Opioid Analgesic Initiation During Pregnancy and the Risk of Adverse Maternal and Neonatal Outcomes: A Target Trial Emulation
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Background
We used sequential target trial emulation (TTE) to examine associations between opioid analgesic initiation and adverse maternal and neonatal outcomes while accounting for gestational timing, time at risk, and potential confounding.
Methods
Using the Early Life Course platform, comprising linked population-based data for births in New South Wales, Australia (2013–2019), we emulated a new trial at each gestational week, comparing women who initiated a prescribed opioid analgesic with eligible non-initiators. Baseline covariates were balanced using inverse probability weighting. Weighted logistic regression estimated odds ratios (ORs) for neonatal outcomes, postpartum haemorrhage, and severe maternal morbidity. Pooled logistic regression estimated hazard ratios (HRs) for other maternal outcomes, combined across gestational weeks using fixed-effects meta-analysis. Sensitivity analyses assessed unmeasured confounding, exposure misclassification, and potential reverse causation.
Findings
Among 511,357 pregnancies, over 80% of opioid initiators received only one dispensing. Opioid initiation was not associated with increased risks of placental abruption (HR 0.94, 95% CI 0.75–1.16), severe maternal morbidity (OR 1.05, 0.97–1.11), postpartum haemorrhage (OR 0.98, 0.95–1.02), low Apgar score (OR 0.99, 0.87–1.08), small for gestational age (OR 0.90, 0.85–0.95), or neonatal abstinence syndrome (OR 0.98, 0.72–1.30). Risks were elevated for PPROM (HR 1.10, 0.98–1.23), preterm birth (HR 1.26, 1.19–1.33), severe neonatal morbidity (OR 1.08, 1.02–1.17), and perinatal death (OR 1.29, 1.10–1.52). Perinatal death estimates attenuated in analyses addressing potential reverse causation.
Interpretation
Using a TTE approach that accounted for gestational timing and time at risk, we found no appreciable increase in most maternal or neonatal outcomes following predominantly short-term opioid initiation. Elevated risks of preterm birth, perinatal death, and third-trimester PPROM may reflect causal effects or confounding by pregnancy-related indications. Studies using time-appropriate designs and detailed information on prescribing indications and their timing are needed to clarify these associations.
Research in Context
Evidence before this study
We searched the electronic databases MEDLINE (PubMed) for published articles, without language restrictions, from 1 January 2000 until 9 September 2026. The search strategy included terms for exposure (e.g. analgesic opioids), population (e.g. pregnancy and neonatal) and maternal and neonatal outcomes (e.g. preterm birth). Our search identified 10 observational studies which examined maternal and neonatal outcomes following opioid analgesic exposure during pregnancy. In these studies, prenatal opioid exposure above certain levels was consistently associated with neonatal abstinence syndrome (NAS). Beyond NAS, findings were inconsistent: some studies reported increased risks of peripartum haemorrhage, stillbirth, small for gestational age, low Apgar scores, preterm birth, and placental abruption, whereas others found no increased risk. It remains unclear whether observed associations are causal or reflect residual confounding. Methodological limitations may also have obscured associations, including immortal time bias when treatment initiation and follow-up were not aligned, and analyses that did not adequately account for gestational timing and therefore may have missed periods of greater susceptibility. As opioid analgesics are among the few options for managing pain during pregnancy, high-quality evidence on their safety is essential for informed clinical decision-making.
Added value of this study
This study applied a sequential target trial emulation framework to estimate the effects of opioid analgesic initiation during pregnancy across a broad range of maternal and neonatal outcomes, aligning eligibility, treatment initiation, and follow-up while accounting for gestational timing. Opioid initiation was not associated with appreciably increased risks of most outcomes, including placental abruption, postpartum haemorrhage, severe maternal morbidity, and low Apgar scores. A small increase was observed for severe neonatal morbidity. Relative risks increased across trimesters for preterm birth, while PPROM and perinatal death were most elevated following third-trimester initiation. These findings may reflect opioid effects, although evolving pregnancy complications that both prompt opioid treatment and independently increase outcome risk remain a plausible explanation. NAS risk was not increased overall, although estimates were higher for oxycodone and higher oral morphine equivalent (OME) exposure.
Implications of all available evidence
Taken together with broader evidence showing no substantial increase in the risk of major congenital malformations or adverse neurodevelopmental outcomes, these findings are generally reassuring for short-term opioid analgesic use in pregnancy, particularly codeine. The observed signals for preterm birth, PPROM and perinatal death, should not, in isolation, deter clinically indicated use, but support existing guidance to use opioids at the lowest effective dose for the shortest necessary duration and highlight the need for further studies that can distinguish direct opioid effects from shared clinical pathways.
