{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:41:47Z","timestamp":1792186907895,"version":"4.4.0"},"reference-count":26,"publisher":"American Medical Association (AMA)","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2023,12,12]]},"abstract":"\n Importance<\/jats:title>\n Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks\u2019 gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022.<\/jats:p>\n <\/jats:sec>\n \n Intervention<\/jats:title>\n Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -&amp;lt;23 weeks) through delivery.<\/jats:p>\n <\/jats:sec>\n \n Main Outcome and Measures<\/jats:title>\n The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants\u2019 mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT02932475<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2023.22949","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T11:21:03Z","timestamp":1702380063000},"page":"2182","source":"Crossref","is-referenced-by-count":80,"title":["Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy"],"prefix":"10.1001","volume":"330","author":[{"given":"Kim A.","family":"Boggess","sequence":"first","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arielle","family":"Valint","sequence":"additional","affiliation":[{"name":"University of North Carolina Gillings School of Global Public Health Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerrie S.","family":"Refuerzo","sequence":"additional","affiliation":[{"name":"University of Texas Health Houston McGovern Medical School Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelia","family":"Zork","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley N.","family":"Battarbee","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham Heersink School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacey","family":"Eichelberger","sequence":"additional","affiliation":[{"name":"University of South Carolina School of Medicine Greenville\/Prisma Health-Upstate"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gladys A.","family":"Ramos","sequence":"additional","affiliation":[{"name":"University of California, San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayle","family":"Olson","sequence":"additional","affiliation":[{"name":"University of Texas Medical Branch Galveston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Durnwald","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Perelman School of Medicine, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark B.","family":"Landon","sequence":"additional","affiliation":[{"name":"The Ohio State University College of Medicine and Wexner Medical Center, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjersti M.","family":"Aagaard","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine and Texas Children\u2019s Hospital, Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kedra","family":"Wallace","sequence":"additional","affiliation":[{"name":"University of Mississippi Medical Center, Jackson"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Scifres","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Rosen","sequence":"additional","affiliation":[{"name":"Rutgers Health\/Robert Wood Johnson Medical School, New Brunswick, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wadia","family":"Mulla","sequence":"additional","affiliation":[{"name":"Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Valent","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherri","family":"Longo","sequence":"additional","affiliation":[{"name":"Ochsner Health, New Orleans, Louisiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Young","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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