Factors in Premature Infants Associated With Low Risk of Developing Retinopathy of Prematurity | Neonatology | JAMA Ophthalmology | JAMA Network
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Figure.  Frequency of Infants Without Retinopathy of Prematurity (ROP) by Gestational Age
Frequency of Infants Without Retinopathy of Prematurity (ROP) by Gestational Age

This graph shows the frequency of infants without ROP during all examinations prior to the study end point, discharge, or transfer, by birth weight and gestational age, among all infants in the e-ROP study cohort. In infants weighing less than 750 g at birth, ROP was absent in 6% before 25 weeks’ gestational age, 15% between 25 and 26 weeks, 15% between 27 and 28 weeks, and 46% between 29 and 30 weeks. In infants who weighed between 750 and 1000 g at birth, ROP was absent in 10% before 25 weeks’ gestational age, 22% between 25 and 26 weeks, 52% between 27 and 28 weeks, 68% between 29 and 30 weeks, and 93% between 31 and 33 weeks. In infants who weighed between 1000 and 1250 g at birth, ROP was absent in 35% between 25 and 26 weeks’ gestational age, 55% between 27 and 28 weeks, 75% between 29 and 30 weeks, and 85% between 31 and 33 weeks.

Table 1.  Infant Characteristicsa
Infant Characteristicsa
Table 2.  Frequency of Infants Without Retinopathy of Prematurity at a Visit by Premenstrual Age and Subsequent Treatment for Severe Retinopathy of Prematurity
Frequency of Infants Without Retinopathy of Prematurity at a Visit by Premenstrual Age and Subsequent Treatment for Severe Retinopathy of Prematurity
Table 3.  Multivariate Analysis for Predictors of No ROP in All Examinations Prior to Study End Point, Discharge, or Transfer Among 247 More Mature (27-33 Weeks’ Gestational Age) Infants
Multivariate Analysis for Predictors of No ROP in All Examinations Prior to Study End Point, Discharge, or Transfer Among 247 More Mature (27-33 Weeks’ Gestational Age) Infants
1.
Fierson  WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists.  Screening examination of premature infants for retinopathy of prematurity.  Pediatrics. 2013;131(1):189-195. doi:10.1542/peds.2012-2996PubMedGoogle ScholarCrossref
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Blencowe  H, Lawn  JE, Vazquez  T, Fielder  A, Gilbert  C.  Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010.  Pediatr Res. 2013;74(suppl 1):35-49. doi:10.1038/pr.2013.205PubMedGoogle ScholarCrossref
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Kemper  AR, Freedman  SF, Wallace  DK.  Retinopathy of prematurity care: patterns of care and workforce analysis.  J AAPOS. 2008;12(4):344-348. doi:10.1016/j.jaapos.2008.02.012PubMedGoogle ScholarCrossref
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Wade  KC, Pistilli  M, Baumritter  A,  et al; e-Retinopathy of Prematurity Study Cooperative Group.  Safety of retinopathy of prematurity examination and imaging in premature infants.  J Pediatr. 2015;167(5):994-1000.e2. doi:10.1016/j.jpeds.2015.07.050PubMedGoogle ScholarCrossref
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Kemper  AR, Wallace  DK.  Neonatologists’ practices and experiences in arranging retinopathy of prematurity screening services.  Pediatrics. 2007;120(3):527-531. doi:10.1542/peds.2007-0378PubMedGoogle ScholarCrossref
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Kemper  AR, Prosser  LA, Wade  KC,  et al; e-ROP Study Cooperative Group.  A comparison of strategies for retinopathy of prematurity detection.  Pediatrics. 2016;137(1). doi:10.1542/peds.2015-2256PubMedGoogle Scholar
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Quinn  GE, Ying  GS, Daniel  E,  et al; e-ROP Cooperative Group.  Validity of a telemedicine system for the evaluation of acute-phase retinopathy of prematurity.  JAMA Ophthalmol. 2014;132(10):1178-1184. doi:10.1001/jamaophthalmol.2014.1604PubMedGoogle ScholarCrossref
8.
Quinn  GE; Graham E Quinn; e-ROP Cooperative Group.  Telemedicine approaches to evaluating acute-phase retinopathy of prematurity: study design.  Ophthalmic Epidemiol. 2014;21(4):256-267. doi:10.3109/09286586.2014.926940PubMedGoogle ScholarCrossref
9.
Kemper  AR, Wade  KC, Hornik  CP, Ying  GS, Baumritter  A, Quinn  GE; Telemedicine Approaches to Evaluating Acute-phase Retinopathy of Prematurity (e-ROP) Study Cooperative Group.  Retinopathy of prematurity risk prediction for infants with birth weight less than 1251 grams.  J Pediatr. 2015;166(2):257-61.e2. doi:10.1016/j.jpeds.2014.09.069PubMedGoogle ScholarCrossref
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Quinn  GE, Barr  C, Bremer  D,  et al.  Changes in course of retinopathy of prematurity from 1986 to 2013: comparison of three studies in the United States.  Ophthalmology. 2016;123(7):1595-1600. doi:10.1016/j.ophtha.2016.03.026PubMedGoogle ScholarCrossref
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Gilbert  C, Wormald  R, Fielder  A,  et al.  Potential for a paradigm change in the detection of retinopathy of prematurity requiring treatment.  Arch Dis Child Fetal Neonatal Ed. 2016;101(1):F6-F9. doi:10.1136/archdischild-2015-308704PubMedGoogle ScholarCrossref
12.
Barry  GP, Tauber  K, Emmanuel  G, Horgan  MJ, Simon  JW.  The effectiveness of policy changes designed to increase the attendance rate for outpatient retinopathy of prematurity (ROP) screening examinations.  J AAPOS. 2013;17(3):296-300. doi:10.1016/j.jaapos.2013.03.010PubMedGoogle ScholarCrossref
13.
Stoll  BJ, Hansen  NI, Bell  EF,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.  JAMA. 2015;314(10):1039-1051. doi:10.1001/jama.2015.10244PubMedGoogle ScholarCrossref
14.
Horbar  JD, Carpenter  JH, Badger  GJ,  et al.  Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009.  Pediatrics. 2012;129(6):1019-1026. doi:10.1542/peds.2011-3028PubMedGoogle ScholarCrossref
15.
Wilkinson  AR, Haines  L, Head  K, Fielder  AR.  UK retinopathy of prematurity guideline.  Early Hum Dev. 2008;84(2):71-74. doi:10.1016/j.earlhumdev.2007.12.004PubMedGoogle ScholarCrossref
16.
Canadian Association of Pediatric Ophthalmologists Ad Hoc Committee on Standards of Screening Examination for Retinopathy of Prematurity.  Guidelines for screening examinations for retinopathy of prematurity.  Can J Ophthalmol. 2000;35(5):251-252. doi:10.1016/S0008-4182(00)80072-1PubMedGoogle ScholarCrossref
Original Investigation
November 15, 2018

Factors in Premature Infants Associated With Low Risk of Developing Retinopathy of Prematurity

Author Affiliations
  • 1Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 2Newborn Care Group at Pennsylvania Hospital, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 3Center for Preventive Ophthalmology and Biostatistics, Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania
  • 4Division of Pediatric Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 5Department of Pediatrics, University of Texas, San Antonio
  • 6Division of Ambulatory Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio
JAMA Ophthalmol. 2019;137(2):160-166. doi:10.1001/jamaophthalmol.2018.5520
Key Points

Question  Can we identify a group of infants at low risk for retinopathy of prematurity (ROP) in North American health care centers who do not benefit from postdischarge ROP surveillance?

Findings  In this study, two-thirds of the infants born at 27 weeks’ gestational age or older with birth weights greater than 750 g did not have ROP by discharge, and none without ROP noted by 37 weeks’ postmenstrual age required ROP treatment.

Meaning  These findings suggest that, if no ROP has been detected by discharge in an infant with larger birth weights and more advanced gestational age, then further examinations have limited value.

Abstract

Importance  Most premature infants will not develop retinopathy of prematurity (ROP) of clinical relevance, yet screening evaluations often continue beyond hospital discharge, even for those infants without ROP.

Objectives  To identify the characteristics of infants at low risk for ROP, for whom further postdischarge screening may be of limited value.

Design, Setting, and Participants  This study took place in North American neonatal intensive care units where clinicians had expertise in ROP. Infants with birth weight less than 1251 g who were born at or transferred into an Telemedicine Approaches to Evaluating Acute-Phase ROP (e-ROP) study center were enrolled. The study included post hoc analysis of prospectively collected in-hospital ROP examination results among infants enrolled in the e-ROP study. We characterized infants without ROP and performed logistic regression on the subset of infants who were 27 to 33 weeks’ gestational age to determine characteristics associated with the absence of ROP during all in-hospital examinations.

Main Outcomes and Measures  The main measure was the absence of ROP prior to hospital discharge; the main outcome was treatment for ROP.

Results  A total of 1257 infants born at 22 to 35 weeks’ gestation (median [interquartile range (IQR)], 26 [25-28] weeks) with birth weights less than 1251 g (median [IQR], 860 [690-1040] g) underwent 4113 ROP examinations between 31 and 47 weeks’ postmenstrual age. Overall, 1153 examinations (38%) showed no ROP, and 456 infants (36%) did not have ROP prior to study center discharge or study end point. Among infants without ROP during examinations at 32 and 33 weeks’ postmenstrual age, 16 (9.4%) and 14 (5.3%) subsequently underwent ROP treatment, respectively. At hospital discharge, there was no ROP in 59% of infants of 27 to 33 weeks’ gestational age, compared with 15% of those who were less than 27 weeks’ gestational age (difference, 44% [95% CI, 38.5%-48.1%]; P ≤ .001). With more than 85% follow-up among infants without ROP by 37 weeks’ postmenstrual age, none (95% CI, 0%-0.98%) were treated for ROP. In multivariate analysis of infants born at 27 to 33 weeks’ gestation, larger birth weight (OR, 4.1 [95% CI, 1.6-10.3]) and higher gestational age (OR, 4.0 [95% CI, 1.5-10.8]) were significantly associated with absence of ROP.

Conclusions and Relevance  These findings suggest that, for infants of 27 weeks’ gestational age or greater and birth weights larger than 750 g, if no ROP has been detected by discharge at near-term postmenstrual age, then further ROP surveillance has limited value. Studies of all infants at risk are needed to develop more specific, objective criteria for termination of ROP surveillance and focus resources on infants at higher risk of ROP.

Trial Registration  ClinicalTrials.gov Identifier: NCT01264276

Introduction

In the United States, most premature infants at risk of retinopathy of prematurity (ROP) will not develop it.1,2 However, because of challenges in determining risk, ROP screening begins early (approximately 32 weeks’ postmenstrual age [PMA]) and is repeated every 1 to 2 weeks until the retinal vessels are mature (typically after 40 weeks’ PMA), any ROP regresses, or ROP treatment is indicated.1 Screening guidelines are designed to be extremely sensitive to decrease the likelihood of missing an infant with severe ROP, for whom timely treatment may reduce the risk of blindness.1 Only 5% of at-risk infants are treated.2 The low specificity of this approach leads to many infants being screened repeatedly with no direct benefit.

The detection of ROP requires an uncomfortable but important procedure for infants and a resource-intensive process undertaken by the limited number of ophthalmologists with ROP expertise.3,4 The need for ongoing ROP examinations as infants mature and the limited availability of specialized ophthalmologists outside regional centers can inhibit transfer of convalescing infants to lower levels of care in neonatal intensive care units (NICUs) closer to home and limit opportunities to lower health care cost.5 After discharge, families often travel long distances to regional centers for outpatient ROP screening.

One way to decrease the burden of repetitive ROP screening examinations would be to identify infants whose birth characteristics and ROP screening examination results prior to NICU discharge are associated with such a low likelihood of developing severe ROP on future examinations that ROP screening can be terminated. In a simulation on a theoretical sample of infants, we found that the likelihood of significant ROP decreased with gestational age and providing an examination at discharge could decrease the need for intensive follow-up.6 The current report expands on this work by better identifying those premature infants with the lowest risk of developing severe ROP after discharge. We performed a secondary analysis of a recent prospective study of high-risk infants who underwent ROP examinations during their NICU hospitalizations.7

Methods

This was a post hoc secondary analysis of the data from the Telemedicine Approaches to Evaluating Acute-Phase ROP (e-ROP) Study,7,8 a multicenter observational cohort study that enrolled infants with an increased likelihood of developing referral-warranted and severe ROP based on a birth weight (BW) less than 1251 g, rather than the standard US screening BW criteria of 1500 g. Infants could be born in an e-ROP center or transferred into an e-ROP center for clinical management of ongoing morbidities, such as respiratory failure, necrotizing enterocolitis, hydrocephalus, or progressive ROP. Exclusion criteria were limited to significant media opacity precluding retinal visualization, major congenital abnormalities, or admission to an e-ROP center at a PMA greater than 39 weeks or with previously treated or regressing ROP. Infants born between May 2011 and October 2013 were included.

Written informed consent was obtained from the parents/guardians of all eligible infants. The study protocol and informed consent process were approved by institutional review boards of Children’s Hospital of Philadelphia and all participating centers.

ROP Examinations and Classification

In the e-ROP Study, the presence or absence of ROP was determined by the results of diagnostic eye examinations performed by study-certified ophthalmologists experienced with ROP. The first eye examination was performed at approximately 32 weeks’ PMA or the age at which an infant was transferred into a study center. Follow-up ROP examinations were conducted every 1 to 2 weeks per local center standard of care until discharge or transfer from study center or until the ophthalmologist noted 1 of the following e-ROP study end points: mature retinal vessels, an immature zone III on 2 occasions at least 7 days apart, ROP that had regressed or was regressing on 2 visits at least 7 days apart, ROP treatment, or the attainment of 40 weeks’ PMA with no ROP or only stage 1 or 2 ROP without plus disease. If an infant did not reach the study end point by the time of discharge or transfer, then investigators attempted to obtain the final ROP end point status from the referral hospitals or outpatient records. Results from ROP examinations performed outside a study center were not available. If the end point data were not available, then investigators reported the reason as the parent/guardian withdrawal of consent, the investigator’s judgment, loss to follow-up, death, or other.

We classified ROP status for each infant as either present or absent based on the combined assessment of both eyes. The presence or absence of ROP was assessed for each examination at a given PMA among infants who had an examination at that PMA. For each infant, a final assessment of ROP status was generated using all examination results obtained prior to study end point, discharge, or transfer. Infant characteristics included gestational age (GA) at birth, BW, and PMA at time of ROP examination. Infants treated for ROP were identified using study end point data.

Statistical Analyses

All analyses were performed in SAS version 9.4 (SAS Institute Inc) from November 2015 to April 2017. Statistical significance was set at P < .05 unless specifically noted. Descriptive statistics were used to characterize infants without ROP at each week’s PMA (restricted to infants with ROP examination at that PMA) and infants without ROP on any examinations prior to study center end point, discharge, or transfer. We determined the proportion of infants without ROP who subsequently received ROP treatment using end point data.

To further characterize infants at lower risk, we evaluated the outcome of no ROP among a subset of more mature infants born at 27 weeks’ GA or later who had had at least 1 eye examination at a PMA of 35 weeks or younger and at least 1 examination at a PMA of 37 weeks or older (eFigure in the Supplement). We characterized this subset using the following birth characteristics: BW (classified as ≤750 g, 751-1000 g, or >1000 g), GA (classified as 27-28, 29, or 30-33 weeks’ GA), multiple birth (yes/no), sex (male/female), and birth site (inborn/outborn [with regard to birth at an e-ROP study center]). Respiratory support (none, noninvasive support, or ventilator) and nutritional support (full enteral feeds, partial feeds, or no enteral feeds) at the time of first study-associated ROP examination were also included because these factors were potentially associated with clinical illness.

We performed logistic regression among this more mature subset to explore infant characteristics associated with an absence of ROP on all examinations prior to study end point, discharge, or transfer. We analyzed associated variables using univariate analysis and included variables with P values less than .10 in multivariate analysis. The performance of the multivariate model for predicting no ROP was assessed by calculating the area under the receiver operating characteristic curve (area under the curve).

Results

The e-ROP Study enrolled 1284 infants born at 22 to 35 weeks’ GA with BWs less than 1251 g from 13 North American health care centers between May 2011 and October 2013.7 The 1257 infants with at least 1 ROP examination had a total of 4113 ROP study examinations between 31 to 47 weeks’ PMA (Table 1). Half of the cohort was born at less than 27 weeks’ GA (median [IQR], 26 [25-28] weeks) and 429 (34.1%) had BWs of 750 g or less. Among infants with at least 2 eye examinations, the median first and last study-associated ROP examination occurred at a median (IQR) of 33 (32-34) weeks’ PMA and 38 (37-40) weeks’ PMA. Infants underwent a median (IQR) of 3 (2-5) ROP examinations during the e-ROP study. There was no ROP present in 1553 examinations (37.8%). By study center end point, discharge, or transfer, 456 infants (36.3%) did not have ROP (Table 1). The absence of ROP was more common among infants with larger BWs and more mature GAs; 344 of 544 infants (63.2%) born at 27 weeks’ GA or older and with BWs greater than 750 g did not have ROP by discharge (Figure and eTable 1 in the Supplement).

Infants Without ROP at Specific PMA Eye Examination

Table 2 reports the frequency of infants without ROP among infants who were examined at a specific PMA. Most infants did not have ROP on their initial examination; 171 infants (77.0%) examined at 32 weeks’ PMA had no ROP. The frequency of infants without ROP decreased with advancing PMA; 175 infants (30.4%) examined at 36 weeks’ PMA had no ROP. The number of infants in each PMA group was different because infants may not have had examinations every week, and outborn infants could have enrolled at older PMAs. Overall, the number of infants undergoing eye examinations declined rapidly after 37 weeks’ PMA, because some infants were discharged home, transferred to another facility, or reached the study end point.

Infants without ROP at initial examinations remained at risk for subsequent treatment of severe ROP. Among infants without ROP at 32 or 33 weeks’ PMA, the subsequent treatment rate was 16 of 222 infants (9.4%) and 14 of 522 infants (5.3%), respectively (Table 2). Infants without ROP at 32 to 35 weeks’ PMA who subsequently received ROP treatment were born at younger gestational age (median [range] GA, 25 [23-28] weeks) and smaller BW (median [range], 645 [390-1130] g) than those who did not receive ROP treatment.

Infants without ROP detected during examinations at near-term or term corrected age (37-42 weeks’ PMA) had low risk for subsequent ROP treatment; only 1 infant required treatment (Table 2). This infant was born at a GA of 25 weeks with a BW of 655 g and had documented ROP during an examination at 36 weeks’ PMA but not 38 weeks’ PMA. The study end point was treatment after discharge. We suspect a misclassification of result at 38 weeks’ PMA, because there was documented ROP at 36 weeks’ PMA and 85% of infants in the e-ROP study who were born at 25 weeks’ GA with BWs of 750 g or less developed ROP (Figure).

Infants Without ROP by Study End Point, Discharge, or Transfer

At the time of study end point, discharge, or transfer, 456 infants (36%) did not have ROP in either eye during any examination (BW: median [IQR], 1020 [880-1136] g; GA: median [IQR], 28 [27-29] weeks). Infants without ROP were more likely born with larger BWs and higher GAs (Table 1). There was no ROP in 59% of infants born at 27 to 33 weeks’ GA compared with 15% of infants born younger than 27 weeks’ GA (difference, 44% [95% CI, 38.5%-48.1%]; P ≤ .001). Among more mature infants (27-33 weeks’ GA), those with larger BWs were less likely to have ROP; 226 of 341 infants (66.3%) with BWs of 1001 to 1250 g did not have ROP, compared with 13 of 61 infants (21%) with BW of 750 g or less (Figure and eTable 1 in the Supplement). Their last eye examination was performed at a median (IQR) of 37 (35-38) weeks’ PMA.

Among infants without ROP, the final study end point was documented for 390 infants (85.5%), and none of these infants (95% CI, 0%-0.98%) had the end point of ROP treatment. Rather, eye end points for these infants were mature retina (57%), no ROP in zone III on 2 examinations at least 7 days apart (23%), and a PMA of 40 weeks with no ROP (19%). One infant who was discharged without ROP had a documented end point of mild, stage 1 ROP that was regressing on 2 examinations at least 7 days apart. The final end point was not met for the remaining 66 infants (14.5%), mostly because of transfer of care to out-of-network inpatient or outpatient facilities and loss to follow-up.

Factors Associated With Absence of ROP Among More Mature Infants Who Had Multiple ROP Examinations

To further explore characteristics associated with the absence of ROP at study end point, discharge, or transfer, we performed multiple logistic regression in a subset of 247 more mature infants (27-33 weeks’ GA) who had at least 2 ROP examinations (eFigure in the Supplement). These infants included 115 girls (46.6%) and 188 infants (76.1%) inborn at e-ROP center, and had a median (range) BWs of 1000 (410-1250) g, and a median (range) GA of 28 (27-33) weeks (Table 1). A total of 237 infants (96.0%) did not receive treatment for ROP, and 122 infants (49.4%) had no ROP prior to study end point, discharge, or transfer.

In univariate analysis, the absence of ROP at end point, discharge, or transfer was associated with larger BWs, older GAs, inborn status at an e-ROP center, and the absence of any respiratory support at the time of first ROP examination (eTable 2 in the Supplement). Sex, multiple births, and feeding status at first ROP examination were not significantly associated. Table 3 shows results of logistic regression analysis; larger BWs (>750 g) and higher GAs (29 and 30-33 weeks) both remained strongly associated with the absence of ROP, but birth site and respiratory support at first ROP examination did not. The prediction model with BW, GA, birth site, and respiratory support had an area under ROC curve (area under the curve) of 0.73 (95% CI, 0.67-0.79).

Discussion

In this North American cohort of infants at high risk of ROP who had BWs less than 1251 g and were receiving care in large, academic NICUs, more mature infants (those born at 27 weeks’ GA or more with BWs more than 750 g) who did not have any ROP detected by 37 weeks’ PMA were at very low risk of subsequent ROP treatment; none were treated for severe ROP. This study is unique in its exploration of infants without ROP and focus on infants of older GAs and larger BWs. For these low-risk infants, ongoing ROP surveillance after discharge should be expected to have a high cost and burden for ophthalmologists, infants, and families, yet limited value in detecting severe ROP requiring treatment.

Monitoring for acute phase ROP until the retina vessels are mature or all ROP has regressed is a high-yield strategy for the care of extremely preterm infants and those already diagnosed with ROP. This analysis confirmed that most infants born at less than 27 weeks’ GA or BWs of 750 g or less develop some stage of ROP.2,9 The absence of ROP at 32 to 34 weeks’ PMA was not reassuring. This is not surprising, because ROP progresses with advancing PMA, and severe ROP is typically seen around 36 weeks’ PMA.10 Severe ROP can also occur at older PMAs, particularly in the most extremely premature infants. Regardless of GA and BW, postdischarge surveillance of infants with ROP seems prudent. The use of limited ophthalmology resources and family travel to outpatient visits appears justified in these higher-risk infants.

In contrast, the utility of postdischarge ROP surveillance beyond 37 weeks’ PMA is less clear among larger, more mature infants without ROP. This study confirms that older GAs (>27 weeks) and larger BWs (>750 g) infants are at lower risk for ROP compared with younger, smaller infants. In the subset of more mature infants, higher GAs, larger BWs, respiratory support at the first ROP examination, and inborn birth were cumulatively associated with 73% of those without ROP at hospital discharge or transfer. Other factors, including ROP examination results, will need to be considered to better define the lowest-risk infant criteria and develop strategies to safely discharge infants from ROP surveillance.

The surveillance of ROP after discharge from tertiary-care NICUs presents difficult obstacles and a timely opportunity to reassess an infant’s risk of developing vision-threatening ROP. Important barriers to ROP surveillance include the inability to transfer infants to NICUs closer to home if ROP services were not available, difficulties arranging postdischarge ROP examinations, and the dilemma of when to discharge an infant from ROP screening.5,11 Outpatient ROP surveillance requires considerable effort to coordinate appointments and ensure family adherence.12 New York families reported traveling an average round-trip distance of 80 miles for ROP-associated ophthalmology visits.12 The challenge is how to best use the limited resources of specialized ophthalmologists and reduce the burden of follow-up visits on infants and families without increasing risk of missing an infant with severe ROP for whom timely treatment may prevent blindness.

When considering resource use for ROP screening, infants with higher GAs and larger BWs are important. They have lower ROP rates and represent a larger proportion of all the infants being screened for ROP. They have greater survival with lower morbidity rates and are thus often discharged from the NICU at younger PMAs, when the retina is not expected to be fully vascularized.9,13,14 Despite their low risk for ROP, most will continue to undergo postdischarge ROP surveillance in specialized ophthalmology practices.9

This study raises the question of whether current US guidelines should include explicit criteria for terminating ROP surveillance in more mature, larger-BW infants without ROP who are at low risk. Current US guidelines1 recommend continuation of ROP screening among at-risk infants until the retina is adequately vascularized well into zone III, any ROP has regressed, or an infant is no longer at risk of sight-threatening ROP. Given the subjective nature of peripheral vascularization, many infants without ROP continue to be examined until the retina is fully vascularized. In this study, the absence of ROP on all in-patient examinations among infants who are more mature and have larger BWs was useful in predicting an even lower-risk group, in which none subsequently developed severe ROP. This is consistent with British15 and Canadian16 guidance that infants without ROP at or beyond 37 weeks’ PMA are unlikely to develop severe ROP. Low-risk ROP surveillance-stopping rules explored in a microsimulation study of digital imaging among this same population (infants with BW <1251 g) found a significant reduction in the need for follow-up after discharge. but a small increase risk of missing type 1 ROP.6 Incorporation of infants with larger BWs and more mature GAs may be important in minimizing risk of missing severe ROP after discharge.

Further studies of all at-risk infants with longitudinal ROP follow-up after discharge are needed to more fully understand infants who do not develop ROP and explore their subsequent likelihood of developing severe ROP after hospital discharge or transfer. More objective criteria for terminating ROP surveillance based on BWs, GAs, and the absence of ROP at near-term PMA could greatly reduce the number of low-yield ROP examinations, reduce the burden of ROP screening visits, and focus limited ophthalmology resources on higher-risk infants.

This study had many strengths regarding our aim to characterize low-risk infants. We used prospectively collected ROP examination results in a cohort that was enriched for higher-risk infants, given the e-ROP inclusion criteria (BWs <1251 g). The e-ROP centers represented large academic hospitals with experience in ROP research, high volumes of extremely premature infants, and heavy burden of morbidities.

Limitations

Models using this cohort might underestimate the absence of ROP in more typical NICUs and overestimate the risk of missing a case of treatment-warranted ROP. The interpretation of this study was also limited by the secondary analysis, the absence of at-risk infants with BWs of 1251 to 1500 g, and the absence of ROP examination results other than study end point after discharge. The study end point was not determined for 14.5% of the infants, who did not have ROP at study center discharge or transfer; it is possible that some of these infants received ROP treatment that the researchers were not aware of. Despite these limitations, these results raise the issue of how the community of neonatologists and ophthalmologists can most effectively focus resources. Finally, these results are derived from a study in North American NICUs and the findings are likely not generalizable to care of premature infants in many other regions of the world.

Conclusions

This study suggests that the combination of a higher GA, larger BW, and absence of ROP at near-term PMAs may identify an infant with the lowest risk of developing vision-threatening ROP for whom postdischarge surveillance has limited value. Studies of all at-risk infants with complete ascertainment of follow-up results are needed to develop more specific, objective criteria to identify the infants at lowest ROP risk, for whom ROP surveillance can be terminated so that resources can be focused on higher-risk infants.

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Article Information

Corresponding Author: Kelly C. Wade, MD, PhD, MSCE, Newborn Care Group at Pennsylvania Hospital, Children’s Hospital of Philadelphia, 800 Spruce St, Philadelphia, PA 19107 (kelly.wade@uphs.upenn.edu).

Accepted for Publication: September 21, 2018.

Published Online: November 15, 2018. doi:10.1001/jamaophthalmol.2018.5520

Author Contributions: Drs Quinn and Ying had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ying, Quinn.

Study concept and design: Wade.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wade, Baumritter.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ying, Quinn.

Obtained funding: Ying, Quinn.

Administrative, technical, or material support: Baumritter.

Supervision: Ying, Quinn.

Group Information: The e-ROP Study Group Investigators are as follows: The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania (Office of Study Chair): Graham E. Quinn, MD, MSCE, Kelly Wade, MD, PhD, Agnieshka Baumritter, MS, Trang B. Duros, BS, and Lisa Erbring; Johns Hopkins University, Baltimore, Maryland: Michael X. Repka, MD, Jennifer A. Shepard, CRNP, David Emmert, BA, and C. Mark Herring, CRA; Boston Children’s Hospital, Boston, Massachusetts: Deborah VanderVeen, MD, Suzanne Johnston, MD, Carolyn Wu, MD, Jason Mantagos, MD, Danille Ledoux, MD, Tamar Winter RN, BSN, IBCLC, Frank Weng, BS, and Theresa Mansfield, RN; Nationwide Children’s Hospital and Ohio State University Hospital, Columbus: Don L. Bremer, MD, Mary Lou McGregor, MD, Catherine Olson Jordan, MD, David L. Rogers, MD, Rae R. Fellows, MEd, CCRC, Suzanne Brandt, RNC, BSN, and Brenda Mann, RNC, BSN; Duke University, Durham, North Carolina: David Wallace, MD, Sharon Freedman, MD, Sarah K Jones, Du Tran-Viet, BS, and Rhonda “Michelle” Young, RN, CPN; University of Louisville, Louisville, Kentucky: Charles C. Barr, MD, Rahul Bhola, MD, Craig Douglas, MD, Peggy Fishman, MD, Michelle Bottorff, Brandi Hubbuch, RN, MSN, NNP-BC, and Rachel Keith, PhD; University of Minnesota, Minneapolis: Erick D. Bothun, MD, Inge DeBecker, MD, Jill Anderson, MD, Ann Marie Holleschau, BA, CCRP, Nichole E. Miller, MA, RN, NNP, and Darla N. Nyquist, MA, RN, NNP; University of Oklahoma, Oklahoma City: R. Michael Siatkowski, MD, Lucas Trigler, MD, Marilyn Escobedo, MD, Karen Corff, MS, ARNP, NNP-BC, Michelle Huynh, MS, ARNP, and Kelli Satnes, MS, ARNP, NNP-BC; Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania: Monte D. Mills, MD, Will Anninger, MD, Gil Binenbaum, MD MSCE, Graham Quinn, MD, MSCE, Karen A. Karp, BSN, and Denise Pearson, COMT; University of Texas, San Antonio: Alice Gong, MD, John Stokes, MD, Clio Armitage Harper, MD, Laurie Weaver, RNC, BSN, Carmen McHenry, BSN, Kathryn Conner. RN, BSN, Rosalind Heemer, BSN, and Elnora Cokley, RNC; University of Utah, Salt Lake City: Robert Hoffman, MD, David Dries, MD, Katie Jo Farnsworth, BS, CRC, Deborah Harrison, MS, Bonnie Carlstrom, COA, and Cyrie Ann Fry, CRA, OCT-C; Vanderbilt University, Nashville, Tennessee: David Morrison, MD, Sean Donahue, MD, Nancy Benegas, MD,; Sandy Owings, COA, CCRP, Sandra Phillips, COT, CR, and Scott Ruark, DO; Hospital of the Foothills Medical Center, Calgary, Alberta, Canada: Anna Ells, MD, FRCS, Patrick Mitchell, MD, April Ingram, BS, and Rosie Sorbie, RN; Data Coordinating Center: University of Pennsylvania School of Medicine, Philadelphia: Gui-Shuang Ying, PhD, Maureen Maguire, PhD, Mary Brightwell-Arnold, BA, SCP, Max Pistilli, MS, Kathleen McWilliams, CCRP, Sandra Harris, BA, and Claressa Whearry; Image Reading Center: University of Pennsylvania School of Medicine, Philadelphia: Ebenezer Daniel, MBBS, MS, MPH, E. Revell Martin, BA, Candace R. Parker Ostroff, BA, Krista Sepielli, BFA, and Eli Smith, BA; Expert Readers: Antonio Capone, MD, The Vision Research Foundation, Royal Oak, Michigan, G. Baker Hubbard, MD, Emory University School of Medicine, Atlanta, Georgia, and Anna Ells, MD, FRCS, University of Calgary Medical Center, Calgary, Alberta, Canada; Image Data Management Center: Inoveon Corporation, Oklahoma City, Oklahoma: Peter Lloyd Hildebrand, MD, Kerry Davis, BA, G. Carl Gibson, BBA, CPA, and Regina Hansen, COT; Cost Effectiveness Component: Alex R. Kemper, MD, MPH, MS, and Lisa Prosser, PhD; Data Management and Oversight Committee: David C. Musch, PhD, MPH, Stephen P. Christiansen, MD, Ditte J. Hess, CRA, Steven M. Kymes, PhD, SriniVas R. Sadda, MD, and Ryan Spaulding, PhD; National Eye Institute: Eleanor B. Schron, PhD, RN.

Conflicts of Interest Disclosures: All authors have complete and submit the ICMJE Form for Disclosure of Potential conflicts of Interest. Dr Ying reports receiving personal fees from Chengdu Kanghong Biotech Co Ltd and Ziemer Ophthalmic Systems AG. No other disclosures are reported.

Funding/ Support: All phases of the e-ROP Study were supported by a cooperative agreement grant (U10 EY017014, Dr Quinn) and biostatistical support studies (grant R21EY025686, Dr Ying) from the National Eye Institute of the National Institutes of Health.

Role of the Funder/Sponsor: The National Eye Institute was not involved in design and conduct of this secondary analysis study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Meeting Presentations: Portions of this study were presented in part at the annual meeting of the Pediatric Academic Society; April 25-28, 2016; Baltimore, Maryland; the annual meeting of the American Association for Pediatric Ophthalmology and Strabismus; March 18-22, 2018; Washington, DC; and the annual meeting of The Association for Research in Vision and Ophthalmology (ARVO); April 29-May 2nd, 2018; Honolulu, Hawaii.

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