5 Prevention and 18-Month Outcome of Serious Pulmonary Hemorrhage in Extremely-Low-Birth-Weight (ELBW) Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

Serious pulmonary hemorrhage (PH) that requires increased respiratory support or transfusion of blood products is associated with significant acute morbidity and mortality in ELBW infants. Long-term outcome is less certain. A patent ductus arteriosus (PDA) is a risk factor for PH. However, despite halving the incidence of PDA, indomethacin prophylaxis (Indo P) did not reduce the overall rate of PH in the TIPP study (N Engl J Med 2001;344:1966). We speculated that a beneficial effect of Indo P on PH may have been masked by the inclusion of mild cases.

Using the TIPP database of 1202 ELBW infants, we examined the effect of Indo P on the cumulative risk of serious PH, the role of PDA as a cause of PH and the 18-month outcome of serious PH.

The cumulative risk of serious PH was estimated for the first week of life, and for the entire NICU stay (Kaplan-Meier). Cox models examined how much of the Indo P effect on PH was explained by a reduced risk of PDA. Poor outcome at 18 months was defined as death or survival with cerebral palsy, cognitive delay, blindness, or deafness.

Indo P reduced the cumulative risk of PH during week 1 by 35% (95% CI 0.04 to 0.57; p=0.033). There was less benefit of Indo P on the cumulative risk of PH during the entire NICU stay: RRR 23% (95% CI −0.10 to 0.46; p=0.153). A reduced risk of PDA explained over 80% of the Indo P effect on PH. Of the 574 infants in the Indo P group with data on the 18-month outcome, 53 had serious PH and 40 (75.5%) died or survived with impairment. Of the 569 infants in the placebo group, 69 had serious PH and 52 (75.4%) had a poor outcome. Among infants without PH, 231/521 (44.3%) had a poor outcome after Indo P as compared with 209/500 (41.8%) after placebo.

ELBW infants with serious PH have an increased risk of death or impairment at 18 months. Indo P reduces early serious PH, mainly through its action on PDA. However, any benefit derived from preventing a serious PH in a very small minority of ELBW infants is offset by the apparent small adverse effect of Indo P on the long-term outcome of the majority of ELBW infants who do not develop serious PH.