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Retinopathy of prematurity - Wikipedia, the free encyclopedia

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Retinopathy of prematurity
From Wikipedia, the free encyclopedia

Retinopathy of prematurity (ROP)

or Terry syndrome,[1] previously
known as retrolental fibroplasia
(RLF), is a disease of the eye
affecting prematurely-born babies
generally having received intensive
neonatal care, in which oxygen
therapy is used on them due to the
premature development of their
lungs. It is thought to be caused by
disorganized growth of retinal blood
vessels which may result in scarring
and retinal detachment. ROP can be
mild and may resolve spontaneously,
but it may lead to blindness in
serious cases. As such, all preterm
babies are at risk for ROP, and very
low birth weight is an additional risk
factor. Both oxygen toxicity and
relative hypoxia can contribute to the
development of ROP.

Retinopathy of prematurity
Classification and external resources



362.20 (
icd9=362.20), 362.21


133780 (

DiseasesDB 11442 (

MedlinePlus 001618

oph/413 ( ped/1998



D012178 (

1 Causes
2 Pathophysiology
3 Risk Factors
4 Screening
4.1 Indications
4.2 Timing
4.3 Procedure
5 Diagnosis
5.1 International classification of retinopathy of prematurity (ICROP)
5.2 Plus disease
5.3 Prognosis
6 Differential diagnosis

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7 Monitoring
8 Management
8.1 Treatment
8.2 Follow up
9 Sequelae
10 History
11 Epidemiology
12 References
13 External links

By the fourth month of pregnancy, the unborn child's retina has begun to develop vascularization. Such
formation of blood vessels appears to be very sensitive to the amount of oxygen supplied, either naturally or
artificially. In rare cases it has been found in some patients with ROP a mutation in the NDP gene, which is
normally associated with the more formidable Norrie disease.[2][3][4]

During development, blood vessels grow from the central part of the retina outwards. This process is completed
a few weeks before the normal time of delivery. However, in premature babies it is incomplete. If blood vessels
grow normally, ROP does not occur. If the vessels grow and branch abnormally the baby develops ROP. These
abnormal blood vessels may grow up from the plane of the retina and may bleed inside the eye. When the blood
and abnormal vessels are reabsorbed, it may give rise to multiple band like membranes which can pull up the
retina, causing detachment of the retina and eventually blindness before 6 months.
Normally, maturation of the retina proceeds in-utero, and at term, the medial portion of the retina is fully
vascularized, while the lateral portion is only incompletely vascularized.[5] The normal growth of the blood
vessels is directed to relatively low-oxygen areas of the retina, but the vessels remain in the plane of the retina
and do not grow into the vitreous humor. If excess oxygen is given, normal blood vessels degrade and cease to
develop. When the excess oxygen environment is removed, the blood vessels rapidly begin forming again and
grow into the vitreous humor of the eye from the retina.[5][6]
The key disease element in ROP is fibrovascular proliferation. This is growth of abnormal new vessels; this may
regress, but frequently progresses. Associated with the growth of these new vessels is fibrous tissue (scar tissue)
that may contract to cause retinal detachment. Multiple factors can determine whether the disease progresses,
including overall health, birth weight, the stage of ROP at initial diagnosis, and the presence or absence of "plus
disease". Supplemental oxygen exposure, while a risk factor, is not the main risk factor for development of this
disease. Restricting supplemental oxygen use reduces the rate of ROP, but may raise the risk of other hypoxiarelated systemic complications, including death.[7]

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Patients with ROP, particularly those who have developed severe disease needing treatment are at greater risk
for strabismus, glaucoma, cataracts and shortsightedness (myopia) later in life and should be examined yearly to
help prevent or detect and treat these conditions.

Risk Factors
Various risk factors contribute to the development of ROP. They are:
High exposure to Oxygen
Low birth weight
Various types of infections
Cardiac defects

Almost all infants with ROP have a gestational age of 31 weeks or less (regardless of birth weight) or a birth
weight of 1250 g (2.76 lbs) or less; these indications are generally used to decide whether a baby should be
screened for ROP, but some centres, especially in developing countries [3] ( extend birth weight screening criteria to 1500 g (3.3 lbs).[9]
Any premature baby with severe illness in perinatal period (Respiratory distress syndrome, sepsis, blood
transfusion, Intra ventricular haemorrhage, apnoeic episodes, etc.) may also be offered ROP screening.

Retinal examination with scleral depression is generally recommended for patients born before 3032 weeks
gestation, or 46 weeks of life, whichever is later. It is then repeated every 13 weeks until vascularization is
complete (or until disease progression mandates treatment).

Following pupillary dilation using eye drops, the retina is examined using a special lighted instrument (an
indirect ophthalmoscope). The peripheral portions of the retina are sometimes pushed into view using scleral
depression. Examination of the retina of a premature infant is performed to determine how far the retinal blood
vessels have grown (the zone), and whether or not the vessels are growing flat along the wall of the eye (the
stage). Once the vessels have grown into Zone 3 (see below) it is usually safe to discharge the child from further
screening for ROP. The stage of ROP refers to the character of the leading edge of growing retinal blood vessels
(at the vascular-avascular border).


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The stages of ROP disease have been defined by the International Classification of Retinopathy of Prematurity
In older patients the appearance of the disease is less well described but includes the residua of the ICROP
stages as well as secondary retinal responses.

International classification of retinopathy of prematurity (ICROP)

The system used for describing the findings of active ROP is entitled The International Classification of
Retinopathy of Prematurity (ICROP).[10] ICROP uses a number of parameters to describe the disease. They are
location of the disease into zones (1, 2, and 3), the circumferential extent of the disease based on the clock hours
(1-12), the severity of the disease (stage 1-5) and the presence or absence of "Plus Disease". Each aspect of the
classification has a technical definition. This classification was used for the major clinical trials. It was revised
in 2005.[11]
The zones are centered on the optic nerve. Zone 1 is the posterior
zone of the retina, defined as the circle with a radius extending from
the optic nerve to double the distance to the macula. Zone 2 is an
annulus with the inner border defined by zone 1 and the outer
border defined by the radius defined as the distance from the optic
nerve to the nasal ora serrata. Zone 3 is the residual temporal
crescent of the retina.

Zones of the retina in ROP

The circumferential extent of the disease is described in segments

as if the top of the eye were 12 on the face of a clock. For example
one might report that there is stage 1 disease for 3 clock hours from
4 to 7 o'clock. (The extent is a bit less important since the treatment

indications from the Early Treatment for ROP[12])

The Stages describe the ophthalmoscopic findings at the junction between the vascularized and avascular retina.
Stage 1 is a faint demarcation line.
Stage 2 is an elevated ridge.
Stage 3 is extraretinal fibrovascular tissue.
Stage 4 is sub-total retinal detachment.
Stage 5 is total retinal detachment.

Plus disease
Plus disease can be present as a major complicating factor at any stage. It is characterised by:
Significant level of vascular dilation and tortuosity observed at the posterior retinal arterioles. This
reflects the increase of blood flow through the retina.[13]

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Vitreous haze and anterior chamber haze[13]

Iris vascular engorgement[13]
Persistent tunica vasculosa lentis or immature blood vessels growing over the lens which also restrict the
dilatation of the pupils.[13]

Stages 1 and 2 do not lead to blindness. However, they can progress to the more severe stages. Threshold
disease is defined as disease that has a 50% likelihood of progressing to retinal detachment. Threshold disease
is considered to be present when stage 3 ROP is present in either zone I or zone II, with at least 5 continuous or
8 total clock hours of disease, and the presence of plus disease.[14] Progression to stage 4 (partial retinal
detachment), or to stage 5 (total retinal detachment), will result in substantial or total loss of vision for the

Differential diagnosis
The most difficult aspect of the differential diagnosis may arise from the similarity of two other diseases:
Familial exudative vitreoretinopathy which is a genetic disorder that also disrupts the retinal
vascularization in full-term infants.
Persistent fetal vasculature syndrome also known as persistent hyperplastic primary vitreous that can
cause a traction retinal detachment difficult to differentiate but typically unilateral.

In order to allow timely intervention, a system of monitoring is undertaken for infants at risk of developing
ROP. These monitoring protocols differ geographically because the definition of high-risk is not uniform or
perfectly defined. In the USA the consensus statement of experts is informed by data derived by clinical trials
and published in Pediatrics 2006. They included infants with birthweights under 1500 grams or under 30 weeks
gestation in most cases. The first examination should take place within the first 4 weeks of life, and regular,
weekly examination is required until it is clear that the eyes are not going to develop disease needing treatment,
or one or both eyes develop disease requiring treatment. Treatment should be administered within a 48 hours, as
the condition can progress rapidly.

Peripheral retinal ablation is the mainstay of ROP treatment. The destruction of the avascular retina is
performed with a solid state laser photocoagulation device, as these are easily portable to the operating

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room or neonatal ICU. Cryotherapy, an earlier technique in which regional retinal destruction was done
using a probe to freeze the desired areas, has also been evaluated in multi-center clinical trials as an
effective modality for prevention and treatment of ROP. However,
when laser treatment is available, cryotherapy is no longer
preferred for routine avascular retinal ablation in premature
babies, due to the side effects of inflammation and lid swelling.
Further more recent trials have shown that treatment at an earlier
stage of the disease gives better results.[15]
Scleral buckling and/or vitrectomy surgery may be considered for
severe ROP (stage 4 and 5) for eyes that progress to retinal
detachment. Few centers in the world specialize in this surgery,
because of its attendant surgical risks and generally poor

The retina (red) is detached at the top

of the eye.

Intravitreal injection of bevacizumab (Avastin) has been reported
as a supportive measure in aggressive posterior retinopathy of
prematurity.[16] In a 2011 clinical trial comparing bevacizumab
with conventional laser therapy, intravitreal bevacizumab
monotherapy showed a significant benefit for zone I but not zone
II disease when used to treat infants with stage 3+ retinopathy of
prematurity.[17] Potential benefits of intravitreal Avastin injection
over laser therapy include: reduction in level of anesthesia
required, preservation of viable peripheral retina, and, possibly,
reduced incidence of subsequent high refractive error. However,
the safety of this new treatment has not yet been established in

The silicone band (scleral buckle,

blue) is placed around the eye. This
brings the wall of the eye into contact
with the detached retina, allowing the
retina to re-attach.

terms of ocular complications as well as systemic complications.

The latter are theoretically possible, as the active ingredient of bevacizumab not only blocks the
development of abnormal blood vessels in the eye but may also prevent the normal development of other
tissues such as the lung and kidney.
Oral propranolol is being evaluated for counteracting the progression of ROP, but safety is a concern. A
prospective randomized trial in which pre-term newborns were randomized to receiving oral propranolol
with standard treatment or standard treatment alone found that oral propranolol showed a 48% relative
risk reduction for progression to stage 3, 58% reduction for progression to stage 3 plus, and 100%
reduction for progression to stage 4. Furthermore, there was a 52% relative risk reduction for the need for
laser treatment or intravitreal bevacizumab. However 19% of the newborns experienced serious adverse
effects including hypotension and bradycardia.[18] A study in a mouse model of human ROP has shown

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that beta-blockade is protective against retinal angiogenesis and ameliorate blood-retinal barrier

Follow up
Once diagnosed with ROP lifelong follow up (yearly) is performed in some centers. In others, only
children treated for ROP are followed yearly.
Follow up after laser or anti-VEGF treatment is individualized.
Follow up of premature children (with or without ROP) is varying among centers and countries, mirroring
the diverse states of health care system in different countries.

Refractive errors (most common)
Retinal detachment and blindness

This disease was first described in the premature baby in 1942. Between 19411953, over 12,000 babies
worldwide were affected by it. Soul musician Stevie Wonder, actor Tom Sullivan as well as jazz singer Diane
Schuur are a few famous people who have the disease.
The first case of the epidemic was seen on St. Valentine's Day in 1941, when a premature baby in Boston was
diagnosed. Cases were then seen all over the world and the cause was, at that point, unknown. By 1951 a clear
link between incidence and affluence became clear: many cases were seen in developed countries with
organized and well-funded health care. Two British scientists suggested that it was oxygen toxicity that caused
the disease. Babies born prematurely in such affluent areas were treated in incubators which had artificially high
levels of oxygen. Studies on rats made this cause seem more likely, but the link was eventually confirmed by a
controversial study undertaken by American pediatricians. The study involved two groups of babies. Some [20]
given the usual oxygen concentrations in their incubators, while the other group had "curtailed" oxygen levels.
The latter group was shown to have a lower incidence of the disease. As a result, oxygen levels in incubators
were lowered and consequently the epidemic was halted. Each case of ROP avoided by withholding oxygen
"may have cost some 16 deaths".[21]


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ROP prevalence varies, from 58% in developed countries with adequate neonatological facilities, to up to 30%
in middle-income developing countries.[22]
There is increasing evidence that ROP and blindness due to ROP are now public health problems in the middle
income countries of Latin America, Eastern Europe and the more advanced economies in South East Asia and
the Middle east region. In these countries ROP is often the most common cause of blindness in children.[23][24]
ROP is highly likely to become an increasing problem in India, China and other countries in Asia as these
countries expand the provision of services for premature infants.
There is also evidence that the population of premature infants at risk of severe ROP varies depending on the
level of neonatal intensive care being provided.[23] In countries with high development indices and very low
neonatal mortality rates (e.g. North America, western Europe), severe ROP is generally limited to extremely
preterm infants i.e. those weighing less than 1 kg (2.2 lbs) at birth. At the other end of the development
spectrum, countries with very low development indices and very high neonatal mortality rates (e.g. much of
subSaharan Africa) ROP is rare as most premature babies do not have access to neonatal intensive care and so
do not survive. Countries with moderate development indices are improving access to neonatal intensive care,
and in these settings bigger, more mature babies are also at risk of severe ROP as neonatal care may be
suboptimal i.e. those weighing 1.52 kg (3.3-4.4 lbs) at birth. These findings have two main implications:
firstly, much can be done in countries with moderate development indices to improve neonatal care, to reduce
the risk of severe ROP in bigger babies and increase survival of extremely preterm infants, and secondly, in
these settings bigger more mature babies need to be included in ROP programs and examined regularly so as to
detect those babies developing ROP requiring treatment.
In 2012, the World Health Organization published data on rates of preterm birth and the number of premature
babies born in different regions of the world.[25] This report contained three main findings:
Premature birth has many different causes, and prevention is challenging,
Prematurity is the most common cause of neonatal death in many countries, totaling as many as 1 million
infants annually due to complications of preterm birth, and
the number of preterm births is currently estimated to be 15 million, and increasing.

1. "Terry Syndrome" ( Stedman's Medical Dictionary.
Lippincott Williams & Wilkins. 2006.
2. Shastry, BS; Pendergast, SD; Hartzer, MK; Liu, X; Trese, MT (May 1997). "Identification of missense mutations in the
Norrie disease gene associated with advanced retinopathy of prematurity.". Archives of ophthalmology 115 (5): 6515.
doi:10.1001/archopht.1997.01100150653015 (
PMID 9152134 (

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3. Dickinson, JL; Sale, MM; Passmore, A; FitzGerald, LM; Wheatley, CM; Burdon, KP; Craig, JE; Tengtrisorn, S; Carden,
SM; Maclean, H; Mackey, DA (SepOct 2006). "Mutations in the NDP gene: contribution to Norrie disease, familial
exudative vitreoretinopathy and retinopathy of prematurity.". Clinical & experimental ophthalmology 34 (7): 6828.
doi:10.1111/j.1442-9071.2006.01314.x ( PMID 16970763
4. Shastry, Barkur S (1 January 2010). "Genetic susceptibility to advanced retinopathy of prematurity (ROP)"
( Journal of Biomedical Science 17 (1): 69. doi:10.1186/14230127-17-69 ( PMC 2933676
( PMID 20738858
5. Kumar, Vinay (2007). "Chapter 29: Eye, Retina and Vitreous, Retinal Vascular Disease". Robbins basic pathology (8th
ed.). Philadelphia: Saunders/Elsevier. ISBN 978-1416029731.
6. Guyton, Arthur; Hall, John (2006). "Chapter 17: Local and Humoral Control of Blood Flow by the Tissues". In Gruliow,
Rebecca. Textbook of Medical Physiology (Book) (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc. p. 200. ISBN 07216-0240-1.
7. Stenson; BOOST ll Cooperative Groups (2013). "Oxygen Saturation and Outcomes in Preterm Infants". New England
Journal of Medicine 368: 20942104. doi:10.1056/nejmoa1302298 (
8. Karna, P.; Muttineni, J.; Angell, L.; Karmaus, W. (2005). "Retinopathy of prematurity and risk factors: A prospective
cohort study" ( BMC Pediatrics 5: 18. doi:10.1186/14712431-5-18 ( PMC 1175091
( PMID 15985170
9. Jefferies, AL; Canadian Paediatric Society; Fetus and Newborn Committee (1 December 2010). "Retinopathy of
prematurity: Recommendations for screening" ( Paediatrics & Child Health 15 (10): 6670. PMC 3006218
( PMID 22131866
( Retrieved 9 March 2013.
10. Committee for the Classification of Retinopathy of Prematurity (Aug 1984). "An international classification of
retinopathy of prematurity". Arch Ophthalmol. 102 (8): 11301134. doi:10.1001/archopht.1984.01040030908011
( PMID 6547831
11. Committee for the Classification of Retinopathy of Prematurity (Jul 2005). "The International Classification of
Retinopathy of Prematurity revisited". Arch Ophthalmol. 123 (7): 991999. doi:10.1001/archopht.123.7.991
( PMID 16009843
12. Early Treatment for Retinopathy of Prematurity Cooperative Group (2003). "Revised indications for the treatment of
retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial". Arch
Ophthalmol. 121 (12): 16841696. doi:10.1001/archopht.121.12.1684
( PMID 14662586

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13. Retinopathy of Prematurity ( at eMedicine

14. Phelps, D.L. (2001). "Retinopathy of Prematurity: History, Classification, and Pathophysiology". NeoReviews 2 (7):
e153e166. doi:10.1542/neo.2-7-e153 (
15. Dobson, V.; Quinn, G. E.; Summers, C. G.; Hardy, R. J.; Tung, B.; Good, W. V.; Good, W. V. (2011). "Grating Visual
Acuity Results in the Early Treatment for Retinopathy of Prematurity Study". Archives of Ophthalmology 129 (7): 840
846. doi:10.1001/archophthalmol.2011.143 ( PMID 21746974
16. Shah PK, Narendran V, Tawansy KA, Raghuram A, Narendran K. (2007). "Intravitreal bevacizumab (Avastin) for post
laser anterior segment ischemia in aggressive posterior retinopathy of prematurity". Indian journal of ophthalmology 55
(1): 7576. doi:10.4103/0301-4738.29505 ( PMID 17189897
17. Mintz-Hittner, HA; Kennedy, KA; Chuang, AZ; Beat-Rop Cooperative, Group (2011). "Efficacy of intravitreal
bevacizumab for stage 3+ retinopathy of prematurity" ( The
New England Journal of Medicine 364 (7): 60315. doi:10.1056/NEJMoa1007374
( PMC 3119530
( PMID 21323540
18. Filippi L (2013). [1] ( J Pediatr. 2013 Dec;163(6):1570-1577.e6
19. Ristori C (2011). [2] ( Invest Ophthalmol Vis Sci. 2011 Jan
20. Silverman, William A. (November 1980). Retrolental fibroplasia: a modern parable (
id=mslsAAAAMAAJ). Grune & Stratton. Retrieved 21 September 2013.
21. Silverman, William A. (November 1980). Retrolental fibroplasia: a modern parable (
id=mslsAAAAMAAJ). Grune & Stratton. Retrieved 21 September 2013. "Chapter 8: "The Consequences of Oxygen
22. Gergely, K.; Gerinec, A. (2010). "Retinopathy of prematurity--epidemics, incidence, prevalence, blindness". Bratislavske
lekarske listy 111 (9): 514517. PMID 21180268 (
23. Gilbert, C.; Fielder, A.; Gordillo, L.; Quinn, G.; Semiglia, R.; Visintin, P.; Zin, A.; International No-Rop, G. (2005).
"Characteristics of Infants with Severe Retinopathy of Prematurity in Countries with Low, Moderate, and High Levels of
Development: Implications for Screening Programs" (
Pediatrics 115 (5): e518e525. doi:10.1542/peds.2004-1180 (
PMID 15805336 ( Retrieved 9 June 2013.
24. Limburg, H.; Gilbert, C.; Hon, D. N.; Dung, N. C.; Hoang, T. H. (2012). "Prevalence and Causes of Blindness in
Children in Vietnam". Ophthalmology 119 (2): 355361. doi:10.1016/j.ophtha.2011.07.037
( PMID 22035577
25. "Born Too Soon: The Global Action Report on Preterm Birth"
( World Health Organization. 2012. Retrieved
9 June 2013.

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External links
Retinopathy of Prematurity ( Resource Guide from the
National Eye Institute (NEI).
Merck Manual entry on ROP
Retinopathy of Prematurity (ROP), with animation
itions/Pages/Retinopathy-of-Prematurity-ROP.aspx) The Hospital for Sick Children
Retinopathy Of The Newborn Is Due To Hypoxia Not Oxygen Toxicity (
Appelbaum, Alfred (October 1952). "Retrolental fibroplasia; blindness in infants of low weight at birth."
( California medicine 77 (4): 25965.
PMC 1521441 ( PMID 13009470
Retinopathy of Prematurity ( on IAPB
Retrieved from ""
Categories: Blindness Disorders of choroid and retina Pediatrics
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