Journal of Pediatric Ophthalmology and Strabismus

Original Article Supplemental Data

Temporal Profile of Retinopathy of Prematurity in Extremely Premature Compared to Premature Infants

Vincent D. Venincasa, MD; Victoria Bugg, MD; Justin Dvorak, PhD; Kai Ding, PhD; Faizah Bhatti, MD; R. Michael Siatkowski, MD

Abstract

Purpose:

To compare the time course of retinopathy of prematurity (ROP) in premature (≥ 28 to 34 weeks' gestational age) and extremely premature (< 28 weeks' gestational age) infants.

Methods:

This study was a retrospective single-center chart review that included 582 eyes (122 premature, 464 extremely premature) of 299 infants (65 premature, 234 extremely premature) diagnosed as having ROP who were born between January 1, 2010, and December 31, 2015. Data collected were analyzed with shared frailty models, chi-square, and Fisher's exact tests.

Results:

Extremely premature infants were diagnosed as having ROP earlier than premature infants at 33.6 weeks (95% CI [confidence interval]: 33.4 to 33.9) versus 36.0 weeks (95% CI: 34.7 to 36.4, P < .0001). The time from diagnosis to spontaneous regression was more than 4 weeks longer for extremely premature infants than premature infants with stage 1 ROP (82.0 vs 50.0 days, P < .0001), and more than 6 weeks longer for extremely premature infants than premature infants with stage 2 ROP (99 vs 55 days, P < .0001). Extremely premature infants had more bilateral ROP (96.6% vs 87.1%, P < .01) and were three times more likely to require treatment than premature infants (29.7% vs 9.9%, P < .0001). On average, infants who required treatment weighed 137 grams less at birth (P < .0001) and gained 37.7 grams less per week than infants who underwent spontaneous regression (P < .0001).

Conclusions:

Extremely premature infants developed ROP earlier, had more bilateral ROP, took longer to achieve spontaneous regression, and required treatment more often than premature infants. Infants who required treatment had a lower birth weight and rate of weight gain than infants who underwent spontaneous regression.

[J Pediatr Ophthalmol Strabismus. 2019;56(2):116–123.]

Abstract

Purpose:

To compare the time course of retinopathy of prematurity (ROP) in premature (≥ 28 to 34 weeks' gestational age) and extremely premature (< 28 weeks' gestational age) infants.

Methods:

This study was a retrospective single-center chart review that included 582 eyes (122 premature, 464 extremely premature) of 299 infants (65 premature, 234 extremely premature) diagnosed as having ROP who were born between January 1, 2010, and December 31, 2015. Data collected were analyzed with shared frailty models, chi-square, and Fisher's exact tests.

Results:

Extremely premature infants were diagnosed as having ROP earlier than premature infants at 33.6 weeks (95% CI [confidence interval]: 33.4 to 33.9) versus 36.0 weeks (95% CI: 34.7 to 36.4, P < .0001). The time from diagnosis to spontaneous regression was more than 4 weeks longer for extremely premature infants than premature infants with stage 1 ROP (82.0 vs 50.0 days, P < .0001), and more than 6 weeks longer for extremely premature infants than premature infants with stage 2 ROP (99 vs 55 days, P < .0001). Extremely premature infants had more bilateral ROP (96.6% vs 87.1%, P < .01) and were three times more likely to require treatment than premature infants (29.7% vs 9.9%, P < .0001). On average, infants who required treatment weighed 137 grams less at birth (P < .0001) and gained 37.7 grams less per week than infants who underwent spontaneous regression (P < .0001).

Conclusions:

Extremely premature infants developed ROP earlier, had more bilateral ROP, took longer to achieve spontaneous regression, and required treatment more often than premature infants. Infants who required treatment had a lower birth weight and rate of weight gain than infants who underwent spontaneous regression.

[J Pediatr Ophthalmol Strabismus. 2019;56(2):116–123.]

Introduction

Retinopathy of prematurity (ROP) is a disease of abnormal retinal vascular development that can lead to severe visual impairment and/or blindness.1–3 Although the risk factors and treatment strategies have been well defined, ROP remains the third most common cause of childhood blindness in the United States, following cortical visual impairment and optic nerve hypoplasia.4 As neonatal care improves, a relatively understudied population is emerging: the extremely premature, defined by the Centers for Disease Control and Prevention as infants born earlier than 28 weeks' gestational age.5 In 2007, 12.7% of infants born in the United States were born premature, defined as birth at 28 to 37 weeks' gestational age, with the extremely premature comprising 0.8% of total births.5 Extremely premature infant survival is increasing and morbidity is decreasing.6–8 In 1993, 52% of infants born at 24 weeks survived compared to 65% in 2012, and 38% of infants born at 28 weeks survived without major morbidity compared to 56% in 2012.8

The incidence of ROP in extremely premature infants is high and varies based on gestational age: 76.1% of infants born at 25 weeks developed ROP compared to 90.5% born at 23 weeks.9 Despite this, there is a paucity of data regarding the temporal profile of ROP in extremely premature infants because the majority of the ROP studies did not specifically examine the extremely premature. Two of the most commonly cited risk factors for ROP are gestational age and birth weight. However, although birth weight,10 rate of weight gain,11 weight at 6 weeks,12 and weight at detection of ROP13 have been shown to predict mild to severe ROP incidence in the premature infant population, their predictive value in the extremely premature infant population is undefined.14 Anecdotal evidence has indicated that extremely premature infants often reach either regression or treatment threshold at a later post-menstrual age than premature infants. Current guidelines support an initial ROP examination at 31 weeks, but data for infants born between 22 and 23 weeks are sparse due to the relatively low number of survivors.15,16 In these cases, clinical discretion in conjunction with the neonatologist is warranted to individually determine the optimal timing of initial ROP examinations.

The inverse relationship of the incidence and severity of ROP to gestational age and birth weight has been well described,17 but to the best of our knowledge, there have been no studies to compare the temporal course of ROP, once diagnosed, in the premature and extremely premature infant populations. Identification of significant differences may result in the need to alter follow-up strategies. A secondary purpose of this study was to examine the effect of birth weight and rate of weight gain, independent of gestational age at birth, on the clinical course of ROP.

Patients and Methods

This retrospective study was approved by the institutional review board at our institution and was conducted in compliance with the Declaration of Helsinki and Health Insurance Portability and Accountability Act. It comprised all patients diagnosed as having ROP at our institution from January 1, 2010, to December 31, 2015, including patients born elsewhere and transferred for a higher level of neonatal care. Patients were examined for disease severity in a standardized fashion by one of the three pediatric attending physicians on a 1- to 4-week basis. ROP screenings were consistent with the current American Academy of Ophthalmology, American Academy of Pediatrics, and American Academy of Pediatric Ophthalmology guidelines.18 Patients were identified by reviewing diagnostic ROP examination notes for a positive diagnosis. Only patients with at least stage 1 ROP were included. Patients who died before the ROP screening concluded were excluded from the study. The patient data collected were demographics (age, sex, and ethnicity), weight at various time points (birth, diagnosis, and regression/treatment), date, location and extent of ROP at diagnosis, and the age at regression or treatment.

The patients were divided into premature and extremely premature groups. Extremely premature infants were stratified by worst ROP stage developed and subdivided into extremely low birth weight (ELBW) (< 750 g) and low birth weight (LBW) (750 to 1,500 g). Spontaneous regression was defined as a complete resolution of disease or full retinal vascularization. Type 1 ROP was defined as ROP that required treatment. Data were analyzed to provide comparative temporal profiles of disease onset and clinical course between these groups.

Statistical methods included descriptive statistics, chi-square tests of independence (or Fisher's exact test where warranted by low cell counts), two-sample t tests (or Wilcoxon rank-sum test where warranted by violation of distributional assumptions), log-rank test, shared frailty models (an extension of Cox proportional hazards models for time-to-event data, accounting for intra-patient correlations), linear mixed models and mixed logit models (for continuous and binary outcomes, respectively, accounting for intra-patient correlations). The specific test used is indicated in the footnotes of the data tables in the results section. Intra-patient correlations were accounted for in the eye-level statistical analyses with random effects (also called frailties for time-to-event outcomes). Statistical significance was defined as P value of less than .05 (two-sided). Statistical Analysis Software (version 9.4; SAS, Cary, NC) was used.

Results

Patient-Level Statistics

A total of 311 patient charts were evaluated. Twelve patients were excluded due to lack of follow-up or death and 299 infants were included in the study. Of these infants, 65 (21.7%) were premature and 234 (78.3%) were extremely premature. Bilateral ROP was more common in extremely premature infants than premature infants (96.6% vs 87.7%, P = .0097). Extremely premature infants had a mean gestational age of 25.6 weeks (range: 22.5 to 27.9 weeks), and premature infants had a mean gestational age of 28.9 weeks (range: 28 to 34 weeks). Extremely premature infants had a lower birth weight than premature infants (770 vs 1,130 g, P < .0001). Complete patient-level statistics are reported in Table 1. Extremely premature infants were further subdivided into two groups: ELBW and LBW. Between 2014 and 2016, 573 patients were screened (premature = 361, extremely premature = 212) and 212 (37%) were diagnosed as having ROP (premature = 71 [20%] and extremely premature = 141 [67%]). The number of patients screened before 2014 was not available. Complete patient-level statistics for the subgroups of extremely premature infants are reported in Table A (available in the online version of this article).

Demographics and Clinical Course of Retinopathy of Prematurity

Table 1:

Demographics and Clinical Course of Retinopathy of Prematurity

Patient-Level Data of Extremely Premature Infants

Table A:

Patient-Level Data of Extremely Premature Infants

ROP Disease Course

Premature and extremely premature infants were stratified by stage 1 disease, stage 2 without plus disease, and stage 2 with plus disease/stage 3 or worse (stage 2+). For all stages at the time of diagnosis, extremely premature infants had a significantly lower post-menstrual age (stage 1: 33.6 vs 34.7 weeks, P = .0002; stage 2: 33.6 vs 36.9 weeks, P < .0001). For all stages at the time of diagnosis, premature infants had a significantly higher rate of disease regression than extremely premature infants (stage 1: 96.8% vs 74.5%, P = .0004; stage 2: 84.7% vs 59.3%, P = .0018), and extremely premature infants had a significantly greater time from diagnosis to regression (stage 1: 82 vs 50 days, P = .0003; stage 2: 99 vs 55 days, P = .0094). Further data are presented in Table 2.

Retinopathy of Prematurity Disease Course in Premature vs Extremely Premature Infants

Table 2:

Retinopathy of Prematurity Disease Course in Premature vs Extremely Premature Infants

Disease Characteristics

Plus disease was present nearly four times more in extremely premature infants than premature infants (23.2% vs 5.9%, P < .0001). Extremely premature infants were treated three times more often than premature infants (29.7% vs 9.9%, P < .0001). Bevacizumab injections were administered to 36 eyes, whereas laser treatments were applied to 110 eyes (extremely premature: 32 vs 102; premature: 4 vs 8). At the time of treatment administration (excluding 9 eyes with missing zone information), the extremely premature group had 120 eyes with ROP in zone II vs 8 with ROP in zone I and the premature group had 7 eyes with ROP in zone II and 2 eyes in zone I. Further data are presented in Table 3 and Table B (available in the online version of this article).

Retinopathy of Prematurity Severity and Treatmenta

Table 3:

Retinopathy of Prematurity Severity and Treatment

ROP Course in Eyes That Underwent Spontaneous Regression

Table B:

ROP Course in Eyes That Underwent Spontaneous Regression

The extremely premature ELBW infants had a higher incidence of plus disease (28.2% vs 17.3%, P = .036) and type I ROP (36.1% vs 23.0%, P = .025) than the extremely premature LBW infants. Although it was not statistically significant, the extremely premature ELBW infants were more likely to require treatment than the extremely premature LBW infants (odds ratio: 1.7, P = .07). Complete data are shown in Tables CD (available in the online version of this article).

Extremely Premature Infants With Severe ROP

Table C:

Extremely Premature Infants With Severe ROP

Retinopathy of Prematurity Stage of Eyes Requiring Treatmenta

Table D:

Retinopathy of Prematurity Stage of Eyes Requiring Treatment

Independent of gestational age, infants with eyes that underwent spontaneous regression were 137.8 grams heavier at birth than infants with eyes that required treatment (882.5 vs 744.6 grams, P < .0001). Infants with ROP who required treatment gained 37.7 grams less per week than infants with ROP who underwent spontaneous regression (122.0 vs 160.8 grams/week, P < .0001). Complete data are shown in Table 4.

Birth Weight and Weight Gain in Patients With Eyes That Underwent SR Versus TX

Table 4:

Birth Weight and Weight Gain in Patients With Eyes That Underwent SR Versus TX

Extremely premature infants who required treatment gained 34.7 grams/week less than extremely premature infants who underwent spontaneous regression (122.4 vs 157.0 grams/week, P < .0001). A similar trend was found in the extremely premature LBW and extremely premature ELBW infant groups where the extremely premature LBW infants who required treatment gained 30.8 grams less per week than the extremely premature LBW infants who underwent spontaneous regression (133.2 vs 165.3 grams/week, P < .0001) and the extremely premature ELBW infants who required treatment gained 34.4 grams less per week than extremely premature ELBW infants who underwent spontaneous regression (114.7 vs 148.9 grams/week, P < .0001). Complete data are shown in Table 5 and Tables EF (available in the online version of this article).

Weight Gain (g/wk) in Patients With Eyes That Underwent SR Versus TX

Table 5:

Weight Gain (g/wk) in Patients With Eyes That Underwent SR Versus TX

Eye-Level Data for ROP Course for All Eyes

Table E:

Eye-Level Data for ROP Course for All Eyes

Eye-Level Data for ROP Course for Extremely Premature Eyes

Table F:

Eye-Level Data for ROP Course for Extremely Premature Eyes

Discussion

Extremely premature infants are a growing population with a unique natural course of ROP. On average, extremely premature infants are more than four times more likely to be diagnosed as having ROP and three times more likely to require treatment than premature infants.

The majority (71%) of extremely premature infants with ROP will reach spontaneous regression, but their temporal profile is expanded. Time between diagnosis and spontaneous regression was longer in extremely premature infants than premature infants (4 weeks longer in stage 1 disease and more than 6 weeks longer in stage 2 disease). Furthermore, the extremely premature ELBW group took 2 weeks longer to achieve spontaneous regression compared to the extremely premature LBW group. This variance in ROP behavior cannot be explained by gestational age alone, and it is likely that biological differences exist at disease onset and persist through its natural course. This is the first study to document these disparities between extremely premature and premature infants and the extremely premature ELBW and LBW infants.

Birth weight and rate of weight gain have recently been implicated as important predictive factors for ROP incidence and severity.19,20 This study demonstrates that although gestational age is inherently linked to birth weight and rate of weight gain, when gestational age is controlled for as in the extremely premature LBW and extremely premature ELBW comparisons, it is not gestational age but rather birth weight and weight of rate gain that are stronger influences in the development of ROP. Infants eventually requiring treatment for ROP were more than 130 grams lighter at birth than infants who underwent spontaneous regression. In addition, infants who required treatment had a lower rate of weight gain per week compared to age-matched infants who underwent spontaneous regression. This trend was demonstrated repeatedly. Based on these results, infants who gain less than 150 grams/week should be considered very high risk for requiring treatment. Although not measured directly in this subset of patients, one could extrapolate from prior studies regarding infant weight gain that extremely premature and extremely premature ELBW infants have lower levels of insulin-like growth factor 1 compared to premature and extremely premature LBW infants, respectively.10,11,21–23 Insulin-like growth factor 1 is required for adequate vascular endothelial growth factor pathway signaling and normal retinal vascular development.22,23 Insulin-like growth factor 1 is likely one of many factors that lead to more severe ROP in infants with lower birth weight or rate of weight gain. This study reemphasizes the importance of monitoring and tracking weight gain in infants with ROP as a potential predictor of severity or, conversely, pursuing therapies that enhance weight gain to attempt to prevent type 1 ROP.

The ROP screening guidelines advise examining at-risk infants at 6 weeks post-natal age or 31 weeks post-gestational age, whichever is earlier and dependent on comorbidities.15 Of the 299 patients in this study, only one extremely premature infant (0.3%) was diagnosed as having ROP at initial screening. This infant was born at 26 weeks' gestational age and weighed 790 grams. The infant was very sick initially, requiring 13 units of blood and 52 days on the ventilator. He was diagnosed as having stage 2, zone II ROP involving 8 clock hours without plus disease in the right eye and stage 2, zone II ROP involving 6 clock hours without plus disease in the left eye at the initial 30-week examination and eventually required bilateral laser treatment. Earlier screening and diagnosis would not have altered the time at treatment or the final outcome. Because only one extremely premature infant was diagnosed as having ROP at the initial examination and it was a case not requiring treatment at that time, the authors believed that an alteration to the screening protocol was unwarranted.

This study has several limitations. Data are from a single center via a retrospective analysis. Although the diagnosis of ROP and classification of type 1 ROP are standardized at this institution, four different ophthalmologists examined the infants. Sato et al.24 showed that intraphysician disagreement on the diagnosis of plus disease is between 10% and 14%. In addition, 382 of 2,907 (13.1%) total encounters were missing weight measurements, most commonly from the final follow-up.

Effective ROP diagnostic examinations are important to ensure optimal patient outcomes and to maximize efficacy among a different pool of trained examiners. All health care providers involved with infant care must be aware that ROP behaves differently in extremely premature and premature infants. Ophthalmologists should be prepared to observe extremely premature infants for several weeks longer than premature infants, until they reach regression or the need for treatment occurs. This will likely include even more coordination with the pediatrician and primary care team. In addition, they must be cognizant of the higher incidence of bilateral and type 1 ROP in extremely premature infants to avoid the devastating consequences of delayed or inadequate care.

Extremely premature infants are a growing population due to advancing technology. Compared to premature infants, extremely premature infants have more bilateral ROP with a longer temporal course that requires treatment more often. Ophthalmologists will likely need to observe extremely premature infants after discharge and be prepared for treatment for at least 12 weeks after birth.

References

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Demographics and Clinical Course of Retinopathy of Prematurity

VariableOverall (N = 299)P (n = 65)EP (n = 234)P
Sex.4260c
  Male156 (52.2%)36 (55.4%)120 (51.3%)
  Female120 (40.1%)23 (35.4%)97 (41.5%)
  Unknown23 (7.7%)6 (9.2%)17 (7.3%)
Race.8777e
  White155 (51.8%)35 (53.8%)120 (51.3%)
  Black44 (14.7%)12 (18.5%)32 (13.7%)
  Hispanic36 (12.0%)5 (7.7%)31 (13.2%)
  Native American12 (4.0%)5 (7.7%)7 (3.0%)
  Asian2 (0.7%)0 (0.0%)2 (0.9%)
  Unknown50 (16.7%)8 (12.3%)42 (17.9%)
Involvement.0097c
  Unilateral, n (%)16 (5.4%)8 (12.3%)8 (3.4%)
  Bilateral, n (%)283 (94.6%)57 (87.7%)226 (96.6%)
GA, weeks, median [95% CI]26.0 [25.9 to 26.3]28.9 [28.6 to 29.3]25.6 [25.6 to 25.7]NAf
Birth weight, grams847.9 ± 253.71129.7 ± 310.3769.6 ± 166.1< .0001d
Transfusion.0288c
  No85 (28.4%)26 (40.0%)59 (25.2%)
  Yes214 (71.6%)39 (60.0%)175 (74.8%)
Units of transfusiona9.8 ± 6.95.0 ± 4.010.9 ± 6.9< .0001d
Ventilator.0546c
  No81 (27.1%)24 (36.9%)57 (24.4%)
  Yes218 (72.9%)41 (63.1%)177 (75.6%)
Days on ventilator,b median [95% CI]37 [29 to 43]10 [4 to 14]44 [36 to 50]< .0001g
Days on TPN, median [95% CI]35 [32 to 38]22 [16 to 26]39 [35 to 45]< .0001g
Weight at 1 week, grams814.8 ± 265.41,117.4 ± 319.4728.4 ± 167.7< .0001d
  Grams/week−29.8 ± 90.6−24.5 ± 111.9−31.3 ± 83.9.4878h
Weight at 6 weeks, grams1,410.6 ± 413.01,873.7 ± 492.61,296.0 ± 295.6< .0001d
  Grams/week95.9 ± 36.4123.8 ± 42.389.0 ± 31.2< .0001h

Retinopathy of Prematurity Disease Course in Premature vs Extremely Premature Infants

VariableStage 1P

Overall (n = 263)P (n = 63)EP (n = 200)
PMA at dx, weeks, median [95% CI]34.0 [33.6 to 34.1]34.7 [34.1 to 35.7]33.6 [33.3 to 34.0].0002a
Weight at dx, grams1,762.8 ± 552.71,895.5 ± 522.41,723.1 ± 556.7.9812b
No. of reg (SR + AVR)210 (79.8%)61 (96.8%)149 (74.5%).0004c
PMA at reg, weeks, median [95% CI]44.6 [44.0 to 46.0]43.1 [41.3 to 43.9]45.6 [44.3 to 47.1].0546a
Weight at reg, grams3,992.5 ± 1159.03,859.2 ± 1133.64,043.4 ± 1168.5.3320b
Days from dx to reg, median [95% CI]72.0 [65.0 to 82.0]50.0 [44.0 to 61.0]82.0 [72.0 to 86.0].0003a
Weight gain (g/week)156.6 ± 38.5176.6 ± 50.5150.3 ± 31.4.0099b
VariableStage 2 Eyes Without Plus DiseaseP

Overall (N = 230)P (n = 50)EP (n = 180)
PMA at dx, weeks, median [95% CI]34.1 [33.7 to 34.6]36.9 [36.0 to 37.9]33.7 [33.6 to 34.0]< .0001a
Weight at dx, grams1,779.2 ± 491.32,148.3 ± 622.01,685.3 ± 403.4< .0001b
No. of reg (SR + AVR)191 (83.0%)46 (92.0%)145 (80.6%).0357f
PMA at reg, weeks, median [95% CI]46.4 [44.4 to 47.3]44.7 [42.9 to 48.3]46.4 [44.4 to 47.4].7842a
Weight at reg, grams4,031.7 ± 1149.63,946.1 ± 1028.84,060.9 ± 1190.3.9434b
Days from dx to reg, median [95% CI]79.0 [70.0 to 92.0]52.0 [42.0 to 70.0]93.0 [75.0 to 98.0].0061a
Weight gain (g/week)155.1 ± 34.2157.9 ± 40.1154.2 ± 32.4.8283b
VariableStage 2 Eyes With Plus Disease or Stage 3 or WorsePe

Overall (N = 81)Pe (n = 7)EP (n = 74)
PMA at dx, weeks, median [95% CI]33.4 [33.1 to 33.7]34.1 [32.7 to 36.4]33.4 [33.0 to 33.7].3799a
Weight at dx, grams1,631.4 ± 347.31,732.2 ± 459.91,621.8 ± 337.9NAb,c
No. of reg (SR + AVR)10 (12.3%)2 (28.6%)8 (10.8%).2597f
PMA at reg, weeks, median [95% CI]62.7 [LCLd: 56.0]63.9 [62.7 to 65.0]57.0 [LCL: 56.0].4899a
Weight at reg, grams4,678.9 ± 1708.46,123.5 ± 320.74,266.1 ± 1726.2NAb,c
Days from dx to reg, median [95% CI]201.0 [LCL: 149.0]212.5 [210.0 to 215.0]161.0 [LCL: 149.0].4868a
Weight gain (g/week)121.5 ± 31.3115.3 ± 46.0122.2 ± 29.5.4782b

Retinopathy of Prematurity Severity and Treatmenta

CharacteristicsOverall (N = 586)P (n = 122)EP (n = 464)P
Presence of plus disease< .0001b
  Yes, n (%)113 (19.7%)7 (5.9%)106 (23.2%)
  No, n (%)462 (80.3%)111 (94.1%)351 (76.8%)
Treatmenta< .000b
  Yes, n (%)150 (25.6%)12 (9.9%)138 (29.7%)
  No, n (%)436 (74.4%)110 (90.2%)326 (70.3%)
PMA at treatment, weeks, median [95% CI]38.3 [38.1 to 38.7]37.6 [LCL = 34.4]d38.3 [37.9 to 38.4].0011c

Birth Weight and Weight Gain in Patients With Eyes That Underwent SR Versus TX

OutcomeMean SRMean TXDifference95% LCL95% UCLP
Birth weight (g)882.5744.6+137.881.5194.1< .0001
Weight at endpoint (g)3,961.62,264.6+1,655.31,412.01,898.6< .0001
Weight gain (g/week)160.8122.0+37.728.646.8< .0001

Weight Gain (g/wk) in Patients With Eyes That Underwent SR Versus TX

Comparison of P and EP InfantsMean SRMean TXDifferencea95% LCL95% UCLPb
P vs EP164.8146.816.13.229.0.0144
P: SR vs treatmentc169.4116.647.24.390.0.0311
EP: SR vs treatment157.7122.434.725.843.5< .0001
EP-LBW vs EP-ELBW157.1136.719.911.128.9< .0001
EP-LBW: SR vs treatment165.3133.230.817.244.4< .0001
EP-ELBW: SR vs treatment148.9114.734.423.845.0< .0001

Patient-Level Data of Extremely Premature Infants

VariableOverall (N = 234)LBW (n = 125)ELBW (n = 109)P
Sex.0284c
  Male120 (51.3%)72 (57.6%)48 (44.0%)
  Female97 (41.5%)43 (34.4%)54 (49.5%)
  Unknown17 (7.3%)10 (8.0%)7 (6.4%)
Race.5534e
  White120 (51.3%)64 (51.2%)56 (51.4%)
  Black32 (13.7%)10 (8.0%)22 (20.2%)
  Hispanic31 (13.2%)18 (14.4%)13 (11.9%)
  Native American7 (3.0%)6 (4.8%)1 (0.9%)
  Asian2 (0.9%)1 (0.8%)1 (0.9%)
  Unknown42 (17.9%)26 (20.8%)16 (14.7%)
Involvement.2899c
  Unilateral, n (%)8 (3.3%)6 (4.7%)2 (1.8%)
  Bilateral, n (%)226 (96.6%)119 (95.2%)107 (98.2%)
GA (birth), weeks, median [95% CI]25.6 [25.4 to 25.9]26.1 [25.7 to 26.4]25.0 [24.7 to 25.3]< .0001g
Birth weight771.8 ± 168.7894.5 ± 110.9626.4 ± 81.7NAf
Transfusion.2272c
  No59 (25.2%)36 (28.8%)23 (21.1%)
  Yes175 (74.8%)89 (71.2%)86 (78.9%)
Units of transfusiona10.8 ± 6.98.6 ± 5.013.3 ± 7.8< .0001d
Ventilator.0957c
  No57 (24.4%)36 (28.8%)21 (19.3%)
  Yes177 (75.6%)89 (71.2%)88 (80.7%)
Days on ventilator,b median [95% CI]44 [36 to 50]32 [24 to 37]54 [50 to 60]< .0001g
Days on TPN, median [95% CI]39 [35 to 45]33 [27 to 39]45 [38 to 51].0099g
Weight at 1 week, grams731.6 ± 170.0843.2 ± 145.5612.3 ± 91.3< .0001d
  Grams/week−30.5 ± 83.8−49.1 ± 97.6−13.3 ± 62.8< .0001h
Weight at 6 weeks, grams1,299.5 ± 296.31,479.9 ± 262.11,100.5 ± 182.4< .0001d
  Grams/week89.2 ± 31.198.2 ± 32.379.1 ± 26.8< .0001h

Worst stage of ROP (eye level)n = 237n = 216
  Stage 148 (20.3%)21 (9.7%)
  Stage 2143 (60.3%)136 (63.0%)
  Stage 346 (19.4%)57 (26.4%)
  Stage 40 (0.0%)1 (0.5%)
  Stage 50 (0.0%)1 (0.5%)

ROP Course in Eyes That Underwent Spontaneous Regression

VariableOverall (N = 326)LBW (n = 188)ELBW (n = 138)P
GA, weeks, median [95% CI]25.8 [25.6 to 26.0]26.1 [25.9 to 26.4]25.3 [25.0 to 25.7]< .0001a
PMA at diagnosis,a weeks, median [95% CI]33.9 [33.6 to 34.0]33.9 [33.7 to 34.6]33.6 [33.3 to 34.0].0693a
Weight at diagnosis, grams1,716.3 ± 477.31,877.8 ± 422.01,500.2 ± 462.8< .0001b
ROP stage at diagnosis.5679c
  Stage 1, n (%)161 (49.4%)65 (47.1%)96 (51.1%)
  Stage 2, n (%)165 (50.6%)73 (52.9%)92 (48.9%)
No. of regression (SR + AVR)286 (87.7%)157 (83.5%)129 (93.5%)
PMA at regression,a weeks, median [95% CI]45.3 [44.3 to 46.4]44.4 [42.9 to 45.9]46.4 [44.7 to 47.6].0194a
Weight at regression, grams4,024.1 ± 1,159.74,112.4 ± 1,182.23,924.9 ± 1,130.4.4381b
Days from dx to reg, median [95% CI]78.0 [72.0 to 85.0]72.0 [65.0 to 79.0]86.0 [77.0 to 98.0].0148a

Extremely Premature Infants With Severe ROP

VariableOverall (N = 460)LBW (n = 244)ELBW (n = 216)P
Treatmenta.0253a
  Yes, n (%)134 (29.1%)56 (23.0%)78 (36.1%)
  No, n (%)326 (70.9%)188 (77.0%)138 (63.9%)
Re-treatmentc.2344b
  Yes, n (%)22 (4.8%)8 (3.3%)14 (6.5%)
  No, n (%)438 (95.2%)236 (96.7%)202 (93.5%)
Presence of plus disease.0361b,d
  Yes, n (%)102 (22.5%)41 (17.3%)61 (28.2%)
  No, n (%)351 (77.5%)196 (82.7%)155 (71.8%)
Missing770

Retinopathy of Prematurity Stage of Eyes Requiring Treatmenta

TreatmentExtremely Premature (n = 134)Premature (n = 12)
Treatment 1
  Bevacizumab32 (23.9%)4 (33.3%)
  Laser102 (76.1%)8 (66.7%)
Treatment 2
  Bevacizumab6 (27.3%)
  Laser16 (72.7%)

Eye-Level Data for ROP Course for All Eyes

VariableOverall (N = 582)P (n = 122)EP (n = 460)P
GA, weeks, median [95% CI]26.0 [25.9 to 26.3]28.9 [28.6 to 29.3]25.6 [25.6 to 225.7]NAa
PMA at diagnosis, weeks, median [95% CI]34.0 [33.7 to 34.1]36.0 [34.7 to 36.4]33.6 [33.4 to 33.9]< .0001b
Weight at diagnosis, grams1,760.6 ± 520.82,025.5 ± 625.91,693.7 ± 468.4.0001c
ROP stage at diagnosis.1706d
  Stage 1263 (45.3%)63 (51.6%)200 (43.7%)
  Stage 2298 (51.4%)57 (46.7%)241 (52.6%)
  Stage 319 (3.3%)2 (1.6%)17 (3.7%)
PMA at regression, weeks, median [95% CI]46.4 [45.1 to 47.1]43.6 [43.0 to 45.3]46.9 [46.0 to 47.6].0833b
Days from dx to reg, median [95% CI]82.0 [75.0 to 91.0]54.0 [49.0 to 61.0]92.0 [84.0 to 98.0]< .0001b

Eye-Level Data for ROP Course for Extremely Premature Eyes

VariableOverall (N = 460)LBW (n = 244)ELBW (n = 216)P
GA (weeks), median [95% CI]25.6 [25.6 to 25.7]26.1 [25.7 to 26.3]25.0 [24.7 to 25.1]< .0001a
PMA (weeks) at diagnosis, median [95% CI]33.6 [33.4 to 33.9]33.8 [33.6 to 34.0]33.3 [33.0 to 33.6].0071a
Weight at diagnosis, grams1,693.7 ± 468.41,871.8 ± 434.21,497.7 ± 425.2< .0001b
ROP stage at diagnosis.4027c
  Stage 1200 (43.7%)112 (45.9%)88 (41.1%)
  Stage 2241 (52.6%)124 (50.8%)117 (54.7%)
  Stage 317 (3.7%)8 (3.3%)9 (4.2%)
PMA (weeks) at regression, median [95% CI]46.9 [46.0 to 47.6]45.1 [44.3 to 47.0]47.9 [46.6 to 49.7].0021a
Days from dx to reg, median [95% CI]92.0 [84.0 to 98.0]77.0 [70.0 to 93.0]104.0 [91.0 to 117.0].0005a
Authors

From the Departments of Ophthalmology (VDV, VB, FB, RMS), Biostatistics and Epidemiology (JD, KD), and Pediatrics (FB), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc.

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: R. Michael Siatkowski, MD, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. E-mail: rmichael-siatkowski@dmei.org

Received: June 03, 2018
Accepted: January 07, 2019

10.3928/01913913-20190205-01

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