Retinopathy Of Prematurity 

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Introduction

Premature birth has numerous complications as a consequence of the systemic immaturity of the newborn. Among these complications, retinopathy of prematurity (ROP) is noticeable by its impact on the development of retinal vasculature. According to the amount of this impact, newborns can experience retinal bleeding or detachment, resulting in impaired visual acuity and blindness.1

Definition

First described in the 1940s, ROP is a disorder that affects the immature retina of premature newborns (born before 37 weeks of gestational age).2 According to the American Academy of Ophthalmology, ROP is even more common in infants born before 31 weeks of gestational age.3 Additionally, according to the National Eye Institute, ROP affects newborns with a very low birthweight (less than 1500g).2

ROP is characterized by an interruption in the normal process of retina blood vessel development, leading to the formation of abnormal blood vessels. These abnormalities may result in long-term visual loss and blindness. ROP is considered as the leading preventable cause of childhood blindness.1

Prevalence

National and population-based studies reported approximately 30% of ROP prevalence in premature newborns. However, the prevalence varies according to gestational age and is partially explained by differences in the healthcare provided to premature newborns. Reference centres, with better resources for neonatal care, and better trained multi-professional teams, may have higher survival rates for extremely premature babies, therefore leading to a higher number of babies at risk for developing ROP. Conversely, centres with limited resources may experience lower survival rates among extremely premature babies, resulting in fewer babies at risk for developing ROP.4,5  

ROP physiopathology

In humans, retinal vascularization begins at around 16 weeks of gestational age, spreading from the optic nerve towards the peripheral retina. By approximately 36-40 weeks of gestational age, vascularisation is complete, reaching the peripheral nasal retina. At full term, during the birth, the variation in oxygen levels between the intrauterine (within the uterus) environment (oxygen saturation around 70%) and the extrauterine (outside the uterus) environment, where oxygen levels gradually increase (relative hyperoxic environment), leads to a phenomenon known as retinal vasoconstriction (the blood vessels within the retina constrict). If premature birth occurs, especially before 32- 34 weeks of gestational age, with immature vasculature, this oxygen level variation results in an interruption of the retinal vascular development. Additionally, if the premature newborn requires neonatal resuscitation with high oxygen concentrations, there is an even greater increase in arterial oxygen saturation and more retinal vasoconstriction. It is believed that an oxygen pressure of PaO2 ≥80 mm Hg is harmful to newly developed retinal capillaries. After the interruption, vascularization resumes due to the action of neuronal cells, which, in an attempt to complete normal angiogenesis (formation of blood vessels), increase their metabolic activity and form abnormal, more fragile vessels, which is what characterises ROP. Thus, ROP has two stages: an initial phase with vessel loss, and a second phase with a rushed, more fragile vessel proliferation.1,6,7

Causes and risk factors

In addition to low gestational age, low birth weight, and difference in oxygen levels between the intrauterine and extrauterine environments, several factors, especially those associated with complications during the first days after birth, are linked to the development of ROP in preterm newborns. Among them are the use of oxygen, nutritional problems, and infection.1

Oxygen

Although the optimal oxygen levels to save the life of a premature baby while reducing ROP and injuries in other systems have not yet been determined, it is recommended to maintain the oxygenation of premature babies between 91% to 95% in neonatal intensive care units.7 For this purpose, supplementary oxygen given to the newborn should be titrated, meaning it should be administered through devices that allow the use of any concentration between 21% and 100%. Additionally, neonatal intensive care units need to have equipment that continuously monitors the baby's blood oxygen levels. However, some centrer, especially in developing countries, lack resources for oxygen titration (where the only options are providing either room air,  21%, or 100% oxygen) or monitoring, leading to excessive oxygen supply. This exacerbates the vasoconstriction of the immature retina, making the baby more susceptible to developing ROP. Moreover, the duration of oxygen use and oxygenation fluctuations are also associated with the development of ROP.8

Nutrition

Lower levels of growth hormones, vitamin A, D and E deficiency, low birth weight, and hyperglycemia are nutritional factors associated with the development of ROP, as they are involved not only in overall growth but also in vascular growth.9,10 During fetal life, growth hormones progressively increase with gestational age. However, after the premature interruption of maternal-fetal interaction, the hormone levels decrease. The subsequent increase in hormone levels is slow, and depends on postnatal nutrition.1

Infections

Neonatal infections, and especially fungal infections, are also risk factors for ROP, possibly due to systemic inflammation.1

Stages and classification

The severity of ROP is determined by the conditions of the retina, specifically the vascular and avascular regions of the retina. Therefore, ROP is classified into stages, zones, and presence of vascular disease.

The stages range from stage 1 (mild) to stage 5 (severe) and are determined by:

·       Stage 1: There is a demarcation line separating the vascular from the avascular retina.

·       Stage 2: The demarcation line is more pronounced.

·       Stage 3: There is vessel restriction even into the retina.

·       Stage 4: Babies in stage 4 have a partially detached retina.

·       Stage 5: At stage 5, the retina detaches completely.

In addition to staging, ROP is also classified based on its location into zones I, II, and III, representing the involvement from the most central to the peripheral retina.

Furthermore, ROP can be classified based on the presence or absence of arteriolar dilation, venous tortuosity, iris vessel engorgement, and pupillary rigidity, known as "plus disease". The presence of arteriolar tortuosity and venular dilation characterises the "pre-plus disease".

Stages and classification estimate the severity and visual outcome of the neonate, in addition to determining the treatment approach.5

Diagnosis

Generally, diagnosis is made through screening exams, which are routine for premature infants admitted to neonatal intensive care units. For the retina examination, the baby's pupil is dilated to allow a detailed analysis by the ophthalmologist. The criteria for inclusion in this routine screening vary between centres, but include newborns with a gestational age of less than 30-32 weeks, or a birthweight of less than 1250-1500g.

The first exam is conducted between 4 to 6 weeks after birth, and the frequency of follow-up examinations is determined by the ophthalmologist. Follow-up eye examinations at established intervals are considered to be a good practice. Typically, these follow-ups occur at intervals of 1 to 2 weeks until the retinal vascularisation process is complete, which happens around 36-40 post-conceptual weeks.11,13

Prevention

Avoiding preterm birth is the best preventative approach for ROP. However, in the case of premature birth, prevention programs with controlled oxygen supplementation should be adopted, and should include training and awareness of the need for close interdisciplinary collaboration to vigilance with oxygen saturation monitoring. Guidance should be provided regarding the risks of hyperoxia and the necessary actions for the immediate correction of oxygen saturation of the premature newborn.12 Furthermore, parenteral nutrition, vitamin supplementation and breastmilk feeding are associated with a lower risk of ROP incidence.13

Treatment

Some babies with ROP present with mild cases and improve without treatment, especially those classified in stages 1 or 2. However, some babies require treatment in order to preserve their vision and prevent blindness. If treatment is required, it should be initiated within 24 to 72 hours after the diagnosis of ROP, and is frequently performed within the neonatal intensive care unit. Current treatment options include:

·         Cryotherapy: Established in the late 1980s as a conventional treatment for ROP, it isless commonly used currently, due to the risk of increased retinal inflammation.

·         Laser Photocoagulation: The standard treatment for severe ROP involves laser ablation of the peripheral avascular retina, alleviating the need for surgery for fibrovascular tractional retinal detachment.

·         Anti-vascular endothelial growth factor (VEGF) Therapy: A recent development in ROP treatment involves injecting anti-VEGF agents into the infant's eyes to inhibit pre-retinal neovascularisation, and facilitate developmental intraretinal angiogenesis.

·         Surgical Treatment: When retinal detachment occurs (stages 4 and 5), surgical intervention becomes necessary. Surgical options include scleral buckling or lens-sparing vitrectomy. However, despite the treatment approach, visual outcomes are generally poor once retinal detachment has happened.2,3,4

Follow-up and prognosis

The visual prognosis is associated with ROP severity in the acute phase, however, ROP that does not require treatment may also affect visual prognosis. It is recognised that there is an increased rate of strabismus, refractive error and amblyopia in such infants, and a lack of long-term visual acuity also was reported. Although there is no uniform agreement as to when and what the follow-up examinations should be for ex-premature infants who have not required treatment for ROP, some form of follow-up is strongly recommended, at least at 3, 6, and 12 months of corrected age. Infants who have required treatment have an increased risk of late ophthalmic complications and require life-long follow-up. However, for stages 4 and 5, diseases have poor results and limited vision, even following surgery.4,11

Summary

ROP is a disease that affects the immature retina of preterm newborns. Despite a variety in treatment approaches, ROP can result in visual acuity impairment or blindness in severe stages of the disorder. It is intricately linked to gestational age, birth weight, and the quality of neonatal care provided in neonatal intensive care units, including oxygen supplementation, nutrition, and infection control.

A multi-professional approach, with oxygen supplementation control, nutritional support, and vigilant monitoring, are key preventive measures.

References

  • Hellstrom A, Smith LE, Dammann O. Retinopathy of prematurity. 2013. The Lancet. 382:1445–57.
  • Retinopathy of prematurity - National Eye Institute [Internet]. Available at: https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/retinopathy-prematurity#:~:text=Retinopathy%20of%20prematurity%20(ROP)%20is,the%20back%20of%20your%20eye
  • American Academy of Ophthalmology [Internet]. 2023. What is retinopathy of prematurity? Available at: https://www.aao.org/eye-health/diseases/what-is-retinopathy-prematurity
  • Hong EH, Shin YU, Cho H. Retinopathy of prematurity: a review of epidemiology and current treatment strategies. Clin Exp Pediatr [Internet]. 2021;65(3):115–26. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898617/
  • Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, et al. International classification of retinopathy of prematurity, third edition. Ophthalmology. 2021;128(10):e51–68.
  • Sun Y, Smith LEH. Retinal vasculature in development and diseases. Annu Rev Vis Sci [Internet]. 2018;4:101–22. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326083/
  • Hartnett ME, Lane RH. Effects of oxygen on the development and severity of retinopathy of prematurity. J AAPOS [Internet]. 2013;17(3):229–34. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740273/
  • Pastro J, Toso BRG de O. Influencia del oxígeno en el desarrollo de retinopatía del premature. [Influence of oxygen in the development of retinopathy of prematurity]. Rev Bras Enferm. 2019;72(3):592–9.
  • Kim ES, Calkins KL, Chu A. Retinopathy of prematurity: the role of nutrition. Pediatr Ann. 2023;52(8):e303–8.
  • Murugeswari P, Vinekar A, Prakalapakorn SG, Anandula VR, Subramani M, Vaidya TA, et al. Correlation between tear levels of vascular endothelial growth factor and vitamin D at retinopathy of prematurity stages in preterm infants. Sci Rep. 2023;13(1):16175.
  • Retinopathy of prematurity screening and treatment guidelines. The Royal Australian and New Zealand College of Ophthalmologists; 2021. Available at: https://ranzco.edu/wp-content/uploads/2022/01/RANZCO-Guidelines-for-Retinopathy-of-Prematurity-ROP_Dec-2021.pdf.  
  • Higgins RD. Oxygen saturation and retinopathy of prematurity. Clin Perinatol. 2019;46(3):593–9.
  • Fang JL, Sorita A, Carey WA, Colby CE, Murad MH, Alahdab F. Interventions to prevent retinopathy of prematurity: a meta-analysis. Pediatrics. 2016;137(4):e20153387.

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Ana Silvia Scavacini Marinonio

PhD in Health Sciences, UNIFESP, São Paulo, Brazil

Ana Sílvia is a physiotherapist with extensive experience in clinical practice, medical affairs, and clinical research. She completed her master's, Ph.D., and postdoctoral studies. She is skilled in big data management and analysis, as well as spatial analysis tools. Additionally, she has a strong background in creating and editing documents and scientific articles.

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