The trigger for the exchange is a secondary analysis of the BeNeDuctus trial, conducted by Hoornenborg and colleagues, which examined extremely preterm infants who received paracetamol for pain relief. According to the letter, that analysis found a significantly increased risk of moderate-to-severe bronchopulmonary dysplasia, a chronic lung condition of prematurity, as well as longer requirements for respiratory support among infants exposed to the drug. Because the sample originated from a randomized controlled trial, the finding carries more weight than the observational studies that have fueled suspicion of paracetamol for the past two decades. The letter’s authors commend the trial team while pressing the point that even these researchers continue to call for yet more studies rather than recommending a change in practice.

Bronchopulmonary dysplasia remains one of the most consequential outcomes in neonatology. It arises when the lungs of infants born extremely early fail to develop normally, often after weeks of mechanical ventilation and oxygen therapy, and it predicts years of respiratory illness, rehospitalization and impaired growth. Any drug that measurably raises the risk of moderate-to-severe disease would represent a serious threat to a vulnerable population, which is precisely why the letter frames the question in such stark terms. The authors ask, in effect, how much evidence is enough before the burden of proof shifts from those who suspect harm to those who assume safety.

The biological plausibility of a paracetamol-lung link rests on the drug’s metabolism. Paracetamol is processed primarily in the liver, but a fraction is converted by cytochrome enzymes into a reactive metabolite, N-acetyl-p-benzoquinone imine, which depletes glutathione, the cell’s principal antioxidant defense. The developing lung expresses xenobiotic-metabolizing enzymes, meaning that pulmonary tissue can locally generate toxic metabolites from circulating paracetamol. In a preterm infant, whose antioxidant systems are immature and whose lungs are already under oxidative assault from oxygen therapy and ventilation, additional glutathione depletion could plausibly tip the balance toward arrested alveolar development. Pharmacokinetic studies in very preterm infants have documented measurable exposure not only to the parent compound but to all of its metabolites at standard intravenous doses, underscoring that these tiny patients handle the drug differently from adults.

This mechanistic concern is not merely theoretical. Preclinical work summarized in the pulmonary physiology literature has explicitly called for animal models to understand why the perinatal lung appears uniquely susceptible to acetaminophen, the American name for the same molecule. Meanwhile, a cohort study of extremely preterm infants detected acetaminophen and its xenobiotic metabolites in human milk and reported associations with both bronchopulmonary dysplasia and retinopathy of prematurity, another disease of oxidative stress. There have even been reports of paracetamol overdose in newborns and infants proving life-threatening, a reminder that the therapeutic window in this population is narrower than commonly assumed. Together, these strands sketch a coherent biological story in which a drug once considered benign for the lung may interfere with redox-sensitive developmental processes at exactly the wrong moment.

The broader epidemiological record adds a second, parallel line of concern. Systematic reviews and meta-analyses stretching back more than a decade have consistently reported associations between paracetamol use in pregnancy and wheezing illness or asthma in offspring, and more recent syntheses of prenatal exposure studies have reached similar conclusions. Research in high-risk birth cohorts has also examined early-life acetaminophen exposure in combination with genetic variation in glutathione S-transferase enzymes, finding evidence that the drug’s oxidative burden may interact with inherited detoxification capacity to shape asthma risk into adolescence. Population studies of childhood asthma prevalence continue to list early paracetamol exposure among the modifiable risk factors under scrutiny, and even lactation, long considered a safe channel, has been questioned in the pediatric literature.

What makes the new trial-based analysis so important is the hierarchy of evidence it occupies. Observational studies of drug exposure are notoriously vulnerable to confounding by indication: children who receive more paracetamol tend to be sicker, and sicker infants develop more lung disease regardless of which painkiller they receive. A secondary analysis nested within a randomized controlled trial does not eliminate that problem entirely, since randomization in the parent BeNeDuctus trial was not designed to allocate paracetamol, but it does allow investigators to control for illness severity far more rigorously than most registry or cohort studies can. The fact that a signal for moderate-to-severe bronchopulmonary dysplasia and prolonged respiratory support survived that scrutiny is what lends the letter its urgency.

Yet the letter’s authors are careful not to overclaim causation, and the trial investigators themselves stopped short of a practice change, calling instead for further research into paracetamol’s respiratory effects in preterm infants. That restraint reflects genuine clinical dilemmas. Preterm infants undergo painful procedures, from cannulation to surgery for patent ductus arteriosus, and untreated pain carries its own documented harms, including stress responses that destabilize cerebral blood flow. Paracetamol has become attractive precisely because it avoids the renal, gastrointestinal and platelet side effects of nonsteroidal anti-inflammatory drugs. An overview of systematic reviews on paracetamol’s efficacy and safety concluded that while the drug offers modest analgesic benefit, its safety profile in vulnerable groups deserves continued attention, a conclusion that now reads differently in light of the neonatal data.

The dilemma is sharpened by trends in neonatal care. A recent analysis of fifteen years of respiratory and hemodynamic management in very premature infants documented evolving approaches to bronchopulmonary dysplasia, and observational multicenter registries have compared conservative and medical strategies for managing the ductus arteriosus, a condition for which paracetamol has itself been trialed as a closing agent. In other words, paracetamol is not merely an incidental exposure in the neonatal unit; it is increasingly embedded in treatment protocols. If the drug independently worsens lung outcomes, the implications extend from analgesia guidelines to the very protocols designed to protect the preterm lung, and clinicians would need to weigh analgesic benefit against a respiratory cost that previous risk-benefit calculations never included.

For now, the letter functions as both a summary and a challenge. It gathers the mechanistic, pharmacokinetic, preclinical and epidemiological threads into a single argument that the evidence base has grown substantial enough to demand action beyond another round of observational studies. The authors, who report no competing interests and no external funding, frame their appeal around the families and clinicians they serve, and their central question, how much evidence is enough, is one that guideline committees, regulators and neonatologists will now have to answer explicitly. Whether the answer comes from adequately powered randomized trials of analgesic strategy in extremely preterm infants or from a precautionary shift in prescribing habits, the era in which paracetamol was assumed to be harmless to the developing lung is drawing to a close.

Subject of Research: The association between paracetamol exposure and bronchopulmonary dysplasia in extremely preterm infants

Article Title: Paracetamol and the developing lung: how much evidence is enough?

Article References: Verd, S., Boo, S., & Costa-Orvay, J.-A. (2026). Paracetamol and the developing lung: how much evidence is enough?. Pediatric Research. https://doi.org/10.1038/s41390-026-05532-0

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05532-0

Keywords: paracetamol, acetaminophen, bronchopulmonary dysplasia, preterm infants, neonatology, respiratory support, glutathione, oxidative stress, asthma risk, BeNeDuctus trial, Pediatric Research, drug safety