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The PDA Conundrum

April 2, 2018
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A patent ductus arteriosus is associated with increased morbidity and mortality, but common treatments are associated with poor outcomes as well. What is a neonatologist to do?

Until the mid-2000s, most neonatologists were pretty sure they knew how to handle a patent ductus arteriosus (PDA) in an infant born preterm – it needed to be closed as soon as possible.

This was the conclusion of decades of research demonstrating that:

  • A patent (or open) ductus allows oxygenated blood from the aorta to leak into the oxygen-poor blood of the pulmonary artery, ultimately straining the heart and lungs
  • PDA is associated with bronchopulmonary dysplasia, respiratory distress syndrome, intraventricular hemorrhage and many other problems, including increased mortality rates
  • An open ductus can be closed by nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, and failing that, by surgical ligation

So a widespread practice developed of trying indomethacin (or ibuprofen) closure in the first few days of a preterm infant’s life, and if that didn’t work, turning to surgery. It makes sense. It’s also a “conceptual trap,” in the words of William Benitz, MD, Philip Sunshine professor in Neonatology and former chief of Neonatology at Lucile Packard Children’s Hospital at Stanford University. Dr. Benitz is the first to admit that he, like the vast majority of his colleagues around the world, was caught in that trap for years.

“I thought I was doing the right thing,” he says. “The whole experience has been humbling.”

Yes, an open ductus arteriosus is a problem. But clinicians weren’t asking other important questions, says Jonathan Slaughter, MD, a neonatologist at Nationwide Children’s Hospital and principal investigator in the Center for Perinatal Research:

Is closing the ductus actually good for every preterm baby who has a PDA? If not, can we figure out the specific babies who would benefit?

“That’s where we’re stuck,” says Dr. Slaughter. “We don’t know which kids.”

 

 

The ductus arteriosus is a blood vessel in the fetus that connects the pulmonary artery and aorta. It directs most of the blood directly from the right ventricle to the aorta, bypassing the fetal lungs. Once in infant is born, the ductus arteriosus should close.

ESCAPING THE TRAP

The answer to Dr. Slaughter’s first question has become clearer. Closure is not good for every preterm baby with a PDA. It’s probably not good for most of those babies, in fact.

The turning point was the 2007 re-analysis of data from the 2001 Trial of Indomethacin Prophylaxis in

Preterm Infants, says Dr. Slaughter. It found an association between surgical ligation of the PDA and increased risks of bronchopulmonary dysplasia, severe retinopathy of prematurity and neurosensory impairment in extremely low birthweight infants.

A 2010 publication from Dr. Benitz also caught people’s attention. He had been asked to present at a conference on his preferred practice – trying closure with indomethacin first, then moving to ligation – and he searched for evidence that the practice helped preterm infants. He couldn’t find it in dozens of published studies.

“It’s not just that we don’t have evidence to support the treatment; we also have a lot of evidence that the treatment is not effective,” he says. “That’s a stronger conclusion.”

Even though clinicians were trying to close a PDA as soon as possible, data had emerged before Dr. Benitz’s review suggesting that most PDAs will spontaneously close without drugs or surgery. The evidence has only become stronger over time.

A 2016 study from Dr. Slaughter and colleagues at Nationwide Children’s examined babies born at 28 weeks of gestational age or less who had PDAs. Some were treated with NSAIDS and some were managed conservatively. There was no difference in the odds of mortality or moderate-to-severe bronchopulmonary dysplasia between the groups.

A 2017 study in Pediatrics found that most PDAs in even the youngest and smallest babies – less than 26 weeks of gestational age and 750 grams weight at birth – will spontaneously close with conservative management.

Still, some PDAs don’t close for weeks or months. Some don’t at all. What should happen for those babies?

“We are left without strong data to guide the practice of evidence-based medicine,” says Carl Backes, MD, a member of The Heart Center and Division of Neonatology at Nationwide Children’s. “We have some data showing there are risks for heart failure, bronchopulmonary dysplasia and worsened outcomes with continued exposure to PDA. Alternatively, we have data showing that many ducts will close on their own without exposing infants to the risks of drug therapy and surgical ligation.”

Knowing which babies have PDAs that won’t close for months, or won’t ever close, would help.

Jonathan Slaughter, MD, neonatologist and principal investigator in the Center for Perinatal Research at Nationwide Children's
Carl Backes, MD, cardiologist and neonatologist at Nationwide Children's

WHO TO TREAT AND WHEN

While that 2017 Pediatrics study did show that most PDAs in preterm infants will close on their own, babies who were at least 26 weeks of gestational age and 750 grams at birth experienced spontaneous closure much more quickly. In contrast, the median time to closure was 71 days for babies born at less than 26 weeks and 48 days for babies with a birth weight of less than 750 grams.

A few babies in the study still had patent ducts at one-year follow-up. It may make sense, then, to focus on this subset of particularly small babies, says Dr. Backes. A PDA treatment algorithm that he helped develop at Nationwide Children’s does take into account a baby’s gestational age. It also assesses the “hemodynamic significance” of the patency by using eight clinical and echocardiographic criteria, such as a minimum PDA size of 1.5 millimeters and persistent hypotension requiring a cardiotropic agent.

The algorithm suggests not considering drug or procedure-based closure until at least 2 weeks of age for any baby, and potentially not even considering closure until after 30 days of age. In highlighted text is the sentence, “There is no evidence of any long-term benefit from treatments that close the PDA.”

Drs. Slaughter and Backes would like to create a spontaneous closure prediction model and are trying to secure National Institutes of Health (NIH) funding for it. Their idea is to regularly perform echocardiograms on preterm infants, collect biomarkers such as B-type natriuretic peptide and follow the babies out to at least 36 weeks of age, paying special attention to bronchopulmonary dysplasia (BPD) and mortality.

The combination of those variables could help the physicians learn which infants are most likely to have persistent patent ductus and which portion of those are most likely to be negatively affected by it. The biomarkers may add important information to the decision-making process.

“If you only treat the kids whose PDA definitely won’t close, then we may actually find a positive effect of treatment,” says Dr. Slaughter. “That is personalized medicine that we’re not able to practice today.”

“If you only treat the kids whose PDA definitely won’t close, then we may actually find a positive effect of treatment. That is personalized medicine that we’re not able to practice today.” — Jonathan Slaughter, MD

HOW TO TREAT THEM

There are three traditional treatments for preterm infants with PDA that can result in closure. Conservative management, which may include fluid restriction and diuretics; NSAIDs, which have known renal and gastroenterological risks; and surgical ligation, with its own concerns.

A fourth has gained prominence in the last decade: catheter-based closure. It is considered among the safest interventional cardiac procedures in general and is the “procedure of choice” for PDA closure once an infant reaches approximately 4 kilograms. But only a handful of academic health care institutions, including Nationwide Children’s, regularly perform percutaneous closure on very small infants.

That’s not because others don’t have the ability; it’s because they have been waiting for a device specifically tailored to those infants, says Darren Berman, MD, co-director of Cardiac Catheterization and Interventional Therapy in The Heart Center at Nationwide Children’s.

Drs. Berman, Backes and colleagues have demonstrated that PDAs in small infants can be closed safely with a catheter-based approach. Nationwide Children’s is now one of eight United States centers participating in a prospective study called “Amplatzer Duct Occluder II Additional Sizes” (NCT03055858), investigating the use of a closure device in infants as small as 700 grams.

“We’re talking about the exact population that is likely to be most affected by a persistent PDA,” says Dr. Berman. “If we can show that this is the right device to close the PDA for them, then we can move on to the studies that we really need, asking, does this really benefit the patient?”

That’s a question clinicians once thought that they had figured out in the 1970s.

“We’re actually living through the answer right now,” says Dr. Berman.

References:

  1. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: Results from the Trial of Indomethacin Prophylaxis in Preterms. The Journal of Pediatrics. 2007 Mar;150(3):229-34.
  2. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: Time to accept the null hypothesis? Journal of Perinatology. 2010 Apr;30(4):241-52.
  3. Slaughter JL, Reagan PB, Newman TB, Klebanoff MA. Comparative effectiveness of nonsteroidal anti-inflammatory drug treatment vs no treatment for patent ductus arteriosus in preterm infants. JAMA Pediatrics. 2017 Mar 6;171(3)
  4. Semberova J, Sirc J, Miletin J, Kucera J, Berka I, Sebkova S, O’Sullivan S, Franklin O, Stranak Z. Spontaneous closure of patent ductus arteriosus in infants ≤1500 g. Pediatrics. 2017 Aug;140(2).
  5. Backes CH, Cheatham SL, Deyo GM, Leopold S, Ball MK, Smith CV, Garg V, Holzer RJ, Cheatham JP, Berman DP. Percutaneous patent ductus arteriosus (PDA) closure in very preterm infants: Feasibility and complications. Journal of the American Heart Association. 2016 Feb 12;5(2).

 

Image credits: Adobe Stock (illustration and infant photo); Nationwide Children’s (portraits)