Diabetes in pregnancy includes pre-pregnancy diabetes and gestational diabetes mellitus (GDM). Since 2003, the total quantity of patients with type 2 diabetes mellitus in China has exceeded India and the USA. The prevalence of GDM in China is 17.5%–19.7%.1,2 Pregnancy complicated with diabetes is associated with adverse maternal, fetal, neonatal, and even childhood, adulthood outcomes. Tight control of glucose level during pregnancy contributes to improve maternal and fetal outcomes and break the vicious cycle of “diabetes begetting diabetes”.
The metformin in gestational diabetes trial published in the New England Journal in 2008 randomized women with GDM requiring pharmacotherapy with either metformin or insulin.3 Pregnancy outcomes were similar between the groups. The neonates of pregnant women with metformin had lower rates of severe hypoglycemia (3.3% vs. 8.1%, P = 0.008). Subsequent smaller trials have been carried out. Recent meta-analyses4 have concluded that metformin is an efficient and safe alternative to insulin for pregnant women with hyperglycemia.
To further confirm the long term safety of metformin, the offspring of women enrolled in the metformin in gestational diabetes trial have been followed up at 7–9 years of age. Metformin or insulin for GDM was associated with similar total and abdominal body fat percent and metabolic measures at offspring of 7–9 years. There were no differences in offspring abdominal fat percentages (visceral adipose tissue, subcutaneous adipose tissue, and liver), fasting glucose, triglyceride, insulin, insulin resistance, glycosylated hemoglobin, cholesterol, liver transaminases, leptin, and adiponectin at 7–9 years.5 Based on the randomized controlled trials and meta-analyses, several latest guidelines from different countries recommend metformin as an alternative of insulin in pregnancy.
Diagnosis and management of pregnancy with diabetes published by national obstetrics group of Chinese society of obstetrics and gynecology (2014)6
For pregnancy with diabetes patients who need large doses of insulin or those refuse to use insulin, the known harm from poor glucose control outweighs potential risks from metformin and glyburide. Therefore, metformin is a reasonable alternative choice for part of the GDM patients, in the context of discussing with the patient the limitations of the safety data. Type 2 diabetes mellitus patients who take metformin pre-pregnancy can continue to use metformin in the context of discussing the benefits and potential risks of metformin with the patients.
The International Federation of Gynecology and Obstetrics initiative on GDM: a pragmatic guide for diagnosis, management, and care (2015)7
Insulin, glyburide, and metformin are safe and effective therapies for GDM during the second and third trimesters, and may be initiated as first-line treatment after failing to achieve glucose control with lifestyle modification. Among oral antidiabetic drugs, metformin may be a better choice than glyburide. Metformin (plus insulin when required) performs slightly better than insulin.
2018 The American College of Obstetricians and Gynecologists practice bulletin number 190: GDM8
Insulin is the first-line treatment of GDM. In women who decline insulin or who the obstetricians or obstetric care providers believe will be unable to safely administer insulin, or for women who cannot afford insulin, metformin (and rarely glyburide) is a reasonable alternative choice in the context of discussing with the patient the limitations of the safety data and a high rate of treatment failure that requires insulin supplementation. Glyburide treatment should not be recommended as a first-choice pharmacologic treatment because, in most studies, it does not yield equivalent outcomes to insulin.
2018 Society for Maternal-Fetal Medicine (SMFM) statement: pharmacological treatment of gestational diabetes9
In women with GDM in which hyperglycemia cannot adequately be controlled with medical nutrition therapy, metformin is a reasonable and safe first-line pharmacologic alternative to insulin, recognizing that one-half of women will still require insulin to achieve glycemic control.
In summarize, the International Federation of Gynecology and Obstetrics and Society for Maternal-Fetal Medicine guidelines hold the opinion that metformin is a safe and first-line alternative to insulin in pregnancy complicated with diabetes. However, the American College of Obstetricians and Gynecologists guideline still emphasizes insulin as the first-line treatment of GDM, and only those who decline or cannot afford insulin, and those who are unable to safely administer insulin can take metformin in the context of discussing with the patient the limitations of the safety data and a high rate of treatment failure that requires insulin supplementation.
Scientific Research Seed Fund of Peking University First Hospital 2018SF017.
Conflicts of Interest
. Juan J, Yang HX, Su RN, et al. Diagnosis of Gestational Diabetes Mellitus in China: Perspective, Progress and Prospects. Maternal-Fetal Medicine 2019;1(1):31–37. doi:10.1097/FM9.0000000000000008.
. Zhu W, Yang H, Wei Y, et al. Comparing the diagnostic criteria for gestational diabetes mellitus of World Health Organization 2013 with 1999 in Chinese population. Chin Med J (Engl) 2015;128(1):125–127. doi:10.4103/0366-6999.147858.
. Rowan JA, Hague WM, Gao W, et al. Metformin
versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358(19):2003–2015. doi:10.1056/NEJMoa0707193.
. Feng Y, Yang H. Metformin
–a potentially effective drug for gestational diabetes mellitus: a systematic review and meta-analysis. J Maternal-Fetal Neonat Med 2017;30(15):1874–1881. doi:10.1080/14767058.2016.1228061.
. 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. doi:10.1136/bmjdrc-2017-000456.
. Yang HX, Xu XM, Wang ZL, et al. Diagnosis and management of pregnancy
with diabetes. World Diabetes 2014;11:002. Available at: http://www.cnki.com.cn/Article/CJFDTOTAL-TNBL201411002.htm
. Hod M, Kapur A, Sacks DA, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet 2015;131(Suppl 3):S173–S211. doi:10.1016/S0020-7292(15)30033-3.
. Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 190: gestational diabetes mellitus. Obstet Gynecol 2018;131(2):e49–e64. doi:10.1097/AOG.0000000000002501.
. Society of Maternal-Fetal Medicine (SMFM) Publications Committee. SMFM statement: pharmacological treatment of gestational diabetes. Am J Obs Gynecol 2018;218(5):B2–B4. doi:10.1016/j.ajog.2018.01.041.