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Metformin Use in Pregnancy Alters Signaling and Metabolism in Fetal Liver Cells

6/24/2024

Microscope with multiple objective lenses focused on a slide, lit brightly in a dimly lit room.

Key takeaways

  • Metformin, an oral glycemic agent used in some pregnancies, may negatively impact the fetus with adverse effects that could extend into childhood.

  • This study used fetal and juvenile animal models to explore the effects of metformin, particularly focusing on the liver and its signaling pathways.

  • Investigators found metformin impacts glucose production, mitochondrial function and oxidative stress pathways in fetal hepatocytes, potentially influencing fetal growth and metabolism.

  • Current in vivo studies seek to validate cellular findings in the fetal liver and better understand metformin's pathways, which could improve clinical decision-making about its use during pregnancy.


Research study background

Metformin is an oral glycemic agent approved for use in pregnancy to treat gestational diabetes, polycystic ovarian syndrome, pre-diabetes or type 2 diabetes. Although metformin’s use is increasing and is considered safe for the fetus, it crosses the placenta, exposing the unborn child to adult levels of the drug, which potentially poses risks.

Previous studies suggest fetal exposure to metformin may increase the risk of lower birth weight and adverse metabolic outcomes in offspring, as well as a higher risk of increased body weight, obesity and metabolic dysfunction in preadolescence.

In this study, Stephanie Wesolowski, PhD, Laura Brown, MD, and Paul Rozance, MD, neonatologists at Children’s Hospital Colorado, collaborated with other institutions to investigate the effects of metformin action. Their lab, located in the Perinatal Research Center at the University of Colorado School of Medicine, focuses on the fetus.

“Metformin may be good for mom, but not for baby. We need more research to better understand the effects of fetal exposure so that clinicians can better weigh the risks to the fetus versus benefits to the mother.”

- STEPHANIE WESOLOWSKI, PHD

Investigators used pre-clinical and translational fetal and juvenile animal models to isolate primary hepatocytes, making this study one of the first to identify pathways affected by metformin in fetal liver. They found that the primary transporter responsible for metformin uptake, OCT1, is present in the fetal liver, and in vivo experiments confirm metformin uptake by fetal hepatic cells. Metformin in fetal liver cells activates AMP-activated protein kinase and lowers glucose production and oxygen consumption, similar to its effects in juvenile liver cells. Fetal liver cells respond uniquely to metformin by activating stress pathways and changing the expression of growth factors and hepatokines (hormone-like proteins secreted by hepatocytes). When signaling and metabolism in fetal livers are disrupted, it could reduce fetal growth by altering the profile of secreted hepatokines and decreasing growth-promoting pathways.

Clinical implications

With metformin’s prevalent use during pregnancy, these findings underscore the necessity for functional studies to inform clinical decisions regarding its use during pregnancy and its impact on fetal growth, organ development, metabolism and mitochondrial function, beyond birthweight alone.

Dr. Wesolowski and colleagues are currently conducting National Institutes of Health-funded in vivo studies using macaques to explore maternal metformin's impacts on fetuses and offspring. They hope to validate cellular findings in the fetal liver and deepen insight into metformin's pathways. These ongoing studies are pivotal in comprehending fetal outcomes and guiding safer glycemic therapies during pregnancy.