Persistent patent ductus arteriosus (PDA) is a problem after birth for very tiny or preterm infants, many of whom require either medical or surgical intervention to close the ductus in the newborn period. Indomethacin is often successful in closing the ductus when used therapeutically, but is associated with many short-term side effects. Before this trial, prophylactic use of indomethacin was known to reduce the frequency of symptomatic PDA and severe cerebroventricular haemorrhage (CVH) in these babies.1 Reducing severe CVH might be expected to improve long-term neurological outcome. However, the mechanism for reducing severe CVH may be diminishing cerebral blood flow, which in turn may cause long-term neurological problems. Therefore, whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in cerebral blood flow, as well as reduced blood flow to other organs, is not certain.

Infants were stratified by birthweight (< 750 g or ≥ 750 g) and individual study centre. This stratification was sensible, as the rate of the major adverse outcomes in the study was much higher in those of < 750 g birthweight (62% [298/481]) than in those of birthweight ≥ 750 g (35% [234/662]), and was bound to differ between individual centres (although individual centre data were not reported).

Most infants (86%) received their allocated treatment within 6 hours of birth, and most (81%) received all three doses; there were no differences in drug administration (compliance) between the treatment groups. Other aspects of care followed an individual unit's protocol.

Blinding was achieved by having a placebo that looked identical to the indomethacin. Although unblinding was theoretically possible through observing urine output, only 7% in the indomethacin group and 4% in the placebo group had treatment withdrawn because of oliguria.

Significantly more babies in the placebo group (46%) subsequently received open-label indomethacin to treat a PDA than did babies in the treated group (17%). The follow-up rates to 18 months corrected age were very high (95%) in each group, which is important methodologically, as babies who are difficult to follow-up have more adverse outcomes than those who are followed up more easily.2 All analyses were by intention to treat.

In infants of extremely low birthweight, prophylaxis with indomethacin did not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of PDA and severe CVH. Before this study, it would have been assumed that because prophylactic indomethacin reduces severe CVH, it should improve long-term outcome. This study highlights the problem of relying on changes in surrogate (or intermediate) endpoints, or in risk factors, to determine the effectiveness of therapies. For any therapy to be introduced into clinical practice, the endpoints in trials must be clinically meaningful.