Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (the STOP-ROP Multicenter Trial)

To test the efficacy, safety, and costs of providing supplemental oxygen in moderately severe retinopathy of prematurity (prethreshold ROP).

ROP remains one of the important morbidities among extremely premature infant survivors who are otherwise experiencing great gains in survival and in pulmonary and neurologic sequelae. While the use of cryo- or laser ablation of peripheral retina during the severe stages of ROP reduces the proportion of infants who progress to retinal detachments, less destructive treatment would be desirable.

More than 80 percent of infants who develop ROP heal the retinal neovascularization spontaneously, while only the minority progress to severe stages. Apparently, the normal physiologic control of retinal vascular growth is usually enough to control ROP. This observation led to basic studies on the control of normal and abnormal retinal vascularization that have identified tissue oxygen levels as important in the control of vessel growth. Combined with the observation of marginally low oxygen levels in the sickest of premature infants during their long convalescence from lung disease, an idea emerged. The hypothesis was that marginally low blood oxygen levels could interfere with control of retinal neovascularization -- the low levels further stimulating the vessel overgrowth. When that proved true in animal studies, the reverse experiment was tested and showed that raising the oxygen slightly over normal was enough to improve the retinopathy in its convalescent stages. Therefore, the STOP-ROP clinical trial was designed to test the hypothesis that supplemental oxygen in moderately severe (prethreshold) ROP would reduce the proportion of eyes that would progress to severe (threshold) levels of ROP.

Infants who develop moderately severe ROP are recruited to participate in STOP-ROP. Following informed consent, eligible infants are randomized to oxygen administration with continuous saturation monitoring at conventional levels (target pulse oximetry, 89-94 percent saturation) versus supplemental levels (target pulse oximetry, 96-99 percent saturation). Pulse oximetry is monitored continuously, and feedback to the bedside nurses is provided in a variety of formats on a laptop computer screen. Compliance with study targets is recorded systematically. Exact severity of ROP is confirmed by two independent, masked ophthalmologists at study entry and again if severe ROP (threshold) occurs. Infants remain on study-assigned oxygen saturation ranges for at least 2 weeks and until both eyes have reached study end points.

An adverse end point is progression to threshold ROP (with referral for possible ablative therapy). A favorable end point is regression of the ROP into zone 3 for at least two examinations, or complete retinal vascularization. Weekly examinations of the infants by study-certified, masked ophthalmologists ensure timely identification of study end points and limit use of study-assigned treatment and equipment to what is absolutely necessary. The pediatric end points of rate of growth, cardiopulmonary stability, and achievement of early motor milestones are also measured as secondary end points. All infants receive a final followup examination to confirm retinal status and pediatric end points at 3 months following their expected full-term due date (usually 5-6 months following birth).

To make it possible to detect a reduction in progression to threshold ROP from 30 percent to 20 percent, 880 infants will be enrolled. The Data and Safety Monitoring Committee monitors primary and secondary outcome measures and all adverse events over the course of the study.

Study Organization
The STOP-ROP study is uniquely funded and organized to promote research on behalf of vision in children. The NEI fully funds the Study Headquarters, the Data and Safety Monitoring Committee, and seven participating centers. The NEI and the National Institute of Child Health and Human Development (NICHD) support another 10 centers through the NICHD Neonatal Network for Clinical Trials. The National Institute of Nursing Research also contributes to the support of the study. The remaining centers are participating with alternative funds or through volunteer efforts and with a capitation from the NEI provided per patient enrolled.

Newborns with prethreshold ROP in one or both eyes are eligible.

No longer recruiting. Comments: Completed. Recruitment was completed on March 31, 1999 with 649 infants enrolled.

Completed, with results published. Comments: Completed with results published in February 2000.

A total of 649 infants were enrolled from 30 centers over 5 years. Of that number, 325 received conventional oxygen supplementation (89 percent to 94 percent pulse oximetry saturation) and 324 received supplemental oxygen (96 percent to 99 percent pulse oximetry saturation). Five hundred ninety-seven (92.0 percent) infants attained known ophthalmic endpoints, and 600 (92 percent) completed the ophthalmic 3-month assessment.

Use of supplemental oxygen did not cause additional progression of prethreshold 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 without plus disease, but this finding requires additional study. Supplemental oxygen increased the risk of adverse pulmonary events including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age. Although the relative risk/benefit of supplemental oxygen for each infant must be individually considered, clinicians need no longer be concerned that supplemental oxygen, as used in this study, will worsen active prethreshold ROP.