MANUSCRIPT CITATION
Rozé JC, Cambonie G, Flamant C, Patkai J, Mühlbacher T, Gascoin G, et al. Prophylactic Treatment of Patent Ductus Arteriosus with Acetaminophen, A Randomized Clinical Trial. JAMA Pediatrics; 180(4):374-383. PMID 41697673
REVIEWED BY
Megan Lantz, MD*
PGY-1 Pediatrics Resident
Section of Neonatology
Department of Pediatrics
Children’s Hospital Colorado and
University of Colorado School of Medicine
Megan.lantz@cuanschutz.edu
Moira Moore, MD, MPH*
PGY-2 Pediatrics Resident
Section of Neonatology
Department of Pediatrics
Arkansas Children’s Hospital and
University of Arkansas for Medical Sciences
MEMoore@UAMS.edu
Clyde J. Wright, MD
Professor
Section of Neonatology
Department of Pediatrics
Children’s Hospital Colorado and
University of Colorado School of Medicine
Clyde.wright@cuanschutz.edu
Alexandra Woodle, MD
Assistant Professor
Section of Neonatology
Department of Pediatrics
Arkansas Children’s Hospital and
University of Arkansas for Medical Sciences
AGWoodle@uams.edu
*These authors contributed equally to this work.
TYPE OF INVESTIGATION
Randomized Clinical Trial
QUESTION
In neonates 23-28 weeks’ gestation (P), does prophylactic treatment with acetaminophen within 12 hours of birth(I) increase survival without increased morbidity (O) compared to placebo (C) at 36 weeks’ Post Menstrual Age [PMA] (T)?
METHODS
• Design:
o Multicenter, double-blind, randomized, placebo-controlled superiority clinical trial
• Allocation:
o Centralized allocation concealment using eCRF platform respecting blinding and pre-specified stratification criteria
• Blinding:
o Double-blinded treatment number allocation
• Follow-up period:
o 36 weeks’ postmenstrual age or at first discharge home, whichever came first
• Setting:
o Multicenter, 43 neonatal intensive care units across 14 European countries between Oct 2020 and April 2024
• Patients:
o Inclusion: Gestational age at birth 23 weeks 0 days- 28 weeks 6 days, postnatal age of 12 hours or less, written parental consent obtained after birth.
o Exclusion: congenital anomaly, uncured twin-to-twin transfusion syndrome, suspicion of pulmonary hypoplasia, hepatic impairment suspected in cases of hemorrhagic syndrome or severe hypoglycemia, clinical instability and high risk of rapid death, failure to start treatment before 12 hours of life, parents placed under judicial protection, and participation in another clinical trial using acetaminophen, indomethacin, ibuprofen during the first few days after birth
• Intervention:
o Infants were randomized to the acetaminophen or placebo groups. in the acetaminophen group, treatment with optimal dose of acetaminophen based on gestational age (established in previous studies) started within 12 hours of birth with loading dose, followed by continued treatment every 6 hours for 5 days. For infants 23-26 weeks’ gestation, the loading dose was 25 mg/kg, with the following doses being 10 mg/kg. For infants 27-28 weeks’ gestation, the loading dose was 20 mg/kg with the following doses being 7.5 mg/kg. In the placebo group, patients received isotonic normal saline in a polyethylene ampoule identical in appearance to the acetaminophen ampoule.
• Outcomes:
o Primary outcome: Survival without severe morbidity at 36 weeks’ PMA or first discharge home. Severe morbidities included severe bronchopulmonary dysplasia (grade 3 per NIH 2018 consensus), necrotizing enterocolitis [NEC] (bell stage II or III), Interventricular Hemorrhage [IVH] (grade III or IV via papile classification), or cystic leukomalacia
o Secondary outcomes: Rates of patients with closed patent ductus arteriosus [PDA], rates of patients receiving backup treatment for PDA
• Analysis and Sample Size:
o 794 patients were needed to detect a 10% difference in percentages of survival without severe morbidity between the two arms.
o Authors used a modified intention-to-treat analysis including all randomized infants, excluding ineligible patients who were randomized by error (infants with congenital abnormality, infants unable to receive acetaminophen before 12 hours of life, infants whose parents withdrew from the study before the primary outcome). Patients were stratified into pre-defined subgroups (23-26 weeks’ gestation, 27-28 weeks gestation, sex) for analysis.
• Patient follow-up:
o Parents of 1352 preterm infants were informed of the study, 803 had written consent, 791 were randomized, and 778 were ultimately included in analysis (98.4% of patients randomized).
MAIN RESULTS
Demographics:
Median gestational age was 26 weeks, and median birth weight was 850 g. 48.2% of infants were female and 51.8% of infants were male. 51.4% were born between 23 and 26 weeks, and 48.6% were born from 27-28 weeks. It was reported that baseline characteristics were balanced between acetaminophen and placebo groups in each subgroup.
Primary outcomes:
Survival without severe morbidity
Acetaminophen group 259/391 (66.2%)
Placebo group 246/387 (63.6%)
Absolute Risk Difference [ARD] 2.7 (95% CI –4.0-9.3)
Relative Risk [RR] 1.04 (95% CI 0.94-1.16)
Secondary outcomes:
Ductus arteriosus closure
Acetaminophen group 264/371 (71.2%)
Placebo group 191/366 (52.2%)
Absolute Risk Difference [ARD] 19.0 (95% CI 12.0-25.7)
Relative Risk [RR] 1.36 (95% CI 1.21-1.53)
Backup treatment needed to close ductus arteriosus
Acetaminophen group 56/387 (14.3%)
Placebo group 82/387 (21.2%)
Absolute Risk Difference [ARD] 6.9 (95% CI 1.5-12.2)
Relative Risk [RR] 0.68 (95% CI 0.50-0.92)
No statistically significant differences in ventilatory, hemodynamic, or nutritional support were reported between the two groups, despite earlier closure of the ductus arteriosus.
Differences in liver enzymes and electrolytes were not observed between the two groups, and adverse events were reported to not have significant differences in rates with the exception of cholestasis.
Cholestasis
Acetaminophen group 25/392 (6.4%)
Placebo group 10/386 (2.6%)
Absolute Risk Difference [ARD] 3.8 (95% CI 0.9-6.9)
Relative Risk [RR] 2.46 (95% CI 1.20-5.41)
Results were reportedly similar in all pre-defined subgroups.
CONCLUSION
In neonates, 23-28 weeks’ gestation, prophylactic treatment with acetaminophen within 12 hours of birth did not increase survival without increased morbidity compared to placebo at 36 weeks PMA despite a statistically significant increase in closure of ductus arteriosus. There was a statistically significant increase in cholestasis, though it was rare in both groups and most of the investigators considered the adverse event not to be related to the investigational product. There was overall found to be a reassuring safety profile, though the authors suggest that the cholestasis could suggest some liver damage, arguing against a prophylactic strategy. There was a slight non-significant increase in survival without morbidity in the 23-26 weeks’ gestation, with authors suggesting further studies with lower expected effects. Limitations of this study included that cardiac ultrasonography at day 7 of life, when it was defined if the ductus arteriosus was closed, was not centrally blinded.
COMMENTARY
Rozé et al conducted a randomized control trial (RCT) investigating prophylactic treatment of the patent ductus arteriosus (PDA) with acetaminophen (1). While previous studies have shown Non-steroidal Anti-inflammatory Drug (NSAID) prophylaxis does not improve survival without significant morbidity, this study utilized acetaminophen, hypothesized to offer a more favorable side effect profile compared to NSAIDs.(2, 3)
This large, multicenter study of 778 infants provided sufficient power to detect a 10% difference in the primary outcome of survival without severe morbidity. Although there was no significant difference between groups in the primary outcome, 73.4% of the patients had a closed or closing PDA at 7 days of life in the placebo group. The high rate of spontaneous resolution of any hemodynamically significant duct potentially dilutes any beneficial treatment effect. Determining whether subgroups at high risk for sustained ductal patency and related complications may benefit from prophylaxis remains an important area for future research.
With that in mind, a strength of this study was the inclusion of a large number of 23-26 week gestational age (GA) infants. This group, comprising ~50% of the subjects, has not been well-represented in prior studies, and is less likely to experience spontaneous PDA closure and thus may experience greater benefit with prophylactic treatment. While a non-significant trend for improved survival without significant morbidity was noted in this subgroup, further investigation is needed to confirm this finding. Although the authors reported no differences in ventilatory, hemodynamic, or nutritional support between treatment arms during the first week of life, these differences were not reported by subgroup and based on comparisons of means (eg, minimal diastolic pressure, maximal FiO2, weight, percentage enteral volume) thus limiting robust assessment.
One limitation of the Rozé et al. study is the lack of standardization of obtaining and assessing cardiac echocardiography after treatment. While most subjects were assessed ~ 7 days of life, interpretation was “according to local practice” by cardiologists or trained neonatologists. Variability could have introduced misclassification bias within the study leading to differences in assessment of the effectiveness of the intervention. Subsequent treatments based on this assessment, either diluting or confounding the findings related to the primary outcome. Furthermore, cholestasis, defined as a conjugated bilirubin >20% of total bilirubin, occurred more frequently in the treatment group with 20% of cases remaining unresolved at 36 weeks corrected gestational age (CGA). While the causality remains unclear, application of a prophylactic therapy with potential serious side effects to a population where the majority does not stand to benefit from the intervention requires additional investigation and challenges the idea of acetaminophen having a more favorable side effect profile.
The findings are consistent with previous trials utilizing NSAIDs. The TIPP trial (4) demonstrated that prophylactic indomethacin failed to reduce rates of mortality or severe impairment in very low birth weight infants. Furthermore, observational NRN data demonstrate that prophylactic indomethacin use is not associated with lower rates of bronchopulmonary dysplasia (BPD) or death in extremely preterm infants.(5) Collectively these studies demonstrate that safe and effective application of prophylactic PDA treatment remains elusive.
REFERENCES
1. Rozé JC, Cambonie G, Flamant C, Patkai J, Mühlbacher T, Gascoin G, et al. Prophylactic Treatment of Patent Ductus Arteriosus with Acetaminophen, A Randomized Clinical Trial. JAMA Pediatrics; 180(4):374-383.
2. Mitra S, Scrivens A, von Kursell AM, Disher T. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev 2020; 12 12:CD013278.
3. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev 2020; 1 1:CD010061.
4. 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 26:1966–72.
5. Jensen EA, Dysart KC, Gantz MG, Carper B, Higgins RD, Keszler M, et al. Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants. J Pediatr 2017; 186:34–40 e2.
