Personalizing Treatment for Preterm Babies with PDA

Standard indomethacin regimen may fail in infants with CYP2C9*2 variant.

Preterm babies with patent ductus arteriosus (PDA) are typically treated with indomethacin, a non-steroidal anti-inflammatory, to achieve closure. Approximately one-fourth of infants who are treated fail to respond and are referred for catheter-based coil occlusion or surgical ligation.

There is evidence that infants with variants in genes involved in drug metabolism are more likely to fail treatment with indomethacin. Researchers at Vanderbilt University Medical Center, the University of Iowa Stead Family Children’s Hospital and the University of California, San Francisco, recently joined forces to examine the impact these polymorphisms have on likelihood of indomethacin failure.

Prince Kannankeril, M.D., professor of pediatrics at Vanderbilt, was principal investigator on the study, which analyzed DNA samples and histories from 131 infants across the three centers. Additional cases were drawn from the Vanderbilt BioVU repository. The research team found that one particular polymorphism, the cytochrome P450 2C9*2 (CYP2C9*2) variant, was present in 16.7 percent of the infants studied, and that these infants failed indomethacin treatment at a significantly higher rate.

“If this study is replicated with similar outcomes, it could potentially steer clinicians toward ligation without an indomethacin trial in infants with this genetic variant.”

“This is a relatively common variant. If this study is replicated with similar outcomes, it could potentially steer clinicians toward ligation without an indomethacin trial in infants with this genetic variant,” Kannankeril said.

Risks of PDA and Its Treatment

 About two in 1,000 full-term and eight in 1,000 preterm babies have a PDA, with a gradation from mild to severe. In a typical newborn, the PDA closes with the cessation of prostaglandins from the placental blood, and with higher blood oxygenation from the lungs. Untreated PDA in preterm infants is associated with increased risk of cardiovascular and pulmonary morbidities as well as intracranial hemorrhage.

The prostaglandin synthase inhibitor, indomethacin, is commonly used to treat PDA and is administered over the course of several days.

Treatment for PDA is not without its own risks. Potential adverse consequences from indomethacin include renal dysfunction, necrotizing enterocolitis, gastrointestinal bleeding and intestinal perforation. Since clinical response and toxicity from indomethacin are highly variable, the decision to administer treatment or move straight to an invasive intervention is not clear-cut.

A Culprit in Poor Drug Metabolism

 To help identify infants at higher risk, Kannankeril and colleagues designed a study to assess four genetic variants thought to influence ductus response to indomethacin: TFAP2B, EPAS1, CYP2C9*2 and CYP2C9*3. The goal was to isolate factors associated with indomethacin failure, defined as surgical ligation for persistent PDA.

Inclusion criteria included birth between 22-32 weeks gestation, persistent flow through a clinically significant PDA, and at least one treatment dose of indomethacin.

Of the four alleles studies, the CYP2C9*2 variant was the only one to be associated with increased risk of indomethacin failure. Fifty-four percent of the infants with the CYP2C9*2 variant failed indomethacin treatment versus 35 percent of the total cohort.

Impact on Clinical Decisions

“When a child is ill with a PDA, a couple more days of worsening respiratory failure or decreased systemic blood flow are serious considerations.”

The roughly 50/50 odds that infants with the CYP2C9*2 variant will achieve closure following indomethacin treatment makes proceeding with the drug an arguably reasonable treatment decision. However, the risks of failing indomethacin treatment must be accounted for as well. “When a child is ill with a PDA, a couple more days of worsening respiratory failure or decreased systemic blood flow are serious considerations,” Kannankeril said.

Kannankeril foresees a time when bedside genetic testing for the CYP2C9*2 variant might better inform a treatment decision. “This will depend on study replication, but even then, it is a matter for clinical judgment, since there are many factors to consider in a complex preterm birth.”