Retinopathy of prematurity among infants admitted to two neonatal intensive care units in Ethiopia

Introduction

Retinopathy of prematurity (ROP) is a vasoproliferative disorder that affects the developing retinal vessels of premature newborns.1 ROP is a leading preventable cause of blindness in children, particularly in middle-income countries. In 2010, the annual incidence of blindness and vision impairment due to ROP was estimated to be 32 300 infants.2

In sub-Saharan Africa, ROP is beginning to emerge as a cause of blindness in children as neonatal intensive care services expand.3

The risk of ROP is inversely related to gestational age (GA) and birth weight (BW) and the risk is higher in those with neonatal comorbidities.4 Poorly monitored supplemental oxygen leading to hyperoxia is a recognised risk factor for treatment-requiring ROP,5 as are low serum IGF-1, poor postnatal weight gain, sepsis, blood transfusion4 and thrombocytopenia.6

In high-income countries, treatment-requiring Type 1 ROP usually only affects extremely preterm (<30 weeks), low BW (<1000 g) infants, with the risk being much lower in more mature preterm infants.5 These findings reflect the high quality of perinatal and neonatal care these infants receive. In low-income countries, rates of Type 1 ROP can also be low, as most infants at risk do not survive. A different picture is seen in middle-income countries, where neonatal care can be suboptimal, and infants are exposed to risk factors, such as poorly regulated supplemental oxygen and sepsis, which are largely controlled in high-income settings. In middle-income countries, rates of Type 1 can be high, and can affect infants with a GA of >34 weeks or BW of >1500 g.3 7 8 The same picture is beginning to emerge in sub-Saharan African countries,9 where neonatal care is developing and expanding, but where infants can be exposed to poorly regulated oxygen and other risk factors.

In 2014, the global preterm birth rate was estimated to be 10.6%, with 14.84 million live preterm births; Asia and Sub-Saharan Africa accounted for 12 million preterm births (81.1%).10 Survival rates for preterm infants have improved in many low-income and middle-income countries as neonatal systems have improved. ROP has not been documented as a significant cause of blindness in low-income countries, but the expansion of neonatal care11 12 has increased survival and hence the risk of developing ROP. In Africa, South Africa, Nigeria and Kenya have ROP screening guidelines.9 13 14

Ethiopia planned to reduce neonatal mortality from 28/1000 in 2015/2016 to 10/1000 in 2019/2020, and to end preventable deaths among newborns and children under 5 years by 2030.15 Ethiopia is the second most populous country in Africa, and 11.4% of births are preterm (<37 weeks of gestation), that is, approximately 320 000 babies each year.16 Before 2020, blindness from ROP was not reported in Ethiopia, including from studies in school for the blind.17 18 However, in 2020, a retrospective study by a paediatric ophthalmologist in a private eye centre showed that 12.9% of the infants born preterm who presented were blind from advanced ROP.19 The study was undertaken in two neonatal intensive care units (NICUs) in the capital city, Addis Ababa: Tikur Anbessa Specialized Hospital (TASH), which is a leading government owned university teaching hospital, and Menelik II, a government referral hospital. The purpose of this prospective study was to determine the proportion of preterm newborns who develop ROP, to identify risk factors for ROP and to describe the outcomes of ROP management.

Methods

Results

During the study period, 4382 infants (1240 at Menelik II hospital; 3142 at TASH) were admitted. Two hundred and two infants (158 at Menilik II; 44 at TASH) met the criteria for ROP screening and were included in this study.

ROP and risk factors

In both NICUs, the mode of oxygen delivery was either through a nasal cannula or continuous positive airway pressure. None of the neonates were intubated for resuscitation.

Overall, 65 (32.2%) of the neonates had any stage of ROP: 35 (15.9%) had stage 1, 18 (8.9%) had stage 2, 11 (5.4%) had stage 3 and 1 had stage 4 (0.05%). No neonates had aggressive posterior ROP (APROP). There was no statistically significant difference in characteristics of the infants screened nor in the proportion of infants developing ROP between the two NICUs (table 2). Overall, 12 neonates (5.9%) had Type 1 ROP, and 1 had stage 4. Four (9.1%) of the severe ROP cases (ie, Type 1 ROP or worse) were from TASH, and 9 (5.7%) from Menelik II hospital (p=0.42).

The mean GA of the 65 neonates with any ROP was 31.3±1.7 weeks (range: 26–34 weeks) and 32.91±1.59 weeks (range: 26–34 weeks) for neonates without ROP (p<0.05) (table 3). Fifty-five neonates (84.6%) with any ROP had a GA of <32 weeks and the mean GA for those with stages 3 or 4 ROP was 28.2 weeks. The mean BW was 1367.31±344.42 g (700–2300 g) among infants with ROP and 1795.99±391.03 g (900–2700 g) in infants without ROP (p<0.05). The mean BW of neonates with stages 3 or 4 ROP was 1324.08±343.69 g (700–2000 g).

Table 3

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ROP in relation to GA and BW

Most neonates with severe ROP (10/13) had BW <1500 g (table 3). Fifty five of the 65 neonates with any ROP had a GA ≤32 weeks and all had a BW of less than 2500 g. Only 1 neonate with severe ROP had a GA of >32 weeks and a BW of >1500 g (figure 1). The mean BW and GA of neonates with severe ROP were 1236.5+264.2 g and 30.3+1.9 weeks, respectively.

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Figure 1

GA and BW of infants with Type 1 or stage 4/5 ROP at Menelik II and TASH NICUs, Addis Ababa, Ethiopia (n=13). BW, birth weight; GA, gestational age; NICUs, neonatal intensive care units; ROP, retinopathy of prematurity; TASH, Tikur Anbessa Specialised Hospital.

Discussion

This is the first prospective, descriptive study of rates of and risk factors for ROP in Ethiopia’s leading teaching NICUs, and one of only a few studies from sub-Saharan Africa. The rate of neonatal death in sub-Saharan Africa has decreased by 40% since 1990, reflecting improvements in newborn care, which is likely to lead to an increase in ROP.32 Although Africa has been described as the ‘new frontier’ of ROP blindness,33 data on ROP in sub-Saharan Africa are limited, and studies in schools for the visually impaired and hospitals in eastern Africa suggest currently that only a low proportion of children of school-going age have retinal disorders, including ROP.17 18 23 34

Since 2013, intensive neonatal care has expanded in many public hospitals and private NICUs in Ethiopia,24 and neonatal mortality per thousand live births has declined modestly from 39 in 2000 to 33 in 2019.15 Despite the increasing number of NICUs, there are no national screening guidelines nor a programme for ROP, apart from pilot screening at TASH and Menelik II hospital.

In our study, a third of neonates had ROP of any severity. Similar findings have been reported from South Africa (29.6%),25 India (30%),26 Pakistan (32.4%),27 Oman (34%)28 and Iran (29%),25 which is perhaps surprising given the variation in screening criteria, and likely variation in the quality of neonatal care and survival of preterm infants most at risk.7 The findings in our study are comparable with those from other low-income and middle-income countries, indicating that more mature and heavier newborns also develop severe ROP. In our study, severe ROP developed in 6.9% of neonates, which is comparable to other studies in Africa, that is, from Rwanda (3.9%),29 South Africa (5.9%),30 Sudan (5.2%),31 Nigeria (7.5%)35 and Kenya (8.7%)36 (online supplemental table 1). All studies showed that more mature, heavier newborns were affected than in high-income countries. In our study, no infant developed APROP, as in other studies from sub-Saharan Africa, and none became blind from ROP. APROP usually occurs in extremely preterm, low BW infants, the majority of whom do not survive in this setting.21

In univariate analysis, the following variables were associated with ROP of any severity: lower BW, lower GA, being female, RDS, oxygen supplementation and oxygen therapy for more than 7 days. In multivariable analysis, lower BW and GA, RDS and oxygen supplementation were independent risk factors for ROP. Lower BW and GA are well-recognised risk factors for ROP, as is exposure to supplemental oxygen.4 Measuring exposure to hyperoxia in preterm infants is challenging, as this requires continuous monitoring over several weeks using monitors which record the periods when oxygen saturation is above or below specified thresholds. A large cohort study showed that the number of days infants received supplemental oxygen in the first 4 weeks of postnatal life was associated with severe ROP,5 but this was not an independent risk factor in our study. The advantage of using days in oxygen as an exposure measure is that it is easier to collect these data rather than measuring the duration and degree of exposure to hyperoxia over several weeks.

Over half of the neonates in our study with a BW <1500 g and a GA <32 weeks developed ROP. This is consistent with the findings from Singapore,37 Brazil38 and the USA.39 In our study, the mean GA of newborns with severe ROP was higher than the GA of 26 weeks reported in industrialised countries; the mean BW was 1236.5 g. Both of these values are within the range reported in other low-income and middle-income countries (903–1527 g and 26.8–33.5 weeks, respectively).7

Poorer control of potentially modifiable risk factors, such as hyperoxia, sepsis and poor weight gain, is the likely explanation. In our study, mode of delivery, which is not consistently associated with ROP in other studies,4 was not associated with ROP.

Being female was a statistically significant risk factor in our study, but sex differences have not been consistently reported in other studies. Indeed, a recent meta-analysis reported no sex differences among infants treated for ROP.4

All 12 infants with Type 1 ROP were treated with IVB, only two of whom required a repeat injection. In our setting, IVB is the only treatment possible, as a portable laser and general anaesthesia for neonates are not available.

A strength of the study is that it was a multicentre, prospective cohort study. Limitations are that data were not collected on thrombocytopenia, and the 2005 revision of the International Classification of ROP was used and not the 2021 revision.40 However, the definition of Type 1 ROP has not changed.

Conclusions

In conclusion, rates of ROP in these two units in Ethiopia were comparable to findings from other sub-Saharan African countries. Lower GA and BW, RDS and oxygen administration were all significant risk factors for severe ROP. As the two NICUs included in the study are the main neonatal referral centres in Ethiopia, it can be postulated that ROP is emerging as a potentially avoidable cause of blindness in Ethiopia, which is likely to increase as neonatal care services continue to expand. ROP screening criteria should encompass neonates most at risk of Type 1 ROP, which in these two NICUs would be a BW of <1800 g or a GA of ≤33 weeks. Further studies are needed to refine the criteria in level 2 and private NICUs. Screening and treatment guidelines need be developed, and ROP services provided in all hospitals with neonatal care facilities, which is likely to require raising awareness among neonatologists and paediatricians.