The Incidence and Course of Retinopathy of Prematurity: Findings From the Early Treatment for Retinopathy of Prematurity Study
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《小儿科》
the Smith-Kettlewell Eye Research Institute, San Francisco, California
ABSTRACT
Objectives. To estimate the incidence of retinopathy of prematurity (ROP) in the Early Treatment for Retinopathy of Prematurity (ETROP) Study and compare these results with those reported in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study.
Methods. The ETROP Study, as part of its protocol, screened 6998 infants at 26 centers throughout the United States. Serial eye examinations were conducted for infants born weighing <1251 g, making it possible to estimate the frequency of ROP in different birth weight and gestational age categories. ROP was categorized according to the International Classification for ROP.
Results. The incidence of any ROP was 68% among infants of <1251 g. The findings were compared with those for infants born in 1986 and 1987 in the CRYO-ROP Study. The overall incidences of ROP were similar in the 2 studies, but there was more zone I ROP in the ETROP Study. Among infants with ROP, more-severe ROP (prethreshold) occurred for 36.9% of infants in the ETROP Study and 27.1% of infants in the CRYO-ROP Study. The gestational age of onset of ROP of different severities has changed very little since the CRYO-ROP Study was conducted.
Conclusions. ROP remains a common important problem among infants with birth weights of <1251 g. The incidence of ROP, time of onset, rate of progression, and time of onset of prethreshold disease have changed little since the CRYO-ROP natural-history study.
Key Words: retinopathy of prematurity incidence
Abbreviations: ROP, retinopathy of prematurity CRYO-ROP, Cryotherapy for Retinopathy of Prematurity ICROP, International Classification for Retinopathy of Prematurity ETROP, Early Treatment for Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is a disease in which retinal blood vessels of premature infants fail to grow and develop normally, sometimes resulting in visual impairment and blindness. In the largest previous study of a natural-history cohort that reported the incidence of ROP, the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study reported an incidence of ROP of 65.8% among infants of <1251 g, all of whom were born between January 1, 1986, and November 30, 1987.1 Since the time of enrollment of infants in that study, advances in neonatal care, with accompanying decreases in mortality rates, have occurred, and it is reasonable to consider that such changes in care could have affected the incidence and severity of ROP. This assumption is supported, in part, by the knowledge that ROP is a disorder associated with, and affected by, survival and systemic disease.2–5 However, studies conducted during the past 15 years on the incidence of ROP have shown differing results, some indicating a decrease in the incidence of ROP and others suggesting no change.4,6–8
The Early Treatment for Retinopathy of Prematurity (ETROP) Study, as part of its protocol, screened 6998 infants at 26 centers throughout the United States. The study design included serial eye examinations of infants born weighing <1251 g, for the purposes of identifying infants with high-risk prethreshold ROP for randomization to early versus conventional treatment and of estimating the frequency of ROP in different birth weight and gestational age categories. ROP was categorized according to the International Classification for Retinopathy of Prematurity (ICROP).9
The purpose of this report was to estimate the incidence of ROP in the ETROP Study and to compare these results with those reported in the CRYO-ROP Study. The tracking of infants in the ETROP Study provided the opportunity to estimate the incidence of ROP in a 21st century cohort and, where possible, to compare this with the results of previous studies, particularly the CRYO-ROP natural-history study, conducted 15 years earlier.
METHODS
Study Group
The institutional review boards for each participating hospital approved the study protocol. From October 1, 2000, to September 30, 2002, investigators logged all infants weighing <1251 g at each of the 26 participating centers. Each nursery was checked at least weekly for the admission of such infants, with identifying information being recorded in a logbook. These census reports were transmitted every 2 weeks to the coordinating center, where a central log of potential participating infants was maintained.
Infants were included in this study if they were born in one of the study center hospitals, remained in the hospital, and were monitored by a study-certified ophthalmologist or they were transferred to a study center hospital before 42 days of age, remained in the hospital, and were monitored by a study-certified ophthalmologist. Infants were monitored until a diagnosis of ROP was established or an eye examination showed vascularization into zone III. If ROP developed, then parents were asked to sign a consent form to allow the more frequent examinations necessary to track the course and severity of ROP in the ETROP Study.
Birth weight, gestational age, and race were recorded when the infant was logged. Gestational age was assigned by the neonatologist caring for the patient and was based on obstetric data such as early ultrasound findings and menstrual history when available or physical examination findings at the time of birth. The race of the infants was based on the race of the mother.
Exclusion criteria included severe systemic anomalies or ocular anomalies in 1 or both eyes that would prevent entry into the randomization phase of the study. Additional details of this procedure and study protocol have been published.10,11
Standardization of Examination Techniques
All ophthalmologists involved in the diagnosis and monitoring of ROP in this study were required to be certified by the American Board of Ophthalmology and experienced in managing ROP. They were certified for the study by attending a 2-day course at the beginning of the study. Alternatively, watching a videotape describing the study and its procedures and reading the manual of procedures12 could be used to obtain certification, as long as the ophthalmologist was board certified, with experience in the diagnosis of ROP. Experience criteria included either participation in 1 of the prior multicenter ROP clinical trials (the CRYO-ROP Study, the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity Study, or the Effects of Light Reduction on Retinopathy of Prematurity Study) or participation in 3 masked paired examinations of infants with ROP with a study-certified ophthalmologist. Results of these examinations were evaluated for concordance at the study headquarters in San Francisco. When agreement between examiners was unsatisfactory, additional examinations were required until good agreement was achieved. Principal investigators from each center met at 6-month intervals to review ROP findings, cases of ROP with photographs, and diagnostic criteria for zones, stages, and plus disease.
For eye examinations, infants' pupils were dilated with cyclomydril (Alcon Laboratories, Inc [Fort Worth, TX]; 0.2% cyclopentolate and 1.0% phenylephrine). If necessary because of poor dilation, 0.5% cyclopentolate and/or 2.5% phenylephrine was used. The examination procedure involved the use of sterile eyelid specula and scleral depressors as necessary, to see the peripheral retina. A binocular indirect ophthalmoscope was used with a hand-held lens. Ophthalmologists also followed any other local criteria for maintaining sterility.
The use of topical anesthetic agents for examinations was optional, because of concern that their use might cloud the cornea and obscure visibility of the retina. Infants were examined while being carefully monitored for signs of any distress caused by the examination. Infants who could not tolerate the examination were reevaluated later or on another day.
Diagnosis of ROP and Examination Schedule
All infants of <1251 g underwent eye examinations, whether or not they developed any ROP. When no ROP was present, the location where blood vessels terminated was recorded. For infants with blood vessels ending in zone I (an imaginary circle whose radius is twice the distance from the optic disc to the macula) in 1 or both eyes, follow-up examinations were conducted on a weekly basis. All other infants for whom no ROP was present were examined every 2 weeks. Infants with no ROP were monitored until retinal vessels had developed to within 1 disc diameter of the ora serrata on the nasal side in 2 contiguous clock hours (sectors). If a second examination conducted 2 weeks later confirmed this maturation of vessels, then additional follow-up monitoring occurred at the discretion of the physician caring for the child.
In eyes in which ROP was observed, the location and severity were recorded according to the ICROP.9 Zone I ROP was diagnosed when 1 clock hour (sector) of ROP was seen within zone I (defined above). Zone II ROP was diagnosed when retinal vessel maturation had not occurred to within 1 disk diameter of the nasal ora serrata in those 2 contiguous clock hours and 1 clock hour of ROP was present, with no ROP in zone I. Zone III ROP was diagnosed when retinal vessel maturation had occurred to within 1 disk diameter of the nasal ora serrata in those 2 contiguous clock hours and 1 clock hour of ROP was present elsewhere in the eye (Table 1). After diagnosis of zone III ROP, infants were examined 1 more time, not more than 2 weeks later, and then at the discretion of the physician caring for the infant.
The stage of ROP was also diagnosed according to the ICROP.9 Flat neovascularization in zone I was considered stage 3, even when an actual ridge did not exist. Plus disease required 2 quadrants of dilation and tortuosity of posterior pole retinal blood vessels, equal to or exceeding that of a standard published photograph (Fig 1). 13
Examinations were conducted at least every 2 weeks after ROP was first seen. When "near-prethreshold" (zone II, stage 2) ROP was diagnosed, examinations were conducted at least weekly. Prethreshold ROP was defined as (1) any ROP in zone I, (2) ROP in zone II with plus disease, (3) zone II with stage 3 ROP and no plus disease, or (4) zone II with plus disease and stage 3 ROP but with less than the 5 contiguous or 8 cumulative clock hours of stage 3 ROP required for diagnosis of threshold ROP (Table 1).
When prethreshold ROP was observed, in the absence of threshold ROP in either eye, a multivariate logistic risk model based on infant and eye characteristics (RM-ROP2) was used to calculate whether the infant was at high or low risk for retinal detachment. An earlier publication gives a detailed description of the RM-ROP2 model,14 and access to the risk model is available online (at www.sph.uth.tmc.edu/rmrop/Riskcalc/disclaimer.aspx). If high-risk prethreshold ROP was observed in 1 or both eyes and was confirmed by a second examiner, then the infant was eligible for entry into the randomized trial. Infants with bilateral, high-risk, prethreshold disease had 1 eye randomized to treatment within 48 hours, whereas the fellow eye received conventional management, with examinations occurring at intervals of 1 week and with treatment if threshold ROP was diagnosed. Infants with high-risk prethreshold ROP in only 1 eye had that eye randomized to treatment within 48 hours or to conventional management. The fellow eye was not included in the study and was treated conventionally (eg, treated at the conventional threshold, if ROP progressed to this point). Infants with low-risk prethreshold ROP were examined at least every 4 days for at least 2 weeks (total of 5 examinations). If ROP did not progress to high-risk prethreshold or threshold ROP, then infants were monitored at the physician's discretion but at least once per week as long as prethreshold ROP persisted.
Statistical Methods
In some cases, infants were logged into the study and screened but were transferred to nonparticipating hospitals, were discharged from the hospital, or died before all ROP screening examinations that might have revealed ROP had been completed ("ROP not observed, follow-up incomplete") (Fig 2). Their actual ROP status is consequently unknown. If ROP was observed in one of the early screening examinations, then the infants were included in the study cohort; therefore, dropping those infants with no ROP would produce a bias. To estimate the incidence of ROP, we used the data for infants who were monitored and whose ROP status was known ("ROP observed, or mature") (Fig 2) to provide an equation that was then applied to all 6998 infants in the study, to establish the rate of ROP.
A logistic risk equation based on infant characteristics (birth weight, gestational age, race, inborn/outborn status, single/multiple status, and gender) was obtained from the analysis of data for infants who were actually observed and whose ROP status was known. A risk value was then computed from the logistic equation for each of these infants. With the same logistic equation and data on birth weight, gestational age, race, inborn/outborn status, single/multiple status, and gender, a risk value for ROP was imputed only for children who received 1 screening examination but were not observed in additional follow-up examinations to have developed ROP or to have mature retinal vascularizaton. This provided risk values for infants who were actually monitored and risk values for infants who were not monitored. All calculations used the same equation with the characteristics for each infant to calculate the 6998 risk values. The incidence of ROP was obtained for all infants by taking the average of the 6998 risk values. The incidence of ROP for subgroups was obtained by using the average risk for infants within the subgroup.
RESULTS
Data for 9721 infants were entered into nursery accession logs. The natural-history cohort for the ETROP Study is composed of 6998 of these patients. Data were not obtained for 2723 infants who died before the first examination, were transferred to another hospital before the first examination, were discharged from the hospital without an eye examination, or were ineligible for the study because of systemic and ocular anomalies (Fig 2). The remaining 6998 infants received their first eye examination by a certified examiner and, of those, 5541 are known to have developed ROP or to have proceeded to zone III vascularization without ROP. After the diagnosis of ROP in 1 or both eyes, consent for inclusion of follow-up eye examination results and for examinations that were more frequent than usual, as part of the ETROP Study, was obtained from the parents or guardians of 2320 infants.
The median postmenstrual age at which stage 1 ROP, stage 2 ROP, stage 3 ROP, and plus disease were diagnosed among infants with ROP whose parents consented to the prospective study is shown in Table 5, with similar data for the infants in the CRYO-ROP Study. The median postmenstrual ages for the first diagnosis of stage 1 to 3 ROP and for diagnosis of plus disease were very similar in the 2 studies. The median postmenstrual ages at the first diagnosis of prethreshold ROP (Table 6) in the 2 studies were also remarkably similar, although the median chronologic age at the diagnosis of prethreshold ROP was 1 week less in the CRYO-ROP Study than in the ETROP Study.
DISCUSSION
The ETROP Study is the largest multicenter study on the incidence of ROP to take place in >15 years. Nearly 10000 infants at 26 centers were logged, resulting in 6998 infants who could be examined at least once and 5541 who were monitored for the development and progression of ROP. Examinations were standardized carefully and were performed by board-certified and study-certified examiners, with a protocol very similar to that used in the CRYO-ROP Study. The results of this collaborative effort showed that the incidence of ROP was 68% among infants of <1251 g. Although the overall incidence of ROP was similar to that found in the CRYO-ROP Study (Table 3),1 more zone I ROP was observed. The overall incidence of more-severe ROP (prethreshold) was 36.9% among infants with ROP in the ETROP Study, whereas the incidence was 27.1% for patients in the CRYO-ROP Study who developed ROP (recomputed for patients with ROP).1
In comparing the rates between the ETROP Study and the CRYO-ROP Study, the differences between protocols should be noted. In the ETROP Study, once zone II stage 2 or zone I immature vessels developed, infants were examined on a weekly basis, ie, more frequently than in the CRYO-ROP Study. In the CRYO-ROP Study, infants could be examined at up to 2-week intervals until prethreshold ROP was seen. This would not affect the comparison of the overall incidences of ROP, but prethreshold and threshold ROP might have been diagnosed at a slightly earlier age in the ETROP Study, because infants with signs of possible future development of prethreshold disease were monitored more closely, to ensure prompt diagnosis of prethreshold disease.
Another difference between these 2 studies concerns the timing of consent for study. In the ETROP Study, consent was obtained for possibly more frequent examinations only after ROP was diagnosed. In the CRYO-ROP Study, consent was obtained before the first eye examination and therefore before ROP was diagnosed. It is unlikely that these different approaches would affect a comparison of the overall incidences of ROP, as calculated in this report. In both studies, there were some infants who escaped surveillance (and possibly consent) by being transferred out of a study center or discharged from the hospital before the first eye examination.
Comparisons with other incidence studies are limited in value, because the studies often have different entry criteria and methods or are based on small sample sizes.6,15,16 In 1 large retrospective study covering the years 1989–1997, the incidence of ROP was 34% for infants of <1251 g,6 approximately one half the rate in the ETROP Study. The Vermont Oxford Network Database reported an incidence of ROP of 57.2% in 1997,7 still less than the incidences in the ETROP Study and the CRYO-ROP Study. One single-center study reported an incidence of 36.1%8 and rates of prethreshold and threshold disease that were lower than those in the ETROP Study. Although these studies reported low incidence rates for ROP, relative to those in the CRYO-ROP Study, the ETROP Study did not, which suggests that the low incidence values resulted partly from the use of small nonrepresentative samples of infants. Other factors that could affect incidence figures in smaller studies include high rates of back-transfers, lack of collection of ROP data after discharge home, and relatively small proportions of infants with birth weights of <750 g.
In the ETROP Study, some infants who had been screened were transferred out of study hospitals before investigators had the chance to observe whether ROP would develop. This led to the formulation of an incidence figure based on a multivariate logistic-regression analysis of data for infants who were actually observed for their possible development of ROP coupled with an imputed value for infants who left the hospital or died before completing follow-up evaluations for ROP (see "Methods"). This calculation was made for infants who underwent 1 screening examination.
Imputing reduces the bias in estimating rates of ROP. Another approach to deal with the infants who were transferred out before completing examinations for ROP at one of our participating hospitals is to report 2 figures for the incidence. First, all infants who were transferred with no ROP are deleted from the denominator. This gives an incidence of 70.3%, which is an overestimate. Second, these infants are included in the denominator and it is assumed that none of them ever developed ROP. The resulting figure for the incidence is 55.7%, which is an underestimate of the true incidence. Our estimate obtained with the imputing method is 68.0%, which is between these 2 values.
The average birth weight and gestational age for infants with prethreshold ROP in the ETROP Study were less than those in the CRYO-ROP Study (740 vs 831 g and 25.6 vs 26.5 weeks),14 indicating that prethreshold ROP occurred among smaller and younger infants in the ETROP Study cohort than in the CRYO-ROP Study cohort. With postmenstrual age as the time factor, the average age of onset of each ICROP category of disease in the ETROP Study is remarkably similar to that found in the CRYO-ROP Study (Tables 5 and 6). The development of ROP might have changed slightly in 15 years; therefore, factors responsible for its occurrence might have changed. However, factors responsible for the timing of onset of ROP and its ultimate progression probably have not changed or have changed in a manner in which the net effect on onset and progression of ROP is negligible.
In the ETROP Study, the incidences of ROP were the same among white and black infants, but severe (prethreshold) ROP occurred more commonly among white children. This finding confirms similar findings in many other studies.1,17,18 Outborn infants continued to bear a greater risk of developing ROP than did infants born in study-affiliated hospitals.
More infants with zone I ROP were observed in this study than previously. The incidence of zone I ROP was 9.1% for infants with ROP and parental consent in the ETROP Study, compared with 2.0% in the CRYO-ROP Study.14 ROP is fundamentally a developmental disease of retinal blood vessel growth; therefore, the earlier in gestation that an infant is born, and thus presumably the earlier the onset of retinal vessel injury, the more likely it is that the vessels will be in zone I at birth/injury, resulting in ROP in zone I. More infants with low birth weights and low gestational ages were observed in this study than in the CRYO-ROP Study. Other factors could also have contributed to the increase in cases of zone I ROP in the ETROP Study. In the ETROP Study, any ROP in zone I was considered prethreshold and triggered a potential randomization process. Observers might have viewed zone I ROP with the perspective that its diagnosis would potentially lead to a known effective treatment and therefore might have diagnosed as zone I ROP some cases that were marginal between zones I and II. Also, immature vessels in zone I in the ETROP Study triggered more frequent examinations. In the CRYO-ROP Study, infants with immature vessels in zone I were examined every 2 weeks. Some of the infants in the CRYO-ROP Study might have had ROP that passed undiagnosed through zone I ROP before becoming zone II ROP.
Without doubt, many factors are involved in the development and progression of ROP and cause it to proceed regularly to an end point defined by postmenstrual age. This inexorable progression of ROP suggests that factors that are inherent in the infant, or even maternally transmitted across the placenta before or around the time of premature delivery, could play a role in the genesis and progression of ROP. A partially inherent causation for ROP is also suggested by the incidence and severity data for different ethnic groupings in this study. White infants were much more likely to have severe ROP than were black infants.
Oxygenation of infants in the hours and days after birth is once again under investigation as a possible etiologic factor for ROP.19,20 The mechanism that would impugn early oxygenation as causative invokes oxygen-induced retinal vascular ischemia and subsequent upregulated angiogenesis in the immediate days after birth. This perinatal oxygenation/disease theory does not account entirely for the onset of prethreshold disease being so tightly linked to gestational age. The predictable timing of the onset of prethreshold ROP based on the postmenstrual age of the infant suggests that factors that are present from the time of conception may play a significant role in ROP progression.
Clearly, ROP remains an important and common disease.21 Potentially more-severe ROP (prethreshold ROP and zone I ROP) is probably more common now than in the CRYO-ROP Study. Future research is needed to learn ways to prevent ROP from developing and to prevent it from progressing.
ACKNOWLEDGMENTS
This work was supported by cooperative agreements (5U10 EY12471 and 5U10 EY12472) with the National Eye Institute of the National Institutes of Health, US Department of Health and Human Services (Bethesda, MD).
ETROP STUDY INVESTIGATORS
Writing Committee: William V. Good, MD (Chair), Robert J. Hardy, PhD, Velma Dobson, PhD, Earl A. Palmer, MD, Dale L. Phelps, MD, Michelle Quintos, BA, and Betty Tung, MS.
Stanford Center (Palo Alto, CA): Lucille Packard Children's Hospital and Stanford University; Ashima Madan, MD, and Michael Gaynon, MD (co-principal investigators); M. Bethany Ball, BS, Patricia N. Hartsell, RN, BA, and Dottie Inguillo, RN (study center coordinators); Deborah Alcorn, MD, William V. Good, MD, Donna Ornitz, MD, and David Stevenson, MD (coinvestigators).
San Francisco Center (San Francisco, CA): California Pacific Medical Center, Oakland Children's Hospital, and University of California, San Francisco Medical Center; William V. Good, MD (principal investigator); Monica Hubbard, MS, PNP, and Jason Lee, MD (study center coordinators); Daniel Brinton, MD, Susan Day, MD, David Durand, MD, Douglas Fredrick, MD, Roderic H. Phibbs, MD, Daniel Schwartz, MD, Terri Slagle, MD, and Gordon Smith, MD (coinvestigators).
Chicago Center (Chicago, IL): University of Illinois at Chicago Hospital and Medical Center; Michael Shapiro, MD (principal investigator); Yesenia Garcia, Maria Genio, Jeffrey Parker, and Bernadine Rupar (study center coordinators); Herbert Becker, MD, Rama Bhat, MD, Jeffrey N. Bloom, MD, Jessica V. Corsino, MD, Lawrence Kaufman, MD, Wico Waikwan Lai, MD, Jose Pulido, MD, MS, Tonse N. K. Raju, MD, Arvid K. Shukla, MD, Benjamin Ticho, MD, and Dharmapuri Vidyasagar, MD (coinvestigators).
Indianapolis Center (Indianapolis, IN): (Indiana University School of Medicine) James Whitcomb Riley Hospital for Children, Indiana University Hospital, Wishard Memorial Hospital, Methodist Hospital, and Community Hospitals of Indianapolis; James Lemons, MD (principal investigator); Daniel Neely, MD (co-principal investigator); Dee Dee Appel, RN, Elizabeth A. Hynes, RN, and Leslie Wright, RN (study center coordinators); David Plager, MD, Naval Sondhi, MD, and Derek Sprunger, MD (coinvestigators).
Louisville Center (Louisville, KY): Kosair Children's Hospital, and University of Louisville Hospital; Charles C. Barr, MD (principal investigator); Greg K. Whittington, PsyS (study center coordinator); Marianne Cowley, MD, Craig H. Douglas, MD, Peggy H. Fishman, MD, Tonya Robinson, MD, and Paul J. Rychwalski, MD (coinvestigators).
New Orleans Center (New Orleans, LA): Tulane University Medical Center and Medical Center of Louisiana at New Orleans; Robert A. Gordon, MD (principal investigator); Deborah S. Neff, LPN (study center coordinator); Douglas B. Babel, OD, MD, James G. Diamond, MD, and William L. Gill, MD (coinvestigators).
Baltimore G Center (Baltimore, MD): University of Maryland Medical Systems, Mercy Medical Center, and Franklin Square Hospital; Ira H. Gewolb, MD (principal investigator); Kelly A. Hutcheson, MD (co-principal investigator); Loni Huynh, COA, Rani Kalsi, BA, COA, Xiaonong Liu, and L. Jennifer Smell, RN (study center coordinators); Susan J. Dulkerian, MD, Michael J. Elman, MD, Eric Jones, MD, Mark W. Preslan, MD, and Scott M. Steidl, MD, DMA (coinvestigators).
Baltimore R Center (Baltimore, MD): Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, Greater Baltimore Medical Center, and St. Joseph Medical Center; Michael X. Repka, MD (principal investigator); Jennifer A. Shepard, NNP, and Pamela Donahue, PhD (study center coordinators); Susan W. Aucott, MD, Tuvia Blechman, MD, Mary Louise Collins, MD, Maureen M. Gilmore, MD, James T. Handa, MD, Ananth Vijay Mudgil, MD, Quan Dong Nguyen, MD, Cameron F. Parsa, MD, Dante Pieramici, MD, David Plotsky, MD, and Jeffrey J. Pomerance, MD (coinvestigators).
Boston Center (Boston, MA): New England Medical Center, Children's Hospital, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Lowell General Hospital, Lawrence General Hospital, Winchester Hospital, Newton-Wellesley Hospital, South Shore Hospital, Melrose-Wakefield Hospital, and Beverly Hospital; Cynthia H. Cole, MD, MPH (principal investigator); Deborah Vanderveen, MD (co-principal investigator); Lacy Berman, Christy Faherty, RN, BSN, Caitlin Hurley, BS, Terry Mansfield, RN, Brenda McKinnon, RNC, and Marianne Moore, RN (study center coordinators); Caroline Baumal, MD, FRCSC, Amita Bhatt, MD, Mark Dacey, MD, Jay Duker, MD, Janine Eagle, MD, Anthony Fraioli, MD, Paul Greenberg, MD, Mark Hughes, MD, Robert Lacy, MD, O'ine McCabe, MD, Robert Peterson, MD, Elias Reichel, MD, Adam Rogers, MD, William Stinson, MD, and Mitchell Strominger, MD (coinvestigators).
Detroit Center (Detroit, MI): William Beaumont Hospital, Children's Hospital of Michigan, and St. John's Hospital Detroit; John Baker, MD (principal investigator); Kristi Cumming, MSN, Michelle Kulak, RN, and Pat Manatrey, RN (study center coordinators); Daniel Batton, MD, Mary Bedard, MD, Antonio Capone, MD, Renato Casabar, MD, Edward O'Malley, MD, Rajesh Rao, MD, John Roarty, MD, Michael Trese, MD, and George Williams, MD (coinvestigators).
Minneapolis Center (Minneapolis, MN): Fairview University Medical Center, Children's Health Care, Minneapolis, and Hennepin County Medical Center; Stephen P. Christiansen, MD (principal investigator); Sally Cook, BA, Ann Holleschau, BA, Molly Maxwell, RN, Marla Mills, RN, MSN, Carol Miller, RN, Kristin Rebertus, RN, NNP, and Nancy Trower, RN, NNP (study center coordinators); Steven Bennett, MD, David Brasel, MD, Robert Couser, MD, Sundeep Dev, MD, Allison Jensen, MD, Richard Lussky, MD, George Miller, MD, Robert Mittra, MD, Timothy Olsen, MD, Robert Ramsey, MD, William Rosen, MD, Edwin Ryan, MD, Shelley Springer, MD, Eric Steuer, MD, C. Gail Summers, MD, and David Williams, MD (co-investigators).
St Louis Center (St Louis, MO): Cardinal Glennon Children's Hospital and St. Mary's Health Center; Bradley V. Davitt, MD (principal investigator); Julie Breuer, RN, and Linda Breuer, LPN (study center coordinators); Oscar Cruz, MD, Stephen Feman, MD, William Keenan, MD, and Greg Mantych, MD (coinvestigators).
North Carolina Center (Durham and Chapel Hill, NC): Duke University Medical Center and University of North Carolina Hospital; Sharon Freedman, MD (principal investigator); David Wallace, MD (co-principal investigator); Eileen Camp, RN, Sharon Clark, RN, Lori Hutchins, RN, and Lora Lake, RN (study center coordinators); Edward Buckley, MD, Laura Enyedi, MD, Ricki Goldstein, MD, Maurice Landers III, MD, Diane Marshall, MD, Travis Meredith, MD, Kean Oh, MD, and Joan Roberts, MD (coinvestigators).
Buffalo Center (Buffalo, NY): Women's and Children's Hospital of Buffalo and Sisters of Charity Hospital; James D. Reynolds, MD (principal investigator); Dawn C. Gordon, RNC, and Barbara Kuppel, RN, BSN (study center coordinators); George P. Albert, MD, Steven Awner, MD, and Rita Ryan, MD (coinvestigators).
Long Island/Westchester Center (New York): Stony Brook University Hospital and Westchester Medical Center; Pamela Ann Weber, MD (principal investigator); Adriann Combs, RNC, and Natalie Dweck, RN (study center coordinators); Howard Charles, MD, Tina Chou, MD, Joseph DeCristofaro, MD, Corina Gerontis, MD, Marc Horowitz, MD, Richard Koty, MD, Edmund LaGamma, MD, and Maury Marmor, MD (coinvestigators).
New York Center (New York, NY): New York Presbyterian Hospital, Columbia Campus and New York Presbyterian Hospital, Cornell Campus; John Flynn, MD (principal investigator); Thomas Lee, MD (co-principal investigator); Osode Coki, RNC, BSN (study center coordinator); Michael Chiang, MD, Steven Kane, MD, Alfred Krauss, MD, Robert Lopez, MD, and Richard Polin, MD (coinvestigators).
Rochester/Syracuse Center (New York): University of Rochester Medical Center and Crouse-Irving Memorial Hospital; Dale L. Phelps, MD (principal investigator); Steven J. Gross, MD, and David Hakanson, MD (co-principal investigators); Marcia Dodge, RN, Cassandra Horihan, MS, Pamela Parker, BA, and Jane Phillips (study center coordinators); Dennis Asselin, MD, Shi-Hwa W. Chang, MD, Ernest Guillet, MD, Robert Hampton, MD, Gary Markowitz, MD, Walter Merriam, MD, Leon-Paul Noel, MD, Robert Olsen, MD, Suzanne Pesce, MD, Steven Rose, MD, Bryan Rutledge, MD, Richard Simon, MD, Sam Spalding, MD, Donald Tingley, MD, Paul Torrisi, MD, and Robert Vanderlinde, MD (coinvestigators).
Columbus Center (Columbus, OH): Columbus Children's Hospital, Ohio State University Hospital, Mount Carmel Medical Center, Grant Medical Center, Riverside Methodist Hospital, Mount Carmel East Hospital, and St. Ann's Hospital; Gary L. Rogers, MD (principal investigator); Don Bremer, MD (co-principal investigator); Rae Fellows, MEd, Sharon Klamfoth, LPN, and Brenda Mann, RNC (study center coordinators); Leandro Cordero, MD, Richard Hertle, MD, Alan Letson, MD, Richard McClead, MD, Mary Lou McGregor, MD, and Patrick Wall, MD (coinvestigators).
Oklahoma City Center (Oklahoma City, OK): Children's Hospital of Oklahoma; R. Michael Siatkowski, MD (principal investigator); Karen E. Corff, MS, ARNP, and Melissa Fuhr, RN (study center coordinators); Reagan H. Bradford, MD, Robert E. Leonard, MD, and Mark H. Scott, MD (coinvestigators).
Portland Center (Portland, OR): Doernbecher Children's Hospital at Oregon Health and Science University, Legacy Emanuel Children's Hospital, and Providence St. Vincent's Hospital; David T. Wheeler, MD (principal investigator); Karen Davis, RN, Nancy Dolphin, RN, and Sharon Dunham, RN (study center coordinators); Aazy Aaby, MD, Shawn Goodman, MD, Andreas Lauer, MD, Valerie Newman, MD, Earl A. Palmer, MD, De-Ann Pillers, MD, PhD, Joseph Robertson, MD, Ann Stout, MD, Tim Stout, MD, and Andrea Tongue, MD (coinvestigators).
Philadelphia Center (Philadelphia, PA): The Children's Hospital of Philadelphia, The Hospital of the University of Pennsylvania, and Pennsylvania Hospital; Graham E. Quinn, MD, MSCE (principal investigator); Jamie G. Koh, RN, MSN, CCRC, Marianne E. Letterio, RN, BSN, and Molly McDaniel, BA (study center coordinators); Soraya Abbasi, MD, Jane C. Edmond, MD, Brian J. Forbes, MD, PhD, Albert M. Maguire, MD, Monte D. Mills, MD, Eric A. Pierce, MD, PhD, and Terri L. Young, MD (coinvestigators).
Pittsburgh Center (Pittsburgh, PA): Magee-Women's Hospital; Kenneth Cheng, MD (principal investigator); Judith Jones, RNC, BSN (study center coordinator); Robert Bergren, MD, Beverly Brozanski, MD, Bernard Doft, MD, Mitchell Fineman, MD, Louis Lobes, MD, and Karl Olsen, MD (coinvestigators).
Charleston Center (Charleston, SC): Medical University of South Carolina; Richard A. Saunders, MD (principal investigator); Lisa Langdale, RN (study center coordinator); Amy Hutchinson, MD, M. Millicent Peterseim, MD, and Dilip Purohit, MD (coinvestigators).
Houston Center (Houston, TX): Baylor College of Medicine, Texas Children's Hospital, Texas Woman's Hospital, and Ben Taub General Hospital; David K. Coats, MD (principal investigator); Laura Gonzalez, Nataliya Kazymyrko, MD, Alma Sanchez, COT, and Michele L. Fulton, COT (study center coordinators); Kathryn Brady-McCreery, MD, Joseph Garcia-Prats, MD, Eric Holz, MD, Scott Jarriel, MD, Karen Johnson, MD, George Mandy, MD, Evelyn A. Paysee, MD, A. Melinda Rainey, MD, and Kimberly G. Yen, MD (coinvestigators).
San Antonio Center (San Antonio, TX): University Hospital and Christus Santa Rosa Children's Hospital; Wichard A. J. van Heuven, MD (principal investigator); Alice K. Gong, MD (co-principal investigator); Melanie H. Drummond, RN (study center coordinator); Timothy Paul Cleland, MD, James C. MacDonald, MD, Lina M. Marouf, MD, and Juan Elian Rubio, MD (coinvestigators).
Salt Lake City Center (Salt Lake City, UT): University of Utah Health Science Center and Primary Children's Medical Center; Robert Hoffman, MD (principal investigator); Susan Bracken, RN (study center coordinator); Paul Bernstein, MD, David Dries, MD, Jerald King, MD, Richard Olson, MD, Michael Teske, MD, and Kimberly Yen, MD (coinvestigators).
National Eye Institute (Bethesda, MD): Maryann Redford, DDS, MPH (program officer, June 2001–Present); Richard L. Mowery, PhD (program officer, October 2000–May 2001); Donald F. Everett, MA (program officer, September 1999–September 2000).
Study Headquarters: Smith-Kettlewell Eye Research Institute, San Francisco, CA; William V. Good, MD (principal investigator); Michelle Quintos, BA (project coordinator).
Coordinating Center: School of Public Health, Coordinating Center for Clinical Trials, University of Texas Health Science Center, Houston, TX; Robert J. Hardy, PhD (principal investigator); Betty Tung, MS (project manager); Gordon Tsai, MS (Coordinating Center staff).
Vision Testing Center: University of Arizona, School of Medicine, Tucson, AZ; Velma Dobson, PhD (principal investigator); Graham E. Quinn, MD (coinvestigator); Kathleen M. Mohan, MA, and Meigan B. Baldwin, BA (vision testers); Suzanne M. Delaney, PhD (Vision Testing Center coordinator).
Data and Safety Monitoring Committee: John Connett, PhD (Chair); Edward F. Donovan, MD, Argye Hillis, PhD, Jonathan M. Holmes, MD, Joseph M. Miller, MD, and Carol R. Taylor, RN, CSFN, PhD (members); William V. Good, MD, Robert J. Hardy, PhD, and Maryann Redford, DDS, MPH (ex-officio members).
Executive Committee, Permanent Members: Chair: William V. Good, MD; Robert J. Hardy, PhD, Velma Dobson, PhD, Earl A. Palmer, MD, and Dale L. Phelps, MD; Ex-officio member: Maryann Redford, DDS, MPH.
Executive Committee, Elected Members: W.A.J. van Heuven, MD (2000–2001), Charles Barr, MD (2001–2002), Michael Gaynon, MD (2002–2003), Michael Shapiro, MD (2003–2004), Rae Fellows, MEd (2000–2001), Judith Jones, RNC, BSN (2001–2002), Kristi Cumming, MSN (2002–2003), and Deborah S. Neff, LPN (2003–2004).
Editorial Committee, Chair: William V. Good, MD; Robert J. Hardy, PhD, Velma Dobson, PhD, Earl A. Palmer, MD, Dale L. Phelps, MD, Michelle Quintos, BA, and Betty Tung, MS.
FOOTNOTES
Accepted Oct 22, 2004.
No conflict of interest declared.
REFERENCES
Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and early course of retinopathy of prematurity. Ophthalmology. 1991;98 :1628 –1640
Noyola DE, Bohra L, Paysee EA, Fernandez M, Coats DK. Association of candidemia and retinopathy of prematurity in very low birth weight infants. Ophthalmology. 2002;109 :80 –84
McGregor ML, Bremer DL, Cole C, et al. Retinopathy of prematurity outcome in infants with prethreshold retinopathy of prematurity and oxygen saturation >94% in room air: the high oxygen percentage in retinopathy of prematurity study. Pediatrics. 2002;110 :540 –544
Allegaert K, De Coen K, Devlieger H, EpiBel Study Group. Threshold retinopathy at threshold of viability: the EpiBel study. Br J Ophthalmol. 2004;88 :239 –242
Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF. The role of blood transfusions and iron intake on retinopathy of prematurity. Early Hum Dev. 2001;62 :57 –63
Bullard SR, Donahue SP, Feman SS, Sinatra RB, Walsh WF. The decreasing incidence and severity of retinopathy of prematurity. J AAPOS. 1999;3 :46 –52
Blair BM, O'Halloran HS, Pauly TH, Stevens JL. Decreased incidence of retinopathy of prematurity, 1995–1997. J AAPOS. 2001;5 :118 –122
Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;102 :1130 –1134
Early Treatment for Retinopathy of Prematurity Cooperative Group. Multicenter trial of early treatment for retinopathy of prematurity: study design. Controlled Clin Trials. 2004;25 :311 –325
Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121 :1684 –1696
Early Treatment for Retinopathy of Prematurity Cooperative Group. Manual of Procedures. Springfield, VA: National Technical Information Service; 2004
Multicenter Trial of Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106 :471 –479
Hardy RJ, Palmer EA, Dobson V, et al. Risk analysis of prethreshold ROP. Arch Ophthalmol. 2003;121 :1699 –1701
Fledelius HC, Kjer B. Surveillance for retinopathy of prematurity in a Danish country: epidemiological experience over 20 years. Acta Ophthalmol Scand. 2004;82 :38 –41
Conrath JG, Hadjadj EJ, Forzano O, et al. Screening for retinopathy of prematurity: results of a retrospective 3-year study of 502 infants. J Pediatr Ophthalmol Strabismus. 2004;41 :31 –34
Saunders RA, Donahue ML, Christmann LM, et al. Racial variation in retinopathy of prematurity. Arch Ophthalmol. 1997;115 :604 –608
Tadesse M, Dhanireddy R, Mittal M, Higgins RD. Race, candida sepsis, and retinopathy of prematurity. Biol Neonate. 2002;81 :86 –90
Chow LC, Wright KW, Sola A, CSMC Oxygen Administration Study Group. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants Pediatrics. 2003;111 :339 –345
Cole CH, Wright KW, Tarnow-Mordi W, Phelps DL, Pulse Oximetry Saturation Trial for Prevention of Retinopathy of Prematurity Planning Study Group. Resolving our uncertainty about oxygen therapy. Pediatrics. 2003;112 :1415 –1419
Hameed B, Shyamanur K, Kotecha S, et al. Trends in the incidence of severe retinopathy of prematurity in a geographically defined population over a 10-year period. Pediatrics. 2004;113 :1653 –1657(Early Treatment for Retin)
ABSTRACT
Objectives. To estimate the incidence of retinopathy of prematurity (ROP) in the Early Treatment for Retinopathy of Prematurity (ETROP) Study and compare these results with those reported in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study.
Methods. The ETROP Study, as part of its protocol, screened 6998 infants at 26 centers throughout the United States. Serial eye examinations were conducted for infants born weighing <1251 g, making it possible to estimate the frequency of ROP in different birth weight and gestational age categories. ROP was categorized according to the International Classification for ROP.
Results. The incidence of any ROP was 68% among infants of <1251 g. The findings were compared with those for infants born in 1986 and 1987 in the CRYO-ROP Study. The overall incidences of ROP were similar in the 2 studies, but there was more zone I ROP in the ETROP Study. Among infants with ROP, more-severe ROP (prethreshold) occurred for 36.9% of infants in the ETROP Study and 27.1% of infants in the CRYO-ROP Study. The gestational age of onset of ROP of different severities has changed very little since the CRYO-ROP Study was conducted.
Conclusions. ROP remains a common important problem among infants with birth weights of <1251 g. The incidence of ROP, time of onset, rate of progression, and time of onset of prethreshold disease have changed little since the CRYO-ROP natural-history study.
Key Words: retinopathy of prematurity incidence
Abbreviations: ROP, retinopathy of prematurity CRYO-ROP, Cryotherapy for Retinopathy of Prematurity ICROP, International Classification for Retinopathy of Prematurity ETROP, Early Treatment for Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is a disease in which retinal blood vessels of premature infants fail to grow and develop normally, sometimes resulting in visual impairment and blindness. In the largest previous study of a natural-history cohort that reported the incidence of ROP, the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study reported an incidence of ROP of 65.8% among infants of <1251 g, all of whom were born between January 1, 1986, and November 30, 1987.1 Since the time of enrollment of infants in that study, advances in neonatal care, with accompanying decreases in mortality rates, have occurred, and it is reasonable to consider that such changes in care could have affected the incidence and severity of ROP. This assumption is supported, in part, by the knowledge that ROP is a disorder associated with, and affected by, survival and systemic disease.2–5 However, studies conducted during the past 15 years on the incidence of ROP have shown differing results, some indicating a decrease in the incidence of ROP and others suggesting no change.4,6–8
The Early Treatment for Retinopathy of Prematurity (ETROP) Study, as part of its protocol, screened 6998 infants at 26 centers throughout the United States. The study design included serial eye examinations of infants born weighing <1251 g, for the purposes of identifying infants with high-risk prethreshold ROP for randomization to early versus conventional treatment and of estimating the frequency of ROP in different birth weight and gestational age categories. ROP was categorized according to the International Classification for Retinopathy of Prematurity (ICROP).9
The purpose of this report was to estimate the incidence of ROP in the ETROP Study and to compare these results with those reported in the CRYO-ROP Study. The tracking of infants in the ETROP Study provided the opportunity to estimate the incidence of ROP in a 21st century cohort and, where possible, to compare this with the results of previous studies, particularly the CRYO-ROP natural-history study, conducted 15 years earlier.
METHODS
Study Group
The institutional review boards for each participating hospital approved the study protocol. From October 1, 2000, to September 30, 2002, investigators logged all infants weighing <1251 g at each of the 26 participating centers. Each nursery was checked at least weekly for the admission of such infants, with identifying information being recorded in a logbook. These census reports were transmitted every 2 weeks to the coordinating center, where a central log of potential participating infants was maintained.
Infants were included in this study if they were born in one of the study center hospitals, remained in the hospital, and were monitored by a study-certified ophthalmologist or they were transferred to a study center hospital before 42 days of age, remained in the hospital, and were monitored by a study-certified ophthalmologist. Infants were monitored until a diagnosis of ROP was established or an eye examination showed vascularization into zone III. If ROP developed, then parents were asked to sign a consent form to allow the more frequent examinations necessary to track the course and severity of ROP in the ETROP Study.
Birth weight, gestational age, and race were recorded when the infant was logged. Gestational age was assigned by the neonatologist caring for the patient and was based on obstetric data such as early ultrasound findings and menstrual history when available or physical examination findings at the time of birth. The race of the infants was based on the race of the mother.
Exclusion criteria included severe systemic anomalies or ocular anomalies in 1 or both eyes that would prevent entry into the randomization phase of the study. Additional details of this procedure and study protocol have been published.10,11
Standardization of Examination Techniques
All ophthalmologists involved in the diagnosis and monitoring of ROP in this study were required to be certified by the American Board of Ophthalmology and experienced in managing ROP. They were certified for the study by attending a 2-day course at the beginning of the study. Alternatively, watching a videotape describing the study and its procedures and reading the manual of procedures12 could be used to obtain certification, as long as the ophthalmologist was board certified, with experience in the diagnosis of ROP. Experience criteria included either participation in 1 of the prior multicenter ROP clinical trials (the CRYO-ROP Study, the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity Study, or the Effects of Light Reduction on Retinopathy of Prematurity Study) or participation in 3 masked paired examinations of infants with ROP with a study-certified ophthalmologist. Results of these examinations were evaluated for concordance at the study headquarters in San Francisco. When agreement between examiners was unsatisfactory, additional examinations were required until good agreement was achieved. Principal investigators from each center met at 6-month intervals to review ROP findings, cases of ROP with photographs, and diagnostic criteria for zones, stages, and plus disease.
For eye examinations, infants' pupils were dilated with cyclomydril (Alcon Laboratories, Inc [Fort Worth, TX]; 0.2% cyclopentolate and 1.0% phenylephrine). If necessary because of poor dilation, 0.5% cyclopentolate and/or 2.5% phenylephrine was used. The examination procedure involved the use of sterile eyelid specula and scleral depressors as necessary, to see the peripheral retina. A binocular indirect ophthalmoscope was used with a hand-held lens. Ophthalmologists also followed any other local criteria for maintaining sterility.
The use of topical anesthetic agents for examinations was optional, because of concern that their use might cloud the cornea and obscure visibility of the retina. Infants were examined while being carefully monitored for signs of any distress caused by the examination. Infants who could not tolerate the examination were reevaluated later or on another day.
Diagnosis of ROP and Examination Schedule
All infants of <1251 g underwent eye examinations, whether or not they developed any ROP. When no ROP was present, the location where blood vessels terminated was recorded. For infants with blood vessels ending in zone I (an imaginary circle whose radius is twice the distance from the optic disc to the macula) in 1 or both eyes, follow-up examinations were conducted on a weekly basis. All other infants for whom no ROP was present were examined every 2 weeks. Infants with no ROP were monitored until retinal vessels had developed to within 1 disc diameter of the ora serrata on the nasal side in 2 contiguous clock hours (sectors). If a second examination conducted 2 weeks later confirmed this maturation of vessels, then additional follow-up monitoring occurred at the discretion of the physician caring for the child.
In eyes in which ROP was observed, the location and severity were recorded according to the ICROP.9 Zone I ROP was diagnosed when 1 clock hour (sector) of ROP was seen within zone I (defined above). Zone II ROP was diagnosed when retinal vessel maturation had not occurred to within 1 disk diameter of the nasal ora serrata in those 2 contiguous clock hours and 1 clock hour of ROP was present, with no ROP in zone I. Zone III ROP was diagnosed when retinal vessel maturation had occurred to within 1 disk diameter of the nasal ora serrata in those 2 contiguous clock hours and 1 clock hour of ROP was present elsewhere in the eye (Table 1). After diagnosis of zone III ROP, infants were examined 1 more time, not more than 2 weeks later, and then at the discretion of the physician caring for the infant.
The stage of ROP was also diagnosed according to the ICROP.9 Flat neovascularization in zone I was considered stage 3, even when an actual ridge did not exist. Plus disease required 2 quadrants of dilation and tortuosity of posterior pole retinal blood vessels, equal to or exceeding that of a standard published photograph (Fig 1). 13
Examinations were conducted at least every 2 weeks after ROP was first seen. When "near-prethreshold" (zone II, stage 2) ROP was diagnosed, examinations were conducted at least weekly. Prethreshold ROP was defined as (1) any ROP in zone I, (2) ROP in zone II with plus disease, (3) zone II with stage 3 ROP and no plus disease, or (4) zone II with plus disease and stage 3 ROP but with less than the 5 contiguous or 8 cumulative clock hours of stage 3 ROP required for diagnosis of threshold ROP (Table 1).
When prethreshold ROP was observed, in the absence of threshold ROP in either eye, a multivariate logistic risk model based on infant and eye characteristics (RM-ROP2) was used to calculate whether the infant was at high or low risk for retinal detachment. An earlier publication gives a detailed description of the RM-ROP2 model,14 and access to the risk model is available online (at www.sph.uth.tmc.edu/rmrop/Riskcalc/disclaimer.aspx). If high-risk prethreshold ROP was observed in 1 or both eyes and was confirmed by a second examiner, then the infant was eligible for entry into the randomized trial. Infants with bilateral, high-risk, prethreshold disease had 1 eye randomized to treatment within 48 hours, whereas the fellow eye received conventional management, with examinations occurring at intervals of 1 week and with treatment if threshold ROP was diagnosed. Infants with high-risk prethreshold ROP in only 1 eye had that eye randomized to treatment within 48 hours or to conventional management. The fellow eye was not included in the study and was treated conventionally (eg, treated at the conventional threshold, if ROP progressed to this point). Infants with low-risk prethreshold ROP were examined at least every 4 days for at least 2 weeks (total of 5 examinations). If ROP did not progress to high-risk prethreshold or threshold ROP, then infants were monitored at the physician's discretion but at least once per week as long as prethreshold ROP persisted.
Statistical Methods
In some cases, infants were logged into the study and screened but were transferred to nonparticipating hospitals, were discharged from the hospital, or died before all ROP screening examinations that might have revealed ROP had been completed ("ROP not observed, follow-up incomplete") (Fig 2). Their actual ROP status is consequently unknown. If ROP was observed in one of the early screening examinations, then the infants were included in the study cohort; therefore, dropping those infants with no ROP would produce a bias. To estimate the incidence of ROP, we used the data for infants who were monitored and whose ROP status was known ("ROP observed, or mature") (Fig 2) to provide an equation that was then applied to all 6998 infants in the study, to establish the rate of ROP.
A logistic risk equation based on infant characteristics (birth weight, gestational age, race, inborn/outborn status, single/multiple status, and gender) was obtained from the analysis of data for infants who were actually observed and whose ROP status was known. A risk value was then computed from the logistic equation for each of these infants. With the same logistic equation and data on birth weight, gestational age, race, inborn/outborn status, single/multiple status, and gender, a risk value for ROP was imputed only for children who received 1 screening examination but were not observed in additional follow-up examinations to have developed ROP or to have mature retinal vascularizaton. This provided risk values for infants who were actually monitored and risk values for infants who were not monitored. All calculations used the same equation with the characteristics for each infant to calculate the 6998 risk values. The incidence of ROP was obtained for all infants by taking the average of the 6998 risk values. The incidence of ROP for subgroups was obtained by using the average risk for infants within the subgroup.
RESULTS
Data for 9721 infants were entered into nursery accession logs. The natural-history cohort for the ETROP Study is composed of 6998 of these patients. Data were not obtained for 2723 infants who died before the first examination, were transferred to another hospital before the first examination, were discharged from the hospital without an eye examination, or were ineligible for the study because of systemic and ocular anomalies (Fig 2). The remaining 6998 infants received their first eye examination by a certified examiner and, of those, 5541 are known to have developed ROP or to have proceeded to zone III vascularization without ROP. After the diagnosis of ROP in 1 or both eyes, consent for inclusion of follow-up eye examination results and for examinations that were more frequent than usual, as part of the ETROP Study, was obtained from the parents or guardians of 2320 infants.
The median postmenstrual age at which stage 1 ROP, stage 2 ROP, stage 3 ROP, and plus disease were diagnosed among infants with ROP whose parents consented to the prospective study is shown in Table 5, with similar data for the infants in the CRYO-ROP Study. The median postmenstrual ages for the first diagnosis of stage 1 to 3 ROP and for diagnosis of plus disease were very similar in the 2 studies. The median postmenstrual ages at the first diagnosis of prethreshold ROP (Table 6) in the 2 studies were also remarkably similar, although the median chronologic age at the diagnosis of prethreshold ROP was 1 week less in the CRYO-ROP Study than in the ETROP Study.
DISCUSSION
The ETROP Study is the largest multicenter study on the incidence of ROP to take place in >15 years. Nearly 10000 infants at 26 centers were logged, resulting in 6998 infants who could be examined at least once and 5541 who were monitored for the development and progression of ROP. Examinations were standardized carefully and were performed by board-certified and study-certified examiners, with a protocol very similar to that used in the CRYO-ROP Study. The results of this collaborative effort showed that the incidence of ROP was 68% among infants of <1251 g. Although the overall incidence of ROP was similar to that found in the CRYO-ROP Study (Table 3),1 more zone I ROP was observed. The overall incidence of more-severe ROP (prethreshold) was 36.9% among infants with ROP in the ETROP Study, whereas the incidence was 27.1% for patients in the CRYO-ROP Study who developed ROP (recomputed for patients with ROP).1
In comparing the rates between the ETROP Study and the CRYO-ROP Study, the differences between protocols should be noted. In the ETROP Study, once zone II stage 2 or zone I immature vessels developed, infants were examined on a weekly basis, ie, more frequently than in the CRYO-ROP Study. In the CRYO-ROP Study, infants could be examined at up to 2-week intervals until prethreshold ROP was seen. This would not affect the comparison of the overall incidences of ROP, but prethreshold and threshold ROP might have been diagnosed at a slightly earlier age in the ETROP Study, because infants with signs of possible future development of prethreshold disease were monitored more closely, to ensure prompt diagnosis of prethreshold disease.
Another difference between these 2 studies concerns the timing of consent for study. In the ETROP Study, consent was obtained for possibly more frequent examinations only after ROP was diagnosed. In the CRYO-ROP Study, consent was obtained before the first eye examination and therefore before ROP was diagnosed. It is unlikely that these different approaches would affect a comparison of the overall incidences of ROP, as calculated in this report. In both studies, there were some infants who escaped surveillance (and possibly consent) by being transferred out of a study center or discharged from the hospital before the first eye examination.
Comparisons with other incidence studies are limited in value, because the studies often have different entry criteria and methods or are based on small sample sizes.6,15,16 In 1 large retrospective study covering the years 1989–1997, the incidence of ROP was 34% for infants of <1251 g,6 approximately one half the rate in the ETROP Study. The Vermont Oxford Network Database reported an incidence of ROP of 57.2% in 1997,7 still less than the incidences in the ETROP Study and the CRYO-ROP Study. One single-center study reported an incidence of 36.1%8 and rates of prethreshold and threshold disease that were lower than those in the ETROP Study. Although these studies reported low incidence rates for ROP, relative to those in the CRYO-ROP Study, the ETROP Study did not, which suggests that the low incidence values resulted partly from the use of small nonrepresentative samples of infants. Other factors that could affect incidence figures in smaller studies include high rates of back-transfers, lack of collection of ROP data after discharge home, and relatively small proportions of infants with birth weights of <750 g.
In the ETROP Study, some infants who had been screened were transferred out of study hospitals before investigators had the chance to observe whether ROP would develop. This led to the formulation of an incidence figure based on a multivariate logistic-regression analysis of data for infants who were actually observed for their possible development of ROP coupled with an imputed value for infants who left the hospital or died before completing follow-up evaluations for ROP (see "Methods"). This calculation was made for infants who underwent 1 screening examination.
Imputing reduces the bias in estimating rates of ROP. Another approach to deal with the infants who were transferred out before completing examinations for ROP at one of our participating hospitals is to report 2 figures for the incidence. First, all infants who were transferred with no ROP are deleted from the denominator. This gives an incidence of 70.3%, which is an overestimate. Second, these infants are included in the denominator and it is assumed that none of them ever developed ROP. The resulting figure for the incidence is 55.7%, which is an underestimate of the true incidence. Our estimate obtained with the imputing method is 68.0%, which is between these 2 values.
The average birth weight and gestational age for infants with prethreshold ROP in the ETROP Study were less than those in the CRYO-ROP Study (740 vs 831 g and 25.6 vs 26.5 weeks),14 indicating that prethreshold ROP occurred among smaller and younger infants in the ETROP Study cohort than in the CRYO-ROP Study cohort. With postmenstrual age as the time factor, the average age of onset of each ICROP category of disease in the ETROP Study is remarkably similar to that found in the CRYO-ROP Study (Tables 5 and 6). The development of ROP might have changed slightly in 15 years; therefore, factors responsible for its occurrence might have changed. However, factors responsible for the timing of onset of ROP and its ultimate progression probably have not changed or have changed in a manner in which the net effect on onset and progression of ROP is negligible.
In the ETROP Study, the incidences of ROP were the same among white and black infants, but severe (prethreshold) ROP occurred more commonly among white children. This finding confirms similar findings in many other studies.1,17,18 Outborn infants continued to bear a greater risk of developing ROP than did infants born in study-affiliated hospitals.
More infants with zone I ROP were observed in this study than previously. The incidence of zone I ROP was 9.1% for infants with ROP and parental consent in the ETROP Study, compared with 2.0% in the CRYO-ROP Study.14 ROP is fundamentally a developmental disease of retinal blood vessel growth; therefore, the earlier in gestation that an infant is born, and thus presumably the earlier the onset of retinal vessel injury, the more likely it is that the vessels will be in zone I at birth/injury, resulting in ROP in zone I. More infants with low birth weights and low gestational ages were observed in this study than in the CRYO-ROP Study. Other factors could also have contributed to the increase in cases of zone I ROP in the ETROP Study. In the ETROP Study, any ROP in zone I was considered prethreshold and triggered a potential randomization process. Observers might have viewed zone I ROP with the perspective that its diagnosis would potentially lead to a known effective treatment and therefore might have diagnosed as zone I ROP some cases that were marginal between zones I and II. Also, immature vessels in zone I in the ETROP Study triggered more frequent examinations. In the CRYO-ROP Study, infants with immature vessels in zone I were examined every 2 weeks. Some of the infants in the CRYO-ROP Study might have had ROP that passed undiagnosed through zone I ROP before becoming zone II ROP.
Without doubt, many factors are involved in the development and progression of ROP and cause it to proceed regularly to an end point defined by postmenstrual age. This inexorable progression of ROP suggests that factors that are inherent in the infant, or even maternally transmitted across the placenta before or around the time of premature delivery, could play a role in the genesis and progression of ROP. A partially inherent causation for ROP is also suggested by the incidence and severity data for different ethnic groupings in this study. White infants were much more likely to have severe ROP than were black infants.
Oxygenation of infants in the hours and days after birth is once again under investigation as a possible etiologic factor for ROP.19,20 The mechanism that would impugn early oxygenation as causative invokes oxygen-induced retinal vascular ischemia and subsequent upregulated angiogenesis in the immediate days after birth. This perinatal oxygenation/disease theory does not account entirely for the onset of prethreshold disease being so tightly linked to gestational age. The predictable timing of the onset of prethreshold ROP based on the postmenstrual age of the infant suggests that factors that are present from the time of conception may play a significant role in ROP progression.
Clearly, ROP remains an important and common disease.21 Potentially more-severe ROP (prethreshold ROP and zone I ROP) is probably more common now than in the CRYO-ROP Study. Future research is needed to learn ways to prevent ROP from developing and to prevent it from progressing.
ACKNOWLEDGMENTS
This work was supported by cooperative agreements (5U10 EY12471 and 5U10 EY12472) with the National Eye Institute of the National Institutes of Health, US Department of Health and Human Services (Bethesda, MD).
ETROP STUDY INVESTIGATORS
Writing Committee: William V. Good, MD (Chair), Robert J. Hardy, PhD, Velma Dobson, PhD, Earl A. Palmer, MD, Dale L. Phelps, MD, Michelle Quintos, BA, and Betty Tung, MS.
Stanford Center (Palo Alto, CA): Lucille Packard Children's Hospital and Stanford University; Ashima Madan, MD, and Michael Gaynon, MD (co-principal investigators); M. Bethany Ball, BS, Patricia N. Hartsell, RN, BA, and Dottie Inguillo, RN (study center coordinators); Deborah Alcorn, MD, William V. Good, MD, Donna Ornitz, MD, and David Stevenson, MD (coinvestigators).
San Francisco Center (San Francisco, CA): California Pacific Medical Center, Oakland Children's Hospital, and University of California, San Francisco Medical Center; William V. Good, MD (principal investigator); Monica Hubbard, MS, PNP, and Jason Lee, MD (study center coordinators); Daniel Brinton, MD, Susan Day, MD, David Durand, MD, Douglas Fredrick, MD, Roderic H. Phibbs, MD, Daniel Schwartz, MD, Terri Slagle, MD, and Gordon Smith, MD (coinvestigators).
Chicago Center (Chicago, IL): University of Illinois at Chicago Hospital and Medical Center; Michael Shapiro, MD (principal investigator); Yesenia Garcia, Maria Genio, Jeffrey Parker, and Bernadine Rupar (study center coordinators); Herbert Becker, MD, Rama Bhat, MD, Jeffrey N. Bloom, MD, Jessica V. Corsino, MD, Lawrence Kaufman, MD, Wico Waikwan Lai, MD, Jose Pulido, MD, MS, Tonse N. K. Raju, MD, Arvid K. Shukla, MD, Benjamin Ticho, MD, and Dharmapuri Vidyasagar, MD (coinvestigators).
Indianapolis Center (Indianapolis, IN): (Indiana University School of Medicine) James Whitcomb Riley Hospital for Children, Indiana University Hospital, Wishard Memorial Hospital, Methodist Hospital, and Community Hospitals of Indianapolis; James Lemons, MD (principal investigator); Daniel Neely, MD (co-principal investigator); Dee Dee Appel, RN, Elizabeth A. Hynes, RN, and Leslie Wright, RN (study center coordinators); David Plager, MD, Naval Sondhi, MD, and Derek Sprunger, MD (coinvestigators).
Louisville Center (Louisville, KY): Kosair Children's Hospital, and University of Louisville Hospital; Charles C. Barr, MD (principal investigator); Greg K. Whittington, PsyS (study center coordinator); Marianne Cowley, MD, Craig H. Douglas, MD, Peggy H. Fishman, MD, Tonya Robinson, MD, and Paul J. Rychwalski, MD (coinvestigators).
New Orleans Center (New Orleans, LA): Tulane University Medical Center and Medical Center of Louisiana at New Orleans; Robert A. Gordon, MD (principal investigator); Deborah S. Neff, LPN (study center coordinator); Douglas B. Babel, OD, MD, James G. Diamond, MD, and William L. Gill, MD (coinvestigators).
Baltimore G Center (Baltimore, MD): University of Maryland Medical Systems, Mercy Medical Center, and Franklin Square Hospital; Ira H. Gewolb, MD (principal investigator); Kelly A. Hutcheson, MD (co-principal investigator); Loni Huynh, COA, Rani Kalsi, BA, COA, Xiaonong Liu, and L. Jennifer Smell, RN (study center coordinators); Susan J. Dulkerian, MD, Michael J. Elman, MD, Eric Jones, MD, Mark W. Preslan, MD, and Scott M. Steidl, MD, DMA (coinvestigators).
Baltimore R Center (Baltimore, MD): Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, Greater Baltimore Medical Center, and St. Joseph Medical Center; Michael X. Repka, MD (principal investigator); Jennifer A. Shepard, NNP, and Pamela Donahue, PhD (study center coordinators); Susan W. Aucott, MD, Tuvia Blechman, MD, Mary Louise Collins, MD, Maureen M. Gilmore, MD, James T. Handa, MD, Ananth Vijay Mudgil, MD, Quan Dong Nguyen, MD, Cameron F. Parsa, MD, Dante Pieramici, MD, David Plotsky, MD, and Jeffrey J. Pomerance, MD (coinvestigators).
Boston Center (Boston, MA): New England Medical Center, Children's Hospital, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Lowell General Hospital, Lawrence General Hospital, Winchester Hospital, Newton-Wellesley Hospital, South Shore Hospital, Melrose-Wakefield Hospital, and Beverly Hospital; Cynthia H. Cole, MD, MPH (principal investigator); Deborah Vanderveen, MD (co-principal investigator); Lacy Berman, Christy Faherty, RN, BSN, Caitlin Hurley, BS, Terry Mansfield, RN, Brenda McKinnon, RNC, and Marianne Moore, RN (study center coordinators); Caroline Baumal, MD, FRCSC, Amita Bhatt, MD, Mark Dacey, MD, Jay Duker, MD, Janine Eagle, MD, Anthony Fraioli, MD, Paul Greenberg, MD, Mark Hughes, MD, Robert Lacy, MD, O'ine McCabe, MD, Robert Peterson, MD, Elias Reichel, MD, Adam Rogers, MD, William Stinson, MD, and Mitchell Strominger, MD (coinvestigators).
Detroit Center (Detroit, MI): William Beaumont Hospital, Children's Hospital of Michigan, and St. John's Hospital Detroit; John Baker, MD (principal investigator); Kristi Cumming, MSN, Michelle Kulak, RN, and Pat Manatrey, RN (study center coordinators); Daniel Batton, MD, Mary Bedard, MD, Antonio Capone, MD, Renato Casabar, MD, Edward O'Malley, MD, Rajesh Rao, MD, John Roarty, MD, Michael Trese, MD, and George Williams, MD (coinvestigators).
Minneapolis Center (Minneapolis, MN): Fairview University Medical Center, Children's Health Care, Minneapolis, and Hennepin County Medical Center; Stephen P. Christiansen, MD (principal investigator); Sally Cook, BA, Ann Holleschau, BA, Molly Maxwell, RN, Marla Mills, RN, MSN, Carol Miller, RN, Kristin Rebertus, RN, NNP, and Nancy Trower, RN, NNP (study center coordinators); Steven Bennett, MD, David Brasel, MD, Robert Couser, MD, Sundeep Dev, MD, Allison Jensen, MD, Richard Lussky, MD, George Miller, MD, Robert Mittra, MD, Timothy Olsen, MD, Robert Ramsey, MD, William Rosen, MD, Edwin Ryan, MD, Shelley Springer, MD, Eric Steuer, MD, C. Gail Summers, MD, and David Williams, MD (co-investigators).
St Louis Center (St Louis, MO): Cardinal Glennon Children's Hospital and St. Mary's Health Center; Bradley V. Davitt, MD (principal investigator); Julie Breuer, RN, and Linda Breuer, LPN (study center coordinators); Oscar Cruz, MD, Stephen Feman, MD, William Keenan, MD, and Greg Mantych, MD (coinvestigators).
North Carolina Center (Durham and Chapel Hill, NC): Duke University Medical Center and University of North Carolina Hospital; Sharon Freedman, MD (principal investigator); David Wallace, MD (co-principal investigator); Eileen Camp, RN, Sharon Clark, RN, Lori Hutchins, RN, and Lora Lake, RN (study center coordinators); Edward Buckley, MD, Laura Enyedi, MD, Ricki Goldstein, MD, Maurice Landers III, MD, Diane Marshall, MD, Travis Meredith, MD, Kean Oh, MD, and Joan Roberts, MD (coinvestigators).
Buffalo Center (Buffalo, NY): Women's and Children's Hospital of Buffalo and Sisters of Charity Hospital; James D. Reynolds, MD (principal investigator); Dawn C. Gordon, RNC, and Barbara Kuppel, RN, BSN (study center coordinators); George P. Albert, MD, Steven Awner, MD, and Rita Ryan, MD (coinvestigators).
Long Island/Westchester Center (New York): Stony Brook University Hospital and Westchester Medical Center; Pamela Ann Weber, MD (principal investigator); Adriann Combs, RNC, and Natalie Dweck, RN (study center coordinators); Howard Charles, MD, Tina Chou, MD, Joseph DeCristofaro, MD, Corina Gerontis, MD, Marc Horowitz, MD, Richard Koty, MD, Edmund LaGamma, MD, and Maury Marmor, MD (coinvestigators).
New York Center (New York, NY): New York Presbyterian Hospital, Columbia Campus and New York Presbyterian Hospital, Cornell Campus; John Flynn, MD (principal investigator); Thomas Lee, MD (co-principal investigator); Osode Coki, RNC, BSN (study center coordinator); Michael Chiang, MD, Steven Kane, MD, Alfred Krauss, MD, Robert Lopez, MD, and Richard Polin, MD (coinvestigators).
Rochester/Syracuse Center (New York): University of Rochester Medical Center and Crouse-Irving Memorial Hospital; Dale L. Phelps, MD (principal investigator); Steven J. Gross, MD, and David Hakanson, MD (co-principal investigators); Marcia Dodge, RN, Cassandra Horihan, MS, Pamela Parker, BA, and Jane Phillips (study center coordinators); Dennis Asselin, MD, Shi-Hwa W. Chang, MD, Ernest Guillet, MD, Robert Hampton, MD, Gary Markowitz, MD, Walter Merriam, MD, Leon-Paul Noel, MD, Robert Olsen, MD, Suzanne Pesce, MD, Steven Rose, MD, Bryan Rutledge, MD, Richard Simon, MD, Sam Spalding, MD, Donald Tingley, MD, Paul Torrisi, MD, and Robert Vanderlinde, MD (coinvestigators).
Columbus Center (Columbus, OH): Columbus Children's Hospital, Ohio State University Hospital, Mount Carmel Medical Center, Grant Medical Center, Riverside Methodist Hospital, Mount Carmel East Hospital, and St. Ann's Hospital; Gary L. Rogers, MD (principal investigator); Don Bremer, MD (co-principal investigator); Rae Fellows, MEd, Sharon Klamfoth, LPN, and Brenda Mann, RNC (study center coordinators); Leandro Cordero, MD, Richard Hertle, MD, Alan Letson, MD, Richard McClead, MD, Mary Lou McGregor, MD, and Patrick Wall, MD (coinvestigators).
Oklahoma City Center (Oklahoma City, OK): Children's Hospital of Oklahoma; R. Michael Siatkowski, MD (principal investigator); Karen E. Corff, MS, ARNP, and Melissa Fuhr, RN (study center coordinators); Reagan H. Bradford, MD, Robert E. Leonard, MD, and Mark H. Scott, MD (coinvestigators).
Portland Center (Portland, OR): Doernbecher Children's Hospital at Oregon Health and Science University, Legacy Emanuel Children's Hospital, and Providence St. Vincent's Hospital; David T. Wheeler, MD (principal investigator); Karen Davis, RN, Nancy Dolphin, RN, and Sharon Dunham, RN (study center coordinators); Aazy Aaby, MD, Shawn Goodman, MD, Andreas Lauer, MD, Valerie Newman, MD, Earl A. Palmer, MD, De-Ann Pillers, MD, PhD, Joseph Robertson, MD, Ann Stout, MD, Tim Stout, MD, and Andrea Tongue, MD (coinvestigators).
Philadelphia Center (Philadelphia, PA): The Children's Hospital of Philadelphia, The Hospital of the University of Pennsylvania, and Pennsylvania Hospital; Graham E. Quinn, MD, MSCE (principal investigator); Jamie G. Koh, RN, MSN, CCRC, Marianne E. Letterio, RN, BSN, and Molly McDaniel, BA (study center coordinators); Soraya Abbasi, MD, Jane C. Edmond, MD, Brian J. Forbes, MD, PhD, Albert M. Maguire, MD, Monte D. Mills, MD, Eric A. Pierce, MD, PhD, and Terri L. Young, MD (coinvestigators).
Pittsburgh Center (Pittsburgh, PA): Magee-Women's Hospital; Kenneth Cheng, MD (principal investigator); Judith Jones, RNC, BSN (study center coordinator); Robert Bergren, MD, Beverly Brozanski, MD, Bernard Doft, MD, Mitchell Fineman, MD, Louis Lobes, MD, and Karl Olsen, MD (coinvestigators).
Charleston Center (Charleston, SC): Medical University of South Carolina; Richard A. Saunders, MD (principal investigator); Lisa Langdale, RN (study center coordinator); Amy Hutchinson, MD, M. Millicent Peterseim, MD, and Dilip Purohit, MD (coinvestigators).
Houston Center (Houston, TX): Baylor College of Medicine, Texas Children's Hospital, Texas Woman's Hospital, and Ben Taub General Hospital; David K. Coats, MD (principal investigator); Laura Gonzalez, Nataliya Kazymyrko, MD, Alma Sanchez, COT, and Michele L. Fulton, COT (study center coordinators); Kathryn Brady-McCreery, MD, Joseph Garcia-Prats, MD, Eric Holz, MD, Scott Jarriel, MD, Karen Johnson, MD, George Mandy, MD, Evelyn A. Paysee, MD, A. Melinda Rainey, MD, and Kimberly G. Yen, MD (coinvestigators).
San Antonio Center (San Antonio, TX): University Hospital and Christus Santa Rosa Children's Hospital; Wichard A. J. van Heuven, MD (principal investigator); Alice K. Gong, MD (co-principal investigator); Melanie H. Drummond, RN (study center coordinator); Timothy Paul Cleland, MD, James C. MacDonald, MD, Lina M. Marouf, MD, and Juan Elian Rubio, MD (coinvestigators).
Salt Lake City Center (Salt Lake City, UT): University of Utah Health Science Center and Primary Children's Medical Center; Robert Hoffman, MD (principal investigator); Susan Bracken, RN (study center coordinator); Paul Bernstein, MD, David Dries, MD, Jerald King, MD, Richard Olson, MD, Michael Teske, MD, and Kimberly Yen, MD (coinvestigators).
National Eye Institute (Bethesda, MD): Maryann Redford, DDS, MPH (program officer, June 2001–Present); Richard L. Mowery, PhD (program officer, October 2000–May 2001); Donald F. Everett, MA (program officer, September 1999–September 2000).
Study Headquarters: Smith-Kettlewell Eye Research Institute, San Francisco, CA; William V. Good, MD (principal investigator); Michelle Quintos, BA (project coordinator).
Coordinating Center: School of Public Health, Coordinating Center for Clinical Trials, University of Texas Health Science Center, Houston, TX; Robert J. Hardy, PhD (principal investigator); Betty Tung, MS (project manager); Gordon Tsai, MS (Coordinating Center staff).
Vision Testing Center: University of Arizona, School of Medicine, Tucson, AZ; Velma Dobson, PhD (principal investigator); Graham E. Quinn, MD (coinvestigator); Kathleen M. Mohan, MA, and Meigan B. Baldwin, BA (vision testers); Suzanne M. Delaney, PhD (Vision Testing Center coordinator).
Data and Safety Monitoring Committee: John Connett, PhD (Chair); Edward F. Donovan, MD, Argye Hillis, PhD, Jonathan M. Holmes, MD, Joseph M. Miller, MD, and Carol R. Taylor, RN, CSFN, PhD (members); William V. Good, MD, Robert J. Hardy, PhD, and Maryann Redford, DDS, MPH (ex-officio members).
Executive Committee, Permanent Members: Chair: William V. Good, MD; Robert J. Hardy, PhD, Velma Dobson, PhD, Earl A. Palmer, MD, and Dale L. Phelps, MD; Ex-officio member: Maryann Redford, DDS, MPH.
Executive Committee, Elected Members: W.A.J. van Heuven, MD (2000–2001), Charles Barr, MD (2001–2002), Michael Gaynon, MD (2002–2003), Michael Shapiro, MD (2003–2004), Rae Fellows, MEd (2000–2001), Judith Jones, RNC, BSN (2001–2002), Kristi Cumming, MSN (2002–2003), and Deborah S. Neff, LPN (2003–2004).
Editorial Committee, Chair: William V. Good, MD; Robert J. Hardy, PhD, Velma Dobson, PhD, Earl A. Palmer, MD, Dale L. Phelps, MD, Michelle Quintos, BA, and Betty Tung, MS.
FOOTNOTES
Accepted Oct 22, 2004.
No conflict of interest declared.
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