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Developmental outcome in preterm infants <29 weeks gestation with ⩽ Stage 3 retinopathy of prematurity (ROP): relationship to severity of ROP

Published online by Cambridge University Press:  05 January 2012

D.A. Todd ,
T-A. Goyen ,
J. Smith  and
M. Rochefort
D.A. Todd*
Affiliation:
Centre for Newborn Care (CNC), Canberra Hospital, Woden ACT 2606, Australia
T-A. Goyen
Affiliation:
CNC, Westmead Hospital, Westmead, NSW 2132, Australia
J. Smith
Affiliation:
Department of Ophthalmology, Westmead Hospital, Westmead, NSW 2132, Australia
M. Rochefort
Affiliation:
CNC, Westmead Hospital, Westmead, NSW 2132, Australia
*
*Address for correspondence: Dr D.A. Todd, Centre for Newborn Care, Canberra Hospital, Woden ACT 2606, Australia. (Email david.todd@act.gov.au)
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Abstract

We have determined the influence of the severity of retinopathy of prematurity (ROP) on development at 3 years of age in infants <29 weeks gestation from a population-based cohort. Primary analysis of surviving infants born <29 weeks gestational age (GA) from 1998 to 2001 in New South Wales and the Australian Capital Territory were grouped according to stage of ROP. Infants with periventricular leukomalacia, Grade III or IV intraventricular haemorrhage, hydrocephalus, major congenital abnormalities, Stage 4 or 5 ROP, cerebral palsy or a severe hearing impairment were excluded. Infants with Stage 3 ROP were matched for GA, birthweight and gender to those with no ROP, Stage 1 and Stage 2 ROP. The four groups were then compared for their 3-year-old developmental outcome, using the Griffiths Mental Development Scale. Development was also compared for those infants with Stage 3 ROP who were either treated or not treated with laser therapy. A secondary multivariate regression analysis on developmental outcome was performed with all infants included in the analysis. In neurologically comparable groups and in the multivariate analysis, there was no association between ROP and developmental outcome. There was also no difference in the Griffiths assessment at 3 years between those who were or were not treated for severe ROP. Neither severity of ROP nor treatment for severe ROP were related to developmental outcome at 3 years of age in a large population-based cohort of infants born <29 weeks gestation.

Keywords

childdevelopmental outcomeretinopathy of prematurity
Type
Original Articles
Information
Journal of Developmental Origins of Health and Disease , Volume 3 , Issue 2 , April 2012 , pp. 116 - 122
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012

Introduction

Preterm infants are at high risk of developing later neurodevelopmentalReference Vohr, Wright and Dusick 1 – Reference Saigal, Szatmari and Rosenbaum 3 and ophthalmological problems.Reference Shapiro, Yanko, Nawratzki and Merin 4 – Reference Keith and Kitchen 8 Retinopathy of prematurity (ROP) is a complication of prematurity that is caused by the disruption of the growth of blood vessels to the developing retina in preterm infants. It is a progressive disease and may progress from mild ROP (Stage 1) to moderate ROP (Stage 2) to severe ROP (Stage 3), that may develop a partial retinal detachment (Stage 4) and then to total retinal detachment with profound loss of vision (Stage 5). 9 We have shown an increase in moderate–severe ROP (Stage 3 ROP) and an increase in those treated for ROP in New South Wales (NSW) and the Australian Capital Territory (ACT) from 1992 to 2002.Reference Todd, Wright, Byth and Smith 11 Prematurity and ROP are associated with visual deficits, including strabismus, myopia and lowered contrast sensitivity.Reference Pennefeather, Clarke and Strong 12 – Reference Ricci 14 Yet, little is known about the impact of ROP on developmental outcome.

In a hospital cohort, we have reported a trend towards poorer developmental outcome at 3 years for infants with moderate–severe (Stage 3) ROPReference Goyen, Todd and Veddovi 15 in neurologically comparable groups with mild (Stages 1 and 2) and no ROP. Others have similarly found that severe ROP is associated with developmental outcome.Reference Bowen, Starte and Arnold 16 – Reference Msall, Phelps and DiGaudios 18 As a greater number of smaller preterm infants are now being resuscitated and surviving and treated for severe ROP,Reference Todd, Wright, Byth and Smith 11 it is important to determine the influence of the severity of ROP on later development. We hypothesized that the initial stage of ROP would have a significant impact on developmental outcome specifically with regard to eye–hand coordination. We also postulated that treatment for ROP with laser therapy would have a significant impact on developmental outcome.

The aim of this study was to determine the influence of the severity of ROP and treatment for severe ROP on development at 3 years of age in infants <29 weeks gestation in a large population-based cohort.

Method

Surviving infants who were born <29 weeks gestational age (GA) from 1998 to 2001 and cared for in one of the 10 neonatal intensive care units in NSW and the ACT in Australia were eligible for the study. While in the Neonatal Intensive Care Unit (NICU), these infants underwent a routine eye examination by a paediatric ophthalmologist and graded according to the international classification of ROP. 9 These infants were enrolled for long-term prospective follow-up, with perinatal and follow-up data prospectively collected and entered into the Neonatal Intensive Care Units Study (NICUS) database. This study was prospectively designed to use this perinatal and 3-year follow-up data that was extracted from the NICUS database.

In the first phase of the analysis, infants with periventricular leukomalacia (PVL), Grade III or IV intraventricular haemorrhage (IVH), hydrocephalus and major congenital abnormalities were excluded as these abnormalities are known to have a significant effect on developmental outcome. Infants with Stages 4–5 ROP were also excluded from the analysis as the validity of the developmental test used at 3 years of age is questionable for children with significant visual impairment. At the 3-year visit, those identified with cerebral palsy (CP) or a severe hearing impairment, as determined by paediatric clinical examination, were also excluded from the study.

Infants with Stage 3 ROP were matched for GA, birthweight (BWt) and gender where numbers permitted to those with no ROP, Stage 1 and Stage 2 ROP who met the inclusion criteria to make neurologically comparable groups. The four groups were then compared for their 3-year-old developmental outcome using the Griffiths Mental Development Scale, which was administered by a certified psychologist or paediatrician. The ophthalmic outcomes of these infants were compared between the four groups. Infants with Stage 3 ROP were further divided into those who were or were not treated with laser therapy and their 3-year developmental outcomes compared. These data are routinely collected and anonymized for audit purposes, thus individual hospital ethical approval was not sought, rather the study was approved by the NSW NICUS Data Collection group. The Griffiths Mental Development Scales (Griffiths, 1954)Reference Griffiths 10 measures development in six domains or subscales: the Locomotor scale, Personal–Social scale, Hearing and Speech scale, Eye–Hand Coordination scale, Performance scale and Practical Reasoning scale. A developmental quotient is obtained for each scale and a general quotient (GQ; mean = 100 ± 13 s.d.) is derived to provide an overall measure of developmental functioning.

In the second phase of the analysis, to determine whether the severity of ROP was an independent predictor of developmental outcome, a multivariate regression analysis was conducted. All infants with a completed Griffiths developmental assessment were included in the analysis.

Statistics

Using SPSS version 19, between-group differences were analysed with the ANOVA with Tukey's post-hoc test, Chi-square, Fishers exact tests and the Mann–Whitney U-test or the Kruskal–Wallis test with post hoc where appropriate. To show a meaningful difference between paired data, with a power of 80% and an estimated effect size between 0.25 and 0.5, a sample size of 66 is required. Multivariate regression analysis was used for the secondary analysis to compare known associated risk factors of poor developmental outcomes. These factors included GA, BWt, gender, multiple birth, IUGR (<10th centile), PVL, Grades III and IV IVH, hydrocephalus, sepsis, patent ductus arteriosus (PDA), chronic lung disease (CLD; oxygen requirement at 36-week-corrected GA) and ROP. Analysis of ROP in the model was for all stages of ROP. The P-value for significance was set at P < 0.05 and was not adjusted for multiple comparisons.

Results

The primary analysis was performed to compare the developmental outcome of the four neurologically similar ROP groups. From the 1214 surviving infants discharged, there were 135 infants with Stage 3 ROP, of which 22 were excluded (4 with PVL, 13 with Grade III/IV IVH, 1 with hydrocephalus, 4 with congenital abnormalities), 18 were not assessed at 3 years as 9 were lost, 8 refused and 1 was overseas, and 27 were excluded at the 3-year assessment (13 had CP, 6 had a hearing impairment and 8 were uncooperative), leaving a total of 68 infants with Stage 3 ROP who were included in the primary analysis. Comparison of the perinatal variables for the group with Stage 3 who were included in the study compared with those excluded from the study revealed no significant differences apart from the severity of IVH as expected as this was an exclusion criteria (Table 1).

Table 1 Comparison of perinatal variables between Stage 3 ROP group with those excluded

ROP, retinopathy of prematurity; IUGR, intrauterine growth restriction; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; IVH, intraventricular haemorrhage; CLD, chronic lung disease; HFV, high-frequency ventilation; LOS, length of stay.

aMean ± s.d.

bMedian (quartiles).

c t-test.

dChi-square test.

eMann–Whitney U-test.

Stage 3 ROP infants included in the study were matched for GA, BWt and gender to infants with Stage 2, Stage 1 and no ROP. Perinatal characteristics of the ROP study groups were comparable; however, the GA was significantly higher for infants with Stage 1 ROP, and Stage 3 infants were ventilated for longer, more with a PDA treated with surgery, they had significantly more days in oxygen, more with CLD and subsequently longer length of stay (Table 2). At 3 years of age, visual outcome showed there were significantly more children who were myopic in the Stage 3 ROP group (Table 3).

Table 2 Comparison of perinatal variables between ROP groups

ROP, retinopathy of prematurity; ns, not significant; IUGR, intrauterine growth restriction; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; IVH, intraventricular haemorrhage; CLD, chronic lung disease, HFV, high-frequency ventilation, LOS, length of stay.

*Significantly higher than all groups.

aMean ± s.d.

bMedian (quartiles).

cANOVA–Tukey post-hoc test.

dChi-square test.

eFisher exact test.

fKruskal–Wallis test.

Table 3 Visual outcome at 3 years

ROP, retinopathy of prematurity; ns, not significant.

aChi-square test between the four groups of ROP.

The Griffiths assessment at 3 years for the study groups are presented in Table 4. There were no significant differences between groups for the GQ or any of the scales other than the Stage 1 group who had significantly higher scores on the Hearing and Speech scale in comparison with the no ROP group.

Table 4 Developmental outcome for ROP groups

ROP, retinopathy of prematurity; ns, not significant.

**Stage 1 significantly higher than no ROP.

aMean ± 1 s.d.

bANOVA–Tukey post-hoc test.

To further examine the influence of severity of ROP, on developmental outcome for Stage 3 infants, we compared those who were treated (laser treatment) for their initial eye disease (n = 27) to those with Stage 3 ROP who did not require treatment (n = 41). There were no significant differences found on any of the Griffiths scales at 3 years between the two groups (Table 5).

Table 5 Developmental outcome for Stage 3 ROP group receiving laser treatment and no treatment

ROP, retinopathy of prematurity; ns, not significant.

aMedian (quartiles)

bMann–Whitney tests used.

Results of the multivariate regression analysis are outlined in Table 6. From the 1214 infants, 51 infants had died (4.2%) and 257 were not seen at 3 years (100 refused, 127 lost and 30 moved overseas), giving a total 75% follow-up rate for the cohort. For the remainder (n = 906), 120 (9.9%) infants did not have Griffiths scores (15 assessed with another test, 28 had outcome information only, 8 were too disabled and 69 uncertain). Owing to the nature of the Griffiths test at 3 years, a Practical Reasoning Quotient is not calculated for all infants including those infants who are too disabled/delayed or too young (<3 years) at the time of test. Therefore, the data for these infants is considered ‘incomplete/missing’ for analysis. There were 178 infants (14.7%) who had incomplete/missing data (no Practical Reasoning) and were excluded from the multivariate regression analysis. The remaining 608 infants (50% of entire cohort) had completed Griffiths assessments at 3 years corrected age and were included in the multivariate analysis. We found GA, BWt, gender, IUGR, PVL, severe IVH (Grade III or IV) and CLD were significantly associated with some or all (only gender) of the developmental scales at 3 years. ROP was not associated with 3-year-old outcome (Table 6).

Table 6 Multivariate regression analysis on 608 infants with complete data

GA, gestational age; BWt, birthweight; IUGR, intrauterine growth restriction (<10th centile), PVL, periventricular leukomalacia; IVH, intraventricular haemorrhage; Hydroc, hydrocephalus; ROP, retinopathy of prematurity (all stages); CLD, chronic lung disease; ns, not significant.

Significant P-values are shown: *significantly associated with scale.

Discussion

The results showed, for the first time, that the severity of ROP, excluding those with Stage 4/5 ROP, was not related to developmental outcome at 3 years of age in a large population-based cohort of infants born <29 weeks gestation. This was despite the fact that there were a higher number of infants with myopia in the Stage 3 group (Table 3). The influence of ROP severity on developmental outcome was also examined and confirmed in neurologically comparable groups in which confounding factors (such as GA, BWt and gender) were controlled.

Retinopathy of prematurity is associated with GA,Reference Todd, Wright, Byth and Smith 11 , Reference Todd, Kennedy and Roberts 21 fluctuating oxygen levels,Reference Cunningham, Fleck, Elton and McIntosh 19 , Reference Kennedy, Todd, Watts and John 20 time of mechanical ventilationReference Todd, Kennedy and Roberts 21 , Reference John and Todd 22 and PDA,Reference Todd, Kennedy and Roberts 21 , Reference John and Todd 22 which was reflected in our study (Table 1 and 2). Although ROP groups were matched on gestation, as close as possible, the GA for the Stage 1 group was significantly higher. This may account for the trend for the slightly higher scores for the Stage 1 group on almost all of the subscales on the Griffiths and the significantly higher hearing and speech scale compared with the no ROP group (Table 4). Others have found speech and language development to be significantly lower in preterm children born earlier.Reference Jennische and Sedin 23 , Reference Wolke, Samara, Bracewell and Marlow 24

Use of the Griffiths as the outcome measure for this study may be questioned in relation to its sensitivity to detect changes. Although the test has been used extensively for clinical and research purposes to assess development, it was not designed to identify subtle and specific differences. However, the Griffiths has been used by others studying preterm infants and found to discriminate preterm children from those born fulltermReference Dall'Oglio, Rossiello and Coletti 25 and used to determine risk factors for poorer outcome in the preterm population.Reference Bowen, Starte and Arnold 16

Results of this study are dissimilar to those obtained in our previous study, which examined developmental outcome in a hospital cohort.Reference Goyen, Todd and Veddovi 15 The previous study found a trend for lower scores in the Stage 3 ROP group, which was significantly lower on the Locomotor scale. This was not supported in current results, in which a considerably larger regional sample of neurologically similar infants were included (n = 15 v. n = 68, respectively). In fact, all the Stage 3 Griffiths scores were much higher in this study, possibly reflecting the impact of modern perinatal care (1986–94Reference Goyen, Todd and Veddovi 15 v. 1998–2001 [current study, Table 4]). All the mean scores for the ROP groups in multivariate analysis were lower than the scores in the primary analysis where there were neurologically comparable groups (performance scores = 84.4 v. 100.1, respectively, for the infants with Stage 3 ROP).

Goyen and LuiReference Goyen and Lui 26 examined minor motor dysfunction in ‘apparently’ normal preterm children at school age. They found ROP was significantly and independently associated with motor dysfunction. Although 100% had motor dysfunction and findings lend support to the view that severity of ROP influences motor dysfunction, there were only three subjects that had Stage 3 ROP.

Comparing all the scale scores, the mean eye–hand coordination score was again the lowest for all the ROP groups, suggesting that this is an area of relative weakness for preterm infants, regardless of severity of ROP. In the previous study,Reference Goyen, Todd and Veddovi 15 the mean eye–hand coordination (mean = 78) was below the normal range on the Griffiths; however, the mean was in the low average range for this study (range 92–95; Table 4).

Poorer visual outcome has been reported for preterm children.Reference Cooke, Foulder-Hughes, Newsham and Clarke 27 , Reference Darlow, Clement, Horwood and Mogridge 28 A study by Cooke et al.Reference Cooke, Foulder-Hughes, Newsham and Clarke 27 found visual problems in preterm children were significantly associated with outcome at schoolage, specifically minor motor difficulties and non-verbal intelligence. ROP did not appear to be related to developmental outcome; however, only eight Stage 3 subjects were included in their study. Our results indicate severity of ROP did not influence developmental outcome, despite a higher number of Stage 3 having myopia. However, only about 65% of infants received an ophthalmic follow-up at 3 years and thus the figures for eye problems at 3 years may be misleading. In a population-based study, Darlow et al.Reference Darlow, Clement, Horwood and Mogridge 28 showed that ROP was associated with an increased risk of visual problems in very low birthweight (VLBW) children at school age, including myopia and strabismus, whereas Holmstrom et al.Reference Holmstrom, el Azazi and Kugelberg 29 suggested that ROP, in association with neurological complications, causes long-term visual problems in VLBW children.

We were interested to determine whether Stage 3 infants with more severe eye disease requiring laser treatment, had poorer developmental outcome (Table 5). This was not the case however and future studies need to be established to detect any difference in subtle visual processing abilities that may not be apparent until school entry age. Others have found a significant number of premature children with ‘normal vision’ have subtle visual impairment.Reference Holmstrom, el Azazi and Kugelberg 29 Visual-based processing difficulties also have been found in preterm groups even in the presence of normal visual acuity and IQ.Reference Foreman, Fielder, Minshell, Hurrion and Sergienko 30 , Reference Langaas, Mon-Williams and Wann 31 At school age, visual-motor skills are frequently reported to be weaker in preterm children,Reference Schraeder, Heverly, O'Brien and McEvoy-Shields 32 – Reference Liebhardt, Sontheimer and Linderkamp 34 although the contribution of visual abnormalities to visual-motor deficits in these high-risk children is unclear.Reference Cooke, Foulder-Hughes, Newsham and Clarke 27 , Reference Langaas, Mon-Williams and Wann 31 Poorer performance on visual processing tests may have implications for visual learning-based tasks, including reading, handwriting and mathematics.

CLD and gender are factors known to be associated with poor performance.Reference Dammann, Kuban and Leviton 35 – Reference Hoekstra, Ferrara and Couser 39 CLD is associated with CP, reduced cognitive scores and poor school performance.Reference Dammann, Kuban and Leviton 35 – Reference Piecuch, Leonard, Cooper and Sehring 37 Males have been found to be at greater risk for morbidity in preterm children, including neurodevelopmental and learning disabilities.Reference Stevenson, Verter and Fanaroff 38 – Reference Hoekstra, Ferrara and Couser 39

A limitation of this study was the low number of infants with Stage 3 ROP following the exclusion of over half the cohort as well as those others unable to complete the Griffiths. The results of the study however were similar regardless of the type of analysis either matching for ROP stage (Table 4) or multivariate analysis (Table 6). The importance of matching following exclusion was that a true indication of developmental outcome could be determined without confounding variables.

In summary, in this large cohort of preterm infants we have found that severity of ROP in neurologically comparable groups, excluding Stage 4/5 ROP, had no significant influence of developmental outcome at 3 years of age. Subtle differences with visual processing may be detected at an older age. Short GA, low BWt and gender were found to be more influential on long-term development than specific clinical problems, such as ROP, PDA and sepsis faced by this preterm population.

Acknowledgement

The authors would like to thank Dr Bruce Shadbolt for his help with the analysis.

Appendix: participating hospitals

  • • Canberra Hospital

  • • John Hunter Children's Hospital (Newcastle)

  • • Liverpool Hospital

  • • Nepean Hospital

  • • Royal Hospital for Women

  • • Royal Prince Alfred Hospital

  • • Royal North Shore Hospital

  • • Sydney Children's Hospital

  • • The Children's Hospital Westmead

  • • Westmead Hospital

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Figure 0

Table 1 Comparison of perinatal variables between Stage 3 ROP group with those excluded

Figure 1

Table 2 Comparison of perinatal variables between ROP groups

Figure 2

Table 3 Visual outcome at 3 years

Figure 3

Table 4 Developmental outcome for ROP groups

Figure 4

Table 5 Developmental outcome for Stage 3 ROP group receiving laser treatment and no treatment

Figure 5

Table 6 Multivariate regression analysis on 608 infants with complete data