Study Finds Phenobarbital Fails to Prevent Brain Bleeding in Premature Infants

National Institute of ChildHealth, and Human DevelopmentEMBARGOED FOR RELEASE, Wednesday, August 13, 1997, 6:30 PM Eastern Time, Robert Bock

Phenobarbital--once thought to be a promising treatment for preventing bleeding in the brains of premature infants when given to pregnant women at risk of premature delivery--appears to be ineffective, according to the largest, most comprehensive clinical trial of its kind to date.

The study, appearing in the August 14 New England Journal of Medicine, was conducted by researchers in the Neonatal Research Network, which is funded by the National Institute of Child Health and Human Development (NICHD). Support for the study was also provided by the National Center for Research Resources, also at the National Institutes of Health.

Bleeding in the brain, a dangerous complication of premature birth, affects 10,000 infants each year. Typically, the bleeding occurs deep in the brain, near the ventricles--the hollow cavities inside the brain. Such bleeding may result in cerebral palsy, mental retardation, or learning disabilities.

A few early clinical trials and a recent meta-analysis suggested that phenobarbital would be effective in reducing the frequency and severity of brain hemorrhaging in newborns. Because half of all such hemorrhaging occurs shortly before or at the time of birth, researchers had hoped that giving phenobarbital to pregnant women just before they delivered prematurely might reduce brain hemorrhaging in their babies after birth.

In the current study, researchers at 10 of the 14 NICHD Neonatal Research Network centers studied 610 women who were between 24 and 32 weeks pregnant and who were expected to give birth within 24 hours. In all, 309 women were randomly assigned to receive intravenous doses of phenobarbital and 301 were assigned to a placebo group.

Of these, 247 women given phenobarbital and 235 of the control women gave birth prematurely. There was no difference in the occurrence of bleeding in the brains between the two groups of premature infants. In all, 23 percent of the phenobarbital group (70 infants) and 23 percent of the control group (64 infants) had a brain hemorrhage.

"Our study shows that phenobarbital administered to a pregnant woman during premature labor simply provides no benefit for the baby," said Linda Wright, NICHD program official for the study.

The principal investigator of the study, Dr. Seetha Shankaran, MD, of Wayne State University in Detroit, MI, noted that the discrepancy between the results of the current study and earlier studies could be explained by a number of factors. First, the current trial was larger than previous studies, enrolling 668 infants. In contrast, earlier studies had enrolled from 38 to 150 infants. Furthermore, some of the earlier studies were not randomized and some did not have a placebo control group. Unlike the previous studies, fewer women in the current trial progressed to the 34th week of pregnancy, after which brain hemorrhaging is much less common.

"The results of our trial do not support the use of antenatal phenobarbital as prophylaxis against neonatal intracranial hemorrhage," the authors concluded.

The authors of the paper were Seetha Shankaran, MD, Wayne State University, Detroit, MI: Lu-Ann Papile, MD, University of Albuquerque, NM; Linda L. Wright, NICHD, Bethesda, MD; Richard A. Ehrenkranz, MD, Yale University, New Haven, CT; Lisa Mele, ScM and Joel Verter, PhD, George Washington University Biostatistics Center, Rockville, MD; James A. Lemons, Indiana University, Indianapolis, IN; Sheldon B. Korones, University of Tennessee at Memphis, TN; David K. Stevenson, MD, Stanford University, Stanford, CA; Edward F. Donovan, MD, University of Cincinnati, Cincinnati, OH; Barbara J. Stoll, MD, Emory University, Atlanta, GA; Avroy A. Fanaroff, MB,BCh, Case Western Reserve University, Cleveland, OH; William Oh, Women and Infants Hospital, Providence, RI; George A. Taylor, MD, Harvard University, Boston, MA; JoAnna Seibert, MD, University of Arkansas, Little Rock, AR; and Michael DiPietro, MD, University of Michigan at Ann Arbor, MI