Zecca E, Romagnoli C, De Carolis MP, Costa S, Marra R, De Luca D. Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics 2009;124:480-4.
Question
Among preterm infants born at <30 weeks gestational age, does prophylaxis for patent ductus arteriosus (PDA) with ibuprofen increase total serum bilirubin (TSB) levels in the first weeks of life?
Design
Comparison of 2 retrospective cohorts, before and after implementation of standard ibuprofen dosing to prevent PDA.
Setting
Single neonatal intensive care unit in Italy.
Participants
A total of 418 infants < 30 weeks gestation from the study's center between 2000 and 2007 given ibuprofen prophylaxis compared with 288 infants < 30 weeks gestation born in the study's center between 1993 and 1999 not given prophylactic ibuprofen. The 2 groups were similar with respect to gestational age (∼27 weeks), birth weight (∼1000 g), sex, 5-minute Apgar score (∼8), clinical risk index for babies (∼2.3), isoimmunization (∼2%), and G6PDH deficiency (∼2%).
Outcomes
Comparison of the 2 cohorts for the outcomes of peak TSB level, the need for and duration of phototherapy, and the need for exchange transfusion. The unbound (unconjugated) bilirubin levels were mathematically calculated from the TSB levels using a previously published correlation curve.
Main Results
The average peak TSB in the ibuprofen exposed infants was statistically higher than that of the non-exposed infants (9.0 mg/dL vs 7.3 mg/dL, P < .001). 95.2% of the ibuprofen treated infants needed phototherapy compared with 88.2% in the nontreated infants (P < .001, number needed to harm = 15). If needed, the duration of phototherapy was 7 hours longer in the treated infants than the untreated infants (94.3 hours vs 87.2 hours, P = .034). Exchange transfusions were needed by an equivalent percentage in each group (4.5% ibuprofen treated vs 4.8% no-ibuprofen treated, P = .870).
Conclusions
Ibuprofen given to premature infants <30 weeks gestational age raises the peak TSB, makes the need for phototherapy more likely and needed for a longer duration, but has no effect on the need for exchange transfusion.
Commentary
Zecca et al compared 2 cohorts of infants <30 weeks of age before and after their neonatal intensive care unit began a protocol of standard ibuprofen dosing in this age group to prevent PDA. Although the groups seem similar by the characteristics given, because it was not randomized, the 2 groups are likely not similar with regard to other unmeasured or as yet undiscovered factors. This is particularly likely given that the 2 cohorts were in 2 separate decades. Although TSB is a disease-oriented and not a patient-oriented outcome, the authors did measure the need for and duration of phototherapy and need for exchange transfusion as outcomes. Follow-up was far too short to measure the ultimate patient-oriented and clinically relevant outcome of neurodevelopment. A small randomized trial of 46 infants <30 weeks of age by the same group1 showed that those treated for their PDA with ibuprofen had a statistically higher rate as compared with placebo of a closed ductus at 72 hours (87% vs 30%), lower need for backup treatment with indomethacin (13% vs 70%), but the same rate statistically of the need for surgical closure (4% vs 13%). Even though this final difference seems quite large, the study was underpowered to find it statistically significant. Outcomes regarding bilirubin were not reported in this study. This leaves the clinician wondering if a closed ductus at 72 hours is worth the higher chance of needing phototherapy and for a longer period. A single large randomized trial comparing ibuprofen, indomethacin, and placebo in this patient group would help clarify the issue.
Reference
1. 1De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al.Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr. 2000;159:364–368. MEDLINE |
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