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New Study Validates Safety of Same-Day Bilateral Anti-VEGF Injections for Preterm Infants with ROP, Highlights Risks in NICU Settings

Study Overview

  • Purpose: Evaluates the safety of same-day bilateral intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in preterm infants with retinopathy of prematurity (ROP).
  • Design: Retrospective, multicenter case series involving 16 tertiary eye care institutes in India, analyzing 9984 eyes of 4992 infants treated between January 2017 and December 2023.
  • Inclusion Criteria: Preterm infants with ROP treated with anti-VEGF injections bilaterally on the same day.
  • Exclusion Criteria: Infants treated in one eye or those receiving anti-VEGF before vitrectomy for stage 4 or 5 ROP.
  • Primary Objective: Report the incidence of presumed endophthalmitis after bilateral same-day anti-VEGF injections.
  • Secondary Objectives: Identify factors associated with complications, types of interventions required, and final anatomical outcomes of ROP.

Demographics and Clinical Characteristics

  • Mean gestational age: 29.8 ± 1.9 weeks.
  • Mean birth weight: 1235.5 ± 331.9 grams.
  • Most common indication: Aggressive ROP (A-ROP) in 4866 eyes (48.7%).
  • Other indications: Zone 1 staged ROP (5.3%), Zone 2 staged ROP (25.3%), hybrid ROP (25.3%), repeat injection for reactivation (1.1%).

Procedure Details

  • Setting: Most procedures performed in ophthalmic operation theater (OT) (8258 eyes, 82.7%), followed by neonatal intensive care unit (NICU) (1716 eyes, 17.2%).
  • Anesthesia: Topical anesthesia used in 99.4% of cases.
  • Needle and Syringe:
    • Most common needle: 29G (45.2%) or 30G (27.5%).
    • Tuberculin syringe used in 73.6% of cases; insulin syringe in 26.4%.
  • Injection Site: All injections administered 1–1.5 mm from the limbus (64.9% at 1 mm, 35.1% at 1.5 mm).
  • Anti-VEGF Agent: Bevacizumab most commonly used (8642 eyes, 86.6%), followed by Ranibizumab and biosimilar Ranibizumab (Razumab).
  • Pre- and Postoperative Care:
    • Preoperative povidone-iodine drops used in 100% of cases.
    • Preoperative antibiotics used in 17.7% of eyes (fluoroquinolones or tobramycin).
    • Postoperative antibiotics used in 54.8% of eyes (tobramycin most common, 42.3%).
    • First postoperative follow-up typically on day 1 (73.6%).

Complications

  • Overall complication rate: 26 eyes (0.3%).
  • Most common complication: Lens injury (15 eyes, 0.15%).
  • Presumed endophthalmitis incidence: 7 eyes (0.07%), with one culture-proven case due to Pseudomonas aeruginosa (0.01%).
    • No bilateral endophthalmitis cases reported.
    • Management: All cases treated with intravitreal antibiotics; 4 required pars plana vitrectomy.
    • Outcomes: 4 eyes had ROP regression with attached retina, 2 developed phthisis bulbi, 1 had detached retina.
  • Lens injury:
    • 6 eyes developed significant cataracts requiring surgical extraction.
    • All eyes with lens injury had ROP regression and attached retina at final follow-up.
  • Other complications:
    • Intraocular inflammation: 2 eyes (0.02%), managed with topical steroids and cycloplegics.
    • Vitreous hemorrhage: 3 eyes (0.03%), none required surgical intervention.
    • Retinal tear: 1 eye (0.01%), treated with laser photocoagulation.

Risk Factors for Complications

  • Endophthalmitis:
    • No association with procedure setting, type of anti-VEGF, or use of antibiotics.
    • Trend toward higher risk with biosimilar Ranibizumab (Razumab) (2.4–7.6 times higher risk), but not statistically significant.

 

  • Lens injury:

    • NICU setting: 7 times higher risk compared to ophthalmic OT (P < 0.001).

    • Ophthalmologist experience: 30 times higher risk when performed by those with <1 year of experience in preterm infant anti-VEGF injections (P < 0.001).

    • Needle type: 31G needle (6 mm, insulin syringe) associated with 3.6–8.6 times higher risk compared to 29G or 30G needles (P = 0.006).

 

  • Vitreous hemorrhage and retinal tear: No significant associations identified.

Key Findings

  • Low incidence of presumed endophthalmitis (0.07%) supports the safety of bilateral same-day anti-VEGF injections in ROP.
  • No bilateral endophthalmitis cases, critical for medicolegal considerations in India where guidelines discourage bilateral injections.
  • Lens injury risk significantly higher in NICU and with less experienced ophthalmologists, emphasizing the need for expertise and optimal setting.
  • Needle direction parallel to the visual axis is critical to minimize lens and retinal injury.
  • Prophylactic antibiotics: No evidence supporting routine use, as endophthalmitis occurred in eyes with antibiotic prophylaxis, while none occurred in eyes without.
  • Bevacizumab preference: Likely due to lower retreatment rates and cost-effectiveness in India.

Comparison with Prior Studies

  • Compared to Patel et al. (1677 eyes):
    • Higher endophthalmitis incidence (0.07% vs. 0%).
    • Lower vitreous hemorrhage rate (0.03% vs. 0.4%).
    • Similar lens injury rate (0.15% vs. 0.2%).
    • Current study had more A-ROP cases (48.7% vs. 17.9%) and preferred ophthalmic OT over NICU.
  • Landmark trials (BEAT-ROP, FIREFLEYE, RAINBOW):
    • Limited reporting of complications due to smaller sample sizes.
    • RAINBOW reported one case each of lens injury and endophthalmitis.

Clinical Implications

  • Bilateral same-day anti-VEGF injections are safe for ROP with low complication rates, particularly when performed in an ophthalmic OT.
  • Training and experience are critical to reduce lens injury risk.
  • NICU procedures require extra caution due to increased lens injury risk, possibly due to lack of operating microscope and globe stabilization challenges.
  • Povidone-iodine use is essential for infection prevention, while antibiotics may not be necessary.
  • Findings may influence AIOS-VRSI guidelines to support bilateral same-day injections in ROP, addressing medicolegal concerns in India.

Limitations

  • Retrospective design limits evaluation of systemic adverse effects or reactivation rates.
  • Lack of data on nasolacrimal duct patency or systemic sepsis as potential contributors to endophthalmitis.
  • Arbitrary definition of ophthalmologist experience (<1 year vs. >1 year) rather than procedure volume.
  • Limited vitreous sampling in endophthalmitis cases (only 2 of 7).

Citation

Gangwe AB, Agrawal A, Jalali S, et al. Bilateral Anti-VEGF on Same-Day Investigation on Safety in Retinopathy of Prematurity: A Multicenter Retrospective Study. Ophthalmology Retina. 2025;9(5):484-492. doi:10.1016/j.oret.2024.11.004