Original article
Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: Further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

https://doi.org/10.1016/j.jpeds.2006.01.047Get rights and content

Objectives

To determine the risk of bronchopulmonary dysplasia (BPD) in subgroups of infants with and without patent ductus arteriosus (PDA) who were randomized to indomethacin prophylaxis or placebo, and to examine whether adverse drug effects on edema formation and oxygenation may explain why indomethacin prophylaxis does not reduce BPD.

Study design

We studied 999 extremely low birth weight infants who participated in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) and who survived to a postmenstrual age of 36 weeks.

Results

The incidence of BPD in the 2 subgroups of infants with PDA was 52% (55/105) after indomethacin prophylaxis and 56% (137/246) after placebo. In contrast, rates of BPD in the 2 subgroups without a PDA were 43% (170/391) after indomethacin prophylaxis and 30% (78/257) after placebo (P [interaction] = .015). Logistic regression analysis with adjustment for prognostic baseline factors showed that adverse and independent effects of indomethacin prophylaxis on the need for supplemental oxygen and on weight loss by the end of the first week of life may increase the risk of BPD in infants without PDA.

Conclusions

Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent BPD even though it reduces PDA.

Section snippets

Study Population

Infants with birth weights ranging from 500 to 999 g were enrolled in the international TIPP study between January 1996 and March 1998.1 The research ethics boards of all clinical centers in Canada, the United States, Australia, New Zealand, and Hong Kong approved the trial protocol, and written informed consent was obtained from a parent or guardian of each infant. Because infants who died before a postmenstrual age 36 weeks could not develop BPD as defined by the TIPP study protocol, only

Study Cohort

In the indomethacin prophylaxis group, 103 of 601 infants (17%) died before postmenstrual age 36 weeks, compared with 96 of 601 infants (16%) in the placebo group. Of the 1003 survivors who were eligible for the current study, 4 children (2 in each treatment group) had missing BPD data. This left 999 infants in our analysis cohort, of whom 496 were assigned to prophylactic indomethacin and 503 to placebo.

Supplemental Oxygen and Urine Volumes After Indomethacin Prophylaxis and Placebo

Figure 1 shows that indomethacin prophylaxis significantly increased the need for

Discussion

Further analysis of the TIPP database reveals that indomethacin prophylaxis increased the need for supplemental oxygen from day 3 to at least day 7 of life. Indomethacin prophylaxis also decreased urine volumes during the first 4 days of life and reduced weight loss by the end of the first week. We explored whether one or both of these harmful drug effects may explain why indomethacin prophylaxis does not alter the incidence of BPD, despite reducing the incidence of PDA. We began this

Cited by (0)

Funded by the Medical Research Council of Canada (grant MT-13288). The US centers were supported in part by NICHD (grants U10 HD21364, U10 HD27851, U10 HD21373, U10 HD27881; M01 RR 00997, U10 HD27880; M01 RR 00070, U10 HD21385, U10 HD27904, and U10 HD34216). The INDOCID PDA was donated by Merck Frosst.

A list of TIPP investigators is available at www.jpeds.com.

View full text