MANUSCRIPT CITATION

Laughon MM, Thomas SM, Watterberg KL, Kennedy KA, Keszler M, Ambalavanan N, et al. Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial. JAMA 2025. PMID 41364689

REVIEWED BY

Tim Hundscheid, MD PhD and Willem P. de Boode, MD PhD
Radboud university medical center, Amalia Children’s Hospital, Nijmegen, The Netherlands

CORRESPONING AUTHOR

Tim Hundscheid, MD PhD, Pediatrician-neonatologist
Radboud university medical center, Amalia Children’s Hospital, Department of Pediatrics, Division of Neonatology
Internal postal code 804, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
tim.hundscheid@radboudumc.nl Phone: +31 24 3614430

TYPE OF INVESTIGATION

Treatment

QUESTION

In preterm infants born at 22 to 28 weeks’ gestation with a protocol-defined symptomatic patent ductus arteriosus (sPDA) at a postnatal age of 48 hours to 21 days (P), does expectant management (I) compared with active pharmacological treatment with acetaminophen, ibuprofen, or indomethacin (C) reduces the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age (PMA) (O)?

METHODS

Design: multi-centre, randomized controlled superiority trial
Allocation: patients were randomly assigned (1:1) via Neonatal Research Network (NRN) data coordinating center at Research Triangle Institute International to expectant management or active treatment. Siblings from multiple births were randomized separately.
Blinding: unblinded studied since infants were randomized to management approach.
Follow-up period: primary outcome assessment at 36 weeks’ PMA. Secondary outcomes were recorded through 120 days’ postnatal age, unless hospital discharge or transfer occured earlier.
Setting: recruitment was from 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network within the United States of America.
Patients:
Inclusion criteria:
– Preterm infant (gestational age 22 weeks 0 days to 28 weeks 6 days’ gestation)
– At a postnatal age of 48 hours to 21 days
– With a protocol defined sPDA, based on the McNamara Scale, defined as
o Mild, moderate or severe clinical criteria with small or medium size PDA on echocardiogram
o Mild or moderate clinical criteria with large PDA on echocardiogram
Exclusion criteria:
– Cardiopulmonary compromise at time of randomization
– Known congenital heart defect, other than atrial or ventricular septal defect
– Known pulmonary malformation such as congenital lobar emphysema or congenital pulmonary adenomatous malformation
– Received prior treatment for symptomatic patent ductus arteriosus (prophylactic indomethacin was not an exclusion criterion according to the study protocol)
– Any condition which, in the opinion of the investigator, would preclude enrollment

Intervention: For infants in the expectant management group, treatments intended to close the PDA were not administered unless they developed cardiopulmonary compromise or reached 36 weeks’ PMA. For those in the active treatment group, pharmacological treatment with either acetaminophen, indomethacin or ibuprofen was to be initiated within 48 hours after sPDA diagnosis.

Outcomes:
Primary outcome: death or BPD, assessed using a physiological definition, at 36 weeks’ PMA.
Secondary outcomes: key secondary outcomes were components of the primary outcome (death or BPD) and BPD severity according to Jensen criteria.
Analysis and Sample Size: analysis was intention-to-treat with a sample size of 482 patients.
Patient follow-up: 99.8 % included in the intention-to-treat analysis, due to withdrawal of parental consent to use data for one infant in the expectant management group.

MAIN RESULTS
Between December 11, 2018 and December 20, 2024, 482 infants (242 expectant management, 240 pharmacological treatment) were enrolled. Median gestational age of 25 [IQR 24-27] weeks and birth weight of 760 [IQR 620-935] gram. At 36 weeks’ PMA, there was no difference in the composite outcome of death or BPD (195 of 241 (80.9%) versus 191 of 240 (79.6%); adjusted risk difference (aRD) 1.2% [95% CI -5.7% to 8.1%]). There was no difference in BPD (185 of 231 infants (80.1%) versus 168 of 217 (77.4%); aRD 2.2 [95% CI -5.2% to 9.6%]) or moderate-to-severe BPD (135 of 222 (60.8%) versus 129 of 211 (61.1%); aRD 0.3 [95% CI -8.3% to 8.9%]). Mortality was significantly lower in the expectant management group (10 of 241 (4.1%) versus 23 of 240 (9.6%); absolute risk difference -5.6% [95% CI -10.0% to -1.2%]. Adverse events and other secondary outcomes were similar, apart from a lower incidence of infections resulting in death in the expectant management group (2 of 241 (0.8%) versus 9 of 240 (3.8%)

CONCLUSION

In preterm infants born at a gestational age of 22+0 to 28+6 weeks with a protocol-defined sPDA at the postnatal age of 48 hours to 21 days the composite outcome of death or BPD did not differ after expectant management as compared to pharmacological treatment. Survival was significantly higher in those randomized to expectant management.

COMMENTARY

The trial by Laughon et al. echoes the findings of two recent trials,(1, 2) in which relevant neonatal morbidities were also not positively influenced after pharmacological treatment for PDA. Apart from the lack of benefit, these findings add to the growing concerns on potential harm of pharmacological treatment with prostaglandin synthesis inhibitors, especially for an increased risk of death.(3)

These previous trials focused on early, at 24 to 72 hours postnatal age, pharmacological treatment specifically with ibuprofen. The current trial has both a longer time frame of enrollment and pharmacological treatment with the choice of treatment, dose and route of administration at the discretion of the clinical team. The administration of ibuprofen (35.4%), indomethacin (28.8%), acetaminophen (25.8%) or more than one of these medications (9.2%) in the active pharmacological treatment group reflects the clinical heterogeneity in neonatal care.(4) One major strength of this pragmatic approach is that the findings of the trial are potentially more generalizable. Nevertheless, since prophylactic indomethacin was used in 9 of 33 recruiting centers during the trial period, it would be interesting to subgroup centers that did and did not use prophylactic indomethacin.

Enrolling patients in PDA trials is challenging, as supported by the flowchart in Figure 1. Nevertheless, the trial succeeded in enrolling a substantial amount of the most immature infants, i.e. those with a gestational age below 26 weeks, often underrepresented in trials. Regarding hemodynamic significance of the PDA, this trial, in comparison to PDA diameter based inclusion in the BeNeDuctus and Baby-OSCAR trial,(1, 2) used a protocol based definition of a symptomatic PDA.(5) Although helpful in better categorizing patients, the validity of this staging, in comparison to the PDA severity score, is questionable.(6) Whereas a PDA severity score based categorization might be the most sophisticated method to select the high-risk babies for PDA treatment, i.e. those most likely to benefit from effective treatment, it requires echocardiographic expertise hampering the generalizability.

Another limitation of PDA trials is the inefficacy of pharmacological closure in a rather large proportion of infants. PDA closure rates are not reported in this study. Although clinical outcomes are far more relevant than achieving PDA closure per se, this information would be interesting. Moreover, since findings from the pilot PDA-RCT, albeit limited in sample size, suggests that those with successful closure of their PDA have lower risk for death or BPD at 36 weeks’ PMA.(7)

The PDA RCT by Laughon et al. further supports the current guideline from the American Association of Pediatrics to refrain from routine treatment of a PDA within the first two weeks of life.(8) Alongside the growing evidence from numerous RCTs on PDA management there is also growing adherence to an interventional closure strategy, which is more effective than pharmacological treatment in closing the PDA and causes less morbidity than surgical ligation.(9) However, prior to the widespread use of this therapeutic intervention, a trial that proves overall benefit of this successful closure strategy as compared to a truly expectant management is of the utmost importance.

REFERENCES

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