An insight into The Safety of Metformin During Pregnancy

The systematic review by Gordon et al., titled “Metformin in Pregnancy and Childhood Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis,” has offered an important understanding into the neurodevelopmental safety of metformin during pregnancy. However, the potential risks related to metformin’s pharmacokinetics and its consequences for fetal development, especially in cases of intrauterine growth restriction (IUGR), warrant further examination.

 Metformin easily crosses the placenta through organic cation transporters, exposing the fetus to drug concentrations alike to those in the maternal bloodstream. Although experimental studies demonstrate that metformin does not increase the risk of congenital anomalies, its ability to stimulate AMPK activity and inhibit mitochondrial respiration and one-carbon metabolism in embryonic stem cells presents serious doubts about how it may affect fetal development. These concerns are specifically pertinent in the cases of intrauterine growth restriction (IUGR), where fetal liver function is already compromised. 

Liver has increased risk of metabolic disturbances, including increased gluconeogenesis, decreased energy production, and overall metabolic dysfunction in IUGR fetus. These vulnerabilities could be made worse by the introduction of metformin, which interferes with glucose synthesis and affects signaling pathways including AMPK and mTOR, further affecting fetal growth and long-term metabolic health. 

Moreover, use of metformin in pregnancies complicated by conditions like polyhydramnios or macrosomia may impede control of optimal blood sugar, which makes insulin a more effective option for managing gestational diabetes. Besides, the comprehensiveness of Gordon et al.'s findings of the safety of metformin was limited by the included studies' inability to either exclude or evaluate IUGR cases separately. In addition, the systemic review did not examine specific risks associated with metformin use in pregnancies affected by IUGR.

To conclude, although the review provided by Gordon et al. offered some positives regarding the neurodevelopmental safety of metformin, the broader implications for fetal growth suggest that its use during pregnancy should be approached with caution. Further research is warranted to understand the long-term effects of in-utero metformin exposure, predominantly in high-risk groups, to ensure safer and more targeted treatment strategies.

Source: Dashtkoohi M, Noorafrooz M, Hantoushzadeh S, Concerns Regarding the Safety of Metformin Use in Pregnancy, American Journal of Obstetrics and Gynecology.2024. doi: https://doi.org/10.1016/j.ajog.2024.09.110.