Retinopathy of prematurity (ROP) is one of the leading causes of childhood blindness worldwide. With increasing survival of the smallest and youngest preterm infants, 14-20% of childhood blindness is attributed to ROP in the United States and worldwide.1,2
In developing countries, there is an added risk of unregulated oxygen inducing damage to newly developed retinal capillaries due to insufficient resources for neonatal care. Genetic predisposition to ROP also has been identified3; several individual studies have presented candidate genes associated with various degrees of severity of ROP, but no one candidate has been identified universally.4 This may be partly due to the influence of external factors on ROP risk, including oxygenation, postnatal growth, neonatal, and perinatal care.5-7
Retinopathy of prematurity is a clinical diagnosis and has been characterized by stage of disease, zone of disease, and presence or absence of plus disease. Stage describes the level of severity of ROP and zone is the region in the retina where ROP stage is present. Plus disease is the dilatation and tortuosity of the posterior pole vessels.8 Laser to the avascular retina is considered the gold standard of treatment for ROP based on seminal clinical trials conducted in the 1980s and '90s, including the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity Study and Early Treatment for Retinopathy of Prematurity Study9,10; however, pharmacologic treatments, especially with agents that inhibit the bioactivity of the angiogenic factor, vascular endothelial growth factor, (anti-VEGF agents) have emerged and become popular since the publication of the clinical trial testing the anti-VEGF agent bevacizumab and laser.11 However, inhibition of this important growth factor for developing and maintaining healthy vascular beds12 suggests need for caution, and clinical studies subsequently identified persistent avascular retina, recurrent severe ROP, total retinal detachment, and reduced serum VEGF levels as real concerns regarding the safety of these agents at the doses reported.13-15
Retinopathy of prematurity was first described in the 1940s, at a time when unregulated oxygen was used in the neonatal intensive care unit (NICU) for resuscitation of preterm infants.16 Early studies by Ashton17 exposed newborn animals to high levels of oxygen and elucidated the connection between oxygen and ROP. Subsequent clinical trials led to the observation that high oxygen at birth was a cause of the early epidemic of ROP.18
Our understanding of ROP has evolved significantly from the days of those early studies. Clinically, the first description of “retrolental fibroplasia” by Terry16 may have represented present day stage 5 ROP or total retinal detachment and the most advanced stage of the disease. Since then several studies have been used to change oxygen levels to meet oxygen saturation targets. The Surfactant Positive Pressure and Pulse Oximetry (SUPPORT)6 and Benefits of Oxygen Saturation Targeting (BOOST) IF studies both found low oxygen saturation targets were associated with reduced severity of ROP but also with increased mortality of infants. However, in SUPPORT there was wide variability in mortality across NICUs and no identified cause for differences was apparent.19 Subsequent analysis of the SUPPORT data revealed that infants who were small for gestational age had increased vulnerability to lower oxygen targets with increased intermittent hypoxemic events and lower survival, accounting for the variability in mortality rates.20 The Canadian Oxygen Trial (COT) tested similar oxygen saturation targets but found no difference in ROP severity or mortality.21
This manuscript will review the current animal models used to study ROP, factors that have been identified as targets for pharmacotherapy based on these animal models, and seminal trials demonstrating the clinical efficacy and clinical implications of the use of these pharmacologic agents.
MODELS OF ROP AND PATHOPHYSIOLOGY
The most widely used animal models to reflect features of ROP are oxygen-induced retinopathy (OIR) models. The mouse OIR model exposes newborn mice to high oxygen levels that damage newly formed retinal capillaries and may reflect some forms of severe ROP.22 In the rat OIR model, pups are exposed to fluctuating levels of oxygen that translate to arterial oxygen measurements in preterm infants who develop severe ROP.23,24 The rat OIR model not only reflects compromised physiologic vascularity from high oxygen but also causes a delay in physiologic retinal vascular development similar to what occurs in today's extremely premature infants who develop severe ROP. The models have been described as having 2 phases. In phase 1, there is compromised physiologic vascularity or vasoobliteration of newly formed capillaries and delay in physiologic retinal vascular development. Phase 2 models the events after an infant's removal from high supplemental oxygen to ambient air, which leads to hypoxia in nonvascular regions of the retina and angiogenic factor-induced vasoproliferation into the vitreous.25 The rat model also demonstrated intrauterine and postnatal growth restriction, which are risk factors for ROP.26 There is also a beagle model of OIR that recreates compromised physiologic vascularity and delay in physiologic retinal vascular development followed by vasoproliferation. This is useful for pharmacologic studies because there is more similarity in eye size between beagles and premature infants than between rat or mouse pups and human infants.27,28
The disadvantage of all animal models is the use of newborn but not preterm animals. Mouse models allow for the use of transgenic mice with specific knockout mutations, whereas the rat model is limited because the rat genome is difficult to manipulate. However, it is more representative of what is seen clinically in ROP in modern practice and gene therapy methods have been used to successfully knockdown factors in specific cells of the retina.29
A unique feature of the human retinal vasculature is its development by vasculogeneis from about 12 to 22 weeks of gestational age.30 Subsequent vascular development is believed to progress by angiogenesis, with proliferation of endothelial cells in response to VEGF level fluctuations.31
Oxygen-induced retinopathy models are useful to identify signaling pathways activated and involved in phase 1 or 2 ROP, thus suggesting possible therapeutic targets at various times in the pathophysiology. A major inciting feature in models of OIR is retinal hypoxia. The response to oxygen tension within the cell is regulated by hypoxia-inducible factors (HIFs), which are transcription factors that direct the expression of gene products that increase glycolysis, hematopoiesis, angiogenesis, and vasculogenesis.32 Prevention of OIR in 2 species using HIF propyl hydrolase domain proteins during phase 1 of disease has been demonstrated.32
Vascular endothelial growth factor is critical for retinal vascular development but triggers signaling through VEGF receptor 2 to disorder developing angiogenesis and lead to aberrant vasoproliferation and plus disease in phase 2 in models of OIR.33,34 Therefore, experimental studies provided evidence that knocking down VEGF levels to those that restored VEGF receptor 2 signaling to a physiologic level reduced both phases of ROP: reducing vasoproliferation of phase 2 into the retina and also improving compromised physiologic vascularity and extended physiologic vascular development of phase 1.33,34 However, use of an intravitreal neutralizing antibody to VEGF at a dose that inhibited vasoproliferation caused a further reduction in physiologic retinal vascularity33,34 and may translate to hypoxia-induced recurrent stage 3 ROP seen in infants treated with anti-VEGF agents.15
Besides pathways involving VEGF, others have been discussed including those involving oxidative signaling,35 inflammation,36,37 and many other angiogenic factors that can also affect angiogenesis and the occurrence of OIR, although a full review of these is beyond the scope of this article.38
CLINICAL IMPLICATIONS/PHARMACOTHERAPY
Oxygen
Oxygen is the most commonly used drug in neonatal care for respiratory support.39 Though unregulated oxygen was shown to be a risk factor for early cases of ROP and retrolental fibroplasia18 and is currently accepted as a cause of ROP today, the relationship between supplemental oxygen and the development of ROP and other neonatal conditions is complex. Therefore, no one recommendation, other than to avoid high oxygen exposure at birth, is universally recognized. The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial, conducted in the late 1990s, compared oxygen saturations of 89-95% in one group of preterm infants to that of 96-99%.40 The trial did not demonstrate any difference between the 2 groups in the development of threshold ROP or the need for ablative treatment to the peripheral retina. There was no difference in mortality. However, in subgroup analysis, there was reduction in progression to severe (then threshold) ROP in infants without plus disease.
The SUPPORT trial in the United States reported decreased ROP but increased mortality in the 85-89% oxygen saturation group as compared with the 91-95% saturation group.6 Similar results were seen in the BOOST II study conducted in Australia, the United Kingdom, and New Zealand.7 A meta analysis investigating all published randomized trials of the effect of restricted versus liberal oxygen did not demonstrate a difference in the development of ROP.41 No difference in ROP or mortality was reported in the COT with the same oxygen saturation groups.42
VEGF Inhibitors
The Bevacizumab Eliminated the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study was the first published clinical trial that tested bevacizumab, a recombinant humanized antibody that binds all isoforms of VEGF-A, compared with laser treatment. A benefit was reported compared with laser in infants with zone I/posterior zone II, stage 3 disease with plus disease.11 The BEAT-ROP study was not sufficiently powered to study safety and future neurodevelopment. The follow-up continued through 54 weeks postgestational age, and late recurrences of ROP, persistent avascular retina, and reduced serum VEGF levels in infants treated with intravitreal bevacizumab monotherapy have been reported.13-15,43,44 A follow-up study of infants in the original BEAT-ROP study reported recurrences in 8.3% with the average peak occurring 16 weeks (±4 days) after injection.45
The BEAT-ROP study evaluated the efficacy of bevacizumab alone; however, subsequent studies investigated the use of ranibizumab for the same indication. Ranibizumab is a recombinant humanized monoclonal IgG1 kappa isotype antibody fragment that has higher affinity for VEGF and a shorter half-life than bevacizumab.46 Unlike bevacizumab, there seems to be less systemic inhibition of VEGF.13 When used at half the adult dose (ie, half the dose that is commonly used to treat conditions such as age-related macular degeneration in adults) of 0.25 mg/0.025 mL, treatment with ranibizumab resulted in a higher rate of recurrence of ROP compared with bevacuzimab, with an overall reactivation rate of 33% at an average of 8.3 ± 2.7 weeks.46
The BEAT-ROP study did not address the optimal dosing of bevacizumab. In the study, 0.625 mg in 0.025 mL, or one half of the adult dose of bevacizumab, was utilized. The Pediatric Eye Disease Investigator Group undertook a dose de-escalation study to investigate the optimal dosing of bevacizumab.47 The investigators treated 1 eye of infants with type 1 ROP with 0.25 mg intravitreous bevacizumab. If an improvement was seen in plus disease or zone I stage 3 ROP by 5 days or sooner after injection and there was no recurrence within 4 weeks, the next group of infants received a lower dose of 0.125 mg, then 0.063 mg, and finally 0.031 mg. The authors concluded that even a bevacizumab dose of 0.031 mg, representing 5% of the dose used in BEAT-ROP, was effective in 9/9 eyes at 4 weeks, although serum VEGF was still reduced and bevacizumab was still detected in the serum. Additionally, with higher concentrations of the drug, there were more failures.
The Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity study compared 0.12 mg of intravitreous ranibizumab with 0.2 mg in type 1 ROP in 19 infants and found equal success rates between the 2 groups in controlling acute ROP, which was defined as not requiring rescue therapy at 24 weeks. However, infants were allowed repeated doses of ranibizumab as reinjection (ie, a favorable initial response was seen lasting at least 28 days and then the patient received the same dose as the original treatment dose) or as rescue therapy (ie, inadequate initial response requiring laser or 0.2 mg ranibizumab therapy). The need for rescue therapy was similar in the 2 groups and the VEGF plasma levels were not altered systemically in either group.48
Pegaptanib sodium, an RNA aptamer targeting VEGF-165, has been reported in conjunction with laser to the avascular retina in the treatment of zone I/posterior zone II, stage 3 ROP with plus disease and levels of severity similar to BEAT-ROP enrolled infants, at a concentration of 0.3 mg in 0.02 mL. The recurrence rate of ROP in 1 or both eyes was significantly lower in the combination treatment group, and the authors felt there was better peripheral vascular development in the pegabtanib group.49
Insulin-Like Growth Factor-1
Insulin-like growth factor-1 (IGF-1) plays a role in endothelial cell growth and angiogenesis via interactions with VEGF and is important in fetal growth, especially in the third trimester.50 Levels of IGF-1 have been shown to be lower in infants who develop ROP,51 and IGF-1 administration in growth restricted mice reduced oxygen-induced retinopathy.52
Supplementation of IGF-1 combined with IGF binding protein 3 (rhIGF1/rhIGFBP3) administered by intravenous infusion in 5 very preterm infants (median gestational age of 26 weeks ± 6 days) during the first week of life brought the IGF-1 levels to the lower end of normal without any obvious adverse effects.53 The IGF-1 levels fell rapidly after the initial infusion, indicating the need for continuous or longer infusion to maintain levels at a physiologic minimum. Of note, none of the 5 patients developed severe ROP or intraventricular hemorrhage. Initial results from a multicenter phase 2 study in which 61 infants with a gestational age of 23-27 weeks were treated with rhIGF1/rhIGF1BP3 showed no effect on ROP prevention compared with age-matched controls, although a large proportion of the patients did not achieve IGF-1 levels in the intended range.54
Erythropoietin
Erythropoietin is a glycoprotein hormone that was first described as responsible for red blood cell production. It is believed that erythropoietin plays a role in the development of visual function and neuroprotection.55 Early administration of erythropoietin stabilized retinal capillaries and reduced high oxygen-induced compromise of physiologic vascularity, but late erythropoietin was believed to increase vasoproliferation.56 Erythropoietin was shown to increase intravitreal neovascularization in a transgenic mouse model of OIR.57 Clinically, retrospective studies on the use of erythropoietin for anemia of prematurity found an association between erythropoietin and increased risk of ROP,58 but ongoing clinical trials have not yet reported outcomes from early erythropoietin administration on ROP.59
Antioxidants
Oxidative phosphorylation, or the breakdown of oxygen in the mitochondria, produces reactive oxygen species (ROS). These are molecules that react with lipids and can lead to DNA damage.60 Excessive ROS production can contribute to retinal mitochondrial damage, especially in preterm infants who do not have mature antioxidant systems.61,62 Antioxidants, therefore, have been proposed for the treatment and prevention of ROP. Despite experimental support for the use of antioxidants, clinical trials have not led to the recommendation of long-term antioxidant treatment.63
Vitamin E has been investigated for the treatment and prevention of ROP with conflicting results and unclear efficacy. A Cochrane review was performed on 26 randomized clinical trials that met criteria. Vitamin E significantly reduced germinal matrix/intraventricular hemorrhage but increased the risk of sepsis. In very low birthweight infants, there was also increased risk of sepsis but reduced risk of ROP.64 Earlier studies had demonstrated increased retinal hemorrhages and grade 3 and 4 intraventricular hemorrhages in infants treated with vitamin E.65,66 However, a meta-analysis of vitamin E supplementation suggested that it was associated with reduced stage 3 ROP.67 Nonetheless, the risks of sepsis are sufficiently concerning that high-dose vitamin E has not been routinely recommended.
N-acetylcysteine, a precursor of cysteine, which in turn is precursor of glutathione, an antioxidant, has been studied in supplementing parenteral nutrition in preterm neonates. A meta-analysis of the efficacy did not demonstrate benefit in the prevention of ROP.68
D-penicillamine is an antioxidant and suppressor of VEGF bioavailability, which was studied in the prevention of ROP with conflicting results.69-71
Superoxide dismutase administered intratracheally showed no difference in the rate of ROP overall but a reduction in severe ROP in a subgroup of infants born at gestational ages younger than 25 weeks.72
Lutein has been studied in a double-blind randomized controlled trial but showed no difference in the incidence of ROP.73
A meta-analysis of vitamin A supplementation suggested a trend toward reduced incidence of ROP but further studies are necessary to confirm this conclusion.74
Cyclooxygenase Inhibitors
The prostaglandin-cyclooxygenase (COX) pathway plays a role in vascular development in a variety of tissues including the retina. Studies in mice and rat models of OIR demonstrated that COX-2 inhibitors suppressed retinal angiogenesis and improved oxygen-induced retinopathy.75,76
Two studies of topical ketorolac for the prevention of ROP were undertaken, 1 showing no benefit and 1 showing a possible decrease in severe ROP in the eye randomized to receive ketorolac drops.77,78
A small cohort study demonstrated decreased rates of severe ROP in infants with antenatal dexamethasone exposure. A large prospective study showed no difference in the rates and severity of ROP in infants who were exposed to antenatal steroids.79,80 Given the significant adverse effects, the role of dexamethasone and steroids remains controversial in the prevention of ROP.
Propranolol
Propranolol is a nonselective beta-adrenergic receptor blocker that has been shown to decrease the incidence of severe ROP.81-83 However, concerns regarding systemic hypotension and bradycardia remain and large-scale clinical trials are ongoing to clarify the role and optimal route of administration of propranolol. One propranolol trial was discontinued due to a high incidence of systemic adverse effects.69
Caffeine
Caffeine is frequently used in the treatment of apnea of prematurity and is frequently prescribed in the NICU. Caffeine is a trimethylxanthine that antagonizes adenosine receptors.84 A large prospective study of apnea of prematurity with caffeine demonstrated a reduction in the severity of ROP.85 A subsequent meta-analysis demonstrated that early caffeine use was associated with decreased risk of ROP requiring laser photocoagulation (odds ratio = 0.447, P = 0.024).86 Caffeine has been demonstrated to inhibit VEGF and apoptosis of endothelial cells.84 Prospective clinical trials are needed to further characterize the relationship between caffeine administration and ROP.
CONCLUSIONS/FUTURE AVENUES OF INVESTIGATION
Despite significant advances in our understanding of ROP since its first description by Terry16 in the 1940s and the evolution of animal models that allow us to develop novel treatment approaches and pharmacotherapies, ROP continues to be a significant cause of blindness in the preterm infant. Part of the difficulty in finding safe and effective therapies lies in the changes in ROP manifestation with regular advances in neonatal treatments and the ability to save ever smaller and younger preterm infants. In addition, ROP varies throughout the world in developmental age at birth and developmental stage and size of infants at presentation. These factors potentially change the steps in the pathophysiologic process, making treatment choices complex regarding efficacy and safety. Future studies both at the bench and bedside will elucidate further the pathophysiology of this complex disease and enlarge our armamentarium for treatment and prevention.
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