Bronchopulmonary dysplasia, or BPD, is a chronic lung disease that develops when the fragile, immature lungs of very preterm infants are damaged by mechanical ventilation, oxygen therapy, and inflammation during the first weeks of life. Infants who develop BPD often require prolonged respiratory support and hospitalization, and they face elevated risks of rehospitalization, neurodevelopmental impairment, and long-term respiratory problems such as asthma-like symptoms and reduced lung function well into childhood and adulthood. Because survival rates for extremely preterm infants have climbed steadily over recent decades, BPD has become one of the most common long-term consequences of prematurity, making effective prevention strategies a major priority for neonatal medicine.

Caffeine is already a workhorse of neonatal care. A methylxanthine compound that crosses the blood-brain barrier readily, caffeine acts primarily as a respiratory stimulant by antagonizing adenosine receptors in the brainstem, increasing the drive to breathe and improving diaphragmatic contractility. Since a landmark 2006 international trial demonstrated that caffeine therapy shortened the duration of mechanical ventilation and reduced the rate of BPD among extremely low-birth-weight infants, caffeine citrate has become standard treatment for apnea of prematurity in neonatal intensive care units worldwide. However, that trial initiated caffeine only once apnea developed or clinicians judged treatment necessary—what neonatologists call therapeutic administration. Whether giving the drug prophylactically, within hours of birth to all very preterm infants regardless of symptoms, could prevent BPD more effectively remained unresolved, and prior smaller studies had produced mixed and inconclusive results.

To address this gap, researchers led by Fangfang Tao and Jiang-Qin Liu of Shanghai First Maternity and Infant Hospital, together with colleagues at Children’s Hospital of Fudan University and the University of Alberta, enrolled 372 very preterm neonates born before 32 weeks and 0 days of gestation between September 2016 and January 2024. In this single-center, randomized clinical trial, infants were assigned to one of two strategies. The prophylactic caffeine administration group received caffeine citrate shortly after birth, beginning with a loading dose of 20 milligrams per kilogram of body weight followed by a daily maintenance dose of 10 milligrams per kilogram. The comparison group received therapeutic caffeine administration, meaning the same drug at the same doses, but only after a diagnosis of apnea was made. The primary endpoint was the composite of BPD at 36 weeks postmenstrual age and/or death before hospital discharge.

The results favored early treatment. BPD or death occurred in 37.1 percent of infants in the prophylactic group—69 of 186 infants—compared with 47.3 percent in the therapeutic group, or 88 of 186. That difference corresponds to a relative risk of 0.77 with a 95 percent confidence interval of 0.62 to 0.95, and a P value of 0.013, meaning the reduction was statistically significant and unlikely to be due to chance alone. In practical terms, for roughly every ten very preterm infants treated prophylactically rather than reactively, one fewer infant would be expected to die before discharge or leave the hospital requiring oxygen for chronic lung disease.

The effect proved robust across five different sensitivity analysis models designed to test whether the finding depended on particular statistical assumptions. Notably, the benefit appeared more pronounced in several clinically meaningful subgroups: female infants, infants whose mothers had received antenatal corticosteroids to accelerate fetal lung maturation, infants who were not intubated in the delivery room, and infants who required only noninvasive ventilation after birth. This pattern is biologically plausible, since these are infants whose lungs were less severely compromised at the outset and who therefore stood to gain the most from protecting the airways and respiratory drive before injury could accumulate.

Caffeine’s protective mechanism in the context of BPD is thought to extend beyond simple respiratory stimulation. Experimental work suggests that caffeine exerts anti-inflammatory effects, modulates cytokine responses, improves diaphragmatic and intercostal muscle function, and enhances respiratory pattern stability, all of which can reduce the need for invasive mechanical ventilation and high oxygen concentrations—the principal drivers of lung injury in preterm infants. By stabilizing breathing from the first hours of life, prophylactic caffeine may prevent the cascade of apnea episodes, desaturations, and escalation of ventilatory support that culminates in chronic lung disease.

The trial was not without signals of potential harm, and the authors were careful to report them. Infants in the prophylactic group received a higher number of blood transfusions than those in the therapeutic group, with a mean difference of 0.42 transfusions (95 percent confidence interval, 0.05 to 0.79; P = 0.027). The clinical significance of this small increase is uncertain, but it aligns with earlier observations that early caffeine use has been associated with more frequent phlebotomy-related blood sampling and transfusion in previous trials. Importantly, no significant differences were observed between the two groups in the incidence of other serious complications of prematurity, including necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, and late-onset sepsis, nor in the duration of mechanical or noninvasive ventilation, oxygen exposure, length of hospital stay, or medical costs.

The researchers emphasized that the study had limitations inherent to its design. As a single-center trial, its findings may reflect the specific practices and patient population of one institution, and confirmation in multicenter settings is needed before the results can be generalized universally. The trial was registered retrospectively in the Chinese Clinical Trial Registry, a point the authors acknowledged transparently. In addition, the composite primary outcome of BPD or death, while standard in neonatal trials, combines two distinct events, and a larger sample would be required to separately power each component. Still, the trial’s seven-and-a-half-year enrollment window, its randomized design, and the consistency of the effect across sensitivity analyses lend considerable weight to the conclusion.

For neonatologists, the study raises the prospect of shifting practice: rather than waiting for apnea to declare itself, starting caffeine citrate routinely within the first hours of life in infants born before 32 weeks could prevent a substantial share of BPD cases and deaths. Prophylactic caffeine is already inexpensive, well tolerated, and familiar to every neonatal unit, which means that if the findings are confirmed, implementation barriers would be minimal compared with entirely new therapies. As BPD continues to burden a growing population of preterm survivors, an intervention this simple—administering earlier a drug already sitting in the NICU pharmacy—represents exactly the kind of low-cost, high-reach strategy that could reshape outcomes for the most vulnerable newborns. The study was funded through the CHINA-CANADA Clinical Research program, and the full open-access article is available in BMC Pediatrics.

Subject of Research: Prophylactic caffeine administration to prevent bronchopulmonary dysplasia in very preterm infants

Article Title: Prophylactic administration of caffeine reduces bronchopulmonary dysplasia in very preterm infants: a single center, randomized controlled trial

Article References: Tao, F., Zhou, M., Fu, Y., Zhou, J., Wang, M., Duan, Y., Li, M., Hua, J., Wang, Y., Chen, C., Cheung, P.-Y., Yuan, L., Yan, W., & Liu, J.-Q. (2026). Prophylactic administration of caffeine reduces bronchopulmonary dysplasia in very preterm infants: a single center, randomized controlled trial. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07625-5

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07625-5

Keywords: caffeine, bronchopulmonary dysplasia, very preterm infants, prophylactic administration, randomized controlled trial, apnea of prematurity, neonatal intensive care, caffeine citrate, chronic lung disease, mechanical ventilation, Prophylactic, administration

The study, led by Gähwiler et al., explores the intriguing link between olfactory activation and respiratory regulation in preterm infants. By delivering specific nasal odors, the researchers aimed to harness the complex neurobiological pathways that connect the olfactory system to brainstem regions responsible for respiratory rhythm generation. This innovative intervention targets the underlying neural circuitry without relying on pharmacological agents, which often carry risks in this delicate population.

In this cross-over trial design, each preterm infant served as their own control, receiving periods of olfactory stimulation alternated with no stimulation. This methodology ensured rigorous comparison while minimizing inter-individual variability. The odors used were carefully selected for their safety and minimal risk of overstimulation.

Results revealed a statistically significant decrease in apnea frequency and duration during periods when nasal olfactory stimulation was applied. The authors hypothesize that olfactory inputs may activate serotonergic and cholinergic neurons in the brainstem, enhancing respiratory drive and stabilizing the autonomic nervous system. Such neuromodulatory effects could represent a previously underappreciated avenue for apnea management.

Beyond efficacy, the study also documents the practical advantages of this sensory-based intervention. Nasal olfactory stimulation is non-invasive, easily administered, and avoids the side effects associated with pharmacotherapy or invasive respiratory support. These factors could make it a valuable adjunct or alternative in neonatal intensive care units worldwide.

The researchers emphasize that while their findings are promising, further work is necessary to refine stimulation protocols, identify optimal odorants, and assess long-term outcomes on neurodevelopmental trajectories. Moreover, mechanistic studies to delineate the precise neural pathways engaged by olfactory stimulation will enhance translational potential.

This study opens up exciting possibilities for sensory-based therapies in neonatal medicine. As we deepen our understanding of how early sensory experiences shape brain function and physiology, interventions like nasal olfactory stimulation could redefine standards of care for premature infants struggling with apnea.

In sum, Gähwiler and colleagues have provided compelling evidence that activating the olfactory system via nasal stimulation can modulate breathing patterns and reduce apnea episodes in preterm babies. This research heralds a shift towards innovative, non-pharmacological strategies that harness the body’s intrinsic neurobiology for therapeutic benefit.

Subject of Research: Apnea of prematurity and nasal olfactory stimulation as an intervention.

Article Title: The effect of nasal olfactory stimulation on apnea of prematurity: a randomized cross-over trial.

Article References:
Gähwiler, K., Rüegger, C.M., Dirler, C. et al. The effect of nasal olfactory stimulation on apnea of prematurity: a randomized cross-over trial. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-05285-w

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05285-w