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Brief Report
April 23, 2020

Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity

Author Affiliations
  • 1Indiana University Department of Ophthalmology, Indianapolis
  • 2Jaeb Center for Health Research, Tampa, Florida
  • 3Duke Eye Center, Durham, North Carolina
  • 4Eastern Virginia Medical School, Norfolk
  • 5Texas Children’s Hospital, Houston
  • 6John A. Moran Eye Center, Salt Lake City, Utah
  • 7Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
  • 8Pediatric Ophthalmology Associates Inc, Columbus, Ohio
  • 9Emory University School of Medicine, Atlanta, Georgia
  • 10Boston Children’s Hospital, Boston, Massachusetts
  • 11Dean McGee Eye Institute, University of Oklahoma, Oklahoma City
  • 12Wilmer Eye Institute, Baltimore, Maryland
  • 13Smith-Kettlewell Eye Research Institute, San Francisco, California
  • 14Baylor College of Medicine, Houston, Texas
  • 15Southern California College of Optometry at Marshall B. Ketchum University, Fullerton,
  • 16Mayo Clinic, Rochester, Minnesota
JAMA Ophthalmol. 2020;138(6):698-701. doi:10.1001/jamaophthalmol.2020.0334
Key Points

Question  What is the lowest effective dose of intravitreous bevacizumab for infants with severe retinopathy of prematurity?

Findings  In this masked phase 1 dose de-escalation study, 55 premature infants with type 1 retinopathy of prematurity were treated with intravitreous bevacizumab. Success, defined as improvement by 5 days and no recurrence requiring additional treatment within 4 weeks, was achieved in 13 of 13 eyes (100%) receiving 0.016 mg, and 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg.

Meaning  These findings suggest that 0.004 mg may be the lowest dose of bevacizumab effective for retinopathy of prematurity.


Importance  Intravitreous bevacizumab (0.25 mg to 0.625 mg) is commonly used to treat type 1 retinopathy of prematurity (ROP), but there are concerns about systemic toxicity, particularly the risk of neurodevelopmental delay. A much lower dose may be effective for ROP while reducing systemic risk. Previously, after testing doses of 0.25 mg to 0.031 mg, doses as low as 0.031 mg were found to be effective in small cohorts of infants.

Objective  To find the lowest dose of intravitreous bevacizumab effective for severe ROP.

Design, Setting, and Participants  Between April 2017 and May 2019, 59 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, dose de-escalation study. In cohorts of 10 to 14 infants, 1 eye per infant received 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreous bevacizumab. Diluted bevacizumab was prepared by individual research pharmacies and delivered using 300-µL syringes with 5/16-inch, 30-guage fixed needles. Analysis began July 2019.

Interventions  Bevacizumab intravitreous injections at 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg.

Main Outcomes and Measures  Success was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks.

Results  Fifty-five of 59 enrolled infants had 4-week outcomes completed; the mean (SD) birth weight was 664 (258) g, and the mean (SD) gestational age was 24.8 (1.6) weeks. A successful 4-week outcome was achieved for 13 of 13 eyes (100%) receiving 0.016 mg, 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg.

Conclusions and Relevance  These data suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP. Further investigation is warranted to confirm effectiveness of very low-dose intravitreous bevacizumab and its effect on plasma vascular endothelial growth factor levels and peripheral retinal vascularization.

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