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Early Human Development (2008) 84, 101–106

Long term ophthalmic sequelae of prematurityAnna O'Connor a,⁎, Alistair R. Fielder b,1

a Division of Orthoptics, Thompson Yates Building, Quadrangle, University of Liverpool, Liverpool, L69 3GB, United Kingdomb Department of Optometry & Visual Science, City University, Northampton Square, London, EC1V 0HB, United Kingdom

⁎ Corresponding author. Tel.: +44 155781.

E-mail addresses: annaoc@liverpooa.fielder@city.ac.uk (A.R. Fielder).1 Tel: +44 20 7040 8339; fax: +44 20

0378-3782/$ - see front matter © 200doi:10.1016/j.earlhumdev.2007.11.005

Abstract

There are numerous reports of an increase in refractive errors and amblyogenic factors in the lowbirth weight population relative to children born at full term. This raises the question of whetheradditional long term ophthalmic screening is required. The current provision of follow up care forpreterm infants in the UK is haphazard and varies in terms of its availability, the type of assessment,age at assessment and age at discharge. This issue needs to be addressed to provide the best care forthese children however there are different possible methodologies. One key aspect of a screeningprogramme is the age at testing as this dictates the possible tests used which impacts on theefficacy. However, although the prevalence of strabismus and refractive errors is well documentedthe development of these conditions is poorly understood so for this and other reasons it is difficultto devise the most effective screening programme.© 2008 Elsevier Ireland Ltd. All rights reserved.

KEYWORDSRefractive error;Strabismus;Amblyopia;Vision screening;Low birth weight

The threat to visual development by being born preterm doesnot end when the retina is fully vascularised and the risk ofROP has passed. Although the conditions which develop, orbecome apparent after the neonatal period, are less likely toresult in irreversible sight loss, there can still be significantdisability which can impact life's activities. This risk existsnot only for the children with extremely short gestationalage, but for all children who were born prematurely whether,or not, they developed ROP.

This article, where possible, will focus on outcome up to5 years of age as during this period those responsible forpaediatric care will be the point of contact for the family. Bythis age in the UK all children should have been screened byan orthoptist as recommended [1]. It is recognised that cer-

1 794 5733; fax: +44 151 794

l.ac.uk (A. O'Connor),

7040 8494.

8 Elsevier Ireland Ltd. All rights re

tain sequelae of prematurity, notably myopia, may developlater however at this age children with these deficits aremore likely to self-report and the impact on the child andvisual system will be less severe.

Formost pretermchildrenborn in theUK,between the timeof discharge from the neonatal unit until national screening at4.5–5 years of age, there is no routine ophthalmic surveillance.This is despite this being the period of most rapid developmentof the visual system and also the time when disruption, forinstance by strabismus, will have the greatest impact.

The impairments resulting from preterm birth encompass awide spectrum ranging from the extremely subtle to total blind-ness. Fortunately, severe visual loss less than 6/60 is relativelyinfrequent (0.8% less than 6/60 at 3.5 years in one epidemio-logical study [2]), although the risk of blindness for babies ofbirth weight b1500 g is increased over 25 times compared tochildren born at full term [3]. The conditions which result insevere visual loss include ROP, cerebral vision impairment,cataracts and optic atrophy,whereas other conditions, primarilyamblyopia, may result in a better visual outcome. Here we will

served.

102 A. O'Connor, A.R. Fielder

discuss the major sequelae to the visual system under two mainheadings: ophthalmic sequelae of prematurity (visual functions,strabismus, refractive state), and screening.

2. Ophthalmic sequelae of prematurity

2.1. Visual functions

The impact of early visual experience on the visual system ispotentially both stimulating and harmful, however, based onERG findings the majority of the evidence shows noretardation or acceleration up to 57 weeks post conceptualage [4]. Further study of acuity measurements after thisperiod showed significantly lower acuities in the low birthweight infants compared to those born full term [4], howeverit is important to note that these are often subtle deficitswhich could not be identified at an early age. In addition,measures after the perinatal period do not allow differentia-tion of whether this represents a slower development or anabsolute deficit. Although a full term child may reach adultlevels of acuity by the age of 5 years it is possible that the lowbirth weight child may have a longer period of developmentso in this case it is pertinent to analyse the longer termoutcome. Thus, at age 10–12 years the acuities of the lowbirth weight children on average are significantly lower thanin the full term population measured at both near anddistance [5]. It is important to note that these acuity deficitsare subtle and although the median value is still better thanwhat is considered a normal level of acuity (6/6) a largeproportion fall below this. Within the same cohort therewere 55 (18.8%) cases that had acuity below 0.0 logMAR (6/6)in both eyes with no known ocular pathology or any findingsto account for this deficit. Ohlsson et al. [6] termed thiscondition Subnormal Visual Acuity Syndrome (SVAS) andreported a prevalence of 1.9% in a population based cohort.The large increase of SVAS in the LBW population has im-portant implications for any vision screening programme.

While it is important to identify vision deficits during theperiod of development, measuring visual acuity at a youngage can be problematic. Indeed, for a number of reasonsacuity measurements during the first 2 years of life may bemisleading in terms of outcome [7]. It is essential to correctfor prematurity when comparing to normative data, espe-cially when looking at acuity in infancy as visual developmentis more closely linked to postmenstrual age than postnatalvisual experience [8]. In addition, tests used at this age arerelatively insensitive to certain visual deficits such asamblyopia. This was demonstrated by Dobson et al. [9] whofound that although there was a good level of agreementoverall between the early grating acuity test results and thelater letter acuity, in 13.2% of the cases there was a normalgrating acuity response at one year but an abnormal laterletter acuity at 5.5 years, reflecting not a deterioration butrather asymptotic behaviour.

2.2. Contrast sensitivity

In addition to the high contrast letter acuity measurementthere are other aspects of vision that may be more rep-resentative of functional ability, such as contrast sensitivity.There are noknown reports of reductions in contrast sensitivity

in children aged 5 years or below, this is probably related to thelimited availability of tests suitable for this age group. How-ever there are reports of reduced contrast sensitivity out-comes in older children with deficits reported by Larsson [10],O'Connor [5] and Cooke [11]. Reduced contrast sensitivitysuggests underlying retinal and/or neurological damage,however these findings are present with or without evidenceof ROP or detectable neurological damage, suggesting a moresubtle undetected central deficit.

2.3. Visual field

This measure of visual function is not routinely evaluatedclinically in children under the age of 6 years due to the com-plexity of the task although therearea fewreports of perimetryfrom this age group. Neurological conditions are known to beassociatedwith visual field loss but one report [12] froma groupof healthy VLBW children showed no detectable effect ofprematurity on the visual field size at 2.5 years, although at thisearly age it would be anticipated that only large defects wouldbe detected. Children who developed severe ROP and receivedcryotherapy sustained a small but significant loss of theperipheral field [13] which was detected at 5.5 years of age.Whilst the magnitude of this deficit is small (6.4°) the possibleimpact on function is unknown.

2.4. Colour defects

Colour defects are not routinely screened for as the conditionis untreatable however it should be noted that in children ofbirth weight b1251 g a significant increase in colour visiondefects, particularly in the uncommon blue/yellow deficits,has been reported [14].

2.5. Strabismus

The increased prevalence of strabismus in the low birth weightpopulation iswell documented, as shown inTable 1, butwhat isless clear is the age at which the different types of strabismusdevelop. This is important both for detection purposes but alsofor the resultant impact on the visual system.

Repka stated that “most of the prematurity associatedstrabismus is evident by one year of age” [21] whereas thereport by Schalij-Delfos et al. [20] found that less than half ofthe cases of strabismus were identified by the age of 1 year,over a third of the caseswere identified after the age of 2 yearsand some as late as 5 years. These conflicting views are a resultof the limited detailed documentation which enables us tounderstand the age at which strabismus emerges in the pre-term population. The evidence from Theng et al. [17] suggeststhat the prevalence of strabismus peaks at 2 years of age.However, it is difficult to make generalisations based on thisretrospective report of 113 children [17], particularly beingfrom Singapore when there are known variations in ophthalmicoutcome between different ethnic groups.

Whilst a frequently encountered type of childhoodstrabismus in the full term population is infantile esotropia(a large inward deviation occurring before 6 months of age),there is considerable variation in the types of strabismus thatoccur in the low birth weight population [22], and the pro-portion being divergent is greater than encountered in

Table 1 The reported rate of strabismus

Age atfollow up

% withstrabismus

ROP criteria BWcriteria

GA criteria

3 months[15]

6.6% None given b1251 g None given

12 months 14.7%6 months[16]

6.4% None given b1701 g None given

1 year[17]

20% (4.7%) ROP (No ROP) b1500 g b34 weeks

2 years 30% (9.7%)3 years 25% (9.8%)2 years[18]

12.5% None given Nonegiven

b32 weeks

36 months[19]

44% Cryotherapy b1500 g b31 weeks26% Laser25% “Subthreshold”

3.5 years[2]

13.5% None given b1500 g None given

5 years[20]

22% None given b1500 g and/or≤32 weeks

103Long term ophthalmic sequelae of prematurity

children born at full term. This is an important factor to betaken into account when considering follow up care, as theonset of the strabismus, and subsequent severity of disrup-tion of the binocular visual system will vary significantlybetween types of strabismus. Children who were bornpreterm are at risk of developing all types of strabismus,but the aetiology of strabismus associated specifically withprematurity has three key factors: prematurity, neurologicaldeficits, and ROP. With respect to ROP there is a proportionalincrease in the prevalence of strabismus with increasingseverity of ROP. The wide age range over which strabismuscan present creates difficulties when designing a follow upscreening programme.

2.6. Refractive state

The key components of the eyewhich determine the refractiveerror are the corneal curvature, lens thickness and overall eyelength. The growth of these eye components is governed pre-dominantly by genetic factors and fine tuned by visual ex-perience with the aim of creating interocular symmetry andultimately no refractive error — a process known as emme-tropisation. However, it has been shown that in the low birthweight population there are factors that may interrupt em-metropisation, notably severe ROP, and result in an increase inall types of refractive errors.

The association of prematurity with myopia is very welldocumented [23–26]. This consists of two types, first, myopiaassociated with prematurity which is independent of ROP andsecond, myopia associated with severe ROP. The former, so-called ‘myopia of prematurity’ is relatively mild and typicallyhas a later onset towards the end of the first decade, whereasmyopia associated with severe ROP can range from mild tosevere and tends to be present during early infancy remainsrelatively stable in early childhood. However there are fewerreports of an increased prevalence of hypermetropia [27],particularly in the early age group. It could be argued that inyoung children low amounts of hypermetropia are not

significant as low amounts can be overcome by the range ofaccommodation that is normal in childhood. However, asaccommodation has never been measured in low birth weightchildren it is not known whether they are able to overcomeany degree of hypermetropia. In addition it is not knownwhatmagnitude of hypermetropia becomes functionally signifi-cant for any child. Atkinson et al. [28] demonstrated in a largestudy that the presence of hypermetropia ≥+3.50DS at9months of age, if left uncorrected until the age of 3.5 years,was associated with a range of developmental deficits in thevisuocognitive and visuomotor domains at the age of 5 years.Also Williams et al. [29] demonstrated a link between hyper-metropia and impaired literacy standards, this suggests thatthere is a need for the use of a test to detect hypermetropia invisual screening as this is not currently undertaken.

Prescribing glasses at an early age may impede or slow theprocess of emmetropisation, although the clinical significanceof this is unknown [30,31]. However, in low birth weight chil-dren the emmetropisation process is already compromised atan early stage with arrested development of the anteriorocular segment. This poses the question ofwhether itwould bebeneficial to prescribe glasses at an earlier age in this popu-lation. Children within the low birth weight population, arereportedas having increased difficulties at school [32], and it isinteresting to speculate, but as yet unknown, that a lack ofrefractive correction by spectacles could potentially be com-pounding these problems.

Astigmatism is another type of refractive error that is morecommon in low birth weight children and results in reducedacuity which can be identified by vision screening [17,27].Whilst astigmatism, myopia and hypermetropia may all resultin a bilateral vision deficit which could potentially be detectedby parents, if severe, anisometropia, when not associatedwithother refractive errors, causes a uniocular reduction in acuitywhich naturally tends to be undetected until vision screening.With the increase in anisometropia in the low birth weightpopulation [33] this would again reinforce the need for visionscreening, but as this can come and go in early childhood theideal age to diagnose anisometropia has not been defined,consequently it is not clear whether additional screening couldbe justified.

3. Screening

As the low birth weight population are at increased risk ofmany conditions they require continuing care and surveil-lance for many conditions, including their neurodevelopment[34] and possible ophthalmic sequelae. The guidelines forthe screening for retinopathy of prematurity (ROP) in the UKrecommend that all infants of birth weight under 1500 g andless than 32 weeks gestational age should be screened by anophthalmologist [35]. However follow up beyond the neo-natal period is only recommended for infants with stage 3ROP and those who have undergone ROP treatment. Cur-rently, no additional recommendations have been made forscreening this group of children after the neonatal period,however it is stated that “the increased risk of other eyeproblems including myopia, squint and cortical visual impair-ment should be remembered” [1]. This raises two key ques-tions, one, should all low birth weight children undergoscreening which is additional to that on offer to all UKchildren by 5 years of age, and two, should screening be

104 A. O'Connor, A.R. Fielder

targeted for a particular group within the low birth weightpopulation.

3.1. Are all preterms equally at risk of long termdeficits?

From the viewpoint of developing ophthalmic sequelae, thepreterm population is heterogeneous. To use limited healthservice resources efficiently it would be helpful to identify thosewho are at high risk of developing ophthalmic sequelae. Inaddition, when devising a surveillance programme it is im-portant to know the ages at which the conditions in questionemerge. For example, one risk factor analysis for ROP [36] founda number of factors that were positive predictors of thresholdROP which were maternal pre-eclampsia, birth weight, pul-monary haemorrhage, duration of ventilation and duration ofcontinuous positive airway pressure. Data from the CRYO-ROP[37] study were utilised to create a model to predict high risksevere ROP, however the factors used in this model varied withthe previous study.Whilst thismodelwas effective at identifyingcases that had an unfavourable outcome (36% of the high riskgroup) there were cases of unfavourable outcome not identifiedby this model (5%). These studies emphasise the multifactorialnature of ROP, which is only one of the conditions that can occurin preterm children so it would be extremely complex to createan accurate model which was sensitive enough to predict all ofthe long term ophthalmic deficits.

Children born prematurely fall into two broad groups:first, those who had either no or mild ROP (stage 1 or 2) andno clinically obvious neurological dysfunction and second,those who had severe ROP or suffered perinatal neurologicalinsults. Based on our experience the latter are likely alreadyto be under ophthalmic care, therefore additional examina-tions would not be required. However those in the formergroup who are likely to have been discharged from oph-thalmic care soon after the neonatal period still have anincreased risk of amblyopia/strabismus, refractive errorcompared to full term controls [38,39].

With the evidence presented above it could be argued thata targeted screening programme for children born prema-turely, in addition to the recommended orthoptic screening at4.5 to 5 years whose target conditions are strabismus,amblyopia and refractive error,would be beneficial. Currently,however, there is considerable variation in the screening of-fered to LBW children around the UK [33], with many childrenhaving no ophthalmic review at all. The key components ofscreening are: the type of assessment, the age at assessmentand the criteria for discharge. Whilst information regardingthe emergence of these ophthalmic conditions is incomplete itis not in doubt that they have a higher incidence. However, thequestion remains as to whether we have sufficient informationto devise a screening programme at this stage, or whetherfurther research is required before a recommendation onfollow up can be made.

There are many factors to be taken into account whendeveloping a screening programme as stated in “Health forAll Children” [1]. The key points to be addressed in assessingwhether additional vision screening is warranted are:

1. there should be a suitable test or examination which is:a. simpleb. valid for the condition in question

c. repeatabled. sensitive and specific

2. the natural history of the condition should be understood3. the cost of screening should be economically balanced in

relation to expenditure on the care and treatment ofpersons with the disorder and to medical care as a whole

4. case finding may need to be a continuous process and nota once and for all project, but there should be explicitjustification for repeated screening procedures.

Dealing with the first point there are a number of suitabletests of visual acuity but lowering the age from the recom-mended 4.5 to 5 years would reduce testability, sensitivity andspecificity. Therefore it may be advisable to alter the referralcriteria so as to avoid a large rate of false positives being re-ferred to specialist services.

An alternative approachwould be to identify the associationsof the reduced vision, for example strabismus and refractiveerrors, rather than assessing the vision directly. The cover test,which is used for the detection and identification of strabismus,probably does not suffer the same magnitude of reductionin testability etc found in visual acuity tests. However, purelyidentifying the presence of strabismus does not determinewhether the infant has a visual deficit, in addition detection of asmall angle strabismus (that will have the same aetiologicalconnotations and impact on vision, as a large deviation) can bevery difficult to detect, especially by non-ophthalmic trainedpersonnel. About 90% of children with amblyopia have arefractive error [40] so assessing refractive state, whether byretinoscopy or by automated-refraction would permit identifi-cation of these children. Whilst it is possible that some visualdeficits may bemissed using this approach these children wouldstill have their visual acuity assessed at 4.5 years.

As stated previously the natural history of the varioussequelae have yet to be fully clarified, but it is known that theyemerge at different ages from infancy to the early teens —which also applies to the full term population. Point threeraised by Health for All Children [1] also relies on under-standing the natural history, this is particularly pertinent interms of amblyopia treatment. It has been deemed appro-priate and safe to leave amblyopia untreated until the age of4.5 to 5 years in full term children. So without evidence toshow that low birth weight children respond differently toamblyopia treatment it is difficult to justify additional andearlier screening on the basis that there will be an improvedoutcome consequent upon earlier identification. This discus-sion has also addressed point four. However, the potentialimpact of uncorrected refractive errors on their education anddevelopment could validate earlier identification.

4. Summary

Whilst the current research studies differ in their inclusioncriteria, ethnicity, previous treatment for amblyopia, pre-valence of ROP and many other factors, they all highlight theincrease in refractive errors and amblyogenic factors in thelow birth weight population relative to children born at fullterm and of ‘normal’ weight.

This resulting question of whether additional long termophthalmic screening is required for this population isdebatable.

105Long term ophthalmic sequelae of prematurity

5. Key guidelines

• Inform parents of long term risks, particularly when ROPexam is normal

• Cautious interpretation of early VA results in the normalrange as they do not indicate that the visionwill continue tobe within normal limits

• When comparing visual acuities of preterm children tonormative data use age corrected for the degree ofprematurity

• Visual acuity of children born prematurely may neverreach 6/6, even when there is no pathology to account forthe deficit, although the deficit is rather subtle.

6. Research directions

• Visual development, does amblyopia respond differentlyto treatment in LBW children?

• Identification of the age at development of strabismus/refractive errors — to develop an effective targetedscreening programme

• Cause of amblyogenic factors, is it possible to predicttheir onset?

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