Terry's original guess that ". . . some new factor has arisen in extreme prematurity . . ." was supported by the retrospective studies of the Doctors Owens in Baltimore. They examined 128 children born between 1935 and 1944 and found no examples of RLF. There was only one instance of RLF (recognized in retrospect at age 16) among more than 200 carefully followed graduates of the Sarah Morris Premature Station in Chicago, born between the years 1922 and 1934. Other retrospective studies, principally by questionnaire, in eight large U.S. cities and in Birmingham, England, had disclosed only an occasional affected person before 1940. Algernon Reese surveyed the ophthalmologic reports published prior to 1944 and concluded that RLF occurred before Terry's report, but that it was rare.
The frequency of occurrence of RLF, first in the United States and later in other developed countries (including Canada, Britain, France, Sweden, Holland, Spain, Switzerland, Italy, Australia, Israel, Cuba, and South Africa) rose sharply at the end of the 1940s. By mid-century, RLF was regarded by ophthalmologists as the principal cause of blindness in infants. Although this opinion was based on incomplete surveys (Table 3-1 and Fig. 3-1) the epidemic of blindness was undeniable; by 1952, peculiar geographic and temporal variations were noted that could not be explained entirely by differences in reporting or in awareness of the condition by observers. The unfortunate preeminence of the "advanced" countries seemed to be explained by the fact that premature infant survival rates were highest in these parts of the world. More than 100 reports on RLF were published throughout the world in the three-year period 1950-1952 inclusive and over 50 separate "causes" were proposed (Appendix A). Approximately half of these factors were examined formally. Systematic sifting of evidence from experiences in the immediately preceding period established associations between RLF and 19 speculated "causes"; only five of these "causes" were tested by experimental (or quasi-experimental) planned clinical trials.
In 1949 Kinsey and Zacharias made the first attempt to seek an explanation for the increased frequency of RLF, by examining the concurrence of RLF and a number of factors relating to mothers and children (298 normal and 53 RLF-affected children) who were delivered in Boston Lying-In Hospital during the years 1938-1948. They found several associations:
When these relationships were examined graphically (Fig. 3-2), it was found that "The correlation between the rise in incidence and dosage was less striking for oxygen than for water-miscible vitamin preparations and for iron."
The findings of this Boston survey with respect to vitamins and iron were of particular interest to the Baltimore ophthalmologists, Owens and Owens. It had been established in the early 1940s that prematurely born infants absorbed milk-fat inefficiently; artificial milk-mixtures (made with a relatively low concentrattion of fat and with a relatively high proportion of the mix as milk protein) appeared to overcome the absorptive handicap. Owens and Owens reasoned that the low-fat milk feedings would not supply premature infants with needed fat-soluble vitamins; and, since the requirement for these substances increased after birth, signs of deficiency would be expected to appear some weeks after delivery. They correlated this postulation with two observations: (1) the earliest changes of RLF did occur about one month after birth, and (2) only vitamin E, of all the fat-soluble vitamins, was not administered routinely to premature infants. In addition they took note of studies in experimental animals which indicated that the requirement of vitamin E increased when vitamin A was administered, and that iron salts destroyed vitamin E. The rise in frequency of RLF found by Kinsey and Zacharias in association with increased use of water-miscible preparations of vitamins (including vitamin A) and iron could be interpreted to indicate that the marginal vitamin E status of newborn premature infants was made worse by the newer treatments. All of these considerations, as well as arguments from studies of the biochemical functions of vitamin E, suggested that vitamin E supplements might prove effective in the treatment or prevention of RLF.
Beginning in 1949, Owens and Owens began to test their hypothesis. They administered a vitamin E preparation (alpha tocopherol acetate) to infants at the time the eyes showed early changes of RLF; the condition appeared to arrest in some infants. Following this experience, they undertook an experimental trial of vitamin E administered from birth. For a period of 10 months, alternate infants admitted to the premature nursery of Johns Hopkins Hospital were given either 150 mg a day of synthetic vitamin E, or no treatment. During this period 11 infants received vitamin E, none developed RLF; among 15 in the untreated control group, 5 developed RLF.
This early trend of difference was sufficient to impress Doctors Jonas Friedenwald and Alan Woods, leading ophthalmologists at Johns Hopkins Hospital. They persuaded the Doctors Owens to abandon the controlled trial. Subsequently all infants in the Baltimore nursery were given supplementary vitamin E by mouth. As word of this experience spread throughout the world, vitamin E prophylactic treatment to prevent RLF was started in many hospitals. The informal experience of nine other groups failed to confirm the Johns Hopkins experience, and the Doctors Owens were unable to demonstrate an impressive protective effect of vitamin E in the years following the aborted formal trial.
Although a decrease in severity did occur in prophylactically treated infants in Baltimore and in Boston, the quixotic temporal variability of the disease led most observers to doubt the significance of these trends. Additionally, no correlation could be found between blood levels of vitamin E and the occurrence of RLF. After a few years all interest in the vitamin E relationship to RLF had waned (see chapter notes).
Soon after a large premature center was opened in the fall of 1949 at Babies Hospital in New York City, my colleagues and I detected the first patient with RLF in this unit. My experience with this infant and subsequent events in New York are so revealing of the desperation felt by all who were faced with the mounting epidemic that it merits recounting. On February 15, 1950, Doctor Frederick Blodi, an ophthalmologist who had been examining the eyes of all infants in the new nursery at weekly intervals, made this note in the chart of an eight-week-old infant:
Increased tortuosity of [retinal] veins!
One week later, February 21, there was no question in Doctor Blodi's mind and Doctor Algernon Reese agreed that the dilated and tortuous veins and diffuse hemorrhages in both eyes were the early signs of RLF.
This affected infant was the prematurely born daughter of a senior member of the Biochemistry Department of the College of Physicians and Surgeons at Columbia University. After six miscarriages, a pregnancy had proceeded to 29 weeks, and a 1.1 kg (2 lb 6 oz) girl was born. She was thriving at two months. The day following the detection of definite signs of RLF by Doctor Blodi, I wrote the following note in the chart:
Following the above-noted opinion [of Doctor Blodi] about the onset of early changes of retrolental fibroplasia, it is clear that any measure undertaken to influence the course of the disease must begin now. It must also be mentioned that at least one instance has been recorded (Owens and Owens) where these changes of tortuosity and angiomatous [numerous blood vessels] appearance of the retina have apparently failed to go on to fibroplastic retrolental membrane stage, and reverted to normal. This admittedly is a very remote possibility, but the fact that it has been observed will make interpretation of the beneficial effect of any therapeutic measure just that uncertain . . . it has been decided to try ACTH [adrenocortocotropic hormone] on the rationale that (1) it is a connective tissue disease, (2) prematures may be ACTH-deficient, and (3) no other agent or therapeutic regime has given any indication of beneficial effect.
ACTH was known to produce heightened activity of the adrenal gland and thereby to inhibit proliferation of blood vessels in connective tissue. Thus, it seemed reasonable to expect that the then-new medication might halt the overgrowth of retinal blood vessels in early RLF. However, the previously untried treatment was started more in desperation than conviction. The blood vessel changes in the eyes improved, and the dose was lowered; the changes became worse and the dose was raised. There was improvement, the eyes returned almost to normal, and ACTH was stopped. The infant gained weight, and she was sent home!
Soon after this dramatic experience, 31 infants with early changes of RLF were treated with ACTH at Babies Hospital. Of the 31 infants, 25 left the hospital with normal eyes, 2 became totally blind, 2 lost all vision in one eye, and 2 had useful vision with only minor retinal scars in one or both eyes. Permission for this innovative approach was obtained from the parents in the same informal manner which had been used when another "miracle drug," penicillin, was used to treat life-threatening infections. Each set of parents was told that we had reason to hope that the untried treatment would be effective, but that we were stepping into the unknown. A written document describing the details of study was not drawn up; this was years before the concepts of signed informed consent and review by a Human Investigation Committee were formalized.
Our results of treatment were especially impressive when compared with 7 infants with early RLF at Lincoln Hospital in New York City who did not receive ACTH, 6 of whom had become totally blind. ACTH seemed to be the cure for the disease! However, we were puzzled about 2 infants, one at Lincoln Hospital and the other an infant who had been followed by Doctor Blodi; in both, early changes subsided without any treatment and they were left with normal eyes. Our exciting results obviously could not satisfy the simplest rules of evidence. The experience in two different nurseries could not be compared fairly, since it was known that RLF incidence varied widely from hospital to hospital. There was no way to avoid the issue that only a randomized concurrently controlled trial within each hospital could definitely settle the ACTH question.
After considerable discussion and soul searching, two formal controlled trials were begun, one at Babies Hospital and the second at Lincoln Hospital. It took only a few months to accumulate the required experience in the premature nurseries of both institutions; a total of 15 infants with early RLF were treated with ACTH and 18 infants observed without treatment. Allotment was decided by drawing from a box containing an equal number of blue and white marbles. Our uncertainty concerning the effectiveness of ACTH was not hidden from the parents, but none were asked to assume our agonizing burden to allow chance to decide on treatment versus nontreatment. Approximately a third of the infants who received ACTH became blind (in one or both eyes) but only one-fifth of the controls went on to blindness. Furthermore, there were more deaths in the ACTH-treated group. When the entire two-year experience of both hospitals was examined, the frequency of cicatricial (scarring) RLF was not startlingly different, but the mortality and morbidity rates were quite disparate; the untreated group had fared better.
Two years later, Doctor Owens reported his observations that three-fourths of the infants with early vascular changes of RLF showed spontaneous regression to normal. This was exactly our experience in New York during the ACTH-treatment episode.
Following this disheartening experience, a formal experiment was undertaken to test the possibility that premature exposure to light was the cause. Once more the results were negative (see chapter notes).
By mid-1952, after ten years of frustrating activity and false leads, most physicians who were immersed in the study of the RLF epidemic were understandably skeptical of all new claims of cause and cure.
The Four Most Frequent Causes of Blindness in
Preschool Children in Four States (1947)
Causes of Blindness Illinois New Jersey New York Wisconsin Retrolental Fibroplasia 20 28 20 8 Cataract 9 18 15 14 Optic Atrophy -- 21 9 5 Glaucoma 3 10 11 -- ... ... ... ... ... Total 48 96 93 38
Causes of Blindness
Fig. 3-1. The field staff of the California School for the Blind found that RLF accounted for more than 80 percent of all cases of blindness in children born in Southern California during the years 1951-1952. (RLF is shown in solid bars, other causes of blindness in empty columns.)
Fig. 3-2. Correlation between the frequency of RLF and three treatments in the premature nursery at the Boston Lying-In Hospital, 1938-1947; its occurrence tracked most closely with iron therapy (ferrous sulfate).
* Days in oxygen, drops of water-miscible vitamins, and drams of ferrous sulfate.