Current treatment of retinopathy of prematurity

Introduction

In retinopathy of prematurity (ROP), physiologic retinal vascular development is delayed and damaged, resulting in avascularity and ischemia of the peripheral retina. This may result in increased production of growth factors, including vascular endothelial growth factor (VEGF), leading to vasoproliferation at the junction between avascular and vascular retina (stage 3 ROP) or flat on the surface of the retina (aggressive posterior ROP). Left untreated, dysregulated angiogenesis may proliferate and potentially progress toward fibrosis, contraction, and ultimately tractional and serous retinal detachment (stage 4–5 ROP). While screening guidelines and ROP diagnosis are described in Chapter 43, this chapter will describe when to treat ROP, methods of ROP treatment and nuances therein, and how to ensure post-treatment disease regression.

When to treat ROP

Guidelines for treatment were first established by the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study which began enrolling patients in 1986, and updated by the Early Treatment for Retinopathy of Prematurity (ETROP) study which began enrolling patients in 2000. It is therefore worth noting that most patients born before 1986 in the United States had no rationally-based ROP treatment available to them. The CRYO-ROP study was a landmark study for the field, reducing unfavorable structural outcomes of “threshold ROP” by 45.8% at 12 months. Subsequently the ETROP study defined current treatment guidelines, including the designation of type 1 and type 2 ROP. Type 1 ROP requires treatment and is defined as the following: zone I, any stage ROP with plus disease; zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 with plus disease. The timing of onset of type 1 ROP is important, with a peak incidence of treatment-requiring ROP near the infant’s due date, and 99% of infants who develop ROP do so by 46.3 weeks.

Management of non-“treatment-requiring” ROP

When ROP is classified as type 2 (zone I, stage 1 and 2 without plus disease, or zone II, stage 3 without plus disease) or lower, close observation with serial examination/photography is the preferred approach. Most type 2 ROP does not progress, as ~20% of type 2 progressed to type 1 in the ETROP study, with a mean time of progression of 9 days from diagnosis.

Several studies have explored modifying environmental factors, including light adaptation, blood transfusions, nutritional status, and oxygen to decrease the incidence of type 1 ROP. Shukla et al. showed that biphasic oxygen supplementation resulted in a greater than 50% reduction in type 1 ROP. This is based on the concept that in phase 1 of ROP, hyperoxygenation results in retinal vascular attenuation and vaso-obliteration, and therefore oxygen parameters were proposed to be set at 88%–92% saturation up to 33–34 weeks estimated postmenstrual age (PMA). In phase 2 of ROP, relative retinal hypo-oxygenation results in pathologic angiogenesis, and therefore oxygen parameters were proposed to be set at 96%–99% saturation if any stage 2 or vascular tortuosity if the infant is >33–34 weeks of age without systemic contraindications.

When treatment is not indicated, spontaneous ROP regression often follows a regular pattern: resolution of pre-plus disease followed by reversal of stage of disease, subsequent growth of “vessels of regression” (straight and unbranched) past the ridge, and ideally full vascular maturation to the ora serrata. The duration and degree of spontaneous ROP regression depends on the presenting stage and zone of disease. While most ROP not requiring treatment does regress in the acute phase, one study found that roughly 2% of infants with type 2 ROP will not regress, exhibiting persistent ROP past 50 weeks, and the number of infants with residual avascular retina is significantly higher. Actual regression may be even less if infants are examined with fluorescein angiography (FA). In those that do exhibit regression, there will be varying degrees of persistent peripheral avascular retina. When present, persistent peripheral avascularity may create a milieu for retinal tears and detachments in teenage years and adulthood. Therefore, the author prefers performing an examination under anesthesia (EUA) with FA and potential laser for babies with significant areas of avascular retina at roughly 60 weeks PMA. This remains controversial, but data that continue to emerge from adult patients with untreated ROP that failed to meet threshold shows that this patient population is at higher risk of retinal holes, tears, and detachments as well as late reactivation of ROP. We believe that ablative laser therapy in this patient population may decreases the lifelong visual morbidity of ROP, but more data are needed to validate this recommendation.