Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy

Abstract

PURPOSE To determine (1) incidence, (2) risk factors, (3) risk period, and (4) characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy. DESIGN Retrospective case series. PARTICIPANTS Premature infants developing Type 1 ROP [subdivided into ROP stage 3+ and aggressive posterior ROP (APROP)] in zone I or zone II posterior, receiving IVB monotherapy, and followed for at least 65 weeks adjusted age (AA). METHODS Retrospective review of infants who developed recurrence of Type 1 ROP following IVB monotherapy was performed including examination of RetCam fundus photographs and fluorescein angiograms. MAIN OUTCOMES MEASURES Incidence, risk factors, risk period, and characteristics of recurrent ROP. RESULTS IVB monotherapy in 241 infants (471 eyes) was reviewed. (1) Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. (2) 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). (3) Recurrence risk period was between ≈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; range 45.7 to 64.9), and mean interval of 16.2 weeks (±4.4) between treatments. (4) Recurrence characteristics included plus disease, (20/20 infants; 100%) and neovascularization appeared at the following sites: (i) ROP stage 3+ with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extra-retinal fibrovascular proliferative complex (12/14 infants; 85.7%). However, (ii) APROP (6/6 infants; 100%) [and ROP stage 3+ with non-confluent neovascularization (2/14 infants; 14.3%)] recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean 1.76 versus 4.48 disc diameters [DD]), and the rate of retinal vascularization was delayed (mean 0.11 versus 0.23 DD/week) in those with versus without recurrence, respectively. Following retreatment with IVB, plus disease persisted, neovascularization regressed, and retinal vascularization proceeded minimally and slowly. CONCLUSIONS Premature children developing 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 when needed. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows tailored clinical management.

Ultra-low-dose intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case series

“…In our series, we found that the need for retreatment arose at a mean of 44 weeks’ PMA (range 40–50), some 9.8 weeks post-IVB (range 6–15 weeks). Our recurrence window was somewhat earlier than that reported by Mintz-Hittner et al (mean 51.2 weeks’ PMA (range 46–65), at a mean of 16.2 weeks post-IVB) 9. It seems reasonable to draw the conclusion that use of ‘ultra-low’-dose IVB may be characterised by a slightly different timeline from the higher ‘standard’ dose, namely that the drug takes effect slightly slower and that any recurrence is likely to present more swiftly.…”

“…Whereas recurrence of neovascularisation and ‘plus’ disease would seem to be uniformly compelling indications for retreatment, we opted to administer additional treatment in other scenarios judiciously (eg, loculated vitreous haemorrhage obscuring the site of previously resolving neovascularisation). Second, even if we assume our ‘retreatment rate’ to be a valid proxy for the ‘recurrence rate’, it is clear that the demographics of our patient group placed them at especially high risk of recurrence, with our cohort generally having a lower GA and BW than the Mintz-Hittner et al series 9. In our series, we found that the need for retreatment arose at a mean of 44 weeks’ PMA (range 40–50), some 9.8 weeks post-IVB (range 6–15 weeks).…”

“…A limitation of our study is the lack of fluorescein angiographic images, which precludes any qualitative interpretation about the posterior pole or peripheral vascular maturation following IVB therapy. However, it has been our clinical impression (and that of others in the literature) that administration of higher dose IVB has the potential to abruptly halt retinal vascularisation, and that in a proportion of eyes normal vascularisation never subsequently resumes 9. Although elevated VEGF drives pathological vasoproliferation witnessed in stage 3 ROP, lower levels of VEGF are crucial for normal retinal vascular development 19.…”

“…Respiratory disease is a major source of morbidity and mortality in premature infants, and VEGF is also known to play an important role in alveolar maturation 8. From an ocular perspective, controversially, IVB has been proposed to have an adverse effect on normal retinal vascularisation, whereby effective cessation of peripheral vascularisation is witnessed in a proportion of eyes, particularly where repeat IVB injections have been administered 9. Additionally, vascular abnormalities have been identified at the posterior pole of eyes having received IVB therapy 10.…”

Role of cytokines and treatment algorithms in retinopathy of prematurity

“…Recurrences at the previous ridge or leading edge were found in former APROP but only in the advancing edge in eyes without confluent neovascularization. Retreatment led to slow regression(30). Although most recurrences were seen within 1 year of adjusted age, a report described late reactivation of ROP after bilateral IVB with a tractional retinal detachment in one eye and milder reactivation in the fellow eye at 2.5 years of age(31).…”