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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.
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BACKGROUND: Post-term gestation beyond 41+6 completed weeks of gestation is known to be associated with a sharp increase in the risk of stillbirth and perinatal mortality. However, the risk of common adverse outcomes related to labour, such as shoulder dystocia and post-partum haemorrhage for those delivering at this advanced gestation, remains poorly characterised. The objective of this study was to examine the risk of adverse, labour-related outcomes for women progressing to 42 weeks gestation or beyond, compared with those giving birth at 39 completed weeks. METHODS: We performed a state-wide cohort study using routinely collected perinatal data in Australia. Comparing the two gestation cohorts, we examined the adjusted relative risk of clinically significant labour-related adverse outcomes, including macrosomia (≥ 4500 at birth), post-partum haemorrhage (≥1000 ml), shoulder dystocia, 3rd or 4th degree perineal tear and unplanned caesarean section. Parity, maternal age and mode of birth were adjusted for using logistic regression. RESULTS: The study cohort included 91,314 women who birthed at 39 completed weeks and 4317 at ≥42 completed weeks. Compared to 39 weeks gestation, those giving birth ≥42 weeks gestation had an adjusted relative risk (aRR) of 1.85 (95% CI 1.55-2.20) for post-partum haemorrhage following vaginal birth, 2.29 (95% CI 1.89-2.78) following instrumental birth and 1.44 (95% CI 1.17-1.78) following emergency caesarean section; 1.43 (95% CI 1.16-1.77) for shoulder dystocia (for non-macrosomic babies); and 1.22 (95% CI 1.03-1.45) for 3rd or 4th degree perineal tear (all women). The adjusted relative risk of giving birth to a macrosomic baby was 10.19 (95% CI 8.26-12.57) among nulliparous women and 4.71 (95% CI 3.90-5.68) among multiparous women. The risk of unplanned caesarean section was 1.96 (95% CI 1.86-2.06) following any labour and 1.47 (95% CI 1.38-1.56) following induction of labour. CONCLUSIONS: Giving birth at ≥42 weeks gestation may be an under-recognised risk factor for several important, labour-related adverse outcomes. Clinicians should be aware that labour at this advanced gestation incurs a higher risk of adverse outcomes. In addition to known perinatal risks, the risk of obstetric complications should be considered in the counselling of women labouring at post-term gestation.