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Am J Obstet Gynecol. 2018 Oct;219(4):367.e1-367.e7. doi: 10.1016/j.ajog.2018.06.013. Epub 2018 Jun 28.

A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes.

Author information

1
Divisions of Endocrinology and Maternal-Fetal Medicine, Departments of Medicine and Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO. Electronic address: Lynn.Barbour@UCDenver.edu.
2
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
3
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR.
4
Divisions of Neonatology, Endocrinology, and Reproductive Sciences, Departments of Pediatrics, Medicine, Biochemistry, and Molecular Genetics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO.
5
Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
6
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Alpert Medical School, Brown University, Providence, RI.
7
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
8
Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR.
9
Department of Reproductive Biology, Center for Reproductive Health, Case Western Reserve University at MetroHealth Medical Center, Cleveland, OH.
10
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Denver, CO.
11
Division of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
12
Arkansas Children's Nutrition Center, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
13
Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine Philadelphia, Philadelphia, PA.
14
Illawarra Area Health Service, Wollongong Hospital, Wollongong, Australia.
15
Department of Research and Evaluation of Nutrition and Metabolism, Kaiser Permanente Southern California, Pasadena, CA.
16
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA.

Abstract

Use of oral agents to treat gestational diabetes mellitus remains controversial. Recent recommendations from the Society for Maternal-Fetal Medicine assert that metformin may be a safe first-line alternative to insulin for gestational diabetes mellitus treatment and preferable to glyburide. However, several issues should give pause to the widespread adoption of metformin use during pregnancy. Fetal concentrations of metformin are equal to maternal, and metformin can inhibit growth, suppress mitochondrial respiration, have epigenetic modifications on gene expression, mimic fetal nutrient restriction, and alter postnatal gluconeogenic responses. Because both the placenta and fetus express metformin transporters and exhibit high mitochondrial activity, these properties raise important questions about developmental programming of metabolic disease in offspring. Animal studies have demonstrated that prenatal metformin exposure results in adverse long-term outcomes on body weight and metabolism. Two recent clinical randomized controlled trials in women with gestational diabetes mellitus or polycystic ovary syndrome provide evidence that metformin exposure in utero may produce a metabolic phenotype that increases childhood weight or obesity. These developmental programming effects challenge the conclusion that metformin is equivalent to insulin. Although the Society for Maternal-Fetal Medicine statement endorsed metformin over glyburide if oral agents are used, there are few studies directly comparing the 2 agents and it is not clear that metformin alone is superior to glyburide. Moreover, it should be noted that prior clinical studies have dosed glyburide in a manner inconsistent with its pharmacokinetic properties, resulting in poor glycemic control and high rates of maternal hypoglycemia. We concur with the American Diabetes Association and American Congress of Obstetricians and Gynecologists, which recommend insulin as the preferred agent, but we believe that it is premature to embrace metformin as equivalent to insulin or superior to glyburide. Due to the uncertainty of the long-term metabolic risks of either metformin or glyburide, we call for carefully controlled studies that optimize oral medication dosing according to their pharmacodynamic and pharmacokinetic properties in pregnancy, appropriately target medications based on individual patterns of hyperglycemia, and follow the offspring long-term for metabolic risk.

KEYWORDS:

diabetes in pregnancy; glyburide; guidelines; metformin

PMID:
29959933
PMCID:
PMC6263936
DOI:
10.1016/j.ajog.2018.06.013
[Indexed for MEDLINE]
Free PMC Article

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