Sildenafil for Newborn Lung Disease: What the Evidence Really Shows

A drug best known to the public as a treatment for erectile dysfunction is at the center of one of neonatal medicine’s most consequential debates. Sildenafil, a phosphodiesterase type 5 inhibitor, is widely prescribed to premature infants who develop pulmonary hypertension as a complication of bronchopulmonary dysplasia, the chronic lung disease that follows extreme prematurity. A new narrative review published in Pediatric Research by Jenyfer Fuentes-Mendoza and colleagues at Universidad Científica del Sur in Lima, Peru, takes an unusually candid look at this practice. Their conclusion is neither a dismissal nor an endorsement, but a call for precision: the drug offers short-term hemodynamic benefits in selected infants, yet the evidence that it reverses the underlying vascular disease or improves survival remains strikingly thin.

To understand why sildenafil is used at all in these fragile patients, it helps to grasp what bronchopulmonary dysplasia-associated pulmonary hypertension actually is. The review frames it not as a simple problem of excessive blood vessel constriction, but as a developmental disorder of the pulmonary circulation. In infants born extremely preterm, the lung’s vascular tree fails to grow in parallel with the airspaces. The result is impaired angiogenesis, a reduced pulmonary vascular surface area, and simplified alveolar architecture, the tiny sacs where gas exchange occurs. As the vascular bed underdevelops, pressure in the pulmonary arteries rises, and the right ventricle, the heart chamber that pumps blood into the lungs, gradually becomes uncoupled from the pulmonary artery it feeds. This progressive uncoupling is what ultimately threatens these infants’ lives.

Sildenafil acts on a well-defined molecular pathway. By inhibiting phosphodiesterase type 5, the enzyme that degrades cyclic guanosine monophosphate, the drug amplifies signaling downstream of nitric oxide, the endogenous vasodilator that keeps pulmonary vessels relaxed. Higher cyclic guanosine monophosphate levels activate protein kinase G, which reduces vascular tone and, at least in theory, lowers pulmonary arterial pressure. The logic is elegant, and it is supported by decades of work in adult pulmonary arterial hypertension, where sildenafil and related agents are established therapies. But the review’s authors emphasize that preterm infants are not small adults. Their pulmonary vasculature is still under construction, and the disease process they face is fundamentally different from the adult condition the drug was designed to treat.

Experimental studies offer a mixed but intriguing picture. Animal models of persistent pulmonary hypertension of the newborn have shown that sildenafil can improve pulmonary vascular remodeling, and research in lambs has demonstrated that decreased cyclic guanosine monophosphate-protein kinase G signaling itself impairs angiogenesis, suggesting the pathway sildenafil targets is genuinely central to the disease. Beyond vasodilation, experimental work points to effects on endothelial cell survival, smooth muscle proliferation, angiogenic signaling, and oxidative stress. Some studies have even explored intra-amniotic sildenafil to improve lung blood flow in models of congenital diaphragmatic hernia. Yet the authors caution that the relevance of these findings to human preterm infants remains incompletely validated, a gap that separates promising bench science from bedside certainty.

The clinical evidence tells a more sobering story. Current data support short-term improvements in echocardiographic hemodynamics and oxygenation in selected infants, meaning that on ultrasound-based measures of heart and lung function, treated babies often look better. What the data do not demonstrate is durable reversal of vascular remodeling or improved survival. Meta-analyses of sildenafil in this population have not established clear long-term benefit, and trials of prophylactic sildenafil to prevent bronchopulmonary dysplasia in the first place have yielded unconvincing results. A 2026 study of extremely premature infants found variable clinical and hemodynamic responses to the drug, underscoring that not every infant benefits equally. Meanwhile, pharmacoepidemiological surveys show that pulmonary vasodilators, sildenafil chief among them, are used extensively in United States children’s hospitals and across Europe, often without the trial evidence that would normally underpin such practice.

Part of the problem lies in pharmacokinetics, the science of how the body handles a drug. The review highlights that sildenafil exposure in neonates is highly variable, shaped by the maturation of CYP3A, the liver enzyme family responsible for metabolizing the drug, as well as by weight, postnatal age, route of administration, and drug interactions. Population pharmacokinetic studies in extremely premature infants and physiologically based modeling have characterized these sources of variability, and one notable interaction involves fluconazole, an antifungal commonly given to preterm infants, which inhibits CYP3A and can raise sildenafil concentrations. The practical consequence is that two infants receiving the same weight-based dose may experience very different drug exposures, complicating both efficacy and safety assessments.

Safety concerns extend beyond drug interactions. The SILDI-SAFE study, a multicenter randomized placebo-controlled dose-escalation trial, was designed specifically to evaluate sildenafil’s safety in premature infants with severe bronchopulmonary dysplasia, and a related phase II trial has targeted infants at risk of the disease. Researchers have also examined whether sildenafil influences retinopathy of prematurity, the abnormal retinal vessel growth that threatens vision in preterm infants, given that the drug’s vascular effects could theoretically extend to the eye. Hypotension is a recognized risk of vasodilator therapy in general, and the developing brain, the growing lung, and the immature retina all represent organs where manipulating vascular signaling demands caution. The review also notes experimental work on sildenafil-mediated neuroprotection, illustrating how broadly the drug’s biology reaches even as its neonatal safety profile continues to be mapped.

Diagnosis presents its own challenge, and it shapes how treatment decisions are made. There is no single gold standard for detecting pulmonary hypertension in infants with bronchopulmonary dysplasia; echocardiography remains the workhorse, supplemented by emerging tools such as MRI-based pulmonary artery flow measurements that can detect lung vascular pathology in preterms. Early echocardiographic indicators of pulmonary vascular disease are being refined, and targeted neonatal echocardiography programs offer a framework for screening and management. Because some infants who appear to resolve their pulmonary hypertension on ultrasound later show persistent disease, longitudinal follow-up matters as much as initial detection. These diagnostic uncertainties feed directly into treatment decisions, since identifying which infants truly have significant pulmonary vascular disease is a prerequisite for knowing who might benefit from sildenafil.

The review’s most important conceptual contribution may be its reframing of the disease itself. By treating bronchopulmonary dysplasia-associated pulmonary hypertension as a disorder of impaired vascular development rather than a purely reactive vasoconstrictive complication, the authors argue that simply relaxing vessels is not enough. A developmental disease may require therapies that promote vascular growth and repair, not just dilation of the vessels that exist. This perspective aligns with emerging work on endotypes of bronchopulmonary dysplasia, which aims to define molecularly distinct subgroups of preterm infants so that precision-based therapies can be matched to the right patients. It also explains why multidisciplinary approaches to severe bronchopulmonary dysplasia, which address nutrition, growth, and respiratory support alongside vasodilators, have been associated with resolution of pulmonary hypertension in some cohorts.

Where does this leave sildenafil and the infants who receive it? The authors recommend individualized, phenotype-guided use rather than routine prescription, and they call for future trials that incorporate pharmacokinetic-guided dosing and longitudinal outcomes rather than short-term surrogate measures. Such trials would need to answer whether the drug changes the trajectory of vascular remodeling, right ventricular function, and survival, not merely the numbers on an echocardiogram. For now, sildenafil remains a widely used therapy whose mechanistic rationale is sound, whose short-term effects are real for some patients, and whose long-term value in this uniquely vulnerable population is unproven. The gap between those facts is precisely where the next generation of neonatal vascular research will be fought, and the stakes could not be higher for the smallest patients in intensive care.

Subject of Research: Sildenafil treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infants

Article Title: Sildenafil in bronchopulmonary dysplasia-associated pulmonary hypertension: developmental and translational insights

Article References: Fuentes-Mendoza, J., Sernaqué-Paz, M., Cruz-Riquelme, D., Zavaleta-Corvera, C., & Samanez-Obeso, A. (2026). Sildenafil in bronchopulmonary dysplasia-associated pulmonary hypertension: developmental and translational insights. Pediatric Research. https://doi.org/10.1038/s41390-026-05480-9

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05480-9

Keywords: sildenafil, bronchopulmonary dysplasia, pulmonary hypertension, preterm infants, neonatology, pulmonary vascular development, phosphodiesterase type 5 inhibitor, nitric oxide signaling, pharmacokinetics, echocardiography, right ventricular function, precision medicine