#392 - [Journal Club] - 📌 Is PDA Treatment Doing More Harm Than Good in Preterm Infants?

In this Journal Club episode, Ben and Daphna review a major randomized clinical trial published in JAMA comparing expectant management with active pharmacologic treatment of patent ductus arteriosus in preterm infants. They walk through the trial design, inclusion criteria, and outcomes, highlighting the unexpected survival difference favoring expectant management despite similar rates of bronchopulmonary dysplasia. The discussion explores the implications for bedside decision-making, the limitations of PDA-focused strategies, and the need for a more physiologic, patient-centered approach to ductal management in extremely preterm infants.

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Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial. 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, Sánchez PJ, D'Angio CT, Patel RM, Johnson BA, Chock VY, Bhatt AJ, Merhar SL, Moore R, Laptook AR, Ghavam S, Fuller J, Vyas-Read S, Kicklighter SD, Steinbrekera B, Anderson K, Reynolds AM, Wyckoff MH, Montoya C, Das A, Do B, Chang S, Higgins RD, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.JAMA. 2025 Dec 9:e2523330. doi: 10.1001/jama.2025.23330. Online ahead of print.PMID: 41364689

Transcript

[00:00.942] Ben: Hello, everybody. Welcome back to a new episode of Journal Club on The Incubator podcast. Happy New Year 2026. Daphna, Happy New Year.

[00:08.709] Daphna: Wow, same to you. It's a big time for transitions and change and looking ahead.

[00:18.188] Ben: Yeah, it's a big transition all around. We're continuing to evolve. I'm very happy actually that our podcast has never really been the same every year. We always take feedback in and we always make small adjustments. For the people who haven't had the chance to listen to our end-of-year episode, definitely go check that out; we go over a lot of the different changes.

[00:45.000] Ben: What's important for you to know if you're listening to Journal Club is that we are creating a new podcast, "The Incubator: Journal Club." It's basically just a repository of the past Journal Clubs for the people who have been asking for a faster way to access them. If scrolling is too much to ask and if the website is too far away—I'm a victim of that sometimes, you know? I just want it right there and then.

[01:09.701] Daphna: Too arduous, too arduous to look through everything. Yeah.

[01:16.226] Ben: Then go subscribe to that podcast and the Journal Clubs will be there. As we said on the end-of-year episode, the exciting thing about 2026 is that through this podcast, what we'll be able to do is potentially offer CME (Continuing Medical Education) credits for Journal Club episodes. We're working actively on making this happen. Whenever that comes through, we will let you know. Until then, stay tuned.

[01:55.417] Daphna: So many articles to review.

[02:03.109] Ben: Well, until that happens, it looks like we're going to hit the ground running with some pretty interesting articles from the end of 2025 as we're opening the new year.

[02:15.490] Ben: Yeah, I mean, you know, we were hoping to take it easy at the end of the year, and every week that went by, you saw one of these papers being released and you're like, "Damn, that's another one we must review."

[02:36.514] Ben: Okay, so the first article this week that we're going to spend time on is an article published in JAMA (Journal of the American Medical Association) that has made the rounds. It is about the PDA (Patent Ductus Arteriosus). It's called "Expectant Management versus Medication for Patent Ductus Arteriosus in Preterm Infants," or the "PDA (Patent Ductus Arteriosus) Randomized Clinical Trial." First author is Matthew Laughlin, authored with a team from the NIH (National Institutes of Health) NRN (Neonatal Research Network).

[02:50.000] Ben: It was a privilege to be able to talk to Matt at Hot Topics. If you haven't listened to this conversation, please go check it out on the podcast. It’s a few weeks back and it's kind of neat to be able to get his thoughts. It’s a 10-15 minute conversation where he walks us through the paper, but we didn't really do a "Journal Club" on it then—we didn't dive deep into the numbers. So that's what I'm hoping we can do today.

[03:30.000] Ben: PDA management, obviously, is something that we know is very controversial. There's lots of variability. The paper starts off by trying to ground itself in hard evidence, mentioning the Cochrane Review looking at active versus expectant management before seven postnatal days. It shows that early treatment of the PDA probably results in little to no difference in mortality based on evidence that is of "moderate certainty."

[04:00.000] Ben: Follow-up meta-analyses published between 2010 and 2024, limited to trials of active treatment begun in the first two postnatal weeks, reported that active treatment was associated with increased mortality, although no individual trial really demonstrated a statistically significant difference. Despite these findings, there continues to be wide variation in clinical practice. One-quarter of infants born at 22 to 28 weeks of gestation in the US receive pharmacologic treatment for PDA closure.

[04:40.000] Ben: Taking into account this ongoing uncertainty, the investigators initiated this randomized clinical trial including preterm infants with a protocol-defined PDA to evaluate the risk and benefit of expectant management compared to active pharmacologic treatment using any medication that the clinical team chose.

[04:54.510] Ben: In terms of the study design, this was a registry-embedded, comparative effectiveness randomized clinical trial conducted at hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network. Infants were screened between 2018 and 2024. We're going to discuss the immediate short-term outcomes, but there's ongoing neurodevelopmental follow-up being collected as we speak, aiming for follow-up at about two years of age.

[05:30.000] Ben: Regarding the babies they were looking at: first, they had to be born between 22 weeks and 28 weeks and 6 days. Second, they had to be between 48 hours and 21 days of age at the time of screening. And third, they had to have a hemodynamically significant PDA defined per trial protocol using echocardiographic and clinical criteria.

[06:00.000] Ben: The diagnosis of a PDA is quite well explained in the supplemental material. Matt mentioned how much the supplemental materials are a treasure trove of information. There are criteria there, including a modified version of the criteria from McNamara and Sehgal. Infants were categorized as having no PDA or a symptomatic PDA—symptomatic meaning echocardiographic criteria of mild, moderate, or severe with a small or medium-sized PDA, or mild to moderate criteria with a large-sized PDA.

[06:30.000] Ben: Then they had this definition of "cardiopulmonary compromise." I invite you to review these criteria. You have both clinical and echocardiographic criteria. When looking at clinical criteria, FiO2 (Fraction of Inspired Oxygen) is a big component; PPV (Positive Pressure Ventilation) or positive airway pressure is another. When you get into the moderate and severe categories, hypotension becomes a factor. For echocardiographic criteria, there’s PDA size, ductal flow, and the LA/Ao (Left Atrium to Aorta) ratio.

[07:13.794] Ben: In the severe form, you have diastolic reversal of flow in the abdominal aorta. Regarding cardiopulmonary compromise, these infants were excluded. That's a big deal. They decided not to look at these babies who were quite sick from their PDA. They also excluded babies who had a known congenital heart defect other than an ASD (Atrial Septal Defect) or VSD (Ventricular Septal Defect), pulmonary malformations like congenital lobar emphysema or CPAM (Congenital Pulmonary Airway Malformation), or if they had prior pharmacological or procedural treatment of their PDA.

[08:10.000] Ben: The rationale for excluding kids with cardiopulmonary compromise was that most neonatologists involved in the trial did not have equipoise to assign those babies to expectant management. Randomization was one-to-one, stratified by gestational age.

[08:40.000] Ben: The intervention was interesting: in the expectant management group, treatments to close the PDA were not to be administered unless the baby reached 36 weeks PMA (Post-Menstrual Age) or developed cardiopulmonary compromise. In the active group, they basically allowed the teams to do whatever they wanted—acetaminophen, ibuprofen, or indomethacin. The choice of agent, dose, and route was left to the clinical team. Initial treatment was to begin within 48 hours of a trial-defined PDA diagnosis.

[09:17.206] Ben: Surgery, meaning PDA ligation or cardiac catheterization with device placement, was also left at the discretion of the clinical team if pharmacological treatment did not succeed.

[09:40.000] Ben: The primary outcome was death or BPD (Bronchopulmonary Dysplasia) assessed using a physiologic definition at 36 weeks PMA. Secondary outcomes included individual components of the primary outcome, NEC (Necrotizing Enterocolitis), ROP (Retinopathy of Prematurity), growth, etc.

[10:10.000] Ben: The investigators hypothesized that expectant management would reduce the incidence of death or BPD from maybe 50% to 40%—an absolute reduction of 10%. That's how they powered the study. However, the trial was stopped early, so they never reached full enrollment. A total of 482 infants were randomly assigned: 242 in the expectant group and 240 in the active treatment group.

[10:50.000] Ben: In the expectant management group, 25% still received treatment before 36 weeks. You might think these kids got really sick, but only 4 out of those 60 were treated for cardiopulmonary compromise or after 36 weeks. A lot of these babies were actually just a "protocol deviation," which is the bane of these trials.

[11:15.000] Ben: In the active treatment group, 99.2% received treatment. About 26% received acetaminophen, 35% received ibuprofen, and 29% received indomethacin. About 9% received a combination. Of all these infants, 19% eventually underwent surgical closure. Cardiopulmonary compromise occurred in 14% of the infants in the expectant group and 9% of the active group.

[11:40.174] Ben: There's no primary outcome, basically. The trial was halted in 2024 by the NICHD for both futility in observing a difference in the primary outcome and for a safety concern related to substantially increased mortality in one of the groups. At the 50% interim analysis, the conditional power for the primary outcome was only 2%. Death or BPD occurred in 81% of the expectant group and 79.6% in the active group—an adjusted risk difference of 1.2%.

[12:30.000] Ben: In terms of secondary outcomes, this is where the bulk of the discussion is. 4.1% of infants in the expectant group died compared with 9.6% in the active treatment group. The adjusted risk difference was negative 5.6% with a p-value of 0.01. Interestingly, the NNT (Number Needed to Treat) is 18—meaning for every 18 infants managed expectantly, one more survived. I think that's staggering.

[13:30.000] Ben: Why was mortality so high? The occurrence of adverse events was similar between groups, however, infections resulting in death occurred in 0.8% of the expectant group compared to 3.8% in the active treatment group. This was statistically significant. There is a suspicion that the increase in mortality is driven in great part by this risk of sepsis.

[14:40.000] Ben: The conclusion is that in extremely preterm infants with a protocol-defined PDA, death or BPD did not differ between expectant management and active treatment in the first 21 days of life. However, survival was substantially higher with expectant management. That’s the big takeaway. Daphna, I'm curious to get your thoughts since you weren't with me at Hot Topics.

[15:08.695] Daphna: I know, I missed out! This PDA debate has been going on for decades. I think this is a huge step—I don't know in which direction, but it's going to give us pause. There’s some confusion, right? Not all PDAs are the same. Even babies who weren't supposed to get treated still got some treatment. We've all seen babies who really seem to respond to treatment. I couldn't quite get a feel for the most common cause of death for the babies in that group. Does this mean the answer is that some PDAs need treatment, but maybe it's the medication itself that's the problem? We’re learning more about individual medications in this postnatal age group. Does this open up the opportunity for more device closures?

[16:29.578] Ben: You’re touching on a few things. Regarding different medications, they found it didn't really matter which medication was used; the outcomes were similar. Even though the medications are different, the way they close the PDA is somewhat similar.

[17:01.590] Ben: I think what you said is very astute. We’re focusing on the treatment modality, but maybe we should flip it on its head—it’s the patient. Can we understand the patients better? Understanding every baby’s physiology and the kind of shunt they have is probably the best way to find a modality that makes sense.

[17:41.349] Daphna: I was just going to say, for trainees—and this took me a long time to figure out—they may ask: "Why do we keep trying to close the PDA if it doesn't make things better and sometimes makes them worse?" But there's all this underlying data that exposure to the PDA is probably not good. We're trying to figure out how to get rid of it without making things worse, and we haven't gotten there yet.

[18:08.462] Ben: And remember, we don't know what happened to these PDAs. It's a pragmatic study. They treated them, but didn't tease out whether they actually closed, got smaller, or didn't close at all. That's a whole different group.

[18:28.168] Daphna: Yeah. So I'm very sorry to report: the discussion continues.

[18:35.887] Ben: That's what we say after every PDA paper. Sorry, guys! We'll see what's coming next. We'll mark a pause here and come back tomorrow with one more paper.