Fetal and neonatal effects of N-acetylcysteine for maternal chorioamnionitis: a systematic review.

BACKGROUND

Maternal chorioamnionitis (mCA) and intra-amniotic infection/inflammation (Triple I) are major causes of fetal inflammatory injury and are associated with preterm birth, white matter injury, cerebral palsy, bronchopulmonary dysplasia (BPD), and necrotising enterocolitis (NEC). No established therapy directly targets the inflammatory and oxidative pathways underlying fetal neuroinjury. N-acetylcysteine (NAC), a glutathione precursor with antioxidant and anti-inflammatory properties, has emerged as a potential adjunctive neuroprotective therapy, although human evidence remains limited.

OBJECTIVE

To evaluate fetal and neonatal outcomes associated with antenatal or intrapartum NAC administration in pregnancies complicated by mCA or Triple I.

METHODS

A systematic review was conducted using MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov from inception to December 23, 2025. Eligible studies included randomised controlled trials, prospective cohorts, non-randomised studies, and translational animal models evaluating NAC exposure in mCA or Triple I. Clinical outcomes, biomarkers, pharmacokinetics, and mechanistic pathways were synthesised narratively. Risk of bias was assessed using RoB 2, ROBINS-I, and SYRCLE tools.

RESULTS

Ten studies met the inclusion criteria, including five human and six translational animal studies. Human evidence involved approximately 143 mother-infant dyads. NAC exposure was associated with preserved cerebrovascular coupling, improved delivery-room adaptation, reduced severe neonatal morbidity, and lower BPD rates without major safety concerns. Pharmacokinetic studies demonstrated rapid placental transfer and gestation-dependent neonatal clearance. Animal studies consistently showed reductions in inflammatory cytokines, oxidative stress, apoptosis, and microstructural brain injury.

CONCLUSION

NAC demonstrates biologically plausible neuroprotective potential in mCA and Triple I; however, the evidence remains preliminary due to small sample sizes and heterogeneous protocols. However, some studies showed no or negative effects. Large multicenter randomised trials with standardised dosing and long-term neurodevelopmental follow-up are needed before routine clinical implementation can be recommended.