On-line version ISSN 2078-5135
Print version ISSN 0256-9574
SAMJ, S. Afr. med. j. vol.103 n.2 Cape Town Feb. 2013
L VisserI; R SinghII; M YoungIII; H LewisIV; N McKerrowV (ROP Working Group, South Africa)
IDepartment of Ophthalmology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban. MB ChB, MMed (Ophth), FCOphth (SA)
IIDepartment of Paediatrics, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban; MB BS, FCPaed (SA), Cert Neonatology (SA)
IIIDepartment of Ophthalmology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, MB ChB, FCOphth (SA)
IVPaediatrician in private practice, Centurion, Gauteng, South Africa; MB ChB, FCPaed
VDepartment of Paediatrics, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban; BA, MB ChB, DCH (SA), FCPaed (SA), MMed (Paed), PG Dip Int Research Ethics
BACKGROUND: Retinopathy of prematurity (ROP), one of the most common causes of preventable blindness in preterm neonates, is emerging as a 'third epidemic' in middle-income countries including South Africa. This is due to the increasing survival of preterm neonates, insufficient monitoring of oxygen saturation (SaO2) in most centres, and lack of an ROP screening guideline in most neonatal units.
OBJECTIVE: To guide the standard of care for SaO2 and ROP screening in preterm neonates weighing <1 500 g.
VALIDATION: This guideline, endorsed by the United South African Neonatal Association (USANA), the Ophthalmological Society of South Africa (OSSA), and the South African Vitreoretinal Society, was developed by the ROP Working Group of South Africa, comprised of neonatologists, ophthalmologists and paediatricians.
RECOMMENDATIONS: All healthcare professionals involved in the care of preterm neonates should be aware of SaO2 and ROP screening guidelines. Mothers should be counselled about the possible complications of prematurity.
As a middle-income country with a limited healthcare budget, South Africa (SA) faces many challenges. The country is making huge efforts to meet the Millennium Development Goals, specifically goals 4 and 5. Maternal and child health represents an important priority to improve morbidity and mortality rates.
Surviving premature infants have many unique healthcare needs, including screening for retinopathy of prematurity (ROP). The importance of this screening cannot be underestimated, as early detection and treatment reduces blindness and permanent disability.
SA has become part of the so-called 'third epidemic of ROP', with an increasing incidence as more premature infants survive due to improved neonatal care. As in other middle-income countries, infants with higher birth weights are at risk of ROP because treatment units may not have the skills or equipment to monitor oxygen appropriately. Resources may also be inadequate to identify at-risk infants.1
Each year >1 million babies are born in SA; 87% in the public healthcare sector, including almost half in district-level facilities, 10% in clinics or community health centres, and 38% in district hospitals. An equal number of neonates are delivered in facilities with specialist-run services; 32% in regional hospitals and 20% in tertiary and central hospitals.2
Data suggest that 12.8% of babies born in the public sector have a birth weight <2 500 g.2 As the sector has limited facilities, few newborns have access to appropriate care. While public health and infrastructure interventions aim to improve facilities to ensure equitable access to care, such improvements take time. Even if these plans are realised, a mismatch in services for babies at risk of ROP will persist. Neonatal intensive care units (NICUs) are to be established in tertiary and regional hospitals, where ophthalmology expertise is often not available. Approximately 16 000 babies are at risk of ROP and require screening each year.1 These disparate services necessitate innovative responses in the implementation of screening programmes to successfully minimise the consequences of ROP.
Studies in SA academic institutions have shown an acceptably low ROP incidence.3 However, these centres have appropriate neonatal care facilities and adequate resources to screen high-risk infants.4-6
Larger, well-resourced centres may follow guidelines such as those of the American Academy of Pediatrics and the Royal College of Ophthalmologists. However, these guidelines may not be appropriate in under-resourced centres. Rather, guidelines proposed in other middle-income regions may be more fitting, e.g. those from South East Asia and Central/South America, where larger, more mature infants at risk have been identified.7
Barriers to screening must also be overcome,8 including: the need to travel to a treatment/screening centre; the affordability and time- constraints of taking infants elsewhere for further screening; and loss to screening/follow-up programmes.
An absolute shortage of ophthalmologists in SA compounds the problem. The few appropriately trained state-employed ophthalmologists are based mainly in the larger urban centres. In remote areas, new technologies such as digital photographic screening devices may offer remote screening via telemedicine. However, these electronic devices are expensive and require a trained technician to capture and transmit the images for evaluation.9
This 2012 consensus guideline, developed by paediatricians, neonatologists and ophthalmologists in SA public and private practice, has been endorsed by the United South African Neonatal Association (USANA), the Ophthalmological Society of South Africa (OSSA), and the South African Vitreoretinal Society. It is intended to guide the screening and appropriate neonatal care of infants at risk of ROP.
2. Oxygen saturation guideline after birth
Different centres in different countries report a varying incidence of severe ROP. The altered regulation of vascular endothelial growth factor from repeated episodes of hyperoxia and hypoxia is one important factor in ROP pathogenesis. Strict management of oxygen delivery and monitoring to minimise these episodes may be associated with decreased rates of ROP.
Oxygen is the most commonly used 'drug' in neonatal units. It is well documented that it is easy to damage the eyes of preterm infants by administering too much oxygen, especially in the first few weeks of life. Studies have shown a relationship between oxygen administration and the development of ROP.10-12 In animal models, repeated cycles of hyperoxia and hypoxia were shown to produce more retinal neovascularisation than hypoxia or hyperoxia alone.13 In the early 1990s, an increased incidence of severe ROP was shown in premature infants in the first several weeks of life with a transcutaneous oxygen tension (tcPO2) >80 mmHg.14
In the first weeks of life, lower oxygen saturation (SaO2) targets in preterm infants reduce ROP and pulmonary complications and may improve growth. Data from NICUs in Northern England15 identified 4 oxygen policies in neonates according to SaO2 limits that were set at: (i) 70 - 90%; (ii) 84 - 94%; (iii) 85 - 95%; and (iv) 88 - 98%. The occurrence of ROP requiring cryotherapy (threshold ROP (tROP)) was 4 times higher in the high SaO2 group (88 - 98%) compared with the low SaO2 group (70 - 90%). This was confirmed in a study which found that neonates nursed in SaO2 >92% had more severe ROP than babies nursed in SaO2 <93%.16
The Australian Benefits Of Oxygen Saturation Targeting (BOOST) trial compared an SaO2 of 91 - 94% v. 95 - 98% in neonates.17 While no difference was found in long-term development, there was an increase in the duration of oxygen therapy, an increase in the occurrence of home oxygen therapy, and more frequent chronic lung disease in the high SaO2 group. High SaO2 targets therefore have a detrimental effect on the lungs and the eye. The unexpected finding of excess deaths from pulmonary causes among infants in the high SaO2 group - albeit not statistically significant - accords with the findings of the only other trial in which preterm infants were randomly assigned to different target SaO2 ranges - namely the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial.18 The trial showed an increased rate of adverse pulmonary sequelae (although not an increased rate of death due to pulmonary causes) among preterm infants with pre-tROP when a higher SaO2 range (96 - 99%) was targeted.
Chow et al.19 emphasised the importance of avoiding peaks in SaO2 and the constant training of staff to keep the saturation within strictly defined limits. Oxygen toxicity, particularly in preterm infants, can inhibit lung healing and contribute to ongoing lung injury.20
A meta-analysis of the association between SaO2 measured by pulse oximetry and risk of severe ROP indicated a statistically significant risk reduction of 52% with low SaO2 (70 - 96%) in the first postnatal weeks and 46% with high SaO2 (>94 - 99%) at a postmenstrual age (PMA) of >32 weeks.21 The analysis revealed that high SaO2 has different effects at postnatal points that correspond roughly to the first and second phases of ROP.
High partial oxygen pressure (PaO2) occurs very rarely in neonates breathing supplemental oxygen when pulse SaO2 values are 85 - 93%. This pulse SaO2 range also is infrequently associated with low PaO2 values. Pulse SaO2 values of >93% are frequently associated with PaO2 values >80 mmHg, which may be of risk for some newborns receiving supplemental oxygen.22
The optimal SaO2 is not known in infants of extremely low birth weight, but data indicate that it should be kept at <93%. In the SUPPORT trial, a target SaO2 range of 85 - 89%, compared with 91 - 95%, did not affect the combined outcome of severe ROP or death. However, it increased mortality while substantially decreasing severe ROP among survivors. Caution should be exercised in targeting levels of SaO2 in the low range for preterm infants, as it may lead to increased mortality.23 Many centres therefore aim for saturations of 88 - 92%. Fluctuations with peaks in SaO2 should be avoided.
Table 1 lists clinical trials which compared outcome parameters in infants according to higher and lower SaO2 groups.
Table 2 summarises the characteristics of studies that assessed the association between high SaO2 and severe ROP risk among preterm infants in the first several weeks of life. Meta-analysis of the pooled estimates showed a significantly decreased risk of ROP with lower SaO2 (relative risk (RR) 0.48; 95% confidence interval (CI) 0.31 - 0.75).
Table 3 summarises the characteristics of studies that evaluated the association between SaO2 and severe ROP risk after a PMA >32 weeks in preterm infants. Meta-analysis of the pooled estimates showed a statistically significant RR of 0.54 (95% CI 0.35 - 0.82).
In a meta-analysis of high or low oxygen saturation and severe ROP, Chen et al.21 concluded that low SaO2 (70 - 96%) in the first several postnatal weeks was associated with a reduced risk of severe ROP (RR 0.48; 95% CI 0.31 - 0.75) and high SaO2 (94 - 99%) after a PMA of 32 weeks was associated with a decreased risk for progression to severe ROP (RR 0.54; 95% CI 0.35 - 0.82).21
Currently, the ongoing Neonatal Oxygen Prospective Meta- analysis (NeOProM) study is questioning whether targeting a lower oxygen range in extremely premature neonates increases or decreases the composite outcome of death or major disability in survivors by >4%.The results of the study will be available in 2014.
All neonates receiving supplemental oxygen (ventilator, continuous positive airways pressure (CPAP), nasal prongs or head box oxygen) should be monitored with a pulse oximeter and SaO2 should be recorded. Oxygen should be humidified. An oxygen saturation guideline (Appendix I) should be displayed in the neonatal ICU.
3. Screening protocol
ROP is a disorder of the developing retina of preterm infants that potentially leads to blindness in a small but significant percentage. ROP cannot occur in term neonates, as the retina is fully developed. The disease is a preventable cause of blindness if supplemental oxygen therapy is used appropriately, and a screening programme is in place for preterm neonates who have received such therapy. An effective goal of a screening programme is to identify the preterm infants at risk of ROP and who require treatment (from the much larger number of at-risk infants), while minimising the number of stressful examinations required for these sick infants. Any screening programme designed to implement an evolving standard of care has inherent defects such as over-referral or under-referral, and by its nature, cannot duplicate the precision and rigor of a scientifically based clinical trial.
The recommendations for screening are modified from the guidelines of the American Academy of Pediatrics and those of the United Kingdom. In SA, most pregnant mothers do not know their gestation, and gestational age assessment is not accurate. It is therefore recommended that weight rather than gestational age is used for screening high-risk preterm neonates. There are few studies regarding the incidence of ROP in sub-Saharan Africa. An early study of children in schools for the blind in SA revealed that 10.6% of blindness was due to ROP; only 1.25% of this was in black children.33 Kirsten et al.6 reported a 30% frequency of ROP (7% with stage 3 or worse) in a multiracial study population. Delport et al.5 reported an ROP frequency of 24.5% in a hospital treating predominantly black patients (Kalafong), with 6.4% developing stage 3 ROP and 4.2% requiring treatment (including 1 neonate with a birth weight >1 250 g).
The incidence of childhood blindness due to ROP in certain Latin American and Eastern European countries has been reported to be as high as 38.6% and 25.9%, respectively.33 The incidence of ROP in a Vietnamese study34 was 45.8% in neonates weighing <2 000 g and 81.2% in babies weighing <1 250 g. In total, 25% of the babies weighing <1 250 g developed tROP.
A large prospective study of ROP at Chris Hani Baragwanath Academic Hospital (CHBAH), Soweto - a tertiary referral centre for indigent South Africans4 - reported a 2.5% overall occurrence rate of stage 3 ROP. Those with tROP requiring treatment represented 1.6% of the total cohort. No tROP was observed in neonates weighing >1 250 g at birth, but many patients with ROP were lost to follow-up before witnessing progression or regression of tROP. The SA studies have been among small cohorts in tertiary centres. Multicentre studies must be performed to establish the actual incidence of ROP. Most level 2 hospitals admit preterm neonates who are given supplemental oxygen. These facilities do not perform ROP screening due to a lack of resources and shortage of ophthalmologists. A screening guideline must be implemented in level 2 centres, to identify and appropriately refer at-risk neonates.
3.1 Screening guideline
3.1.1 Who to screen
- All neonates born prior to 32 weeks' gestation
- All preterm neonates weighing <1 500 g.
- Preterm infants weighing 1 500 - 2 000 g may also be at risk of ROP if they have risk factors such as: a family history of ROP, cardiac arrest, multiple (>2) blood transfusions, exchange transfusion or severe HIE. If their oxygen monitoring has been suboptimal, then screening can be considered if resources allow, but ensuring appropriate oxygen monitoring is more cost- effective.
3.1.2 When to screen
- Screening should be performed at 4 - 6 weeks chronological age or 31 - 33 weeks post-conceptional age (whichever comes later). If gestational age is unknown, then chronological age should be used.
- Threshold is usually reached by 37 weeks - it is therefore important to assess the baby before 37 weeks post-conceptional age.
- After the initial screening, follow-up for ROP will be determined by the ophthalmologist.
3.1.3 Where to screen
- Outpatient screening should be performed in a facility capable of caring for a child who develops apnoea during the examination and where ophthalmological services are available. Where there is limited access to phthalmologists, other screening modalities (such as photographic screening - see below) may be considered.
- A guide for screening for ROP (Appendix II) should be displayed in the neonatal ICU.
3.1.4 Preparation of the infant for screening
- Benoxinate (local anaesthetic): apply 1 drop to each eye at the outset
- Cyclomydril (2 mg cyclopentolate hydrochloride, 10 mg phenylephrine hydrochloride) (to dilate the pupils): apply 1 drop to each eye every 15 - 20 min, commencing approximately 45 minutes prior to the eye examination, until the pupil is dilated (an average of 3 drops)
- Chlorampenicol (topical antibiotic): apply 1 drop at the end of the examination
- Refer to Appendices III, IV and V
4.Guideline for ophthalmologists performing ROP screening
Patients should be referred to the ophthalmologist by the neonatologist according to the referral protocol above. Should an ophthalmologist not be available, photographic screening may be an option (see below).
4.1 Where to screen
To avoid physiological stress on the infant, examination should ideally be performed by the ophthalmologist in the neonatal unit with appropriate monitoring, as guided by the treating neonatal healthcare professionals. Should this not be possible, personnel and equipment needed for neonatal resuscitation should be easily accessible to the ophthalmologist at the time of examination.
4.2 How to screen
- The discomfort and systemic effect of the examination should be minimised by pre-treatment of the eyes with a topical anaesthetic agent such as proparacaine or benoxinate.
- The use of pacifiers or oral sucrose may be considered.
- Pupils should be dilated with Cyclomydril drops, applied every 15 - 20 minutes (1 drop to each eye, commencing 45 - 60 minutes prior to the eye examination - refer to Appendices III, IV and V).
- Examination must be performed by a qualified examiner using binocular indirect ophthalmoscopy (Appendix VI).
- Detailed notes should be kept (e.g. see Appendix VII).
- In the absence of qualified examiners, photographic screening should be done.
4.3 How to follow-up and manage
Follow-up examinations should be recommended by the examining ophthalmologist on the basis of retinal findings classified according to international classification35 (Appendix VIII). The following schedule is suggested:
- 1 week or less follow-up
- Stage 1 or 2 ROP in zone I
- Stage 3 ROP in zone II
- 1 - 2 weeks follow-up
- Immature vascularisation in zone I (no ROP)
- Stage 2 ROP in zone II
- Regressing ROP in zone I
- 2 weeks follow-up
- Stage 1 ROP in zone II
- Regressing ROP in zone II
- 2 - 3 weeks follow-up
- Immature vascularisation in zone II (no ROP)
- Stage 1 or 2 ROP in zone III
- Regressing ROP in zone III.
The presence of plus disease (defined as dilation and tortuosity of the posterior retinal blood vessels) in zones I or II suggests that peripheral ablation, rather than observation, is appropriate.36 Practitioners involved in the ophthalmological care of preterm infants should be aware that the retinal findings that require strong consideration of ablative treatment were revised according to the Early Treatment for Retinopathy of Prematurity (ETROP) randomised trial.37 The identification of tROP, as defined in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CryoROP), may no longer be the preferred time of intervention. Treatment may also be initiated for the following retinal findings:
- Zone I ROP: any stage with plus disease
- Zone I ROP: stage 3, no plus disease
- Zone II ROP: stage 2 or 3 with plus disease.
Special care must be taken in determining the zone of disease. The number of clock hours of disease may no longer be the determining factor in recommending ablative treatment. Treatment should generally be accomplished, when possible, within 72 hours of determination of treatable disease to minimise the risk of retinal detachment.
4.4 When to stop screening
The conclusion of acute retinal screening examinations should be based on age and retinal ophthalmoscopical findings.36 Findings that suggest that examinations can be curtailed include:
- Zone III retinal vascularisation attained without previous zone I or II ROP (if the examiner doubts the zone or if the postmenstrual age is <35 weeks, confirmatory examinations may be warranted)
- Full retinal vascularisation
- Postmenstrual age of 45 weeks and no pre-threshold disease (stage 3 ROP in zone II, any ROP in zone I) or worse ROP is present
- Regression of ROP38 (care should be taken to ensure that no abnormal vascular tissue is present that is capable of reactivation and progression).
5. General information
It is very important that healthcare staff members communicate with guardians. Guardians should be made aware of ROP examinations and be informed if their child has ROP, with subsequent updates on ROP progression. The possible consequences of serious ROP should be discussed at the time that a significant risk of poor visual outcome develops. Documenting such conversations with parents in the nurse or doctor notes is highly recommended.
If hospital discharge or transfer to another neonatal unit or hospital is contemplated before retinal maturation into zone III has occurred, or if the infant has been treated by ablation for ROP and is not yet fully healed, then the availability of an appropriate follow-up ophthalmological examination must be ensured. Specific arrangements for that examination must be made before discharge or transfer. The transferring primary doctor, after communication with the examining ophthalmologist, should be responsible for communicating which eye examinations are needed and their required timing to the infant's new primary doctor. The latter should ascertain the ocular examination status of the infant from the record and via communication with the transferring doctor. Necessary examinations by an ophthalmologist experienced in examining preterm infants for ROP can thereby be arranged promptly at the receiving facility, or as an outpatient if discharge is contemplated before the need for continued examination has ceased.
If guardians are delegated responsibility for arranging follow-up ophthalmological care after discharge, then they should understand: the potential for severe visual loss, including blindness; that there is a critical time window to be met for treatment success; and that timely follow-up examination is essential to successful treatment. This information should preferably be communicated verbally and in writing (Appendix IX). If such arrangements for communication and follow-up after transfer or discharge cannot be made, then the infant should not be transferred or discharged until an appropriate follow- up examination can be arranged by the discharging unit.
6. Telemedicine screening and monitoring of ROP
A lack of skilled personnel to perform screening often restricts both the screening and management of ROP. Proposed revisions in the management of high-risk pregnancies, the improvement in neonatal survival and the development of new neonatal units may dramatically increase the number of premature infants requiring screening. The ability to offer a comprehensive screening service at all hospitals in which neonates at risk are managed may be limited by a lack of suitably trained paediatric ophthalmologists.
The advantages of telemedicine screening in ROP39-43 include the ability to train neonatal nursing staff, medical officers and optometrists to capture and transmit screening photographs to a suitably trained ophthalmologist for assessment.
Use of the digital wide-field retinal imaging Retcam II is well described for ROP screening. The Retcam has the advantage over other digital retinal imaging systems in being a hand-held contact- based camera that is suitable for use in neonatal units or operating theatres and does not require patient co-operation or a seated position. Studies have confirmed the sensitivity and specificity of the Retcam, and its use is a safe, effective alternative for providing screening where appropriate ophthalmologists are not available. The Retcam is also widely used to document disease management and response to treatment.
ROP is a preventable disease. Optimal management of oxygen therapy is the most important preventive measure. Every unit which cares for preterm neonates should have protocols and guidelines on oxygen therapy and SaO2 targets in neonates. Timeous referral to the ophthalmologist for ROP screening is important to enable early diagnosis and treatment of ROP in preterm infants weighing <1 500 g and in larger unstable preterm infants where oxygen monitoring and management has been suboptimal.
We wish to acknowledge Dr Y Cara, Professor Adhikari and Dr L Naidoo for their contribution to this guideline.
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Accepted 28 September 2012.
L Visser (email@example.com)
Additional comments: A Horn (Division of Neonatology, Department of Paediatrics, University of Cape Town), J Smith (Division of Neonatology, Department of Paediatrics and Child Health, Stellenbosch University and Tygerberg Children's Hospital, Cape Town), S Velaphi (Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; on behalf of the United Neonatal Association of South Africa), I Mayet (Department of Ophthalmology, University of the Witwatersrand, Johannesburg), R Grotte (Department of Ophthalmology, University of Cape Town), N Freeman (Department of Ophthalmology, Stellenbosch University).