retinopathy of prematurity.org
Baby-harming medical research
about baby-blinding retinopathy of prematurity
by H. Peter Aleff, 2005 to 2009
Chapter 1: Retinopathy of prematurity: nature, incidence, and treatments
ROP is an often blinding damage to the still developing retina that was first observed in two babies born in 1940, less than two years after the commercial introduction of fluorescent lamps, and that affects many prematurely born babies in intensive care nurseries around the world.
In biological terms, ROP results from a derailed formation of the retinal blood vessels. These grow relatively late in fetal development and are not fully formed in the eyes of babies who are born before they weigh at least about 2000 grams, or before they reach a gestational age of about eight months. Their development follows an innate biological clock, and the accident of premature birth does not appear to affect the speed with which the cells destined to become the retinal blood vessels migrate towards their destinations. However, the early and abrupt change from the dark womb to a brightly lit nursery appears to affect the direction of this then still ongoing migration and to make the vessels grow away from their normal paths.
Until these vessels are developed, the retina is nourished by the blood flowing through the choroid, the layer right underneath the retina that already has blood vessels. As the retina gets thicker, oxygen and nutrients can no longer diffuse easily through it so that it soon needs its own supply of blood.
The small capillary vessels destined to fill this need begin their growth at the optic disc where the optic nerve enters the back of the eye. From there, they progress slowly all around the eyeball through the retinal layer towards the ora serrata, the zigzag margin at the front of the eye which separates the retina from the lens.
In babies affected by ROP, the normal formation of these retinal vessels is disturbed. Instead of continuing to grow smoothly inside the retinal layer, the blood vessels at the forefront of their advance constrict, stop growing, then resume growth in a tortuous fashion and in wrong directions. They cluster and clump along the edge where they had stopped growing, and then they erupt through the surface of the retinal layer to grow wildly into the vitreous body which is the transparent contents of the eyeball.
The early signs of such abnormal growth are observed in the eyes of the afflicted babies typically about five to eight weeks after birth, but 21.5% of the preemies in the CRYO-ROP study report of 1991 did already have ROP at their five-week examination. The advance of the vessels and their behavior is related to their maturity, that is, how far along the vessel cells are on their migration towards the front of the eyeball by the time of their exposure to the outside world. That, in turn, depends on the gestational age of the baby and not on his age since birth. The authors of that study explained that
In many cases, most of these wayward retinal vessels will spontaneously resume their normal growth at some early stage of this process and cause only limited immediately detectable damage to the retina. But if they grow too wildly, the tortuous vessels create tensions in the delicate retinal layer and are often strong enough to pull it away from the choroid. The resulting retinal detachment can be partial, in which case the child may retain some limited but often slowly deteriorating vision, or it can be total and result in total blindness with no light perception.
If this retinal detachment progresses to the late or severe stages of ROP, a white-to-grayish opaque membrane appears to cover the inside of the lens. This is the outward symptom which had caused ROP to be initially named Retrolental Fibroplasia, which means “fibrous tissue behind the lens”. This tissue is formed by pieces of the retina that are flimsy like wet tissue paper and detach themselves from the inner wall of the eyeball due to that abnormal growth of the retinal blood vessels.
Despite the long history and frequent severity of ROP, there are still no systematic statistical records in the U.S. to document its incidence. There are only scattered reports from individual hospitals or trials and occasional extrapolations from such data, beginning with the “educated guess” offered by Dr. William A. Silverman that by 1953, ROP had blinded 7000 children in the U.S. plus about another 3000 in other countries. Then came the rigged oxygen study and in its wake the systematic elimination of the most vulnerable babies so that for more than a decade, there were virtually no more ROP cases to report.
After the oxygen withholding became less strict, and more babies affected by ROP began again to survive, Dr. Dale L. Phelps published in 1981 an estimate for the number of cases among preemies with birth weights of less than 1500 gram in the U.S. during the base year 1979. She compiled the blindness rates from ROP among premature infants with birth weights up to 1000 g and from 1000 to 1500 g from several individual hospital reports published in the 1970s. Then she estimated the annual number of preemies in these birth-weight categories for the entire U.S. and obtained a yearly cohort of about 36,600 preemies below 1500 g.
Based on these estimates, she calculated that, in 1979 in the U.S., about 546 of these less than 1500 gram infants had been totally blinded by ROP, and about 2100 more suffered severe visual impairments from their brush with ROP, such as myopia, strabismus, and possible late retinal detachment. These results suggested that vision impairments from ROP were by then again about as prevalent as during the early 1950s, which had previously been regarded as the peak of the ROP epidemic.
Some hospital reports published after Phelps' estimate found that the incidence of ROP appeared to be rising. For instance, a team at the Vanderbilt University School of Medicine in Nashville, Tennessee, compared the frequencies of ROP among babies born in their hospital in 1972 and in 1981/82 and found in that later period greater numbers of children with ROP.
Similarly, a retrospective review at the University of Washington School of Medicine in Seattle indicated that ROP had blinded there more than three times as many babies per year in the early 1980s than throughout the 1970s, and that the severity of the individual blindings had also increased in the more recent period. The report attributed this to the higher survival rate of the preemies in the lowest birth-weight categories.
In other countries, the incidence of eye damage from ROP seems to have been comparable. Although the evaluation methods for the progress of ROP had not yet been standardized, and the percentages below apply to groups with different birthweights or gestational ages, the numbers from the countries cited suggest that ROP was there a problem of the same magnitude as in the U.S.:
In 1984, a team of researchers at the Baylor College of Medicine in Houston, Texas, estimated that about 20000 newborns weighing less than 1500 grams at birth survived then each year in the U.S., and that about 14000 of these, or 7 out of 10, developed some degree of ROP.
Comparing the Baylor estimate of 20000 babies in that high-risk category with Phelps’ estimate of 36600 preemies in that same group five years earlier conveys an idea of how vague such estimates can be. The actually recorded numbers published later in the National Vital Statistics Reports say that 1.15% of all babies born in 1980 in the U.S. weighed in at 1500 gram or less, which works out to 41540. Of these, about 38% died within a year after birth in 1983, the first year for which this rate was recorded. If that mortality rate was similar in 1980, then it would have left about 25750 survivors at high risk for ROP.
Phelps updated her initial estimate of the yearly blinding toll twice to reflect the meanwhile higher survival rate of babies in that same high-risk birthweight category. She wrote in 1988 that the cases of total blindness and severe vision impairment from ROP among them ranged from 1576 to 3036 children per year.
Four years later, she said in a grant application that with cryotherapy, about 2060 preemies in that category suffered severe vision impairment or total blindness from ROP each year whereas they would number about 4400 without the benefit of that operation.
If the lesser visual impairments that are also included in the legal definition of blindness were added, that number would be several times higher.
A different approach yields a similar result. The Dean of the Hadley School for the Blind said in 1988 that ROP was the major cause of blindness for the majority of the children in his school's Parent/Child correspondence course program. If we take the over 1000 totally blind and severely vision-impaired infants and children enrolled in this program as a representative sample of the then annually about 7000 new blind babies in the U.S., then the extrapolation to half or more of that total yields 3500 or more new ROP victims with severe eye damage per year in America, in the same range as Phelps’ extrapolations from her data.
The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity enrolled in 1986 and 1987 a total of 4099 babies with birth weights up to 1250 gram. Its team reported in 1991 that 66% of these developed ROP to some degree, including 18.3% among them who went on to the severe stage 3. In the subgroup of 2237 infants born below 1000 gram, 81.6% had some ROP, and 26.4% severely.
Comparably, the Study Group for the Multicenter STOP-ROP trial said in the February, 2000, issue of Pediatrics, based on data from 1994, that ROP develops in 84% of the babies born at or before 28 weeks of gestational age, and that it resolves in about 80% of these cases without visual loss from retinal detachments or scars. This leaves 16.8% of an estimated 19000 or so annual 28-weekers in the U.S. with permanent visual impairments or blindness, or about 3200 per year, plus all those among the initially lucky 80% whose ROP-attacked retinae will develop problems in later years.
More encouragingly, a 1999 article from a regional intensive care nursery in Connecticut about the incidence of ROP among its patients over the 1989 to 1997 period reported lower percentages in a group of 950 preemies born at or below 1300 gram and some heavier ones who had received supplemental oxygen.
Its authors found ROP of any degree in 21.3% of those babies, and severe ROP in 4.6%. Among the most vulnerable subgroup of 439 babies born at 28 weeks or less, the percentages were 40.1% for any ROP and 9.8% for severe ROP. These were significant decreases to about half the incidences reported from the CRYO-ROP and STOP-ROP trials, and the authors attributed these better outcomes to their introduction of surfactant at the beginning of their study whereas this drug had not been used in those earlier trials.
However, the authors also mentioned that “Infants were cared for in a low illumination environment with cloth covers over isolettes”, and it may well be this difference from the typical brightly lit nurseries in most other hospitals that best explains the lower rates and severity of ROP among the here at least partly protected preemies.
The ROP numbers posted by the U.S. National Eye Institute on its website for the entire U.S. approximate the exceptionally low incidence in that one low-light nursery and so appear to downplay the embarrassingly persistent epidemic:
This lowball guess is not based on any actual records and does not reflect any average from multiple nurseries. It matches only the outlier data from the above low-light nursery: If the 4.6% severe cases there were extrapolated over those 28000 annual infants with similarly low birth weights, then about 1300 babies a year would wind up with severe ROP. However, most other studies reported much higher rates.
Moreover, virtually all these estimates and reports omit to include those preemies who are born at later gestational ages or with higher birth weights but who also develop ROP. The incidence among this group is lower but the group is much larger. For instance, about 220,000 preemies were born in 1980 with birth weights between 1500 and 2500 gram, and 240,000 in 1999, so a hypothetical ROP rate of just half a per cent in this group would still amount to 1100 or 1200 additional annual cases in the U.S. above the cutoff points of the typical estimates.
Occasionally, even a baby born at term who is kept at the hospital may develop ROP. Furthermore, many other very-low-birthweight children with ultimately severe ROP damage are not included in the above estimates because their retinal damage manifests itself more slowly, and they will lose their sight only several years or even decades later.
In sum, most of the smallest preemies in a typical intensive care nursery are at risk from ROP, and also some of the larger ones. Many hundreds, and possibly several thousands of preemies go blind from it each year in the U.S. alone, and ROP accounts in many countries with American-style intensive care nurseries for the majority of vision problems and blindness among children or even for more than all other causes combined.
Yet, there is still no organized reporting system in the U.S. to provide the most basic epidemiological data for the assessment and study of this continuing epidemic, or for its correlation with any treatment or environmental factors which would be the first step in a rational approach aimed at ending this now 64-year old epidemic.
The continued lack of such essential information about this major threat to preemies raises serious questions about the effectiveness of the medical institutions involved and of the government agencies that are supposed to protect the health of children. This willful ignorance also reflects poorly on the politicians who let those now virtually sovereign medical agencies get away with such a long-standing neglect of their Congressionally mandated duties.
The current medical approach to ROP is to observe its early stages of development in the hope that the malformation of the retinal vessels might regress by itself as it often does. However, if the damage progresses instead, and the retinal vessels begin to proliferate out of the retinal layer into the vitreous, then the treating ophthalmologist estimates the chance for damage from further growth to be about the same as the chance for spontaneous self-healing. At this point, s/he typically recommends to try and stop the further proliferation with surgery.
The goal of this surgery is most often to arrest the growth of those wayward vessels by destroying their free ends as well as the area of the peripheral retina inside the eyeball which they have not yet reached so that they cannot grow further into that area. This destruction is typically achieved with the heat of a laser or the cold of a freezing cryoprobe, and more rarely also with a scalpel.
For instance, in the once highly popular method called transscleral cryotherapy, the surgeon touches the cryoprobe tip to the outside wall of the eyeball, the sclera; the cold goes through the wall and freezes the area inside. This cryotherapy was said to have reduced unfavorable outcomes in a 1986 trial from 43% in untreated eyes to 21.8% in the treated eyes, but it has meanwhile fallen out of fashion in favor of laser therapy which is said to achieve the same or better results but costs less.
Pediatric retinal surgeons work also with a profusion of other old and new techniques to try and reattach some pieces of the preemies' retinal tissue: tightening a buckle around the eyeball to push its wall against the detached retina; surgical reattachment after entering the eyeball with tiny scalpels and needles. Still other methods are cryoprobes inserted directly into the opened eye, and injection of air into the vitreous or even the partial removal of that material.
However, very little follow-up data are available on how this partial destruction of the retina and some of the underlying choroid vessels affects those eyes over the long term. Two groups of Japanese and Israeli investigators evaluated eyes that had been treated with cryotherapy six to eight years earlier. Both teams concluded that the treatment had caused no major problems, but neither of them had any controls for comparative analysis,.
Once the natural development of the retina has been disturbed by that scorched-area therapy of destroying the retinal vessels and their further path, the risk of later retinal detachment and/or other complications remains high. Phelps, one of the organizers of that multicenter cryo-trial, cautioned that the treated eyes could deteriorate and lose vision ten or twenty years later, while many untreated eyes might continue to do better.
The success rates given in the individual surgery reports ranged from 27% to 58% in the 1980s but are now said to reach up to 76% for reattachment and 72% for retaining light perception. However, even if some part of the retina can be successfully reattached, the patient will usually retain some permanent severe visual impairment. An anatomical success will often preserve vision that is only sufficient to count fingers and see hand movements.
Even such partial successes do not necessarily last. In his 1983 handbook Retinal Detachment and Allied Diseases, Dr. Charles L. Schepens listed many postoperative complications as being common to all procedures used for reattaching the retina: edema around the eyelid and conjunctival disturbances, heterotropia (or strabismus), lagophthalmos (or inability to shut the eyes completely), corneal damage, ischemia (or bloodlessness) of the anterior segment, glaucoma, cataract, choroidal detachment, massive preretinal retraction, delayed hemorrhage inside the eye, postoperative visual loss, sympathetic ophthalmia (or inflammation of the other eye), and phthisis bulbi (or shrinkage of the eyeball).
These problems are mostly the same today, even with the latest treatment methods. The outcome of medical treatments for ROP remains thus uncertain and often poor.
Contact us at retinopathyofprematurity.org