Pulmonary Hemorrhage in Premature Infants: Pathophysiology, Risk Factors and Clinical Management

Abstract

Pulmonary hemorrhage (PH) is a life-threatening complication predominantly affecting preterm infants, particularly those with very low birth weight (VLBW) and fetal growth restriction (FGR). Typically occurring within the first 72 h of life, PH is characterized by acute respiratory deterioration and significant morbidity and mortality. This review synthesizes current evidence on the multifactorial pathogenesis of PH, highlighting the roles of immature pulmonary vasculature, surfactant-induced hemodynamic shifts, and left ventricular diastolic dysfunction. Key risk factors include respiratory distress syndrome (RDS), hemodynamically significant patent ductus arteriosus (hsPDA), sepsis, coagulopathies, and genetic predispositions. Diagnostic approaches incorporate clinical signs, chest imaging, lung ultrasound, and echocardiography. Management strategies are multifaceted and include ventilatory support-particularly high-frequency oscillatory ventilation (HFOV)-surfactant re-administration, blood product transfusion, and targeted hemostatic agents. Emerging therapies such as recombinant activated factor VII and antifibrinolytics show promise but require further investigation. Preventive measures like antenatal corticosteroids and early indomethacin prophylaxis may reduce incidence, particularly in high-risk populations. Despite advancements in neonatal care, PH remains a major contributor to neonatal mortality and long-term neurodevelopmental impairment. Future research should focus on individualized risk stratification, early diagnostic tools, and optimized treatment protocols to improve outcomes. Multidisciplinary collaboration and innovation are essential to advancing care for this vulnerable population.

Keywords: coagulopathy; echocardiography; fetal growth restriction (FGR); lung ultrasound; patent ductus arteriosus (PDA); preterm infants; pulmonary hemorrhage; respiratory distress syndrome (RDS); surfactant therapy; very low birth weight (VLBW).

Figure 1

Clinical features of pulmonary hemorrhage in premature infants. Extremely premature infants, especially those small for gestation (SGA) with a hemodynamically significant patent ductus arteriosus that have been exposed to a surfactant, are at risk for pulmonary hemorrhage. Coagulopathy and severe intraventricular hemorrhage (IVH) may be associated with pulmonary hemorrhage. Copyright Satyan Lakshminrusimha.

Figure 2

The pathogenesis of pulmonary hemorrhage. An airspace–capillary interface can be disrupted by the rupture of the epithelial barrier and endothelial dysfunction with increased capillary permeability. Surfactant therapy with decreased pulmonary vascular resistance (PVR) coupled with a hemodynamically significant patent ductus arteriosus (PDA) can increase pulmonary blood flow, disrupt fragile capillaries, and result in neutrophil and red blood cell infiltration and edema in the airspace. Copyright Satyan Lakshminrusimha.

Figure 3

The potential pathophysiology and dynamic interactions contributing to pulmonary hemorrhage in preterm infants with respiratory distress syndrome (RDS) and hemodynamically significant patent ductus arteriosus (hsPDA). (A) Before surfactant administration, preterm infants with RDS have high surface tension in the alveolus with high mean airway pressures due to poor compliance and low pulmonary blood flow due to high pulmonary vascular resistance (PVR). (B) Following surfactant administration, compliance increases, surface tension decreases, and pulmonary blood flow increases (especially with a hsPDA). Concomitant left ventricular (LV) dysfunction with a restrictive patent foramen ovale (PFO) induces capillary stress and the disruption of the epithelial barrier, causing hemorrhagic pulmonary edema. (C) Extubation with non-invasive ventilation (NIV) and the loss of alveolar pressure may potentially contribute to an increase in edema. Airspace tamponades with high mean airway pressures (with PEEP or high-frequency ventilation), endotracheal epinephrine, blood products to correct coagulopathy and anemia, and steroids may be beneficial in management (D). Copyright Satyan Lakshminrusimha.

Figure 4

The contributing factors and pathophysiology of pulmonary hemorrhage in preterm infants. SGA—small for gestational age; FGR—fetal growth restriction; hsPDA—hemodynamically significant patent ductus arteriosus; LV—left ventricle; IVH—intraventricular hemorrhage. Increased pulmonary blood flow due to hsPDA and low PVR combined with restricted outflow due to small PFO and LV dysfunction increases capillary stress. Copyright Satyan Lakshminrusimha.

Figure 5

A chest X-ray of a premature baby with pulmonary hemorrhage showing bilateral fluffy opacities reflecting localized alveolar hemorrhage.

Figure 6

A chest X-ray of a baby with massive pulmonary hemorrhage. Left: Before pulmonary hemorrhage. Right: After massive pulmonary hemorrhage: a “white out” lung appearance can be seen due to extensive pulmonary flooding.