Prophylactic treatment closed the ductus arteriosus faster but did not reduce mortality or severe morbidity in extremely premature infants

Prophylactic intravenous acetaminophen started within 12 hours of birth did not improve survival without severe morbidity in extremely preterm infants despite significantly accelerating ductus arteriosus closure, according to a phase 3 randomized clinical trial published in JAMA Pediatrics.

The TREOCAPA trial enrolled 778 preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation across 43 neonatal intensive care units in 14 European countries. The median gestational age was 26 weeks, and the median birth weight was 850 g. Investigators randomized infants to receive either acetaminophen or placebo for 5 days, with dosing adjusted by gestational age. Infants born at 27 to 28 weeks received a 20-mg/kg loading dose followed by 7.5 mg/kg every 6 hours, while those born at 23 to 26 weeks received a 25-mg/kg loading dose followed by 10 mg/kg every 6 hours.

At 36 weeks' postmenstrual age, survival without severe morbidity occurred in 66% of infants in the acetaminophen group compared with 64% in the placebo group, an absolute risk difference of 3 percentage points with a relative risk of 1.04. The severe morbidities measured included grade 3 bronchopulmonary dysplasia, stage II or III necrotizing enterocolitis, grade III or IV intraventricular hemorrhage, and cystic leukomalacia.

Although the primary outcome showed no benefit, acetaminophen demonstrated efficacy for ductus arteriosus closure. By day 7, the ductus was closed in 71% of infants receiving acetaminophen vs 52% receiving placebo, representing an absolute risk difference of 19 percentage points and a relative risk of 1.36. This increased closure rate was observed across all gestational age subgroups and in both male and female infants. Backup treatment to close the ductus was required in 14% of the acetaminophen group compared with 21% of the placebo group.

Despite earlier ductus closure, investigators found no statistically significant differences in ventilatory, hemodynamic, or nutritional support during the first week following birth. The researchers noted this finding "probably explains the negative result of this study."

Subgroup analyses by gestational age and sex yielded similar results. 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.

Safety analysis revealed one notable concern: cholestasis occurred more frequently in infants receiving acetaminophen (6%) compared with placebo (3%), an absolute risk difference of 4 percentage points. Most cases were mild to moderate, though severe cholestasis occurred in 1% of the acetaminophen group vs 0.5% of the placebo group. Transaminase levels and most other adverse events did not differ between groups. Small increases in serum creatinine were observed on days 3 and 5 in the acetaminophen group.

The trial had several strengths, including enrollment across 14 European countries, precise indications for backup treatment that minimized contamination in the control group, and involvement of parent representatives from the design stage. Limitations included the lack of centralized blinded review of echocardiography findings.

"Prophylactic treatment for patent ductus arteriosus with acetaminophen should not be recommended in very preterm infants," wrote lead study author Jean-Christophe Rozé, MD, of Nantes University Hospital, and colleagues , adding that the increase in cholestasis "argues against a prophylactic strategy that exposes all premature infants to acetaminophen."

The study was funded by conect4children through the Innovative Medicines Initiative 2 Joint Undertaking. Each participating institution received financial compensation for enrolled patients. Several researchers reported grants from Inserm, conect4children, or other organizations during the study.

Source: JAMA Pediatrics