The Journal of Pediatrics
Volume 148, Issue 6 , Pages 713-714, June 2006

Treatment to prevent patency of the ductus arteriosus: Beneficial or harmful?

  • Carl L. Bose, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Carl Bose, Division of Neonatal-Perinatal Medicine, CB #7596, 4th Floor UNC Hospitals, Chapel Hill, North Carolina 27599-7596
    • ,
  • Matthew Laughon, MD, MPH

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7596

Article Outline

 

Despite the strong association between the presence of a patent ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD), treatments that successfully close a PDA have not resulted in a reduction in the incidence of BPD. This apparent paradox has been observed with both of the cyclo-oxygenase (COX) inhibitors used to treat the PDA, indomethacin and ibuprofen. Treatments given either prophylactically, to promote early closure of the PDA, or for persistent patency of the ductus arteriosus have not decreased BPD. In the largest study to date of the use of prophylactic indomethacin, the Trial of Indomethacin Prophylaxis in Preterms (the TIPP Trial), Schmidt et al demonstrated this disconnect between successful prevention of persistent patency of the ductus arteriosus and a reduction in BPD.1 Despite ∼ 50% reduction in the incidence of PDA in infants treated with prophylactic indomethacin, the incidence of BPD among treated infants and those in a placebo group was virtually identical.

See related article, p 730

There are three possible explanations for the apparent lack of benefit of COX inhibitors in reducing BPD:

(1)Prophylactic treatment with COX inhibitors is effective in preventing BPD, but studies have not been designed to demonstrate this benefit. For decades, clinicians and investigators assumed that the short-term benefit of closing the ductus arteriosus would translate into a long-term benefit (eg, reduction in BPD) and designed studies to determine the most efficacious technique for closing the ductus. No study in the modern era has actually tested the hypothesis that PDA closure reduces BPD. All of these studies permitted treatment of infants in the placebo groups. Because of this crossover or “contamination” of the placebo group, one cannot draw conclusions about clinically meaningful benefits, such as a reduction in BPD, or risks of this therapy.

(2)Closure of the PDA reduces the likelihood of BPD, but the adverse effects of COX inhibitors balance the beneficial effects of closure of the PDA to the extent that no net benefit results. In this issue of The Journal, Schmidt et al investigate this possibility in the cohort of infants enrolled in the TIPP Trial who had survived to 36 weeks postmenstrual age.2 In this trial, infants were randomized to receive either indomethacin or placebo with the first dose administered within 12 hours of birth. The incidence of BPD among infants with a PDA in the treatment and placebo groups was similar (52 vs 56%). Among infants without a PDA, however, 43% of those in the treatment group developed BPD compared to only 30% in the placebo group. The authors explore the possibility that adverse effects associated with indomethacin may have accounted for the excess of BPD in the indomethacin-exposed infants who did not have a PDA. After adjustment for a number of infant characteristics that increased the risk of BPD, two factors associated with indomethacin treatment were found to increase risk: decreased urine output (and subsequent decreased weight loss) and increased exposure to oxygen in the first week of life.

Decreased urine output is a recognized side effect of COX inhibitors, and diminished early postnatal weight loss is an expected consequence if appropriate adjustments in free water intake are not made. The inverse relationship between early weight loss and BPD was reported some years ago3 and confirmed in a recent study.4 The hypothetical explanation for this association, and presented by the authors of the latter paper, is that excessive extracellular fluid in the presence of ductal shunting results in increased pulmonary interstitial fluid, leading to the need for increased respiratory support and lung injury. The net result would be an increased likelihood of developing BPD.

Schmidt et al provide an additional explanation. They demonstrate that increased oxygen exposure associated with indomethacin treatment increased the risk for BPD independently of the effect of decreased weight loss. This association may be explained on the basis of a direct toxic effect of indomethacin on the lung. Schmidt et al. refer to several studies in which evidence of toxicity is presented. We would add to these the provocative study of Lukkarinen et al, who demonstrated that COX-2 inhibition increases migration of neutrophils to the lungs in an animal model of surfactant deficiency.5 COX inhibition may be as bad for the lungs as closure of the ductus arteriosus is beneficial.

(3)The relationship between PDA and the development of BPD is not one of cause and effect. The presence of a PDA is merely a marker of inherent risk. Data from Schmidt’s study support this possibility. For example, one can assume that among infants in the indomethacin group who had no PDA, a proportion would have had a PDA in the absence of prophylactic treatment. If the presence of a PDA identifies infants with inherent risk for BPD, and this risk is not altered by closure of the PDA, a portion of infants in the indomethacin group who had no PDA would remain at risk for PBD. The indomethacin group would therefore include “low-risk” infants identified by the absence of a PDA that would have closed spontaneously as well as “high-risk” infants whose duct closed by virtue of indomethacin treatment. The placebo group would include only low-risk infants. Under these circumstances, a higher incidence of BPD among infants without PDA who have been treated prophylactically with indomethacin would be expected.

Of these three possibilities, only the first holds any prospect that prophylactic indomethacin reduces the likelihood of BPD. The other two suggest that this therapy is either of no benefit or is harmful.

For clinicians, there is still the dilemma of what to do in the absence of evidence of benefit and a clear delineation of risk. Fortunately, this dilemma is limited to the care of extremely low gestational age newborns. There is little or no justification for using COX inhibitors for preventing the persistence of ductal patency in more mature infants. Risk of developing BPD is low, and spontaneous closure of the duct is common.6 Unfortunately, the opposite is true in the least mature infants.7 If one finds the reduction in serious intraventricular hemorrhage (IVH), even without certainty of long-term benefit (see TIPP Trial), a sufficient justification for prophylactic use, then selective use in populations in which the rate of IVH is high may be reasonable. However, there appears to be little support for the prophylactic use of COX inhibitors to prevent BPD. In addition, data to support their use for the treatment of either asymptomatic8 or symptomatic PDA9 to prevent BPD is equally discouraging, as are data to support benefit in terms of reduction of other morbidities. Clinicians who believe that biologic plausibility or a beneficial short-term outcome (eg, ductal closure) are sufficient justification for the use of COX inhibitors need only be reminded of other apparently beneficial therapies that proved to be harmful.10

As suggested by Schmidt et al, the uncertainty about the benefits and risks of the use of COX inhibitors can only be resolved by performing randomized, controlled trials, and these trials should include a placebo group in which treatment of a PDA is offered to infants in very limited circumstances only. Given the lack of evidence of benefit and the potential for harm, such studies are not only ethical but essential to permit the practice of informed, evidence-based medicine.

Back to Article Outline

References 

  1. Schmidt B , Davis P , Moddemann D , Ohlsson A , Roberts RS , Saigal S , et al.   Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants . N Engl J Med . 2001;344:1966–1972
  2. Schmidt B , Roberts RS , Fanaroff A , Davis P , Kirpalami HM , Nwaesei C , et al.   Indomethacin prophylaxis, patent ductus arteriosus and the risk of bronchopulmonary dysplasia . J Pediatr . 2006;148:730–734
  3. Marshall DD , Kotelchuck M , Young TE , Bose CL , Kruyer L , O’Shea TM  North Carolina Neonatologists Association . Risk factors for chronic lung disease in the surfactant era (a North Carolina population-based study of very low birth weight infants) . Pediatrics . 1999;104:1345–1350
  4. Oh W , Poindexter BB , Perritt R , Lemons JA , Bauer CR , Ehrenkranz RA , et al.   Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants . J Pediatr . 2005;147:786–790
  5. Lukkarinen H , Laine J , Aho H , Asikainen E , Penttinen P , Kaapa P . Inhibition of COX-2 aggravates neutrophil migration and pneumocyte apoptosis in surfactant-depleted rat lungs . Pediatr Res . 2006;59:412–417
  6. Van Overmeire B , Van de Broek H , Van Laer P , Weyler J , Vanhaesebrouck P . Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome . J Pediatr . 2001;138:205–211
  7. Narayanan M , Cooper B , Weiss H , Clyman RI . Prophylactic indomethacin (factors determining permanent ductus arteriosus closure) . J Pediatr . 2000;136:330–337
  8. Cooke L , Steer P , Woodgate P . Indomethacin for asymptomatic patent ductus arteriosus in preterm infants . Cochrane Database Syst Rev . 2003; CD003745
  9. Knight DB . The treatment of patent ductus arteriosus in preterm infants. A review and overview of randomized trials . Semin Neonatol . 2001;6:63–73
  10. Silverman W . Retrolental fibroplasia (a modern parable) . New York: Grune & Stratton, Inc; 1980;

PII: S0022-3476(06)00199-5

doi:10.1016/j.jpeds.2006.03.015

Refers to article:

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

    Barbara Schmidt, Robin S. Roberts, Avroy Fanaroff, Peter Davis, Haresh M. Kirpalani, Chuks Nwaesei, Michael Vincer, TIPP Investigators
    The Journal of Pediatrics June 2006 (Vol. 148, Issue 6, Pages 730-734.e1)

The Journal of Pediatrics
Volume 148, Issue 6 , Pages 713-714, June 2006

Article Tools