Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.

Educational Outcomes for Children at 7 to 9 Years of Age After Birth at 39 vs 40 to 42 Weeks' Gestation.

Importance: Birth at 39 weeks' gestation is common and thought to be safe for mother and neonate. However, findings of long-term outcomes for children born at this gestational age have been conflicting. Objective: To evaluate the association of birth at 39 weeks' gestation with childhood numeracy and literacy scores at ages 7 to 9 years compared with birth at 40 to 42 weeks' gestation. Design, Setting, and Participants: In this Australian statewide, population-based cohort study using a causal inference framework based on target trial emulation, perinatal data on births between January 1, 2005, and December 31, 2011, were linked to educational outcomes at 7 to 9 years of age. Statistical analyses were performed from December 2022 to June 2023. Exposure: Birth at 39 weeks' gestation compared with birth at 40 to 42 weeks' gestation. Main Outcomes and Measures: Numeracy and literacy outcomes were assessed at 7 to 9 years of age using Australian National Assessment Program-Literacy and Numeracy data and defined by overall z score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Multiple imputation and doubly robust inverse probability weighted regression adjustment were used to estimate population average causal effects. Results: The study population included 155 575 children. Of these children, 49 456 (31.8%; 24 952 boys [50.5%]) were born at 39 weeks' gestation and were compared with 106 119 (68.2%; 52 083 boys [49.1%]) born at 40 to 42 weeks' gestation. Birth at 39 weeks' gestation was not associated with altered educational outcomes for children aged 7 to 9 years compared with their peers born at 40 to 42 weeks' gestation (mean [SE] z score, 0.0008 [0.0019] vs -0.0031 [0.0038]; adjusted risk difference, -0.004 [95% CI, -0.015 to 0.007]). Each educational domain was investigated, and no significant difference was found in grammar and punctuation (risk difference [RD], -0.006 [95% CI, -0.016 to 0.005]), numeracy (RD, -0.009 [95% CI, -0.020 to 0.001]), spelling (RD, 0.001 [95% CI, -0.011 to 0.0013]), reading (RD, -0.008 [95% CI, -0.019 to 0.003]), or writing (RD, 0.006 [95% CI, -0.005 to 0.016]) scores for children born at 39 weeks' gestation compared with those born at 40 to 42 weeks' gestation. Birth at 39 weeks' gestation also did not increase the risk of scoring below national minimum standards in any of the 5 tested domains. Conclusions and Relevance: Using data from a statewide linkage study to emulate the results of a target randomized clinical trial, this study suggests that there is no evidence of an association of birth at 39 weeks' gestation with numeracy and literacy outcomes for children aged 7 to 9 years.