Study Ties anti-VEGF Therapies to PH in Preterm Newborns

Injections that block VEGF protein may increase risk of pulmonary hypertension

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Premature newborns who are treated for eye problems with anti-VEGF therapies may be at increased risk of developing pulmonary hypertension, a new study suggests.

“Future studies evaluating the safety of anti-VEGF therapy should include pulmonary hypertension as a key clinical outcome. This is especially important as anti-VEGF treatment usage is increasing over time,” the researchers 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 the journal JAMA Ophthalmology.

Retinopathy of prematurity, or ROP, is a problem with eye development that affects the majority of preterm infants born with a very low birthweight. ROP can lead to blindness if untreated, so proper early management is important.

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Traditional treatment of ROP is laser photocoagulation, a surgical procedure that uses a laser to destroy abnormal structures in the eye.

An alternative treatment strategy is the use of medications that block VEGF (vascular endothelial growth factor), a signaling protein that helps to coordinate blood vessel development. Injecting anti-VEGF therapies into the eye can lead to better vision-related outcomes for ROP than laser photocoagulation, especially in aggressive cases. However, no anti-VEGF therapies are approved to treat ROP in the U.S., and the safety of these treatments remains incompletely characterized, especially with respect to organs outside the eyes.

Since VEGF is important for blood vessel development, therapies that block its activity could cause blood vessel abnormalities, which theoretically may lead to problems like pulmonary hypertension (PH). A team of U.S. researchers conducted an analysis of preterm infants treated for ROP to explore whether the use of anti-VEGF therapies is associated with PH risk.

“Our objective was to determine whether there was an association with increased risk of PH in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment,” the team wrote.

PHIS data

Using data from the Pediatric Health Information System (PHIS), an administrative database that records outcomes from nearly 50 children’s hospitals in the U.S., the scientists identified data for 1,577 preterm infants admitted to a neonatal intensive care unit from 2010 to 2020. Most of these children were born at 23 to 26 weeks’ gestational age, with a birth weight between 400 and 749 grams (about 14 to 26 ounces), and ROP treatment was started at a median of 36.4 weeks’ postmenstrual age. Postmenstrual age refers to gestational age, the time between the first day of the last menstrual period and a baby’s birth, plus the age since the baby’s birth.

Among the preterm babies, 689 were treated with laser therapy and 888 with anti-VEGF. The researchers noted that use of anti-VEGF treatments became more common in recent years, particularly after 2015, and that use of these therapies varied from site to site. Nearly all patients given anti-VEGF treatment were specifically given a medication called bevacizumab.

Using these data, the researchers conducted a propensity score analysis. They identified 982 patients, half treated with laser and the other half with anti-VEGF, who were similar in terms of other clinical characteristics. The researchers then compared outcomes in terms of PH, as assessed by whether patients were prescribed therapies usually given to manage PH.

In the overall group, rates of PH were significantly higher among patients given anti-VEGF than those treated with laser (8.3% vs 4.8%). A similar significant difference was seen in initial analyses of the propensity-matched group (7.7% vs 4.7%).

However, when the researchers made statistical adjustments to account for the year and site of treatment, the rate of PH was numerically higher among people given anti-VEGF (6.7 vs 4.3%), but the difference was not statistically significant. That means there is a non-negligible mathematical probability that the difference is due to random chance rather than any effect of the treatments.

“Anti-VEGF therapy for ROP was associated with a statistically not significant, but potentially clinically important increase in the rate of treatment for pulmonary hypertension,” the researchers concluded.

They added, “Our findings suggest that exposure to anti-VEGF may be associated with incident PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities [co-existing conditions], an unmeasured association between probability of receiving anti-VEGF therapy and developing PH, or hospital variation in ROP or PH treatment practices.”

Study limits

The team noted this study is limited by its reliance on administrative data, and by not having data regarding duration of PH treatment, long-term ocular outcomes and adverse effects from medications.

They stressed that the safety of ROP treatments is difficult to assess conclusively. Ideally, this might involve clinical trials that directly compare treatments, but the researchers noted that such trials “are expensive to perform and lack statistical power to detect differences in important, yet rare outcomes.” Lacking such well-controlled studies, “pharmacovigilance studies, such as ours, may be the strongest available evidence,” they wrote.

“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,” the researchers added.

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