Guthrie's blood-spot test for phenylketonuria

In 1934 Asbjørn Følling, a professor of nutrition research in Oslo who had trained in chemistry before studying medicine, examined two siblings with intellectual disability. When he tested their urine with ferric chloride he got a green color instead of the expected purple. He identified the substance as phenylpyruvic acid and concluded that it came from phenylalanine in the diet. In Britain, Penrose and Quastel renamed the condition phenylketonuria.

In 1953 Horst Bickel and colleagues in Birmingham reported that a diet low in phenylalanine had brought a dramatic improvement in a girl's behavior. Treatment raised the idea of testing all newborns, which pediatricians at first resisted, L. I. Woolf recalled in 2020. Screening began with urine. From about 1961 Dr. Gibbs, senior medical officer at the public health department in Cardiff, ran the first large-scale British program, first with Phenistix strips on diapers and then with dried, urine-soaked filter paper.

Robert Guthrie, an American scientist, proposed a newborn screening test in 1961. His micro-bacteriological method measured phenylalanine in a spot of blood dried on filter paper, and in September 1963 he and A. Susi described it in Pediatrics as a simple method for detecting phenylketonuria in large populations of newborn infants. The blood spot proved better than urine, largely because the public health nurse collecting it did not have to wait for the baby to pass urine, and it was more reliable. The test spread quickly through industrialized countries; France proposed extending it to all newborns in 1970.

Newborn screening in the United States began in the 1960s and became a state-based public health system. In 2012 CDC reported that more than 98 percent of about 4 million newborns were screened each year and that about 12,500 a year were diagnosed with one of 29 core conditions. Growth beyond the early tests was slow until multiplex testing by tandem mass spectrometry arrived in the early 2000s.