongs to the topical collection Pregnancy and Diabetes, managed by Antonio Secchi and Marina Scavini
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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 58, 615–621 (2021). https://doi.org/10.1007/s00592-020-01665-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-020-01665-8