drug (Kempe, 1955). Most of the studies reviewed as a basis for the recommendations included children and infants (some as young as 1 month) but no newborns. Then, in response to the increasing survival rates for premature newborns, AAP sponsored a seminar in 1956 on a broad range of problems specific to premature and newborn infants. To reduce mortality from infections, some discussants recommended that premature newborns born after premature rupture of membranes (24 to 48 hours prior to delivery) be treated prophylactically with antibiotics, including chloramphenicol (Day and Silverman, 1957), even though no controlled studies had investigated the drug’s safety and efficacy for use with neonates.

In 1959, a report of three newborns who died without explanation during treatment with chloramphenicol (Sutherland, 1959) was soon followed by the report of a randomized clinical trial to evaluate the effectiveness of prophylactic antibiotics in reducing mortality in premature newborns following prolonged premature rupture of membranes (Burns et al., 1959). In the trial, mortality rates for the two groups treated with chloramphenicol were 68 and 60 percent. In contrast, mortality rates for the placebo group and the group treated with different antibiotics (penicillin or streptomycin) were 19 and 18 percent, respectively.

Other studies determined that newborns, in particular, premature newborns, could not eliminate the drug from their bodies as fast as older infants and children (Weiss et al., 1960). As a result, dosing at levels used for older children and adults increased chloramphenicol concentrations to dangerous levels. This led to the “gray syndrome” (or “gray baby syndrome”), which was characterized by abdominal distension beginning 2 to 3 days after the start of chloramphenicol treatment and then by grunting respirations, cardiovascular collapse with gray skin color, and death. Although most off-label use of drugs does not have such dire consequences, the experience with chloramphenicol underscores the potential hazards of using new drugs in children, especially newborns, and the importance of controlled studies to guide decisions about when, how, and whether to use them.


Basic Aspects of Developmental Pharmacology1

The visible changes that occur as a newborn infant grows into a toddler, child, adolescent, and then a young adult are well known. As knowledge of


1 Resources for this discussion include the work of Kearns et al. (2003), Ward and Lugo (2005), and Rakhmanina and van den Anker (2009). The Food and Drug Administration provided draft guidance on the conduct of pediatric pharmacokinetic studies in 1998 (CDER/CBER, 1998a).

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