Retinopathy of prematurity (ROP) is a relatively modern disease, first described in 1942 as retrolental fibroplasia. The very technologies, such as the incubator, that allowed for survival of preterm infants who would have otherwise died, were also found to play a role in the development of organ damage. Supplemental oxygen has long been linked to the development of severe ROP, particularly when delivered to preterm infants at supra-ambient pressures over an extended period of time. Although the pathogenesis of ROP is still far from being fully elucidated and remains an active area of research, the role of non-invasive respiratory support, particularly supplemental oxygen in the absence of supra-ambient pressures, has not been investigated to date. Given the widespread use of non-invasive respiratory support in hospitals around the world, closer investigation may be warranted.
A preterm male infant was born at 29 and 6/7 weeks' gestational age (GA), weighing 1,400 g. The pregnancy was complicated by a twin gestation and premature labor. Two doses of maternal betamethasone were administered at 26 weeks. The infants were born via cesarean section at a community hospital for malpresentation with ongoing labor. Delivery room resuscitation included the administration of blow by oxygen.
The infant was transferred to our neonatal intensive care unit for respiratory support. He received supplemental oxygen varying from 0.21 to 0.40 fraction of inspired oxygen (FiO2) through day of life 3, via non-invasive mechanical ventilation or nasal continuous positive airway pressure, due to a diagnosis of respiratory distress syndrome of prematurity. From day of life 6 to 20 he received high-flow nasal cannula only, with 0.21 FiO2. During this time, he had occasional apneic episodes, feeding intolerance, and concerns for atelectasis. His pulse oximetry (SpO2) remained above 95% from day of life 4 onward (Table 1).
Summary of Respiratory Support
On day of life 28, at post-menstrual age (PMA) 33 and 5/7 weeks, he was diagnosed as having ROP stage 3, zone I, exhibiting fan-like vascularization with plus disease in both eyes (Figure 1). The patient was treated with intravitreal bevicizumab in both eyes due to the posterior and aggressive nature of the ROP. He required 2 to 4 liters of high-flow nasal cannula and 0.21 FiO2 for 2 days surrounding treatment. Complete regression of plus disease in both eyes occurred by 1 week and the neovascularization fully regressed 2 weeks after treatment. Recurrence of ROP began at PMA 41 and 5/7 weeks. At PMA 44 and 5/7 weeks, stage 2, zone I disease with pre-plus disease was noted in both eyes (Figure 2). By PMA 45 and 5/7 weeks, stage 3, zone I with plus disease was noted in both eyes and the patient was re-treated with intravitreal bevicizumab, again due to the posterior nature of the ROP. At PMA 67 and 5/7 weeks, another recurrence occurred, displaying stage 3, zone 2 ROP with pre-plus disease in both eyes. He was treated with panretinal photocoagulation laser in each eye and had complete regression. At 14 months old, his visual acuity was fix and follow in both eyes, with cycloplegic refraction of −7.00 +1.00 × 180° in the right eye and −5.00 +3.00 × 180° in the left eye. He had no persistent respiratory disorder or developmental delays.
Case 1 initial eye examination at post-menstrual age 33 and 5/7 weeks in the right eye (left) and left eye (right).
Case 1 follow-up examination at post-menstrual age 44 and 5/7 weeks in the right eye (left) and left eye (right).
A preterm male infant was born at 29 and 0/7 weeks' gestation, weighing 1,270 g. The pregnancy was complicated by twin gestation, premature labor, premature prolonged rupture of membranes, bleeding, and fetal malpresentation. A single dose of maternal betamethasone was given only a few hours prior to delivery. The infant was born via cesarean section at our academic institution. Delivery room resuscitation included bag mask with up to 0.6 FiO2. He had a diagnosis of respiratory distress syndrome and was briefly intubated to receive surfactant, then received non-invasive mechanical ventilation and nasal continuous positive airway pressure with FiO2 0.21 to 0.40 on day of life 1. For day of life 2 to 5 he received nasal continuous positive airway pressure, then high-flow nasal cannula only for day of life 6 to 28, with FiO2 0.21. His SpO2 was typically over 95%, but he did have occasional oxygen de-saturations and concern for alveolar atelectasis secondary to respiratory distress syndrome (Table 1).
His initial eye examination on day of life 27 revealed stage 0, zone I, without plus disease in both eyes. On day of life 41, at PMA 34 and 6/7 weeks, he was diagnosed as having ROP stage 3, zone I, exhibiting fan-like vascularization with plus disease in both eyes (Figure 3). Intravitreal bevicizumab treatment was administered due to the posterior nature of the ROP. The plus disease fully regressed 1 week later, and the neovascularization fully regressed after 2 weeks. On follow-up at PMA 44 and 6/7 weeks, the patient displayed stage 1, zone III ROP without plus disease. This recurrence remained mild and fully regressed without further intervention by PMA 57 and 6/7 weeks. Last follow-up was at 18 months of age. The patient's retinas were fully vascularized. Visual acuity was fix and follow in both eyes, with cycloplegic refraction of +1.25 +0.75 × 180° in both eyes. No persistent respiratory disorder or developmental delays were noted.
Case 2 initial eye examination at post-menstrual age 34 and 6/7 weeks in the right eye (left) and left eye (right).
The recommended ROP screening criteria include: all infants with birth weights of 1,500 g or less or GA of less than 30 weeks, or infants with birth weights between 1,500 and 2,000 g or a GA of more than 30 weeks whose clinical course places them at increased risk for ROP.1 In developed countries, severe ROP requiring treatment is most common in infants with the earliest GA and lightest birth weights, and becomes less common as GA and birth weights increase.2,3
The infants described above were older and larger than is typical for infants developing ROP requiring treatment. We undertook a chart review to identify factors that may have contributed to the development of severe ROP. Delivery of supra-ambient oxygen is a well-known risk factor for ROP development, so receipt of respiratory support was our primary focus.4 These infants received only 3 and 1 days of supra-ambient oxygen delivery, respectively, prior to ROP development. We believed this amount of respiratory support was within the standard of care and unlikely to have been a significant risk factor for severe ROP development. The infants did receive a variety of non-invasive respiratory support modalities for treatment of respiratory distress syndrome with 0.21 FiO2, primarily from high-flow nasal cannula, from day of life 4 to 20 and 2 to 28, respectively. This finding raises the possibility that non-invasive respiratory support, even in the absence of supra-ambient oxygen delivery, may have contributed to the ROP development in these children.
The use of non-invasive respiratory support (including non-invasive mechanical ventilation, nasal continuous positive airway pressure, and high flow nasal cannula) offers significant benefits in the prevention of alveolar atelectasis. We did not find previous literature suggesting a possible link between ROP and non-invasive respiratory support in the absence of supra-ambient oxygen delivery. However, Testa et al. previously demonstrated that infants receiving high-flow nasal cannula may achieve a higher arterial oxygen partial pressure than similar infants receiving conventional oxygen therapy.4 Manley et al. described the growing popularity of high-flow nasal cannula as a form of non-invasive respiratory support for premature infants, primarily due to ease-of-use, but noted the uncertainty regarding the safety of high-flow nasal cannula in this population.5 The increased flow and pressure support can increase oxygen saturation because even atmospheric oxygen, delivered at supra-ambient pressures, will increase the alveolar oxygen partial pressure, thus increasing the chance of a rise in arterial oxygen partial pressure. Any therapy that increases the amount of circulating oxygen delivered to the retina, even by means of correcting life-threatening atelectasis, may contribute to the development of ROP.6
There are many factors that may contribute to the development of ROP, including in utero factors. The two cases we report are entirely insufficient to demonstrate causality of any of these factors. We made the observation that in these two cases, the use of non-invasive respiratory support for several weeks was noted in two patients who developed severe ROP that was much more aggressive and posterior than would be expected based on the birth weights and GA of the infants. We believe further examination is warranted and would be required to look for a broader association between the use of non-invasive respiratory support, even in the absence of supra-ambient oxygen, and the development of severe ROP. We can make no conclusions about causality based on our limited observations. We also note that non-invasive respiratory support has many demonstrated benefits and is a valuable tool in managing neonates.
- Fierson WMAmerican Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013;131:189–195. doi:10.1542/peds.2012-2996 [CrossRef]
- Gilbert C, Fielder A, Gordillo L, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics. 2015;115:e518–e525. doi:10.1542/peds.2004-1180 [CrossRef]
- Darlow BA, Hutchinson JL, Henderson-Smart DJ, et al. Prenatal risk factors for severe retinopathy of prematurity among very preterm infants of the Australian and New Zealand Neonatal Network. Pediatrics. 2005;115:990–996. doi:10.1542/peds.2004-1309 [CrossRef]
- Testa G, Iodice F, Ricci Z, et al. Comparative evaluation of high-flow nasal cannula and conventional oxygen therapy in paediatric cardiac surgery patients: a randomized controlled trial. Interactive Cardiovasc Thoracic Surgery. 2014;19:456–461. doi:10.1093/icvts/ivu171 [CrossRef]
- Manley BJ, Dold SK, Davis PG, Roehr CC. High-flow nasal cannulae for respiratory support of pre-term infants: a review of the evidence. Neonatology. 2012;102:300–308. doi:10.1159/000341754 [CrossRef]
- Hartnett ME, Lane RH. Effects of oxygen on the development and severity of retinopathy of prematurity. J AAPOS. 2013;17:229–230. doi:10.1016/j.jaapos.2012.12.155 [CrossRef]
Summary of Respiratory Support
|Day of Life||Respiratory Support Type||SpO2 (%)|
| 1||Blow by O2, NIMV 0.3 FiO2||89 to 96|
| 2 to 3||NIMV, NCPAP 0.2 to 0.3 FiO2||86 to 97|
| 4 to 5||NIMV, 5 cm 0.21 FiO2||94 to 99|
| 6 to 14||HFNC 4 L 0.21 FiO2||> 95|
| 15 to 20||HFNC 2 L 0.21 FiO2||> 95|
| > 21||Successfully treated||–|
| 1||Blow by O2, NIMV, NCPAP 5 cm 0.21 to 0.4 FiO2||90 to 98|
| 2 to 4||NIMV 0.21 FiO2||88 to 99|
| 5||NCPAP 5 cm 0.21 FiO2||> 95|
| 6 to 8||HFNC 4 L 0.21 FiO2||> 97|
| 9 to 28||HFNC 2 L 0.21 FiO2||98 to 100|
| > 28||Successfully treated||–|