Incidence and Early Course of Retinopathy of Prematurity EARL A. PALMER, MD/ JOHN T. FLYNN, MD/ ROBERT J. HARDY, PhD,3 DALE L. PHELPS, MD, 4 CYNTHIA L. PHILLIPS, BS/ DAVID B. SCHAFFER, MD, 5 BETTY TUNG, MS, 3 THE CRYOTHERAPY FOR RETINOPATHY OF PREMATURITY COOPERATIVE GROUP
Abstract: In the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (ROP), 4099 infants weighing less than 1251 g at birth underwent sequential ophthalmic examinations, beginning at age 4 to 6 weeks, to monitor the incidence and course of ROP. Overall, 65.8% of the infants developed ROP to some degree; 81.6% for infants of less than 1000 g birth weight. As expected, ROP incidence and severity were higher in lower birth weight and gestational age categories. Black infants appeared less susceptible to ROP, of all severity categories, than nonblack infants. The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events. These results include the current incidence of various severity stages of ROP found in the United States and provide new. insight into the development of ROP. Ophthalmology 1991; 98:1628-1640
Retinopathy of prematurity (ROP) is a disease affecting the formation of retinal blood vessels in the premature infant's retina. Previous reports ofthe incidence ofROP are difficult to compare with each other because of variations in patient selection and methodology of examination. 1- 11 Before the International Classification of ROP (ICROP), 12 the pathognomonic signs of incipient ROP were not uniformly interpreted. Thus, an eye could be
Originally received: January 28, 1991. Revision accepted: May 13, 1991. 1
Department of Ophthalmology, Oregon Health Sciences University, Portland. 2 Department of Ophthalmology, Bascom Palmer Eye Institute, Miami. 3 Coordinating Center for Clinical Trials, School of Public Health, University of Texas, Houston. 4 Department of Ophthalmology, Upstate Medical Center, Rochester, NY. 5 Department of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia. Presented in part at the American Academy of Ophthalmology Annual Meeting, New Orleans, OctjNov 1989. Supported by Cooperative Agreement (No. 5-U01-EY05874) with the National Eye Institute of the National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland. Reprint requests to Earl A. Palmer, MD, Casey Eye Institute, Oregon Health Sciences University, 3375 SW Terwilliger Blvd, Portland, OR 97201-4197.
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defined to have early ROP variously by the finding of terminal vascular irregularity, abrupt color transition from vascularized to nonvascularized retina, or the finding of a physical demarcation line or ridge. Furthermore, because mild ROP may completely resolve within a few weeks or less, if examinations were performed at greater intervals mild ROP could be missed. The design of the Multicenter Trial of Cryotherapy for ROP (CRYO-ROP) included serial examinations of infants born weighing less than 1251 g. 13 •14 This concurrent "Natural History Study" was designed not only to identify suitable patients for enrollment in the clinical trial of cryotherapy, but also to estimate the frequency of ROP in different birth weight and gestational categories using standardized methodology in clarifying use of the ICROP. 12 •15 The conventions of the ICROP were used to describe the ocular disease location from zones 1 to 3, extent of ROP by clock-hour sectors of involvement, severity from stages 1 to 4, and the presence or absence of posterior retinal vascular engorgement (plus disease). 13 This ongoing Natural History Study represents the first systematic multicenter implementation of this classification system. The present report of the current status of ROP incorporates a large sample size representing about 15% of the lowest birth weight infants receiving care in the United States between January 1986 and November 1987. 16 The participating centers represent widely distributed geo-
PALMER et al
•
INCIDENCE AND EARLY COURSE OF ROP
graphic regions of the United States and include a crosssection of population mix and nursery practices. As background for the data concerning ROP, we studied the observed sequence of retinal vascular development in premature infants who never developed ROP. This was considered in relation to two baseline times: from birth and from conception. In this article, the terms "postconceptional age" and "age postconception" refer to the sum of the gestational age at birth plus the postnatal age in weeks. By convention, "gestational age" refers to weeks since last menstruation period (LMP), and 40 weeks of gestational age is considered to be full term. This flawed conventional terminology is entrenched despite the fact that gestation is actually the period from conception (about 2 weeks after the LMP) to birth. Thus, the "gestational age" already includes the 2 extra weeks that typically elapse between the LMP and ovulation/conception. For consistency with the established usage we have adhered to this convention, using the terminology "postconceptional age," or "age postconception," yet recognizing that this really means age post-LMP. This report includes the events in the course of ROP that occur in the infants' first few months of extrauterine life, such as the incidence of sequential ROP stages. The ocular outcome after these events has already been reported for the infants who participated in the randomized trial of cryotherapy 13 •14•17 and will be reported elsewhere for infants who did not enter that trial.
PATIENTS AND METHODS Between January 1986 and November 30, 1987, 14 investigators registered all infants born weighing less than 1251 g. Each nursery at 23 participating study centers (most incorporating more than 1 neonatal intensive care unit) was checked twice weekly for the admission of such infants, and identifying information was recorded in an accession log book. Census reports were submitted to the Coordinating Center every 2 weeks, creating a central log of potential study patients, and the Coordinating Center was notified of any infants who had died or were excluded by 42 days after birth (mortality data among this cohort are reported elsewhere 16). Enrollment in this Natural History Study was permitted for infants who were born in a nonparticipating hospital and then transferred to a participating center, as long as the first study examination could be performed within the required time window (28 to 49 days of age). Such transfers were usually made for general medical reasons, because ROP examinations would ordinarily not yet have commenced. Birth weight and gestational age were obtained at the time the infant was registered. Gestational age was assigned by the neonatologist caring for the patient and represented a best estimate based on menstrual history, obstetrical dating (including early ultrasound data when available), and neonatal physical assessment. Race of the infant was determined by the race of the mother.
Infants were excluded 15 if they had a clearly lethal congenital anomaly or a major congenital ocular anomaly affecting one or both eyes that likely would compromise long-term follow-up for the development ofROP. Minor ocular anomalies that would not be likely to affect the retina or choroid and which would not increase the risk of cryotherapy or make cryotherapy more difficult to perform were included in the study. The institutional review board or human research committee at each participating hospital reviewed and approved the study protocol and consent forms. A CRYOROP booklet provided information about ROP to the parent before formal consent was obtained for the serial eye examinations, and a CRYO-ROP videotape was often used as a teaching aid. Informed consent was sought for frequent eye examinations for the eligible infants who were alive at 28 days of age. STANDARDIZATION OF EXAMINATION TECHNIQUE
To receive training in the systematic and prospective collection of data using the ICROP, ophthalmologists attended a 2-day training and certification course and/or viewed a videotape of the examination and study procedure. Before being certified for protocol examinations, examiners were required to satisfactorily perform and document five masked examinations of premature infants in the nursery, paired with another ophthalmologist who was already certified. At least 60% of the eyes examined for certification had to have ROP. After the two examiners separately recorded their findings, their examination forms were forwarded to a member of the Executive Committee of the study for comparison. The applicant examiner was certified only after satisfactory agreement was found, which often required more than 5 paired examinations (up to 16 paired examinations; mean, 9). Examinations were performed in the nursery area with the approval of an attending neonatologist. The ICROP was used throughout the study. Plus disease was determined by means of comparison with a standard photograph representing the minimal degree of posterior vascular congestion acceptable for designation as "plus" for this study. 13 Plus disease tends to look more severe after pressure on the globe, presumably because the intraocular pressure is then lower and the vessels dilate; therefore, the determination of plus disease was done before scleral depression. The examiner first looked at the posterior pole and then at the periphery. For the nursery examinations, the infants' pupils were dilated with Cyclomydril (Alcon) (cyclopentolate 0.2% and phenylephrine 1.0% ), 1 drop to each eye twice, separated by 2 to 5 minutes. Whenever this was not adequate, 1 to 2 drops of cyclopentolate 0.5% or tropicamide 1% and 1 drop of phenylephrine 2.5% were permitted as alternative mydriatics. Infants who were considered medically unstable, particularly at age 4 to 6 weeks, received dilating drops 30 to 60 minutes before the scheduled feeding, and the infant was examined 30 minutes later. To reduce any risk of aspiration, the next feeding was delayed 1629
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30 minutes to 2 hours after the eye examination, the longer period for those weighing less than 2000 g. For patients who were on a two-hourly feeding schedule, whenever the feeding was delayed more than l hour, a Dextrostix test was performed on the blood to monitor for hypoglycemia. A lid speculum and scleral depressor, each individually sterilized for the particular examination, were used as necessary to visualize the ora serrata or the anterior border of retinal vascularization or retinopathy. The binocular indirect ophthalmoscope was used; the hand-held lens, which may touch the infant's face, was wiped with an alcohol sponge between patients. To distinguish between zone 2 and zone 3 of the retina, the examiners used scleral depression as necessary for visualization of the nasal ora serrata. Whenever an infant was unusually distressed by the examination, ocular topical anesthetic was permitted. Topical anesthesia was not compulsory, because some examiners believed it disturbed corneal epithelial clarity, prolonging and compromising the examination. Whenever an infant's heart rate decreased, manipulation of the globe was interrupted until recovery. Hospitalized infants were continued on close monitoring of vital signs after the examination. For infants who were not on a cardiac monitor, vital signs were recorded every 30 minutes for 3 hours. DETERMINATION OF ZONES, STAGES, AND PLUS DISEASE
The state of retinal vascular development was assessed even in infants who never developed ROP. The location of blood vessel termination (with or without ROP) at each examination was noted according to retinal zone l, 2, or 3. Zone I is bounded by the imaginary circle whose radius is twice the distance from disc to macula (Fig l from ICROP). For this report, vascularization was classified to be in zone l until vascularization had progressed into zone 2 in all sectors. Zones 2 and 3 are mutually exclusive. In practice, the distinction between zone 2 and zone 3 is made on the basis of clinical observation of the position of vessel termination on the nasal side of the retina. In this study, whenever retinal vessels reached within l disc diameter of the ora serrata on the nasal side, in the absence ofROP located in the two nasal-most clock-hour sectors, the vascular status of the eye was defined as zone 3. The vessel terminations, or any retinopathy present elsewhere in the eye when the nasal retina was thus vascularized, were defined as being in zone 3. In eyes not categorized as zone I status, whenever any ROP was present outside zone l on the far nasal side, the eye was categorized as a zone 2 eye. All participating centers used a standard slide atlas showing clinical examples of the stages of ROP to aid in accurate and consistent assessment of the disease. The certification training for ophthalmologists included the identification of plus disease; examiners were instructed to refer to the standard slide whenever in doubt. 13 "Plus disease" refers exclusively to dilatation and tortuosity of the vessels in the posterior pole and did not require iris engorgement, pupillary rigidity, vitreous haze, or retinal 1630
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Fig 1. ICROP zone scheme for locating ROP 12 (courtesy of Arch Ophthalmol 1984; 102:1130-4. Copyright 1984 American Medical Association).
Table 1. Definitions Used in Study Terms
Definitions
No ROP ROP Prethreshold ROP
ROP never seen on any examination Any ROP seen on any examination Zone 1 ROP of any stage less than threshold; zone 2 ROP at stage 2+; zone 2 ROP stage 3 without plus; zone 2 ROP stage 3+ with fewer than the threshold number of sectors of stage 3+ Five or more contiguous or eight cumulative clock hours (30° sectors) of stage 3+ ROP in either zone 1 or 2; an eligibility criterion for enrollment in the randomized clinical trial of cryotherapy 15
Threshold ROP
ROP
=
retinopathy of prematurity.
hemorrhages. In addition to the ICROP stages, ROP was further categorized for this study into four subgroups as shown in Table l. Whenever plus disease was associated with any stage of ROP in zone I, the term "rush disease" was used. Because this variation of ROP may progress extremely rapidly, 18 •19 the next examination in such cases was scheduled to occur 48 hours later. The peripheral neovascular net in "rush" cases sometimes was not visibly elevated, and, through group discussions at the biannual meeting of the principal investigators, the staging classification of zone 1 retinopathy was modified somewhat for these cases. Because the vessels in rush disease may end in a flat neovascular syncytial network that does not necessarily elevate into a classic stage 3 ridge, study criteria were developed by consensus to classify zone I retinopathy as stage 3 whenever this dense peripheral neovascular network coexisted with plus ROP (Fig 2). EXAMINATION SCHEDULE
The first ophthalmic examination was performed between 4 and 6 weeks after birth. Any infant diagnosed with a previously unsuspected eye anomaly at that examination was then excluded. Subsequent examinations
PALMER et al
•
INCIDENCE AND EARLY COURSE OF ROP
Fig 2. Zone I ROP (courtesy of Oregon Health Sciences University Ophthalmic Photography Service). A, composite of fundus photographs shows extreme plus disease and border of abnormal vessels bowing posteriorly (arrows) to the zone I boundary (circle). Center of macula indicated by "+ ." 8 , detail of flat-appearing brush border of "stage 3" ROP discussed in text.
were done at intervals of 2 weeks until either the retina became fully vascularized without retinopathy or retinopathy developed. Although the frequency of the examinations was stipulated, the variable and uncertain clinical course of ROP was emphasized to the examiners, who were encouraged to perform more frequent examinations in patients when clinically indicated. Infants developing retinopathy were followed at 2-week intervals until the retinopathy regressed and the vessels reached full maturity, or until the retinopathy progressed to a "prethreshold" level (defined in Table 1). Whenever prethreshold retinopathy was present, the rate of examinations was increased to at least once per week, until the severity of retinopathy subsided below prethreshold, and then examinations were performed at 2-week intervals until the disease was clearly demonstrated to be regressing. A follow-up examination was done 4 to 8 weeks later to confirm that resolution had occurred. If the retinopathy progressed in zone 1 or 2 to stage 3+, extending 5 or more contiguous clock-hour sectors 12 around the circumference of the periphery, or 8 or more interrupted clock-hour sectors, then the severity ofROP for that eye was considered at "threshold" for the randomized trial of cryotherapy. 13•15
An eye was assumed to be at very low risk of blindness from ROP when the retinal vessels extended into the peripheral zone 3; hence, such eyes were ineligible for the cryotherapy trial. It was required that zone 3 status be confirmed two weeks later, at which time the next examination interval could be extended to 4 to 8 weeks. Infants whose vessels never seemed to progress into zone 3 (again, defined by the presence of vessels without ROP within 1 disc diameter of the nasal ora serrata) were examined every 2 weeks while the infant was hospitalized, and 3 more times thereafter. If the vessels still did not reach into zone 3 and no ROP was present, the infant was examined again in 4 to 8 weeks to ensure stability of the peripheral retinal status. Then such an infant, like all other infants in the study, was seen at 3 and 12 months after the estimated full-term date. PROTOCOL MONITORING
A Study Center Coordinator worked with the Principal Investigator at each center to assure that local adherence to protocol was carried out. Site visits were made by the Executive Committee and staff of the Coordinating Center 1631
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to ensure consistent examination standards and staging criteria from center to center, as well as to audit the accuracy of local records. A Data and Safety Monitoring Committee, comprised of individuals not participating in the study, met every 6 months to review incoming data and to continuously assess study policies and procedures for safety and scientific integrity. This committee continues to meet during the ongoing long-term follow-up.
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9751 Registered Died Before Eye Examination 2803 < 28 d 244 > 28 d Excluded 44 anomalies 1016 transferred 110 terminated
RESULTS Identifying data for 97 51 infants were entered into the nursery accession logs, and 4099 of these patients comprise the Natural History cohort (Fig 3). Exclusions were comprised of3047 who died 16 and 1016 who were transferred out of one of the participating centers before the first eye examination. There were 44 survivors who were excluded because of a developmental anomaly. Enrollment into the study was stopped 6 months ahead of schedule, 13 •17•20•21 and II 0 potentially eligible infants who had already been registered at the participating centers at that time were excluded before their first eye examination for the study. Seventy-three infants did not participate in the required sequential early eye examinations because they were transferred to a participating center from another hospital too late to conform to the protocol schedule (some of these later transfers were made because of a finding ofROP). Excluded from the 5461 otherwise eligible infants were 921 ( 16.9%) whose parents refused consent to participate in the study; however, the demographic characteristics of these patients are similar to the overall cohort, with the exception that the mean birth weight in the "refused consent" group is 48 g heavier than the rest of the cohort. Finally, 441 infants were excluded because their first eye examination by a study-certified ophthalmologist was performed after 49 days oflife, primarily in the early part of the study when not all the examiners had been certified for the study. All of the remaining 4099 eligible infants underwent their initial eye examination according to the study design and form the cohort for this Natural History Study. BASELINE CHARACTERISTICS
Table 2 presents the major demographic findings for these patients. The mean birth weight was 954 g and the mean gestational age was approximately 28 weeks. Most (81.8%) of the 4099 infants were born in one of the 77 participating study hospitals ("inborn"), but 746 (18.2%) were born elsewhere ("outborn") and referred to a participating center within 49 days of birth. EYE FINDINGS
The first eye examinations were conducted at a mean 5.0 (± 0.8) weeks from birth. This proved to represent 32.8 (± 2.3) weeks of postconceptional age (definition 1632
73 infants referred to randomized trial ONLY
-
5461 Eligible
4540 Enrolled
~
921 Refused Consent
441 Certified Exams Begun too late
4099 Natural History Cohort Fig 3. Derivation of study cohort from infants registered at participating centers.
Table 2. Baseline Characteristics of All Natural History Patients (n = 4099) Born in the study hospital (%) Male(%) Race(%) White Black Hispanic Other Multiple birth (%) Single Twins Other Mean (±standard deviation) birth wt (g) Mean (±standard deviation) gestational age (wks)
81.8 48.1
52.7
38.6 6.7
2.0
81.4
16.3
2.3 954 ± 185 27.9 ± 2.2
given previously) for this cohort. By the time they reached full term, the infants had undergone an average of 3.8 reported examinations, ranging from 2.2 examinations for those without ROP to 6.8 for those whose ROP reached threshold severity. Most (80.7%) infants were followed to
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INCIDENCE AND EARLY COURSE OF ROP
Table 3A. Number and Percent of Patients with Various Categories of ROP by Selected Subgroups Highest Stage ROP*
Subgrouping Total Birth weight (g)
Abstract: In the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (ROP), 4099 infants weighing less than 1251 g at birth underwent sequential ophthalmic examinations, beginning at age 4 to 6 weeks, to monitor the incidence and course of ROP. Overall, 65.8% of the infants developed ROP to some degree; 81.6% for infants of less than 1000 g birth weight. As expected, ROP incidence and severity were higher in lower birth weight and gestational age categories. Black infants appeared less susceptible to ROP, of all severity categories, than nonblack infants. The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events. These results include the current incidence of various severity stages of ROP found in the United States and provide new. insight into the development of ROP. Ophthalmology 1991; 98:1628-1640
Retinopathy of prematurity (ROP) is a disease affecting the formation of retinal blood vessels in the premature infant's retina. Previous reports ofthe incidence ofROP are difficult to compare with each other because of variations in patient selection and methodology of examination. 1- 11 Before the International Classification of ROP (ICROP), 12 the pathognomonic signs of incipient ROP were not uniformly interpreted. Thus, an eye could be
Originally received: January 28, 1991. Revision accepted: May 13, 1991. 1
Department of Ophthalmology, Oregon Health Sciences University, Portland. 2 Department of Ophthalmology, Bascom Palmer Eye Institute, Miami. 3 Coordinating Center for Clinical Trials, School of Public Health, University of Texas, Houston. 4 Department of Ophthalmology, Upstate Medical Center, Rochester, NY. 5 Department of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia. Presented in part at the American Academy of Ophthalmology Annual Meeting, New Orleans, OctjNov 1989. Supported by Cooperative Agreement (No. 5-U01-EY05874) with the National Eye Institute of the National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland. Reprint requests to Earl A. Palmer, MD, Casey Eye Institute, Oregon Health Sciences University, 3375 SW Terwilliger Blvd, Portland, OR 97201-4197.
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defined to have early ROP variously by the finding of terminal vascular irregularity, abrupt color transition from vascularized to nonvascularized retina, or the finding of a physical demarcation line or ridge. Furthermore, because mild ROP may completely resolve within a few weeks or less, if examinations were performed at greater intervals mild ROP could be missed. The design of the Multicenter Trial of Cryotherapy for ROP (CRYO-ROP) included serial examinations of infants born weighing less than 1251 g. 13 •14 This concurrent "Natural History Study" was designed not only to identify suitable patients for enrollment in the clinical trial of cryotherapy, but also to estimate the frequency of ROP in different birth weight and gestational categories using standardized methodology in clarifying use of the ICROP. 12 •15 The conventions of the ICROP were used to describe the ocular disease location from zones 1 to 3, extent of ROP by clock-hour sectors of involvement, severity from stages 1 to 4, and the presence or absence of posterior retinal vascular engorgement (plus disease). 13 This ongoing Natural History Study represents the first systematic multicenter implementation of this classification system. The present report of the current status of ROP incorporates a large sample size representing about 15% of the lowest birth weight infants receiving care in the United States between January 1986 and November 1987. 16 The participating centers represent widely distributed geo-
PALMER et al
•
INCIDENCE AND EARLY COURSE OF ROP
graphic regions of the United States and include a crosssection of population mix and nursery practices. As background for the data concerning ROP, we studied the observed sequence of retinal vascular development in premature infants who never developed ROP. This was considered in relation to two baseline times: from birth and from conception. In this article, the terms "postconceptional age" and "age postconception" refer to the sum of the gestational age at birth plus the postnatal age in weeks. By convention, "gestational age" refers to weeks since last menstruation period (LMP), and 40 weeks of gestational age is considered to be full term. This flawed conventional terminology is entrenched despite the fact that gestation is actually the period from conception (about 2 weeks after the LMP) to birth. Thus, the "gestational age" already includes the 2 extra weeks that typically elapse between the LMP and ovulation/conception. For consistency with the established usage we have adhered to this convention, using the terminology "postconceptional age," or "age postconception," yet recognizing that this really means age post-LMP. This report includes the events in the course of ROP that occur in the infants' first few months of extrauterine life, such as the incidence of sequential ROP stages. The ocular outcome after these events has already been reported for the infants who participated in the randomized trial of cryotherapy 13 •14•17 and will be reported elsewhere for infants who did not enter that trial.
PATIENTS AND METHODS Between January 1986 and November 30, 1987, 14 investigators registered all infants born weighing less than 1251 g. Each nursery at 23 participating study centers (most incorporating more than 1 neonatal intensive care unit) was checked twice weekly for the admission of such infants, and identifying information was recorded in an accession log book. Census reports were submitted to the Coordinating Center every 2 weeks, creating a central log of potential study patients, and the Coordinating Center was notified of any infants who had died or were excluded by 42 days after birth (mortality data among this cohort are reported elsewhere 16). Enrollment in this Natural History Study was permitted for infants who were born in a nonparticipating hospital and then transferred to a participating center, as long as the first study examination could be performed within the required time window (28 to 49 days of age). Such transfers were usually made for general medical reasons, because ROP examinations would ordinarily not yet have commenced. Birth weight and gestational age were obtained at the time the infant was registered. Gestational age was assigned by the neonatologist caring for the patient and represented a best estimate based on menstrual history, obstetrical dating (including early ultrasound data when available), and neonatal physical assessment. Race of the infant was determined by the race of the mother.
Infants were excluded 15 if they had a clearly lethal congenital anomaly or a major congenital ocular anomaly affecting one or both eyes that likely would compromise long-term follow-up for the development ofROP. Minor ocular anomalies that would not be likely to affect the retina or choroid and which would not increase the risk of cryotherapy or make cryotherapy more difficult to perform were included in the study. The institutional review board or human research committee at each participating hospital reviewed and approved the study protocol and consent forms. A CRYOROP booklet provided information about ROP to the parent before formal consent was obtained for the serial eye examinations, and a CRYO-ROP videotape was often used as a teaching aid. Informed consent was sought for frequent eye examinations for the eligible infants who were alive at 28 days of age. STANDARDIZATION OF EXAMINATION TECHNIQUE
To receive training in the systematic and prospective collection of data using the ICROP, ophthalmologists attended a 2-day training and certification course and/or viewed a videotape of the examination and study procedure. Before being certified for protocol examinations, examiners were required to satisfactorily perform and document five masked examinations of premature infants in the nursery, paired with another ophthalmologist who was already certified. At least 60% of the eyes examined for certification had to have ROP. After the two examiners separately recorded their findings, their examination forms were forwarded to a member of the Executive Committee of the study for comparison. The applicant examiner was certified only after satisfactory agreement was found, which often required more than 5 paired examinations (up to 16 paired examinations; mean, 9). Examinations were performed in the nursery area with the approval of an attending neonatologist. The ICROP was used throughout the study. Plus disease was determined by means of comparison with a standard photograph representing the minimal degree of posterior vascular congestion acceptable for designation as "plus" for this study. 13 Plus disease tends to look more severe after pressure on the globe, presumably because the intraocular pressure is then lower and the vessels dilate; therefore, the determination of plus disease was done before scleral depression. The examiner first looked at the posterior pole and then at the periphery. For the nursery examinations, the infants' pupils were dilated with Cyclomydril (Alcon) (cyclopentolate 0.2% and phenylephrine 1.0% ), 1 drop to each eye twice, separated by 2 to 5 minutes. Whenever this was not adequate, 1 to 2 drops of cyclopentolate 0.5% or tropicamide 1% and 1 drop of phenylephrine 2.5% were permitted as alternative mydriatics. Infants who were considered medically unstable, particularly at age 4 to 6 weeks, received dilating drops 30 to 60 minutes before the scheduled feeding, and the infant was examined 30 minutes later. To reduce any risk of aspiration, the next feeding was delayed 1629
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30 minutes to 2 hours after the eye examination, the longer period for those weighing less than 2000 g. For patients who were on a two-hourly feeding schedule, whenever the feeding was delayed more than l hour, a Dextrostix test was performed on the blood to monitor for hypoglycemia. A lid speculum and scleral depressor, each individually sterilized for the particular examination, were used as necessary to visualize the ora serrata or the anterior border of retinal vascularization or retinopathy. The binocular indirect ophthalmoscope was used; the hand-held lens, which may touch the infant's face, was wiped with an alcohol sponge between patients. To distinguish between zone 2 and zone 3 of the retina, the examiners used scleral depression as necessary for visualization of the nasal ora serrata. Whenever an infant was unusually distressed by the examination, ocular topical anesthetic was permitted. Topical anesthesia was not compulsory, because some examiners believed it disturbed corneal epithelial clarity, prolonging and compromising the examination. Whenever an infant's heart rate decreased, manipulation of the globe was interrupted until recovery. Hospitalized infants were continued on close monitoring of vital signs after the examination. For infants who were not on a cardiac monitor, vital signs were recorded every 30 minutes for 3 hours. DETERMINATION OF ZONES, STAGES, AND PLUS DISEASE
The state of retinal vascular development was assessed even in infants who never developed ROP. The location of blood vessel termination (with or without ROP) at each examination was noted according to retinal zone l, 2, or 3. Zone I is bounded by the imaginary circle whose radius is twice the distance from disc to macula (Fig l from ICROP). For this report, vascularization was classified to be in zone l until vascularization had progressed into zone 2 in all sectors. Zones 2 and 3 are mutually exclusive. In practice, the distinction between zone 2 and zone 3 is made on the basis of clinical observation of the position of vessel termination on the nasal side of the retina. In this study, whenever retinal vessels reached within l disc diameter of the ora serrata on the nasal side, in the absence ofROP located in the two nasal-most clock-hour sectors, the vascular status of the eye was defined as zone 3. The vessel terminations, or any retinopathy present elsewhere in the eye when the nasal retina was thus vascularized, were defined as being in zone 3. In eyes not categorized as zone I status, whenever any ROP was present outside zone l on the far nasal side, the eye was categorized as a zone 2 eye. All participating centers used a standard slide atlas showing clinical examples of the stages of ROP to aid in accurate and consistent assessment of the disease. The certification training for ophthalmologists included the identification of plus disease; examiners were instructed to refer to the standard slide whenever in doubt. 13 "Plus disease" refers exclusively to dilatation and tortuosity of the vessels in the posterior pole and did not require iris engorgement, pupillary rigidity, vitreous haze, or retinal 1630
•
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G .
9-
Fig 1. ICROP zone scheme for locating ROP 12 (courtesy of Arch Ophthalmol 1984; 102:1130-4. Copyright 1984 American Medical Association).
Table 1. Definitions Used in Study Terms
Definitions
No ROP ROP Prethreshold ROP
ROP never seen on any examination Any ROP seen on any examination Zone 1 ROP of any stage less than threshold; zone 2 ROP at stage 2+; zone 2 ROP stage 3 without plus; zone 2 ROP stage 3+ with fewer than the threshold number of sectors of stage 3+ Five or more contiguous or eight cumulative clock hours (30° sectors) of stage 3+ ROP in either zone 1 or 2; an eligibility criterion for enrollment in the randomized clinical trial of cryotherapy 15
Threshold ROP
ROP
=
retinopathy of prematurity.
hemorrhages. In addition to the ICROP stages, ROP was further categorized for this study into four subgroups as shown in Table l. Whenever plus disease was associated with any stage of ROP in zone I, the term "rush disease" was used. Because this variation of ROP may progress extremely rapidly, 18 •19 the next examination in such cases was scheduled to occur 48 hours later. The peripheral neovascular net in "rush" cases sometimes was not visibly elevated, and, through group discussions at the biannual meeting of the principal investigators, the staging classification of zone 1 retinopathy was modified somewhat for these cases. Because the vessels in rush disease may end in a flat neovascular syncytial network that does not necessarily elevate into a classic stage 3 ridge, study criteria were developed by consensus to classify zone I retinopathy as stage 3 whenever this dense peripheral neovascular network coexisted with plus ROP (Fig 2). EXAMINATION SCHEDULE
The first ophthalmic examination was performed between 4 and 6 weeks after birth. Any infant diagnosed with a previously unsuspected eye anomaly at that examination was then excluded. Subsequent examinations
PALMER et al
•
INCIDENCE AND EARLY COURSE OF ROP
Fig 2. Zone I ROP (courtesy of Oregon Health Sciences University Ophthalmic Photography Service). A, composite of fundus photographs shows extreme plus disease and border of abnormal vessels bowing posteriorly (arrows) to the zone I boundary (circle). Center of macula indicated by "+ ." 8 , detail of flat-appearing brush border of "stage 3" ROP discussed in text.
were done at intervals of 2 weeks until either the retina became fully vascularized without retinopathy or retinopathy developed. Although the frequency of the examinations was stipulated, the variable and uncertain clinical course of ROP was emphasized to the examiners, who were encouraged to perform more frequent examinations in patients when clinically indicated. Infants developing retinopathy were followed at 2-week intervals until the retinopathy regressed and the vessels reached full maturity, or until the retinopathy progressed to a "prethreshold" level (defined in Table 1). Whenever prethreshold retinopathy was present, the rate of examinations was increased to at least once per week, until the severity of retinopathy subsided below prethreshold, and then examinations were performed at 2-week intervals until the disease was clearly demonstrated to be regressing. A follow-up examination was done 4 to 8 weeks later to confirm that resolution had occurred. If the retinopathy progressed in zone 1 or 2 to stage 3+, extending 5 or more contiguous clock-hour sectors 12 around the circumference of the periphery, or 8 or more interrupted clock-hour sectors, then the severity ofROP for that eye was considered at "threshold" for the randomized trial of cryotherapy. 13•15
An eye was assumed to be at very low risk of blindness from ROP when the retinal vessels extended into the peripheral zone 3; hence, such eyes were ineligible for the cryotherapy trial. It was required that zone 3 status be confirmed two weeks later, at which time the next examination interval could be extended to 4 to 8 weeks. Infants whose vessels never seemed to progress into zone 3 (again, defined by the presence of vessels without ROP within 1 disc diameter of the nasal ora serrata) were examined every 2 weeks while the infant was hospitalized, and 3 more times thereafter. If the vessels still did not reach into zone 3 and no ROP was present, the infant was examined again in 4 to 8 weeks to ensure stability of the peripheral retinal status. Then such an infant, like all other infants in the study, was seen at 3 and 12 months after the estimated full-term date. PROTOCOL MONITORING
A Study Center Coordinator worked with the Principal Investigator at each center to assure that local adherence to protocol was carried out. Site visits were made by the Executive Committee and staff of the Coordinating Center 1631
OPHTHALMOLOGY
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NOVEMBER 1991
to ensure consistent examination standards and staging criteria from center to center, as well as to audit the accuracy of local records. A Data and Safety Monitoring Committee, comprised of individuals not participating in the study, met every 6 months to review incoming data and to continuously assess study policies and procedures for safety and scientific integrity. This committee continues to meet during the ongoing long-term follow-up.
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VOLUME 98
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NUMBER 11
9751 Registered Died Before Eye Examination 2803 < 28 d 244 > 28 d Excluded 44 anomalies 1016 transferred 110 terminated
RESULTS Identifying data for 97 51 infants were entered into the nursery accession logs, and 4099 of these patients comprise the Natural History cohort (Fig 3). Exclusions were comprised of3047 who died 16 and 1016 who were transferred out of one of the participating centers before the first eye examination. There were 44 survivors who were excluded because of a developmental anomaly. Enrollment into the study was stopped 6 months ahead of schedule, 13 •17•20•21 and II 0 potentially eligible infants who had already been registered at the participating centers at that time were excluded before their first eye examination for the study. Seventy-three infants did not participate in the required sequential early eye examinations because they were transferred to a participating center from another hospital too late to conform to the protocol schedule (some of these later transfers were made because of a finding ofROP). Excluded from the 5461 otherwise eligible infants were 921 ( 16.9%) whose parents refused consent to participate in the study; however, the demographic characteristics of these patients are similar to the overall cohort, with the exception that the mean birth weight in the "refused consent" group is 48 g heavier than the rest of the cohort. Finally, 441 infants were excluded because their first eye examination by a study-certified ophthalmologist was performed after 49 days oflife, primarily in the early part of the study when not all the examiners had been certified for the study. All of the remaining 4099 eligible infants underwent their initial eye examination according to the study design and form the cohort for this Natural History Study. BASELINE CHARACTERISTICS
Table 2 presents the major demographic findings for these patients. The mean birth weight was 954 g and the mean gestational age was approximately 28 weeks. Most (81.8%) of the 4099 infants were born in one of the 77 participating study hospitals ("inborn"), but 746 (18.2%) were born elsewhere ("outborn") and referred to a participating center within 49 days of birth. EYE FINDINGS
The first eye examinations were conducted at a mean 5.0 (± 0.8) weeks from birth. This proved to represent 32.8 (± 2.3) weeks of postconceptional age (definition 1632
73 infants referred to randomized trial ONLY
-
5461 Eligible
4540 Enrolled
~
921 Refused Consent
441 Certified Exams Begun too late
4099 Natural History Cohort Fig 3. Derivation of study cohort from infants registered at participating centers.
Table 2. Baseline Characteristics of All Natural History Patients (n = 4099) Born in the study hospital (%) Male(%) Race(%) White Black Hispanic Other Multiple birth (%) Single Twins Other Mean (±standard deviation) birth wt (g) Mean (±standard deviation) gestational age (wks)
81.8 48.1
52.7
38.6 6.7
2.0
81.4
16.3
2.3 954 ± 185 27.9 ± 2.2
given previously) for this cohort. By the time they reached full term, the infants had undergone an average of 3.8 reported examinations, ranging from 2.2 examinations for those without ROP to 6.8 for those whose ROP reached threshold severity. Most (80.7%) infants were followed to
PALMER et al
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INCIDENCE AND EARLY COURSE OF ROP
Table 3A. Number and Percent of Patients with Various Categories of ROP by Selected Subgroups Highest Stage ROP*
Subgrouping Total Birth weight (g)
