Retinopathy of prematurity (ROP) is a proliferative disorder of the immature retinal vasculature. The retina has no blood vessels until around 16 weeks' gestation; the vessels grow out from the optic disc and only reach the periphery of the eye 1 month after birth (Kanski, 2011). ROP was recognised in 1942 in Boston, USA, by Theodore L Terry, and was initially named retrolental fibroplasia. It was described as a ‘fibroplastic overgrowth of persistent vascular sheath behind each crystalline lens’ (Fleck and McIntosh, 2008: 84). While Terry identified ‘fibroblastic overgrowth’, he did not identify the specific aetiological connection to oxygen. Further research, undertaken by Dr Patz in the 1950s in Washington DC, showed that premature infants now cared for in closed cots/incubators, who received high concentrations of oxygen in a confined space, were more likely to develop ROP than those who received low levels. This discovery resulted in oxygen levels administered to preterm infants being restricted to a maximum of 40%, which resulted in increased levels of morbidity and mortality. Thus, the importance of adequate oxygenation with careful monitoring of blood gas measurement and saturation monitoring was seen as the way forward in preventing ROP.
Advances in neonatal care in the 1980s led to improved survival rates for very premature infants, but the increased immaturity of these infants made them far more likely to develop ROP, causing its re-emergence as a significant cause of sight loss in the developed world (Fleck and McIntosh, 2008). According to Brennan et al (2003), around 30% of all premature infants with a birth weight < 1500 g develop ROP in the first weeks of life. This increase has led to the need for health professionals caring for neonates to have an increased knowledge and understanding of ROP, to ensure optimum care is delivered.
Possible causes
It is difficult to identify the cause of ROP due to the complexity of the physiological instability of very premature infants. However, the delivery of appropriate oxygen levels is thought to be an important factor in the prevention of ROP. Oxygen therapy for premature infants often fluctuates due to their susceptibility to apnoeic episodes and bradycardias. In utero, oxygen saturations are 65–70% at best, resulting in high levels of vascular endothelial growth factor (VEGF), which is thought to contribute to normal retinal development (Kanski, 2011). After premature birth, immature lungs and cardiac circulation (i.e. patent ductus arteriosis) result in the infant requiring oxygenation, which causes VEGF levels to drop, which—in turn—slows down retinal growth.
York et al (2004) hypothesised that fluctuations in arterial oxygenation place the infant at higher risk, rather than the amount and duration of oxygen delivery. Chen et al (2010) advocated the initial use of low rates of oxygenation for infants born at less than 32 weeks' gestation, and the later use of high rates of oxygen delivery to reduce the risk of developing ROP. Castillo et al (2011) focused their research on the need for careful pulse oximetry and the choice of oximetry monitoring equipment, which were recognised as important factors in reducing the frequency of wide changes in oxygenation and hyperoxaemic episodes.
Another factor thought to cause ROP is general growth of the premature infant, as hyperglycaemia and metabolic disturbances would appear to contribute to the formation of an abnormal retina. Low levels of insulin-like growth factor-1 (IGF-1) may affect retinal progress (Hellström et al, 2003). Appropriate nutrition can help to prevent ROP; Hylander et al (2001) reported that breast milk helped to prevent the disease. However, Kao et al (2011) explored the association between serum bilirubin levels and breastfeeding with ROP, and found that high serum bilirubin levels appeared to protect against ROP, but that breast milk alone appeared to have no effect on development of ROP.
Most studies that look at the causes of ROP concentrate on the infant post-birth (Chen et al, 2010; Castillo et al, 2011; Kao et al, 2011), but Fortes Filho et al (2011) considered maternal health as a determinant of an infant developing ROP. They reported, in a study of 324 infants, that some anti-angiogenic factors produced by the pre-eclamptic mother might cross the placental barrier to the fetus, providing protection from ROP for several months following birth (Fortes Filho et al, 2011). They also discovered that very low-birth-weight infants born to mothers with pre-eclampsia had a 60% reduction in risk of developing ROP. Other factors that would appear to put the infant at an increased risk of developing ROP include: low weight for gestational age, low Apgar scores at 5 minutes, use of continuous positive airway pressure (CPAP), use of erythropoietin or surfactant, the presence of sepsis, meningitis, patent ductus arteriosis, intraventricular haemorrhage, abdominal distension, diet intolerance or needing blood transfusions (Fortes Filho et al, 2011; Eckert et al, 2012; Neutze and Ferracotta, 2013). In general, studies report that the smallest, sickest babies are those most at risk of developing ROP.
Screening
Guidelines for the screening and treatment of ROP were developed collaboratively with the Royal College of Paediatrics and Child Health (RCPCH), the Royal College of Ophthalmologists, the British Association of Perinatal Medicine and the premature baby charity Bliss (RCPCH et al, 2008). Current guidelines on screening are:
Ideally, screening should take place at either 30–31 weeks post-menstrual age for infants born before 27 completed weeks' gestation, and 4–5 weeks post-delivery for infants born between 27–32 weeks' gestation. If, for any reason, an infant is unable to be screened—for example, if the infant is too unwell—this must be clearly stated in the medical notes and the screening rescheduled within 1 week of the intended examination.
Screening can be stressful for both infants and their parents, and the need for careful preparation is vital. Written information should be given to parents prior to screening, to explain the reasons for screening and the implications of its findings (Smith, 2011). Time should be allowed for parents to ask questions and voice any concerns they may have. Preparation of infants begins 1 hour before with the instillation of eye drops; mydriatics such as cyclopentolate and phenylephrine are most commonly used for pupil dilation, although their use can cause difficulties in this vulnerable patient group. Phenylephrine can cause tachycardia and systemic hypertension in preterm infants; Hered and Gyland (2010) advocated the use of 2.5% solution to reduce the risk of adverse effects, but careful observation during and after screening is of importance. Bonthala et al (2000) reported a slowing down of gastric emptying with cyclopentolate drops, which may have a direct effect on the overall condition of the preterm infant. Neonatal and ophthalmic practitioners involved in screening should possess an awareness of these adverse effects, as per the Nursing and Midwifery Council (NMC, 2007) Standards for Medicines Management, to ensure the safety of infants during and after screening.
Pain control within the preterm infant population has long been problematic, as the neonate vulnerability often limits the use of pharmacological analgesic measures. ROP screening involves using an eyelid speculum, which is thought to be the main source of pain in infants; Mitchell et al (2011) reported a significant increase in apnoeic episodes 24–28 hours after screening. Dempsey and McCreery (2011) noted a reduction in pain scores when topical local anaesthetic drops (proparacaine) were administered 30 seconds prior to commencement of screening. The use of oral glucose has been identified as an effective means of providing comfort for infants during painful procedures (Dilen and Elseviers, 2010). However, Olsson and Eriksson (2011) have disputed its effectiveness in the relief of pain during ROP screening. Some centres use cotton buds instead of an eyelid speculum, as a means of reducing pain levels. Mehta et al (2005) compared three different methods of screening and found that using a RetCam and the indirect ophthalmoscope with a speculum appeared to cause greater discomfort to infants than the indirect ophthalmoscope without a speculum, and this less invasive method should be considered for screening, particularly in sick infants. Whichever method is used, all comfort measures possible should be in place e.g. swaddling, non-nutritive sucking or oral feeding.
Treatment
Treatment under sedation and analgesia plus elective ventilation in the neonatal unit seems the most popular choice for ROP. The guidelines also advocate treatment in theatre under anaesthesia, if time and resources allow (RCPCH et al, 2008). Topical anaesthesia alone is thought to be unsuitable (Smith, 2011). The type of treatment is dependent on the stage and severity of the disease.
The development of therapy including cryotherapy and, later, laser photocoagulation, followed detailed evaluation of stages and distribution of ROP (Committee for the Classification of Retinopathy of Prematurity, 1984). For less severe ROP, laser therapy is the treatment of choice as it has the ability to target tiny vessels more precisely, burning the abnormal ones without affecting the surrounding tissue, which is important for subsequent vascularisation. The laser can make more refined burns on the retina, improving accuracy of treatment of the vessels. However, cryotherapy is still used in many developing countries where laser therapy is not available. Good et al (2010) state that ROP laser treatment can result in extensive amounts of peripheral retinal ablation with the loss of visual field. However, it would appear the benefits of laser treatment far outweigh the risks (RCPCH et al, 2008).
Laser is only suitable for less severe stages of ROP, with more severe stages requiring vitreoretinal surgery. This may include:
Any treatment is usually given to both eyes as the severity and progression of ROP can affect both eyes. Post-operative drop regimes include the administration of mydriatics, steroids, and sometimes antibiotics. The eye should be re-examined 5–7 days later, and re-treatment should be carried out 10–14 days after initial treatment if there has been a poor response.
Future of ROP
Due to the increased survival rate of premature infants, there is a need to target infants who require screening in a more efficient manner. Multiprofessional working should be enhanced in relation to the support of parents whose baby may have a visual morbidity; for example, the midwife, neonatal nurse and/or public health midwife. Further support for parents post-screening is also required in terms of longer-term health and social issues of visual impairment to the individual and society.
Eckert et al (2012) stated that the number of eye examinations performed on preterm infants could be reduced with the introduction of a scoring system. The score suggested takes into consideration other factors, such as comorbidity in the infant and obstetric history, not merely deciding whether an infant should be screened on the basis of gestational age and birth weight. They argue that screening sessions are costly and demand a heavy workload. Moreover, repeated ophthalmological examinations may lead to stress and unnecessary discomfort for already vulnerable infants. However, the suggested scoring system fails to include other predictive factors such as insulin levels, white blood cell counts and the absence of elevated C-reactive protein. The implementation of any scoring system in the UK would need to be cognisant of all of these factors.
Some strategies in the fight against ROP are looking at replacing VEGF to prevent ROP developing. As previously discussed, VEGF levels are known to fall after premature birth. Bevacizumab is a humanised form of VEGF, which has been administered via intravitreal injection to premature infants with some degree of success in preventing ROP, but complications have occurred such as regression to neovascularisation (Neutze and Ferracotta, 2013).
Conclusion
Midwives and neonatal practitioners have a pivotal role to play in the prevention and treatment of ROP (Smith, 2011). Practitioners caring for premature infants are responsible for oxygen administration and monitoring, and should therefore be fully informed of the importance of avoiding fluctuations in oxygen levels. Madden and Bobola (2010) advocated the development of more formal practice guidelines, education, standardisation of practice in oxygen administration, and greater collaboration between health professionals and respiratory therapists.
ROP is a treatable disease which, owing to the number of premature infants born, will continue to be seen by ophthalmologists. Screening and treatment with laser would appear to be the most effective forms of limiting its progression, although research continues to attempt to find other means of prevention and treatment. There has been some development aimed at the prediction and screening of infants most at risk. More research and evidence is required before such a practice could be fully implemented in the UK.