A reliable answer to the above question would require a large multicentre RCT comparing intravitreal bevacizumab (IVB) to laser, powered for long term outcomes. Such a trial does not currently exist.
As a result, 2 groups have just published systematic reviews of the observational studies that have compared outcomes of non-randomized cohorts with bevacizumab compared to either no treatment or to laser therapy.
The 2 reviews come to opposite conclusions!
Kaushal M, et al. Neurodevelopmental outcomes following bevacizumab treatment for retinopathy of prematurity: a systematic review and meta-analysis. J Perinatol. 2020, state “Bevacizumab treatment for severe ROP is associated with increased risk of cognitive impairment and lower cognitive and language scores in preterm infants”.
Tsai CY, et al. Neurodevelopmental Outcomes After Bevacizumab Treatment for Retinopathy of Prematurity-A Meta-Analysis. Ophthalmology. 2020. on the other hand state “severe NeuroDevelopmental Impairment risk was not increased in ROP patients after IVB treatment. Bayley-III scores were similar in the IVB and control groups, except for a minor difference in motor performance”.
In addition to cohort comparisons there is a small amount of data (n=16) from one of the centres involved in the BEAT-RoP RCT. All of the other studies reviewed were comparisons of non-randomized cohorts.
Such studies are fraught with potential bias. In our centre, for example, we were at first only using IVB for babies with BPD who were extubated and fragile and who we really didn’t want to re-intubate for laser surgery. They were therefore higher risk than laser treated babies. We also were using IVB mostly for babies with posterior disease who are not necessarily comparable to babies with zone 2 retinopathy.
Why would 2 almost simultaneous systematic reviews produce diametrically opposite results?
The first thing I did was to look at the tables with the included studies. Kaushal et al includes 13 studies, whereas Tsai has 8, three of which are not in Kaushal.
The discrepancies seem to be because Tsai included 2 studies that compared outcomes of babies who received IVB to babies with no treatment, and in one of those cases to a second control group of babies without retinopathy. You would think that such studies would show a difference in outcomes between IVB and control but in fact they showed very little. Those studies were not eligible for the review of Kaushal et al.
Kaushal includes 2 studies only reported as abstracts, which were not in Tsai’s publication list, and included 2 studies published in 2020 which may have appeared after Tsai finished their literature review. In addition 2 of the studies in Kaushal’s review only supplied mortality data, and one other does not appear to have supplied any data used in their analyses. The main difference in data sources, therefore, seems to be that Kaushal included Zayek et al and Arima et al from 2020, whereas Tsai included the above-mentioned studies with untreated controls.
As for the results, the definitions of “Severe Neurodevelopmental Impairment” are similar in the 2 reviews, and both reviews conclude that the 95% CI include an RR of 1.0, but Tsai’s analysis includes 5 studies and an RR of 1.52 (95% CI 0.91, 2.54) whereas Kaushal includes 3 studies (only 2 of which are in the Tsai analysis) and an RR of 1.33 (95% CI 0.74, 2.39).
As for the scores on the cognitive composite of the Bayley 3 evaluation, the Kaushal review, based on 6 studies, shows that cognitive scores are 1.8 points less with IVB than laser (the figure axis title wrongly states that this result “favours IVB”) 95% CI -3.5, -0.1; whereas Tsai et al also have 6 studies of IVB vs laser (only 3 of the studies are in both reviews) and a difference in cognitive scores of 1.69, 95% CI -4.9, +1.6. The 2 studies in Tsai’s review that compared laser to no treatment are calculated separately as showing little difference with wide confidence intervals (-2.6, 95% CI -8.2, +3).
In a similar way, but with a more marked difference, the scores on the Bayley 3 language composite are lower in the Kaushal review, 5.4 points less with IVB than laser (95% CI -9.2, -1.6), but in the Tsai review the difference in scores is only 1.36, (95% CI -5.5, +2.8).
What does this all mean? Basically, I don’t think you can rely on the results of these SRs to give an answer to the question. Systematic reviews of observational studies suffer from the same problems as the observational studies they are based on. Differences in characteristics of the babies treated with either therapy are likely, and, no matter how the data are adjusted, such biases remain.
Long-term visual outcomes are clearly better with IVB, with much lower rates of severe myopia. I think all that you can say about long term developmental and neurological outcomes is that there remains a concern that there could be adverse impacts of IVB, but the data collected so far are conflicting. I think we should give parents a choice when retinopathy treatment is required, informing them that for aggressive or posterior disease there are advantages of IVB, and also major unknowns for the long term. Of course the ophthalmologists treating the babies have to agree to that also!
Clearly, the large multicentre RCT, powered for long term outcomes, that I mentioned at the beginning of this post, is needed. These systematic reviews suggest that such a trial should be powered to find a 5 point difference in cognitive scores on the Bayley version 3, which would need close to 150 patients per group, or alternatively a 10% difference in the proportion of children with neurological impairment or developmental delay, in this high-risk group that would need somewhere in the region of 200 babies per group, depending on what the hypothesized baseline rate is. Those sample sizes seem achievable to me without too much difficulty, and I think this should be considered a priority for our community.