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Intrauterine Exposure to Metformin Can Affect Neonatal Growth

Nov 26, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Nadeen Ayad, BCPS, PharmD Candidate, Skaggs School of Pharmacy, University of Colorado

A systematic review to investigate the impact of intrauterine exposure to metformin on neonatal growth vs. insulin

Gestational diabetes is a common complication in pregnancy and can be associated with serious adverse outcomes for both the mother and the baby. Metformin is considered to be the preferred treatment and an acceptable alternative to insulin for the treatment of gestational diabetes (GDM). Therefore, it is important to investigate and fully understand the effect that metformin may have on the baby in the womb and also after birth. This study aimed to investigate the impact of metformin has on neonatal birth weight in GDM-affected pregnancies.

The researchers performed a systematic review of 28 studies that included 3976 mothers who were randomized to receive either metformin or insulin for the treatment of GDM. The primary outcome was birth weight.

The researchers observed a significant decrease in the birth weight of neonates born to mothers treated with metformin vs. those treated with insulin during pregnancy. On average, metformin-exposed neonates were 107.7 g smaller than those whose mothers were treated with insulin (95% CI 32.7-182.3 p= 0.005). In addition to that, neonatal head circumference was significantly lower in the metformin group than the insulin group ( -0.21 cm,95% CI -0.39 to -0.03 p=0.02) as well as chest circumference ( -0.34 cm 95% CI -0.62 to -0.05 p= 0.02).

Furthermore, weight during infancy was reported to be significantly higher in the metformin-exposed group than the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830 p=0.03). However, infant height was not significantly different between the treatment groups ( 0.65 cm, 95% CI -1.31 to 2.61). Childhood BMI was reported in two of the studies to be significantly higher in the metformin-exposed group than the insulin-exposed group (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, p= 0.005). There was no significant difference in height in childhood between the two treatment groups. Finally, the risk of macrosomia was 40% lower in the exposed metformin group compared to the insulin exposed group.

This meta-analysis had several strengths and limitations. In terms of strengths, the findings of this meta-analysis appear to be robust across different populations, including low and high-income countries. In addition to that, the analysis was limited only to studies of women with confirmed GDM.  Some of the limitations were that the majority of the clinical trials included were powered only for primary outcomes at the time of birth. Further longitudinal studies are needed to examine growth and body composition following intrauterine metformin exposure. In addition to that, the risk of bias in some of the studies was high and did not perform an intention-to-treat analysis.

The researchers concluded that metformin-exposed babies are born smaller than those exposed to insulin, but then undergo accelerated postnatal growth demonstrated as a higher weight in infancy and a higher BMI by childhood. This may be associated with a higher risk of adverse long-term cardio-metabolic outcomes, including obesity, type 2 diabetes, and cardiovascular disease, as data from some previous studies have suggested. The growth pattern seen in infants exposed to metformin compared to insulin closely resembles that of a nutritionally deprived fetus. Further studies are needed to examine the very long-term consequences of fetal metformin exposure.

Practice Pearls:

  • This systematic review included 28 studies and a total of 3976 pregnant women with gestational diabetes mellitus. Mothers were randomized to receive either metformin or insulin and followed to examine the effect of treatment on fetal birth weight.
  • Neonates exposed to intrauterine metformin were born smaller with a lower birth weight than those exposed to insulin. However, weight during infancy was higher in the metformin group as well as childhood BMI.
  • These findings suggest that metformin- exposed babies are born smaller but undergo an accelerated postnatal growth, which can increase the risk of cardiovascular disease and type 2 diabetes later in life. However, further studies are needed to investigate the very-long term effects of intrauterine metformin exposure.

Tarry-Adkins JL, et al. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis. PLos Med; 2019 Aug

Nadeen Ayad, BCPS, PharmD candidate, Skaggs School of Pharmacy, University of Colorado