Supplementary Material for: A meta-analysis of neurodevelopmental outcomes following intravitreal bevacizumab for the treatment of retinopathy of prematurity

Background: Retinopathy of prematurity (ROP) is the most common cause of preventable blindness in preterm infants. First-line treatments include intravitreal bevacizumab (IVB) or laser photocoagulation (LPC). Objectives: To evaluate neurodevelopmental safety of IVB compared to LPC for ROP. Methods: MEDLINE, EMBASE and Cochrane were searched up to September 2022. Studies were included with at least 12-month follow-up of primary outcomes such as severe neurodevelopmental impairment (sNDI), cerebral palsy (CP), and hearing impairment (HI). Secondary outcomes were moderate-to-severe impairment (msNDI), Bayley Scores of Infant Development (BSID-III) and visual impairment. Results: 1231 patients from 11 comparative studies were included. Quality of evidence was rated low for all outcomes. IVB was associated with a higher risk for sNDI (risk ratio [RR]=1.25, 95% confidence interval [CI] 1.01, 1.53, P=0.04) and CP (RR=1.40, CI [1.08, 1.81], P=0.01) compared to LPC. There was no significant difference between IVB and LPC for msNDI (RR=1.15, CI [0.98, 1.35], P=0.08) and HI (RR=1.43, CI [0.86, 2.39], P=0.17). BSID-III percentile scores were similar between IVB and LPC, with weighted mean differences of 1.51 [CI=-1.25, 4.27], 2.43 [CI=-1.36, 6.22] and 1.97 [CI=-1.06, 5.01] for cognitive, language, and motor domains, respectively (P>0.05). Conclusion: To our knowledge, this is the largest meta-analysis on neurodevelopmental outcomes and the first to rigorously examine IVB monotherapy in ROP treatment. Compared to LPC, there was a marginally increased risk for sNDI and CP with IVB but little or no difference in the risk of msNDI and HI. Further randomized studies are needed to strengthen these findings.