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Retinopathy of Prematurity

ROP

Retinopathy of prematurity refers to the abnormal development of blood vessels within the retina of very premature infants. Mild forms may have no adverse consequences but severe cases may cause vision loss. It is a major cause of blindness in children.


Presentation

There are no outward symptoms of early retinopathy of prematurity in the neonate. The only way to see if the disease is developing, is to have an ophthalmologist regularly examine the retina via an ophthalmoscope from about four weeks after delivery. As the disease progresses, sometimes iris rubeosis can be seen externally, with new blood vessels seen on the surface of the iris. However, only once the disease has progressed severely, can eye testing detect actual vision loss. Even without vision loss children with healed retinopathy of prematurity are at increased risk of developing near-sightedness, strabismus, or amblyopia within the early years of life.

Delayed Gastric Emptying
  • Eyedrops used for mydriasis and cycloplegia can be systemically absorbed, causing serious side effects, including oxygen desaturation, apnea, bradycardia, transient hypertension, delayed gastric emptying, and transient paralytic ileus.[ncbi.nlm.nih.gov]
Neonatal Jaundice
  • ., oxygen therapy for respiratory distress, sepsis, neonatal jaundice). A premature infant presented with "hybrid" zone 1 disease in the right eye and aggressive posterior ROP in the left eye.[ncbi.nlm.nih.gov]
Flushing
  • Fluorescein angiography was undertaken following administration of an intravenous bolus of 0.1 ml/kg saline fluorescein 10 % followed by a 3.0-ml isotonic saline flush, with the assistance of the neonatologist; the right and left eyes were imaged.[ncbi.nlm.nih.gov]
Retinal Hemorrhage
  • In the only other previously reported case, the retinal hemorrhages were limited to the posterior pole of an eye with preexisting vitreous hemorrhage, and the child had a history of severe necrotizing enterocolitis that required surgery.[ncbi.nlm.nih.gov]
  • A preterm baby born at 32 weeks gestation age developed extensive posterior retinal hemorrhages during retinal imaging using the RetCam. Retinal hemorrhages spontaneously resolved.[ncbi.nlm.nih.gov]
  • In addition, retinal hemorrhage and low BW were significantly associated with recurrence and retreatment in non-retinal detachment APROP.[ncbi.nlm.nih.gov]
  • One eye developed recurrent retinal hemorrhage with localized retinal detachment 21 weeks after initial treatment, which resolved after a second injection. There were no ocular or systemic complications in these patients.[ncbi.nlm.nih.gov]
  • Common symptoms of retrolental fibroplasias in preterm infants are visual disturbance, retinal detachment, absent papillary light reflexes, potential blindness, dilated or twisted eye vessels, opaque retrolental eye membrane, retinal edema & retinal hemorrhages[signssymptoms.org]
Corneal Edema
  • Signs of anterior segment ischemia were present in all 3 eyes before the cataract extraction, including shallow anterior chamber, corneal edema, iris atrophy, and posterior synechiae.[ncbi.nlm.nih.gov]
Lipemia Retinalis
  • Lipemia retinalis is an unusual ocular finding associated with hypertriglyceridemia. We report the case of an infant treated for retinopathy of prematurity who later developed lipemia retinalis, with triglyceride levels of 4736 mg/dl.[ncbi.nlm.nih.gov]

Workup

Screening for retinopathy of prematurity is based on regular ophthalmoscopic examinations by an ophthalmologist. This is usually done bedside by an experienced examiner. It is necessary to dilate the pupil and use scleral depression to visualize the retina properly. The ophthalmologist usually creates hand-drawn documentation of the findings, using the international classification of retinopathy of prematurity [10] [11].

Screening is performed in all infants born at less than 30 weeks gestation and in those weighing less than 1500 grams. Screening begins about four weeks after birth or when the neonate hits approximately the equivalent of 31 weeks gestation. Ophthalmologic examinations are then conducted every 1-3 weeks, depending on the severity of the retinopathy, until the retina is completely vascularized (at an age equivalent to term).

Newborns with retinopathy of prematurity should have bi-annual or annual eye examinations for the rest of their life because of their increased risk of other eye issues.

Gliosis
  • Abstract Massive retinal gliosis (MRG) is a rare, benign intraocular condition that may develop in association with long-standing eye conditions including chronic inflammation, vascular disorders, glaucoma, trauma, or congenital abnormalities.[ncbi.nlm.nih.gov]

Treatment

Currently, the mainstays of treatment for retinopathy of prematurity are cryotherapy and laser photocoagulation, the latter being the preferred treatment. Both of these therapies are targeted at the avascular retina. The treatment causes a downregulation in the production of vascular growth factors. Both treatments have been found to reduce the incidence of retinal folds and retinal detachment and improve vision outcomes [4] [12].

Bevacizumab, a monoclonal antibody targeted at vascular endothelial growth factor, has been shown to lead to fewer structural abnormalities and a lower rate of recurrence of retinopathy of prematurity compared to laser photocoagulation. However, this therapy still remains a second-line therapy because of the risk of serious side effects. There are concerns about the effects of systemic absorption as well as possible infection. There are also unknowns regarding the optimal dose and the timing of follow-ups (as recurrence can occur months after). It has been used to treat severe disease and in conjunction with laser therapy [12].

The above treatments are better if performed early in the disease progression. Once retinal detachments occur, the prognosis is poor. Scleral buckle surgery can be used to repair a detached retina or removal of the vitreous and lens, however these are late rescue efforts that have poorer outcomes. Infants that do have retinal detachments need to be monitored for the development of glaucoma and inadequate eye development, with early referral to programs for the visually impaired.

Any refractive errors, strabismus, or amblyopia are best corrected in the first year of life to optimize visual outcomes.

Prognosis

In most premature neonates, particularly those older and bigger babies with more mature retinas at birth, the abnormal vessels subside spontaneously. However, in about 4% of neonates weighing less than one kilogram at birth, without treatment, retinal detachment and vision loss occurs within 2-12 months of age.

Children that have had healed retinopathy of prematurity, have a greater incidence of other eye issues, such as myopia, strabismus, and amblyopia during life. In general, approximately 20% of all very premature babies will develop strabismus or a refractive error by age three.

Some children with healed retinopathy of prematurity maintain retinal scars, which makes them a risk for retinal detachment later in life. Glaucoma and cataracts may also rarely occur.

Increased knowledge of the risk factors, routine screening of all at risk infants, and early pre-emptive treatment has dramatically improved the visual outcome of premature infants.

Etiology

Retinopathy of prematurity only affects premature babies. The risk group are those babies born at less than 32 weeks of gestation and/or those weighing less than 1500 grams at birth. The risk increases with lower gestational age and lower birth weight [4] and with other factors, such as maternal illness during gestation, unregulated (especially prolonged) oxygen supplementation after birth, and illness in the fetus and neonate [4] [5]. Clinical studies have shown an association between the supplementation of high concentrations of oxygen after birth and retinopathy of prematurity [6].

Epidemiology

Retinopathy of prematurity is most prevalent in developed countries, where technology has enabled more premature infants to survive. However, there is an increased awareness in these countries of the risk factors for retinopathy of prematurity. By regulating oxygen supplementation and screening every at risk infant, the adverse outcomes have been somewhat reduced.

In contrast, the incidence of retinopathy of prematurity is increasing in the developing world. This is as more developing countries gain better access to the technologies that enable more premature infants to survive. At the same time, these countries often use unregulated oxygen supplementation and also lack adequate screening programs and pre-emptive treatment, leading to worse outcomes [3].

Sex distribution
Age distribution

Pathophysiology

In the growing fetus, the retina becomes vascularised by the sprouting and growth of new blood vessels from the center of the retina towards the periphery. These vessels begin forming around mid-gestation and cover the entire retina by term.

A number of factors influence retinal blood vessel growth. Primary amongst these is hypoxia at the periphery of the retina. As the retina matures, it become more metabolically active and the demand for oxygen increases. The available oxygen is used up, leading to hypoxia. The low oxygen level promotes the expression of growth factors, like vascular endothelial growth factor, which signal for new vessels to grow outwards towards the low oxygenated areas at the periphery. Maternal growth factors passed across the placenta also play a significant role.

The still developing retina in the fetus is fragile. If a baby is born prematurely, the immature retina is exposed to a highly oxygenated environment (air) and there is a loss of access to the maternal growth factors.

The pathogenesis of retinopathy of prematurity is believed to be a two-step process that occurs from birth.

An early model of pathogenesis proposed an initial phase of retinal blood vessel destruction followed by the aggressive and irregular growth of new vessels. In the first phase, exposure of the fragile retina to high levels of oxygen caused the retinal blood vessels to constrict and die. The subsequent ischemia then caused an upregulation of vascular growth factors, promoting the sprouting of new blood vessels. These new blood vessels were immature and did not respond normally to regulation, resulting in their tortuous and excessive development [7] [8].

In the newest model, rather than destruction of vessels during the first phase, instead there is an arrest of normal vascular development of the retina. The exposure to high levels of oxygen and the loss of maternal-fetal interactions causes a downregulation of vascular growth factors. This causes a cessation of normal retinal vascularisation. In the second phase, the maturing retina, which is becoming increasingly metabolically active, becomes short of oxygen and the hypoxia causes an abnormally high compensatory upregulation of vascular growth factors. This leads to a pathologically prolific and abnormal vascularization of the retina [2] [3] [9].

It is proposed that there may also be a pre-phase, in which maternal or fetal illness, causing subsequent inflammation in utero, may make the retina more susceptible to this pathological process [5].

In both models, the second phase is a compensatory, abnormally excessive and tortuous pattern of growth of vascularisation of the retina. This second phase is more aggressive in smaller, more premature babies, in which the percentage of retina that has been vascularized at birth is lower. It is also more devastating where there is a persistent delay in vascular development in the first phase, due to exposure to harmful factors (such as high supplemental oxygen or inflammatory products due to illness) and deficiencies of growth factors (such as due to poor nutrition).

In less affected neonates, the abnormal vessels may regress, with no or only mild vision loss. However, the rapidly growing vessels can bleed. This can lead to scarring and fibrosis, and can cause detachment of the retina in those places. In severe disease, the vessels can invade the vitreous and the whole vasculature of the eye can become engorged (called Plus disease).

Prevention

The biggest risk factors for retinopathy of prematurity are low gestation age and low birth weight. Screening of all infants within the risk group can detect the development of the disease early and lead to early treatment intervention, which can help prevent vision loss.

Unregulated excess oxygen supplementation in the neonate has also been linked to an increase in the incidence and severity of the disease. Oxygen supplementation should be used only as needed and swings in oxygen should be avoided as this has been found to increase the risk of the disease.

The newborn premature baby faces a deficiency of essential growth factors, such as insulin-like growth factor-1 (IGF-1), which it no longer receives from its mother when it is removed from the uterine environment. Optimizing nutrition, so that the neonate can normalize its own essential factors, such as IGF-1 and omega-3 polyunsaturated fatty acids, may help prevent severe disease [2].

Reducing comorbidities in both the pregnant mother and the neonate may be important. Infection and inflammation can suppress normal neurovascular development and has been linked to increased risk of retinopathy of prematurity and its severity.

Previous strategies, such as supplemental vitamin E and restricted light have been found to be ineffective [7].

Summary

Retinopathy of prematurity is a disease that only affects very premature infants (less than 32 weeks gestation or less than 1500 grams birth weight) [1] and is one of the leading causes of childhood blindness in the world today [2] [3]. Retinopathy of prematurity develops when a very premature birth causes disruption to the formation of blood vessels in the still fragile retina. What follows is the compensatory, excessive and abnormal formation of new blood vessels. These vessels may regress without any detrimental effect but they may also cause bleeding, with subsequent scarring, tissue contraction, and even retinal detachment [3]. Many very premature infants are affected to some degree and depending on the severity, present with no or only mild visual impairment while severe cases may lead to blindness. All affected children are at risk of other ocular complications later in life. Early detection programs and treatment can protect vision.

Patient Information

Retinopathy of prematurity is an eye disorder that only occurs is premature babies, usually those born before 32 weeks of gestation or weighing less than 1500 grams. It is a disorder where the blood vessels at the back of the eye (the retina) develop abnormally. In many affected babies, the abnormal blood vessels correct themselves and return to normal, without any severe consequences. However, in some cases, the rapid growth of the abnormal vessels will cause them to bleed. This bleeding can lead to scarring, which can cause the retina to come away (detach) from the back of the eye. This leads to partial or full vision loss.

Premature newborns with early stages of the disease have no symptoms. The only way to detect the disease is to have an eye specialist carefully exam the back of the eye regularly after birth. Many countries have routine screening programs in place to detect the disease in babies at risk. Eye examinations must occur until the baby reaches the equivalent of full term.

In most cases, the disease is mild and will resolve without treatment. In more severe cases, laser treatment is used to prevent vision loss.

Regular yearly or twice-yearly eye examinations are advised in all premature babies because they have a slightly increased risk of needing glasses or corrective eye treatment later in life.

References

Article

  1. Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Quintos M, Tung B. Early Treatment for Retinopathy of Prematurity Cooperative Group. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics. 2005; 116(1):15-23.
  2. Heidary G, Vanderveen D, Smith LE. Retinopathy of prematurity: current concepts in molecular pathogenesis. Semin Ophthalmol. 2009; 24(2):77-81.
  3. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012; 367(26):2515-2526.
  4. Lad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am J Ophthalmol. 2009;148(3):451-458.
  5. Lee J, Dammann O. Perinatal infection, inflammation, and retinopathy of prematurity. Semin Fetal Neonatal Med. 2012;17(1):26-29.
  6. Patz A, Hoeck LE, De La Cruz E. Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol. 1952; 35(9):1248-1253.
  7. Kretzer FL, Hittner HM. Retinopathy of prematurity: clinical implications of retinal development. Arch Dis Child. 1988; 63(10 Spec No):1151-1167.
  8. Ashton N. Oxygen and the retinal blood vessels. Trans Ophthalmol Soc U.K. 1980; 100(3):359-362.
  9. Chen J, Smith LE. Retinopathy of prematurity. Angiogenesis. 2007;10(2):133-140.
  10. An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Arch Ophthalmol. 1984;102(8):1130-1134.
  11. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991-999.
  12. Ng EY, Connolly BP, McNamara JA, Regillo CD, Vander JF, Tasman W. A comparison of laser photocoagulation with cryotherapy for threshold retinopathy of prematurity at 10 years: part 1. Visual function and structural outcome. Ophthalmology. 2002;109(5):928-935.

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Last updated: 2019-07-11 20:28