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Watchful Waiting: The New Recommendation for Most Preterm Infants With PDA

Watchful Waiting: The New Recommendation for Most Preterm Infants With PDA 1024 683 Abbie Miller

A study published in JAMA found that treating patent ductus arteriosus with medication did not help with disease management but was associated with higher mortality.

 

A new study from the Neonatal Research Network, published in JAMA, found that treating patent ductus arteriosus (PDA) in preterm infants with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen at ≤21 days of age did not help with disease management. In fact, the treatment was associated with more deaths compared to expectant management or watchful waiting.

“These findings will change neonatal practice here and everywhere,” says Jonathan Slaughter, MD, MPH, co-author of the study, neonatologist and principal investigator in the Center for Perinatal Research at Nationwide Children’s. “For every 18 infants treated with expectant management, one more infant survived. This upends our understanding and practice of the last 50 years.”

The Study

Funded by the Eunice Kennedy Shriver National Institute for Child Health and Development (NICHD) and led by Matthew Laughon, MD, MPH, professor of neonatal-perinatal medicine at the University of North Carolina at Chapel Hill (UNC) School of Medicine, the study sought to better understand the risks and benefits of two commonly used approaches to PDA in preterm infants.

The prospective study enrolled preterm infants of  22 to 28 weeks’ gestational age at ≤21 days of age. The participants were randomized into one of two groups: expectant management, in which the PDA was only treated with closure medications when the infant had cardiopulmonary compromise, or immediate active treatment with acetaminophen, ibuprofen or indomethacin. Treating clinicians were able to select which of these medications to give to infants randomized to the active treatment arm of the study.

Notably, preterm infants with cardiopulmonary compromise, known congenital heart or pulmonary malformations, or prior treatment for PDA were excluded.

“It’s important that we acknowledge that infants with a large PDA who either were already on mechanical ventilation with a high oxygen requirement or who required multiple vasopressor medications to maintain their blood pressure, were excluded,” says Pablo Sánchez, MD, neonatologist, infectious disease expert and principal investigator in the Center for Perinatal Research at Nationwide Children’s. “This study did not include the sickest babies, so our results are not generalizable to that specific population.”

A Brief History

PDA is essential in fetal life, and in term babies, it usually closes 24 to 48 hours after birth. In preterm infants, however, the PDA often stays open for some time after birth. How long exactly varies.

“In preterm infants, we often see PDAs spontaneously close on their own. But that isn’t always the case, and we don’t fully understand the best timing for PDA closure in preterm infants,” says Dr. Sánchez. “And so, there’s been two approaches over the years. Try to medicate to encourage closure or wait and see if the PDA closes or becomes problematic.”

Historically, the idea to treat PDA with medication was supported by research in 28- to 32-week-old infants. It started as an attempt to avoid potential negative impacts of too much blood to the lungs and, importantly, to avoid surgical ligation, which tended to have poor outcomes, says Dr. Sánchez.

“Neonatologists have been treating PDA with NSAIDs since 1976,” says Dr. Slaughter. “However, we didn’t have much data on the smallest babies we now care for in the NICU. This study was designed to include younger preemies, down to 22 weeks’ gestation.”

Results

In December 2024, the trial stopped early because of futility and safety at the 50% interim analysis. A total of 482 participants were randomized with 242 in the expectant management group and 240 receiving active treatment.

Rates of BPD in each group were similar: 81% for expectant management and 80% for active treatment. However, 10% of infants in the active treatment group died compared to 4% in the expectant management group.

“When we started, our hypothesis was that we’d find no difference between groups. We didn’t expect to observe mortality in the active treatment group to double that of expectant management,” says Dr. Slaughter. “This is a clear association that deserves more investigation and an immediate change in clinical practice.”

Deaths occurred closer to treatment, a median of 9 days, in the active group compared to 32 days following initiation of expectant management. Among the adverse events resulting in death in this study, there were more infections in the treated group. In the active treatment group, Escherichia coli, Staphylococcus aureus, Enterobacter  spp., and Klebsiella spp. were all implicated in the deadly infections.

The researchers say they do not know the mechanism that made infants in the active treatment more susceptible to these bacterial infections, but additional analysis of the data is planned. They did confirm that central line days were the same across groups, so central line days were not associated with an increase in infections in the treated  group.

“Based on these data, it’s clear that treating PDA with these medications could do harm and does not offer any benefit,” adds Dr. Sánchez. “Sometimes in neonatology, less is best. I think this is true here.”

Moving Forward

So, what about when the PDA does not close spontaneously? At a certain age, the PDA can become problematic and catheter closure may be the best option.

At Nationwide Children’s, Dr. Slaughter and Carl Backes, MD, cardiologist, neonatologist and principal investigator in the Center for Perinatal Research, are leading the National Heart Lung and Blood Institute-funded PIVOTAL trial, which compares catheter closure to responsive management in the NICU with closure only if symptoms worsen. That trial is past 50% enrollment and the data safety monitoring board permitted the study to continue after a planned interim safety analysis.

“We’re looking forward to the completion of the PIVOTAL trial and understanding where catheterization closure of PDA fits into the broader picture,” says Dr. Slaughter. “But for now, we know our next step: stop medicating stable preterm infants with acetaminophen and NSAIDs for PDA closure.”

 

Reference:

Laughon MM, Thomas SM, Watterberg KL, Kennedy, KA, Keszler M, Ambalavanan N, Davis AS, Slaughter JL, Guillet R, Colaizy TT, Cotten CM, Dhawan MA, Bose CL, Talbert J, Smucny S, Benitz WE, Rysavy MA, Ohls RK, Baserga MC, DeMauro SB, Jaleel M, Jackson WM, Carlo WA, Puopolo KM, Hibbs AM, Katheria A, Sanchez PJ, D’Angio CT, Patel RM, Johnson BA, Chock VY, Bhatt AJ, Merhar SL, Moore R, Steinbrekera B, Anderson K, Reynolds AM, Wyckoff MH, Montoya C, Das A, Do B, Chang S, Higgins RD, Walsh MC, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Expectant management vs medication for patent ductus arteriosus in preterm infants: The PDA randomized clinical trial. JAMA. Published online December 09, 2025. doi:10.1001/jama.2025.23330

About the author

Abbie (Roth) Miller, MS, MWC, is a passionate communicator of science. As the manager of medical and science content at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association, and received her masters of science in Health Communication from Boston University.

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