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Ocular Growth and Refractive Error Development inPremature Infants with or without Retinopathyof Prematurity

Anne Cook,1 Sarah White,2 Mark Batterbury,3 and David Clark4

PURPOSE. To study factors involved in the development ofrefractive error in premature infants with or without retinop-athy of prematurity (ROP).

METHODS. Premature infants in the national ROP screeningprogram were recruited and examined longitudinally between32 and 52 weeks postmenstrual age. Axial length (AL), ante-rior chamber depth (ACD), and lens thickness (LT) were mea-sured on the A-scan biometer. Corneal curvature was recordedwith video-ophthalmophakometry and refractive state was de-termined with routine cycloplegic retinoscopy. Multilevelmodeling techniques were used to study relationships betweenall the variables and stage of ROP throughout the study period,as well as individual growth rates.

RESULTS. One hundred thirty-six infants were included. AL andACD showed linear patterns of growth, whereas LT changedlittle over the study. Corneal curvature showed quadraticgrowth patterns in infants unaffected by ROP, but showedlinear growth if ROP developed. Corneal curvature correlatedwell with refractive state. Most infants were myopic at the startof the study, became emmetropic around term, and werehypermetropic toward the end of the study. However, the eyesthat were treated for ROP showed little change in refractiveerror; with significantly less hypermetropia by the end of thestudy.

CONCLUSIONS. Eyes of premature infants have shorter axiallengths, shallower anterior chambers, and more highly curvedcorneas than eyes of full-term infants. These differences be-come more significant as the severity of ROP increases. Prema-ture eyes develop less of the expected hypermetropia in full-term eyes, mainly due to differences in ACD and cornealcurvature. These differences are most significant in eyes thatreceive laser treatment for ROP. (Invest Ophthalmol Vis Sci.2008;49:51995207) DOI:10.1167/iovs.06-0114

Myopia has been classified by the World Health Organiza-tion (WHO) as one of the leading causes of blindness andvisual impairment in the world today.1 The prevalence ofmyopia varies, depending on age at examination, family his-tory,2,3 ethnicity,2 and occupation.4

Environmental factors, genetic factors, premature birth, andthe development of retinopathy of prematurity (ROP) are allknown to be associated with the development of a specificform of myopia.

Although there is a wealth of data on the development ofmyopia with ROP, few studies have prospectively documented

changes in ocular growth along with alterations in refractiveerror during the earliest measurable weeks of premature life.Most studies commence after 3 months corrected age, and fewprospectively record changes in all the biometric componentsand refractive error simultaneously.

Our previous publication5 documented all such parametersin premature infants without ROP. The purpose of this study isto look prospectively at premature infants affected by ROPduring the early phases of ocular growth and to identify factorscontributing to refractive status at this time. It is hoped thatcomparing this group with a cohort without ROP who werestudied at the same time may add to the existing knowledge ofthe factors that affect emmetropization after premature birth.

METHODSThis cohort of infants was recruited from the neonatal intensive care

unit of Liverpool Womens Hospital. Regional ethics committee ap-

proval and parental consent were obtained. The infants examined

included those falling within the screening criteria for the ROP screen-

ing program: infants born before 32 weeks gestational age and/or

infants with birth weight below 1500 g.

Any infant too unfit for the examination necessary for the study was

excluded. Infants were examined longitudinally at 32 (time point

[T]1), 36 (T2), 40 (T3), 44 (T4), and 52 (T5) weeks postmenstrual age.

These time points were deliberately chosen to be adequately spaced

without interfering with or delaying the usual ROP examinations.

Descriptions of the measurement methods follow. All methodology

adhered to the tenets of the Declaration of Helsinki.

Biometry

Axial length (AL), anterior chamber depth (ACD), and lens thickness

(LT) were measured with an A-scan biometer (Carl Zeiss Meditec,

Oberkochen, Germany), which was calibrated using the technique

described by Butcher and OBrien.6 The method involves applanation

of the cornea with the A-scan probe after the instillation of the topical

anesthetic benoxinate hydrochloride 0.4%. The probe is placed lightly

on the center of the cornea, perpendicular to its axis. It is maintained

in this position until three clear traces are obtained on the screen. The

average value from the three best images is recorded for all axial

dimensions. (Posterior segment length [PSL] was calculated by sub-

From the 1Manchester Royal Eye Hospital, Manchester, UnitedKingdom; the 2Division of Mental Health, University of London, Lon-

don, United Kingdom; the 3St. Pauls Eye Unit, Royal Liverpool Univer-sity Hospital, Liverpool, United Kingdom; and the 4University Hospital

Aintree, Foundation Trust, Liverpool, United Kingdom.Supported by The Iris Fund for the Prevention of Blindness.Submitted for publication February 2, 2006; revised June 28 and

November 30, 2006, April 18 and September 21, 2007, and January 14and April 2, 2008; accepted October 21, 2008.

Disclosure: A. Cook, None; S. White, None; M. Batterbury,None; D. Clark, None

The publication costs of this article were defrayed in part by pagecharge payment. This article must therefore be marked advertise-ment in accordance with 18 U.S.C. 1734 solely to indicate this fact.

Corresponding author: Anne Cook, Manchester Royal Eye Hospi-tal, Oxford Road, Manchester, M13 9WH UK; [email protected]

Investigative Ophthalmology & Visual Science, December 2008, Vol. 49, No. 12

Copyright Association for Research in Vision and Ophthalmology 5199

A R T I C L E S

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tracting the sum of ACD and LT from AL, and the result was checked

with the printed scan.)

Corneal Curvature

The corneal curvature (CC) was measured with a video-based kerato-

phakometer, previously described by Wood et al.7 The unit consists of

a camera coupled to a video recorder. The camera has a Perspex

faceplate that has illuminating infrared LEDs distributed around its

perimeter. The mires are focused around the infants cornea and theimage is captured on the video recorder for later analysis of CC. The

camera was calibrated with a series of stainless-steel ball bearings of

known radius of curvature at the start of each session.

Spherical Equivalent

Full cycloplegic retinoscopy was performed with a streak retinoscope,

30 minutes after the administration of 0.5% cyclopentolate and 2.5%

phenylephrine. All refraction was performed by the same examiner

(AC), with intermittent verification by the optometrist at University

Hospital Aintree, to ensure accuracy. Handheld lenses were used to

enable the examiner to ensure that the streak was kept on axis. The

procedure proved to be relatively simple as, given the infants age,

ocular movements were minimal during the refraction. An allow-

ance of 1.5 D was made for a working distance of 23 m. Refractive

error was recorded in the form of spherical equivalent (SE): SE

Sphere Cyl/2.

Retinopathy of Prematurity

All infants were screened by the same examiner (DC) who has 16

years experience in screening premature infants. After instillation of

an additional drop of benoxinate hydrochloride 0.4%, a lid specu-

lum was placed gently between lids. Scleral indentation was then

performed to allow examination of the far periphery. ROP grading

was performed according to The International Classifi cation of

Retinopathy of Prematurity.8 All treatme nts were performed with a

Diode laser.

Statistical Analysis

Analysis of the refractive and biometric data from 44 pairs of eyes

showed no significant difference between the right and left eyes (t

0.722, P 0.474), with a mean difference 0.018 (95% CI, 0.033

0.069). On average, the difference in AL between pairs of eyes was

only 0.018 mm. For this reason, the right eye of each infant was used

for further data analysis.

One-way analysis of variance was used to test whether stage of ROP

was related to gestational age at birth and birth weight. Comparison of

the stages of ROP at 3 months post term in term infants of the

biometric parameters (AL, ACD, LT, and CC) was also made in this

manner. Post hoc pair-wise comparisons were performed with Bonfer-

roni correction.

The relationship between stage of ROP, ocular growth, and refrac-

tive error was examined using multilevel modeling for repeated mea-

sures. This method was chosen as different observations in the samechild are not independent, and simple regression analysis would not

correct for the lack of independence between observations. Many

methods of analyzing longitudinal data require the same number of

measurements to be collected from every subject (e.g., repeated-

measures ANOVA), and for each subject to attend at every time period.

In a clinical setting, this would have been unrealistic. Therefore this

more appropriate analytical technique was used.

Multilevel regression models (using PROC MIXED in SAS ver. 8.1;

SAS, Cary, NC, for SunOS; Sun Microsystems, Santa Clara, CA) were

used to look at how stage of ROP and postmenstrual age are related to

AL, ACD, LT, CC, and refractive error (RE). The biometric parameters

were regressed against postmenstrual age (weeks) to allow for the

unequally spaced time intervals between examinations.

Models were first fitted for infants at all stages of ROP. In this way,

differences between stages of ROP could be examined, as well as a

comparison of the growth rates between stages by including the

interaction term of stage of ROP and postmenstrual age. The multilevel

regression methodology allowed for the fitting of a linear relationship

or a quadratic relationship with postmenstrual age, depending on the

growth curve exhibited. The method was decided on by testing the

significance of a quadratic term in each model to explore whether the

parameter estimate for the quadratic term differed significantly from 0

at the 5% significance level, after the linear term was fitted.

TABLE 1. Gestational Age and Birth Weight for Each Stage of ROP

Stage

Gestation at Birth Birth Weight

n Mean (SD) n Mean (SD)

0 67 29.4 (1.87) 66 1256.9 (334.99)1 19 28.1 (1.63) 19 1042.4 (270.82)2 26 26.7 (1.73) 25 903.1 (230.07)3 12 27.0 (2.30) 12 944.3 (297.16)3 12 26.4 (2.05) 12 769.3 (170.89)Overall 136 28.2 (2.23) 134 1088.8 (340.37)

TABLE 2. Gestational Age and Range with Total Number of InfantsExamined at Each Time Point

TimePoint

Gestational Age (wk)

Range (wk)MinMaxn Mean

T1 107 32.84 30.7134.50T2 113 36.23 34.0038.86

T3 120 40.34 36.0042.71T4 115 44.63 42.0055.00T5 90 53.48 48.0062.00

TABLE 3. Ocular Parameters at Term (Intercept) According toStage of ROP

Parameter StageIntercept

(SE) Slope (SE)

Axial length (mm) 0 16.66 (0.04) 0.159 (0.004)1 16.51 (0.08) 0.151 (0.007)2 16.45 (0.08) 0.162 (0.001)3 16.63 (0.13) 0.172 (0.013)3 16.37 (0.13) 0.120 (0.011)

Anterior chamber 0 2.26 (0.02) 0.041 (0.002)depth (mm) 1 2.24 (0.05) 0.037 (0.005)

2 2.17 (0.04) 0.033 (0.004)3 2.18 (0.05) 0.046 (0.005)3 2.14 (0.03) 0.027 (0.005)

Posterior segment 0 10.47 (0.044) 0.113 (0.004)

length (mm) 1 10.35 (0.077) 0.113 (0.007)2 10.28 (0.066) 0.123 (0.008)3 10.47 (0.127) 0.122 (0.013)3 10.18 (0.121) 0.084 (0.009)

Lens thickness (mm) 0 3.93 (0.018) 0.006 (0.002)1 3.93 (0.043) 0.002 (0.002)*2 3.99 (0.028) 0.003 (0.003)*3 4.02 (0.029) 0.004 (0.004)*3 4.04 (0.030) 0.005 (0.005)*

Spherical equivalent (D) 0 0.009 (0.20)* 0.240 (0.016)1 0.355 (0.34)* 0.161 (0.021)2 0.466 (0.28)* 0.176 (0.026)3 0.277 (0.48)* 0.169 (0.034)3 0.912 (0.69)* 0.006 (0.051)*

* Nonsignificant parameter change (i.e., slope or intercept 0).

SE, standard error.

5200 Cook et al. IOVS, December 2008, Vol. 49, No. 12

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Appropriate models were thus found for the biometric parameters

and refractive state. Next, each model was refitted with sex as the

variable, to identify whether, at this early stage of ocular development,

there was any effect of sex on ocular growth. In addition, gestation at

birth and birth weight were included in the models to investigate

whether differences between stages of ROP were still present when

these confounders were included.

Additional analyses explored the following relationships between

AL, stage of ROP, and refractive error; between ACD, stage of ROP, and

refractive error; between LT, stage of ROP, and refractive error; andbetween CC, stage of ROP, and refractive error. In all cases, after

adjustment for postmenstrual age, a significance level of 5% was as-

sumed in the models.

Estimates of the intercept a (value at term) and slope coefficient b

(rate of growth) of the fitted relationship are presented with their

standard errors for each stage of ROP (Table 3). These estimates were

calculated by fitting a model for each stage separately. The slope

parameter in a linear model (i.e., linear growth rate) indicates the rate

of change (the number of millimeters of change per week). Where a

quadratic term is included in the model, the coefficient is indicated by

how much the rate of change is changing. To find the predicted value

of a parameter y at a given postmenstrual age x, given the intercept a,

the slope coefficient b, and quadratic term c

y a b x 40 c x 40 2

For a linear relationship, the last part of the equation is excluded.

All statistical analyses were performed with commercial software(SPSS ver. 12 for Windows; SPSS, Chicago, IL, and SAS v. 8.1; SAS, for

SunOS; Sun Microsystems).

RESULTS

A total of 136 infants were recruited. Sixty-seven did notdevelop ROP. Nineteen developed stage 1, 26 stage 2, and 12stage 3, and 12 developed threshold disease and received lasertreatment (stage 3).

Birth weight and gestational age vary significantly accordingto stage of ROP (F 12.3, P 0.001 and F 15.4, P 0.001),respectively. Post hoc analysis shows that for both gestationand birth weight, stage 0 is significantly different from all other

stages, with longer average gestation and higher birth weight.The other stages do not differ significantly from each other.Summary statistics for these variables are shown in Table 1,with age ranges at each examination and by stage of ROP inTable 2, model parameter estimates in Tables 3 and 4, andsummary data of the parameters presented in Table 5.

Of the total 136 infants, 99 had complete data sets collectedat 32 weeks, 111 at 36 weeks, 116 at 40 weeks, 112 at 44weeks, and 91 at 52 weeks. In addition, 46 had complete datasets for all five time points, 43 were complete for four, 36 for

TABLE 4. Corneal Curvature at Term (Intercept) According toStage of ROP

Stageof ROP n

Intercept(SE) (mm) Slope (SE) Slope 2 (SE)

0 67 6.87 (0.03) 0.095 (0.004) 0.0034 (0.0005)1 19 6.55 (0.06) 0.079 (0.006)*2 26 6.54 (0.06) 0.070 (0.005)*3 12 6.75 (0.11) 0.072 (0.011)*3 12 6.58 (0.18) 0.060 (0.009)*

* Nonsignificant parameter change (i.e., slope or intercept 0).SE, standard error.

TABLE 5. Summary Statistics, at Each Time Point, for Each Stage of ROP

Parameter StageT1

(32 wk)T2

(36 wk)T3

(40 wk)T4

(44 wk)T5

(52 wk)

AL (mm) 0 15.4 (0.42) 16.1 (0.45) 16.8 (0.46) 17.4 (0.48) 18.6 (0.54)1 15.2 (0.33) 16.1 (0.37) 16.6 (0.61) 17.2 (0.55) 18.6 (0.39)2 15.1 (0.50) 15.8 (0.44) 16.7 (0.51) 17.2 (0.57) 18.6 (0.75)3 15.3 (0.51) 16.2 (0.63) 16.8 (0.44) 17.4 (0.56) 18.8 (0.82)3 14.9 (0.38) 15.9 (0.50) 16.4 (0.40) 16.9 (0.65) 18.2 (1.1)

ACD (mm) 0 2.0 (0.19) 2.1 (0.32) 2.3 (0.19) 2.4 (0.23) 2.8 (0.25)1 2.1 (0.38) 2.1 (0.24) 2.2 (0.23) 2.3 (0.22) 2.8 (0.25)2 2.0 (0.19) 2.0 (0.21) 2.2 (0.20) 2.3 (0.34) 2.7 (0.35)3 1.9 (0.29) 2.0 (0.38) 2.2 (0.28) 2.4 (0.18) 2.8 (0.21)3 2.0 (0.05) 2.0 (0.17) 2.1 (0.11) 2.3 (0.25) 2.5 (0.29)

PSL (mm) 0 9.6 (0.43) 10.1 (0.46) 10.6 (0.45) 11.0 (0.45) 11.8 (0.54)1 9.3 (0.54) 10.0 (0.28) 10.5 (0.43) 10.9 (0.51) 11.9 (0.42)2 9.3 (0.39) 9.8 (0.33) 10.4 (0.38) 10.8 (0.48) 11.9 (0.58)3 9.9 (1.29) 10.1 (0.40) 10.6 (0.44) 11.0 (0.64) 12.1 (0.93)3 9.1 (0.33) 9.8 (0.43) 10.2 (0.43) 10.6 (0.53) 11.4 (0.86)

LT (mm) 0 3.8 (0.22) 3.9 (0.18) 4.0 (0.19) 4.0 (0.22) 4.0 (0.21)1 3.8 (0.23) 4.0 (0.15) 4.0 (0.27) 4.0 (0.15) 3.9 (0.19)2 3.9 (0.33) 4.0 (0.21) 4.0 (0.14) 4.1 (0.26) 4.0 (0.14)3 4.0 (0.14) 4.1 (0.14) 4.0 (0.29) 4.0 (0.19) 3.9 (0.17)3 3.9 (0.00) 4.0 (0.11) 4.1 (0.11) 4.1 (0.21) 4.1 (0.31)

Refraction (D) 0 2.1 (2.27) 1.2 (2.17) 0.74 (1.83) 1.9 (1.76) 2.1 (1.25)1 2.1 (2.19) 1.2 (2.15) 0.07 (1.67) 0.93 (1.22) 1.4 (1.10)2 2.0 (2.72) 1.4 (1.98) 0.03 (1.74) 0.60 (2.18) 1.7 (1.52)3 1.6 (2.01) 1.5 (2.22) 0.55 (1.71) 0.80 (2.34) 1.3 (2.03)3 2.9 (4.27) 0.12 (3.62) 1.6 (2.25) 0.90 (1.56) 0.65 (2.60)

CC (mm) 0 6.1 (0.41) 6.4 (0.24) 6.9 (0.24) 7.2 (0.28) 7.6 (0.31)1 5.9 (0.34) 6.2 (0.26) 6.8 (0.23) 7.1 (0.29) 7.5 (0.36)2 5.9 (0.30) 6.3 (0.28) 6.6 (0.39) 7.0 (0.48) 7.5 (0.17)3 5.7 (0.23) 6.5 (0.48) 6.9 (0.44) 7.2 (0.24) 7.5 (0.26)3 4.9 (0.00) 6.2 (0.18) 6.7 (0.44) 7.1 (0.34) 7.3 (0.31)

Data are expressed as the mean (SD).

IOVS, December 2008, Vol. 49, No. 12 Infant Eye Growth and Refractive Error Development 5201

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three, 6 for two, and 5 for one. Overall, 125 infants hadcomplete data sets for three or more time points, illustratingthe longitudinal nature of the study. Five infants died after thestudy period; four of these had reached a maximum stage 2ROP, and one had reached stage 3 and had received lasertreatment. The number of valid data points for each parameterat each time point is presented in Table 6.

AL showed a linear growth throughout the study period.Values differed significantly between stages of ROP (F 2.72,P 0.033). In addition, growth rates also differed significantlybetween the stages (F 3.30, P 0.014).

As the stage of ROP increased, the average AL decreased(Tables 3, 5; Fig. 1). The values for stage 3 did not fit thegeneral trend, perhaps because of the small sample and thehigher SEM of this group.

Average ACD differed little between stages of ROP (F 2.24, P 0.068). In addition, growth rates did not differ (F 2.27, P 0.068). As the stage of ROP increased, however, theaverage ACD decreased, and the slope (i.e., the growth rate)also decreased. Stage 3 infants had the shallowest anteriorchambers, which grew at the slowest rate (Tables 3, 5; Fig. 2).

There was evidence that PSL differs between stages of ROP,as the more severe stages showed shorter posterior segments(F 2.73, P 0.0319). In addition, growth rates differed,slowing down as the severity of ROP worsened (F 2.73, P 0.0331; Tables 3, 5).

Average LT did not vary significantly between stages of ROP(F 2.16, P 0.077). In addition, growth rates did not differsignificantly (F 1.32, P 0.267). There was very littleevidence of any change in LT with time among all the groups(Tables 3, 5).

The average CC differed significantly between stages ofROP (F 4.64, P 0.002), but the growth rates did not differ

(F 0.46, P 0.761)that is, all slopes remained parallel.Throughout the study, stage 3 eyes show consistently smallerradii of curvature than in all the other groups (Table 4, Fig. 3).

A quadratic term was found to be appropriate for stage 0eyes, but could not be fitted for the higher stages, perhapsbecause of the smaller sample sizes. The coefficient for thequadratic effect is negative, indicating that the growth rate wasslowing down.

When all the biometric variables were fitted against refrac-tion, CC was found to be the most significant contributor (F 35.48, P 0.0001).

Stages 1, 2, and 3 showed similar rates of change of refrac-tive error throughout the study, although as severity of diseaseincreased, rates slowed down slightly. However, in stage 3eyes, refractive error changed very little up to 3 monthscorrected age. This explains why they showed the leastamount of hypermetropia by the end of the study (Tables 3, 5;Fig. 4). Throughout the study, the average refractive error didnot differ significantly between stages of ROP (F 1.43, P 0.229), although the rate of change did (F 7.69, P 0.0001).

TABLE 6. Minimum and Maximum Number of Observations Contributing to Each Parameter at Each Examination by Stage

StageT1

MinMaxT2

MinMaxT3

MinMaxT4

MinMaxT5

MinMax

Biometric parameters and refraction (n) 0 5458 5253 5455 5354 381 1415 1618 16 14 142 2122 24 24 22 133 78 1011 13 14 12133 23 7 12 12 1112

CC (n) 0 33 44 50 47 271 14 11 11 6 122 13 12 15 13 113 4 7 11 10 103 1 3 7 8 8

FIGURE 1. Changes in AL with age.


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The average fitted values for refractive error at term do notdiffer significantly from 0.

Adjustments for Gestational Age and Birth Weight

As mentioned, gestational age and birth weight differ betweenstages of ROP, particularly in stage 0 compared with the otherstages. Thus, it was thought important that the effect of gesta-tional age and birth weight be added to the model to assesstheir association on the parameters of interest. When addinggestational age and birth weight the following occurs.

There was no significant difference in AL values betweenthe different stages of ROP (F 1.97, P 0.102). However,growth rates differed between stages of ROP (F 3.3, P

0.014; Fig. 1). Both gestational age and birth weight werefound to be significant in this model.

For ACD, there was no significant difference in the averagevalue between stages of ROP early on in the study (F 0.79,P 0.533), although there is still some suggestion that thegrowth rates differed between stages (F 2.4, P 0.056; Fig.2). By 3 months, however, a significant difference existed

between the stages of ROP (F 2.55, P 0.045; Table 7, Fig.2). Again, both gestational age and birth weight were signifi-cant in this model. Post hoc analysis indicates that stage 0 andstage 3 differed significantly.

Neither gestational age nor birth weight altered the modelfor LT.

For CC, birth weight exerted a significant effect in themodel. There was no difference in the average value be-tween stages of ROP (F 2.32, P 0.062). Similarly, therewas no difference between the growth rates in the stages ofROP (Fig. 3).

Birth weight had a significant effect on refractive errordevelopment. Throughout the overall time course of the study,there was no difference in the average values between the

stages of ROP (F 1.65, P 0.166), but the significantdifference in growth rates still existed (F 7.09, P 0.0001).However, by 3 months corrected age, a difference emergedbetween stage 0 and treated (3) eyes (F 2.16, P 0.008;Table 7, Fig. 4).

When sex was fitted to the models, there were no signifi-cant differences between the sexes at this early stage.

FIGURE 2. Changes in ACD withage.

FIGURE 3. Changes in CC with age.


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DISCUSSION

Simple cross-sectional studies comparing premature with full-term infants have revealed that premature infants are moreprone to development of myopia from an early age and mayremain myopic later on in childhood and adolescence. This isknown as myopia of prematurity,914 and it can continue toincrease up to 2 years of age.15,16

Low birth weight and ROP have long been known to beimplicated in the development of myopia, astigmatism, andanisometropia.13,14,1720 The risk of myopia at 12 months ofage has been shown to double with each increasing stage ofthe disease, with a birth weight of less than 751 g contributingto a threefold increase in the risk of developing myopia.15

Fledelius has contributed much to our knowledge of theassociation between myopia and ROP and its treat-ment.10,12,21,22 Still, it is notoriously difficult to differentiatebetween the effects of disease and the effects of treatment.Eyes that develop more severe ROP are the ones more likely toneed treatment, and both these factors are known to have aneffect on ocular growth. Thus, treated infants have higherincidences of myopia than nontreated infants.16,23,24 The inci-dence of myopia ranges from 1% to 16% in eyes with stage 0disease.16,25,26 If mild ROP is present, this incidence rangesfrom 17% to 50%,1517,25 increasing in some publications up to100% in eyes with stage 3 disease.16

The most comprehensive prospective data come from theCRYO-ROP series of publications.16,17,27 In eyes randomized tono treatment, there was found to be an overall incidence ofmyopia of 21% at 1 year, falling to 16% at 4.5 years of age. Theincidence of myopia in eyes with stage 0 disease was 10%; in

eyes with spontaneously regressed ROP, 20%; and in eyes withsevere ROP and sequelae, 80%.

Extensive comparisons have also been made between thetwo main treatment modalities. Of those eyes receiving treat-

ment, those treated with cryotherapy show an increase in boththe incidence and degree of myopia compared to laser-treatedeyes.2836

The biometric components that have been shown to con-tribute to this refractive error include a shallower ACD,21

increased lens power,14 increased CC,21,37,38 and a shorteroverall AL than would be expected for the dioptric value of theeye.21,37 Later on, reports of increased PSL are noted.28,39 Itseems that the early effect of growth restriction associatedwith ROP is followed later by a deregulation of ocular growthwithin the posterior segment.

Our finding that AL displays a linear growth agrees with thefindings of others. Although Tucker et al.40 found the averagegrowth rate to be 0.3 mm/wk over their study period, Laws et

al.35 and Harayama et al.41 found more similar rates of growth(0.18 and 0.19 mm/wk, respectively) to our own (0.152 mm/wk).

In addition, average values for AL agree with other pub-lished data. Our value for stage 0 eyes at term of 16.84 mmcompares well with that of Laws et al.35 (16.65 mm), Tucker etal.40 (16.6 mm), and OBrien and Clark42 (16.73 mm).

The finding that AL changes at this early time period areinversely proportional to the severity of ROP concurs withothers,20,35 such that the shortest ALs are seen in eyes thathave been treated.

When the effects of gestational age and body weight wereremoved, the difference in ALs in each stage of ROP wasreduced. This finding is not so surprising when one considers

that others have found no difference in AL between the stagesof ROP, except in eyes with more severe ROP or that have

FIGURE 4. Changes in refractive er-ror with age.

TABLE 7. Comparison of Ocular Parameters at 3 Months Post-Term by Stage of ROP

ParameterStage 0n 38

Stage 1n 14

Stage 2n 13

Stage 3n 12

Stage 3n 12

AL (mm) 18.6 (0.54) 18.6 (0.39) 18.6 (0.75) 18.8 (0.82) 18.2 (1.08)ACD (mm) 2.8 (0.25) 2.8 (0.25) 2.7 (0.35) 2.8 (0.21) 2.5 (0.29)LT (mm) 4.0 (0.21) 3.9 (0.19) 4.0 (0.14) 3.9 (0.17) 4.1 (0.31)PSL (mm) 11.8 (0.54) 11.9 (0.42) 11.9 (0.58) 12.1 (0.93) 11.4 (0.86)Refraction (D) 2.12 (1.25) 1.43 (1.10) 1.73 (1.52) 1.30 (2.03) 0.65 (2.60)CC (mm) 7.6 (0.31) 7.5 (0.36) 7.5 (0.17) 7.5 (0.26) 7.3 (0.31)

Data are expressed as the mean (SD).


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undergone treatment.20,28,35 In addition, their studies mea-sured values at times later than those in our study, when anydifferences may be expected to be greater.

ACD changed very little relative to AL as a whole (Table 8).This may explain why ACD is not strongly associated withrefractive error during this early time period.

Kent et al.28 found the shallowest anterior chambers in thetreated eyes, especially the cryotherapy group. Their resultsagree with this study, although values are not directly compa-rable due to differences in age at examination.

CC underwent a greater degree of change during this earlytime period than did the other variables, and exerted more of

an influence on refractive error. The relationship betweensteeper CC and more severe ROP has been known for a longtime.43 Our data for CC at term (6.87 mm for stage 0) comparewell with those of Inagaki44 taken at 38.3 weeks (6.8 mm). Sniret al.38 measured eyes with mild regressed ROP at term as 6.84mm (49.45 D). Their result compares with an average value of6.65 mm in eyes with stage 2 or less in our study. Blomdahl45

measured full-term infants at 2 to 4 days after birth, and hisresult of 7.0 mm highlights the difference between prematureand full-term eyes.

When each variable is studied as a proportion of the totalAL, as time goes by, some interesting trends emerge (Table 8).ACD increases as a proportion of AL throughout the studyperiod. However, the tendency for it to do so is much less inthe eyes that have been treated with the laser (13%13.7% in

stage 3 eyes, compared with 13.6%15.1% in stage 0 eyes).Refractive error changes show that by 3 months postmen-

strual age, stage 3 eyes have less hypermetropia than at otherstages, with the difference being greater in the treated eyes.The finding that only insignificant differences exist betweenthe milder stages has been reported previously.20,26

At 3 months, treated eyes showed an average value of0.648 D, which is less myopic than Laws and Clark33 foundat the same time (3.25 D). However, two points should beborne in mind. First, there is a time difference between thesetwo studies of 3 to 4 years. During this time, there have beenadvances in neonatal care and outcomes. This may well havean influence on the growth of the eye at this early time.Second, one of the infants (infant A) who received laser treat-ment in this study group showed consistently high levels ofhypermetropia throughout the study period. When this case

was analyzed in more detail, interesting differences were re-vealed (Table 9).

It is apparent that this infant was born relatively early, withvery low birth weight. The AL was significantly shorter thanaverage for the group of treated eyes. More specifically, theanterior chamber was very much shallower than that of therest of the group. CC and LT did not differ significantly. Theformer differences could quite conceivably account for therefractive error discrepancy. If the value for this infant isremoved from the data, the average value for refractive error isless hypermetropic (0.24 D) for treated eyes at 3/12 cor-rected age.

The refractive status of this cohort of infants can be com-pared with those of full-term infants at similar ages (Table 10).There is consistently less hypermetropia noted at term inpremature infants, with or without ROP, when compared withfull-term infants. By 3 months corrected age, this difference ismuch less in those premature eyes without ROP. Eyes withROP, however, still maintain less hypermetropia than full-termeyes by the end of the study period.

Figure 5 shows the frequency distribution of refractiveerror for the subgroup of eyes without ROP from this studyat 3 months corrected age. These data have been comparedwith data from two othe r studies. The data from Mayer etal.46 consist of data from full-term eyes. The data from Quinnet al.17 include only those eyes without ROP. The graphhighlights the similarity of the data sets at 3 months; con-

firming the attempt at emmetropization by premature eyeswithout ROP.

The exact cause of the alteration in refractive error de-velopment associated with ROP is not fully understoo d. In1955, Birge13 recognized that children who had been bornprematurely developed a more severe form of myopia thanthe usual developmental type of refractive error. He refer-enced the earlier work by Szewczyk18 and Ryan in 1952,47

who looke d at the role of oxygen in premature birth, andpostulated that the sudden withdrawal of oxygen precipi-tated a vascular crisis that affected the vascularity of thechoroid, resulting in myopia.

Fielder48 later postulated that the ROP lesion, being locatedin the part of the eye undergoing maximum growth during latefetal and early neonatal life, may exert a mechanical effect onthe anterior sclera and anterior segment. This would fit with

TABLE 9. Infant A Data Compared with the Stage 3 Group Average

Variable Infant A Average Stage 3 Eye

Gestational age (wk) 25 26Birth weight (g) 680 769

AL (mm) 17.13 18.16ACD (mm) 2.46 2.53LT (mm) 4.07 4.09CC (mm) 7.2 7.3

Infant born very early with very low birth weight. Showed con-sistent hypermetropia compared to rest of group 3. The anterior

chamber was very shallow.

TABLE 8. Proportion of AL for Each Variable at Each Stage

Proportion of AL at Term (%) Proportion of AL at 3/12 Corrected Age (%)

0 1 2 3 3 0 1 2 3 3

ACD 13.6 13.6 13.2 13.1 13.0 15.1 15.1 14.5 14.9 3.7LT 23.6 23.6 23.8 24.3 24.7 21.3 21.1 21.3 20.8 2.5PSL 62.9 62.9 62.5 62.9 62.2 63.6 63.9 64.2 64.3 2.9

TABLE 10. Comparison of Refractive Errors in Premature andFull-Term Eyes at Term and 3 Months

StudySE at Term

(D)SE at 3/12

(D)

This study Stage 1 0 2.12Stage 3 0.9 0.65

Blomdahl45 3.6Wood et al.7 0.5Mayer et al.51 2.2 2.44Kent et al.28 2.75

SE, spherical equivalent.


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the fact that the axis of astigmatism is seen to rotate as ROPseverity increases,20 and with the theory of anterior segmentgrowth arrest, of which the hallmark is a shallower anteriorchamber, and more highly curved cornea.

It is clear that the present study supports the theory ofanterior segment growth arrest, as eyes with more severe ROPdeveloped shallower anterior chambers with more highlycurved corneas. Gestational age and birth weight clearly bothhave an early effect on ocular growth, but they do not explainall the differences in the growth rates of the biometric variablesand refractive error demonstrated by this study. Retinopathy ofprematurity itself appears exert an influence on the growth ofthe eye at this early stage of development. Also significantduring this early time period is the effect that treatment for

ROP may be starting to demonstrate. It is important to con-sider, however, that there may be other environmental factorsstill unaccounted for that affect ocular development at such asensitive time.

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