Prophylactic Acetaminophen Did Not Improve PDA Outcomes

Key Takeaways

• Prophylactic acetaminophen was not associated with a higher rate of survival without severe morbidity at 36 weeks' postmenstrual age than placebo.
• Day-7 ductus arteriosus closure was more frequent with acetaminophen in the exploratory analysis.
• Cholestasis was more common with acetaminophen, while other adverse events were otherwise similar between groups.

In very preterm infants treated within 12 hours of birth, prophylactic intravenous acetaminophen increased day-7 ductus arteriosus closure to 71.2% versus 52.2% with placebo. Survival without severe neonatal morbidity at 36 weeks' postmenstrual age was 66.2% with acetaminophen and 63.6% with placebo, with no significant improvement. Earlier ductal closure was not accompanied by better survival without severe morbidity by 36 weeks' postmenstrual age.

A double-blind, randomized, placebo-controlled JAMA Pediatrics trial enrolled 778 infants born at 23 weeks 0 days to 28 weeks 6 days. Enrollment ran from October 2020 to April 2024 across 43 neonatal intensive care units in 14 European countries, with 391 infants assigned to acetaminophen and 387 to placebo. Median gestational age was 26 weeks, the interquartile range was 25 to 27 weeks, 48.2% of infants were female, and data analysis ran from January to June 2025. Placebo was isotonic sodium chloride. In infants at 27 to 28 weeks, prophylaxis started within 12 hours with a 20 mg/kg loading dose followed by 7.5 mg/kg every 6 hours for 5 days. In those at 23 to 26 weeks, a 25 mg/kg loading dose followed by 10 mg/kg every 6 hours for 5 days was used; endpoints were survival without severe neonatal morbidity at 36 weeks' postmenstrual age and day-7 echocardiographic closure.

For the primary endpoint, survival without severe morbidities at 36 weeks' postmenstrual age occurred in 259 of 391 infants (66.2%) given acetaminophen and 246 of 387 (63.6%) given placebo. The absolute risk difference was 2.7 percentage points, with a 95% CI from -4.0 to 9.3. The relative risk was 1.04, with a 95% CI from 0.94 to 1.16, indicating no significant increase in survival without severe morbidity. Both confidence intervals were compatible with no clear advantage for acetaminophen over placebo in the primary analysis. The authors concluded that prophylactic acetaminophen did not increase survival without neonatal morbidities in this very preterm population.

As an exploratory outcome, echocardiography showed day-7 ductus arteriosus closure in 264 of 371 infants (71.2%) with acetaminophen and 191 of 366 (52.2%) with placebo. The absolute risk difference was 19.0 percentage points and the relative risk was 1.36, with 95% CIs of 12.0 to 25.7 and 1.21 to 1.53. In safety analyses, cholestasis occurred in 25 of 392 infants (6.4%) given acetaminophen and 10 of 386 (2.6%) given placebo. The cholestasis absolute risk difference was 3.8 percentage points, with a 95% CI from 0.9 to 6.9, and other adverse events were otherwise similar. Acetaminophen was associated with more early ductal closure and more cholestasis, without a corresponding improvement in the primary clinical outcome.