A Method for Interdicting the Development of Severe Jaundice in Newborns by Inhibiting the Production of Bilirubin

Severe jaundice, with its potential for producing brain damage, remains a continuing and controversial problem in newborn medicine. Central issues in this problem are the unpredictable course of hyperbilirubinemia in some newborns, the undefined susceptibility of an individual infant to bilirubin toxicity, and the uncertain blood level at which bilirubin threatens the brain, an uncertainty that is intrinsic to the clinical circumstances and therapeutic context of severe newborn jaundice. My laboratory group at Rockefeller University Hospital, together with collaborating pediatricians at other institutions, has developed a method for effectively controlling the production of bilirubin in newborns that can help to resolve these issues. The method involves use of an inhibitor that is targeted directly at the enzyme that controls heme degradation to bilirubin and permits physicians to rapidly, and predictably, interdict hyperbilirubinemia at any point in the progression of jaundice that they choose. Bilirubin is a normal product of heme degradation, and the rate-limiting step in its formation is controlled by the enzyme heme oxygenase (Fig 1, top). Newborns produce bilirubin faster than they can dispose of it and thus experience a mild, transient jaundice after birth. This jaundice generally peaks at ∼96 hours, well after the mother and infant leave the hospital, according to current practice. In some infants, jaundice can run a severe course, unrecognized and then unmanageable. Substantial brain damage then may occur. The damage can take place rapidly and produce within hours the severe neurologic deterioration known as kernicterus. More subtle neurologic impairment caused by bilirubin is now being detected by better diagnostic means. The long-term consequences of such impairment are not known. Fig 1. Several hundred thousand infants, of the 4 million births annually in the United States, receive phototherapy to treat jaundice. Light treatment is effective in reducing the incidence of bilirubin brain damage, although … Address correspondence to Attallah Kappas, MD, Rockefeller University, 1230 York Ave, New York, NY 10021. E-mail: kappas{at}rockefeller.edu