TY - JOUR
T1 - Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy The MOMPOD Randomized Clinical Trial
AU - Boggess, Kim A.
AU - Valint, Arielle
AU - Refuerzo, Jerrie S.
AU - Zork, Noelia
AU - Battarbee, Ashley N.
AU - Eichelberger, Kacey
AU - Ramos, Gladys A.
AU - Olson, Gayle
AU - Durnwald, Celeste
AU - Landon, Mark B.
AU - Aagaard, Kjersti M.
AU - Wallace, Kedra
AU - Scifres, Christina
AU - Rosen, Todd
AU - Mulla, Wadia
AU - Valent, Amy
AU - Longo, Sherri
AU - Young, Laura
AU - Marquis, M. Alison
AU - Thomas, Sonia
AU - Britt, Ashley
AU - Berry, Diane
N1 - Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
PY - 2023/12/12
Y1 - 2023/12/12
N2 - IMPORTANCE 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. OBJECTIVE 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. DESIGN, SETTING, AND PARTICIPANTS 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’ 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. INTERVENTION Metformin 1000mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. MAIN OUTCOME AND MEASURES The primary outcomewas 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. RESULTS 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’ 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. CONCLUSIONS AND RELEVANCE 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. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02932475.
AB - IMPORTANCE 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. OBJECTIVE 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. DESIGN, SETTING, AND PARTICIPANTS 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’ 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. INTERVENTION Metformin 1000mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. MAIN OUTCOME AND MEASURES The primary outcomewas 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. RESULTS 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’ 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. CONCLUSIONS AND RELEVANCE 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. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02932475.
UR - http://www.scopus.com/inward/record.url?scp=85179648596&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85179648596&partnerID=8YFLogxK
U2 - 10.1001/jama.2023.22949
DO - 10.1001/jama.2023.22949
M3 - Article
C2 - 38085312
AN - SCOPUS:85179648596
SN - 0098-7484
VL - 330
SP - 2182
EP - 2190
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 22
ER -