Managing Pulmonary Hypertension in Preterm Neonates: Updates in an Emerging Field

Of the 3.1 million neonatal deaths that occur each year worldwide, an estimated 35% are caused by complications associated with preterm birth, which is the second leading cause of death in children under age 5 following pneumonia.¹ In addition, these infants suffer from a range of comorbidities. The most common chronic respiratory morbidity affecting this patient population is bronchopulmonary dysplasia (BPD), particularly in infants weighing <1500 g or of a gestational age (GA) <28 weeks.²

Previously, BPD was most often observed in infants >28 weeks GA, as survival was rare in infants <28 weeks GA. According to a review published in Children, “With the advent of antenatal glucocorticoid therapy, surfactant administration and gentle ventilation strategies, BPD is now more frequent in infants <1000 g birthweight or in <28 weeks GA infants.”³

“Bronchopulmonary dysplasia has primarily become a function of lung development in extremely low birth weight (ELBW) infants, altered by ventilation, oxygen, chorioamnionitis and genetic factors.” Infants who are affected have an elevated risk for pulmonary hypertension (PH).

Preterm infants in the late canalicular or early saccular stage of lung development are especially vulnerable to alterations resulting in the impaired alveolar and vascular development that can lead to BPD. Prenatal factors that disrupt lung development include preeclampsia, chorioamnionitis, and intrauterine growth retardation, while postnatal factors include oxygen administration, mechanical ventilation, and cytokine responses from inflammation or infection.^4-6 These factors result in alveolar simplification, which “is the defining lung characteristic of infants with BPD, and along with [PH], increasingly contributes to both respiratory morbidity and mortality in these infants.” the researchers wrote.

Previous findings show BPD and PH in approximately one-third and one-fifth of infants who are ELBW, respectively. In a recent meta-analysis, higher odds for PH were found in infants with all forms of BPD vs no BPD, with the incidence ranging from 4% to33% based on the level of BPD severity.⁷ In addition to LBW, risk factors for the development of PH in infants include perinatal stress, oligohydramnios, small for gestational age (SGA), sepsis, and prolonged mechanical ventilation.

Early detection of PH in at-risk infants is essential for appropriate management of the disease. To learn more about the most notable recent advances, diagnostic and treatment challenges, and additional research and other needs in this emerging field, Pulmonology Advisor checked in with the study investigator, Vasantha H.S. Kumar, an associate professor of pediatrics and director of the Neonatal-Perinatal Medicine Fellowship Program at the University at Buffalo in New York.

Pulmonary Advisor: What are some of the most notable recent advances regarding our understanding of PH in premature neonates?

Dr Kumar: BPD in infants born preterm results in altered airway and vessel development and is a major risk factor for PH. However, recently, we are beginning to understand that certain prenatal factors such as intrauterine growth retardation, infection, and placental inflammation can alter the growth and development of the pulmonary vessels in utero, and hence can modulate the progress of PH after birth. So, what happens after birth in terms of PH to some extent is decided by how vessels have grown before birth.  

Pulmonary Advisor: What are the diagnostic challenges and emerging screening approaches for PH in this population?

Dr Kumar: The challenge is predicting which infants will go on to develop PH, even though premature infants who are SGA are particularly at risk. About a third of infants with BPD develop PH. Echocardiography is the most commonly used noninvasive screening tool, and B-type natriuretic peptide (BNP) is being studied as a prognostic marker in infants with PH. Catheterization and cardiac MR are specialized investigations, and subjecting sick premature infants to catheterization is a matter of concern.

Pulmonary Advisor: How is PH in premature neonates treated, and what are some of the challenges?

Dr Kumar: As PH in premature infants is closely linked to lung growth, attention to oxygen saturations, ventilation strategies, and nutrition is important. Infants with prolonged rupture of membranes seem to respond better to inhaled nitric oxide (iNO). Oral sildenafil is the next commonly used vasodilator after iNO. Prostanoids are the second line of therapy in infants with severe PH who require combination therapy. Despite the lack of evidence of beneficial effects, including with iNO, these drugs are used extensively in the management of PH. The challenge is in conducting large-scale studies to generate safety and efficacy data for these drugs in this vulnerable population.

Pulmonary Advisor: What are the future needs in this area, in terms of research or otherwise?

Dr Kumar: We are beginning to understand fetal origins of pulmonary vascular disease, especially in infants born preterm. The implications of intrauterine growth restriction on vessel reactivity and late onset pulmonary or systemic hypertension in adults need to be explored. This opens up a vast area of fetal and perinatal origins of adult-oriented disease for further research. The impact of reducing prematurity and LBW will have a tremendous effect on both the economics and the health burden on a global scale.

Please note this interview was edited for length and clarity. 

References

1. Blencowe H, Cousens S, Chou D. Born too soon: The global epidemiology of 15 million preterm births. Reprod Health. 2013;10(Suppl 1):S2. doi:10.1186/1742-4755-10-S1-S2 
2. Bokodi G, Treszl A, Kovacs L, Tulassay T, Vasarhelyi B. Dysplasia: a review. Pediatr Pulmonol. 2007;42(10):952-961. doi:10.1002/ppul.20689
3. Kumar VHS. Diagnostic approach to pulmonary hypertension in premature neonates. Children. 2017;4(9):75. doi:10.3390/children4090075
4. Rocha, G. Chorioamnionitis and lung injury in preterm newborns. Crit Care Res Pract. 2013;2013:890987. doi:10.1155/2013/890987
5. Gortner L, Reiss I, Hilgendorff A. Bronchopulmonary dysplasia and intrauterine growth restriction. Lancet. 2006;368(9529):28. doi:10.1016/S0140-6736(06)68964-2
6. Al-Ghanem G, Shah P, Thomas S, et al. Bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis. J Perinatol. 2017;37:414-419. doi:10.1038/jp.2016.250
7. Ryan RM, Ahmed Q, Lakshminrusimha S. Inflammatory mediators in the immunobiology of bronchopulmonary dysplasia. Clin Rev Allergy Immunol. 2008;34(2):174-190. doi:10.1007/s12016-007-8031-4