Antenatal N-acetylcysteine supplementation in pregnant women with impending preterm birth: a prospective randomized placebo-controlled trial

BACKGROUND: Depletion of glutathione (GSH) stores is associated with preterm birth and is not corrected by neonatal supplementation with N-acetylcysteine (NAC), a GSH precursor. Whether antenatal NAC would do so, remains unknown. METHODS: In a pilot, randomized, single-blinded trial (NCT03596125), women pregnant with singletons at-either severe or moderate-risk for impending preterm birth, received either N-acetylcysteine (n = 20) or placebo (n = 19). The moderate-risk group received oral NAC (80 mg/kg/day, days 0-7, then 40 mg/kg/day until 37 weeks or delivery). The severe-risk group, received an intravenous bolus (20 mg/kg over 1 h) and infusion (105 mg/kg over 4 h) doses prior to oral NAC. Primary outcome was umbilical venous cord erythrocyte GSH; secondary included pregnancy-duration, infant outcomes, and exploratory investigation of sulfur metabolites. RESULTS: NAC supplementation failed to impact median GSH (full analysis set/per protocol: 402/465 vs. 459/398 µmol/L, P 0.38/1.0). However, NAC was associated with prolonged pregnancy duration (44.5 vs. 36 days), a larger number of infants free of neonatal complications (17 (85%) vs. 10 (52.6%)), and altered sulfur pathways. CONCLUSIONS: In pregnancies at risk for preterm delivery, high-dose N-acetylcysteine failed to restore glutathione levels but was safe. The trend toward prolonged pregnancy and reduced neonatal morbidity would require confirmation in larger trials. IMPACT: High-dose NAC administration is safe in pregnancies at risk of preterm delivery. Antenatal NAC administration did not significantly alter neonatal glutathione concentrations. Antenatal NAC administration was associated with prolonged pregnancy and reduced neonatal morbidity in pregnancies at risk of preterm delivery. Antenatal NAC administration was associated with changes in maternal and neonatal blood metabolomic signatures related to sulfur and nitric-oxide pathways.