Anti-VEGF Therapy for ROP May Be Associated with Incident Pulmonary Hypertension

Christopher R. Nitkin, MD

Anti-vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) was associated with a statistically not significant increase in the rate of treatment for pulmonary hypertension (PH), compared with laser treatment.

Specifically, preterm infants treated with anti-VEGF therapy had a 2.4% statistically not significant higher absolute risk of receiving pulmonary vasodilators over a 10-year period.

The findings from a multicenter cohort of children’s hospitals in the United States suggest that exposure to anti-VEGF may be associated with incident PH. Yet, study investigators could not exclude the potential of residual confounding factors such as systemic comorbidities or variation in practice.

“Future studies evaluating the safety of anti-VEGF therapy should include pulmonary hypertension as a key clinical outcome,” wrote corresponding author Christopher R. Nitkin, MD, Division of Neonatology, Department of Pediatrics, University of Missouri Kansas City School of Medicine.

Currently, there is no anti-VEGF agent labeled for use in ROP treatment by the US Food and Drug Administration (FDA). Intravitreal bevacizumab lowers serum VEGF levels for up to 8 weeks and thus could inhibit vascular development in developing organ systems.

Due to ongoing pulmonary angiogenesis in preterm infants, investigators stressed the antibody-based ROP therapy could induce or worsen PH, previously demonstrated in preclinical models.

The retrospective cohort study used the Pediatric Health Information System (PHIS) to collect infant hospitalization data from 48 children’s hospitals in the US from 2010 to 2020. Study participants were preterm infants with documented gestational age 23 to 32 weeks who had ROP and were treated with either anti-VEGF therapy or laser photocoagulation.

The identified main outcomes included the initiation of first pulmonary vasodilator treatment (inhaled nitric oxide, sildenafil, bosentan, milrinone, epoprostenol, or treprostinil) beginning at least 7 days after ROP therapy and matched using propensity scores generated from pre exposure variables.

From the identified hospitalizations (n = 477,550), a total of 1577 patients (55.9%) met inclusion criteria. In this population, 689 received laser photocoagulation and 868 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab).

Data show infants were first treated for ROP at a median 36.4 weeks’ postmenstrual age (interquartile range [IQR], 34.6 - 38.7). Within the full cohort, infants who received anti-VEGF treatment had significantly younger GA at birth and lower birth weight.

In the propensity score analysis, 491 infants from each treatment group were matched. Investigators noted an overall good covariate balance achieved as indicated by a model variance ratio of 1.15.

The study period yielded a significant increase in the proportion of infants treated with anti-VEGF therapy compared with laser, and in 2015, anti-VEGF therapy became the prominent therapy. Increases were not uniform across study sites, according to investigators, with 11 sites using anti-VEGF therapy 75% or more of the time and 4 using laser photocoagulation 75% or more of the time.

The findings indicated more infants who received anti-VEGF therapy were treated for PH (7.7% vs 4.7%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.00 - 2.95; P = .05). However, when adjusted for study site and year, the difference was no longer statistically significant (6.7% vs 4.3%; OR, 1.62; 95% CI, 0.90 - 2.89; P = .10).

“Neonatal clinicians should continue to partner with families to evaluate possible adverse effects of anti-VEGF therapy, evaluate the relative systemic risks of different anti-VEGF agents, and consider the potential harms of these medications alongside their potential benefits,” Nitkin wrote.

The study, “Pulmonary Hypertension in Preterm Infants Treated with Laser vs Anti-Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity,” was published in JAMA Ophthalmology.