EPIDEMIOLOGY

Retinopathy of prematurity is a disease that primarily affects preterm infants born before 31 weeks’ gestational age (GA) and exacerbated by low birthweight (BW ≤1250g). ^, From 1981 to 2006, preterm births had been steadily increasing to a rate of 12% to 13% of all births in the United States. From 2007 to 2014, preterm birth rates saw a gradual decline driven by a reduction in births by teens and younger women. Recently, however, from 2014 to 2018, rates have again risen to 10% of all births in the United States.

Multiple studies have examined the trends of ROP incidence across time in the United States, typically focusing on public health hospitals and academic centers. ^, Most studies have reported ROP incidence as remaining steady or gradually increasing. Conversely, mean BW and GA in ROP infants have decreased over time. ^, Medical and technological advances in neonatal care are partly responsible for the increased survival of younger and smaller infants as well as the rising popularity of artificial reproductive technology (ART) leading to premature birth and multiple gestation leading to lower-BW infants. ^, As a result, these factors have led to an increased prevalence of at-risk infants. Quinn et al. established that, in the 1980s, 15.8% of infants born preterm weighed <750 g, and 43.8% were born at ≤27 weeks’ GA. These rates have risen dramatically in the past decade (2010-2019) to 33.4% and 68.1%, respectively. These studies have determined that up to 68% of these low-BW infants (<1250 g) consistently develop some stage of acute ROP. ^,

ROP CLASSIFICATION

The International Classification of ROP (ICROP) was developed in 1984 and aimed to classify ROP by stage, grade, and zone. This classification established a uniform language for ophthalmologists. Moving forward, advances in classification have been led by consensus agreement among the ROP community. Using the ICROP criteria enabled a standardization of ROP diagnoses and ROP severity grading. Demonstration and illustration of ROP zone and stage severity are outlined in Figure 1 and Figure 2 , respectively.

Retinopathy of prematurity zones. Fundus photograph demonstrating zone I as defined by a circle centered upon the optic nerve with a radius of twice the distance from the nerve to the macula, zone II as defined by the area from the edge of zone I to a circle with a radius extending from the optic nerve to the nasal ora serrata, and zone III as defined by the residual temporal crescent anterior beyond zone II.

Retinopathy of prematurity staging criteria. A. Stage 1, defined as a demarcation line. B. Stage 2, defined as an elevated ridge of retinal tissue. C. Stage 3, defined as a ridge of retinal tissue with extraretinal neovascularization or fibrovascular proliferation. D. Stage 4, defined as extrafoveal retinal detachment or subtotal retinal detachment. E. Stage 5, defined as total retinal detachment.

The ETROP defined treatment guidelines for a newly recognized threshold. The ETROP used a complex algorithm to stage ROP, coupled with a treatment guideline. Pre-threshold ROP was defined as zone I, any stage; zone II, stage 2 with plus; zone II, stage 3 without plus; zone II, stage 3 with plus but fewer than 5 contiguous or 8 composite clock hours of disease, and threshold ROP was defined by zone I or II, stage 3 with 5 contiguous or 8 composite clock hours of disease with plus; zone I, any stage with plus. ETROP recommended treatment for type 1 ROP which was defined as zone I, any stage with plus disease, or zone I, stage 3 plus/minus disease, or zone II, stage 2 or 3 with plus disease were treated. Follow-up screening intervals were conducted according to the recommendations by the AAO/AAP as outlined in Table 1 .

Historically, the presence of vessel tortuosity and engorgement was noted to be associated with ROP as early as 1949. ^, As more authors began including the designation of ROP “plus” or “+” disease in their classification schemes, the popularity of the term increased. Finally, in 1984, the ICROP defined plus disease as “the vascular changes are so marked that the posterior veins are enlarged and the arterioles tortuous,” and incorporated it into their classifications for ROP. Thereafter, the definition of plus disease underwent several modifications and quickly became as important as the zone and stage of ROP. In the ETROP trial, plus disease was recognized for the first time as being critical in the evaluation of treatment-warranted threshold ROP. ^, It was defined by comparison of the perineural vasculature to gold standard images. The presence of plus disease became a driving indication for treatment of ROP beginning in 2003. ^,

Other examination risk factors for the development of treatment-warranted ROP have been identified by our group and others. The presence of a persistent tunica vasculosa lentis (TVL) has been noted to have higher rates of zone 1 disease and treatment-warranted disease in a case-matched study. Light (versus medium or dark) fundus pigmentation has also been found to be associated with higher-risk ROP. Specifically, a lighter fundus pigmentation was associated with a diagnosis of plus disease, more posterior zone, higher-stage disease, and treatment for ROP. These additional risk factors help to identify at-risk infants and to make NICU screening more timely and efficient.

Changes in Neonatal Care

Advances in neonatal care have significantly impacted infant survival. Low birthweight and very-low-birthweight infants are now commonly surviving within the NICU, resulting in a clear shift towards a unique at-risk subpopulation. ^{, ,} Furthermore, this population demonstrates significant comorbidities including multiparous gestation, bronchopulmonary dysplasia, intraventricular hemorrhages, and necrotizing enterocolitis and coexisting infections that were much less commonly associated with prematurity in the prior 2 decades.

In 1956, Kinsey first discovered the link between prolonged exposure to oxygen-rich environments and the proliferation of retrolental fibroplasia. Multiple large-scale studies have since corroborated his findings. The Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) found that lower oxygen target saturations of 85% to 89% were not associated with a significant increase in mortality and were in fact associated with a lower rate of ROP as compared to the higher oxygen target saturation group of 91% to 95%. Similarly, the Canadian Oxygen Trial (COT) in 2013 confirmed that rates of death were similar among lower target and higher target oxygen saturation groups. In contrast, 2 major studies, the Benefits of Oxygen Saturation Targeting (BOOST II) study and the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) collaboration have shown that mortality rates were higher in the lower target oxygen saturation group versus the higher saturation target group, although rates of ROP were improved in the lower target group. ^, These studies have not defined a consensus to oxygen target saturations, although current recommendations suggest targeting 91% to 95% saturation range as a way to both minimize mortality and maintain acceptable rates of ROP. ^,

More widespread use of surfactant and maternal antenatal steroids has also been attributed to increased infant survival, and potentially a decreased incidence and severity of ROP over time. ^, Surfactant has been found to decrease postnatal time on mechanical ventilation, increase pulmonary stability, and decrease ROP incidence. ^, Antenatal steroids have also been proved to decrease rates of pulmonary complications as well as intraventricular hemorrhage (IVH), which in turn improves infant survival. ^, Although these risk factors may increase the number of surviving preterm infants, some studies suggest that reducing pulmonary complications and IVH may also reduce the incidence of ROP. ^,

Internationally, the World Health Organization (WHO) has targeted infant mortality broadly within multiple economically challenged regions. The focus of many of these interventions targets educational strategies that typically require minimal resources. In 1983, a focus on enhanced skin-to-skin contact, exclusive breastfeeding, and early recognition of perinatal complications was proposed to decrease infant mortality. Beginning in the early 2000s, the WHO published guidelines recommending this practice. ^, Using these simple measures, multiple studies have demonstrated up to a 51% reduction of preterm neonatal deaths. These studies did not specifically investigate the impact of these strategies on the development of ROP. ^,

Assisted reproductive technology (ART) has also been a significant factor in the increase in preterm births, multiple gestational pregnancies, and infants at risk for ROP. ^, Each year, there is an annual increase in the rate of ART by at least 10% globally. A number of investigations have confirmed the association between ART and the development of ROP. In 1 such study, 23% of all ART infants developed some stage of ROP. Others have found that ART is associated with nearly a 5-fold increase in the risk of developing treatment-warranted ROP.

As these trends in neonatal medicine continue, we can expect rising number of preterm infants at risk for ROP. Furthermore, these advances are associated with earlier gestational age and lower-BW premature infants. ^{, ,} These data support the increasing need for targeted ROP screening. Like many areas within ophthalmology, the increasing burden will require unique solutions. One such approach is the incorporation of remote screening, both with and without the integration of artificial intelligence both to evaluate the quality of the obtained images and to classify these images based on risk.

Screening Guidelines

Screening guidelines for ROP have been a persistent focus of discussion. In 1997, the American Academy of Pediatrics (AAP) and the American Academy of Ophthalmology (AAO) recommended routine screening for ROP in all infants younger than 28 weeks’ GA or <1500 g BW. This recommendation changed in 2006 when the criteria were set for all infants of GA 32 weeks or younger, or <1500 g BW. In 2013, the AAP and AAO recommendations were updated again to include screening for infants 30 weeks or younger or <1500 g BW. At present, these guidelines remain essentially unchanged, with the caveat that high-risk infants outside of the traditional screening parameters may benefit from screening at the discretion of the neonatologist.

Critically, the first ophthalmic screening is recommended at either 6 weeks’ post-conceptual age (even if earlier than 31 weeks) or at 31 weeks’ gestational age. Follow-up screening intervals are also pivotal in the determination of progression and/or risk. The AAP/AAO recommend 1 week or less of follow-up for those infants with the highest risk attributes, with extended screening intervals for moderate- and lower-risk examination findings ( Table 1 ).

Challenges in Screening

Retinopathy of prematurity is more than a complex medical disease: it is also a significant public health challenge. As our knowledge of the pathophysiology of ROP and its at-risk patient population evolves, there continues to be an ongoing discussion on optimal screening and treatment guidelines.

Multiple different issues contribute to the challenges in ROP screening. The difficulty in determining the optimal guidelines is reflected by the range of different screening protocols across countries. For example, the Royal College of Paediatrics and Child Health (RCPCH) recommends screening all infants <32 weeks’ GA or <1501 g BW. In Canada, the recommendation is to screen any infant ≤ 30 and 6/7 weeks GA regardless of birthweight and any infant with a BW ≤1250. This screening is recommended to begin based on the post-menstrual age (GA plus chronological age). Both of these recommendations, from independent economically developed nations, are different from those of the AAP/AAO.

An additional factor that has complicated ROP screening is the rapid advancement of neonatal care and evolving demographics of preterm infants in NICUs across the United States and around the world. Longitudinal tracking of these demographics is difficult. Adding to the complexity is that many studies evaluating ROP risk factors are often regionally focused and have differed in outcomes, suggesting that even regional factors may influence ROP risks. For example, the incidence of ROP has been reported to vary from as low as 15% to 20% to as high as 68%. ^{, , , ,} Generalizability, therefore, becomes an issue.

Further complicating the challenge of ROP is the existence of both known and unknown variables as predictors of risk. This has led to the lack of universal algorithms or protocols that fully capture and predict with high sensitivity and specificity which infants will eventually develop ROP. ^, Factors beyond GA and BW have been proposed as helpful predictors for developing ROP, such as insulin-like growth factor and weight gain, but still need further validation.

The complexity of screening has led multiple investigators to propose algorithms capable of predicting high risk ROP using both natal and postnatal factors. Well-known algorithms include CHOP-ROP (Children’s Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulin-like growth factor, neonatal ROP), DIGIROP (Digital ROP), and CO-ROP (Colorado-ROP). In 2009, Lofqvist et al validated a screening algorithm called WINROP using weekly measures of body weight, serum insulin-like growth factor (IGF-1) levels, GA, BW, and IGF-binding protein. Although the utility of the complex WINROP algorithm was validated, recent external re-validation studies have demonstrated sensitivities as low as 55%. ^, The CHOP-ROP algorithm was described in 2011 by Binenbaum et al. It uses a combination of BW, GA, and daily weight gain to stratify risk. ^, The sensitivity of predicting type 1 or 2 ROP was reported to be 98%, but the authors recommended further validation before widespread adoption. More recently, in 2019, the DIGIROP algorithm was proposed as a simplified method using BW and GA to predict ROP risk, and was both internally and externally validated to be comparable in its accuracy to CHOP-ROP, OMA-ROP, and WINROP (using area-under-the-curve comparative analysis). The abundance of ROP screening algorithms is helpful, but clearly suggests that no single algorithm has yet been identified to meet both the clinical need and to maintain excellent sensitivity and specificity.

Finally, generalized guidelines that aim to maximize the inclusion of at-risk infants can expose infants to a stressful examination, ^, whereas more targeted guidelines may allow certain infants at risk for ROP to be delayed in their screening. This same logic applies to screening intervals. Clearly, screening guidelines are critical to identify those at-risk infants who will require initial and ongoing screening to eliminate the late consequences of advanced ROP.

Evolution of ROP Treatment

In the 1970s, Japanese investigators first published several trials documenting the positive treatment impact of cryotherapy in acute-stage ROP. ^{, ,} Prior to this, attempts at treating and preventing progression of ROP with other approaches had not succeeded, with surgical intervention being the only treatment in very severe cases of what was then considered retrolental fibroplasia.

The CRYO-ROP trial in 1988 demonstrated a 50% reduction of unfavorable outcomes in ROP eyes treated by cryotherapy versus untreated eyes. Soon thereafter, several factors led to the adoption of laser photocoagulation over cryotherapy for treatment of ROP, including both the complications of cryotherapy and the ease of treatment by way of indirect laser ophthalmoscopy to maintain favorable anatomic and visual outcomes. ^, In our institution, the transition from cryotherapy to targeted laser therapy occurred in the late 1990s. In the early 2000s, the ETROP study supported the importance of early treatment, using laser photocoagulation to reduce the rates of unfavorable outcomes in high-risk ROP. Recognizing this outcome, the AAO shifted its treatment recommendations to laser photocoagulation as an initial therapy whenever possible. As with any invasive treatment, long-term complications may occur. For laser photocoagulation, visually unfavorable outcomes included permanent restriction of visual field, increased incidence of high myopia, amblyopia, cataracts, nyctalopia, pachyphakia, microcornea, and angle closure (PMAC). These complications highlighted the need for alternative therapies and prompted much of the advanced investigations leading to the adoption of anti−vascular endothelial growth factor (anti-VEGF) therapy, initially as a salvage therapy, then ultimately as primary therapy for treatment-warranted ROP.

Current treatment paradigms often include both anti-VEGF and/or laser photocoagulation. Although safety and efficacy trials are ongoing, several recently published trials, including BEAT-ROP and ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW), have demonstrated positive structural outcomes from treatment with anti-VEGF. ^{, ,} Initial results looking at adverse effects have reported lower rates of posttreatment refractive error, anterior segment complications, and visual field constriction. The major controversy in the direct use of intravitreal anti-VEGF has focused on the theoretical risk on developing vascular systems within the premature infant. Internationally, the standard of care of advanced treatment-warranted ROP is intravitreal anti-VEGF, whereas in the United States, several academic centers continue to focus on laser ablative approaches to primary therapy. ^,

PURPOSE OF THE STUDY

The aim of this study is to focus on the longitudinal evaluation of high-risk infants for the development of ROP at a single tertiary NICU, and to evaluate evolving demographics of ROP and the transition of treatment-warranted disease using an integrated screening/treating surgeon approach enabling reduction in bias often associated with extended study timelines.

SUBJECTS AND METHODS

This study was compliant with the Health Insurance Portability and Accountability Act of 1996, adhered to the tenets of the Declaration of Helsinki, and was approved by the Institutional Review Board of the University of Miami Miller School of Medicine.

Data Collection

The BPEI/JMH data set demographic data was abstracted to include BW, GA, GA at time of examination, dates of initial examination and follow-up examinations, multiple-gestation birth status, survival status, and birth location at primary institution or transfer from another institution. Screening data collected included laterality of eye, presence of ROP, zone, stage, number of clock hours of involvement, presence of plus disease, presence of tunica vasculosa lentis, degree of fundus pigmentation, concurrent ocular comorbidities, and clarity of view during examination. Each child was identified with the most advanced stage and zone reached at any time during the study window. Fundus pigmentation was graded on a scale of 1 to 3, with 1 indicating light fundus pigmentation, 2 indicating medium fundus pigmentation, and 3 indicating dark fundus pigmentation ( Figure 3 ) .

Grading of fundus pigmentation. Examples of fundus pigmentation grading to assess all screened patients with (A) representing examples of light (grade 1) fundus pigmentation, (B) medium (grade 2) fundus pigmentation, and (C) dark (grade 3) fundus pigmentation. Figure and caption reproduced with permission from Fan et al.

Treatment-related data included fluorescein angiography photography, fundus RetCam photography (Natus Medical Incorporated, Pleasanton, CA), type of treatment (cryotherapy, laser photocoagulation, intravitreal anti-VEGF, surgery), whether a combination of treatments was required, need for re-treatment, date of additional follow-up treatment, and time to re-treatment if deemed necessary by the treating physician. All data for infants were collected at each examination continuing until the time of discharge from the NICU, until ROP had regressed, or until the infant expired.

RESULTS

Between January 1, 1990, and June 20, 2019, a total of 25,567 examinations were performed. For this analysis, 7436 infants were included who met our study criteria requiring birth demographics and inborn status. For these 7436 infants, the mean BW and mean GA were 1101g and 28.4 weeks, respectively (Table 2) . This final cohort included 1322 multiple-gestational births (17.8%). Retinopathy of prematurity of any severity was diagnosed in 2198 (29.6%) infants ( Table 3 ). For infants weighing ≤1250 g, the proportion of infants diagnosed with ROP was 43.1%. The overall mean zone and stage severity was zone 2.0 and stage 1.8, respectively. The mean BW and mean GA for infants with ROP were significantly lower at 822.9 and 26.3 weeks, respectively ( P < .001) ( Table 3 ), compared to the non-ROP population.

evolution of BirthWeight and Gestational Age

For all infants enrolled and screened over a 30-year period, mean BW increased each decade cohort (1990-1999, 2000-2009, and 2010-2019), from 1076.3 g to 1091.0 g to 1150.4 g, respectively (Figure 4) . Mean GA for all infants also increased across decade cohorts, from 28.3 weeks in the first 2 decades to 28.6 weeks in the last decade ( Table 4 ). For infants diagnosed with ROP, mean BW decreased with each decade (858.0 g to 815.1 g, to 780.7 g, respectively). Similarly, mean GA also decreased (26.7 weeks to 26.3 weeks to 25.8 weeks, respectively) ( Table 4 ).

Change over time of BW and GA from 1990 to 2019, demonstrating a gradual increase in both BW and GA over 30 years. BW = birthweight; GA = gestational age.

Table 4

Change in Patient Characteristics Over Time.

Characteristic	1990-1999		2000-2009		2010-2019		P Value
All patients
Total no. of patients	2626		2929		1881
Multiple gestation, n, %	401	15%	470	16%	451	24%	<.001 a
Birthweight, mean, g	1076.3		1091.0		1150.4		<.001 b
Proportion, n, %
< 750 g	527	21%	730	26%	435	23%
750-999 g	555	22%	551	19%	333	18%
1000-1249 g	619	25%	514	18%	316	17%
1250-1500 g	469	19%	567	20%	375	20%
>1500 g	317	13%	485	17%	404	22%
GA, mean, wk	28.3		28.3		28.6		<.001 b
Proportion, n, %
<27 wk	756	30%	912	32%	563	30%
27-32 wk	1317	53%	1401	49%	958	51%
>32 wk	415	17%	522	18%	354	19%
ROP patients
No. of patients, % of total	831	32%	894	31%	473	25%	<.001 a
Multiple gestation, n, %	123	15%	139	16%	92	19%	.075 a
Birthweight, mean, g	858.0		815.1		780.7		<.001 b
Proportion, n, %
<750 g	267	35%	411	47%	257	55%
750-999 g	304	40%	283	33%	138	29%
1000-1249 g	143	19%	123	14%	48	10%
1250-1500 g	38	5.0%	40	4.6%	23	4.9%
>1500 g	6	0.8%	12	1.4%	5	1.1%
GA, mean, wk	26.7		26.3		25.8		<.001 b
Proportion, n, %
<27 wk	408	54%	529	61%	338	72%
27-32 wk	310	41%	325	37%	128	27%
>32 wk	39	5.2%	16	1.8%	5	1.1%
Non-ROP patients
No. of patients, % of total	1795	68%	2035	69%	1408	75%
Multiple gestation, n, %	278	15%	331	16%	359	25%	<.001 a
Birthweight, mean, g	1275.5		1212.2		1172.0
Proportion, n, %
<750 g	260	15%	319	16%	178	13%
750-999 g	251	15%	268	14%	195	14%
1000-1249 g	476	28%	391	20%	268	19%
1250-1500 g	431	25%	527	27%	352	25%
>1500 g	311	18%	473	24%	399	29%
GA, mean, wk	29.6		29.2		29.0
Proportion, n, %
<27 wk	348	20%	383	19%	225	16%
27-32 wk	1007	58%	1076	55%	830	59%
>32 wk	376	22%	506	26%	349	25%

 

BW = birthweight, GA = gestational age, ROP = retinopathy of prematurity.

a χ ² Analysis comparing change across decades.

b Analysis of variance comparing change across time.

In the non-ROP infant cohort, the proportion born at lower BW remained stable over time, whereas the proportion of infants born at higher BW increased across the 30-year period ( Table 4 ). However, over the same 30-year period, infants with ROP born at lower BW increased over time. Within each decade, rates of multiparous births showed a continuous increase.

Plus Disease

Plus disease was identified in 416 (18.9%) ROP infants ( Table 5 ). The mean BW and GA of this group were 670.2 g and 24.9 weeks, respectively. Both BW and GA were significantly reduced among infants with plus disease ( P <.001) compared to all ROP infants. In addition, a higher proportion of infants in the plus disease cohort were born at a BW <750 g (75.8%) and GA <27 weeks (87.4%) compared with the overall ROP cohort (44.6% with BW <750 g and 60.8% GA <27 weeks). A total of 935 infants weighing <750 g BW were diagnosed with ROP, and 298 of those infants were found to have plus disease (31.8%).

Table 5

Characteristics of Patients Diagnosed With Plus Disease

Characteristic			P Value
No. of patients, % of ROP patients	416	18.9%
Multiple gestation, n, %	75	18.0%	.236
Birthweight
Mean, SD, g	670.2	160.4	<.001 a
Proportion, n, %
<750 g	298	75.8%	<.001 b
751-1000 g	76	19.3%
1001-1250 g	18	4.6%
1251-1500 g	–	0.0%
>1500 g	1	0.3%
Gestational age
Mean, SD, wk	24.9	1.6	<.001 a
Proportion, n, %
<27 wk	346	87.4%	<.001 c
27-32 wk	47	11.9%
>32 wk	3	0.8%

 

a t -Test, birthweight and gestational age comparison between patients with versus without diagnosis of plus disease.

b χ ² , Incidence of plus disease in ROP infants with birthweight <750 g versus >750 g.

c χ ² , Incidence of plus disease in ROP infants with gestational age <27 wk versus >27 wk.

Plus disease evaluated with trend analysis over time is presented in Table 6 . The incidence of plus disease is seen to rise from the 1990s to the 2000s but has stabilized in the last decade. Similar to all infants with ROP, those with plus disease have shown a gradual trend toward lower BW ( P = .005 for BW over time) and earlier GA ( P < .001 for GA over time), with an increasing percentage of infants <750 g BW and <27 weeks GA. Significantly, a higher percentage of infants with plus disease were diagnosed with zone I ROP (48%), showing an increasing trend into the most recent decade ( P < .001).

Table 6

Characteristics Over Time for ROP Patients With Plus Disease.

Characteristic	1990-1999		2000-2009		2010-2019		P Value
Plus disease
No., % of ROP patients	98	12%	241	27%	77	16%	<.001 a
Birthweight, mean, SD, g	721.9	193.6	674.0	152.9	604.5	118.0
Proportion, n, %
< 750 g	53	65%	175	74%	70	91%	.005 a
750-999 g	21	26%	48	20%	7	9.1%
1000-1249 g	6	7.4%	12	5%	0	0%
1250-1500 g	1	1.2%	0	0%	0	0%
Gestational age, mean, SD, wk	25.4	2.2	24.9	1.5	24.4	1.1
Proportion, n, %
<27 wk	65	78%	205	87%	76	99%	<.001 b
27-32 wk	15	18%	31	13%	1	1.3%
>32 wk	3	3.6%	0	0%	0	0%
Multiple gestation, n, %	17	17%	39	16%	19	25%	.236 a
Severity
% Zone 1 disease	4	4%	41	17%	37	48%	<.001 a
% Stage 3+ disease	71	72%	181	75%	27	35%	<.001 a

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