Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants.

BACKGROUND: The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and may contribute to increased morbidity. Intravenous preparations of ibuprofen constitute one of the standard therapies for closure of a PDA. However, the unavailability of intravenous ibuprofen in certain regions of the world and the availability of inexpensive oral preparations has led to off-label nasogastric administration of oral ibuprofen in preterm infants with PDA.

OBJECTIVE: This article reviews and comments on the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of necrotizing enterocolitis (NEC).

METHODS: MEDLINE, Current Contents, and Google Scholar were searched in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or low-birth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites were also searched for relevant abstracts.

RESULTS: The literature search identified 2 pharmacokinetic studies involving 32 infants and 13 clinical efficacy studies involving 306 infants treated with enteral ibuprofen. The clinical studies reported some benefit for enteral ibuprofen relative to the comparators. However, these studies had methodologic limitations, including small numbers of subjects, lack of blinding, inclusion of preterm infants with a higher gestational age, customized treatment regimens, and second-order statistical error that prevented conduct of a systematic review. When the results of all studies were pooled, NEC was reported in a total of 46 of 281 infants (16%) receiving enteral ibuprofen and 21 of 83 infants (25%) receiving indomethacin. This rate of NEC with enteral ibuprofen was twice that reported for intravenous ibuprofen in a recent meta-analysis (27/356 [8%]).

CONCLUSIONS: The evidence supporting the off-label use of enteral ibuprofen for PDA in preterm infants is weak. Well-designed, appropriately powered pharmacologic and controlled clinical studies are needed before use of enteral ibuprofen can be recommended. In countries where an intravenous formulation of racemic ibuprofen is approved, off-label use of enteral racemic ibuprofen cannot be supported.