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Should we be using bevacizumab for retinopathy of prematurity?



Geloneck MM, Cet al: Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol 2014, 132(11):1327-1333.

In this follow-up of the BEAT-RoP trial, eyes randomized to have laser were more likely to have severe myopia on follow-up at about 2.5 years than those randomized to bevacizumab. The difference is very large, 51% with laser, and 4% with bevacizumab. The severe (very high) myopia was defined as worse than 8 diopters, which is bad. The advantage of bevacizumab was for eyes treated both for zone 1 disease and for zone 2 disease.

The results are very similar to a small case-control study (Harder BC, et al: Early refractive outcome after intravitreous bevacizumab for retinopathy of prematurity. Arch Ophthalmol 2012, 130(6):800-801), which showed a mean refractive error after laser of between 5 and 8 diopters.

Another observational study showed much the same thing: (Chen YH, et al: Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes. Eye (Lond) 2014, 28(9):1080-1086; quiz 1087.).

As yet there is no evidence of systemic toxicity from bevacizumab, although I can't find a formal publication of other clinical or developmental outcomes. Such severe myopia, in infants with a destroyed peripheral retina, can't be a good thing.

Bevacizumab does get into the circulation, and, like other antibodies has a long half-life (21 days in this study : Kong L, et al: Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity. Invest Ophthalmol Vis Sci 2015, 56(2):956-961). Those authors also showed that serum VEGF levels were lower after beva.... (Im getting tired of typing that over and over, Ill call it BVZ) than after laser, and that seemed to persist for 60 days, although I can't tell from the way the data are reported whether the differences between the laser and BVZ groups were statistically important, (they say that the decrease in the BVZ groups was 'more significant' than the laser group, which is not clear to me). There also didn't seem much difference in this paper between the 2 different doses of BVZ, 0.625 mg, which the BEAT-RoP trial used, or a lower dose of 0.25 mg.

Which is a shame, as a lower dose seems to be effective, (Harder BC et al: Intravitreal low-dosage bevacizumab for retinopathy of prematurity. Acta Ophthalmol 2014, 92(6):577-581.) These authors trialed a dose of 0.375 mg and found good effects, with regression of disease in all babies, one very sick baby needed a second treatment.

We should add into the mix the need for anaesthesia, and usually intubation, for laser therapy, whereas intravitreal injections cause very little pain. (Castellanos MA et al: Pain assessment in premature infants treated with intravitreal antiangiogenic therapy for retinopathy of prematurity under topical anesthesia. Graefes Arch Clin Exp Ophthalmol 2013, 251(2):491-494).

What to do now? We have a treatment which appears highly effective, with only 4% recurrence, which leaves the peripheral retina intact and dramatically reduces the incidence of very severe myopia. But for which there remain uncertainties about extra-ocular safety.

I think the answer is that we should ask parents.

We should ask parent representatives about their opinions about standards for this potential off-label use, and we should ensure that individual parents are fully informed about the options prior to a decision about what treatment should be used for babies who qualify for treatment.

If a parent might reasonably opt for BVZ rather than laser, do we have enough reason to deny them that option?

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