New evidence from researchers at Monroe Carell Jr. Children’s Hospital at Vanderbilt indicates that a single prophylactic dose of indomethacin (SD-INDO) may result in decreased patent ductus arteriosis (PDA) and better long-term outcomes, while reducing drug exposure for preterm infants.
Common practices surrounding management of PDA range from no preventative measures – with later treatment if a hemodynamically significant PDA (hsPDA) develops – to the prophylactic administration of three to six doses of indomethacin shortly after birth. Not only does prophylactic indomethacin promote ductus closure, but it also decreases risk of severe intraventricular hemorrhage (IVH), a common cause of disability and death in preterm infants.
Maria Gillam-Krakauer, M.D., a neonatologist, and colleagues studied 384 infants born 22-28 weeks of gestation to determine the impact of SD-INDO. Results published in the Journal of Perinatology show SD-INDO lowered rates of PDA, IVH and cerebral palsy, and improved survival. It also decreased overall drug exposure by reducing the need for later treatment.
“Clinical practice on management of PDA in extremely preterm infants is missing a compass,” Gillam-Krakauer said. “This area demands updated data and practice strategies for the contemporary neonatologist.”
The PDA Controversy
Controversy on PDA closure and indomethacin use centers around the targeted patient population and ideal intervention timing. While indomethacin is the most efficacious medication for PDA treatment, it has the potential to contribute to renal dysfunction and gastrointestinal conditions already prevalent in this population, Gillam-Krakauer says. On the other hand, awaiting natural closure increases the risk for chronic lung disease and mortality.
With these caveats in mind, Vanderbilt’s late neonatology chief, Robert B. Cotton, M.D., instituted a single-dose indomethacin practice in 1987. “He accrued pharmacokinetic data showing one dose of INDO shortly after birth achieved therapeutic drug levels due to low glomerular filtration rates,” Gillam-Krakauer said. Vanderbilt is one of the few centers to use the SD-INDO approach.
“Clinical practice on management of PDA in extremely preterm infants is missing a compass.”
Since Cotton’s pioneering work, the field of neonatology has evolved to enable babies born as early as 22 weeks to survive. Said Gillam-Krakauer, “This study aimed to determine if SD-INDO was effective in decreasing PDA and IVH in this population of very early gestational age, and to determine if there was long-term neurologic benefit to this practice.”
Of the 384 infants in the retrospective study, 299 received prophylactic SD-INDO and 85 did not. Reasons the 85 did not receive SD-INDO included drug shortage and medical provider preference.
Infants receiving SD-INDO were:
- 27 percent less likely to develop hsPDA,
- 18 percent less likely to receive later treatment with INDO for hsPDA,
- More likely to survive and be discharged, and
- Less likely to develop a high grade IVH, when adjusted for gestational age.
The study found no evidence of adverse effects of SD-INDO with no higher odds of acute kidney injury, oliguria, gastrointestinal perforation or necrotizing enterocolitis, coagulopathy or hemorrhage. Babies in the SD-INDO group were more immature and more ill at baseline, with lower APGAR scores and higher illness scores. Despite this, treated babies performed just as well on tests of neurodevelopment, and experienced less cerebral palsy and less severe impairment in those who did develop cerebral palsy.
Evolving Best Practices
While this study supports efficacy of SD-INDO, Gillam-Krakauer says other considerations merit attention, such as using early echocardiography (on the day of birth) and frequently during the first week. This may avoid SD-INDO in those babies whose PDA does close spontaneously.
Frequent targeted echo during the critical first week can enable early intervention if the PDA doesn’t close with indomethacin or if it reopens. “We hope that others will consider adopting this strategy now that our data confirms its value in the tiniest preemies,” Gillam-Krakauer said.
“We hope that others will consider adopting this strategy now that our data confirms its value in the tiniest preemies.”
The researchers also note that babies who are genetically predisposed to be slow- or non-responders to indomethacin may require higher doses or alternative treatment.