Long-Term Visual Outcomes in Prematurely Born Children

ABSTRACT

Purpose

Prematurely born children are at risk of numerous complications that affect the visual system. Retinopathy of prematurity (ROP) and cerebral visual impairment (CVI) are among two major causes of childhood blindness and visual impairment in industrialized nations, and large countries with emerging economies are seeing increasing childhood blindness from ROP alone, adding to the burden of disease worldwide. The purpose of this paper is to review the long-term impacts of prematurity, ROP and CVI on vision in children who were born preterm.

Method

The topics in this review of the literature include the burden of vision loss in prematurely born children world-wide, a description of ROP and CVI, effects on visual acuity, refractive errors, strabismus and binocularity, visual fields and contrast sensitivity, and risk factors for visual complications.

Results

Children who are most at risk of visual complications are those with the smallest gestational age at birth and birth weight in general. Although ROP severity and the presence of neurological impairments including CVI play a large role in the development of poor visual outcomes, premature birth alone without CVI or severe ROP increases the risk of future visual complications. Awareness of signs and symptoms of CVI are important in the management of affected children.

Conclusion

Children born preterm are at increased risk of reduced visual acuity, refractive errors, strabismus and amblyopia, complications of ROP, CVI, visual field abnormalities and reduced contrast sensitivity. Awareness of risk factors warranting close monitoring and signs and symptoms of CVI are critical to optimize the visual outcomes and overall development.

KEYWORDS:

• Prematurity
• retinopathy of prematurity
• cerebral visual impairment
• visual acuity
• long-term outcomes
• refractive errors
• strabismus
• visual fields
• contrast sensitivity

Background

An invitation to deliver the John Pratt-Johnson Lecture is a tremendous honor for anyone practicing in pediatric ophthalmology and strabismus. John Pratt-Johnson was a giant in Pediatric Ophthalmology, an internationally respected clinician, teacher, researcher and patient advocate who exemplified the CanMEDS principles decades before the framework was developed. I did have the opportunity to meet him at the beginning of my practice and was immediately struck by his personality, his energy and accomplishments. Now nearing the end of my career, I can appreciate these qualities and achievements so much more and, the opportunity to participate in this prestigious Lecture series is indeed, very humbling.

Prematurely born infants face numerous risks to their health. Retinopathy of prematurity (ROP) is a well-recognized condition that can lead to complications that cause visual impairment, including blindness, and preterm infants that meet ROP screening criteria are closely monitored for disease requiring treatment to reduce the risk of vision loss during the weeks following birth. However, beyond the effects of ROP complications on visual acuity, prematurely born children are particularly susceptible to the development of several long-term ophthalmological complications that, with early recognition, may be amenable to management and reduce negative impacts on the visual system and activities of daily living. The aim of this lecture is to present an overview of the effects of prematurity on the visual system. This is particularly relevant as ROP and cerebral visual impairment (CVI), a condition commonly associated with prematurity, are major causes of childhood blindness in industrialized nations such as the UK¹ and USA.² Very large countries with emerging economies in Africa and Asia, including India and China, are seeing increasing childhood blindness caused by ROP alone, adding significantly to the burden of disease worldwide.^3–5 This lead to the World Health Organization designation of ROP as the leading cause of avoidable childhood blindness in middle-income countries and advocation for trained ophthalmologists and ROP screening among the VISION 2020 targets.⁶

Retinopathy of prematurity (ROP)

First described in the 1940s, ROP results from a disruption of retinal vascular development caused by preterm birth. The retinal vascular supply emerges around 12–14 weeks gestation, starting at the optic nerve, and completes its peripheral growth around term gestation (40 weeks). Premature birth disrupts normal retinal vascularization due to a series of differences in development in an external environment vs that of the womb. Since the initial reports describing end-stage ROP, much research has focused on the role of oxygen, among other, as a risk factor for severe ROP and exposure ranges to minimize ROP complications associated with higher oxygen exposure and neurological complications, including cerebral palsy and cerebral visual impairment (CVI), and death associated with lower oxygen delivery.⁷ Optimization of care, including oxygen exposure, is critical to reduce risks for vision loss associated with complications affecting the retina and the central nervous system (CNS).

ROP is classified in stages that describe the disease severity. Retinal vascular tortuosity and caliber in the posterior pole are utilized as a measure of disease activity, with degrees of severity qualifying as plus disease or pre-plus requiring attention due to imminent risk for disease progression to blinding complications. A combination of ROP stage, location based on proximity of the ROP edges to the optic nerve, and vascular tortuosity and caliber determine the risk of vision loss and need for interventions to reduce this risk.⁸ ROP typically progresses to maximum severity between 30 and 37 weeks post-gestational age followed by regression after 40 weeks with or without treatment.⁷

The goal of ROP screening is to reduce vision loss in infants that develop severe disease. However, most infants will experience a benign form of ROP or none, i.e., the vessel growth will progress normally as it would have in the case of full-term birth without developing ROP. In the USA, two thirds of infants at risk develop ROP and 9% require treatment.⁹ In Canada, the Canadian Neonatal Network (CNN) captures the health outcomes of prematurely born infants in approximately 90% of Canadian hospitals that care for prematurely born infants. In the 2021 CNN report, approximately 40% of infants at risk developed ROP and 5% required treatment.¹⁰ World-wide, ROP severity and rates vary significantly (25–91% develop any ROP, and treatment rates range from 4% to 30%), even among higher-income countries. This may be due to different screening criteria, medical practices, social and cultural influences as well as genetic predisposing factors. Indeed, screening guidelines need to be adapted to match regional needs, as poor outcomes are seen in infants with larger birth weight and greater gestational age at birth in middle-income countries compared to those with higher incomes.^5,11–16 Typically, regardless of regional differences, severe ROP and resulting vision loss are more likely to occur in those infants who are born at an earlier gestational age and who have lower birth weight and post-natal growth, among other risk factors.^7,17

Two treatments are available: laser and anti-VEGF agents. Laser is applied to the avascular retina, i.e., peripheral to the ROP edge, and aims to destroy the avascular retina in a confluent manner thus stopping the production of vascular endothelial growth factors (VEGF), a major driver of abnormal neovascularization. Intraocular injections of anti-VEGF agents neutralize VEGF generated by the hypoxic avascular retina and may require laser to the residual non-perfused retina later. Each treatment has pros and cons, and research is ongoing to establish best practices in the short- and long-term.^18,19

Cerebral visual impairment (CVI)

While vision loss due to severe ROP affects a minority of prematurely born infants, these infants are at much greater risk of vision impairment from other causes, including intraventricular hemorrhages (IVH) that occur in the days following birth, periventricular leukomalacia (PVL) typically diagnosed in the first year of life, hypoxic ischemic encephalopathy and hydrocephalus. These may result in isolated CVI, defined as visual impairment caused by lesions posterior to the chiasm, or CVI combined with anterior pathway conditions also common in prematurely born children including optic nerve atrophy, optic nerve hypoplasia and increased optic nerve cup–disk ratio, depending on the type, extent and timing of the injury. The developing CNS, including its evolving circulation, is susceptible to damage in several areas that are important for vision in prematurely born infants.^20,21 The periventricular area, a watershed zone in the developing fetus, is particularly sensitive to injury from bleeding (IVH) and hypoxia, among other perinatal insults, that may damage the corticospinal tracts and optic radiations.^22,23 Severe IVH causing enlargement of the ventricles (grade 3) and seepage of hemorrhage into the brain tissue around the ventricles (grade 4) is known to contribute to periventricular damage, but even lower grades can impart a risk for neurodevelopmental disorders including visual impairment.²⁴ In 2021, the CNN reported an overall IVH incidence of 15% and 4% for PVL, with highest risks in the most immature and smallest infants when stratifying for gestational age at birth and birth weight.¹⁰

The consequences of PVL are variable, ranging from severe CVI with cerebral palsy and developmental delays to strabismus only and mild learning disabilities. Similarly, the visual acuity in CVI due to damage to the periventricular areas and generalized hypoxic encephalopathy is variable and although commonly reduced, may range from no light perception to 20/20 with symptoms associated with CVI only. Normal Snellen acuity, stereoacuity and neuroimaging do not preclude cognitive visual dysfunction, and the suspicion of milder forms of CVI may come from combining perinatal medical history looking for risk factors for CVI with visual symptoms and examination outside of the clinic environment.^20,25

Damage to two major streams may cause CVI presenting with different characteristics: the dorsal and the ventral streams. The dorsal stream guides visual-spatial tasks and visually guided movement and is responsible for handling complex visual scenes. When damaged, this may result in difficulties finding a toy in a toy box or on a complex floor pattern, identifying objects at distance, or in a busy environment such as a mall or supermarket, reading when the print size diminishes, navigating street curbs or patterned flooring, including changes in patterns, going down staircases, etc. This stream is commonly affected in children with cerebral palsy. Conversely, the ventral stream is concerned with visual object recognition and route finding and is important for facial recognition and visual memory that may affect copying or drawing recall. This stream is particularly susceptible to damage from hydrocephalus.²⁵ Knowledge of visual symptoms is critical during history intake to help children, families and health care workers in the circle of care by identifying the visual challenges that will guide management approaches and improve daily function.

Other than visual acuity and visual functions mentioned above, CVI may present with impaired contrast sensitivity, delayed saccades, a variety of visual field defects, looking away from an object that is being viewed (possibly due to use of peripheral vision in those with central visual field defects), nystagmus due to PVL, poor fixation, photophobia, and paradoxical light gazing. The effect of CVI on color vision is less clear. Fluctuations in visual behavior are common in CVI, and binocular visual acuity measures correlate better with visual function in general.^20,22 The presence of large cup-to-disk ratio associated with PVL and likely caused by retrograde degeneration of axons from optic radiation damage late in gestation^26,27 is an indicator for possible CVI and not necessarily vision loss due to enlarged cupping by itself.

Combination of sources of vision loss is common even in those infants with severe ROP and good structural outcomes: CVI was the primary cause of vision loss in two-thirds of six-year-old children with blindness despite favorable structural outcomes following laser in the ETROP multicentre trial,²⁸ occurring in 7% of all of those that required treatment. Of those, one-third had combined anterior and posterior cerebral pathway disease. Common clinical characteristics included nystagmus, latent and/or manifest (77%), developmental delays (72%), optic atrophy (46%), and large disc cupping (8%).

Visual acuity (VA)

CVI is the most common cause of childhood vision loss in higher-income countries followed by ROP, inherited retina and optic nerve disease in various order of frequency, depending on the study and location.^1,2 Among infants with ROP-warranting treatment, the anatomic success of laser treatment in the ETROP multicentre trial at 6 years²⁹ approached 90% while VA of 20/40 or better was achieved in only 34.6%, and VA worse than 20/40 and better than or equal to 20/60 in 14.3%, leaving 25% legally blind and a similar proportion with significant visual impairment. Although the anatomic success of laser-treated ROP is high, the VA outcomes remain problematic with most not meeting driving vision standards. Long-term VA outcomes comparing laser and anti-VEGF in large, randomized trials are lacking. However, given the current evidence demonstrating overall reduced myopia and amblyopia and, in those infants with aggressive posterior ROP, improved structural outcomes in favor of anti-VEGF agents,^30–32 a reasonable expectation is that VA will improve with the addition of anti-VEGF agents as a treatment option, as suggested in a recent publication from a multicentre study in Japan.³³

Even preterm infants who do not require treatment for ROP may be at risk of reduced VA, typically by 1–2 Snellen lines, as demonstrated in one study evaluating adults who were born between 22 and 25 weeks gestation, although the etiology remains unclear and may include mild CVI.³⁴ In another study including preterm infants with higher gestational ages, this effect was not as prominent, but did highlight reduced visual outcomes in those that did develop more severe ROP and in those with lower birth weights.³⁵

Refractive outcomes

Refractive errors are the most common ophthalmic consequence of prematurity, especially in those who required ROP treatment.³⁶ Prematurity and ROP can alter the development of the anterior chamber with steeper corneal curvature, corneal astigmatism, anterior position of the iris-lens diaphragm and increased lens thickness.^37–39 Myopia, astigmatism and anisometropia are most pronounced in infants that were treated for ROP and starts early, typically by 6 months of age, while myopia in cases with naturally regressed ROP and infants who never developed ROP is milder and much less frequent, but in all cases, are a risk factor for amblyopia.^40,41 Myopia and astigmatism are caused by anterior segment changes, as the axial length in these children is paradoxically shorter.^38,39 The ROP treatment type also influences refractive error outcomes, with the most severe associated with cryotherapy, a treatment that was used prior to laser, followed by laser, and is least severe following anti-VEGF treatment.^{31–33,42,43}

Visual fields

Premature birth without severe ROP has not been demonstrated to influence visual fields. In studies from large randomized trials, the reduction of the field of vision was similar whether cryotherapy or laser were used compared to a group of children who developed severe ROP that resolved without developing a retinal detachment and were randomized to observation alone.^44–46 No decrease in visual field due to treatment was detected when the treatment criteria changed to advocate for earlier treatment, suggesting the effect of ROP requiring treatment is greater than the effect of treatment (cryotherapy or laser) or timing of treatment using updated criteria.⁴⁴ As the peripheral retina does revascularize to some extent following anti-VEGF treatment, it is hypothesized that the visual fields may be improved, but a large, randomized comparative study is lacking. It remains possible that retinal function may be irreversibly damaged despite partial or complete peripheral vascularization in those that developed severe ROP requiring treatment. In addition, a variety of visual field defects may be present in those with anterior pathway disease such as optic atrophy and neurodevelopmental deficits, including CVI.^20,22

Contrast sensitivity

Similar to the visual fields, the effect of ROP severity on contrast sensitivity is greater than that of treatment when using cryotherapy or laser.^47,48 One study⁴⁹ reported subnormal contrast sensitivity in adults born preterm, independent of ROP or neurological status, while another also reported reduced contrast sensitivity in those born prematurely regardless of ROP status,³⁵ suggesting that a history of prematurity alone with or without neurological involvement, could influence contrast measures. Meanwhile, a separate group did not find such a difference.³⁴ Neurological impairments may also significantly impair contrast vision.^20,22 Contrast sensitivity outcomes are unknown in those who were treated with anti-VEGF agents.

Strabismus and binocularity

The overall prevalence of strabismus in prematurely born children, regardless of ROP status, ranges from 14% at age 2 according to a study evaluating a large cohort of infants born at less 28 weeks gestation in the USA⁵⁰ to 5% by age 2.5 years in one population study from Sweden that followed infants born less than 32 weeks gestation,⁵¹ while 14% of children born before 27 weeks gestation, also in a Swedish cohort, manifested strabismus at 30 months corrected age.⁵² Strabismus rates increase significantly with more severe ROP and neurological complications. Among those with a history of ROP requiring treatment, the six-year outcome ETROP study found strabismus in 42% in a cohort of 342 children.⁵³ A similar prevalence of 38% was found in a Swedish population-based study in 6.5-year-old children previously treated for ROP.⁵⁴ Esotropia was more common followed by exotropia and, least frequently, vertical deviations. Risk factors that have been associated with strabismus include ROP requiring treatment, lower gestational age at birth, poor fetal growth, maternal history of aspirin ingestion, high illness severity, central nervous system ventriculomegaly, PVL, cognitive disability, cerebral palsy, and severe bronchopulmonary dysplasia.^49–51 In a large US cohort of healthy children (0–21 years old) born preterm, a birth weight less than 2000 g imparted a 61% increased risk of strabismus compared with those born with higher weight.⁵⁵ The strabismus risk was inversely correlated with birth weight.

Children born prematurely without a history of ROP are also at higher risk of strabismus, amblyopia, and anisometropia. A German cohort of children aged 4–10 years had a rate of strabismus of 12% in children without ROP born at gestational ages 29–32 weeks that increased to 22% in those born at less than or equal to 28 weeks gestation, while those who developed any stage ROP and born at less than or equal to 32 weeks gestation had a 26% rate of strabismus, in contrasts to 2% in those who were born full term.⁵⁶ Investigators reported lower gestational age at birth and higher refractive errors as independent risk factors for strabismus.

Treatment with anti-VEGF agents may decrease events that reduce binocularity compared to those treated with laser⁵⁷ and may be associated with decreased incidence of amblyopia.³¹ More research is needed to determine the effect of treatment on binocularity.

Strabismus surgery in this population requires special considerations. Undetected neurological deficits in this group are particularly challenging to isolate from the effects imparted solely by severe ROP. In addition, accommodation^58,59 and convergence⁵⁹ may be reduced in those with a history of prematurity that may influence the development and management of strabismus. Higher rates of overcorrection have been described in children with developmental delays and cerebral palsy in general and in preterm vs term groups, with or without neurological impairment, suggesting the possibility of higher rates of reoperations in this group and poorer binocular potential compared to otherwise healthy children who were born full-term, especially if prematurity is associated with neurological impairments.^59–62 One study⁶³ reported the natural history of strabismus in 11 prematurely born children with neurological impairment between the ages of two and 13 (i.e., 12-year follow-up for each child). Four with exotropia were esotropic by age 13, four of seven with esotropia became exotropic and the remaining three of seven with esotropia were less esotropic.

Conclusions

The visual system is particularly vulnerable to damage in those who are born preterm. Common complications include subnormal VA, visual function deficits, refractive errors, strabismus, binocularity deficits, amblyopia and visual field defects. In addition, some may experience nystagmus, contrast sensitivity and accommodation deficits. Risk factors for visual complications include gestational age at birth, birth weight, perinatal neurological event, ROP, in particular ROP requiring treatment, and other factors including maternal health among others.

Three prospective population-based studies in the past decade exemplify the long-term risks to the visual system. In Norway, among 52 six-seven year-olds born between 22 and 27 weeks gestation, subnormal vision down by 1–2 Snellen lines was present in 46% in their best eye, strabismus in 10%, all esotropia (half of those affected did not have ROP or neurological events), mild myopia in 8%, latent strabismus in 51% (all exophoric except one), and nystagmus in two of those with strabismus.⁶⁴ In that cohort, 15% had stage 3 ROP or higher, 1% were diagnosed with PVL and 26% had IVH. In the UK and Ireland, among 128 19-year-old participants born at 22–25 weeks gestation, strabismus was recorded in 36%, nystagmus in 13% compared to 0% for each in the control group, and refractive errors in 50% (note that the latter was found in 41% in age matched full-term adults).³⁴ In that group, 48% did not develop ROP and 13% were treated with laser or cryotherapy. Finally, 59 adults 25–29 years of age in Sweden born less than 34 weeks gestation manifested strabismus in 12% (all with onset less than 4 years of age, 7% with esotropia and 5% with exotropia), reduced stereoacuity in 36% (vs 2% in the control group), and reduced accommodation and contrast sensitivity in those with subnormal vision.⁵⁸

Finally, recognizing the risks for CVI, with careful history and examination targeting these complications is critical to optimize the visual outcomes and management of these children and adults with complicated medical histories. A multi-disciplinary approach to the management of individuals born preterm can enable the implementation of strategies that can positively impact their general development, learning abilities and activities of daily living.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the None.