PEDIATRICS Vol. 107 No. 1 January 2001, pp. 215

Retinopathy of Prematurity: Taking the Next Step

To the Editor.

Present understanding of the pathogenesis of retinopathy of prematurity (ROP) can be summarized in describing preproliferative and proliferative stages of the disease process. The preproliferative stages probably involve actual or relative hyperoxic and perhaps hypoxic and ischemic injury of and hypercarbia-induced barotrauma to immature retinal capillaries, resulting in shunt formation. An arrest in peripheral retinal vessel development occurs. The inner portion of the peripheral avascular retina (PAR), presumably attributable to an oxygen deficit, begins to elaborate factors that promote neovasculogenesis, thus ushering in the proliferative stages of the disease. With continued progression, fronds of aberrant blood vessels flourish and grow into the vitreous along with myofibroblasts. Contraction of these vascular complexes results in traction retinal detachment.

Knowledge of the pathogenesis of ROP, as understood today, allows for the identification of potential modalities of medical therapy to ameliorate the disease. Indeed, the conceptual basis for performing cryotherapy is to eliminate the potential of the PAR to elaborate factors that stimulate aberrant vessel growth. Similarly, the idea of maintaining a higher blood oxygen saturation for the ROP-affected infant in the STOP-ROP Study¹ was to raise the tissue oxygen level of the inner PAR, which it was hoped would halt the formation of neovascular attracting factors² by this tissue. The marginal results obtained were somewhat disappointing but may be explained by a number of factors, not the least of which were waiting for prethreshold disease to enroll study patients and the physiologic instability of many very low birth weight preterm infants. The study did apparently establish the safety of the prescribed oxygen therapy, when used according to the study protocol. Could starting the oxygen therapy earlier in the disease process have improved outcome?

It is probable that whenever oxygen therapy is started in the proliferative stages of ROP, that time will be required to "quiet down" the undesirable biochemical reactions in the PAR. To "buy this time," an agent that might directly retard neovascularization and fibroplasia could be simultaneously administered. Such an agent may very well be D-alpha-Tocopherol (DAT) provided in doses to achieve pharmacologic blood levels.³ DAT used in this manner has been shown not to carry an increased risk for sepsis and necrotizing enterocolitis after an age of 8 postnatal weeks.³

As previously suggested,⁴ new or combinations of medical treatments may yet allow for improved outcomes in ROP. Adequate suppression of neovascularization to allow for spontaneous retinal repair in ROP may yet be achievable. Now is the time to consider additional basic science studies and potential future clinical trials involving single or combinations of therapies to halt ROP pathogenesis.

Gerald H. Katzman
Midwest Health Center
Dearborn, MI 48126

REFERENCES

1. The 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 [Abstract/Free Full Text]
2. Ezra DB Neovasculogenesis. Triggering factors and possible mechanisms. Surv Ophthalmol. 1979; 24:167-175 [CrossRef][Medline]
3. Johnson L, Quinn GE, Abassi S, Severe retinopathy of prematurity in infants with birth weights less than 1250 grams: incidence and outcome of treatment with pharmacologic serum levels of vitamin E in addition to cryotherapy from 1985 to 1991. J Pediatr. 1995; 127:632-639 [CrossRef][Medline]
4. Katzman GH Retinopathy of prematurity: is suppression of neovascularization achievable? J Pediatr. 1996; 129:618 [Medline]