OXYGEN USE IN PREMATURE INFANTS AND BLINDNESS

Oxygen seemed like just what premature infants needed to address the underdevelopment of their lungs, which often led to pneumonia and death. Thus in the 1940s, after effective means were developed to administer oxygen to pilots in World War II, physicians began to routinely administer high-dose oxygen to nearly all premature infants. The unexpected association between high-dose oxygen and blindness only became established after over 10,000 premature infants, including its most famous victim, Stevie Wonder, developed blindness.

The first hint of a problem came in 1942, when a report of five cases of blindness of premature infants in which no other cause could be determined appeared in the research literature. Once the condition became known, many more cases were identified that met this definition. The process that produced blindness could be seen upon examining the back of the eye during a clinical examination. Proliferation of blood vessels followed by scarring or fibrosis called retrolental fibrosis (RLF), with subsequent detachment of the retina, could be seen in severe cases that had produced blindness.

Using case-control studies, researchers quickly recognized an association between state-of-the-art medical care provided at the most up-to-date medical centers and blindness due to severe RLF. They examined a range of factors associated with state-of-the-art medical care. Reports of constriction of the retinal arteries in fighter pilots given high-dose oxygen led researchers to look for and find similar findings in infants. They found that longer durations of oxygen administration were associated with longer term and more severe retinal artery constriction.

Reinforcing the accumulating clinical evidence were studies of high-dose oxygen use in a variety of animal species. High-dose oxygen used in premature kittens produced retinal damage similar to RLF. The pattern of constriction of the retinal arteries of kittens while on high-dose oxygen was followed by proliferation of new blood vessels similar to that seen leading to scarring or fibrosis in human infants with RLF.

A cohort study was soon conducted in three hospitals in Melbourne, Australia. One had incubators that could give premature infants air with 2 or 3 times the 20% concentration of oxygen in atmospheric air. The second used a less efficient way of delivering oxygen. The third required patients to pay for supplementary oxygen, so oxygen was rarely used. The medical records for 1948 through 1950 revealed that at the hospitals where oxygen was given most intensively, 19% of premature babies developed evidence of RLF. At the other two, where it was used less aggressively, the rate was only 7%.

A large randomized controlled trial was needed to convince clinicians to restrict the use of oxygen for premature infants, especially because clinicians were concerned that restrictions in oxygen use would result in brain damage and a higher mortality rate. A large randomized controlled trial sponsored by NIH was soon conducted at 18 institutions by randomizing infants at 2 days of age to routine supplemental oxygen or to a curtailed-oxygen group that received lower concentration oxygen only as needed.

The study showed that RLF severe enough to produce blindness, if continued, occurred in 17% of the babies receiving routine high oxygen, but in only 5% of the curtailed-oxygen group. The death rate in the two groups was similar. The investigation was continued with all infants assigned to curtailed oxygen. The follow-up study found that the duration of oxygen use was key to the risk of developing RLF and that supplemental oxygen at even low levels increased the risk of developing RLF.

Recommendations of the American Academy of Pediatrics and other authorities, published soon after the release of the study, were key to changing the attitudes and practices of clinicians. By the mid-1950s, follow-up studies showed that the use of routine oxygen for premature infants was on the decline, and so was the rate of RLF. By the late 1950s, RLF had declined to rates seen only before the widespread use of high-dose oxygen.

The evaluation of the impact of oxygen use for premature infants was not over. Soon after the rapid reduction in oxygen use began, the death rates among premature infants began to increase. Investigators in the United States and Britain found an increased mortality rate and rate of brain damage and paralysis among premature infants with underdeveloped lung function. Investigators noted that the randomized controlled trial included only infants who had survived for 2 days, the period of the highest number of deaths from respiratory related causes. Thus, by the early 1960s, it was clear that a trade-off existed between the use of oxygen to reduce early mortality and morbidity and limiting oxygen use to reduce the incidence of RLF.

Evidence-based recommendations encouraged the use of oxygen to limit the impact of too little oxygen while minimizing the level and duration of oxygen. When oxygen was used, clinicians were expected to conduct frequent examinations of the retina to identify early evidence of RLF.

In recent years, there has been an increase in RLF even as clinicians have limited and monitored the use of supplemental oxygen. The increase has been largely attributed to the increased number of premature infants and the ability to keep very premature infants alive. The greater the degree of prematurity, the greater the risk of RLF. In fact, this process may occur in premature infants even without the use of oxygen. Therefore, in recent years, the name of the condition has been changed to retinopathy of prematurity, or ROP.

Clinicians now monitor the retina of premature infants, looking for early signs of ROP. Interventions to treat early ROP, including laser treatments and surgical interventions, are now part of the effort to detect and treat ROP at an early stage to prevent blindness. Evidence-based recommendations of the American Academy of Pediatrics outline this approach and provide specific recommendations for its implementation.

Prevention, detection, and treatment of ROP is now seen as part of an overall approach to the care of premature infants. The success of the current approach requires ongoing evaluation and continued efforts to look for ways to improve the care of newborns.