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Retinopathy of Prematurity

Latest Evidence Regarding the Use of Supplemental Oxygen

by John D. Zoidis, MD

Modern neonatal care has curbed the incidence of ROP, yet because the survival rate of low
birth weight infants is much higher, the exposure of surviving babies to required oxygen
levels is increasing

Retinopathy of prematurity (ROP), originally called retrolental fibroplasia, is a vasoproliferative

disorder that affects the retina of newborn infants. The condition was first described in 1942, 1 and
in the early 1950s investigators theorized that it was caused by the use of oxygen therapy to treat
respiratory distress in premature infants.2 Today, ROP causes blindness in 50,000 children
worldwide each year,3 and a number of causes have been identified, including high levels of
oxygen. Because low levels of oxygen can lead to additional respiratory complications in
newborns, particularly in premature infants, there has been a growing recognition of the fine line
between too much and too little oxygen. Today, better oxygen monitoring has led to better control
of oxygen administered to newborns. Yet, although the rate of blindness from ROP has dropped
since the years before treatment was available, there are still many new cases of blindness each
year from this disorder—it remains a leading cause of childhood blindness and visual disability in
the United States.4

In the normal fetus, from about 16 weeks until birth, blood vessels grow outward from the optic
nerve toward the peripheral retina. The last 12 weeks of a normal 40-week gestation period are a
critical period in the development of the fetal eyes. In infants born prematurely, normal retinal
blood vessel growth sometimes stops, and abnormal blood vessels can develop in the retina. This
is called neovascularization. ROP occurs when the abnormal blood vessels grow and spread
throughout the retina, leading to scarring and retinal detachment.

Two pathogenic phases have been described.5 Phase I begins with delayed retinal vascular growth
after premature birth. Phase II follows when Phase I-induced hypoxia releases various factors to
stimulate new blood vessel growth. Both oxygen-regulated and non-oxygen–regulated factors
contribute to normal vascular development and retinal neovascularization. An important oxygen-
regulated factor is vascular endothelial growth factor (VEGF). The non-oxygen–regulated growth
factor, insulin-like growth factor-I (IGF-I), also has been implicated in the pathogenesis of ROP.
Investigators have shown that in knockout mice, lack of IGF-I prevents normal retinal vascular
growth, despite the presence of VEGF, which is important to vessel development. 6 Premature
infants who develop ROP have been found to have low levels of serum IGF-I compared to age-
matched infants without ROP.7 IGF-I therefore appears to be critical to normal vascular

Clinical Stages

ROP is classified into five clinically distinct stages, depending on severity.8-10 Stage I disease is
characterized by mildly abnormal blood vessel growth. Many children whodevelop Stage I
disease eventually develop normal vision. Stage II disease is characterized by moderately
abnormal blood vessel growth. As with Stage I disease, many children who develop Stage II
disease eventually develop normal vision. In Stage III disease, there is severely abnormal blood
vessel growth. The abnormal blood vessels grow toward the center of the
eye instead of following their normal growth pattern along the surface of
the retina. If the blood vessels of the retina become enlarged and twisted
as a result of the neovascularization (often designated as “plus disease”),
then treatment is warranted. Treatment of Stage III disease has a good
chance of preventing retinal detachment. Stage IV disease is defined by a
partially detached retina. Scarring and bleeding cause traction on the
retina, which might be pulled away from the wall of the eye. There also
can be scleral buckling. In Stage V disease, the retina is completely detached. If untreated, there
will invariably be severe visual impairment or blindness.

A number of risk factors for ROP have been identified (see Table).10-12

Supplemental Oxygen and ROP

The National Eye Institute (NEI) performed a randomized trial 13,14 to evaluate the efficacy and
safety of supplemental oxygen for the treatment of moderate-to-severe ROP. This trial was called
the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP)
study. In this study, 649 premature infants were enrolled at 30 centers over 5 years. 325 infants
received conventional oxygen supplementation (89% to 94% O2 saturation by pulse oximetry)
and 324 received “high” supplemental oxygen (96% to 99% O2 saturation by pulse oximetry).
The use of supplemental oxygen did not cause additional progression of moderate-to-severe ROP
but also did not significantly reduce the number of infants requiring peripheral retinal ablative
surgery. A subgroup analysis suggested a benefit of supplemental oxygen among infants who
have prethreshold ROP (moderate-to-severe ROP without “plus disease”), but this finding was
said to require additional study.

The investigators of the NEI study13,14 concluded that modest supplemental oxygen given to
premature infants with moderate-to-severe ROP might not significantly improve ROP, but it
definitely does not make it worse. In this study, use of supplemental oxygen increased the risk of
adverse pulmonary events, including pneumonia; exacerbations of chronic lung disease; and the
need for oxygen, diuretics, and hospitalization at 3 months of corrected age.

Interestingly, in premature infants excluded from the STOP-ROP study because their median
arterial oxygen saturation was >94% in room air at the time of prethreshold diagnosis, the rate of
ROP progression was less than that of infants included in the study.15 Fifteen of the 30 centers
that participated in STOP-ROP elected to participate in the High Oxygen Percentage in
Retinopathy of Prematurity (HOPE-ROP) study. A total of 136 HOPE-ROP infants were
compared with 229 STOP-ROP infants enrolled during the same time period from the same 15
hospitals. HOPE-ROP infants were of greater gestational age at birth (26 versus 25 weeks) and
greater postmenstrual age (37 versus 35 weeks) at the time of prethreshold ROP diagnosis.
HOPE-ROP infants progressed to threshold ROP 25% of the time, compared with 46% of STOP-
ROP infants. After gestational age, race, postmenstrual age at prethreshold diagnosis, and
presence of plus disease at prethreshold diagnosis were controlled for, logistic regression analysis
showed that HOPE-ROP infants progressed from prethreshold to threshold ROP less often than
STOP-ROP infants. The reasons for the better ROP outcome among HOPE-ROP versus STOP-
ROP subjects are not completely understood, but the investigators noted that an infant’s median
arterial oxygen saturation by pulse oximetry value at the time of prethreshold diagnosis may be a
prognostic indicator for which infants might progress to severe ROP.

Recently, a prospective study was performed to determine whether lowering O2 saturation alarm
limits for infants at risk of ROP reduces its incidence and/or severity.16 Oximetry alarm limits
were lowered to 85% and 93% for all infants with a birth weight of 1,250 g and/or gestational age
28 weeks and maintained until 32 weeks postmenstrual age or until oxygen saturations were
consistently greater than 93% in room air. In the year after the oximeter alarm limit policy
change, 4 of 72 infants developed prethreshold ROP, compared with 44 of 251 infants in the
previous 3-year period . Similarly, only 6 of 144 eyes developed prethreshold ROP in the year
after the policy change, compared with 84 of 502 in the previous 3 years. The investigators
concluded that a simple change in oximeter alarm parameters in the first weeks of life for infants
with a birthweight 1,250 g or less may decrease the incidence of prethreshold ROP.

The use of high supplemental oxygen in premature infants with pre-threshold ROP seems to be
more closely related to other pulmonary adverse events than it does to the progression of ROP. It
also would appear, based on the most recent evidence, that by strictly avoiding hyperoxia (O2
saturation 92% to 93% by pulse oximetry) and avoiding fluctuations in O2 saturation in premature
infants, it might be possible to control and prevent severe ROP in most cases.

John D. Zoidis, MD, is a contributing writer for RT. For more information, contact

1. Terry TL. Retrolental fibroplasia in the premature infant. V. Further studies on fibroplastic
overgrowth of the persistent tunica vasculosa lentis. Proc Trans Am Ophthalmol Soc. 1944;

2. Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical

approach. Med J Aust. 1951; 2:48-50.

3. Saugstad OD. Oxygen and retinopathy of prematurity. J Perinatol. 2006; 26(suppl):S46-50.

4. Drack A. Retinopathy of prematurity. Adv Pediatr. 2006; 53:211-26.

5. Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res. 2004;

6. Smith LE. Pathogenesis of retinopathy of prematurity. Acta Paediatr Suppl. 2002; 91:26-8.

7. Smith LE. Pathogenesis of retinopathy of prematurity. Semin Neonatol. 2003; 8:469-73.

8. An international classification of retinopathy of prematurity. II. The classification of retinal
detachment. International Committee for the Classification of the Late Stages of Retinopathy of
Prematurity. Arch Ophthalmol. 1987; 105:906-12.

9. Flynn JT. An International Classification of Retinopathy of Prematurity: development of the

classification of the late stages of retinopathy of prematurity. Birth Defects Orig Artic Ser. 1988;

10. Machemer R. Description and pathogenesis of late stages of retinopathy of prematurity. Birth
Defects Orig Artic Ser. 1988; 24:275-80.

11. Karna P, Muttineni J, Angell L, Karmaus W. Retinopathy of prematurity and risk factors: a
prospective cohort study. BMC Pediatr. 2005; 5:18-23.

12. Liu PM, Fang PC, Huang CB, et al. Risk factors of retinopathy of prematurity in premature
infants weighing less than 1,600 g. Am J Perinatol. 2005; 22:115-20.

13. National Eye Institute. Supplemental Therapeutic Oxygen for Pre-threshold Retinopathy of
Prematurity (the STOP-ROP Multicenter Trial). 2000. Available at: Accessed November 25, 2006.

14. STOP-ROP Multicenter Study Group. Supplemental Therapeutic Oxygen for Prethreshold
Retinopathy of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes.
Pediatrics. 2000; 105:295-310.

15. McGregor ML, Bremer DL, Cole C, et al. Retinopathy of prematurity outcome in infants with
prethreshold retinopathy of prematurity and oxygen saturation >94% in room air: the high oxygen
percentage in retinopathy of prematurity study. Pediatrics. 2002; 110:540-4.

16. Vanderveen DK, Mansfield TA, Eichenwald EC. Lower oxygen saturation alarm limits
decrease the severity of retinopathy of prematurity. J AAPOS. 2006; 10:445-8.
Premature Infant Retinal Disorder- Retinopathy of Prematurity (ROP)
Introduction | Anatomy | Causes | Symptoms | Diagnosis | Treatment
Retinopathy of Prematurity (ROP), also called retrolental fribroplasia, is abnormal blood vessel
development that may occur in some premature babies. The retina is located at the back of the
eye. The retina transmits nerve messages about what is seen to the brain for processing. When
some babies are born prematurely, the blood vessels that supply the retina are not developed
completely, leaving the retina without a blood supply. Severe ROP may lead to vision problems
or blindness. Infants with mild ROP may make full recoveries. ROP may be treated with

The eyes and brain work together with amazing efficiency. Light rays enter the front of the eye
and are interpreted by the brain as images. Light rays first enter your child’s eye through the
cornea, the “window” of the eye. The cornea is a clear dome that helps the eyes focus.

The anterior chamber is located behind the cornea and in front of the iris. The anterior chamber
is filled with a fluid that maintains eye pressure, nourishes the eye, and keeps it healthy. The iris
is the colored part of your child’s eye. Eye color varies from person to person and includes
shades of blue, green, brown, and hazel. The iris contains two sets of muscles. The muscles
work to make the pupil of the eye larger or smaller. The pupil is the black circle in the center of
the iris. It changes size to allow more or less light to enter your child’s eye.

After light comes through the pupil, it enters the lens. The lens is a clear curved disc. Muscles
adjust the curve in the lens to focus clear images on the retina. The retina is located at the back
of your child’s eye.

The inner eye, the space between the posterior chamber behind the lens and the retina, is called
the vitreous body. It is filled with a clear gel substance that gives the eye its shape. Light rays
pass through the gel on their way from the lens to the retina.

The retina is a thin tissue layer that contains millions of nerve cells. The nerve cells are sensitive
to light. Cones and rods are specialized receptor cells. Cones are specialized for color vision
and detailed vision, such as for reading or identifying distant objects. Cones work best with
bright light. The greatest concentration of cones is found in the macula and fovea at the center of
the retina. The macula is the center of visual attention. The fovea is the site of visual acuity or
best visual sharpness. Rods are located throughout the rest of the retina.

The eyes contain more rods than cones. Rods work best in low light. Rods perceive blacks,
whites, and grays, but not colors. They detect general shapes. Rods are used for night vision and
peripheral vision. High concentrations of rods at the outer portions of the retina act as motion
detectors in your child’s peripheral or side vision.

The receptor cells in the retina send nerve messages about what your child sees to the optic
nerve. The optic nerves extend from the back of each eye and join together in the brain at the
optic chiasm. From the optic chiasm, the nerve signals travel along two optic tracts, and
eventually to the occipital cortex where vision is processed and perceived.
The blood vessels in a developing baby begin to grow during the third month of pregnancy and
finish developing by the time of normal birth. Babies that are born prematurely may not have
fully developed blood vessels in their retinas. Premature babies are at risk for ROP if the blood
vessels grow abnormally. The blood vessels may break and bleed. In turn, scar tissue may
develop that can cause retinal detachment. Retinal detachment can reduce vision or result in

Many premature infants are able to attain healthy retinal blood vessel growth. However, a small
percentage of premature infants develop more severe retinal problems. The smallest premature
babies, regardless of gestational age, have the highest risk for ROP.

There may be few signs that ROP is developing. ROP may cause leukocoria, a condition in
which the pupil turns white. ROP may cause abnormal eye movements, crossed eyes, or severe

It is important to have babies that are born prematurely screened by an ophthalmologist. The
examination is painless. Eyedrops are placed in the infant’s eyes so that the doctor may view the
retinas. The examinations are conducted about every two weeks.

Laser therapy or cryotherapy may be used to treat areas of the retina that do not have normal
blood vessels or to reattach the retina. Cryotherapy uses cold temperatures to destroy abnormal
blood vessels. Laser therapy uses high-energy light to eliminate abnormal blood vessels. These
are both very short procedures.

The majority of premature infants with mild ROP experience good recoveries. Children
with visual problems from ROP may benefit from rehabilitation and vision aids.
Because a possible outcome is blindness, early detection and early treatment are vital.