PH Risk High in Very Premature Infants, But Might Be Treatable

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Infants born extremely premature — at 23 to 25 weeks of pregnancy — are at a high risk of developing pulmonary hypertension (PH) before they are 3 months old but can be helped with treatment, a recent study reported.

Initial signs of disease, evident on echocardiographs in these infants, had resolved for a majority of them at 1 year old after an off-label course of PH-targeted therapy.

“Our data may support the assumption that PH-targeted therapy is safe even” in extremely premature infants, “and can improve echocardiographic parameters of biventricular [the heart’s two ventricles] size and function at 12 months of chronological age,” its researchers wrote. But findings here “require confirmation in larger systematic investigations.”

The study, “Extremely premature infants born at 23–25 weeks gestation are at substantial risk for pulmonary hypertension,” was published in the Journal of Perinatology

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Premature birth — that before 37 weeks, when a pregnancy is first considered as full term — is associated with the development in infants of bronchopulmonary dysplasia (BPD), a lung disease marked by damage to the airways and tiny air sacs in the lungs (alveoli) where the exchange of gases takes place.

BPD can increase pressure in the arteries that supply blood to the lungs, resulting in pulmonary hypertension. About a quarter of infants born before 32 weeks of gestation and with moderate-to-severe BPD ultimately develop PH.

However, data on the risk of PH among extremely premature infants, those born at before 26 weeks of a pregnancy, are sparse.

Researchers in Germany and Austria examined the incidence of PH among 34 infants born prematurely (23 to 25 weeks of gestation) at a neonatal intensive care unit between January 2016 and December 2018.

Echocardiography — a technique used to image the heart — found signs of PH at 3 months of age in 15 of these 34 babies (44%).

PH indications included elevated right ventricular systolic pressure (RVSP), a measure to estimate the pressure in the artery that supplies blood to the lungs, and dysfunction of the heart’s right ventricle, a common PH feature.

Blood levels of NT-proBNP, a marker of heart failure, were also higher among PH infants. NT-proBNP is released from heart cells in response to strain.

All 15 children with signs of PH had either moderate (10 children) or severe (five children) BPD. The others had either mild BPD (16 children) or no signs of BPD (three children). While these three children did not meet BPD criteria at the time, all required some respiratory support, and they would be considered as having BPD under more recent diagnostic criteria, the team noted.

On average, infants with PH required longer treatment with supplemental oxygen, mechanical ventilation assistance, and continuous positive airway pressure, which helps keep the airways open, than did infants without PH. The PH group also had significantly lower birth weights (mean of 650 grams or 1.43 lbs vs. 726 grams or 1.6 lbs), and they were discharged from the hospital later than infants without PH.

Infants with PH also had a higher rate of sepsis — a severe immune response to infection in the bloodstream — suggesting “that early inflammation … may play a role in PH etiology [causes],” the researchers wrote.

After diagnosis, all 15 children were given PH-targeted therapies, with no observed side effects, the researchers reported. At age 3 months, 11 infants started treatment with Pfizer’s Revatio (sildenafil), and four — all with severe PH — received a combination of Revatio and Janssen’s Opsumit (macitentan).

“Off-label use of sildenafil is increasing in premature infants with PH, but based on limited safety and efficacy data,” the researchers noted. “We used sildenafil as first line treatment in all patients with signs of mild or moderate BPD-PH, and macitentan as an add-on drug only in those cases with signs of severe, resistant BPD-PH.”

In our patient group, “side effects (e.g., flushing for sildenafil; or low red blood cell count, common cold-like symptoms for macitentan) of the drugs were not observed,” they added.

The 19 babies with no previous PH signs continued to show no indications of the disease as 1 year olds. Among the 15 with signs of PH and given PH therapies, nine showed clinical improvement at 1 year of age and treatment was stopped.

“These results indicate that infants with moderate BPD are more likely to show resolution of BPD-PH throughout the first 12 months of life,” the researchers wrote.

Six continued to show signs of chronic BPD and PH on echocardiographs, with elevated RVSP values and evidence of heart dysfunction. Five of them had severe BPD, while in one the dysplasia was moderate.

NT-proBNP levels also remained high in these six children despite treatment, supporting previous reports that these levels could be a noninvasive, prognostic biomarker of PH in infants.

All six required continued treatment at 12 months old, with four given Revatio as monotherapy and the two others receiving Revatio with Opsumit.

These results show that extremely premature infants are “at substantial risk for developing BPD-PH,” and they further suggest that “early, sufficiently dosed PH-targeted pharmacotherapy” can be of benefit, the researchers wrote.

However, “large controlled trials are required to assess safety and efficacy of PH-targeted therapy in the vulnerable population of preterm infants,” they added.

Mechanisms that might underlie the development of PH in these at-risk infants also remains to be investigated.