Paracetamol/acetaminophen to avoid PDA ligation: how to interpret impact on 18-24 month outcomes

January 13, 2022

MANUSCRIPT CITATION

Mashally S, Banihani R, Jasani B, Nield LE, Martins FF, Jain A, Weisz DE. Is late treatment with acetaminophen safe and effective in avoiding surgical ligation among extremely preterm neonates with persistent patent ductus arteriosus? J Perinatol 2021; Aug 21; 1-7. Online ahead of print. PMID 34453113.

REVIEWED BY

Clyde J. Wright, MD
Associate Professor
Section of Neonatology
Department of Pediatrics
Children’s Hospital Colorado and
University of Colorado School of Medicine

Erik A. Jensen, MD MSCE
Assistant Professor
Department of Pediatrics, Division of Neonatology, The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

TYPE OF INVESTIGATION

Treatment

QUESTION

In extremely low gestational age newborns (ELGAN) with persistent patent ductus arteriosus (P), does acetaminophen (APAP) (I) compared to surgical ligation (C) decrease death or neurodevelopmental impairment (O) at 18-24 months corrected age (T).

METHODS

  • Design: Two-epoch retrospective cohort study comparing different PDA treatment strategies. Epoch 1 (PDA ligation epoch, July 1, 2009 – July 1, 2012). Epoch 2 (late acetaminophen EPOCH, July 1, 2012 – June 30, 2015)
  • Allocation: n/a
  • Blinding: It is not stated if those performing neurodevelopmental assessments were aware of the PDA treatment status or change in PDA treatment approach across epochs
  • Follow-up period: 18-24 months
  • Setting: Single, tertiary perinatal center (~200 ELGAN admits annually)
  • Patients and intervention:
    • PDA Ligation epoch (July 1, 2009 – July 1, 2012): Infants with persistent large PDA (pDPA) after unsuccessful pharmacological and/or conservative therapy and concomitant respiratory insufficiency (defined as mechanical ventilation and/or high non-invasive mean airway pressure [MAP≥8cm H2O] or fraction of inspired oxygen≥0.3) and/or end-organ hypoperfusion (e.g., renal insufficiency, inability to tolerate increases in enteral feeding volume) were considered candidates for surgical ligation. Infants were transported to a local quaternary center for the procedure, which included a left lateral thoracotomy, and an intra- or extra-pleural approach using a clip or ligature at the discretion of the attending surgeon.
    • APAP epoch (July 1, 2012 – June 30, 2015): Neonates with pPDA after cyclooxegenase (COX) inhibitor therapy or a contraindication to COX inhibitors received acetaminophen (orally at a dose of 15 mg/kg every 6 h x 7 days, PO). Infants underwent echocardiography within 3 days of completing acetaminophen treatment and those with persistent clinical and echocardiography signs of large PDA after completion of the treatment course were referred for surgical ligation. Of note, percutaneous transcatheter device closure for PDA was not performed in any infant.
  • Outcomes:
    • Primary outcome: Death or neurodevelopmental impairment (18-24 months).
      • Neurodevelopmental impairment (NDI) was defined as a composite of neuromotor, neurocognitive and/or neurosensory impairment. NDI was defined as presence of cerebral palsy with GMFCS 1 or higher; Bayley-III score <85 for motor, cognitive of language; sensorineural mixed hearing loss; unilateral visual impairment.
    • Secondary outcomes:
      • Secondary outcomes (all estimated at 18–24 months corrected age) included death or severe NDI, mortality alone, NDI alone (any and severe), autism spectrum disorder, and PDA ligation.
  • Analysis and Sample Size:
    • Sample size calculations not provided
    • Infant characteristics were compared using the Student’s t test, Wilcoxon rank-sum test or the chi-square test or Fisher’s exact test where appropriate.
    • Multivariable logistic regression analysis was used to estimate the association between epoch and all outcomes, adjusting for perinatal and postnatal, pre-enrolment confounders.
      • Regression models were adjusted for the following variables that were associated with the primary outcome in univariate analysis (p < 0.20): female sex, outborn, delivery room intubation, magnesium sulfate for fetal neuroprotection, SNAPII score, inotropic treatment, sepsis (culture negative or culture positive).
  • Patient follow-up: % included in analysis
    • PDA LIGATION epoch: 33/38 (86.8%)
    • APAP epoch: 44/49 (90%)

MAIN RESULTS

Outcomes were reported in 38 of 43 subjects referred for PDA ligation from epoch1 (Immediate surgical ligation). In this epoch, 31/43 underwent PDA ligation, but it is not clear from the data reported in the manuscript how many of these 31 infants were included in the follow-up data analyses. In epoch2, 49 subjects had pPDA. Importantly, 9 were referred for immediate ligation, of which 7 were immediately ligated without exposure to APAP and 2 had spontaneous resolution of their PDA. Ultimately, 40 subjects received APAP. Of the original 49, outcomes were available for 44. It is not possible from the provided data to discern what percentage of these 44 subjects received APAP.

The average gestational age was similar between study infants in epoch1 [25.1 (24.6, 26.0)] and epoch2 [25.3 (24.3-26.3)]. The use of prophylactic indomethacin was significantly higher during epoch 2. More infants were intubated in the delivery room in epoch 1.

No difference was found in the primary composite outcome of death or NDI at 18-24 months [(70% vs. 66%; aOR 1.03 (0.3-3.56).]

Rates of PDA ligation were higher in epoch1 (31/43, 72%) compared to epoch2 (26/49, 53%). Of note, the authors comment in the methods that a prior published analysis of the study data found that exposure to late treatment with acetaminophen was associated with an increase in chronic lung disease. In the current report, rates of moderate-severe bronchopulmonary dysplasia were 65% in epoch1 and 81% in epoch2 (p=0.11)

CONCLUSION

The authors conclude that APAP for pPDA did not increase the risk of death of NDI. They state: “These results support the safety and effectiveness of late acetaminophen treatment for PDA to avoid surgical ligation.”

COMMENTARY

Acetaminophen (APAP) use among ELBW infants is increasing worldwide.(1, 2) There is an urgent need to evaluate both the safety and efficacy of APAP for PDA treatment. In this retrospective study, Mashally and colleagues have compared outcomes of ELGANS in which differing approaches across two epochs were used for the treatment of a persistent PDA (pPDA) at a single center: surgical ligation and APAP with ligation after failed closure. Comparing the neurodevelopmental outcomes of these infants at 18-24 months corrected age, the authors found no difference in the risk of NDI or death between infants treated for a pPDA between the two epochs. They conclude that APAP is a safe and effective therapy for late treatment of the PDA to avoid surgical ligation.

These results add to the growing body of literature evaluating the use of APAP for PDA treatment. However, a number of issues must be considered. Although the authors state that the objective was to evaluate the “association of late treatment with acetaminophen vs. immediate surgical ligation with death or neurodevelopmental impairment (NDI) among extremely low gestational age neonates (ELGANs) with persistent patent ductus arteriosus (pPDA),” this precise goal could not be met with the retrospective design and included subjects. Specifically, in epoch1 – the PDA ligation epoch – over 25% of the subjects did not undergo PDA ligation. In epoch2 – the APAP epoch– 20% were not exposed to APAP. Therefore, it is more accurate to state that this study compared outcomes across epochs with different prevailing clinical approaches to treatment of a late PDA. Furthermore, the small sample size also limits the ability to detect clinically relevant differences in outcomes. Larger observational and interventional studies that balance patient characteristics, avoid treatment contamination, and minimize treatment selection bias are needed to determine the safety of APAP for pPDA.

Lastly, any conclusion regarding the “safety” of APAP must be considered in relation to the comparison therapy. In this study, the comparison was  surgical ligation, which is an independent risk factor for poor neurodevelopmental outcomes.(3) Given the risks of ligation, it could be argued that a pharmacologic approach that limits this exposures, and yet is not clearly safer, may potentially carry underappreciated risks that must be considered. The authors previously reported that late APAP exposure was associated with an increase in chronic lung disease.(4) Although referenced in their methods, they do not comment further on this association here. The present report indicates that rates of moderate-severe bronchopulmonary dysplasia were 65% in epoch1 and 81% in epoch2 (p=.11). Although this difference did not reach statistical significance, a 16% absolute increase in the rates of this outcome is of possible clinical significance, particularly in light of the reduced frequency of PDA ligation. This potential signal for harm, as well as the potential impact of APAP exposures on the developing lung, brain, and endocrine function, reminds us that studies evaluating APAP safety should include broad measures of end-organ injury.(5-7) With these points in mind, the conclusion regarding the safety of APAP should be regarded cautiously.

REFERENCES

  1. Stark A, Smith PB, Hornik CP, Zimmerman KO, Hornik CD, Pradeep S, et al. Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018. J Pediatr 2021.
  2. Gouyon B, Martin-Mons S, Iacobelli S, Razafimahefa H, Kermorvant-Duchemin E, Brat R, et al. Characteristics of prescription in 29 Level 3 Neonatal Wards over a 2-year period (2017-2018). An inventory for future research. PLoS One 2019; 14 9:e0222667.
  3. Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, et al. Patent Ductus Arteriosus of the Preterm Infant. Pediatrics 2020; 146 5.
  4. Mashally S, Banihani R, Jasani B, Nield LE, Martins FF, Jain A, et al. Is late treatment with acetaminophen safe and effective in avoiding surgical ligation among extremely preterm neonates with persistent patent ductus arteriosus? J Perinatol 2021; 41 10:2519-25.
  5. Bauer AZ, Swan SH, Kriebel D, Liew Z, Taylor HS, Bornehag CG, et al. Paracetamol use during pregnancy – a call for precautionary action. Nat Rev Endocrinol 2021.
  6. Wright CJ. Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences? J Pediatr 2021; 235:264-76 e1.
  7. Angelis D, Chalak L. Acetaminophen and the developing brain: A critical review of the evidence. Early Hum Dev 2021; 159:105411.
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