Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial

Abstract

Importance: The management of patent ductus arteriosus (PDA) in preterm infants is controversial.

Objective: To determine whether expectant management compared with active treatment of a protocol-defined PDA in preterm infants decreases the incidence of death or bronchopulmonary dysplasia (BPD).

Design, setting, and participants: A randomized clinical trial including infants born at 22 to 28 weeks' gestation and diagnosed with a protocol-defined PDA between the age of 48 hours and 21 days at screening. The trial was conducted from December 2018 to December 2024 at 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. The final date of follow-up was June 2025.

Interventions: Infants with PDA were randomized to expectant management (n = 242) or active treatment (n = 240; acetaminophen, ibuprofen, or indomethacin) to close the PDA.

Main outcomes and measures: The primary outcome was death or BPD at 36 weeks' postmenstrual age. The secondary outcomes included the components of the primary outcome and other morbidities of prematurity.

Results: A total of 482 infants were randomized (median gestational age, 25 weeks [IQR, 24 to 27 weeks]; median birth weight, 760 g [IQR, 620 to 935 g]). The trial was stopped for futility and safety after the 50% interim analysis for the primary outcome due to higher survival in the expectant management group. The incidence of death or BPD was 80.9% (195/241) of infants in the expectant management group vs 79.6% (191/240) of infants in the active treatment group (adjusted risk difference, 1.2% [95% CI, -5.7% to 8.1%]; P = .73). The incidence of death before 36 weeks' postmenstrual age was 4.1% (10/241) of infants in the expectant management group vs 9.6% (23/240) of infants in the active treatment group (adjusted risk difference, -5.6% [95% CI, -10.1% to -1.2%]; P = .01). Infections resulting in death occurred in 0.8% (2/241) of infants in the expectant management group vs 3.8% (9/240) of infants in the active treatment group.

Conclusions and relevance: In extremely preterm infants with a protocol-defined PDA, death or BPD did not differ between the expectant management group and the active treatment group. Survival was substantially higher with expectant management.

Trial registration: ClinicalTrials.gov Identifier: NCT03456336.

Figure 1.. Flow Diagram of Preterm Infants With Patent Ductus Arteriosus (PDA)

^aMay have met more than 1 criterion. ^bRequired steroid treatment or had kidney insufficiency, low platelet count, active bleeding, or necrotizing enterocolitis. ^cCommonly specified reasons include infant already treated, physician preference to treat, language or communication barrier with parent, parent not willing or interested in participating in any research study, and infections or other clinical conditions. ^dOne infant was later found to be ineligible due to cardiopulmonary compromise at time of screening. This infant is included in all analyses. ^eStratified by Neonatal Research Network center and gestational age strata (22–25 weeks’ and 26–28 weeks’ gestation). ^fInfants in the expectant management group received treatment only after cardiopulmonary compromise (received acetaminophen, ibuprofen, or indomethacin; underwent cardiac catheterization or surgical ligation; or continued expected management). Infants in the active treatment group received pharmacological treatment within 48 hours of diagnosis (received acetaminophen, ibuprofen, or indomethacin). ^gThe data for this infant were excluded from all analyses. ^hDid not receive treatment. The data for this infant were included in all analyses. ⁱIncludes all randomized infants with parental consent. In the expectant management group, 8 infants were still in the hospital at 120 days; 1 infant died in the hospital and 5 infants were alive and still in the hospital at 1 year; and 2 infants had not reached 1-year follow-up. In the active treatment group, 10 infants were still in the hospital at 120 days; 6 infants were alive and still in the hospital at 1 year; 2 infants had been discharged or transferred to another facility; and 2 infants had not reached 1-year follow-up.

Figure 2.. Secondary Outcomes of Death by 36 Weeks’ Postmenstrual Age and Severity Grades for Bronchopulmonary Dysplasia (BPD)

A, The median observation time was 60 days (IQR, 50–70 days). The P value was calculated using an unadjusted Kaplan-Meier log-rank test. B, The severity of BPD was based on the Jensen et al definition.