BCC Lam, KY Wong, YK Ng, CW Leung, SP Hui, CY Yeung

Abstract

Retinopathy of prematurity (ROP) has become an increasing problem with improved survival of low birth weight infants. The etiology of ROP appears to be multifactorial. We have analysed the relationship between 30 perinatal risk factors and the development of RQP in 75 consecutive very low birth weight (VLBW) Chinese infants. The overall frequency of occurrence of RQP was 24% and severe ROP was 7% which were lower compared with previous studies. Eighteen of the 30 perinatal factors were significantly associated with the development of ROP. However, stepwise logistic regression analysis showed that only the duration of mechanical ventilation, indomethacin administration, respiratory distress syndrome(RDS) and bronchopulmonary dysplasia (BPD) were found to be important perinatal risk factors for development of ROP in our series.

Introduction

Retinopathy of prematurity has become an increasing problem with improved survival of low birth weight infants. Improving survival rates are in part due to the introduction of surfactant replacement therapy for respiratory distress syndrome. In modern neonatal care, new methods for treatment and new medications are continuously introduced. Thus it is important to study the risk factors from time to time. Besides, the increasing demand for eye examination of VLBW infants has created considerable workload and problems in many centres. The present study was undertaken to identify the important perinatal risk-factors under the current neonatal management with the aim of improving the cost effectiveness of the screening programme.

Patients and Method

We studied all inborn infants admitted to the neonatal unit at Tsan Yuk Maternity Hospital which is a university teaching hospital with an annual delivery rate of five thousand from January 1993 to December 1995. They were less than 1500 gm and less than 32 weeks at birth who had survived upon hospital discharge; and they had all completed the routine ophthalmological assessments. All neonates with clinical diagnosis of respiratory distress syndrome requiring mechanical ventilation with more than 40% oxygen were treated with one to three doses of natural surfactant (Survanta-TA) as rescue therapy. Indwelling umbilical artery catheters were also inserted in infants with respiratory problems requiring more than 40% oxygen for arterial blood gas monitoring. Routine cranial ultrasound examinations were performed on day 3, day 7 and then weekly or twice weekly when indicated to detect periventricular or intraventricular haemorrhage or other lesions. Patent ductus arteriosus were confirmed by echocardiogram and treated with indomethacin as indicated clinically.

The first ophthalmologic examination was performed by the ophthalmologist at 32-34 weeks post-menstrual age. Subsequent examinations were done at intervals of 2 weeks until the retina became fully vascularised without retinopathy developed. Infants who had developed retinopathy were followed at weekly or shorter intervals according to the eye condition until the retinopathy had regressed and the vessels had reached full maturity. A follow up examination was done post term to confirm that resolution had occurred. If the retinopathy had progressed to threshold disease (i.e. Zone 1 or 2, 5 contagious o'clock or cumulative 8 o'clock involvement by stage III disease especially with plus disease) cryotherapy would be instituted.

The final visual outcome was assessed by an optometrist at the corrected age of 1.5 year. All the patients' demographic data and perinatal factors were collected by standard charts. The factors studied included: prenatal steroid administration, RDS with surfactant replacement, duration of mechanical ventilation and oxygen therapy, maximum oxygen concentration, arterial PO2>12.0KPa, PO2<6.0KPa, arterial PCO2>8.4KPa, arterial PCO2<4.0KPa, duration of hyperbilirubinaemia, phototherapy, total duration of parenteral nutrition, total volume of blood transfused, patent ductus arteriosus, indomethacin administration, bronchopulmonary dysplasia (oxygen requirement beyond 28 days), treatment with systemic steroid. All these factors were analysed by the student's t-test or the chi-square test. Factors correlating significantly with ROP were then analysed by stepwise logistic regression analysis.

Results

Seventy-nine infants fulfilling the criteria were included in the study. Four infants had incomplete data and therefore 75 infants comprised the study population. The mean birth weight was 1192±233gm and the mean gestational age was 29.4±2.5 weeks. The first ophthalmological examinations were performed at 34±2.2 weeks.

ROP was found in 18 of the 75 infants (24%). Five patients (7%) had stage 3 plus disease and they were treated by cryotherapy. Visual assessment at 1.5 year showed normal visual outcome in 4 and severe myopia in one. No patient had become blind from ROP. The relationship between birth weight and gestational age and the development of ROP is shown in Fig. 1 and 2. Severe ROP requiring cryotherapy occurred exclusively in babies with birth weight less than 1000 grams or less than 26 week gestations.

Fig 1

Fig 2

When comparing risk factors between infants with and without ROP, 18 of the 30 perinatal factors were significantly associated with the development of ROP (Tables I and II). When stepwise logistic regression analysis was applied, only the duration of mechanical ventilation, RDS with surfactant replacement therapy, indomethacin treatment and BPD were found to be related to ROP. When the actual duration of mechanical ventilation is further analysed, all babies who developed severe ROP were ventilated for 7 days or more. The odds ratio and relative risk for ROP are 46.4 and 4.2 respectively. Only four babies who were ventilated for less than 7 days developed ROP but all have had the additional risk factor of BPD.

Discussion

We have analysed the relationship between 30 perinatal factors and the development of ROP in a group of high risk infants. The overall frequency of occurrence of ROP was 24%, and severe ROP ( = stage 3) was 7%; the figures were lower compared with other studies.^1-3 (Table III) All infants without ROP had at least one examination before 35 weeks and were examined again until the retina had become fully vascularised. This should have minimized the possibility of overlooking acute ROP changes. With the current neonatal management protocol and screening programme, no baby had developed blindness as a result of ROP, such results compared favourably with other studies.^1-3 We have found an association between 18 perinatal factors and the development of ROP. Most of these factors have been described previously.^2,4-6 There was a concern that natural surfactant preparation may induce a rapid improvement of oxygenation which may increase the risk of ROP.⁷ However, meta-analysis of both prophylactic and rescue treatment with natural surfactant did not reveal an increase incidence of ROP after surfactant. ⁸ Prenatal steroid administration which facilitates lung maturation and reduces the risk of RDS has been found to confer a protective effect against the development of ROP. RDS with surfactant administration, however, was associated with the development of ROP. Our study design was not aimed at investigating whether surfactant administration increased the risk of ROP. We think, however, RDS which necessitates surfactant administration is probably the important risk factor associated with the development of ROP.

Our study showed a positive association of indomethacin treatment in the development of ROP. ROP is a vascular disorder of the developing retinal arteries caused by vaso-constriction followed by abnormal vaso-proliferation. Indomethacin, an inhibitor of prostaglandin synthetase, can cause vaso-constriction and therefore the closure of the ductus. The similarity between retinal vessels and the ductus arteriosus in their response to oxygen, may suggest a mechanism of development of ROP and the use of indomethacin. Hyperbilirubinaemia is a common problem in Chinese infants.^9-10 Two previous reports have suggested the possible protective effect of bilirubin as an anti-oxidant on the development of ROP.^11-12 This however, was not confirmed by subsequent studies.^13-14 Whether the higher incidence of neonatal jaundice contributed to the lower risk of ROP in our patients remains unclear. However, our study did not find any relationship between the development of ROP and the duration of phototherapy. Transfusions have been previously implicated in the aetiology of retinopathy. ¹⁴ The transfused adult haemoglobin increases oxygen delivery to the retina which may increase the risk of ROP. Our study has shown that the total volume of blood transfused is associated with the development ROP. However, logistic regression analysis failed to support this as an important factor. We suggest that the total volume of blood transfused often correlates with the degree of immaturity and the severity of the neonatal diseases which may contribute to the development of ROP.

Guidelines for screening for ROP and indications for treatment are well established. Un doubtedly the occurrence of blindness and visual impairment due to ROP can be reduced by implementation of an effective screening and treatment program and an improvement of quality of perinatal care. Such screening program needs to cover more than five hundred infants in Hong Kong each year which is well beyond the capabilities of the currently available ophthalmic resources. Based on our results, the development of severe ROP occurred predominantly in premature babies less than 1000 gm or less than 26 week gestation. Under the present neonatal management, the four most important factors identified are the duration of mechanical ventilation, occurrence of RDS, indomethacin administration and bronchopulmonary dysplasia. In order to improve the cost-effectiveness of the screening programme, we suggest to screen all babies less than 26 weeks gestation or less than 1000gms. For babies between 1000-1500gm, we should selectively screen those with RDS requiring ventilatory support for 7 or more days and / or babies with BPD (oxygen dependence >= 28 days).

In summary, the overall incidence of ROP and blindness due to ROP is lower in our study population of Chinese infants. Among the 18 perinatal factors associated with the development of ROP, RDS, duration of mechanical ventilation, indomethacin treatment and bronchopulmonary dysplasia have been identified to be the most important risk factors. For babies more than 1000 grams or 26 weeks gestations, we can selectively screen those babies with RDS who required mechanical ventilation for 7 or more days and / or who required oxygen for more than 28 days.

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