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Acetaminophen Safety for Patent Ductus Arteriosus in Extremely Preterm Neonates

6/25/2024

A baby in the neonatal intensive care unit lies in an isolette with a breathing tube while holding a felt heart.

Key Takeaways

  • Acetaminophen's use for patent ductus arteriosus (PDA) in extremely preterm neonates has surged in recent years but there has not been strong data demonstrating its safety.

  • Limited research suggests acetaminophen reduces PDA without liver damage, but there are new concerns about lung toxicity in these patients.

  • Available clinical studies lack adequate sample sizes and often under-evaluate extremely preterm infants.

  • We need additional studies on CYP2E1 expression and acetaminophen toxicity as well as large trials assessing pulmonary outcomes and evaluating acetaminophen safety in preterm infants.


Research study background

Patent ductus arteriosus (PDA) is the predominant cardiovascular condition in premature infants. The long-standing primary pharmacological intervention, non-steroidal anti-inflammatory drugs (NSAIDs), lack consistent evidence of improved breathing and sustained brain health and are associated with adverse effects. In 2011, acetaminophen (also called paracetamol) emerged from a small 2011 case series as an alternative treatment, leading to an international surge in use in extremely preterm neonates.

In this journal commentary, Children’s Hospital Colorado neonatologist Clyde Wright, MD, and a multi-institutional team of investigators reviewed recent clinical findings on acetaminophen use and outcomes in premature infants alongside preclinical studies, shedding light on potentially overlooked mechanisms of its adverse pulmonary effects. Dr. Wright and his colleagues at Children’s Colorado and the University of Colorado Anschutz Medical Campus have conducted several studies on this topic.

Multiple small trials have assessed acetaminophen's effectiveness in closing PDA in preterm infants. A 2022 Cochrane review of 27 studies found acetaminophen reduced PDA incidence versus placebo (16.8% vs. 61.1%), with efficacy similar to ibuprofen and indomethacin. Yet, acetaminophen's mechanism for PDA closure, akin to NSAIDs, remains unclear and its safety compared to NSAIDS warrants further consideration.

Limited preclinical data shows acetaminophen reduces PDA without apparent liver damage, as fetal and neonatal liver cells express low levels of the enzyme CYP2E1 responsible for acetaminophen-induced cellular injury. However, recent preclinical investigations have raised concerns about lung toxicity. CYP2E1 is found in adult lung cells and dynamically expressed during murine lung development. Lung mesenchymal myofibroblasts expressing CYP2E1 could be vulnerable to acetaminophen exposure, potentially impacting lung development in preterm infants.

Some clinicians have expressed renewed scrutiny about the safety of acetaminophen during pregnancy despite its long-standing use. However, others have criticized the emerging clinical data that suggest potential harm to offspring. Studies have linked acetaminophen exposure to asthma, though experts debate causality. Evidence on acetaminophen's contribution to poor pulmonary outcomes in preterm infants is limited and there are conflicting findings on its potential association with the risk of bronchopulmonary dysplasia.

Study authors note that trials assessing acetaminophen’s use for PDA mostly overlook pulmonary effects, focusing on ductal closure benefits and the scarcity of data prevents definitive conclusions on acetaminophen's pulmonary risks.

Relevance to future research

Questions remain about the safety of increased acetaminophen use in neonatal intensive care units, particularly for preterm infants who have unique factors, such as oxygen supplementation, that may worsen oxidative stress and pulmonary function. The distinct metabolism of acetaminophen by preterm infants warrants further investigation into potential toxicity and clinical implications. Next, Dr. Wright and his cross-campus collaborators will examine the metabolic, histologic, developmental and functional impact of early life acetaminophen exposure. Study authors are optimistic that ongoing large clinical trials of acetaminophen for PDA in this population will yield meaningful risk-benefit data on this therapy.