Original Articles

Retinopathy of prematurity in a South Australian neonatal intensive care unit

Justine Smith, MB BS* Nicola Spurrier, MB BSt Michael Goggin, FRCS, FRCOphth"

Abstract

Purpose: To establish the incidence and severity of retinopathy of prematurity (ROP) in an Australian population of premature infants, and define risk factors for this population.

Methods: A survey of neonates born weighing less than 1501 g andlor with gestational age below 33 weeks, was undertaken at a neonatal intensive care unit in South Australia.

Results: ROP was diagnosed in 16.0% of the 94 neonates who were screened until retinal vascular- isation was complete. Threshold disease occurred in 4.2%. Logistic regression identified three signifi- cant risk factors for the development of ROP: days of mechanical ventilation, multiple birth and female sex.

Conclusions: The incidence of ROP was relatively low when compared with figures recently published for two large populations studied in the United States and England. This difference was due to a lower incidence of mild forms of the disease. Days of mechanical ventilation, multiple birth and female sex were independently predictive of the occur- rence of ROP. As small numbers of infants with ROP are managed at individual Australian centres each year, a national ROP register is recom- mended to facilitate the study of the disease in this country.

Key words: Retinopathy of prematurity, incidence, severity, risk factors, register.

Retinal vascularisation begins at 16 weeks' gesta- tion and is complete at term. After premature birth this process may be complicated by retinopathy of prematurity (ROP), a potentially blinding condition. During the past 20 years the incidence of ROP has risen, attributed to improvements in neonatal care, with survival of younger and smaller premature infants.' The disease now accounts for around one-tenth of childhood blindness in Western countries.'

Recently, groups in Victoria and New South Wales have presented epidemiological data describing ROP in their premature nurseries. The neonatal intensive care unit at Flinders Medical Centre is one of two units serving the population of South Australia and some commu- nities situated over the State's borders. Our clinical impression suggested the incidence of ROP in this unit was less than that reported in overseas studies, but similar to that described by the other Australian authors. Over a two-year period we recorded the incidence and severity of ROP in an Australian unit, and established risk factors for this population.

Fmm the Depanments of Ophthalmology* and Paediatrics,i Flinders Medical Centre, Bedford Park, South Australia 5042 Reprints: Dr J Smith.

Retinopathy of prematurity in a South Australian neonatal intensive care unit 49

Table 1 Incidence of complications

Incidence

Complication Birth weight Birth weight <1501 g <1251 g

n=67 n=38

Hyalinc membranc disease 70.1 % 76.3% Bronchopulmonary dysplasia 55.2% 76.3% Inrravcntricular haernorrhage 25.4% 31.6% Patent ductus arreriosus

causing cardiovascular compromise 34.3% 47.4%

Culture proven sepsis 9.0% 5.3%

Patients and methods

From August 1990 to July 1992, 103 patients of the neonatal intensive care unit at Flinders Medical Centre were examined for ROP. Infants reviewed were born before 33 weeks’ gestation andor had a birth weight less than 1501 g.

During the period of study the survival rates for babies born weighing below 1501 g and 1251 g were 91.3% and 87.1% respectively. Table 1 records the incidence of medical complications occurring in this group.

Screening took place in the intensive care unit. A neonatal registered nurse assisted, and babies were monitored throughout the examination as appropriate for their medical condition. Chloral hydrate administered in a dose of 50 to 100 mg/kg provided sedation. Pupils were dilated with cyclopentolate 0.5% and phenylephrine 2.5%. Topical amethocaine 0.5% was given, and an eyelid speculum was inserted. Examinations involved indirect ophthalmoscopy using a 28 dioptre lens, with scleral indentation. All infants were reviewed by the same ophthalmologist. Findings were recorded using the International Classification of ROP.3.‘

Examinations began six weeks after birth and were performed fortnightly. Where retinal vascu- larisation proceeded to completion without complication, the patient was discharged from review. If ROP was found the infant was followed more frequently, weekly or biweekly as clinically indicated. Retinal cryotherapy was used to treat neonates with threshold disease according to the recommendations published in the Multicenter Trial of Cryotherapy for ROP.’ All patients who developed ROP remain under regular ophthal- mological review.

For infants who completed follow-up, 31 potential risk factors for development of ROP were recorded. The uncorrected x2 test was used to investigate categorical variables, and con- tinuous variables were analysed using the Student’s t test. Logistic regression was employed to determine the combination of risk factors best predictive for ROP.

Results One hundred and three infants qualifying for the screening criteria were examined. Eight babies were transferred to other neonatal services before full vascularisation of the retina had occurred. One baby died during the screening programme. The remaining 94 infants (91.3%) form the study group.

Of those babies completing follow-up, 15 (16.0%) were found to have ROP. The mean age of onset was 35.4 weeks’ (SD, 1.78) post-con- ceptual age, In 11 (1 1.7%) disease did not reach threshold level, but four (4.4%) progressed to threshold ROP. For subthreshold disease, the maximum stage reached in one or both eyes before regression was stage 1 in four infants and stage 2 in seven infants. Three of the four neonates who developed threshold ROP (two reaching stage 3 and one reaching stage 4) received retinal cryotherapy. In each case regres- sion of disease commenced within one week of treatment. The fourth patient was discharged to another neonatal service at 35 weeks’ post- conceptual age with no ROP observed to that date. At 17 months of age she was referred back to our clinic with unilateral stage 5 disease and a normal fellow eye.

Disease was not detected in those patients who did not complete the screening programme. Communication with the units who received five of the transferred infants revealed that none of these patients had showed evidence of ROP subsequently. No information is available for a set of triplets transferred overseas.

Refractions performed during the first year of life revealed that three of the babies who had suffered ROP were myopic, one also being anisometropic, esotropic and amblyopic. Two of these infants had developed threshold ROP. Two babies with subthreshold ROP were astigmatic at one year of age. One further infant with subthreshold disease exhibited intermittent horizontal jerk nystagmus from six months. The

50 Australian and New Zealand Journal of Ophthalmology 1995; 23(1)

Table 2 Continuous variables significantly associated with retinopathy of prematurity

Mean 5 SD for Mean f SD for Variable infants with ROP infants without ROP P

r F 15 1 ~ 7 9

Birth weight (g) 1035.471-342.72 1396,342295.40 <0.001 Gestational age (weeks) 27.6052.26 29.9521.90 <0.001 Days of oxygen supplementation 94.60269.50 33.25234.63 <0.001 Days of mechanical ventilation 36.33224.65 11.88? 13.86 <0.001 Number of episodes pa02 <50 mmHg 17.53218.62 3.71 27.68 <0.001 Number of episodes paCO2 >45 mmHg 25.801-29.47 5.76211.26 <0.001 Number of episodes apH <7.30 31.53t33.32 10.60215.31 <0.001

Number of top-up transfusions 6.80k4.66 2.3322.38 <0.001 Days in level 3 nursery 58.87-1.39.23 33.80119.93 <0.001

Days of parenteral nutrition 27.202 12.36 16.64112.11 0.007

eye which progressed to stage 5 disease was irre- versibly blind.

Tables 2 and 3 list 14 factors shown by x' and t tests to have a statistically significant association (P<0.05) with the development of ROP. Seventeen other variables had no statistical asso- ciation with the disease (Table 4). Logistic regression found three factors to be independent predictors of the occurrence ofROP. These were days of mechanical ventilation, multiple birth and female sex.

Discussion This study documents the incidence of ROP in a small population of Australian premature infants. Ninety-four subjects with birth weights less than 1501 g and/or born before 33 weeks' gestation were screened until retinal vascularisation was complete. The disease was found in 16.0%. Regression occurred at an early stage in the majority, with 4.2% of all neonates screened reaching threshold. Only one eye became irre- versibly blind during the study period, the fellow eye in this patient remaining normal.

Table 3 Categorical variables significantly associated with retinopathy of prematurity

Infants Infants

i F 1 5 n=79 Variable with ROP without ROP P

Female sex 73.3% 35.4% 0.006 Multiple birrh 40.0% 15.2% 0.025 Intraventricular haemorrhage 46.7% 17.7% 0.014

Administration of surfactant 46.7% 21.5% 0.041

Large-scale studies have recently been under- taken by Palmer et d h in the United States and by Ng et al.' in England, investigating the epidemiology of ROP. Table 5 compares the incidence of disease in our study with the find- ings of these reports, presenting the subpopula- tion of our cohort which fulfilled the selection criteria of each comparison study. Although the incidence of severe ROP is comparable in all studies, mild ROP (subthreshold disease for the study by Palmer ec al.,'and stage 1 and 2 for the report of Ng et al.') was less frequently detected in our population, resulting overall in a lower incidence of ROP.

Severe ROP may lead to blindness or severe visual impairment, but infants who develop ROP of any stage are at significantly increased risk of a variety of other visual disorders.* Examples include myopia, astigmatism, anisometropia,

Table 4 Variables not significantly associ- ated with retinopathy of prematurity

Race Hyaline membrane disease Bronchopulmonary dysplasia Pneumothorax Patent ductus arteriosus Culture proven sepsis Apnoea and/or bradycardia requiring intervention Administration of theophylline Administration of indomethacin Number of episodes pa02 >80 mmHg Number of episodes paCO? <35 mmHg Number of episodes apH >7.45 Intrauterine growth retardation Maternal pre-eclampsia Antepartum haemorrhage Fetal distress Birth asphyxia

Retinopathy of prematurity in a South Australian neonatal intensive care unit 51

Table 5 Incidence of retinopathy of prematurity

Study (Selection criteria)

~~ ~

This study Incidence of ROP

Total Severe+ Total Severet

Number Incidence of ROP n*

~ ~~

Palmer et al.' (Birth weight < 125 1 g) 4099 65.8% 6.0% 38 34.2% 7.9% Ng et ul.' (Birth weight <1701 g) 505$ 60.1% 6.3% 67 19.4% 6.0% Todd er UP (Gestation <30 weeks) 91 40.7% 8.8% 44 27.3% 6.8% Keith et a[." (Gestation <31 weeks) 719 23.5% 11.3% 58 20.7% 5.2% Yu er al." (Gestation <29 weeks) 328 30.2% 11.9% 30 40.0% 10.0'K

(Birth weight < 1000 g) 201 40.3% 15.9% 13 61.5% 15.4%

*n=the subpopulation who fulfill the selection criteria of the comparison study. tSevere=threshold disease for the study by Palmer et aLb and stage 3 or worse for all other studies. $Results tabulated are for the 331 neonates with birth weights less than 1501 g.

strabismus, amblyopia and nystagmus, as found in this study.

A number of reasons may account for the apparent difference between the incidence of ROP in our cohort and the populations studied in North America and England. Firstly, the rela- tively small numbers of infants we studied may cause some bias.

Variations in the incidence of ROP reported by different groups may reflect differences in the examination schedule. In the study by Palmer et a1.' examinations could begin up to two weeks earlier than in this survey although the programmes were otherwise identical. Ng et al.' set a more rigorous protocol, but conditions were not met for just under half the infants screened.

Lower birth weight infants are more suscep- tible to ROP. A population with a relatively small proportion of lower birth weight infants should therefore have a relatively low incidence of ROP. For the report by Palmer et aL654.6% of neo- nates with birth weights below 1251 g were less than 1000 g at birth and 15.8% were less than 750 g. These percentages were 34.2% and 13.2% respectively for the corresponding subpopula- tions in our study. In the study of Ng et aL7 21.1% of infants born at less than 1500 g were below 1001 g and 2.1% were below 751 g. The respective percentages for this study were 19.4% and 7.5%.

Using multiple regression analysis Darlow et aLq identified 'principal hospital caring for the infant' as a statistically significant independent contributor to the risk of ROP. This 'centre effect' might contribute to the difference between our results and the findings of the American and English researchers. The comparison studies

involved the collaboration of a number of neonatal units, their results representing an average incidence for all participating units.

Finally, it is tempting to postulate some feature specific to the Australian neonate or the care he receives which lowers his susceptibility to ROP.

The incidence and severity of ROP in the Australian population has been recorded by several other groups. Todd et al.'" studied 91 infants born at gestational age less than 30 weeks at Westmead Hospital, Sydney in 1986 and 1987. Over a ten-year period ending in 1986, Keith et al. I ' reviewed 7 19 babies born before 3 1 weeks' gestation at the Royal Women's Hospital, Melbourne. Yu et al.'* reported results for neonates managed between 1977 and 1988 at Monash Medical Centre, Melbourne, including 328 born at less than 29 weeks' gestational age and 20 1 born weighing less than 1000 g. Results from these studies seem comparable to the find- ings of this report (Table 5). It is however diffi- cult to draw a comparison between the Australian studies and the reports by Palmer et aL6 and Ng et a1.7 because of differing data sets. The studies of Keith et aL" and Yu et a1.'2were largely conducted prior to the development of the International Classification of ROP'.' and a classification of disease current at that time was employed. The incidence of stage 3 or worse ROP reported in these studies may therefore not exactly represent the incidence of such disease as it is now defined.

Recent publications6"3,14 have demonstrated the association of the onset and progression of ROP with post-conceptual age rather than postnatal age. The mean post-conceptual age at onset of disease in this group was 35 weeks. This finding

52 Australian and New Zealand Journal of Ophthalmology 1995; 23(1)

agrees with the other studies, confirming that screening should be carried out on the basis of post-conceptual age, not postnatal age as currently recommended. l i ~ ' 6

Days of mechanical ventilation and multiple birth were identified as independent predictors of the occurrence of ROP. This finding fits with the observation that in general, neonates who develop ROP are born at early gestational age, have low birth weight, and are medically unstable, requiring maximum intervention."

All infants born weighing under 1000 g are initially mechanically ventilated. The indication for ventilation otherwise implies a sick infant. Mechanical ventilation may itself cause signifi- cant morbidity. One example is broncho- pulmonary dysplasia. Others have found venti- lator time to be predictive of ROP using multiple regression analysis.18,'q Todd e t al."' showed mechanical ventilation to be a risk factor for progression beyond stage 2 disease.

In general, twins are born at an earlier post- conceptual age than singletons and are usually smaller for gestational age. An association between multiple birth and ROP has been noted previously.2o In the American cohort described earlier,6 the incidence of ROP was independent of multiple birth. However, twins were found to bc at significantly increased risk of reaching threshold disease should they develop ROP.Z'

It was unexpected to identify female sex as an independent predictor of ROP. There is no obvious reason why the disease should afflict females preferentially, and it is likely that this finding relates to the small population size. Larger epidemiological studies have noted no sex difference in the incidence of

In our study, incidence of ROP was not signif- icantly associated with the number of episodes of elevated arterial oxygen tension. Flynn et ~1 . ' ' have described a relationship between the incidence and severity of ROP and the duration of exposure to arterial oxygen levels of 80 mmHg or higher, measured continuously transcuta- neously. We measurrd oxygen tension using intermittent arterial blood gas analysis. Failure to demonstrate a relationship may be a conse- quence of the intermittent method of recording.

The problems of a small population size have been mentioned. Large cohorts provide the most reliable results. Each Australian centre will manage small numbers of neonates with ROP

each year. Keith et al." screened more than 700 infants, but this took ten years, and during that time there were many changes in our under- standing of the disease. Collaboration of neonatal centres around the country is required. We advocate the establishment of an Australian ROP register. A register would allow the epidemiology of the disease to be more readily examined and if, as this study suggests, our infants are at lowered risk of ROP, may help to provide an explanation. Other problems could be addressed. For example, racial differences in susceptibility to ROP are recognised,h.7 but nothing is known of ROP among the indigenous people of Australia. With knowledge of the outcome of retinal cryotherapy we may redefine threshold disease to suit our population. New modalities of treatment such as diode laser retinal photocoagulation await evaluation in Australia.

Acknowledgements We thank the staff of the neonatal care unit for their assistance, and Adrian Esterman who performed the statistical analysis.

References 1. Anonymous. Ketinopathy of prematurity [Editorial].

Iancet 1991;337:83-4. 2. Goggin IM, O'Kccfc M. Childhood blindness in the

Republic of Ireland: a national survey. Br J Ophthalmol 199 1;75:425-9.

3. Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity, Arch Ophthalmol 1984;lOZ: 1130-4.

4. International Committee for Classification of the Late Stages of Retinopathy of Prematurity. An international classification of retinopathy of prematurity 11: the classifi- cation of retinal detachment. Arch Ophthalmol 1987;105:906-12.

5. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial for cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988; 106:47 1-9.

6. Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL, Schaffer DB et ul. Incidence and early course of retinopathy of prematurity. Ophthalmology 199 1;98: 1628-40.

7. Ng YK, Fielder AR, Shaw DE, Levene MI. Epidemiology of retinopathy of prematurity. Lancet 198812: 1235-8.

8. Kushner BJ. Long-term follow-up of regressed retin- opathy of prematurity. Birth Defects 1988;24:193-9.

9. Darlow BA, Honvood LJ, Clemett RS. Retinopathy of prematurity: risk factors in a prospective population- based study. Paediatr Perinat Epidemiol 1992; 6: 62-80.

10. Todd D, Kennedy J, Roberts V, John E. Risk factors in progression beyond stage 2 retinopathy of prematurity. Aust NZ J Ophthalmol 1990; 18: 57-60.

11. Keith CG, Doyle LW, Kitchen W'H, Murton LJ. Retinopathy of prematurity in infants of 24-30 weeks' gestational age. Med J Aust 1989;150:293-6.

Retinopathy of prematurity in a South Australian neonatal intensive care unit 53

12. Yu W H , Lim CT, Downe LM. A 12-year experience of retinopathy of prematurity in infants 128 weeks gestation or 1000 g birth weight. J Paediatr Child Health 1990;26: 205-8.

13. Fielder AR, Shaw DE, Robinson J, Ng YK. Natural history of retinopathy of prematurity: a prospective study. Eye 1992;6:233-42.

14. Goggin M, O’Keefe M. Diode laser for retinopathy of prematurity - early outcome. Br J Ophthalmol 1993;77: 559-62.

15. Anonymous. College News: ROP screening duty. Quarterly Bulletin of the College of Ophthalmologists (U.K.) 1990; Autumn: 6.

16. Fielder AR, Lsvene MI. Screening for retinopathy of prematurity. Arch Dis Child 1992;67:860-7.

17. Avery GB, Glass P. Retinopathy of prematurity: what causes it? Clin Perinatol 1988;15:917-28.

18. Hammer ME, Mullen PW, Ferguson JG, Pai S, Cosby C, Jackson KL. Logistic risk factor analysis of risk factors in retinopathy of prematurity. Am J Ophthalmol 1986;102: 1-6.

ABRIDGED P R O D U C T INFORMATION

Product Name: HEALON

T h c full Product Information is availablc on request from

Pharmacia and should be consulted before prescribing.

APPROVED INDICATIONS F O R USE: Ophthalmosurgical aid for use In intra- and extra-apsular cataraci

surgery, intraocular lens (IOL) implantation, glaucoma surgery,

vitreous replacement after vitrectomy and retinal detachment

surgery

CONTRAINDICATIONS.

None known to the use of Healon.

CLINICALLY SIGNIFICANT PRECAUTIONS FOR USE:

To prevent postoperative elevation of intraocular pressure ilOPi - d o not overhll the eye chamber with Healon,

- remove excess Healon by irrigation or aspiration at the close of

surgery;

- carefully monitor the lop especially during the hrst week

19. Flynn JT. Acute proliferative retrolental fibroplasia: i multivariate risk analysis. Trans Am Ophthalmol Sac I Healon I S extracted from avian t isues therefore, immunological

postoperatively. and treat as necessary.

1983;31: 549-91. 20. Kinsey VE. Retrolental fibroplasia: cooperative study of

retrolental fibroplasia and the use of oxygen. Arch Ophthal 1956:56:481-543.

21. Schaffer DB, Palmer EA, Plotsky DF, Metz HS, Flynn JT, Tung B et el. Prognostic factors in the natural course of retinopathy of prematurity. Ophthalmology 1993;IOO: 230-7.

22. Flynn JT, Bancalari E, Snyder ES, Goldberg RN, Feuer W, Cassady J, er el. A cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity. N Engl J Med 1992;326: 1050-4.

and other reactions can occur with the injection vspecially on

repeated m,ection Healon IS for ocular indications only

CLINICALLY SIGNIFICANT ADVERSE EFFECTS

A transient rire of IOP postoperatively and mild uvettis have been

reported. DOSAGE REGIMENS A N D R O U T E S OF ADMINISTRATION. T h e dosage varies with the type of

surgery Usually a dose of 0 2 to 0 6 mL is introduced I n the

anterior segmenr of the eye, whereas much larger amounts are

used in the posterior segment (Refer also to the full Product

Information).

STORAGE: Store at 2 to 8 T 110 not freeze Protect trom light

PRESENTATION: Sodium hyaluronate rolution 1 X. Disposabk,

single use syringe supplied with sterile cingle use cannula 0 4 ml., u 55 mL. 0.7TmL. 0 85ml., 2 0 mL

P O I S O N SCHEDULES: 54

DISTRIBUTOR: Pharmacia (,4ustralia) Pry Ltd.

Full Product Information approved by TCA: 28 July 1989

REFERENCES: I Pedersen 00, Comparison of the protective

cftects of methyl cellulose and sodium hyaluronate on corneal

swelling following phacoemulsification J Cataract Refract Surg,

16. 594-596. 2 Jaffe GF, Planned ECCE ireats cornca better than

phaco in prospcctivc evaluation, Ocular Surgery News, August

I5 1989 3. Ratuse FE, Nicols OD, Effecrs of Healon Vr ViScodt

on cndothelial ccll count and morphology after phacoemul-

sitication and posterior chamber lens implantation, Can J

Ophthalmol IY92; 27,125-129 4 Orher R, Slow motion phaco

may reduce trauma, Speeds visual recovery, Ophthalmology Tme5, ]\.lay I , 1992 5 Arshmoff S, T h e physjcal propertics of

ophthalmic viscoelastics in Lataract surgery, Proceedings from

National Ophthalmics Speakers Program (NOSP), Medicopea,

1992 6 hlichelson M, fndocapsular phaco the storm within the

calm, Ocular Surgery News, September 15, I989 7 Pop M, The

cllnlcal performance of viscoelamcs during phacoemulsification.

Proceedings from National Ophthalmics Speakers Program

(NOSPI, Medicopea, 1992 8 Pharmacia data on file.

Pharmacia (Australia) Pry Ltd, A C N 001 025 814. 4 Byheld

Street North Ryde NSW 21 13 KAB6000A

Australian and New Zealand Journal of Ophthalmology 1995; 23(1) 54