Extremely premature babies: paracetamol helps the hearts of the most fragile, but does not change their overall prognosis

A major clinical issue in neonatology

Every year in Europe, tens of thousands of children are born extremely premature (between 23 and 28 weeks of pregnancy, weighing 400 to 1200g). In these extremely fragile newborns, the canal arterial, a small blood vessel in the heart essential during fetal life, may remain open after birth. This situation, known as persistent ductus arteriosus, is common in the most immature and often leads to cardiac, respiratory, digestive and neurological complications. Although treatments exist, they expose these infants to side effects, particularly at renal and digestive levels. This is why paracetamol, already used in neonatology to treat pain, has emerged in recent years as a potentially better-tolerated alternative. It was to scientifically validate this lead that the TREOCAPA study was set up on an international scale.

TREOCAPA: a large-scale European study

Coordinated by Pr Jean-Christophe Rozé, a member of the PedStart network and professor emeritus at Nantes University, the TREOCAPA, Inserm-promoted trial, followed 778 infants(403 boys and 375 girls),born very prematurely between 23 and 28 weeks' gestation in 43 neonatal intensive care units in 14 European countries. From the first hours of life, newborns received either paracetamol infusion for five days, or a placebo. The study delivers major results for the management of newborns:

• the trial shows that paracetamol promotes closure of the ductus arteriosus even in the most immature,
• but has little impact on overall prognosis: at 36 weeks, morbidity-free survival concerned 66.2% of babies treated with paracetamol, versus 63.6% in the placebo group, but the difference was not significant.

No benefit for the most mature babies, born between 27 and 28 weeks' gestation.

This study shows that there is no benefit to early closure of the ductus arteriosus in these premature babies putting an end to a debate on the management of ductus arteriosus: to treat or not to treat.

A trend towards a benefit for the most immature babies and for girls

The study shows, for babies born between 23 and 26 weeks treated with paracetamol, a 5% improvement in morbidity-free survival in boys, compared with 8% in girls. While this result does not reach statistical significance, it raises important questions about biological differences between girls and boys from the very first days of life, and about the possibility of personalized therapeutic approaches.

A globally reassuring safety profile, with a signal to be explored

Paracetamol appears globally safe in this indication. Nevertheless, the study highlights a higher number of cases of cholestasis, a liver disorder that can lead to jaundice, in treated infants. These events were mostly non-serious, but require further investigation and serve as a reminder of the importance of careful monitoring.

Notably, 60% of the families approached agreed to take part in the trial, an exceptional rate in such a sensitive context. European parents' representatives, notably via the Global Foundation for the Care of Newborn Infants (GFCNI), were involved right from the design stage of the protocol. This collaboration helped reinforce the acceptability and methodological quality of the project.

Beyond its clinical results, TREOCAPA illustrates the ability of structured research networks to conduct international academic trials in extremely vulnerable populations. The involvement of the PedStart national pediatric clinical research network was decisive in obtaining European funding under the conect4children (C4C) program, dedicated to pediatric drug research in Europe, coordinating the trial and involving the pediatric clinical investigation centers and teams that took part in the trial in France and Europe.