Original Article
A Cohort Study of Transcutaneous Oxygen Tension and the Incidence and Severity of Retinopathy of Prematurity
N Engl J Med 1992; 326:1050-1054April 16, 1992
- Abstract
- Abstract
Background.
Retinopathy of prematurity is a disease affecting the blood vessels of the retina in premature infants that may result in scarring, retinal detachment, and loss of vision. An association between this condition and the exposure of premature infants to supplemental oxygen has been postulated, but the relation between retinopathy of prematurity and blood oxygen levels has not been defined. The purpose of this study of a cohort of preterm infants was to correlate the incidence and severity of retinopathy of prematurity with the duration of exposure to different ranges of oxygen tension as measured by transcutaneous monitoring (tcPO2).
Methods.
One hundred one premature infants (birth weight, 500 to 1300 g) requiring supplemental oxygen had continuous monitoring of tcPO2. The number of hours during which the tcPO2 was 80 mm Hg or higher was tabulated for each infant during the first four weeks of life.
Results.
There was a significant association between the amount of time that the tcPO2 was ≥80 mm Hg and the incidence and severity of retinopathy of prematurity. The odds ratio for each 12-hour period in which the tcPO2 was ≥80 mm Hg was 1.9 (95 percent confidence interval, 1.2 to 3.0) after adjustment for the following factors: birth weight ≤1300 g (odds ratio, 2.3 [95 percent confidence interval, 1.6 to 3.4]), five-minute Apgar score of 7 or less (odds ratio, 7.2 [95 percent confidence interval, 2.5 to 21]), and exposure to inspired oxygen at a fractional concentration ≥0.4 (odds ratio, 1.0 [95 percent confidence interval, 0.97 to 1.05]). The association was stronger for tcPO2 values of ≥80 mm Hg occurring from the second through the fourth week of life; during this period, the adjusted odds ratio for a 12-hour period of such exposure was 3.1 (95 percent confidence interval, 1.6 to 6.1).
Conclusions.
This study supports an association between the incidence and severity of retinopathy of prematurity and the duration of exposure to arterial oxygen levels of 80 mm Hg or higher, measured transcutaneously. (N Engl J Med 1992;326:1050–4.)
Media in This Article
Table 1
Clinical Characteristics of the 101 Infants Studied, According to Birth Weight and Presence of Retinopathy.Table 2
Respiratory Therapy Used during the First 28 Days of Life in the Infants Studied.Article Activity
- Article
RETINOPATHY of prematurity is a disease affecting the blood vessels of the developing retina that occurs primarily in premature infants. It results in the formation of vascular shunts, the development of neovascular membranes, and in its more severe forms traction retinal detachment (i.e., without retinal breaks),1 2 3 leading to visual impairment and blindness.4 Although the causes are probably multiple,5 previous studies suggest a relation between retinopathy of prematurity and the duration of exposure to supplemental oxygen.6 7 8 9 However, no specific threshold level of arterial oxygen tension has been identified. A multicenter case–control study10 undertaken to identify the relation of this condition to specific levels of intermittently sampled blood oxygen tension failed to demonstrate such a relation.
The present study was part of a clinical trial designed to evaluate whether continuous monitoring of transcutaneous oxygen tension (tcPO2) to prevent the occurrence of tcPO2 ≥70 mm Hg in neonates requiring oxygen therapy could reduce the incidence and severity of retinopathy of prematurity.11 12 13 Although that study demonstrated that such monitoring was associated with a lower incidence of retinopathy in infants weighing between 1100 and 1300 g at birth but not in those weighing less than 1100g, it did not examine the role of specific levels of arterial oxygen tension in this condition. This report presents an analysis of the relation between arterial oxygen tensions of 80 mm Hg or higher, as measured by transcutaneous monitoring, and the incidence and severity of retinopathy of prematurity in the infants in this trial.
Methods
Study Population
Four hundred thirty-eight infants weighing 500 to 1300 g were born at the Jackson Memorial Medical Center of the University of Miami between November 1, 1982, and May 31, 1984. One hundred forty-two infants were excluded from the study because parental consent could not be obtained, or because they were either not viable or had major congenital anomalies. Two hundred ninety-six infants who required supplemental oxygen during the first week of life were enrolled in the clinical trial. Of these infants, 148 were randomly assigned to continuous transcutaneous monitoring, and 148 to standard care. Forty-seven infants in the continuously monitored group died before ophthalmoscopic examination was performed. The 101 surviving infants in the continuously monitored group are the subject of this report.
Monitoring
Detailed information about the study protocol has been published elsewhere.11 In brief, each infant was connected to a transcutaneous oxygen monitor that recorded the tcPO2 while supplemental oxygen or mechanical ventilation was administered to maintain the infant's arterial oxygen tension above 50 mm Hg. During the first week of life, the monitoring electrode was attached to the skin of the upper chest. Thereafter, it was placed on either the trunk or the thighs, depending on the infant's condition. A microprocessor attached to the monitor recorded the number of minutes the tcPO2 value occupied each increment on a scale divided into increments of 10 mm Hg, and the number of minutes in each increment was tabulated weekly for each infant. The outcome measure of exposure for each infant was the number of hours in which the tcPO2 was 80 mm Hg or higher during the first four weeks of life. A cutoff value of 80 mm Hg was chosen to represent the upper limit of the physiologic range, a value that coincides with the recommendation of the American Academy of Pediatrics.14 It was thought that above this level the infant's retinal vasculature might be exposed to damage due to oxygen.
Arterial oxygen tension was measured intermittently by umbilical or peripheral arterial catheters approximately every four hours while the infants were receiving oxygen or mechanical ventilation, and less frequently after they were weaned from ventilatory assistance. A research assistant was responsible for calibrating and positioning the monitoring electrode and adjusting the settings of inspired oxygen and ventilation so that the tcPO2 would be maintained between 50 and 70 mm Hg. Infants whose values for tcPO2 and arterial oxygen tension differed by more than 10 mm Hg had their fraction of inspired oxygen adjusted according to the arterial blood gas measurements rather than the tcPO2 values. The tcPO2 values were not included in the analysis in these cases.
The percentage of infants who received supplemental oxygen and transcutaneous monitoring fell from 100 percent during the first week of life to 49 percent by the beginning of the second week. After the fourth week, the number fell to less than 10 percent. This decline occurred because the clinical trial required infants to be monitored only as long as supplemental oxygen was administered. The readings of the tcPO2 were classified according to increments of 10 mm Hg 91 percent of the time the transcutaneous electrode was positioned on the infant. The failure to classify the remaining 9 percent of the "monitored" hours was due to the time spent repositioning the electrode and to other technical difficulties. During these hours, as well as the time when the infants were not receiving supplemental oxygen therapy, the tcPO2 was coded for purposes of analysis as being below 80 mm Hg.
Diagnosis of Retinopathy of Prematurity
Retinopathy of prematurity was diagnosed when indirect ophthalmoscopy performed by an experienced pediatric ophthalmologist demonstrated the presence of a structure perpendicular to and located at the tips of the developing retinal blood vessels that divide the vascular from the avascular retina.15 The examiner was unaware of each infant's identity, treatment-group assignment, and the results of previous examinations. Examinations were begun when the infants reached the postconceptional age of 32 weeks and were in stable clinical condition. They were repeated every two to four weeks until discharge. Each infant had a minimum of two examinations, with one taking place when the infant reached the conceptional age of 35 to 45 weeks.
Severity of Retinopathy of Prematurity
A severity index was devised to encompass the most important characteristics of each infant's retinal disease,16 17 18 including the location of the disease in the retina and its extent (measured in clock hours in relation to the circumference of the eye), the degree of neovascular-membrane formation, and the extent of vascular tortuosity. A numerical score was assigned to each of these characteristics. This index, developed before the publication of the International Classification of Retinopathy of Prematurity, was based on the same clinical characteristics that appear therein.19 , 20 An ordinal rating of the severity of retinopathy on a scale with three levels, in which 0 denoted no disease, 1 to 20 mild disease, and 21 to 36 moderate-to-severe disease, served as the primary outcome variable in this study.
Analytic Methods
The infants were stratified according to birth weight (in categories of <900 g and 900 to 1300 g21) and status of retinopathy of prematurity. In the description of clinical characteristics the mean, standard deviation, median, minimum, and maximum were used. Indicators of respiratory status (hours of ventilation and arterial blood gas measurements) and hours of exposure to tcPO2 ≥80 mm Hg during the first four weeks of life were described similarly.
Ordinal logistic regression with the proportional odds model22 23 24 25 was used to examine the relation between tcPO2 and the incidence and severity of retinopathy of prematurity. Dichotomous logistic regression22 , 23 was used to examine the relation between the incidence of retinopathy of any severity and the variables for tcPO2 exposure in the subgroup of infants weighing ≥900 g at birth. These methods allowed the calculation of odds ratios and 95 percent confidence intervals from the coefficients and standard errors in the model, with adjustment for the potential influence of confounding factors.
Many factors (including respiratory distress syndrome, broncho-pulmonary dysplasia, intraventricular hemorrhage, apnea with bradycardia, and a number of therapeutic interventions) were assessed by univariate analysis in order to explore their potential influence on the incidence and severity of retinopathy of prematurity in the cohort. Those that appeared important were included in multivariate models relating tcPO2 of 80 mm Hg or higher to severity of disease. Three potentially confounding variables were identified: the total duration of supplemental oxygen in concentrations equal to or exceeding a fraction of inspired oxygen of 0.4 (a measure of the severity of the respiratory illness); the five-minute Apgar score, dichotomized as ≤7 and >7 (an indicator of the infant's condition at birth); and birth weight (a measure of the infant's state of development).
Unadjusted and adjusted odds ratios are presented for each 12-hour period of exposure to specific tcPO2 levels. All reported P values are two-tailed.
Protocol Monitoring
The protocol for the randomized clinical trial that served as the parent of this study was approved by the Committee for Protection of Human Subjects, Jackson Memorial Medical Center, University of Miami. An Ad Hoc Data Monitoring and Safety Committee approved the manual of operations and monitored the progress of the study.
Results
Retinopathy of prematurity developed in 52 of the 101 infants studied (51 percent). Nineteen of 22 infants weighing less than 900 g (86 percent) had the disease; it was mild in 10 and moderate to severe in 9, and 4 of these 9 had cicatricial disease.26 Thirty-three of 79 infants weighing ≥900 g (42 percent) had retinopathy of prematurity; it was mild in 27 and moderate to severe in 6. No infant weighing ≥900 g had cicatricial disease. The infants in whom retinopathy of prematurity developed weighed less at birth (P<0.001), had lower five-minute Apgar scores (P<0.001), and had more hours of supplemental oxygen at a fractional concentration ≥0.4 than did the infants in whom the disease did not develop (P = 0.029) (Table 1Table 1
Clinical Characteristics of the 101 Infants Studied, According to Birth Weight and Presence of Retinopathy.). Data on the respiratory therapy in the study infants during the first 28 days after birth are presented in Table 2Table 2Respiratory Therapy Used during the First 28 Days of Life in the Infants Studied..Retinopathy and the Duration of tcPO2≥80 mm Hg
Table 3Table 3
Exposure to tcPO2 ≥80 mm Hg during Weeks 1 through 4 in the 101 Infants Studied. shows the duration of tcPO2≥80 mm Hg during the first four weeks after birth. These data suggest that longer exposure to this level of oxygen tension was associated with an increase in both the incidence and the severity of retinopathy of prematurity. In Table 3 the infants are also categorized according to the duration of oxygen exposure:≥12 hours or <12 hours. Seventy-five percent of the infants with ≥12 hours of tcPO2≥80 mm Hg had retinopathy of prematurity, in contrast to only 26 percent of those with less than 12 hours of such exposure. The association between the duration of tcPO2 ≥80 mm Hg during the first four weeks of life and the incidence and severity of retinopathy was explored with ordinal logistic regression (Table 4Table 4
Unadjusted and Adjusted Odds Ratios and 95 Percent Confidence Intervals in the Ordinal Logistic-Regression Model for the 101 Infants Studied.*). The unadjusted odds ratio for each 12-hour period during which the tcPO2 was 80 mm Hg or higher was 3.0 (95 percent confidence interval, 2.0 to 4.5). After adjustment for birth weight, five-minute Apgar score, and the duration of supplemental oxygen at a fractional concentration ≥0.4, this odds ratio remained significant; it was 1.9 (95 percent confidence interval, 1.2 to 3.0). The adjusted and unadjusted odds ratios for birth weight (in 100-g increments), five-minute Apgar score≤7, and hours of supplemental oxygen at a fractional concentration ≥0.4 are also presented in Table 4. The adjusted odds ratio for each of these factors, except for hours of supplemental oxygen, was statistically significant.In an ancillary analysis, exposure to tcPO2 ≥80 mm Hg during the first week after birth was considered separately from that during weeks 2 through 4. The two periods were treated separately because of the possibility that the tcPO2 values recorded during week 1 in infants with unstable pulmonary and hemodynamic function may not have reflected the true levels of arterial oxygen tension as well as the values recorded during weeks 2 through 4. When this approach was used, the unadjusted odds ratio for week 1 for a 12-hour period of exposure was 1.0 (95 percent confidence interval, 0.5 to 2.3). For weeks 2 through 4, after we controlled for confounding factors and for the number of hours of tcPO2 ≥80 mm Hg during week 1, this association was strong (odds ratio, 3.1 [95 percent confidence interval, 1.6 to 6.1]).
An analysis of the subgroup of infants weighing ≥900 g was performed with dichotomous logistic regression to examine the relation between the incidence of retinopathy of prematurity of any severity and tcPO2 ≥80 mm Hg. This analysis was not performed in the smaller (<900 g) infants, since they almost all (86 percent) had retinopathy of prematurity. Infants weighing ≥900 g who had retinopathy accumulated a higher mean (±SD) number of hours of exposure to tcPO2 ≥80 mm Hg ( 19.6± 14.0) than did infants without this diagnosis (8.7±7.7) (P<0.001). The odds ratio was 1.6 (95 percent confidence interval, 0.7 to 3.5) after we controlled for birth weight, five-minute Apgar score ≤7, and total duration of supplemental oxygen at a fractional concentration ≥0.4. Although this ratio was not statistically significant, it did not rule out a clinically important effect.
Adjustment for the use of supplemental oxygen at a fractional concentration ≥0.4 could theoretically have led to an underestimation of any relation between tcPO2, ≥80 mm Hg and retinopathy of prematurity, because high levels of inspired oxygen are in part directly responsible for elevated tcPO2. To examine this possibility, a second set of multivariate models was constructed that did not include the duration of use of supplemental oxygen as a covariate. The results of these analyses were virtually identical to those of the analyses that incorporated supplemental oxygen as a covariate.
Discussion
This study presents evidence supporting an association between prolonged exposure to transcutaneously monitored arterial oxygen tensions of 80 mm Hg or higher and the incidence and severity of retinopathy of prematurity in infants weighing ≤1300 g at birth and surviving at least 28 days. This association could not be attributed to the confounding influence of birth weight, low Apgar score, or the duration of supplemental oxygen therapy.
Several earlier studies have shown that premature infants treated with oxygen regimens of longer durations or higher concentrations of inspired oxygen had significantly more retinopathy of prematurity than control infants.6 7 8 9 The Second National Cooperative Study of Retrolental Fibroplasia (retinopathy of prematurity)10 was designed to identify the relation between specific levels of arterial oxygen tension and this disease. Although that study could not demonstrate such a relation, it did confirm that longer durations of oxygen therapy were associated with the development of retinopathy in infants weighing less than 1200 g at birth.
The clinical trial that served as the basis for this study11 12 13 detected no overall effect of tcPO2 monitoring on the incidence of retinopathy of prematurity, but analysis showed that a subgroup of infants weighing ≥1100 g at birth had substantial reductions in the incidence of the disease with continuous monitoring. That study, however, did not clarify whether the protective mechanism of such monitoring was through the avoidance of specific levels of oxygen exposure. The current study, which was part of that clinical trial, supports a role for oxygen in the pathogenesis of retinopathy of prematurity and implicates transcutaneous oxygen tension of 80 mm Hg or higher in the occurrence and severity of this disease. Blood oxygen levels were measured by continuous transcutaneous monitoring in this study, in contrast to previous studies that used only intermittent measurements of arterial oxygen tension with arterial blood gases. This difference in the method of monitoring blood oxygen tension may explain why the previous studies could not detect such an association.
The fact that retinopathy of prematurity occurs in some infants receiving no supplemental oxygen and does not occur in some babies exposed to oxygen for long periods demonstrates that high oxygen levels are neither necessary nor sufficient to induce the disease.5 These observations suggest the role of other factors in the pathogenesis of retinopathy of prematurity. These associations were confirmed in this study with regard to birth weight, five-minute Apgar score, and severity of respiratory failure as measured by the number of hours of supplemental oxygen at a fractional concentration ≥0.4. Of these three confounding variables, only birth weight and five-minute Apgar score were independently associated with the incidence of retinopathy of prematurity. Other factors than those implicated here have also been identified in the literature.5 Although the confounding influence of one or more of these factors may have influenced the results of this study, most are highly correlated with birth weight, five-minute Apgar score, and the number of hours of supplemental oxygen and were therefore controlled for by the analytic techniques used.
A precise threshold level of tcPO2 that was toxic to the retina could not be identified and may not exist. Since tcPO2 was recorded in increments of 10 mm Hg, exposure could be defined only as time of exposure to ≥70 mm Hg and ≥80 mm Hg. We could not explore the independent influence on retinopathy of prematurity of exposure to ≥90 mm Hg because of the small number of hours in which infants were exposed to tcPO2 in this range. Analyses using the number of hours of exposure to 70 mm Hg or higher did, however, demonstrate the same associations as those using ≥80 mm Hg, but the associations were of smaller magnitude.
The results of this observational study must be interpreted cautiously. The study was not a randomized clinical trial of the effect of levels of hyperoxic exposure on the occurrence and severity of retinopathy of prematurity. We believe such a trial would be unethical. Other constraints arise from the design of the clinical trial. No monitoring took place while the infants were not receiving supplemental oxygen. The transcutaneous oxygen tension was assumed to be less than 80 mm Hg during these unmonitored periods. Underestimation of the exposure to tcPO2 of 80 mm Hg or higher, a theoretical concern, was unlikely, because the infants received no supplemental oxygen during unmonitored periods. During the time that monitoring was performed, an average of 9 percent of the hours were not classifiable as values on the range for tcPO2. For purposes of analysis, transcutaneous oxygen tension was also assumed to be less than 80 mm Hg during these hours. However, it is conceivable that for a proportion of these unclassified hours, unlike the unmonitored hours, the infants were actually exposed to tcPO2 ≥80 mm Hg. This potential mis-classification may have reduced the magnitude of the observed relation between the incidence and severity of retinopathy of prematurity and tcPO2 ≥80 mm Hg, because underestimation of these hours was more likely in the case of infants who had more severe retinopathy.
Because of the schedule of ophthalmologic examinations (every two weeks when feasible), neither the onset nor the timing of maximally severe retinopathy of prematurity could be determined precisely. The period of risk during which oxygen may influence the development of the disease was, however, assumed to precede the fifth week of life. This definition was based on the observed natural history of the disease9 in newborns. It has been estimated that by the end of the third week of life only 1.7 percent of premature newborns weighing ≤1300 g have diagnosable retinopathy of prematurity. By the end of the fourth week, this percentage rises to approximately 3 percent.8 Despite these observations, uncertainty about the timing of retinopathy of prematurity may have led to the inclusion of hours of exposure to oxygen after the development of maximally severe disease, the effect of which may have been either to inflate or to diminish the apparent effect of tcPO2 exposure.
The clinical-trial portion of this study11 12 13 demonstrated that continuous transcutaneous monitoring to prevent the occurrence of tcPO2 values ≥70 mm Hg was not effective in reducing the incidence or severity of retinopathy of prematurity in the infants at highest risk (those weighing <1100 g). From both this current report and the trial,11 12 13 it would appear that it is not possible to prevent this disease with current methods of monitoring. The development of a system that adjusts the concentration of supplemental oxygen accurately and proportionately to prevent fluctuations in the arterial oxygen tension might ameliorate the occurrence of retinopathy of prematurity. Research into other characteristics that may enhance the susceptibility of the immature retinal vessels to damage by oxygen may result in a lowered incidence and severity of this disease.
Supported in part by research grants (R01–EY03513 and 3P0 EY 02180) from the Public Health Service, Department of Health and Human Services, National Institutes of Health, National Eye Institute, Bethesda, Md.; by the Alex J. Weinstein Foundation, New York; and by grants to the Fight for Sight Children's Diagnostic Eye Clinic of the Bascom Palmer Eye Institute from Fight for Sight, Inc., New York; the Department of Health and Rehabilitative Services, State of Florida; Children's Medical Services, Tallahassee, Fla.; and University of Miami Project Newborn.
Source Information
From the Department of Ophthalmology, Bascom Palmer Eye Institute, Miami (J.T.F., W.F., J.S., B.B., E. Buckley); the Division of Neonatology, Department of Pediatrics, University of Miami School of Medicine, Miami (E. Bancalari, R.N.G., J.C., J.R.); the Clinical Epidemiology Unit, University of Pennsylvania School of Medicine, Philadelphia (E.S.S., H.I.F.); and the Department of Biostatistics, School of Public Health, University of North Carolina, Chapel Hill (D.G.). Address reprint requests to Dr. Flynn at the Bascom Palmer Eye Institute, P.O. Box 016880, Miami, FL 33101.
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