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

Authors: Abed (Abdulrahman) Baiad¹, Imaan Kherani², Marko M. Popovic³, Glen Katsnelson², Rajeev H. Muni⁴, Kamiar Mireskandari⁵, Nasrin N. Tehrani⁵, Tianwei Ellen Zhou³, Peter J. Kertes⁶. ¹Faculty of Medicine and Health Sciences, McGill University, ²Temerty Faculty of Medicine, University of Toronto, ³Department of Ophthalmology and Vision Sciences, University of Toronto, ⁴Department of Ophthalmology and Vision Sciences, University of Toronto and Department of Ophthalmology, St. Michael’s Hospital/Unity Health Toronto, ⁵Department of Ophthalmology and Vision Sciences, University of Toronto and Department of Ophthalmology, Hospital for Sick Children, ⁶Department of Ophthalmology and Vision Sciences, University of Toronto and John and Liz Tory Eye Centre, Sunnybrook Health Sciences Centre.

Author Disclosures: A. Baiad: None. I. Kherani: None. M.M. Popovic: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); PSI Foundation, Fighting Blindness Canada. Financial support (to institution). G. Katsnelson: None. R.H. Muni: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Bayer. Any direct financial payments including receipt of honoraria; Description of relationship(s); Financial Support (to institution). Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Bayer, Novartis, Allergan, Roche. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Advisory Board. K. Mireskandari: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Bayer. Any direct financial payments including receipt of honoraria; Description of relationship(s); Financial Support (to institution). Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Santen Inc, Bayer, Novartis. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Advisory board. N.N. Tehrani: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Bayer. Any direct financial payments including receipt of honoraria; Description of relationship(s); Financial Support (to institution) – Bayer. T. Zhou: None. P.J. Kertes: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Allergan, Bayer, Roche, Novartis, Bayer, ArcticDx. Any direct financial payments including receipt of honoraria; Description of relationship(s); Financial support (to institution), Financial support (to institution), Financial support (to institution), Financial support, Financial support, Equity owner. Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Novartis, Alcon, Bayer, Novelty Nobility. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Advisory board.


Abstract Body: 

Purpose: To evaluate neurodevelopmental safety of intravitreal bevacizumab (IVB) compared to laser photocoagulation (LPC) for the treatment of retinopathy of prematurity (ROP). ROP is the most common cause of preventable blindness in preterm infants. First-line treatments include LPC or IVB, an anti-VEGF agent that inhibits retinal neovascularization. Despite promising efficacy and increasing clinical use over the last decade, concerns for the safety of IVB have been raised. 

Study Design: Meta-Analysis 

Methods: MEDLINE, EMBASE and Cochrane Library databases were searched up to September 2022 to select studies comparing IVB alone to LPC in ROP patients. Studies were included if they reported at least 12-month follow-up data of any primary neurological outcomes such as severe neuro-developmental impairment (sNDI), cerebral palsy (CP), and hearing impairment (HI). Secondary outcomes were moderate-to-severe impairment (msNDI) and neurodevelopment measured using the composite Bayley Scores of Infant Development 3rd Edition (BSID-III). A random effects meta-analysis was performed. 

Results: Overall, 1998 articles were identified. 927 patients from 9 comparative studies were included. 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 comparators 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). Quality of evidence was rated low. 

Conclusions: 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 slightly increased risk for sNDI and CP with IVB but little or no difference in the risk of msNDI and HI. Moreover, infants who received IVB performed similarly on Bayley-III scales of infant development as infants who received LPC. Further randomized studies are needed to strengthen these findings.

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