Rethinking Acetaminophen in the NICU

A recent phase 3 clinical trial investigated whether giving acetaminophen to extremely premature infants shortly after birth could prevent a potentially dangerous heart condition. While the medication did accelerate closure of the ductus arteriosus, it did not improve overall survival or reduce the incidence of severe health problems in these vulnerable newborns.

Accelerated Closure, No Overall Benefit

The study, known as the TREOCAPA trial, involved 778 preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation, cared for across 43 neonatal intensive care units in 14 European countries. The median gestational age of the infants was 26 weeks, with a median birth weight of 850 g. Infants were randomly assigned to receive either acetaminophen or a placebo for five days.

Did You Know? The trial involved neonatal intensive care units in 14 European countries.

Researchers found that by day 7, 71% of infants receiving acetaminophen had a closed ductus arteriosus, compared to 52% in the placebo group – a 19 percentage point difference. However, at 36 weeks postmenstrual age, survival without severe morbidity was 66% in the acetaminophen group and 64% in the placebo group, a difference of only 3 percentage points.

What is Severe Morbidity?

The study defined severe morbidity as grade 3 bronchopulmonary dysplasia, stage II or III necrotizing enterocolitis, grade III or IV intraventricular hemorrhage, or cystic leukomalacia. No statistically significant differences were observed in the need for ventilatory, hemodynamic, or nutritional support during the first week after birth between the two groups.

Safety Concerns and Future Considerations

The study did reveal a potential safety concern. Cholestasis, a liver condition, occurred more frequently in infants receiving acetaminophen (6%) compared to those receiving the placebo (3%). Severe cholestasis was observed in 1% of the acetaminophen group versus 0.5% of the placebo group.

Expert Insight: The finding that acetaminophen accelerated ductus arteriosus closure without improving overall outcomes suggests that simply closing the ductus may not be the primary goal in managing this condition in extremely premature infants. The observed increase in cholestasis further complicates the risk-benefit assessment of a prophylactic approach.

According to lead study author Jean-Christophe Rozé, MD, of Nantes University Hospital, “Prophylactic treatment for patent ductus arteriosus with acetaminophen should not be recommended in very preterm infants.” He and his colleagues added that the increased risk of cholestasis “argues against a prophylactic strategy that exposes all premature infants to acetaminophen.”

What Might Happen Next

Further research could focus on identifying which infants, if any, might benefit from acetaminophen treatment for patent ductus arteriosus. A more targeted approach, based on individual risk factors, could yield different results. Researchers may also investigate alternative strategies for managing patent ductus arteriosus in preterm infants.

Frequently Asked Questions

What was the primary goal of the TREOCAPA trial?

The primary goal was to determine if prophylactic intravenous acetaminophen, started within 12 hours of birth, could improve survival without severe morbidity in extremely preterm infants.

Did acetaminophen affect the need for additional treatment to close the ductus arteriosus?

Yes, backup treatment to close the ductus was required in 14% of the acetaminophen group compared with 21% of the placebo group.

Were there any differences in outcomes based on gestational age?

Subgroup analyses showed similar results across gestational age groups. Among infants born at 23 to 26 weeks, survival without severe morbidity was 56% with acetaminophen vs 51% with placebo. For those born at 27 to 28 weeks, rates were identical at 77% in both groups.

Given these findings, what role do you think ongoing research will play in refining the care of extremely premature infants?