Author
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BARBOUR, LINDA - University Of Colorado |
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SCIFRES, CHRISTINA - University Of Oklahoma |
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VALENT, AMY - Oregon Health & Science University |
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FREIDMAN, JACOB - University Of Colorado |
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BUCHANAN, THOMAS - University Of Southern California |
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COUSTAN, DAN - University Arkansas For Medical Sciences (UAMS) |
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AAAGARD, KJERSTI - Baylor College Of Medicine |
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THORNBURG, KENT - University Of Oregon |
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CATALANO, PATRICK - Tufts University |
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GALAN, HENRY - University Of Colorado |
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HAY, WILLIAM - University Of Colorado |
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FRIAS, ANTONIO - Oregon Health & Science University |
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SHANKAR, KARTIK - University Of Colorado |
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SIMMONS, REBECCA - University Of Pennsylvania |
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MOSES, ROBERT - Wollongong Hospital |
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SACKS, DAVID - Kaiser Permanente |
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LOEKEN, MARY - Harvard Medical School |
Submitted to: American Journal of Obstetrics and Gynecology
Publication Type: Other Publication Acceptance Date: 6/20/2018 Publication Date: 6/27/2018 Citation: Barbour, L., Scifres, C., Valent, A., Freidman, J., Buchanan, T., Coustan, D., Aaagard, K., Thornburg, K., Catalano, P., Galan, H., Hay, W., Frias, A., Shankar, K., Simmons, R., Moses, R., Sacks, D.A., Loeken, M. 2018. A cautionary response to SMFM statement: Pharmacological treatment of gestational diabetes. American Journal of Obstetrics and Gynecology. 9378(18): 30529-30535. http://doi.org/10.1016/j.ajog.2018.06.013. DOI: https://doi.org/10.1016/j.ajog.2018.06.013 Interpretive Summary: Technical Abstract: Use of oral agents to treat gestational diabetes (GDM) remains controversial. Recent SMFM recommendations assert that metformin may be a safe first line alternative to insulin for GDM treatment. However, several issues should give pause to metformin’s widespread adoption. Fetal concentrations of metformin are equal to maternal high, and metformin has growth inhibitory and anti-cancer effects, suppresses mitochondrial respiration, and inhibits hepatic gluconeogenesis. These properties raise important questions about fetal safety and potential influences on offspring developmental programming of metabolic disease. Both the placenta and fetus have metformin transporters and require high mitochondrial activity. Although metformin has favorable effects to reduce anti-angiogenic factors that may decrease preeclampsia, animal studies have demonstrated that prenatal metformin results in smaller birthweights, abnormal hepatic development, and adverse long-term outcomes in offspring later fed a western style diet. Findings from the Metformin in Gestational Diabetes (MiG) RCT found that nearly half of women treated with metformin failed and required supplemental insulin, rates of preterm birth were higher, and offspring had increased subcutaneous fat at age 2. These were similar to findings from a RCT in PCOS mothers. Two RCTs have used metformin in obese pregnancies. In neither trial was GDM or large-for-gestational age (LGA) reduced. Although metformin is beneficial in adults with diabetes or cancer, its anti-proliferative, nutrient restrictive, and respiratory suppressive effects could be responsible for its fetal growth effects rather than due to improved maternal glycemic control. Newer meta-analyses concur that it is impossible to determine the superiority of one oral antidiabetic agent over another due to study limitations, especially given that glyburide is typically dosed in a manner inconsistent with its pharmacokinetic properties, resulting in poor glycemic control and a high rate of hypoglycemia. We concur with both the ADA and ACOG recommendations that insulin is the preferred agent and believe it is premature to embrace metformin as equivalent to insulin or superior to glyburide. Carefully controlled studies that optimize oral medication dosing according to their pharmacokinetic properties, appropriately target medications based on individual patterns of hyperglycemia, and which follow the offspring long term for metabolic risk are gravely needed. |