Dl. Phelps et al., Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes, PEDIATRICS, 105(2), 2000, pp. 295-310
Objective. To determine the efficacy and safety of supplemental therapeutic
oxygen for infants with prethreshold retinopathy of prematurity (ROP) to r
educe the probability of progression to threshold ROP and the need for peri
pheral retinal ablation.
Methods. Premature infants with confirmed prethreshold ROP in at least 1 ey
e and median pulse oximetry <94% saturation were randomized to a convention
al oxygen arm with pulse oximetry targeted at 89% to 94% saturation or a su
pplemental arm with pulse oximetry targeted at 96% to 99% saturation, for a
t least 2 weeks, and until both eyes were at study endpoints. Certified exa
miners masked to treatment assignment conducted weekly eye examinations unt
il each study eye reached ophthalmic endpoint. An adverse ophthalmic endpoi
nt for an infant was defined as reaching threshold criteria for laser or cr
yotherapy in at least 1 study eye. A favorable ophthalmic endpoint was regr
ession of the ROP into zone III for at least 2 consecutive weekly examinati
ons or full retinal vascularization. At 3 months after the due date of the
infant, ophthalmic findings, pulmonary status, growth, and interim illnesse
s were again recorded.
Results. Six hundred forty-nine infants (325 conventional and 324 supplemen
tal) were enrolled from 30 centers over 5 years. Five hundred ninety-seven
(92.0%) infants attained known ophthalmic endpoints, and 600 (92%) complete
d the ophthalmic 3-month assessment. The rate of progression to threshold i
n at least 1 eye was 48% in the conventional arm and 41% in the supplementa
l arm. After adjustment for baseline ROP severity stratum, plus disease, ra
ce, and gestational age, the odds ratio (supplemental vs conventional) for
progression was .72 (95% confidence interval: .52, 1.01). Final structural
status of all study eyes at 3 months of corrected age showed similar rates
of severe sequelae in both treatment arms: retinal detachments or folds (4.
4% conventional vs 4.1% supplemental), and macular ectopia (3.9% convention
al vs 3.9% supplemental). Within the prespecified ROP severity strata, ROP
progression rates were lower with supplemental oxygen than with conventiona
l oxygen, but the differences were not statistically significant. A post ho
c subgroup analysis of plus disease (dilated and tortuous vessels in at lea
st 2 quadrants of the posterior pole) suggested that infants without plus d
isease may be more responsive to supplemental therapy (46% progression in t
he conventional arm vs 32% in the supplemental arm) than infants with plus
disease (52% progression in conventional vs 57% in supplemental).
Pneumonia and/or exacerbations of chronic lung disease occurred in more inf
ants in the supplemental arm (8.5% conventional vs 13.2% supplemental). Als
o, at 50 weeks of postmenstrual age, fewer conventional than supplemental i
nfants remained hospitalized (6.8% vs 12.7%), on oxygen (37.0% vs 46.8%), a
nd on diuretics (24.4% vs 35.8%). Growth and developmental milestones did n
ot differ between the 2 arms.
Conclusions. Use of supplemental oxygen at pulse oximetry saturations of 96
% to 99% did not cause additional progression of prethreshold ROP but also
did not significantly reduce the number of infants requiring peripheral abl
ative surgery. A subgroup analysis suggested a benefit of supplemental oxyg
en among infants who have prethreshold ROP without plus disease, but this f
inding requires additional study. Supplemental oxygen increased the risk of
adverse pulmonary events including pneumonia and/or exacerbations of chron
ic lung disease and the need for oxygen, diuretics, and hospitalization at
3 months of corrected age. Although the relative risk/benefit of supplement
al oxygen for each infant must be individually considered, clinicians need
no longer be concerned that supplemental oxygen, as used in this study, wil
l exacerbate active prethreshold ROP.