Delhi Journal of Ophthalmology

APROP - A Reflection of Neonatal Care

Dr. Parveen Sen (MS)
Senior Consultant, Vitreoretina Department
Sankara Nethralaya, Chennai

Corresponding Author:

Dr. Parveen Sen (MS)
Senior Consultant, Vitreoretina Department
Sankara Nethralaya, Chennai

Published Online: 08-OCT-2020



Keywords :

Retinopathy of prematurity (ROP) is a menace and Aggressive posterior ROP (APROP) is the most severe, rapidly progressive form of this vision threatening devastating disease that happens to the smallest and the most preterm of babies. Inspite of its aggressive behavior, its formal recognition as a distinct entity happened only in 2005 by the International Committee for the Classification of ROP.1 Though APROP is characterized by a posterior presentation in zone 1 or posterior zone 2 with prominent dilatation and tortuosity of retinal vessels, the disease can be missed by an inexperienced observer because of a deceptively featureless demarcation between vascular and avascular retina, flat network of neovascularization and intraretinal shunts not necessarily at the junction between vascular and avascular retina, and rapid progress to Stage 5 without going through the intermediate stages of disease progression. 

The article in this issue by Mitra et al2 highlights that the single most important modifiable risk factor in these babies with APROP was prolonged unblended oxygen supplementation seen in 76.6% and ventilator dependence seen in 50%. Uncontrolled and unsupervised oxygen therapy as a major cause of injury to the developing blood vessels in the immature retina leading to ROP was established as early as 1940s; even today the most important cause of ROP remains unmonitored use of oxygen. In a recent study, the cause of excessive oxygen supplementation in India was lack of air-oxygen blenders, absence of continuous oxygen monitoring and overcrowding even in the “special neonatal units” in district hospitals.3 “OWL” Oxygen with Love is of paramount importance if we want to give “life” as well as “quality of life” to our babies. Current guidelines suggest, oxygen saturation (SpO2) target of 85 – 93% from birth to 36 weeks’ postmenstrual age for infants <28 weeks gestation with oximeter alarm limit set at 80 – 95%. For infants born at 28-34 weeks of gestation, the SpO2 target range of 90-95% is recommended with the oxygen saturation alarm limits set at 85-98%.4 Oxygen as a risk factor for APROP is even more important because many clinicians believe APROP, especially in the low and middle income countries (LMIC) where it is seen in larger and heavier babies,5 to be largely oxygen induced because of the phenotypic similarities seen between APROP and the mouse model of “oxygen induced retinopathy”6 characterized by hyperoxia induced vaso-obliteration as seen in APROP from LMIC. This is in contrast to APROP that is seen in very low birth weight and very premature babies in the developed nations where the retinal vasculature doesn’t develop beyond posterior pole. 

The clinical presentation and treatment response in APROP has also been explained by Flynn et al.7 on the basis of two phase hypothesis of retinal vascular development; an early phase of “Vasculogenesis” seen between 14-21 weeks’ gestation that results in formation of the four major arcades in the posterior pole and a later phase of “Angiogenesis” which results in increasing capillary density and formation of the peripheral vessels. While angiogenesis is largely driven by hypoxia induced VEGF 165, vasculogenesis is less dependent on VEGF 165. When the injury to the vascular development happens very early, it affects the “vasculogenic” pathway resulting in a posterior disease and a later insult to the “angiogenic” pathway affects the peripheral retina. Presence of ridge and capillary budding process are suggestive of an insult to the angiogenic phase. Also, injury to the mesenchymal primordial cells causing vasculogenesis results in extensive damage to the main vascular arcades as seen in APROP.7 Because of this, laser to the peripheral avascular retina does not cause complete disease regression in majority of cases of APROP or zone 1 ROP and is associated with poor outcome to treatment as compared to peripheral zone 2 and zone 3 ROP; rates of tractional retinal detachment can be as high as 45% in APROP.8 Flynn et al also hypothesized that the beneficial effect of Bevacizumab in posterior ROP could be because of inhibition of abnormal vasculogenesis upstream from VEGF 165 or direct neutralization of “vitreal macrophages” which are an alternate source of VEGF in these eyes. Fundus fluorescein angiography (FFA) gives a better “in vivo” insight into this abnormal vasculature seen in APROP. Post treatment with antiVEGF has shown abnormal retinal vasculature even months to years after regression of disease in posterior ROP.9

The other important systemic risk factor known for development as well as progression of APROP includes Respiratory distress syndrome (RDS), caused by surfactant deficiency in the lungs. Prolonged RDS leads to bronchpulmonary dysplasia (BPD) due to lung injury caused by oxygen toxicity and mechanical ventilation; this further results in progression to severe forms of ROP. Blood transfusions often required by babies in NICU can also contribute to the progression of ROP, since adult hemoglobin has a lower affinity for oxygen than fetal hemoglobin, resulting in increased oxygen delivery to the immature retina, thus reducing the hypoxia driven angiogenesis.

Thrombocytopenia, though common in neonates, has not often been discussed as a risk factor for APROP. Platelets are known to play an important role in transport of angiogenic regulatory proteins, VEGF, cytokines and thrombospondin.9

Lower levels of platelets in premature babies may add “insult to injury” and lead to rapid progression of APROP; a timely platelet transfusion can even allow spontaneous regression of ROP.9  

Babies with ROP are also known to have abnormalities of central nervous system like Intraventricular haemorrhage (IVH), Periventricular leukomalacia (PVL) and hydrocephalus. This is more due to similar underlying pathologic mechanism of immature labile vasculature and fluctuating oxygen levels.10  

Like in many other systemic diseases, retina in ROP bears the brunt of the insult caused by the systemic turmoil experience by the premature babies in their fight for survival. Understanding of these underlying pathogenic pathways and a coordinated effort with the neonatologist is the need of the hour for effective prevention and treatment of ROP, especially its severest form. This can lead to targeted treatment regimens and prevent the destructive ablation of large areas of avascular retina especially in APROP. 

  1. International committee for the classification of retinopathy of prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005. Jul; 123(7):991–9.
  2. Mitra S, Sarpal S, Chattopadhyay A, Paul S, Roy JG. Retrospective Analysis of Risk factors in Aggressive Posterior Retinopathy of Prematurity (APROP). Delhi J Ophthalmology 2020, 31(1): 23-25 
  3. Sabherwal S, Gilbert C, Foster A, Kumar P. Status of Oxygen Monitoring in Four Selected Special Care Newborn Units in India Indian Pediatr. 2020 Apr 15;57(4):317-320. 
  4. Garcia-Serrano JL, Uberos Fernández J, Anaya-Alaminos R, et al "Oxygen with love" and diode laser treatment decreases comorbidity and avoidable blindness due to retinopathy of prematurity: results achieved in the past 12 years. Pediatr Neonatol. 2013 Dec;54(6):397-401.
  5. Shah PK, Narendran V, Kalpana N. Aggressive posterior retinopathy of prematurity in large preterm babies in South India. Arch Dis Child Fetal Neonatal Ed 2012;97: F371-375.
  6. Smith LE, Wesolowski E, McLellan A, et al. Oxygen-induced retinopathy in the mouse. Invest Ophth Vis Sci. 1994; 35:101-11.
  7. Flynn JT, Chan-Ling T. Retinopathy of prematurity: two distinct mechanisms that underlie zone 1 and zone 2 disease. Am J Ophthalmol 2006; 142:46–59.
  8. Vinekar A, M. T. Trese, and A.Capone Jr., “Evolution of retinal detachment in posterior retinopathy of prematurity: impact on treatment approach,” American Journal of Ophthalmology, vol.154, no. 3, pp. 548–555, 2008. 
  9. Vinekar A, Hegde K, Gilbert C, Braganza S, Pradeep M, Shetty R, Shetty KB Do platelets have a role in the pathogenesis of aggressive posterior retinopathy of prematurity? Retina. 2010 Apr;30(4 Suppl): S20-3.
  10. Sjakon G Tahija, Rini Hersetyati, Geoffrey C Lam, Shunji Kusaka, and Paul G McMenamin. Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol. 2014 Apr; 98(4): 507–512
  11. Steck J, Blueml C, Kampmann S, Greene B, Maier RF, Arnhold S, et al. Retinal vessel pathologies in a rat model of periventricular leukomalacia: a new model for retinopathy of prematurity? Investigative ophthalmology & visual science. 2015; 56(3):1830–41.

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