Drug Protects Brain Development in Premature Babies, Yale Study Shows

An anti-inflammatory drug used for adults with arthritis also is very effective in protecting brain development in premature babies, a Yale-led study shows.

The non-steroidal drug, indomethacin, was randomly administered to the premature infants, who then were tested from infancy until they reached the age of eight. The hope was that the drug would prevent neonatal intraventricular hemorrhage, or bleeding into the germinal matrix tissues of the developing brain, which is one of several conditions associated with future developmental problems.

“When the need for special services within the school setting was assessed for the children at the age of eight, the indomethacin children required significantly less special services than those children who were given a placebo – 31 percent vs 58 percent,” said Laura Ment, M.D., a pediatric neurologist at Yale School of Medicine and chief investigator on the study. “Also, almost three times the number of placebo children required speech and language therapy when compared to the indomethacin subjects.”

Her findings were presented May 15 at the Joint Meeting of the Pediatric Academic Societies and the American Academy of Pediatrics May 12-16 in Boston.

The trial was funded at Yale, Brown University School of Medicine, and Maine Medical Center by the National Institutes of Health. The study is considered significant because it is the largest of its kind of low-birth weight babies and the results indicate that the drug treatment might minimize future cognitive problems.

“Premature babies are never as smart as their full-term siblings,” said Ment. “Their IQ is 10 to 15 points lower than full-term babies.”

There were several preliminary studies, two of them at Yale, to gauge when the indomethacin should be administered and at what dose. This most recent trial enrolled 505 newborns between 1989 and 1992. The infants on average were born at 27 weeks and weighed about 2 pounds.

Each baby received a cranial ultrasound at six hours of age. The infants were then tested at seven months, 18 months, three years, six years and eight years. The data is based on tests administered at ages six and eight. The last child in the study will reach the age of eight in August.

Of the 505 enrolled infants, 431 showed no evidence of bleeding in the brain based on the ultrasound. In this primary group of 431, a total of 384 infants survived, “which is a very good survival rate,” Ment said.

The surviving infants who received indomethacin had less intraventricular hemorrhage and brain atrophy than those infants who were given a placebo, she said. There were no differences between the two groups in the incidences of cerebral palsy, seizures, low vision or hearing loss.

The children who were administered the anti-inflammatory medication showed higher verbal IQ scores, vocabulary scores and reading recognition scores. They also scored higher in adaptive communication tests and were less withdrawn.

Indomethacin is prescribed for adults with arthritis and works by blocking the synthesis of prostaglandins, which are hormone-like substances found in various tissues in the body. Prostaglandins mediate functions such as cerebral blood flow and inflammatory responses.

Neonatologists in the mid-1970s began to administer indomethacin to infants to close the patent ductus arteriosus, which is a tiny blood vessel that goes from the heart to the lungs. The blood vessel is open in fetuses but usually closes in full-term infants following birth.

The indomethacin, as administered in the study of premature infants, was most effective in those babies who never suffered any hemorrhaging in the brain, Ment said. But it did selectively protect language systems in the brains of all of the infants, regardless of whether there had been any intracranial bleeding. The language systems are located in the temporal and sensory motor regions of the brain, which basically is the swatch of brain from one ear to another.

“Almost all other studies of protective agents in the newborn period do not have long lasting effects,” Ment said. “This drug does, in fact, appear to protect the developing brain.”