For release: Monday, April 11, 1994
Very low-birthweight babies who are treated with indomethacin within 6-12 hours after birth have a lower incidence and reduced severity of brain hemorrhage, a frequent and often debilitating complication of such births. This conclusion is being published in the April 1994 issue of Pediatrics ,* based on the results of a large multicenter clinical trial sponsored by the National Institute of Neurological Disorders and Stroke (NINDS).
According to principal investigator and lead author Laura R. Ment, M.D., of Yale University School of Medicine, only one baby in the treatment group had a grade 4 hemorrhage, the most severe type, which can result in mental retardation, seizures and cerebral palsy, as opposed to 10 of the babies in the placebo group. The low-dose indomethacin treatment also appeared to be safe, the researchers reported.
Dr. Ment oversaw the clinical trial at Yale-New Haven Hospital, one of three centers participating in the study. The other study leaders were William Oh, M.D., at the Women and Infants' Hospital, Providence, RI; and Alistair G.S. Philip, M.D., and Walter Allan, M.D., at the Maine Medical Center, Portland.
"Between 20 to 40 percent of very low birthweight infants have intracranial hemorrhages, putting them at very high risk for major neurodevelopmental problems. This study provides us with important new information about preventing hemorrhages in this population of babies," said Patricia A. Grady, Ph.D., acting director of NINDS.
Most intraventricular hemorrhages (IVH) occur within the first days of life. The severity of these brain hemorrhages is ranked on a scale of grades from 1 through 4. While infants with the smaller hemorrhages can survive the bleeding episode and do well, the prognosis for infants with the most severe form of hemorrhage is almost always poor; the incidence of neurodevelopmental problems in these patients is as high as 86 percent.
"The fact that indomethacin controlled the most severe types of hemorrhages and did so without side effects is striking," said Dr. Ment, "It really decreased the incidence of a major medical problem that pediatric neurologists and neonatologists have been confronting for years."
The study involved 431 babies, weighing between 600 and 1250 grams (the mean weight of the babies in the study was 2 pounds), who had no evidence of brain hemorrhage within the first 6 to 11 hours after delivery as determined by a cranial ultrasound. The babies were randomized to either a treatment group that received an intravenous infusion of low-dose indomethacin (0.1 mg/kg) once at 6-12 hours after birth and then every 24 hours for two more doses, or to a placebo group that received an equal volume of saline solution on the same schedule.
Within the first 5 days, 25 (12 percent) of the 209 indomethacin-treated babies and 40 (18 percent) of the 222 in the placebo group developed IVH. Most importantly, the babies in the placebo group were more likely to have grade 4 IVH (10) than the babies in the treatment group (1). Twenty-two of the babies in the treatment group and 29 of the babies in the placebo group developed grades 1 and 2 IVH. Sixteen of the babies in the treatment group and 29 of those in the placebo group died.
Preterm babies also frequently have a medical problem called patent ductus arteriosus (PDA), an opening between the aorta and the pulmonary artery, resulting in too much blood flow to the lungs, which may contribute to severe respiratory problems. When administered within the first 5 days of life, indomethacin is an established treatment for closure of the PDA. In this study, 90 percent of the babies treated with indomethacin in the first 3 days had full closure of the PDA by the fifth day, as opposed to 66 percent in the placebo group.
Researchers are not sure exactly how and why indomethacin, a non-steroidal, anti-inflammatory agent, reduces the incidence and severity of IVH. However, previous studies have shown that the drug decreases the synthesis of prostaglandins, fatty acids that regulate the dilation of certain blood vessels, lowers cerebral blood flow, and prevents sudden increases of blood to the brain. It also causes maturation of blood vessels in the germinal matrix, the site of IVH in the brain.
This study provides the first multi-site documentation that the use of a relatively low dose of indomethacin prevents and reduces the severity of IVH. Dr. Ment and her colleagues also concluded that it is safe to give indomethacin to low birthweight babies in their first 6 to 12 hours without a preliminary cranial ultrasound, which may be impractical at many birth centers.
Because of the high incidence of respiratory problems in low-birthweight babies, at-risk mothers often receive prenatal treatment of corticosteroids, which help the infant's lungs to mature. Some of the mothers are also treated with tocolytic drugs, which are given to stop pre-term labor. In analyzing all of the data, the study authors concluded that the babies who were the least likely to develop IVH were those who not only received indomethacin treatment but whose mothers had received prenatal doses of both corticosteroids and tocolytic drugs.
"Even though these study results point to an exciting new advance in medical management of low-birthweight babies, researchers must continue to look at the many causes of brain hemorrhage, in the hope of preventing more disabilities in the future," Dr. Grady added.
The NINDS, one of the National Institutes of Health located in Bethesda, MD, is the nation's principal supporter of research on the brain and nervous system. The Institute is a lead agency for the Congressionally designated Decade of the Brain.
*Laura R. Ment, MD; William Oh, MD; Richard A. Ehrenkranz, MD; Alistair G.S. Philip, MD; Betty Vohr, MD; Walter Allan, MD; Charles C. Duncan, MD; David T. Scott, PhD; Kenneth J.W. Taylor, MD; Karol H. Katz, MS; Karen C. Schneider, MPH; and Robert W. Makuch, PhD, "Low-dose indomethacin and prevention of intraventricular hemorrhage: A multicenter randomized trial," Pediatrics, Vol. 93, No. 4, April 1994.
Last Modified August 7, 2009