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Retinopathy of Prematurity
Introduction
Retinopathy of prematurity (ROP) is a disease of retinal vascular and capillary proliferation affecting premature infants undergoing oxygen therapy.[1] Oxygen treatment results in pathologic growth of vessels in the developing retina that may lead to permanent damage to the retina as well as retinal detachment and macular folds.[2][3][4]
Screening guidelines for this leading cause of childhood blindness are based upon gestational age and birth weight, although numerous factors increase both the incidence and severity of disease development.[5] Early treatment of disease with cryotherapy, laser photocoagulation, and anti-vascular endothelial growth factor (VEGF) therapy has improved visual outcomes for patients, however, early recognition through screening is critical.[5] Prevention of ROP requires a multidisciplinary approach beginning before the infant is born and continuing throughout childhood.
Etiology
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Etiology
In utero, the retina is in a state of physiological hypoxia. Elevated levels of vascular endothelial growth factor (VEGF) facilitate retinal angiogenesis.[5][6][7][6] The two phases of normal vascular development are characterized as vasculogenesis, from the 14th week until the 21st week, and angiogenesis, beginning in the 22nd week and continuing until the retina is fully vascularized after term.[8]
Because the nasal and temporal portions of the retina form late in pregnancy, 32 and 40 weeks respectively, preterm infants are born with incomplete vascularization of these portions. The physiologic hypoxia that was previously driving vessel development is replaced with a state of hyperoxia, as many premature infants are exposed to supplemental in addition to atmospheric oxygen.
Epidemiology
Many important epidemiological risk factors for ROP were established in the Early Treatment for Retinopathy of Prematurity study. This randomized, prospective multicenter trial compared the safety of earlier vs. conventionally timed ablation of peripheral retina.[2] The incidence of any stage of ROP was 68% among infants weighing less than 1251g. In the year 2010, a global number of 184,700 infants and 14.9 million preterm infants developed any stage ROP.[3] Of those afflicted, 20,000 became blind or severely visually impaired, and 12,300 developed mild to moderate visual impairment.
The two strongest known risk factors for ROP are gestational age (GA) and birth weight (BW). A multicenter study of over 4000 infants with birthweight ≤1251g found that for each 100g increase in BW, odds of developing threshold ROP decreased by 27%, and for each extra week in GA, the odds of developing threshold ROP decreased by 19%.[9]
Another important risk factor is oxygen. As mentioned above, the use of supplemental oxygen in combination with atmospheric oxygen results in the reversal of physiologic hypoxia, which then contributes to retinal ischemia and subsequent overgrowth of retinal vessels in ROP. Additionally, the concentration of oxygen delivered is an independent risk factor for ROP, whereby increased concentrations of O2 increase the risk of ROP.[10] For every 12 hour period with transcutaneous PO2≥80mmHg, the risk of ROP doubles.[7] Duration of oxygen therapy is a significant risk factor for severe ROP.[11] Possible risk factors include hypertensive disorders of pregnancy, maternal diabetes, medication use, age, smoking, assisted conception, birth outside of a study center hospital, and multiple gestations.[12]
Pathophysiology
Events during the two phases of healthy vascular development, vasculogenesis, and angiogenesis underlie the zone 1 and zone 2 pathologies seen in ROP.[8] During vasculogenesis, vascular precursor cells (VPCs) exit from the optic nerve to form the four major arcades of the posterior retina. Angiogenesis is characterized by the proliferation of endothelial cells, arising from the existing vasculature formed during vasculogenesis.[8]
Vascular development in the retina is not completed in certain portions of the retina until after term. Specifically, the nasal and temporal portions do not complete development until 32 and 40 weeks, respectively. After birth, exposure to atmospheric oxygen and supplemental oxygen results in a rapid swing from relative hypoxia in utero to hyperoxia. Synthesis of IGF1, a vitally important hormone that regulates VEGF mediated vascular growth, is dependent upon adequate amino acid and energy supplies. A relative nutritional deficiency after birth in preterm infants results in depressed serum IGF1 levels. Together, hyperoxia and low IGF1 result in delayed retinal vascularization. Developing capillaries undergo vasoconstriction and eventual obliteration. These changes constitute phase 1 of ROP. Phase 2 of ROP consists of a decline of normal angiogenesis with predominant pathologic angiogenesis.
There is an increase of VEGF release into the vitreous, a drop of IGF1 levels, and peripheral avascular retinal neurons are damaged through hypoxic injury. High levels of VEGF in the vitreous results in the growth of pathologic vessels out of the retina.[13]
History and Physical
Screening for ROP is of crucial importance for premature or low birth weight (BW) infants. Guidelines from the American Academy of Ophthalmology, American Academy of Pediatrics, and the American Association for Pediatric Ophthalmology and Strabismus state that infants born ≤30 weeks gestational age (GA) or ≤1500 g BW should be screened for ROP. Depending on the clinical course, larger infants May benefit from screening as well.[14] On average, each infant requires 3.4 serial examinations.[15]
Evaluation
A dilated fundus exam should be performed on all infants born at ≤30 week GA and infants with BW ≤1500g.[5] Screening should begin at 4 weeks postnatal age or corrected GA of 30 to 31 weeks in the neonatal intensive care unit or the special newborn care unit but may be performed outpatient as well.[6][5] Before evaluation, dilation of the pupils is achieved with 2.5% phenylephrine hypochloride and 1% cyclopentolate or tropicamide with two instillations in a 15 minute period.[6] Care should be taken to prevent systemic absorption. Pupils may fail to dilate in advanced ROP.[14] Because infants may experience apnea and bradycardia during the examination, a nurse should be present.[5]
In an effort to limit the number of unnecessary screenings while capturing every case of ROP, the Postnatal Growth and Retinopathy of Prematurity Screening Criteria (G-ROP) was developed. In a validation study of 3981 infants, these guidelines were 100% sensitive and reduced infants screened by 30%.[16] This screening tool differs from traditional guidelines in that it includes weight gain as a variable in deciding whether or not to. Though the 2019 study demonstrated excellent sensitivity and improved specificity, all new prediction models should be tested and validated to compare performance to clinical and low-resource settings.[17]
Classification is described in terms of zone and stage of the disease.[18] The International Classification of Retinopathy of Prematurity is a consensus statement of the grading of ROP. Zone refers to the location of the leading edge of vascularization. The retina is divided into three zones: Zone I refers to a concentric area centered on the optic disc with a diameter twice the distance between the center of the optic nerve and the fovea, Zone II is a circle centered on the optic disc ending at the ora serrata and Zone III includes the temporal retina not included in the previous zones.[18] There are 5 stages with which to describe the severity of ROP. Each step refers to a specific retinal and vascular pattern at the border of the vascular and avascular retina.
Stage 1 is a thin but clear demarcation or structure that separates avascular retina anteriorly from vascularized retina posteriorly. The demarcation line is typically flat and white, with abnormal branching of vessels leading up to it.[18] Stage 2 is characterized by the presence of a ridge in the region of the demarcation line that extends above the plane of the retina.[18] “Popcorn” tufts of neovascular tissue may be seen posterior to the ridge. Stage 3 features the growth of extraretinal fibrovascular proliferation or neovascularization extending from the ridge into the vitreous. This tissue may give the ridge a ragged appearance. Stage 4 classification is given when a partial retinal detachment develops. This may be extrafoveal, stage 4A, or foveal, stage 4B. The most severe classification, Stage 5, is the tractional total retinal detachment. These detachments are often funnel-shaped or concave. Plus disease is a classification that may be present at any stage. It is described as increased venous dilation and arteriolar tortuosity of posterior pole retinal vessels. Plus disease indicates vascular shunting and severe ROP.[18]
Threshold ROP is diagnosed when 5 contiguous or 8 cumulative clock hours of stage 3 ROP, in zone 1 or 2, with plus disease.[19]
Treatment / Management
While early detection of ROP is crucial, not every case will require treatment. Based upon findings in the Early Treatment for Retinopathy of Prematurity study (ET-ROP), the decision to treat is dependent on the type of ROP. Type I ROP, including any stage zone I ROP with plus disease, zone I stage 3 with or without plus disease or zone II stage 2 or 3 with plus disease, should be treated. Observation is recommended for Type II ROP, including zone I stage 1 or 2 without plus disease or zone II stage 3 without plus disease.[2](A1)
Treatment of ROP is primarily surgical. The first surgical treatment considered both safe and effective for ROP was cryotherapy to the avascular retina. (CRYO-ROP study) In cryotherapy, the sclera, choroid, and full-thickness of the avascular retina are frozen from the surface of the eye.[6] While this treatment resulted in a 50% reduction in retinal detachments in threshold eyes, it was considered time-consuming and required general anesthesia as well as surgical displacement of the conjunctiva.[6] Argon and diode laser photocoagulation treatment to the avascular retina has further reduced unfavorable outcomes and has become the standard of treatment for ROP.[2](A1)
Due to the role of VEGF in the development of ROP, the use of anti-VEGF agents is a possible treatment strategy. The Bevacizumab Eliminated the Angiogenic Threat of Retinopathy of Prematurity study (BEAT-ROP) randomly assigned infants with stage 3 ROP in zone I or posterior zone II to receive therapy with an anti-VEGF agent, intravitreal bevacizumab, or conventional laser. The primary outcome in this study was the recurrence of ROP requiring treatment before 54 weeks postmenstrual age. There was a statistically significant difference in recurrence with 19 cases in the laser-treated group and 4 in the bevacizumab group. The treatment effect was significant patients in the zone I but not zone II. Macular dragging and retinal detachment were seen more frequently after laser treatment for zone 1 disease.[20] Though this study did not observe any systemic or toxic effects of IVB therapy, some concerns about its use persist. First, peripheral retinal vessel development continued after treatment with IVB, and subsequent case reports have reported late reactivation of ROP, up to 3 years after birth.[21][22] (B2)
The beneficial effects of VEGF, a hormone that is both neurotrophic and neuroprotective, should not be ignored as it helps to maintain the blood-brain barrier, generate surfactant in the lungs, create glomeruli in the kidneys and stimulate skeletal growth.[6] A 2019 study demonstrated higher mortality and poor cognitive outcomes in infants treated with bevacizumab than other treatment modalities.[23]
Retinal detachment confers a much higher risk of poor visual outcome.[24][25][26][27][28] For this reason, in advanced ROP, Stage 4A, Stage 4B, and Stage 5 surgery are indicated. Modalities for surgical intervention in stage 4 ROP include scleral buckling or lens sparing vitrectomy. In stage 5 disease, scleral buckling plays a limited role, and the most common approaches include lensectomy with vitrectomy or open sky vitrectomy. Surgical outcomes are considered for anatomical success, the attachment of posterior retina, and functional success, visual acuity. Functional success is challenging to measure and slow. Rates of anatomical success range between 13% and 45.5%.[29](A1)
Differential Diagnosis
- Familial exudative vitreoretinopathy
- Persistent fetal vasculature
- Incontinetia pigmenti
Prognosis
Advances have improved outcomes in treatment; nonetheless, many treated patients have adverse results in visual acuity. One of the goals of treatment is the avoidance of unfavorable retinal structural outcomes, defined by the ETROP study as a posterior retinal fold involving the macula, a retinal detachment involving the macula, retrolental tissue or mass obscuring the view of the posterior pole or vitrectomy or scleral buckling procedure. A follow up to the ETROP study found that at 2 years, unfavorable structural outcomes had been reduced to 9.1% in high-risk pre-threshold eyes treated early.[30]
The 6-year follow up of the same sample found that 34.6% of children had a visual acuity (VA) of 20/40 or better, 40.3% had an acuity greater than 20/40 and less than 20/200, and 23.7% had an acuity worse than 20/200 including light perception and blindness.[31]
Complications
Retinal detachment is the most frequent complication of ROP and is strongly associated with a poor visual outcome.[3][2] Macular folds are another common complication.[4] Threats to visual acuity persist through childhood, the most common sequelae is myopia.[5] Other late complications include glaucoma, amblyopia, cataract, and strabismus.[5]
Low vision secondary to retinopathy of prematurity is associated with higher rates of developmental, education and social challenges. A followup to the CRYO-ROP study evaluated a cohort of children born at a weight of <1251 g and threshold ROP at 5 and 8 years. Children in this cohort with unfavorable visual status, classified as vision limited to light perception or no light perception, had significantly higher rates of developmental disability, epilepsy, special education and below-grade-level academic performance.[32]
Postoperative and Rehabilitation Care
Postoperatively, premature infants require ventilation, either mechanical or positive pressure ventilation, parenteral feeding, and antibiotic treatment. Patients should be monitored via pulse oximetry, neurologic screening, ultrasounds screening, and assessment for bronchopulmonary dysplasia and patent ductus arteriosus.[33] Long term therapy for amblyopia includes the use of glasses, patching for 6 to 12 hours a day, or pharmacologic penalization, wherein a miotic agent such as atropine is used to “blur” vision in the sound eye.[34][35]
Deterrence and Patient Education
The role of oxygen therapy in the prevention of ROP is of crucial importance. There is a history of targeting SpO2 to reduce rates of ROP. In 2001, an observational study suggested that rates ROP could be decreased by using a lower SpO2 target without increasing the risk of death.[36] With the results of this and other studies suggesting lower SpO2 targets for neonates, the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) collaboration was formed. NeOProM consisted of an international group of neonatologists with the goal of determining the optimal SpO2 level in premature infants.[37] Study authors sought to compare SpO2 targets of 85% to 89% in infants born at <28 weeks gestation with the primary outcome of death or major disability at 18-24 months of age.[37] A total of five studies were funded. Analysis of the data showed that too little oxygen increases the risk of death and that the SpO2 target should be 90% to 94%.[38]
With such strong data suggesting that lowering SpO2 is an unacceptable solution for the problem of increasing rates of ROP, other solutions have been suggested. International data networks that monitor neonatal outcomes have demonstrated that Severe ROP is associated with financial investment, both within and between countries. Best practices in neonatal care include improved nutrition, infection control, pain control, temperature control, and supportive developmental care. These basic neonatal best care practices were outlined by Darlow et al. in 2019.[38]
Enhancing Healthcare Team Outcomes
Antenatal, delivery suite, and NICU personnel have a role in preventing ROP. Antenatal prevention includes the use of corticosteroids prior to preterm delivery, a treatment shown to reduce morbidity and mortality. [39] The World Health Organization recommends that antenatal corticosteroids be used at <35 weeks’ gestation if preterm birth is imminent and obstetric care is available.[40] Delivery suite interventions such as delayed cord clamping may reduce the risk of anemia and the need for blood transfusions, two potential risk factors for the development of ROP.[41] Mechanisms to prevent hypothermia, such as plastic occlusive wrapping, should be utilized as it was found that infants <33 weeks with NICU admission temperature of 36.5 degrees C to 37.2 degrees C had the lowest rate of ROP.[42]
NICU interventions to prevent ROP are of critical importance and have been discussed above.
References
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