How safe is metformin when initiated in early pregnancy? A retrospective 5-year study of pregnant women with gestational diabetes mellitus from India

Highlights

• Is a safe option when compared to metformin initiated after first trimester or insulin during pregnancy.

• Associated with numerically higher preterm births which warrants close monitoring.

• Not associated with increase in number of stillbirths/congenital malformations/intra-uterine death.

Abstract

Background

The initiation of metformin in early pregnancy in Gestational Diabetes mellitus (GDM) remains controversial. The aim of our study was to assess the influence of Metformin on maternal and fetal outcomes when initiated within the first trimester of pregnancy in GDM.

Methods and materials

A retrospective analysis of 540 women with diabetes complicating pregnancy (IADPSG criteria) over five years (January 2011 to May 2016) was done. The study population comprised of patients initiated on (a) metformin within the first trimester (Group A:n = 186), (b) metformin after the first trimester (Group B:n = 203) and (c) insulin at any time during their pregnancy (Group C:n = 151). The primary outcomes compared were prematurity, respiratory distress, birth trauma, 5-min APGAR score, neonatal hypoglycaemia and need for phototherapy, while secondary outcomes compared were neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance.

Results

Individual and composite primary or secondary outcomes in group A were similar to Groups B and C, though numerically higher premature births were seen in Group A. There was a 1.3% overall incidence of stillbirths/IUD, while 1.11% congenital anomalies were noted of which 2.15% were in group A and 1.32% were in Group C (p = .16).

Conclusions

The initiation of metformin within the first trimester of pregnancy has no significant adverse maternal or fetal outcomes. However, vigilance for premature births is recommended in women exposed to metformin in early pregnancy.

Introduction

Gestational diabetes mellitus (GDM) has been defined as, “Glucose intolerance of varying severity with onset or first recognition during pregnancy” [1]. The relationship between maternal glucose levels and fetal growth and fetal outcome is a basic biological phenomenon [2], yet it is associated with several adverse maternal and fetal outcomes along with a long term risk of developing subsequent impaired glucose tolerance. Diagnosed early and treated intensively, the risk of intrauterine fetal death and the overall frequency and severity of perinatal morbidities in GDM is not in excess of the general obstetric population [1].

The treatment options for GDM include mainly medical nutritional therapy and insulin. Among the oral antidiabetic agents, glibenclamide has been approved for use during pregnancy while the use of metformin during the early period of gestation remains controversial. Though metformin has also been shown to facilitate conception and prevent early pregnancy loss in patients with polycystic ovarian syndrome [3], [4], a maternal to fetal transfer rate of 10–16%, has led to concerns with the use of metformin in early gestation. Even standard guidelines like those of the Endocrine society’s Clinical practice guidelines advocate metformin therapy after the first trimester [5]. A number of studies including a randomised controlled trial from our centre, have reported that the composite of neonatal complications including neonatal hypoglycaemia, were significantly less in neonates of women treated with metformin than those treated with glibenclamide [6]. Given the lack of consensus on the use of metformin in the first trimester of pregnancy in GDM, we conducted this study with the objective of comparing the maternal and fetal outcomes in women with gestational diabetes mellitus who were initiated on metformin within the first trimester to those initiated on metformin after the first trimester or those initiated on insulin during their pregnancy.