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Brain injury caused by intraventricular hemorrhage: is indomethacin the silver bullet for prevention?

After a series of promising but inconclusive reports concerning the role of neonatal administration of indomethacin in prevention of IVH (see earlier discussion), the largest and most recent study (n = 431), reported by Ment et al,4 indicates that indomethacin led to a decrease in incidence and severity of the lesion. The clinically important grade 4 IVH appeared to be nearly eliminated in the indomethacin-treated group. Thus, is it now clear that indomethacin should be administered at 6 to 12 hours of life to all very low birth weight neonates? Although such a recommendation might be appropriate, I have several concerns.
 First, as discussed earlier, experimental studies and observations of human infants indicate that indomethacin is a cerebral vasoconstrictor, leads to a decrease in cerebral blood flow, blunts adaptive vasodilatory responses, and may cause decreases in cerebral oxygen delivery marked enough to impair oxygen utilization. The threat of cerebral ischemia after indomethacin seems real, but notably in the study of Ment et al4 the frequency of ultrasonographic evidence of cerebral ischemic injury was no different in the indomethacin versus the placebo-treated neonates. This reassuring finding must be tempered by the awareness that cranial ultrasonography is somewhat insensitive in the detection of periventricular ischemic injury in the premature infant.41,42
 A second concern relates to factors associated with the study of Ment et al.4 As discussed earlier, the placebo-treated group had an unusual preponderance of grade 4 versus grade 3 IVH, and the relatively large proportion of neonates with onset of IVH before 6 to 11 hours of age were not included in the study. Would earlier administration of indomethacin benefit the neonates with early IVH, or would complications be more prominent?
 A third concern relates to the recent study of the neonatal complications in infants exposed antenatally to indomethacin for treatment of preterm labor.43 Thus, when compared with a matched group of untreated infants, infants exposed to indomethacin before delivery exhibited a higher incidence of IVH (28% vs 9%, P = .02) and of necrotizing enterocolitis (29% vs 8%, P = .005). However, it is quite possible that the adverse effect of antenatal indomethacin on the occurrence of IVH related to the interaction of factors associated with labor and delivery (eg, increases in cerebral venous pressure) and associated with indomethacin (eg, inhibition of platelet aggregation). Such an interaction of factors would not occur with postnatal administration of indomethacin. Nevertheless, the findings of Norton et al43 are arresting in this context.
 Finally, Ment et al4 are to be congratulated for a carefully designed and well-executed study. The data are very promising and indicate the importance of a multicenter study to evaluate the role of indomethacin administered at or very shortly after birth on the subsequent occurrence of IVH and periventricular hemorrhagic infarction.