Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy

Abstract

Purpose: To determine incidence, risk factors, risk period, and characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy.

Design: Retrospective case series.

Participants: Premature infants with type 1 ROP (subdivided into stage 3+ ROP and aggressive posterior ROP [APROP]) in zone I or zone II posterior who received IVB monotherapy and were followed up for at least 65 weeks adjusted age (AA).

Methods: Retrospective review of infants who demonstrated recurrence of type 1 ROP after IVB monotherapy, including examination of RetCam fundus photographs and fluorescein angiograms.

Main outcomes measures: Incidence, risk factors, risk period, and characteristics of recurrent ROP.

Results: Intravitreal bevacizumab monotherapy in 241 infants (471 eyes) was reviewed. Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. Recurrence risk factors of greatest significance were appearance of neovascularization as APROP (P = 0.006), extended duration of hospitalization (P = 0.01), and lower birth weight (P = 0.024). Recurrence risk period was between approximately 45 and 55 weeks AA (90.0% [18/20] for infants and 94.1% [32/34] for eyes), with mean recurrence of 51.2 weeks AA (±4.6 weeks; range, 45.7-64.9 weeks) and mean interval of 16.2 weeks (±4.4 weeks) between treatments. Recurrence characteristics included plus disease (20/20 infants [100%]) and neovascularization, which appeared at the following sites: stage 3+ ROP with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extraretinal fibrovascular proliferative complex (12/14 infants [85.7%]). However, APROP (6/6 infants [100%]) and stage 3+ ROP with nonconfluent neovascularization (2/14 infants [14.3%]) recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean, 1.76 disc diameters [DD] vs. 4.48 DD), and the rate of retinal vascularization was delayed (mean, 0.11 DD/week vs. 0.23 DD/week) in those with versus without recurrence, respectively. After retreatment with IVB, retinal vascularization proceeded minimally and slowly.

Conclusions: Premature children with severe ROP are being treated successfully with IVB monotherapy. However, recurrence is not uncommon, so vigilant follow-up is necessary to ensure timely re-treatment. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows for tailored clinical management.

Figure 1

The Kaplan-Meier survival curve for the probability for NO RECURRENCE with Type 1 ROP was found for infants Stage 3+ to be 93.7% (208/222) and for infants with APROP to be 68.4% (13/19).

Figure 2

The right eye of Patient 9 had ROP stage 3+ requiring 2 injections of bevacizumab for initial and recurrent disease (470 grams, 24 weeks at birth). A. Photograph just prior to first injection for ROP stage 3+ ROP (35.1 weeks AA). B. Fluorescein angiogram of same eye (A) after completion of retinal vascularization (77.9 weeks AA). C. Photograph and D. Fluorescein angiogram just prior to second injection for recurrent ROP at two sites (52.7 weeks AA). (Arrows).

Figure 3

The left eye of Patient 2 had APROP requiring 2 injections of bevacizumab for initial and recurrent disease (450 grams, 23 weeks at birth). A. Photograph just prior to first injection for APROP (34.0 weeks AA). B. Fluorescein angiogram of same eye (A) after completion of retinal vascularization (96.0 weeks AA). C. Photograph and D. Fluorescein angiogram just prior to second injection for recurrent ROP at a single site (48.9 weeks AA). (Arrows).

Figure 4

The eyes of infants matched for BW (490 to 510 grams) and GA (23 to 24 weeks) at time of initial successful injection of bevacizumab (A) for ROP stage 3+ or (C) for APROP, and (E) for no treatment for spontaneously regressed ROP compared to the same eyes when retinal vascularization reached the fullest extent possible based on GA in B, D, and F, respectively. A. Photograph of right eye treated for ROP Stage 3+ (495 grams, 23 weeks at birth) at 35.6 weeks AA. B. Fluorescein angiogram of same eye (A) after completion of retinal vascularization (79.6 weeks AA). C. Photograph of right eye treated for APROP (490 grams, 24 weeks at birth) at 34.6 weeks AA. D. Fluorescein angiogram of same eye (C) after completion of retinal vascularization (131.1 weeks AA). E. Photograph of right eye untreated (spontaneously regressed ROP stage 2) (510 grams, 23 weeks at birth) at 113.4 weeks AA. F. Fluorescein angiogram of same eye (E) after completion of retinal vascularization (113.4 weeks AA).