Abstract
Purpose
Compare infant and retinopathy of prematurity (ROP) characteristics from three clinical studies conducted over a 27-year period in the United States.
Design
secondary analysis of results of three clinical studies
Subjects
Infants with birth weights <1251g
Methods
analysis of data from the Cryotherapy for ROP (CRYO-ROP) and Early Treatment for ROP (ETROP) trials (Ophthalmology 1991;98:1628–40, Pediatrics 2005;116:15–23) and the primary data from “Telemedicine approaches for the evaluation of acute-phase ROP - e-ROP” study (JAMA Ophthalmology 2014;132:1178).
Main outcome measures
infant characteristics and onset, severity, and time course of ROP
Results
Across the three studies, mean (standard deviation) birth weight (BW) and mean gestational age (GA) decreased over time from CRYO-ROP [954g (185), 27.9 weeks (2.2)] to ETROP [907g (205), 27.4 weeks (2.2)] to e-ROP [864g (212), 27.0 weeks (2.2) with an increase in % infants enrolled <750g (15.8% CRYO, 24.9% ETROP, 33.4% e-ROP, p<0.0001). The percentage of infants who developed ROP varied only minimally (65.8% CRYO, 68.0% ETROP, 63.7% e-ROP, p=0.003). Moderately severe ROP (defined as prethreshold or referral-warranted) varied (17.8% CRYO, 12.3% ETROP, 19.4% e-ROP, p<0.0001), while the time of onset of any ROP did not vary (34.3wks CRYO, 34.1wks ETROP, 34.8wks e-ROP).
Conclusions
BW and GA of infants enrolled in ROP studies in the US have decreased over the last 27 years, while ROP prevalence and onset of disease are stable.
Retinopathy of prematurity (ROP) is a disease seen almost exclusively in premature infants although the incidence varies widely across the world.1,2 Fewer than 10% of those infants who develop ROP will develop severe enough ROP to require treatment though, even with treatment, ROP can lead to visual impairment and blindness.3 In countries with well-developed neonatal intensive care units, the proportion of smaller birth weight (BW) and lower gestational age (GA) infants who survive to discharge is increasing, though there is variation when individual institutions are compared in terms of treatment given and outcome.4–8 Among large multicenter ROP clinical studies conducted in the United States over the last few decades, three studies shared many of the participating centers and in total enrolled more than 12000 premature infants with birth weights of <1251g. These studies reported the incidence and course of acute phase ROP. The Cryotherapy for ROP (CRYO-ROP) study enrolled 4099 babies from January 1986 through November 1987,9,10 the Early Treatment for ROP (ETROP) study screened 6998 babies and enrolled 2320 babies with ROP from October 1, 2000 to September 30, 2002,3,11 and the Telemedicine Approaches for the Evaluation of Acute-Phase Retinopathy of Prematurity (e-ROP) study enrolled 1284 babies from May 2011 through October 2013.12
The purpose of this report is to examine the demographic characteristics and the onset, severity, and time course of acute phase ROP among the infants in these studies.
Methods
The three studies were conducted with cooperative agreements with the National Eye Institute of the National Institutes of Health. Each was approved by the Institutional Review Board at the Study Headquarters and at all clinical centers. In each study, detailed information was collected on infant demographics and the natural history of ROP found during the eye examinations conducted during the at-risk period for ROP by study-certified ophthalmologists. The timing of initial and subsequent exams for acute phase ROP was based on clinical guidelines in place at the time and was essentially the same for the 3 studies. In each study, the International Classification for ROP13,14 was used by study-certified ophthalmologists for documenting the presence and severity of ROP.
Most of the data evaluated for this report was in the same format. For some of the analyses, the data required adjustment to allow comparison. The CRYO-ROP Study10 and the ETROP3 trial used the same definition of “threshold” and “prethreshold” ROP. Threshold ROP was defined as zone I or II, 5 contiguous or 8 composite hours of stage 3 ROP, with plus disease. Prethreshold ROP was defined as zone I any ROP; zone II, stage 2 ROP with plus disease; zone II, any amount of stage 3 ROP and no plus disease; or zone II, stage 3 ROP with plus disease but less than required threshold clock hours. In 2003 the ETROP trial established a new treatment level for severe ROP, termed type 1 ROP, defined as zone I ROP any stage with plus disease, zone I stage 3 ROP, or zone II, stage 2 or 3 ROP with plus disease, as well as less severe ROP that requires increased surveillance, termed type 2 ROP, defined as zone I, stage 1 or 2 without plus, or zone II, stage 3 without plus.
The e-ROP study did not specifically use the terms, threshold or prethreshold. Rather the e-ROP study used the term “referral warranted ROP” (RW-ROP)15 to designate those eyes that needed to be evaluated by an ophthalmologist to consider treatment. RW-ROP was defined for an eye as having any ROP in zone I ROP, stage 3 ROP or worse, or plus disease. RW-ROP is therefore consistent with ROP defined in CRYO-ROP and ETROP as at least prethreshold ROP severity. One key difference between e-ROP and the previous studies is that plus disease alone was considered RW-ROP while in the CRYO-ROP and ETROP treatment studies, peripheral changes of ROP were also required. This would bias to slightly greater severity in the e-ROP study period.
In addition, for the ETROP study which screened 6998 infants and enrolled 2320 infants, the incidence of ROP was estimated by the investigators based on “the data for infants who were monitored and whose ROP status was known (“ROP observed, or mature”) to provide an estimate that was then applied to all 6998 infants in the study, to establish the rate of ROP.11 Based on the available dataset and using multivariate logistic regression to include all patients in the ETROP study, we were able to estimate the percentage of infants in ETROP that develop prethreshold or worse ROP and plus disease.
For this report, “moderately severe or worse ROP” will be used to indicate prethreshold ROP or worse using the CRYO-ROP and ETROP terminology and to indicate RW-ROP in e-ROP.
Because our main purpose is to describe the baseline infant and ROP characteristics from 3 large ROP studies, we do not make frequent use of formal statistical comparisons across these 3 studies, as the large sample sizes can lead to very high statistical power to detect small, but not clinically meaningful differences.
Results
Over the 27-year period from 1986 to 2013, there were more than 12,000 infants with BW of <1251g enrolled or screened in 3 ROP studies (Table 1). The mean BW of these infants decreased over time across the 3 studies from 954g (SD 185) in CRYO-ROP to 907g (SD 205) in ETROP to 864g (SD 212) in e-ROP. The mean GA also decreased by almost 1 week on average (from 27.9 weeks in CRYO-ROP to 27.0 weeks in e-ROP) during this period.
Table 1.
CHARACTERISTICS OF STUDY INFANTS
| CRYO-ROP (N=4099) January 1986 – November 1987 |
ETROP (N=6998) October 2000 – September 2002 |
e-ROP (N=1257) May 2011 – October 2013 |
|
|---|---|---|---|
| Birth weight: mean (SD) | 954 (185) | 907 (205) | 864 (212) |
| Gestational age: mean (SD) | 27.9 (2.2) | 27.4 (2.2) | 27.0 (2.2) |
| Race: n(%) | |||
| Black | 1583 (38.6) | 2114 (30.2) | 31 (29.5) |
| Non-black | 2516 (61.4) | 4884 (69.8) | 763 (60.7) |
| Unable to answer | 123 (9.8) | ||
| Gender: n(%) | |||
| Male | 1970 (48.1) | 3585 (51.2) | 638 (50.8) |
| Female | 2129 (51.9) | 3413 (48.8) | 619 (49.2) |
| Birth weight: n(%) | |||
| <750g | 647 (15.8) | 1745 (24.9) | 420 (33.4) |
| 750–999g | 1590 (38.8) | 2640 (37.7) | 444 (35.3) |
| 1000–1250g | 1862 (45.4) | 2613 (37.2) | 393 (31.3) |
| Gestational age: | |||
| GA≤27 weeks | 1794 (43.8) | 3305 (47.2) | 856 (68.1) |
| >27–31 weeks | 2027 (49.5) | 3454 (49.4) | 370 (29.4) |
| ≥32 weeks | 278 (6.8) | 239 (3.4) | 31 (2.5) |
| Born at enrolling site: n(%) | |||
| Inborn | 3353 (81.8) | 5887 (84.1) | 792 (63.0) |
| Outborn | 746 (18.2) | 1111 (15.9) | 465 (37.0) |
| Multiple birth: n(%) | |||
| Single birth | 3335 (81.4) | 5162 (73.8) | 882 (70.2) |
| Multiple birth | 764 (18.6) | 1836 (26.2) | 375 (29.8) |
The percentage of infants with BW <750g increased over time from CRYO-ROP to ETROP to e-ROP (15.8% to 24.9% to 33.4%). Similarly, the percentage of infants with GAs of ≤27 weeks increased from 43.8% to 47.2% to 68.1%.
The majority of infants in all three studies were inborn, but there were more outborn infants in e-ROP (37%). The number of multiple births increased from 18.6% to 26.2% to 29.8% from CRYO-ROP to ETROP to e-ROP.
The overall incidence of ROP across the time period of the 3 studies was similar with approximately two-thirds of the infants < 1251g developing some stage of acute ROP (Table 2). There was a decrease in the incidence of ROP between the ETROP and e-ROP studies among the >750g BW infants (61.3%, 59.8% and 51.4% for CRYO, ETROP and e-ROP respectively, p<0.0001) and among the >27 weeks GA infants (52.1%, 50.2% and 33.9% for CRYO, ETROP and e-ROP respectively, p<0.0001).
TABLE 2.
NUMBER AND PERCENT OF INFANTS WITH ROP OF ANY STAGE
| CRYO-ROP (N=4099) n/N (%) |
ETROP* (N=6998) n/N (%) |
e-ROP (N=1257) n/N (%) |
|
|---|---|---|---|
| Black | 1000/1583 (63.2%) | 1429/2144 (67.6%) | 218/371 (58.8%) |
| Non-black | 1699/2516 (67.5%) | 3331/4884 (68.2%) | 510/763 (66.8%) |
| Unable to answer | 73/123 (59.4%) | ||
| Male | 1309/1970 (66.4%) | 2429/3583 (67.8%) | 413/638 (64.7%) |
| Female | 1300/2129 (65.3%) | 233/3415 (68.3%) | 388/619 (62.7%) |
| <750g | 582/647 (90.0%) | 1618/1745 (92.7%) | 371/420 (88.3%) |
| 750–999g | 1243/1590 (78.2%) | 2001/2640 (75.8%) | 283/444 (63.7%) |
| 1000–1250g | 874/1862 (46.9%) | 1142/2613 (43.7%) | 147/393 (37.4%) |
| ≤27 weeks | 1497/1794 (83.4%) | 2941/3305 (89.0%) | 665/856 (77.7%) |
| >27–31 weeks | 1120/2027 (55.3%) | 1820/3454 (52.7%) | 131/370 (35.4%) |
| ≥32 weeks | 82/278 (29.5%) | 34/239 (14.2%) | 5/31 (16.1%) |
| Inborn | 2155/3353 (64.3%) | 3944/5887 (67.0%) | 459/792 (58.0%) |
| Outborn | 544/746 (72.9%) | 815/1111 (73.4%) | 342/465 (73.6%) |
| Single birth | 2202/3335 (66.0%) | 3510/5162 (68.0%) | 562/882 (63.7%) |
| Multiple birth | 497/764 (65.1%) | 1248/1836 (68.0%) | 239/375 (63.7%) |
| TOTAL | 2699/4099 (65.8%) | 4759/6998 (68.0%) | 801/1257 (63.7%) |
estimated with a multivariate logistic-regression equation to include all patients screened for ROP in the ETROP study.
It is more difficult to interpret change in incidence. The overall incidence of prethreshold or worse ROP across the 3 studies has varied minimally.(Table 3) The percentage of prethreshold or worse ROP decreased among larger BW (1000–1250g) infants from 7.3% in CRYO-ROP to 3.9% in ETROP and 3.8% in e-ROP. Among infants with BW between 750 and 999g the percentage decreased from 21.4% in CRYO-ROP to 13.2% in ETROP, but was up slightly to 14.9% in e-ROP. Among the most at risk group of infants with BW < 750 grams, the percentage of prethreshold or worse ROP decreased from 39.4% in CRYO to 31.5% in ETROP, but then rebounded to 38.8% in e-ROP. There was no change by race or sex.
Table 3.
Prethreshold ROP worse in CRYO-ROP study or ETROP and RW-ROP in e-ROP
| CRYO-ROP (N=4099) | ETROP (N=6998)§ | e-ROP (N=1257) | |
|---|---|---|---|
| Black | 208/1583 (13.1%) | 233/2114 (11.0%) | 51/371 (13.8%) |
| Non-black | 523/2516 (20.8%) | 768/4884 (15.7%) | 162/763 (21.2%) |
| Unable to answer | 31/123 (25.2%) | ||
| Male | 367/1970 (18.8%) | 543/3585 (15.2%) | 136/638 (21.3%) |
| Female | 364/2129 (17.1%) | 457/3413 (13.4%) | 108/619 (17.5%) |
| <750g | 255/647 (39.4%) | 550/1745 (31.5%) | 163/420 (38.8%) |
| 750–999g | 341/1590 (21.4%) | 349/2640 (13.2%) | 66/444 (14.9%) |
| 1000–1250g | 135/1862 (7.3%) | 102/2613 (3.89%) | 15/393 (3.82%) |
| ≤27 weeks | 519/1794 (28.9%) | 893/4172 (21.4%) | 232/856 (27.1%) |
| >27–31 weeks | 204/2027 (10.1%) | 105/2587 (4.07%) | 11/370 (2.97%) |
| ≥32 weeks | 8/278 (2.9%) | 2/239 (2.34%) | 1/31 (3.23%) |
| Inborn | 551/3353 (16.4%) | 821/5887 (13.9%) | 102/792 (12.9%) |
| Outborn | 180/746 (24.1%) | 180/1111 (16.2%) | 142/465 (30.5%) |
| Single birth | 573/3335 (17.2%) | 703/5162 (13.6%) | 169/882 (19.2%) |
| Multiple birth | 158/764 (20.7%) | 298/1836 (16.2%) | 75/375 (20.0%) |
| Total | 731/4099 (17.8%) | 1001/6998 (14.3%) | 244/1257 (19.4%) |
Estimated from multivariate logistic regression equation to include all patients screened for ROP in the ETROP Study.
There was little difference in the overall percentage of infants with plus disease across the three studies (11.0% for CRYO-ROP, 9.3% for ETROP and 10.7% for e-ROP). However, plus disease was more commonly observed in non-black infants in all three studies and, among infants with GA >32 weeks, the incidence of plus disease decreased from 2.9% (8/278) in CRYO to 0% (0/31) in e-ROP (Table 4).
TABLE 4.
Number and percent of infants with plus disease
| CRYO-ROP (N=4099) | ETROP (N=6998)§ | e-ROP (N=1257) | |
|---|---|---|---|
| Black | 107/1583 (6.8%) | 109/2114 (5.17%) | 22/371 (5.93%) |
| Non-black | 343/2516 (13.6%) | 540/4884 (11.0%) | 96/763 (12.6%) |
| Unable to answer | 17/123 (13.8%) | ||
| Male | 229/1970 (11.6%) | 350/3585 (9.77%) | 76/638 (11.9%) |
| Female | 221/2129 (10.4%) | 298/3413 (8.74%) | 59/619 (9.53%) |
| <750g | 159/647 (24.6%) | 364/1745 (20.9%) | 92/420 (21.9%) |
| 750–999g | 204/1590 (12.8%) | 221/2640 (8.36%) | 37/444 (8.33%) |
| 1000–1250g | 87/1862 (4.7%) | 64/2613 (2.45%) | 6/393 (1.53%) |
| ≤27 weeks | 319/1794 (17.8%) | 582/4172 (14.0%) | 130/856 (15.2%) |
| >27–31 weeks | 123/2027 (6.1%) | 65/2587 (2.51%) | 5/370 (1.35%) |
| ≥32 weeks | 8/278 (2.9%) | 2/239 (0.61%) | 0/31 (0.00%) |
| Inborn | 338/3353 (10.1%) | 527/5887 (8.95%) | 54/792 (6.82%) |
| Outborn | 112/746 (15.0%) | 122/1111 (11.0%) | 81/465 (17.4%) |
| Single birth | 350/3335 (10.5%) | 452/5162 (8.75%) | 98/882 (11.1%) |
| Multiple birth | 100/764 (13.1%) | 197/1836 (10.7%) | 37/375 (9.87%) |
| Total | 450/4099 (11.0%) | 649/6998 (9.27%) | 135/1257 (10.7%) |
Estimated from multivariate logistic regression equation to include all patients screened for ROP in the ETROP Study.
With respect to the timing of the onset of the stages of acute ROP, plus disease, and prethreshold or worse ROP, there was no clinically significant change identified over this period (Table 5).
TABLE 5.
ONSET OF DIFFERENT ROP STATUS BY PMA (median, 5th and 95th percentile)
| CRYO-ROP (N=4099) |
ETROP (N=6998) | e-ROP (N=1257) | |
|---|---|---|---|
| Stage 1 ROP | 34.3 (-, 39.1) | 34.1 (-, 38.9) | 34.8 (32.3, 39.4) |
| Stage 2 ROP | 35.4 (32.0, 40.7) | 35.1 (32.4, 40.1) | 35.0 (32.7, 39.4) |
| Stage 3 ROP | 36.6 (32.9, 42.4) | 36.6 (33.4, 41.6) | 36.3 (33.0, 40.7) |
| Plus disease | 36.3 (32.6, 42.9) | 36.0 (33.0, 41.4) | 36.8 (33.0, 41.1) |
| Prethreshold/threshold ROP – RW-ROP | 36.1 (32.4, 41.5) | 36.1 (32.1, 42.1) | 36.1 (32.5, 40.4) |
The data were available to allow us to examine the comparison of rate of prethreshold ROP among infants in the 2000–2 ETROP study and 2011–13 e-ROP study in terms of BW and GA. Figure 1 shows that the differences in rate of prethreshold ROP vary with BW and GA. In the lowest birth weight and least mature infants (BW<1000 grams and GA<=27 weeks), the prethreshold ROP rate was higher in e-ROP than ETROP (30.6% vs. 22.0%, p<0.0001), while in the most mature infants (GA>=28 weeks or BW>=1000 grams), the rate of the prethreshold ROP was similar (4.1% vs. 2.9%, p=0.13).
Figure 1.
The rate of prethreshold ROP by combination of BW and GA in ETROP and e-ROP.
Since 1986, average birth weight and gestational age of <1251g birth weight premature infants at risk for ROP have decreased while ROP prevalence and onset have changed little.
Discussion
Over the last 3 decades, the incidence of ROP among infants with BW <1251g has remained relatively stable in large clinical centers in the US. When comparing the CRYO-ROP, ETROP and e-ROP studies, overall about 65% of infants developed some stage of ROP and approximately 1 in 6 infants developed more serious disease. This was observed despite the fact that the infants most at risk were found in increasing numbers. The mean BW decreased from 954g in CRYO-ROP to 864g 25 years later in e-ROP. Similarly, the mean gestational age of infants in the CRYO-ROP study was 28 weeks with 44% of infants born at less than 27 weeks; in the e-ROP study the mean GA was 27 weeks with 68% born at less than 27 weeks. Thus the population of infants in the <1251g BW group has shifted to smaller, less mature infants, but despite this increased survival of the most at-risk population, the overall proportion of infants who develop ROP has varied little. The most plausible explanation for this observation is the care that premature infants receive has improved since infants were enrolled in the CRYO-ROP study. The numerous innovations have included advances in obstetrical care including the use of antenatal steroids, expectant delivery protocols, and close monitoring of preterm labor. In the NICU itself, there has been improved care provided with better oxygen monitoring and ventilator support, increased awareness of the importance of nutritional support including human breast milk, and increased awareness of the environment for the infants including reducing stress when possible.16 Importantly, the use of surfactant became routine in the early 1990s.17 It is of interest that, in the clinical centers represented in this study, the percentage of infants who were not born in the center doubled over the 27-year period, perhaps reflecting that there is an increased likelihood of referral of the sicker, more critically ill infants with severe respiratory failure or surgical necrotizing enterocolitis for neonatal intensive care or even referral for ROP care. It is also important to note that some of the clinical centers in these studies increased capacity for referrals during the intervening years.
These improvements in survival of at risk infants have not had an effect on the onset of ROP and progression to more serious disease (Table 5).13 An effect would not be expected as the development of ROP is tightly correlated with the development of the retina rather than the specific GA or BW of an individual infant.9
The results of these comparisons are not necessarily generalizable to all NICU settings, even to all NICUs in the US, but the results are encouraging. As care of the premature infant improves in middle- and low-income countries and expertise in ROP develops, a decrease in the incidence of ROP and serious ROP in larger and more mature infants will likely be observed.
There are limitations to a study of this type as only a broad overview can be provided since only mean/median and incidence data were available in all 3 studies, and further, values had to be imputed in ETROP for more serious acute phase ROP. Further, there has likely been an evolution of the definition of plus disease and its clinical diagnosis over the time period covered by these studies. Before the results of the CRYO-ROP study were known, there was likely a bias toward requiring more severe abnormalities of the posterior pole vessels than when the prognostic importance of plus disease became evident in the ETROP study.
Several strengths are also important. Ten clinical centers in the US participated in each of these three studies with at least one investigator participating from 7 of these centers. Further, all of the study ophthalmologists had undergone rigorous certification to be an examiner, thus strengthening the findings of this report. In addition, these three studies represent a large sample of the infants born in the US during each time period and, though individual centers have likely changed practice over this time, the sample is sufficiently large to suggest the findings are representative of practice in the US.
In summary, the incidence of ROP and serious ROP has remained relatively stable over the last 3 decades in the US while the percentage of the most at risk infants has increased over this period. This likely reflects improved neonatal and obstetrical care and is an encouraging sign that ROP remains a risk, but not necessarily an increasing risk for premature infants in the US.
Acknowledgments
Financial support: Funded by the National Eye Institute of the National Institutes of Health, Department of Health and Human Services [U10 EY017014].
Footnotes
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Meeting presentation: Presented at ARVO 2015 Denver, Colorado
No conflicting relationship exists for any author.
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