Preterm infants – the drug Avastin is effective for preventing blindness

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Babies born prematurely who require treatment to prevent blindness from retinopathy of prematurity (ROP) could be treated with a dose of Avastin (bevacizumab) that is a fraction of the dose commonly used for ROP currently.

Results from the dose-finding study were published April 23 in JAMA Ophthalmology.

The study was conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and supported by the National Eye Institute (NEI), part of the National Institutes of Health.

Preterm babies are at high risk of abnormal blood vessel growth in the retina, the light-sensitive tissue in the back of the eye.

These abnormal blood vessels are fragile and prone to leaking. If left untreated, vessel growth can lead to scarring and retinal detachment, the main cause of ROP-related vision loss. ROP is one of the leading causes of blindness in children.

Established ROP treatments include laser therapy and cryotherapy. Both interventions work by causing the abnormal blood vessels to stop growing before they can cause scarring and retinal detachment.

Avastin is one of several available drugs that inhibit abnormal blood vessel growth by suppressing the overproduction of a signal protein called vascular endothelial growth factor (VEGF).

The U.S. Food and Drug Administration approved Avastin in 2004 as a cancer therapy. Since then, ophthalmologists have used it off-label to inhibit abnormal blood vessel growth in ROP, as well as in other ocular disorders.

Results from a clinical trial published in 2011 confirmed the benefit of using Avastin over laser therapy for treating the most severe cases of ROP, which occur in a region of the retina known as posterior zone 1.

“As a faster and easier treatment option, anti-VEGF eye injections were a welcomed alternative to laser therapy for treating severe ROP,” said the new study’s protocol chair, David Wallace, M.D., MPH, chair of ophthalmology at the Indiana University School of Medicine.

Laser therapy requires sedating the baby for as long as 90 minutes; an Avastin injection takes much less time and is generally less stressful to the infant.

“But we know that anti-VEGF agents injected into the eye also get into the bloodstream, and doctors worry that inhibiting VEGF systemically could interfere with normal development of brain, lung, bone, and kidney tissues,” he said.

Evidence suggests that injections of anti-VEGF in the eye reduce levels of VEGF in the bloodstream.

In this study, Wallace and colleagues in the NEI-funded PEDIG hoped to pinpoint the lowest possible therapeutic dose of Avastin by testing progressively lower doses in 10-14 infants per dose.

“We didn’t want to start by testing an ineffective dose and risk a child going blind, so we started with 40% of the dose commonly used for ROP. When a dose was successful, we halved it and then tested that dose. Eventually we cut the dose in half seven times,” he said.

“In the current study, we found that 0.004 mg of Avastin – a dose that’s merely 0.6% of the dose used in the 2011 study of Avastin for ROP – may be the lower limit to be effective for most infants with ROP,” said Wallace.

The findings set the stage for a randomized controlled trial comparing long-term effects of low-dose Avastin with laser therapy for treating ROP,” he said.

They plan to follow children over time to compare the long-term effects of each strategy on vision and organ development.

Previous studies suggest that babies treated with Avastin versus laser may be less likely to become myopic and require glasses for nearsightedness as they grow older.

The study involved 59 preterm infants with type 1 ROP, the most severe form. Each infant had one eye treated by a single injection containing 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of Avastin.

If the other eye required treatment, it received twice the concentration (one dose level higher). By comparison, currently used doses of Avastin for ROP range from 0.25 mg to 0.625 mg.

Treatment was considered a short-term success if ROP improved by day four after therapy, and if there was no recurrence or need for additional treatment within four weeks.

Such success was achieved in all eyes treated with the 0.016 mg and 0.008 mg doses, and in 9 of 10 eyes receiving 0.004 mg, but only in 17 of 23 eyes receiving 0.002 mg, resulting in the conclusion that 0.004 mg may be the lowest effective dose.


Retinopathy of prematurity (ROP) is a blinding morbidity affecting preterm infants. It is a significant clinical problem and currently represents the leading preventable cause of childhood blindness worldwide.[1],[2]

The prevalence varies by population though is estimated overall between 10% and 25%[3],[4],[5] and incidence between approximately 50% and 70% in infants weighing <1500 g at the time of birth.[1],[4]

According to the World Health Organization estimates, there are 1.4 million [1] blind children worldwide, two-thirds of whom live in developing countries.[6] ROP is the cause of blindness in about 50,000 of these children.[7]

ROP is a condition of the developing retinal vascular system; the incidence and severity of ROP are highly correlated with the degree of prematurity at birth.[8],[9] Nearly, all cases occur in neonates with a birth weight of below 1500 g and gestational age of below 32 weeks.[9] ROP is a treatable, vascular proliferative disorder that affects the incompletely vascularized retina in premature neonates.[8]

Neonates with ROP are prone to develop visual complications, both structural and functional in long terms. Structural complications include refractive errors and strabismus, whereas functional complications include visual dysfunction from mild to severe, even complete blindness, reduced contrast sensitivity, visual field defects, and abnormal color vision and perception.[10]

Most data indicate an increasing incidence of ROP disease as industrialized countries report increased incidence by approximately 10-fold since the 1990s.[11] In the most severe stages of the disease retinal traction and detachment develop leading to permanent blindness.[12]

Recent work demonstrates the rates of severe, treatment-worthy, ROP rose from 1.7 to 14.8/1000 preterm infants between the years 1990 and 2011.[11] The National Eye Institute reports that approximately 1100–1500 infants will develop ROP requiring treatment each year in the US and approximately 400–600 will become legally blind from ROP.[13] Thus, ROP is an increasing and significant clinical problem.

When it was first described in 1942 by Terry,[14] this disease was not commonly seen, and hence had little interest, but 10 years later, it became a major problem to all pediatricians and ophthalmologists. It now affects thousands of children worldwide.[15]

The introduction of neonatal intensive care units (NICUs) in Europe and the United States during the 1940s and 1950s led to the unmonitored supplemental oxygen in preterm and low birth weight infants.

This resulted in the first epidemic of ROP. This epidemic ceased following the implementation of controlled oxygen administration. However, advances in neonatal care led to the survival of premature neonates with increasingly low gestational ages and low birth weights. This had led to the so-called “second epidemic” of ROP.

More recently, ROP is again emerging as a major cause of pediatric blindness and visual impairment in the developing world and middle-income countries of Latin America, Eastern Europe, and Asia where cases of ROP are increasingly being reported.

Rates of this potentially blinding disease requiring treatment also tend to be higher in middle- and low-income countries suggesting that babies are being exposed to risk factors which are, to a large extent, being controlled in industrialized countries. This phenomenon is considered as the “third ROP epidemic.”[7] Hence, it is imperative that every pediatrician and neonatologist should know how to address this growing menace.

Classification of Retinopathy of Prematurity Top

In the past, there were several classifications of ROP which led to much confusion among pediatricians, neonatologists, and ophthalmologists. To resolve this issue, a committee for ROP classification was formed in 1984, which proposed an international classification of ROP (ICROP) by dividing the retina into three zones, extending from posterior to anterior retina and describing the extent of ROP in clock-hours of involvement.[18] The retinal changes are divided into stages of severity. However, with the advances in retinal imaging techniques, a revised ICROP classification was put forth which described the zones better.[19]

Zones

Three concentric zones, centered on the retina, define the anteroposterior location of retinopathy [Figure 1].

Figure 1: Schematic representation of different zones used in classifying retinopathy of prematurity
Figure 1: Schematic representation of different zones used in classifying retinopathy of prematurity

  • Zone I: With optic disc as the center, and twice the distance from the disc to fovea, the circle formed is Zone I. Using a 25 or 28 diopter (D) condensing lens, when the nasal edge of the optic disc is kept at one edge, the temporal field of view is Zone I extent
  • Zone II: It starts from the edge of Zone I and extends till the anterior edge of retina (also called as ora serrata) nasally, with a corresponding area temporally
  • Zone III: Zone III is the remaining crescent of retina temporally.

Extent of retinopathy

The extent of the ROP is documented by the number of clock hours involved. For the observer examining each eye, the temporal side of the right eye is 9 o’clock, and that of the left eye is 3 o’clock and vice versa.

Stages of retinopathy of prematurity

It denotes the degree or severity of retinal changes [Figure 2] and [Figure 3]. There are five stages.

Figure 2: Schematic representation of different stages in retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity, (b) Stage 2: retinopathy of prematurity, (c) Stage 3: retinopathy of prematurity, (d) Stage 4: retinopathy of prematurity. (From: Kanski JJ. Clinical ophthalmology: A systematic approach. 6th ed. Edinburgh: Butterworth–Heinemann/Elsevier)
Figure 2: Schematic representation of different stages in retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity, (b) Stage 2: retinopathy of prematurity, (c) Stage 3: retinopathy of prematurity, (d) Stage 4: retinopathy of prematurity. (From: Kanski JJ. Clinical ophthalmology: A systematic approach. 6th ed. Edinburgh: Butterworth–Heinemann/Elsevier)
Figure 3: Fundus images from RetCam Fundus Camera showing different stages of retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity (the black arrows indicate demarcation line between posterior vascularized retina and abnormal anterior avascular retina), (b) Stage 2: retinopathy of prematurity (black arrows indicate the ridge), (c) Stage 3: retinopathy of prematurity (black arrows indicate the ridge with extraretinal fibrovascular proliferation), (d) Stage 4: retinopathy of prematurity with partial retinal detachment involving the macula (image source: Figures a, c and d from the American Academy of Ophthalmology)
Figure 3: Fundus images from RetCam Fundus Camera showing different stages of retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity (the black arrows indicate demarcation line between posterior vascularized retina and abnormal anterior avascular retina), (b) Stage 2: retinopathy of prematurity (black arrows indicate the ridge), (c) Stage 3: retinopathy of prematurity (black arrows indicate the ridge with extraretinal fibrovascular proliferation), (d) Stage 4: retinopathy of prematurity with partial retinal detachment involving the macula (image source: Figures a, c and d from the American Academy of Ophthalmology)
  • Stage 1 – Demarcation line: A demarcation line is seen between the vascular and avascular retina. It is a thin structure that lies in the plane of the retina [Figure 2]a and [Figure 3]a
  • Stage 2 – Ridge: The demarcation line grows to occupy a volume and has a height and width to form a ridge above the plane of retina. Small tufts of new vessels also called as “popcorn” vessels may be seen posterior to the ridge [Figure 2]b and [Figure 3]b
  • Stage 3 – Ridge with extraretinal fibrovascular proliferation: In this stage extraretinal fibrovascular tissue is seen arising from the ridge into the vitreous. It may be continuous or noncontinuous and is posterior to the ridge [Figure 2]c and [Figure 3]c
  • Stage 4 – Subtotal retinal detachment: Here, a partial detachment of the retina is seen which may be exudative or tractional. It is subdivided into the following two substages 4a and 4b: (1) Partial retinal detachment not involving the fovea labeled as Stage 4a, and (2) Partial retinal detachment involving the fovea labeled as Stage 4b [Figure 2]d and [Figure 3]d
  • Stage 5 – Total retinal detachment: Here, a total retinal detachment is seen as a child usually presents with leukocoria also called as white pupillary reflex [Figure 4]b
  • Plus disease: It is an indicator of the severity of the disease and is defined as venous dilation and arterial tortuosity of the posterior pole vessels [Figure 4]a
    Preplus disease: It is defined as posterior pole vascular dilation and tortuosity which is more than normal but less than plus disease.
Figure 4: (a) Fundus image showing venous dilation and arterial tortuosity of the posterior pole vessels, indicating “Plus disease.” (b) Stage 5: retinopathy of prematurity. Total retinal detachment (image source: American Academy of Ophthalmology)
Figure 4: (a) Fundus image showing venous dilation and arterial tortuosity of the posterior pole vessels, indicating “Plus disease.” (b) Stage 5: retinopathy of prematurity. Total retinal detachment (image source: American Academy of Ophthalmology)

Aggressive posterior retinopathy of prematurity

This refers to an uncommon, rapidly progressive, form of ROP previously referred to as “rush disease.” It is characterized by a posterior location, severe-plus disease, and flat intraretinal neovascularization. It can progress very fast to Stage 5 ROP and blindness, if not intervened early. The flat neovascularization can be quite subtle and can easily confuse less experienced examiners.

The Early Treatment of ROP (ETROP),[20] a clinical trial funded by National Eye Institute, United States of America, produced a new clinical algorithm in December 2003 as a guide for the treatment intervention as follows:

Type 1: Zone I with any Stage with plus disease, Zone I with Stage 3 without plus disease, and Zone II with Stage 2 or 3 with Plus disease
Type 2: Zone I with Stage 1 or 2 without plus disease, Zone II with Stage 3 without plus disease.

Screening for Retinopathy of Prematurity Top

Because ROP can progress to blindness during the first few months of life and treatment is available to arrest this irreversible blindness in many cases, a protocol for examining the eyes of preterm infants is essential. There are neither symptoms of acute ROP nor can a specific visual behavior in a preterm infant herald a concern for ROP.

Hence, an effective screening is essential for prompt diagnosis of ROP. The screening protocol at each NICU should be evidence-based, should be based on preferences of neonatologists, ophthalmologists, and NICU nurses. All at-risk infants should be identified and receive adequate dilated retinal examinations at appropriate times.

The current recommendations from the American Academy of Ophthalmology and the American Academy of Pediatrics are that infants born at ≤30 weeks or <1500 g should be screened for ROP.[21]

Those babies born at gestational age of ≤27 weeks should have a first examination at 31 weeks and babies born between 28 weeks and 32 weeks, should have the first examination at 4 weeks after birth. The subsequent examination schedule is determined by findings on the first examination,[22] as mentioned later in this article.

However, it is also important to note that the NICU for each country needs to understand that ROP is diverse in presentation owing to the geographic variations, available infrastructure, and altered temporal development of retinopathy in different locations in the retina.

In developing countries, some babies may develop early aggressive posterior (AP) ROP. Thus, in developing countries, to enable early identification and treatment of AP-ROP, infants <28 weeks or <1200 g birth weight should be screened relatively earlier at 2–3 weeks of age.[23]

Hence, it is important to emphasize that the screening protocol which is commonly followed in North America, may not be suitable for other countries.[24] Other risk factors for ROP include severe respiratory distress syndrome, anemia, neonatal sepsis, thrombocytopenia, multiple blood transfusions, and apnea.

If these risk factors are not seriously taken into consideration, affected infants may inadvertently get excluded and hence careful review for risk factors should be taken by the pediatrician.

Examination Technique

The retinal examination should be performed at the request and approval of the attending neonatologist/pediatrician. The examination involves two steps namely the dilatation of pupil by mydriatic eye drops and then retinal examination by binocular indirect ophthalmoscope with a condensing lens (+25 D lens).

It is preferred to perform pupillary dilatation 45 min prior to commencement of the examination. Dilating drops used are a mixture of cyclopentolate (0.5%), and phenylephrine (2.5%) drops to be applied two times about 10–15 min apart. The excess drops should immediately be blotted from the lids to minimize systemic side effects such as hypertension, tachycardia, hyperthermia, and intestinal ileus.[25] 

If the pupil is resistant to dilatation, it may indicate the presence of persistent iris vessels (tunica vasculosa lentis) and must be confirmed by the ophthalmologist before applying more drops.

The infant’s hands should be physically restrained, and a nurse usually assists with the examination. The United Kingdom guidelines do not mandate the use of eyelid speculum and scleral depression with topical anesthesia. Some ophthalmologists may prefer to use eyelid speculum with scleral depression routinely.

However, meticulous examination, especially in situations where the examining ophthalmologist is not happy with the satisfactory view of the retina, warrants the use of eyelid speculum and scleral depression.

As a precaution against any infection transfer, the lid speculum, if used, must be sterile for each infant and the examination lens should be wiped with an alcohol sponge between babies whenever the lens has come into contact with the infant’s face/eye lids. The universal precaution regarding infection control should be followed during each examination.

After every examination, follow-up examinations are scheduled for infants who do not meet treatment criteria depending on the retinal findings. This is the recommended protocol: [22]

  • One week or less follow-up:
  • One–two weeks of follow-up:
  • Two-week follow-up:
  • Two–three weeks of follow-up:

In majority of neonates, the ROP disease process regresses over few weeks to few months. However, in up to 10% of babies, the ROP may progress to a stage which can progress to the potentially blinding stage. The aim of the screening and close follow-up protocol is to identify this stage of ROP. It is the responsibility of the staff of the neonatal unit and the attending pediatrician to ensure that every infant will continue the ROP screening at the time of transfer or discharge from the neonatal unit. Screening examinations for ROP can be discontinued, when the following conditions are met:

  1. Postmenstrual age of 45 weeks
  2. Intraretinal normal vascularization has progressed to Zone III without previous Zone II ROP
  3. Complete normal retinal vascularization determined on two consecutive occasions.

References Top

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More information: Wallace DK, Kraker RT, Freedman SF, Crouch ER, Bhatt AR, Hartnett ME, Yang MB, Rogers DL, Hutchinson AK, VanderVeen DK, Haider KM, Siatkowski RM, Dean TW, Beck RW, Repka MX, Smith LE, Good WV, Kong L, Cotter SA, Holmes JM for the Pediatric Eye Disease Investigator Group (PEDIG). “Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity.” Published April 23, 2020 in JAMA Ophthalmology.

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