Fig. 14.1
Number of reported cases of ROP in premature. a First epidemic; b second and third epidemics
The WHO has estimated that there are 19 million visually impaired children, 1.4 million of whom are blind. Its incidence is between 0.2 and 7.8/10,000 children, depending on the mortality rates of children younger than 5 years old, based on data that are available from each region and country. In industrialized countries such as the UK, [3] which recently published a comprehensive study on the subject, it was noted that cases doubled from 0.17 to 0.41/10,000 children by the age of 15 years old [4]. Cataracts, diabetic retinopathy, glaucoma, and ROP are the major causes of childhood blindness and visual impairment (Table 14.1) [5], and they are among the priorities of the Pan American Health Organization (PAHO). The Action Plan on Eye Health VISION 2020 Latin America was officially launched in 2004 as a partnership among PAHO, the Pan American Association of Ophthalmology (PAAO), Initiatives for Blind Prevention of the WHO, and nongovernmental organizations such as VISION 2020 “Right to Sight”, and it has made changes to the work of health systems and the development of national plans for children in many countries [6]. The strategies of vitamin A supplementation and measles immunization have increased coverage, and the blindness from these causes has been eliminated in many developing countries [7]. ROP is now the foremost problem, especially in most industrializing countries in Latin America and Asia, where the survival of VLBW infants has improved considerably over the last decade. Cases are concentrated in less developed countries that have a higher incidence of prematurity (Table 14.2).
Table 14.1
The different causes of childhood severe visual impairment/ blindness
Causes by anatomical site | % |
|---|---|
Cerebral visual pathways | 40 |
Retina | 24 |
Optic nerve | 23 |
Whole globe and anterior ocular segment | 6 |
Cornea/Lens/Uvea | 3 |
Glucoma | 2 |
Other | 2 |
Table 14.2
Preterm birth rates by country
Country | Preterm birth/100 livebirths |
|---|---|
Latvia | 5.3 |
Croatia | 5.5 |
Finland | 5.5 |
Lithuania | 5.7 |
Estonia | 5.7 |
Japan | 5.9 |
Sweden | 5.9 |
Norway | 6.0 |
Slovakia | 6.3 |
Ireland | 6.4 |
Italy | 6.5 |
Greece | 6.6 |
Denmark | 6.7 |
France | 6.7 |
Poland | 6.7 |
Chile | 7.1 |
Czech Republic | 7.3 |
Switzerland | 7.4 |
Spain | 7.4 |
Slovenia | 7.5 |
New Zealand | 7.6 |
United Arab Emirates | 7.6 |
Australia | 7.6 |
Portugal | 7.7 |
Argentina | 8.0 |
Israel | 8.0 |
Germany | 9.2 |
Austria | 10.9 |
USA | 12.0 |
Costa Rica | 13.6 |
Ghana | 14.5 |
Cyprus | 14.7 |
Pakistan | 15.8 |
Mozambique | 16.4 |
Zimbabwe | 16.6 |
Congo | 16.6 |
Malawi | 18.1 |
Perinatal Strategies in the Prevention of ROP
Neonatologists should focus their work in ROP on various strategies applied at different times in clinical practice.
Prenatal Care
Fetuses grow and develop in a relatively hypoxic environment, but with sufficient oxygen (O2) to meet their needs. If available oxygen decreases, the fetus has specifics mechanisms of adaptation and compensation. The fetal arterial O2 pressure is close to 20–25 mm Hg. This low pressure is “misleading”, and oxygen availability during stress depends on the amount of oxygen delivery with blood perfusion (systemic oxygen transport) and tissue requirements (oxygen demand) and not only oxygen stress. Fetal hemoglobin (Hb F) provides the fetus with the ability to carry more oxygen from the placenta. It requires more oxygen than adult hemoglobin in the same concentrations, which allows it to absorb oxygen placental hemoglobin, with an oxygen pressure less than that in the maternal lung.
Prevention of preterm birth should be a joint effort with the obstetric team [8], sensitizing doctors to the impact of prematurity on the visual health of children and optimizing interventions in pregnant women. The use of antenatal steroids has small protective effects, so steroids should work to improve coverage of those at risk for preterm birth [9].
It has been postulated that vascular development and angiogenesis are the results of complex interactions between growth factors and mitogens, both locally and systemically produced, which stimulate or inhibit cell differentiation, proliferation, migration, and maturation of endothelial cells. Hellstrom et al. reported that low levels of insulin-like growth factor (IGF-I) in preterm patients were associated with ROP; in addition, these levels are as good a predictor of the disease as gestational age and birth weight. Recently, IGF levels were associated with ROP by intraocular quantification, varying with repeated fluctuations between hyperoxia and hypoxia [10]. This finding suggests that these cytokines might increase understanding of the observed clinical findings after these fluctuations in ROP. The regulation of the expression of vascular endothelial growth factor (VEGF) and other cytokines can contribute both to normal retinal vascular growth and to abnormal disruption and subsequent neovascularization. VEGF gene expression is regulated by many factors, including hypoxia, which is a potent inducer of VEGF by increasing gene transcription and stability in RNA, growth factors, cytokines, and other extracellular molecules [11, 12].
Perinatal Strategies to Be Implemented (Table 14.3) [13]
Surveillance of risk factors for preterm birth and controlling them.
Table 14.3
Contribution of risk factors to extremely, very, and moderately preterm births—register-based analysis of 1,390,742 singleton births
Adjusted odds ratio by risk factor | Extremely preterm OR (IC) | Very preterm OR (IC) |
|---|---|---|
Maternal age: 30–39 (years) | 1.25 (1.16–1.36) | 1.24 (1.17–1.33) |
Pregravid BMI ≥ 30 | 1.48 (1.20–1.82) | 1.46 (1.24–1.74) |
Smoking | 1.21 (1.09–1.34) | 1.23 (1,33–1.34) |
Not married or cohabiting | 1.31 (1.12–1.54) | 1.32 (1.16–1.50) |
Prior miscarriages | 1.41 (1.36–1.46) | 1.26 (1.22–1.31) |
In vitro fertilization | 2.14 (1.63–2.82) | 1.52 (1.18–1.96) |
Anemia ≤ 100 g/l | 2.48 (1.82–3.38) | 1.48 (1.08–2.04) |
Chorionic villus biopsy | 1.80 (1.38–2.33) | 1.20 (0.93–1.56) |
Amniocentesis | 2.04 (1.75–2.37) | 1.58 (1.38–1.82) |
SGA | 7.35 (6.69–8.09) | 7.93 (7.35–8.55) |
Mayor congenital anomaly | 3.57 (3.17–4.01) | 4.70 (4.31–5.12) |
Stillbirth | 4.46 (3.68–5.42) | 3.73 (3.10–4.49) |
Screening for urinary tract infections of pregnant women.
Treatment of bacterial vaginal infections.
Surveillance of twin pregnancies.
Length measurement of the uterine cervix at 20–22 weeks of gestation; if less than 25 mm in longitude, it is associated with a 40% rate of preterm birth.
Uterine artery Doppler ultrasound at 22–24 weeks to identify the risk of changes due to preeclampsia.
Treatment with progesterone or cervical cerclage perhaps indicated.
Use of tocolytics to delay delivery in cases of early labor.
Use of antenatal steroids.
Postnatal Care
Advances in the Neonatological Treatment of Prematurity, the “Better Practices”
The principal risk factors described are prematurity, oxygen therapy, male sex, and white race. Other risk factors have also been identified: delays in pre- and postnatal growth, assisted ventilation for more than 1 week, surfactant therapy, high volume blood transfusions, the use of erythropoietin and severe disease have been independently associated with higher rates of ROP.
The key is the prevention of ROP, for which we should emphasize the importance of identifying and reducing known risk factors.
Oxygen as a Principal Risk Factor
Oxygen is essential for cell functioning. The fetus develops normally in a hypoxic environment, and mechanisms to neutralize the adverse effects of high levels of oxygen are not fully developed. The range of oxygen and its requirements are not known and are variable during fetal development. Oxygen plays an important role in the pathogenesis of ROP; both hypoxia and hyperoxia will trigger a cascade of events that can lead to retinopathy [2, 14, 15]. Longer and uncontrolled high inspiration of oxygen concentration therapy severely increases the risk of ROP.
Excess oxygen interrupts normal vascular development and starts stimuli that can lead to ROP [16]. The retina is rich in polyunsaturated fatty acids, and it can easily produce lipid peroxidation and free radicals. Prostaglandin generation plays an important role in the regulation of ocular blood flow. Nitric oxide is very active in the choroid coat of the globe of the newborn, and it also regulates local flow. Interaction between increased PaO2 and the perfusion pressure in the retina causes hyperoxia and initiates vascular alterations with the aberrant vessel characteristics of ROP. The most cost-effective action in the prevention of ROP is the prevention of preterm birth and rational and controlled use of oxygen [17].
Cautious administration of oxygen should be considered in three periods in premature infants: immediately after birth; during the acute phase of respiratory illness and recovery of neonatal distress; and at the time when bronchopulmonary dysplasia (BPD) begins.
After birth, many premature infants require supplemental oxygen to achieve adequate levels of oxygenation in the first 20 min of life. In the resuscitation of preterm infants <32 weeks old, an initial oxygen concentration between 30 and 40% is appropriate to reach saturation of 80–85% at 5 min of life and to stabilize at 88–92% at 20 min [18].
Early in the acute stages of illness, oxygen-saturation targets should be maintained at a low range of 88–92% to reduce the risk of ROP. Pulse oximetry is the best method to measure O2 saturation (SpO2) [19]. The correlation between SpO2 and PaO2 can be difficult to interpret because the affinity of fetal Hb to oxygen can be affected under different physiological conditions. Castillo et al. showed in preterm infants that SpO2 values between 85 and 93% were correlated well with a mean PaO2 of 56 ± 14.7 mm Hg, whereas SpO2 was 93%, and PaO2 increased to 107.3 ± 59.3. SpO2 limits must be maintained in the prescribed range. Surfactant use in RDS allows for less use of O2 in quantity and duration (Table 14.4).
Table 14.4
Summary meta-analysis of severe ROP in infants in low versus high oxygen-saturation target
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