Pulmonary hypertension in preterm infants is emerging as one of the most difficult cardiovascular and respiratory problems in neonatal medicine, according to a new narrative review published in the Journal of Perinatology. The condition can intensify hypoxic respiratory failure, contribute to bronchopulmonary dysplasia and substantially increase the risk of death. Yet the authors emphasize that pulmonary hypertension in premature babies is not a single disease with a single treatment. Instead, it represents a collection of overlapping physiological disorders that can look similar at the bedside while requiring very different interventions.
In term infants, pulmonary hypertension is often associated with relatively recognizable disturbances in the transition from fetal to newborn circulation. In preterm infants, that transition is complicated by immature lungs, incomplete vascular development, inflammation, mechanical ventilation, infection, patent ductus arteriosus and unstable cardiac function. These factors can act together to increase resistance in the pulmonary circulation, limiting blood flow through the lungs and reducing oxygen transfer. The result may be severe hypoxemia that does not respond predictably to conventional respiratory support.
The review by Mohamed M. Elgendy and Sandeep Nath describes several possible hemodynamic phenotypes behind acute pulmonary hypertension. Some infants may have severely elevated pulmonary vascular resistance, which restricts blood flow from the right ventricle into the lungs. Others may have right ventricular dysfunction, left ventricular impairment or inadequate systemic blood flow. A large patent ductus arteriosus can further alter the direction and volume of blood flow between the pulmonary artery and aorta. In such cases, the same oxygen saturation pattern may arise from entirely different mechanisms, making a uniform treatment strategy potentially ineffective or harmful.
Bronchopulmonary dysplasia is another major part of the problem. Premature lungs may contain fewer and smaller pulmonary vessels, while ongoing inflammation and oxygen exposure can damage the developing vascular bed. This structural limitation can raise pulmonary vascular resistance and place additional stress on the right ventricle. At the same time, areas of collapsed or poorly aerated lung can create ventilation–perfusion mismatch, in which blood reaches regions that cannot adequately oxygenate it. The combination of abnormal lung mechanics and cardiovascular strain can rapidly progress to hypoxic respiratory failure.
For clinicians, distinguishing these mechanisms requires more than measuring oxygen saturation or blood pressure. The authors highlight the growing importance of targeted neonatal echocardiography and functional echocardiographic assessment. These bedside techniques can evaluate right and left ventricular performance, estimate pulmonary pressures, examine the direction of ductal shunting and identify whether the heart is failing to deliver sufficient systemic blood flow. Serial examinations are particularly important because the physiology of a critically ill preterm infant can change quickly in response to ventilation, fluids, infection, medications or changes in ductal flow.
One of the most controversial treatments is inhaled nitric oxide, or iNO. Nitric oxide is a naturally occurring signaling molecule that relaxes smooth muscle in the pulmonary arteries. When inhaled, it reaches ventilated areas of the lung and can selectively widen nearby pulmonary vessels, potentially improving the match between ventilation and blood flow. In carefully selected infants with pulmonary hypertension and severe oxygenation failure, this mechanism may produce a rapid rise in oxygen levels and reduce the pressure burden on the right ventricle.
However, the review stresses that short-term improvement in oxygenation is not the same as improved survival or healthier development. Randomized clinical trials in preterm infants have not shown that routine iNO treatment reduces mortality or the incidence of bronchopulmonary dysplasia. Concerns have also persisted about a possible increase in severe intraventricular hemorrhage, a serious form of bleeding into the immature brain. Because premature infants have fragile cerebral blood vessels and unstable cerebral blood flow, any therapy that alters vascular resistance or produces abrupt hemodynamic changes must be used with considerable caution.
The evidence therefore does not support treating every preterm infant with hypoxic respiratory failure as though pulmonary hypertension were the same condition in each case. iNO may be considered when echocardiography and the clinical picture indicate significant pulmonary vascular constriction, particularly when oxygenation remains poor despite optimized lung recruitment and ventilation. But indiscriminate use could expose infants to risk without addressing the actual cause of their deterioration. If the dominant problem is left ventricular dysfunction, excessive pulmonary blood flow through a ductus or inadequate systemic perfusion, pulmonary vasodilation alone may fail to correct the underlying physiology.
Vasoactive and inotropic medications may have an important role when cardiovascular dysfunction accompanies pulmonary hypertension. Inotropes can increase the force of cardiac contraction, while vasoactive agents can alter systemic vascular tone and support blood pressure. Their effects, however, are not interchangeable. Raising systemic vascular resistance may improve coronary and cerebral perfusion in one infant but increase cardiac workload in another. Similarly, increasing contractility may support a failing ventricle but also raise myocardial oxygen demand. The review argues that these therapies should be selected according to the infant’s measured hemodynamic phenotype rather than administered through a generalized protocol.
The authors ultimately call for a physiology-based approach that combines careful clinical observation, advanced respiratory support, serial functional echocardiography and targeted cardiovascular treatment. Such an approach recognizes that pulmonary hypertension in preterm infants is a dynamic interaction between the lungs, pulmonary vessels, heart and systemic circulation. Although iNO can offer meaningful oxygenation benefits in selected cases, it should not be viewed as a universal solution. More precise phenotyping, standardized bedside assessment and future trials focused on clinically relevant outcomes will be essential to determine which infants benefit from specific therapies—and which may be placed at risk by them.
Subject of Research: Pulmonary hypertension and acute hypoxic respiratory failure in preterm neonates
Article Title: Pulmonary hypertension and acute hypoxic respiratory failure in preterm neonates
Article References: Elgendy, M.M., Nath, S. Pulmonary hypertension and acute hypoxic respiratory failure in preterm neonates. J Perinatol (2026). https://doi.org/10.1038/s41372-026-02858-9
Image Credits: AI Generated
DOI: 10.1038/s41372-026-02858-9
Keywords: pulmonary hypertension, preterm infants, hypoxic respiratory failure, bronchopulmonary dysplasia, inhaled nitric oxide, neonatal echocardiography, pulmonary vascular resistance, vasoactive agents, intraventricular hemorrhage
Tags: bronchopulmonary dysplasiafetal to neonatal circulation transitionhypoxemia management in preemiesimmature lung developmentneonatal cardiovascular instabilityneonatal hypoxic respiratory failureneonatal mechanical ventilation complicationsneonatal pulmonary vascular resistanceoverlapping pulmonary disorders in neonatesPatent Ductus Arteriosus in Preterm InfantsPreterm infant pulmonary hypertensionpulmonary circulation resistance
