Severity of disease

The peripheral changes at the leading edge of the developing retinal vessels have been divided into five stages.

Stage 1

A flat gray-white demarcation line separates the vascularized from non-vascularized retina. Often faint, it can be difficult to identify. Retinal vessels run up to the line but do not cross it (Figs 43.4 and 43.5).

Fig. 43.4 Stage 1 ROP. Thin line separates vascularized from avascular retinal regions. The bluish tint is due to dark fundus.

Fig. 43.5 ROP stages 1 and 2. Stage 1 in its lower part, but the line becomes thicker (ridge) toward the top of the image. Differentiating stages 1 and 2 is not always easy – or necessarily important.

Stage 2

The demarcation line has increased in volume and extends out of the plane of the retina (Figs 43.5–43.7). The color of the ridge may be white or pink and small neovascular tufts may be seen posterior to the ridge. Differentiating stage 1 and early stage 2 is difficult but usually not prognostically important.

Fig. 43.6 Stage 2 ROP.

Fig. 43.7 Stage 2 and stage 3 ROP. Stage 2 at top and bottom of the image with about 1 clock hour of mild stage 3 disease that curls away from the ridge at its lower edge.

Stage 3

Stage 3 has the features of stage 2, but is characterized by extraretinal neovascularization (Figs 43.7 and 43.8). The new vessels may be continuous with, or disconnected from, the posterior border of the ridge, or extend into the vitreous. The extraretinal neovascularization may extend from the region of the ridge into the vitreous or, typically in more posterior disease, lies back across the surface of the vascularized retina.

Fig. 43.8 Stage 3 ROP that has developed in the eye with stage 2 disease shown in Figure 43.6. Note the peripheral tortuosity and dilation as the vessels become close to the ROP lesion (compare with Figure 43.6). The shadow, just behind the lesion, indicates that the lesion is off the retinal surface.

Stage 5

There is a funnel-shaped total retinal detachment (Fig. 43.9). This stage is further defined according to the anterior and posterior characteristics of the funnel.

Fig. 43.9 Acute stage 5 funnel retinal detachment.

Aggressive posterior ROP (AP-ROP)

This severe form of ROP¹¹³ is characterized by a posterior location (zone I or posterior zone II) and a prominence of plus disease out of proportion with the rather innocuous appearance of the vascular abnormality at the vascular/avascular junction. The severity often makes it difficult to distinguish arterioles and venules (Fig. 43.10). Over time, the progression from stage 1 to stage 2 and stage 3 is not apparent; the flat network of new vessels can easily be missed.

Fig. 43.10 Examples of aggressive posterior retinopathy of prematurity (AP-ROP). (A) View of AP-ROP – note the posterior locations, prominence of plus disease, and the modest appearance of the peripheral retinopathy. (B) AP-ROP image showing plus disease with a brushlike neovascular proliferation at junction between vascular and avascular retina.

(Reproduced with permission from Arch Ophthalmol 2005; 123: 991–9.)

Plus disease

The first signs of plus disease (Figs. 43.11) are tortuosity of the retinal arterioles and congestion of the retinal veins close to the optic disk. Later, the vessels of the iris become engorged and the pupil fails to dilate to mydriatics. The vitreous becomes hazy. Signs of plus disease may appear at any ROP stage and occasionally as a precursor. The diagnosis is clinical comparing with a reference photograph; at least two quadrants must be involved and the peripheral changes of ROP must be present. Plus disease does not refer to vascular changes in the retinal periphery. The diagnosis of plus disease is critical; it is an indicator of severe ROP¹¹⁴ that may require treatment,¹¹⁵ and increased likelihood of an unfavorable outcome.⁶⁶

Fig. 43.11 Two examples of plus disease. Note the different appearance with different magnification and field of view between (A) and (B).

(Reproduced with permission from Arch Ophthalmol 2005; 123: 991–9.)

Pre-plus disease

The posterior vascular abnormalities that occur in ROP with plus disease are the most severe. The term “pre-plus”¹¹³ indicates posterior vascular abnormalities with insufficient arteriolar tortuosity and venular dilation to be termed plus disease although still abnormal (Fig. 43.12). It alerts to the possibility of peripheral retinopathy.

Fig. 43.12 Examples of pre-plus disease showing increased tortuosity and dilation compared to normal, but insufficient to be designated plus disease.

(Reproduced with permission from Arch Ophthalmol 2005; 123: 991–9.)

Location

The retina is divided into three zones centered on the optic disk, in contrast to retinal neural organization, which centers on the fovea:

Extent

The extent of disease is described in clock hours or by 30° sectors. As the examiner looks at the eyes, the 3 o’clock position is on the right for both eyes, i.e. on the nasal side of the right eye and temporal side of the left eye.

Regression and resolution

Resolution of acute retinopathy has been less well studied, because, once the need for surgical intervention has passed, there is less need for surveillance and recording.¹¹¹ The rate of regression reflects PMA;¹¹⁶ the first signs are failure to progress and the lessening of any signs of plus disease. The ridge thins and breaks up. Later, vessels grow through the ridge into the peripheral avascular retina.¹¹⁷ Involution is characterized by vascular remodeling with gradual movement of vessels toward the periphery: in some eyes, vascularization to the ora serrata does not occur. The acute ROP lesion becomes white and vessels may be seen extending beyond the lesion into the periphery. Vasoproliferative lesions become fibrotic.^109,111 All exclusively stage 1 and 2 ROP undergo complete resolution. Stage 3 may or may not resolve, depending on severity. A sign of incomplete resolution is retinal dragging (Figs 43.13 and 43.14). The mean time of onset of signs of involution in children with birth weights of less than 1251 g was 38.6 weeks; 74% of all ROP had begun to involute by 40 weeks of PMA 90% by 44 weeks.¹¹⁶

Fig. 43.13 Mild dragging of the retinal vessels. Note response to cryotherapy on upper border of picture.

Fig. 43.14 Fundus photograph showing late cicatricial changes including stage 4B retinal detachment with extensive temporal dragging of vessels and macula.

(Reproduced with permission from Arch Ophthalmol 2005; 123: 991–9.)

Advanced cicatricial changes involving the anterior vitreous and retina (Table 43.2) may push the lens/iris diaphragm forward and cause shallowing of the anterior chamber, glaucoma, and corneal decompensation. In such cases, lensectomy is indicated to relieve narrow angle glaucoma.

Table 43.2 Cicatricial changes in retinopathy of prematurity

Acute phase ROP

Early publications^{15,66,118,119,120} were mostly from single centers, but prospective geographic studies^40,121 were undertaken, one of which was carried out after treatment was introduced.¹²²

The multicenter study of cryotherapy for retinopathy of prematurity (CRYO-ROP study) was conducted in 23 nurseries in the USA.⁷⁰ Over 4000 children with birth weights of less than 1251 g had serial eye examinations. ROP was observed in one or both eyes of 65.8% of these infants, with ROP observed in 90% of children with birth weights of less than 750 g, in 78% of those with birth weights of 751–1000 g, and in 47% of those with birth weights of 1001–1250 g. The CRYO-ROP study reported on the residua of ROP (the cicatricial phase in the eyes of 2759 children at age 1 year). None of these eyes had undergone cryotherapy. There was advanced scarring involving the posterior pole in approximately 4%, with 2% likely to have severe visual loss due to posterior pole scarring or retinal detachment.¹²³

ROP may have declined in incidence,^49,123–125 but not universally.^126,127 The overall incidence of ROP in an intensive care nursery¹²⁸ in infants with birth weights of less than 1251 g was 34% compared to 65.8% for CRYO-ROP study patients. For infants with birth weights of less than 1000 g, there was an incidence rate for ROP of 46%, compared to 81.6% for CRYO-ROP patients in the same birth weight group. However, there are several biases in single-center studies,¹²⁹ including survival rates,¹³⁰ ethnicity, and standard of care.

The ETROP study enrolled babies with birth weights of less than 1251 g in 26 neonatal intensive care unit (NICU) systems in the USA and imposed a rigorously controlled examination technique and frequency. The incidence of ROP in the ETROP study was 68% among infants of 1251 g birth weight, which is a very similar incidence to that for the CRYO-ROP study (65.8% among infants of similar birth weights). However, in the ETROP study, the incidence of more severe prethreshold ROP was 36.9% among infants with ROP while the incidence was 27.1% for patients in the CRYO-ROP study. The mean birth weight and gestational age for babies developing prethreshold ROP in the ETROP study were less than those in the CRYO-ROP study (740 vs. 831 g and 25.6 vs. 26.5 weeks),¹⁴ indicating that prethreshold ROP occurred among smaller and younger infants in the ETROP study cohort than in the CRYO-ROP study cohort.

Despite these caveats, in countries with well developed NICU systems, both the incidence and severity of ROP rise with the degree of prematurity, and more than 50% of babies under 1000 g at birth develop some stage of ROP; babies under 1251 g birth weight have an incidence of stage 3 ROP of around 18%. Approximately 6–8% of babies under 1251 g birth weight will develop ROP sufficiently severe to require treatment with peripheral retinal ablation.¹³¹

In industrialized countries, severe ROP is largely confined to infants with birth weights of less than 1000 g and gestational age of 31 weeks or less, and blinding disease is rare in larger babies.¹³² However, the prevalence in developing and industrializing countries appears to be increasing and blinding ROP is not confined to very low birth weight infants. When the infant mortality rates fall between 10 and 50 per 1000 births in an industrializing country, the risk for blindness due to ROP increases dramatically. The risk is very low in those countries with infant mortality rates of more than 50 per 1000 births¹³³ (Fig. 43.15 and Table 43.3). In settings where only the premature babies with higher birth weights survive (e.g. the ROP epidemic of the 1940–1950s), extent of prematurity and low birth weight have minimal contributions because oxygen supplementation as a surrogate for the level of neonatal care is the prominent risk factor. Now that more babies with the lowest birth weights survive due to improvements in neonatal and perinatal care (as in the nurseries of the 1990s and 2000s), the extent of the infant’s prematurity becomes more important.

Fig. 43.15 Likely distribution of blindness in children due to retinopathy of prematurity as a public health problem, using infant mortality rates as an indicator.

(Reproduced with permission from Eye 2007; 21: 1338−43.)

Table 43.3 Risk factors for retinopathy of prematurity: an historical perspective

ROP disability: the three epidemics

There have been three ROP epidemics:^{108,133–137}

Countries can be subdivided according to health–socioeconomic criteria into high-, middle-, or low-income according to the health provision (Fig. 43.16). There may be diverse health–socioeconomic communities within a single country. In high-income countries, where wealth and technology permit generally high-quality health care and neonatal intensive care, ROP-induced disability accounts for 3–8% of childhood vision impairment.^139–142 In middle-income communities, technology permits increased survival of preterm babies, but limited health resources may limit the standard of care.¹³³ Consequently, babies with higher birth weights and gestational ages are at risk of severe ROP; ROP-induced blindness contributes up to 39% of childhood vision impairment due to increased survival and associated limited resources with poor quality neonatal care^108,143 (see Table 43.3). In low-income countries, very few preterm babies survive to develop ROP.^108,109

Fig. 43.16 (A) Birth weights and gestational ages of babies treated for threshold ROP in Canada, the USA, and UK (2000 to 2004). (B) Birth weights and gestational ages of babies with severe retinopathy of prematurity in low- and middle-income countries between 2000 and 2004.

(Reproduced with permission from Pediatrics 2005; 115: 518−25 by the American Academy of Pediatrics.)

The evidence that ROP-induced disability has been reduced by treatment comes from two sources. First, from studies such as the CRYO-ROP study, which demonstrated that the beneficial effects of treatment are maintained at least 15 years after treatment.¹⁴⁴ Second, epidemiologic studies such as the report from the UK which showed that, between 1976 and 1985, ROP contributed 5% of childhood vision impairment; this proportion rose to 8% between 1986 and 1990¹⁴⁰ and subsequently fell to 3% by 2000.¹⁴⁵ Given the increase in survival of the most immature babies,¹⁴³ in the absence of treatment, a considerable increase would have been anticipated.

1 Age at onset and rate of progression

ROP affects only immature retinal vessels and cannot develop after retinal vascularization is complete. One would expect the most premature, often ill, neonate with a very immature retinal vascular system to develop ROP sooner postnatally than a larger and more mature baby. However, this is not so (Fig. 43.17); ROP develops over a relatively narrow PMA range.^{40,119,146,147} The time of ROP onset is linked more to the stage of development of the infant, by PMA, than neonatal events such as oxygen therapy or illnesses,^40,119 acknowledging that the latter contribute to ROP occurrence and severity. The time during which ROP can develop is governed by PMA, but is terminated by complete retinal vascularization (also related to PMA). The narrowness of this “window” is exhibited by the occasional example of a baby of > 33 weeks gestational age and > 2000 g body weight (by which time the time remaining to develop ROP is very limited) who has received prolonged and excessive 100% oxygen and has reached stage 5 by 37 weeks PMA.

Fig. 43.17 ROP developing over narrow postmenstrual age.

As with onset, the rate of progression is also governed predominantly by the stage of development (PMA) rather than by postnatal age, or neonatal events. Data^{119,130,132,148} show remarkable consistency in the behavior of ROP. The median PMA at which the various ROP stages and features develop is as follows:

In the CRYO-ROP study, babies were randomized for treatment (i.e. within 72 hours of diagnosis of threshold ROP) at a mean age of 37.7 weeks PMA (range 32–50 weeks).¹⁴⁹ The mean age at treatment for prethreshold and threshold eyes in ETROP was 35.2 weeks and 37.0 weeks, respectively. The extremes of the age range at which eyes require treatment are notable, the earliest being 31 weeks PMA,^119,130,149 Yet, almost all babies (99%) that develop severe ROP will have done so by 46.3 weeks PMA.¹⁴⁸ The literature cited so far has all come from countries with high standards of neonatal care.

In countries with more variability in the standard of care, sight-threatening disease affects more mature and larger babies.^108,109,150 In regions developing neonatal care systems, ROP progression also behaves according to PMA.

2 Zone of involvement

The propensity for severity of ROP is governed by the state of retinal vascularization, so that zone is the most important predictor of outcome.^42,131 Incomplete vascularization in zone I carries a 54% risk of reaching threshold, but this risk falls to 8% when vessels have reached zone II. For ROP developing in zone III the risk of an adverse outcome is almost nil.¹⁵¹

3 Site of onset

ROP commences in the temporal retina in the more mature neonates when the nasal retina is already vascularized. However, in the immature neonate ROP commences preferentially in the nasal retina and later extends to other regions.^39,152 The zones of vascular development were depicted by the international classification as being circular, but when this was revised in 2005¹¹³ their elliptical shape was recognized; retinopathy in the nasal retina is frequently closer to the optic disk than ROP in the temporal retina.¹⁵³ The vertical retinal regions are less likely to be involved at onset and are only involved when ROP involves most of the circumference. The finding of ROP in these regions early in the course of the disease is a useful indicator of the possibility of future severity. The more premature the neonate, the more posterior by zone the location of the retinopathy and the greater the potential for progression. Thus, zone I disease is very likely to progress to stage 3, but ROP confined entirely to zone III rarely does.¹¹⁹

4 Plus disease

Plus disease is a critical sign of ROP activity and is now the main driver for treatment.¹³² Plus disease may be superimposed on any ROP stage and is a sign that ROP is, or is about to become, severe.^40,114 Advanced plus disease is obvious, but if mild, is the least robust diagnostic aspect of ROP. To overcome this, attempts are being made to quantify some components of plus disease by digital imaging.

5 Regression

How ROP regresses is less well documented than its onset and progression, but proceeds according to PMA rather than postnatal age. This is not surprising because the process of regression, unless it fails to occur, does not require clinical decisions.

Which infants should undergo ROP examinations?

In high-income countries, severe ROP (stage 3 or more) is largely confined to infants of birth weight < 1501 g and < 32 weeks gestational age.¹⁵⁹ Thus, in the UK, these are the current guidelines for those babies who require ROP examinations. In the USA, ROP examinations are recommended for all babies < 1501 g or with a gestational age of < 30 weeks and for babies between 1500 and 2000 g birth weight who had an unstable clinical course and are considered at risk of ROP.¹⁵⁸

For high-income countries, the UK criteria include most, if not all, babies who develop severe ROP (stage 3 or more).^160–165 Can we safely reduce the number of babies screened for ROP? Many of the larger and more mature babies who currently undergo examination are at very low risk of developing severe ROP. Of 16 000 babies, there was only one baby over 1200 g with severe ROP.¹⁶⁶ Two studies from the UK have shown that the criteria of < 1251 g birth weight and/or < 30 weeks gestational age included all babies with stage 3;^160,161 however, three US studies have reported stage 3 in larger babies.^162,163,167

For low- and middle-income countries, larger babies also develop severe ROP, and the UK and US criteria may not include all babies at risk.¹³³ It is essential in these communities for ROP examination guidelines to be based on local data.

Timing of examinations

Examinations can be timed on the principle that the onset and progression of ROP are predominantly determined by PMA rather than by neonatal events. While most guidelines recommend commencing ROP examinations between 4 and 7 weeks, Reynolds et al.¹⁴⁸ developed an algorithm for examining the most immature baby later postnatally than the more mature baby. Timing of examinations is critical; there is only a narrow, imperfectly determined window for treatment. Onset of any stage of ROP is rare before 30 weeks PMA, and ROP commencing once vascularization has entered zone III and/or after 36–38 weeks PMA is most unlikely to reach severe disease.

After the initial ROP examination, weekly or every other week examinations are indicated, but as ROP progresses, more frequent examinations will be required. A weekly visit to the NICU allows examination of those babies likely to be discharged home soon and decreases the need for babies to be recalled, decreasing the likelihood of missed examinations and their potentially disastrous consequences.¹⁶⁸ For the baby transferred to another hospital while still at risk, arrangements must be made for the continuation of ROP examinations.

ROP examinations can cease when the retinal vessels have grown well into zone III. This can only be ascertained with certainty when the nasal retina is vascularized so that there is no doubt of the extent of vascularization. It is safer to require vascularization into zone III on two occasions.

ROP detection protocol

The next paragraph is written with developed countries in mind; it is not generalizable to all preterm populations.

All infants determined to be at risk for ROP should be examined at 30–32 weeks PMA and then every 1–2 weeks at least until 36–38 weeks PMA or until vascularization has progressed into zone III and the risk of severe ROP requiring treatment has passed. Some larger babies may be discharged before an initial ROP examination. In such situations, an examination before discharge is recommended. This can indicate the potential for ROP and frequently obviate the need for later examination.

Methods of examination

Eye examinations are stressful for the preterm baby,^169–173 but this can be reduced by supportive neonatal care. Infants should be handled gently. It is helpful if a trained nurse is in attendance to help and to monitor the infant’s wellbeing. The ophthalmic examination should be performed using the indirect ophthalmoscope, with a 28- or 20-diopter lens, through dilated pupils, achieved by instilling dilating drops well prior to examination. A child’s lid speculum and scleral indenter (for ocular rotation rather than indentation), after anesthetic eye drops, may be used to permit complete evaluation of the peripheral retina. Although it can be argued that very peripheral disease so observed is of no clinical importance, identifying peripheral nasal retinopathy can be a clue to later progression. Only by observing the state of vascularization of the nasal retina can the ophthalmologist determine whether zone III has been entered.

Clinical findings

The ophthalmoscopic appearance of the neonate is different from that of the older infant.¹⁷² Before examining the retina it is important to use the indirect lens as a simple magnifier to examine the anterior segment, for instance, to see the amount of regression of the tunica vasculosa lentis as an indicator of maturity (regressing between 28 and 34 weeks gestational age).¹⁷³

The retinal periphery is white-gray in its non-vascularized regions; the extent of this depends on the degree of immaturity (see Fig. 43.1). The optic disk frequently has a grayish and a double-ring appearance but the disk is a normal size. The macular area is relatively ill defined, there being no macular or foveolar reflexes until 36 and 42 weeks PMA, respectively.²⁶ The retinal arterioles in the early neonatal period are not tortuous, tending to become so later, in part related to ROP severity.³⁹

Acute phase retinopathy of prematurity

The purpose of ROP examinations is to identify severe ROP which might require treatment. The four parameters by which ROP is classified, according to the international classification, should be noted at each location at every examination:

1. Zone

2. Severity by stage

3. Extent by clock hour or sector

4. The presence of plus disease.

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