SummaryBackgroundPrescribed opioid analgesics are frequently used to manage pain in pregnancy. However, the available literature regarding the teratogenic potential of opioid use during pregnancy has not been systematically summarised. This systematic review and meta‐analysis aimed to assess the quality of the evidence on these potential risks and calculate a pooled estimate of risk for any opioid analgesic and individual opioids.MethodsWe searched PubMed, Embase and CINAHL for published studies assessing the risk of major congenital malformations in infants following first‐trimester exposure to opioid analgesics compared with a reference group, excluding studies examining opioid agonist therapy or illicit opioid use. We assessed the risk of bias using the Risk of Bias in Non‐Randomised Studies of Intervention tool. We pooled adjusted risk estimates from studies rated at serious risk of bias or better in a random‐effects meta‐analysis.ResultsOf 12 identified studies, 11 were at high risk of bias (eight serious; three critical). Relative to unexposed infants, those exposed to any opioid use during the first trimester of pregnancy were not at an increased risk of major congenital malformations overall (relative risk 1.04, 95%CI 0.98–1.11); cardiovascular malformations (relative risk 1.07, 95%CI 0.96–1.20); or central nervous system malformations (relative risk 1.06, 95%CI 0.92–1.21). Raised risk estimates were observed for gastrointestinal malformations (relative risk 1.40, 95%CI 0.38–5.16) and cleft palate (relative risk 1.57, 95%CI 0.48–5.13) following any opioid exposure and atrial septal defects (relative risk 1.20, 95%CI 1.05–1.36) following codeine exposure.ConclusionsAlthough the meta‐analysis did not indicate substantial increased risk for most malformations examined, this risk remains uncertain due to the methodological limitations of the included studies. Healthcare professionals and pharmaceutical regulators should be aware of the issues related to the quality of research in this field.

中文翻译：

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妊娠前三个月阿片类镇痛剂暴露与婴儿严重先天畸形的风险：系统评价和荟萃分析†

摘要背景处方阿片类镇痛药经常用于控制妊娠期疼痛。然而，关于怀孕期间使用阿片类药物致畸潜力的现有文献尚未系统总结。这项系统回顾和荟萃分析旨在评估这些潜在风险的证据质量，并计算任何阿片类镇痛药和个别阿片类药物的风险汇总估计值。方法我们检索了 PubMed、Embase 和 CINAHL 来评估已发表的评估主要先天性心脏病风险的研究。与参考组相比，妊娠早期接触阿片类镇痛药后婴儿畸形的情况，不包括检查阿片类激动剂治疗或非法阿片类药物使用的研究。我们使用干预非随机研究中的偏倚风险工具评估了偏倚风险。我们汇总了随机效应荟萃分析中被评为严重偏倚风险或更好的研究的调整后风险估计。结果在 12 项已确定的研究中，11 项存在高偏倚风险（8 项严重；3 项严重）。相对于未接触过阿片类药物的婴儿，那些在怀孕前三个月接触过任何阿片类药物的婴儿总体上发生重大先天畸形的风险并未增加（相对风险 1.04，95%CI 0.98-1.11）；心血管畸形（相对风险 1.07，95%CI 0.96–1.20）；或中枢神经系统畸形（相对风险 1.06，95%CI 0.92–1.21）。在阿片类药物暴露和房间隔缺损（相对风险 1.20，95%）后，胃肠道畸形（相对风险 1.40，95%CI 0.38–5.16）和腭裂（相对风险 1.57，95%CI 0.48–5.13）的风险估计值升高CI 1.05–1.36）可待因暴露后。结论虽然荟萃分析并未表明大多数所检查的畸形的风险显着增加，但由于纳入研究的方法学限制，这种风险仍然不确定。医疗保健专业人员和药品监管机构应该意识到与该领域研究质量相关的问题。