Saving lives by testing treatments

In the late 1940s, groups of researchers in Europe and the USA led one of the most important developments of medical research by refining the methods for testing treatments in random trials.

William Silverman
William Silverman

At that time, neonatologists were worried about a major outbreak of a new kind of visual loss affecting thousands of the prematurely born babies. They called this disease retrolental fibroplasia (retinopathy of prematurity). A few years earlier, some other doctors in the USA had seen that babies born preterm or premature appeared to do better if they got a lot more oxygen than normal. With the arrival of the incubator during the 1940s, it was now possible to keep tiny premature babies in a completely controlled environment and regulate the amount of oxygen around them. This was one of many developments happening at the same time – and there were dramatic improvements in the chances of survival for these tiny babies. But there was also this outbreak of blindness of epidemic proportions in the babies. Nurses in England and Australia suggested it could be the oxygen and published some analyses of the outcomes in their hospitals – but there were many other theories too. As always when there is a new disease or a new treatment, competing theories develop quickly. The role of science is to test these so-called hypotheses to find out which are more likely to be right. But most forms of research are not formal tests. Medical journals fill with individual reports and all sorts of studies that are not designed to be able to reliably test a hypothesis. It does not take long for a confusing picture of conflicting research results to build.

That process of contradictory research piling up happened quickly as large numbers of babies started developing ROP. Hospitals around the world started publishing reports that appeared to show that babies exposed to high concentrations of oxygen did not get ROP. Other researchers tried to compare what was happening in different groups of babies. That research put a major question mark on the use of high levels of oxygen, but it could not provide a definitive answer either.

At the big new Babies Hospital in New York, a group of neonatal specialists had done their first trial of a treatment for babies having these eye problems. One of them was William Silverman (1924-2004). He was one of the founders of American neonatal medicine. He explained what happened next: “By early 1953, controversy about the causal role of supplemental oxygen rose to a fever pitch. Finally, the US Public Health Service convened a conference in Bethesda, Maryland in the hope of devising a plan that might put an end to the international disaster (by this time the strange disease had blinded around 10,000 infants throughout the world). It was immediately clear that there were 2 highly vocal opposing camps at the meeting. One side argued that a formal, randomized trial of oxygen restriction must be conducted without further delay, because there were 3 competing outcomes of interest: blindness, death, and brain damage. The opposition maintained that there was sufficient evidence to prove that oxygen was the cause of blindness; a controlled trial was not only unnecessary, they argued, it was immoral! Finally, after an all-night debate, a compromise was hammered out. Eighteen hospitals agreed to participate in a randomized clinical trial for 3 months.”

There was still a lot of opposition – one expert had told a national funding agency considering an application for a trial, “…these guys are going to kill a lot of babies by anoxia to test a wild idea.

The “wild idea” turned out to be right. The trial results were made public in 1954, and the publicity that followed ensured that the level of oxygen in incubators was reduced, ending that ROP epidemic. Only one-third as many babies in the control group of the trial had developed ROP as the babies getting the high oxygen. Because the trial had not been done before the incubators were introduced into wide use, it had taken 12 years for the problem to be understood and for this particular part of the oxygen controversy to be solved. Until proper RCTs are done, it is almost never possible to be certain that a treatment works as it meant to do.

Researchers continued to struggle with the question of exactly how much oxygen is ideal: when the oxygen levels are lower, more sight will be saved but more babies might die. Because of this trial, however, many more people had come to realize the importance of the randomized trials.

Silverman criticized what he called “the impatient let’s-try-it-and-see approach” that can fill the field with misleading information and lead to people being convinced in hypotheses that have not been properly tested: “The twelve-year struggle to halt the outbreak provided a sobering demonstration of the need for planned evaluation of all medical innovations before they are accepted for general use.”

Silverman  was honored repeatedly as one of the pioneers in his specialty and had helped to establish The Cochrane Collaboration.


Why is it important for people to be “randomized” in trials? A cautionary tale of medically-caused blindness” The German Institute for Quality and Efficiency in Health Care (IQWiG).