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Retinopathy of Prematurity

Author: KN Siva Subramanian, MD; Chief Editor: Ted Rosenkrantz, MD more...

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Updated: Mar 01, 2015


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Background

Pathophysiology

Epidemiology

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Background

Retinopathy of prematurity (ROP) is a serious vasoproliferative disorder that affects


extremely premature infants. Retinopathy of prematurity often regresses or heals but can
lead to severe visual impairment or blindness. Significant retinopathy of prematurity can
lead to lifelong disabilities for the smallest survivors of neonatal ICUs (NICUs). It
remains a serious problem despite striking advances in neonatology.
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Pathophysiology
Retinopathy of prematurity primarily occurs in extremely low birth weight (ELBW)
infants. Most research suggests that a low birth weight, a young gestational age (GA; see
the Gestational Age from Estimated Date of Delivery calculator), and the severity of
illness (eg, respiratory distress syndrome [RDS], bronchopulmonary
dysplasia [BPD], sepsis) are associated factors. Recently, other associations have been
described. However, the severity of the illness appears to be a major predictor of severe
disease. The smallest, sickest, and most immature infants are at the highest risk for
serious disease. Black infants appear to have less severe retinopathy of prematurity.[1, 2]
Retinal vasculature begins to develop around 16 weeks' gestation. It grows
circumferentially and becomes fully mature at term. Premature birth results in the
cessation of normal retinal vascular maturation. Exposure of newborn premature infants
to hyperoxia downregulates retinal vascular endothelial growth factor (VEGF). Blood
vessels constrict and can become obliterated, resulting in delays of normal retinal
vascular development. This hyperoxia-vasocessation is known as stage I of retinopathy of
prematurity. See the image below.

Stage I retinopathy of
prematurity.
Early on, oxygen and nutrients can be delivered to the retina by means of diffusion from
the underlying choroid capillary bed. The retina continues to grow in thickness and
eventually outgrows its vascular supply. Over time, retinal hypoxia occurs and results in
an overgrowth of vessels; this hypoxia-vasoproliferation is stage II of retinopathy of
prematurity. See the image below.

Stage II retinopathy of
prematurity.

This process is mediated, in part, by VEGF and is affected by insulinlike growth factor-1
(IGF-1) and other cytokines. These changes in the retina result in retinopathy of
prematurity.
Dhaliwal et al found that retinopathy of prematurity occurred with significantly greater
frequency and severity in small-for-GA (SGA) infants compared with appropriate-for-GA
(AGA) infants.[3] In a review of 1413 infants with birth weight less than 1500 g and/or
GA of 26-31 weeks, infants with a birth weight below the tenth percentile for GA were
more likely to develop any stage of retinopathy of prematurity than their AGA peers (p<
0.01) and were more likely to develop severe retinopathy of prematurity (GA of 26-27
weeks, p< 0.01; GA of 28-31 weeks, p = 0.01).
Previous
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Epidemiology
Frequency
United States
The incidence varies with birth weight but is reported to be approximately 50-70% in
infants whose weight is less than 1250 g at birth.
Hussain et al reviewed the incidence and the need for surgery in neonates with
retinopathy of prematurity who were born at 22-36 weeks' gestation between July 1989
and June 30, 1997.[4] The incidences were 21.3% (202 of 950 patients) for retinopathy of
prematurity of any stage and 4.6% (44 of 950 patients) for retinopathy of prematurity at
stage III or worse. No retinopathy of prematurity was noted in infants born after 32
weeks' gestation. No infant born after 28 weeks' gestation needed retinal surgery in this
study. Despite the increased survival of ELBW infants, they found a considerable
reduction in the incidence and severity of retinopathy of prematurity compared with
reports from an earlier period. However, infants born before 28 weeks' gestation and
those with birth weights less than 1000 g were at risk to need retinal surgical treatment
for retinopathy of prematurity.
Investigators from the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of
Prematurity (STOP-ROP) multicenter trial concluded that maintaining oxygen saturation
in the high-90% range did not reduce the severity of the retinopathy when compared with
the saturations in the low-90% range.[5] However, it did result in more adverse pulmonary
events. In a subanalysis of infants who did not have plus disease (ie, tortuosity of vessels)
at the time of study entry, the progression to threshold was significantly decreased when
compared with the progression in infants with plus disease. Thus, a critical window for
oxygen administration may be determined.
International

Retinopathy of prematurity is prevalent worldwide and several reports have detailed the
incidence and risk factors associated with the disease.
A Korean study reported a 20.7% incidence (88 of 425 premature babies) and reported
that a GA of 28 weeks or less and a birth weight of 1000 g or less were the most
significant risk factors.[6] Another study from Singapore reported a 29.2% incidence (165
of 564 ELBW infants).[7] The median age of onset of retinopathy of prematurity was 35
weeks (range, 31-40 wk) postmenstrual age. The risk factors for development of
threshold retinopathy of prematurity by regression analysis were maternal preeclampsia,
birth weight, pulmonary hemorrhage, duration of ventilation, and duration of continuous
positive airway pressure (CPAP).
An observational study from United Kingdom designed to compare the characteristics of
infants with severe retinopathy of prematurity in countries with low, moderate, and high
levels of development found that the mean birth weights of infants from highly developed
countries was 737-763 g compared with 903-1527 g in less-developed countries.[8] Mean
GAs of infants from highly developed countries were 25.3-25.6 weeks compared with
26.3-33.5 weeks in less-developed countries. Thus, larger and more mature infants
seemed to be developing severe retinopathy of prematurity in less-developed nations.
This suggests that individual countries need to develop their own screening programs
with criteria suited to their local population.

Mortality/Morbidity
Long-term outcomes for serious disease include severe visual impairment and blindness.
In addition, myopia, amblyopia, and strabismus may occur. Repka et al described the
need for subsequent ophthalmic intervention in patients with retinopathy of prematurity.[9]

Race
Some reports indicate a decreased incidence of progression to threshold disease in black
infants. Most evidence comes from the Cryotherapy for Retinopathy of Prematurity
(CRYO-ROP) study.[10] Further evidence that black infants are less likely to develop
severe retinopathy of prematurity has been reported in studies of candidemia in ELBW
infants.[11] The exact mechanism for the decreased incidence of progression to surgery in
black infants has not been described. Bizzaro et al showed a strong genetic predisposition
to retinopathy of prematurity when comparing monozygotic twins with dizygotic twins.
[12]

Sex
Although some reports indicate a male predilection, the CRYO-ROP study revealed no
differences based on sex.[10]

Age

Retinopathy of prematurity is a disease of the immature retina, and the occurrence of


retinopathy of prematurity is inversely related to GA. The more premature the infant, the
more likely retinopathy of prematurity is to develop.
Previous
Clinical Presentation
Contributor Information and Disclosures
Author
KN Siva Subramanian, MD Professor of Pediatrics and Obstetrics/Gynecology, Chief
of Neonatal Perinatal Medicine, Hospital Ethicist, Medstar Georgetown University
Hospital
KN Siva Subramanian, MD is a member of the following medical societies: American
Academy of Pediatrics, American Association for the Advancement of Science, American
Society for Parenteral and Enteral Nutrition, New York Academy of Sciences, American
College of Nutrition, American Society of Law, Medicine & Ethics, Southern Society for
Pediatric Research
Disclosure: Nothing to disclose.
Coauthor(s)
Monisha Bahri, MBBS, MD Attending Physician, Department of Neonatalogy,
Washington Hospital Center
Monisha Bahri, MBBS, MD is a member of the following medical societies: American
Academy of Pediatrics, Medical Council of India, Indian Academy of Pediatrics
Disclosure: Nothing to disclose.
Gonzalo (Vike) Vicente, MD, FAAP Consulting Ophthalmologist, Eye Doctors of
Washington
Gonzalo (Vike) Vicente, MD, FAAP is a member of the following medical
societies: American Academy of Ophthalmology, American Academy of
Pediatrics, American Association for Pediatric Ophthalmology and Strabismus, American
Medical Association
Disclosure: Nothing to disclose.
Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical


Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Arun K Pramanik, MD, MBBS Professor of Pediatrics, Louisiana State University
Health Sciences Center
Arun K Pramanik, MD, MBBS is a member of the following medical societies: American
Academy of Pediatrics, American Thoracic Society, National Perinatal
Association, Southern Society for Pediatric Research
Disclosure: Nothing to disclose.
Chief Editor
Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology,
Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American
Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric
Research, American Medical Association,Connecticut State Medical Society, Society for
Pediatric Research
Disclosure: Nothing to disclose.
Additional Contributors
Oussama Itani, MD, FAAP, FACN Clinical Associate Professor of Pediatrics and
Human Development, Michigan State University; Medical Director, Department of
Neonatology, Borgess Medical Center
Oussama Itani, MD, FAAP, FACN is a member of the following medical
societies: American Academy of Pediatrics, American Association for Physician
Leadership, American Heart Association, American College of Nutrition
Disclosure: Nothing to disclose.
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Stage I retinopathy of prematurity.

Scheme of retina of right eye (RE) and left eye (LE) showing zone borders and clock
hours used to describe location and extent of retinopathy of prematurity.
Zone I retinopathy of prematurity.
Zone II retinopathy of prematurity.
Zone III retinopathy of prematurity.
Stage II retinopathy of prematurity.
Stage III retinopathy of prematurity.
Retinopathy of prematurity.
Retinopathy of prematurity.
Retinopathy of prematurity.
Retinopathy of prematurity.
Retinopathy of prematurity threshold, according to the Cryotherapy for Retinopathy of
Prematurity (CRYO-ROP) cooperative group.
Treatment guidelines, according to the Early Treatment for Retinopathy of Prematurity
(ET-ROP) study.
Laser photocoagulation.
Cryotherapy probe application.

Table. Timing of First Eye Examination Based on Gestational Age at Birth

Table. Timing of First Eye Examination Based on Gestational Age at Birth


Gestational Age at Birth (wk)
22 *
23 *
24
25
26
27
28
29
30
31 (if necessary)
32 (if necessary)

Chronologic Age (wk)


9
8
7
6
5
4
4
4
4
4
4

Postmenstrual Age (wk)


31
31
31
31
31
31
32
33
34
35
36