Modern neonatal care has curbed the incidence of ROP, yet because the survival rate of low birth weight infants is much higher, the exposure of surviving babies to required oxygen levels is increasing

Retinopathy of prematurity (ROP), originally called retrolental fibroplasia, is a vasoproliferative disorder that affects the retina of newborn infants. The condition was first described in 1942,¹ and in the early 1950s investigators theorized that it was caused by the use of oxygen therapy to treat respiratory distress in premature infants.² Today, ROP causes blindness in 50,000 children worldwide each year,³ and a number of causes have been identified, including high levels of oxygen. Because low levels of oxygen can lead to additional respiratory complications in newborns, particularly in premature infants, there has been a growing recognition of the fine line between too much and too little oxygen. Today, better oxygen monitoring has led to better control of oxygen administered to newborns. Yet, although the rate of blindness from ROP has dropped since the years before treatment was available, there are still many new cases of blindness each year from this disorder—it remains a leading cause of childhood blindness and visual disability in the United States.⁴ 

Pathogenesis
In the normal fetus, from about 16 weeks until birth, blood vessels grow outward from the optic nerve toward the peripheral retina. The last 12 weeks of a normal 40-week gestation period are a critical period in the development of the fetal eyes. In infants born prematurely, normal retinal blood vessel growth sometimes stops, and abnormal blood vessels can develop in the retina. This is called neovascularization. ROP occurs when the abnormal blood vessels grow and spread throughout the retina, leading to scarring and retinal detachment.

Two pathogenic phases have been described.⁵ Phase I begins with delayed retinal vascular growth after premature birth. Phase II follows when Phase I-induced hypoxia releases various factors to stimulate new blood vessel growth. Both oxygen-regulated and non-oxygen–regulated factors contribute to normal vascular development and retinal neovascularization. An important oxygen-regulated factor is vascular endothelial growth factor (VEGF). The non-oxygen–regulated growth factor, insulin-like growth factor-I (IGF-I), also has been implicated in the pathogenesis of ROP. Investigators have shown that in knockout mice, lack of IGF-I prevents normal retinal vascular growth, despite the presence of VEGF, which is important to vessel development.⁶ Premature infants who develop ROP have been found to have low levels of serum IGF-I compared to age-matched infants without ROP.⁷ IGF-I therefore appears to be critical to normal vascular development.

Clinical Stages
ROP is classified into five clinically distinct stages, depending on severity.^8-10 Stage I disease is characterized by mildly abnormal blood vessel growth. Many children whodevelop Stage I disease eventually develop normal vision. Stage II disease is characterized by moderately abnormal blood vessel growth. As with Stage I disease, many children who develop Stage II disease eventually develop normal vision. In Stage III disease, there is severely abnormal blood vessel growth. The abnormal blood vessels grow toward the center of the eye instead of following their normal growth pattern along the surface of the retina. If the blood vessels of the retina become enlarged and twisted as a result of the neovascularization (often designated as “plus disease”), then treatment is warranted. Treatment of Stage III disease has a good chance of preventing retinal detachment. Stage IV disease is defined by a partially detached retina. Scarring and bleeding cause traction on the retina, which might be pulled away from the wall of the eye. There also can be scleral buckling. In Stage V disease, the retina is completely detached. If untreated, there will invariably be severe visual impairment or blindness.

A number of risk factors for ROP have been identified (see Table).^10-12 

Supplemental Oxygen and ROP
The National Eye Institute (NEI) performed a randomized trial ^13,14 to evaluate the efficacy and safety of supplemental oxygen for the treatment of moderate-to-severe ROP. This trial was called the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) study. In this study, 649 premature infants were enrolled at 30 centers over 5 years. 325 infants received conventional oxygen supplementation (89% to 94% O₂ saturation by pulse oximetry) and 324 received “high” supplemental oxygen (96% to 99% O₂ saturation by pulse oximetry). The use of supplemental oxygen did not cause additional progression of moderate-to-severe ROP but also did not significantly reduce the number of infants requiring peripheral retinal ablative surgery. A subgroup analysis suggested a benefit of supplemental oxygen among infants who have prethreshold ROP (moderate-to-severe ROP without “plus disease”), but this finding was said to require additional study.

The investigators of the NEI study^13,14 concluded that modest supplemental oxygen given to premature infants with moderate-to-severe ROP might not significantly improve ROP, but it definitely does not make it worse. In this study, use of supplemental oxygen increased the risk of adverse pulmonary events, including pneumonia; exacerbations of chronic lung disease; and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age.

Interestingly, in premature infants excluded from the STOP-ROP study because their median arterial oxygen saturation was >94% in room air at the time of prethreshold diagnosis, the rate of ROP progression was less than that of infants included in the study.¹⁵ Fifteen of the 30 centers that participated in STOP-ROP elected to participate in the High Oxygen Percentage in Retinopathy of Prematurity (HOPE-ROP) study. A total of 136 HOPE-ROP infants were compared with 229 STOP-ROP infants enrolled during the same time period from the same 15 hospitals. HOPE-ROP infants were of greater gestational age at birth (26 versus 25 weeks) and greater postmenstrual age (37 versus 35 weeks) at the time of prethreshold ROP diagnosis. HOPE-ROP infants progressed to threshold ROP 25% of the time, compared with 46% of STOP-ROP infants. After gestational age, race, postmenstrual age at prethreshold diagnosis, and presence of plus disease at prethreshold diagnosis were controlled for, logistic regression analysis showed that HOPE-ROP infants progressed from prethreshold to threshold ROP less often than STOP-ROP infants. The reasons for the better ROP outcome among HOPE-ROP versus STOP-ROP subjects are not completely understood, but the investigators noted that an infant’s median arterial oxygen saturation by pulse oximetry value at the time of prethreshold diagnosis may be a prognostic indicator for which infants might progress to severe ROP.

Recently, a prospective study was performed to determine whether lowering O₂ saturation alarm limits for infants at risk of ROP reduces its incidence and/or severity.¹⁶ Oximetry alarm limits were lowered to 85% and 93% for all infants with a birth weight of 1,250 g and/or gestational age 28 weeks and maintained until 32 weeks postmenstrual age or until oxygen saturations were consistently greater than 93% in room air. In the year after the oximeter alarm limit policy change, 4 of 72 infants developed prethreshold ROP, compared with 44 of 251 infants in the previous 3-year period . Similarly, only 6 of 144 eyes developed prethreshold ROP in the year after the policy change, compared with 84 of 502 in the previous 3 years. The investigators concluded that a simple change in oximeter alarm parameters in the first weeks of life for infants with a birthweight 1,250 g or less may decrease the incidence of prethreshold ROP.

Summary
The use of high supplemental oxygen in premature infants with prethreshold ROP seems to be more closely related to other pulmonary adverse events than it does to the progression of ROP. It also would appear, based on the most recent evidence, that by strictly avoiding hyperoxia (O₂ saturation 92% to 93% by pulse oximetry) and avoiding fluctuations in O₂ saturation in premature infants, it might be possible to control and prevent severe ROP in most cases.

John D. Zoidis, MD, is a contributing writer for RT. For more information, contact RTeditor@ascendmedia.com.

References
1. Terry TL. Retrolental fibroplasia in the premature infant. V. Further studies on fibroplastic overgrowth of the persistent tunica vasculosa lentis. Proc Trans Am Ophthalmol Soc. 1944; 42:383-96.

2. Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical approach. Med J Aust. 1951; 2:48-50.

3. Saugstad OD. Oxygen and retinopathy of prematurity. J Perinatol. 2006; 26(suppl):S46-50.

4. Drack A. Retinopathy of prematurity. Adv Pediatr. 2006; 53:211-26.

5. Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res. 2004; 14(suppl):S140-4.

6. Smith LE. Pathogenesis of retinopathy of prematurity. Acta Paediatr Suppl. 2002; 91:26-8.

7. Smith LE. Pathogenesis of retinopathy of prematurity. Semin Neonatol. 2003; 8:469-73.

8. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. Arch Ophthalmol. 1987; 105:906-12.

9. Flynn JT. An International Classification of Retinopathy of Prematurity: development of the classification of the late stages of retinopathy of prematurity. Birth Defects Orig Artic Ser. 1988; 24:175-83.

10. Machemer R. Description and pathogenesis of late stages of retinopathy of prematurity. Birth Defects Orig Artic Ser. 1988; 24:275-80.

11. Karna P, Muttineni J, Angell L, Karmaus W. Retinopathy of prematurity and risk factors: a prospective cohort study. BMC Pediatr. 2005; 5:18-23.

12. Liu PM, Fang PC, Huang CB, et al. Risk factors of retinopathy of prematurity in premature infants weighing less than 1,600 g. Am J Perinatol. 2005; 22:115-20.

13. National Eye Institute. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (the STOP-ROP Multicenter Trial). 2000. Available at: www.nei.nih.gov/neitrials/static/study40.asp. Accessed November 25, 2006.

14. STOP-ROP Multicenter Study Group. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics. 2000; 105:295-310.

15. McGregor ML, Bremer DL, Cole C, et al. Retinopathy of prematurity outcome in infants with prethreshold retinopathy of prematurity and oxygen saturation >94% in room air: the high oxygen percentage in retinopathy of prematurity study. Pediatrics. 2002; 110:540-4.

16. Vanderveen DK, Mansfield TA, Eichenwald EC. Lower oxygen saturation alarm limits decrease the severity of retinopathy of prematurity. J AAPOS. 2006; 10:445-8.