#317 - 📑 Journal Club - The Complete Episode from June 8th 2025

Hello friends 👋

In this week’s Journal Club, Ben and Daphna dive into the latest report from the American Academy of Pediatrics on the management of patent ductus arteriosus (PDA) in preterm infants. They dissect the nuances of prophylactic versus selective treatment, review recent meta-analyses, and explore why early intervention might not yield better outcomes despite effective PDA closure. They also break down new echocardiographic criteria for diagnosing a hemodynamically significant PDA and discuss the role of transcatheter procedures.

The conversation then shifts to MRI timing and classification in neonatal encephalopathy, highlighting recent Canadian consensus recommendations for standardizing imaging protocols post-therapeutic hypothermia. The episode wraps up with a look at the TOHOP trial on permissive hypotension, challenging long-standing blood pressure treatment thresholds in preterm infants.

Listeners will gain a pragmatic view of evolving clinical practices and research gaps in neonatal care, particularly for infants with PDA and hypoxic-ischemic encephalopathy. If you’re looking to stay current on evidence-based recommendations without the fluff, this episode is for you.

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The articles covered on today’s episode of the podcast can be found here 👇

Consensus Approach for Standardization of the Timing of Brain Magnetic Resonance Imaging and Classification of Brain Injury in Neonates With Neonatal Encephalopathy/Hypoxic-Ischemic Encephalopathy: A Canadian Perspective.

Mohammad K, Reddy Gurram Venkata SK, Wintermark P, Farooqui M, Beltempo M, Hicks M, Zein H, Shah PS, Garfinkle J, Sandesh S, Cizmeci MN, Fajardo C, Guillot M, de Vries LS, Pinchefsky E, Shroff M, Scott JN; Newborn Brain Health Working Group of the Canadian Neonatal Network.Pediatr Neurol. 2025 May;166:16-31. doi: 10.1016/j.pediatrneurol.2025.01.021. Epub 2025 Feb 12.PMID: 40048833 Free article.

Active Treatment vs Expectant Management of Patent Ductus Arteriosus in Preterm Infants: A Meta-Analysis.

Buvaneswarran S, Wong YL, Liang S, Quek SC, Lee J.JAMA Pediatr. 2025 May 27:e251025. doi: 10.1001/jamapediatrics.2025.1025. Online ahead of print.PMID: 40423988 Free PMC 

Patent Ductus Arteriosus in Preterm Infants.

Ambalavanan N, Aucott SW, Salavitabar A, Levy VY; Committee on Fetus and Newborn; Section on Cardiology and Cardiac Surgery.Pediatrics. 2025 May 1;155(5):e2025071425. doi: 10.1542/peds.2025-071425.PMID: 40288780 Review.

Shifting outlooks after neonatal encephalopathy in the era of therapeutic hypothermia.

Christoffel K, Mulkey SB.Pediatr Res. 2025 Jun 4. doi: 10.1038/s41390-025-04156-0. Online ahead of print.PMID: 40467976 Review.

Treatment of Hypotension of Prematurity: a randomised trial.

Alderliesten T, Arasteh E, van Alphen A, Groenendaal F, Dudink J, Benders MJ, van Bel F, Lemmers P.Arch Dis Child Fetal Neonatal Ed. 2025 May 24:fetalneonatal-2024-328253. doi: 10.1136/archdischild-2024-328253. Online ahead of print.PMID: 40413017

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Watch this week's Journal Club on YouTube 👇

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The transcript of today's episode can be found below 👇

Ben:

Hello everybody, welcome back to the Incubator podcast. We are back today for an episode of Journal Club. Daphna, good morning. How are you?

Daphna:

Good morning! I'm doing really well. I'm really looking forward to today. I like my set of articles, but I’m especially looking forward to your set of articles. Am I too quiet today? That’s not something you usually complain about—me being too quiet.

Ben:

I had a long night, so maybe my hearing is a little bit dampened. Anyway, it's a very interesting set of articles. A lot has come out, and this is an episode we've both been looking forward to recording and releasing. So we're going to get into it momentarily. I wanted to do a few announcements, if that’s okay with you.

The first announcement is that, as you know, May has now passed, and we usually celebrate our podcast anniversary on May 4th. We had a giveaway that people could enter to win all sorts of prizes—this year, a laptop computer, some headphones, Incubator swag, and more. The way to enter is very straightforward. There’s a form on our website. It takes literally three minutes to fill out. It’s a survey that gives us some insight into what the community thinks about the podcast—what we could do to improve, topics we could cover. It really helps us, and it helps you, because it’s a very simple way to enter the giveaway. We like to give people notice because we are procrastinators too, so this will be the last week to enter. We'll be closing the form in a week—Sunday, June 15th, I believe. So you have until Saturday night, June 14th. After that, that’s it. But if you miss it, there’s always next year!

Another thing I wanted to mention is that we have some fan mail to go over. Some people have sent in messages. I want to remind folks that when you send fan mail through the website, it’s not something we manage directly—our podcast hosting platform does it. So we can't respond to you directly unless it's on air. One person asked if we could send the link to the article from Michelle Kelly’s episode, our guest from last week. All the links to all articles are always included on the episode webpage at our website: the-incubator.org. Go check it out there—all the articles are listed.

We also want to remind people about the upcoming Delphi Conference, which is ramping up. We're very excited to release the names of the speakers and some of the topics. Now is the time to secure your spot. There’s limited seating. And we’re not talking about those "limited" conferences where the cap is 6,000 people. We really try to keep this conference cozy—intimate, so people can connect with each other and the speakers. There are about 200 spots, and they fill up. To secure your seat, go to delphiconference.org or www.the-incubator.org/delphi. The location will be the same this year, and we’re excited to share more details soon. We may even have a special video recording from Daphna and Isun.

Another shout-out today goes to someone who reached out on LinkedIn, Paige Pedrolli. She’s been working on a book called Welcome to the NIC-Zoo. Paige has experience with the NICU and created this book to help families explain what’s going on when a sibling is in the NICU. The book is absolutely beautiful, and I highly recommend it. She gave us a free copy—such a cool perk of doing the podcast. It’s really good, and I wanted to highlight her work. Welcome to the NIC-Zoo is a dual-purpose children’s book. It’s great for parents to read to older siblings (ages 0–5), helping explain the NICU in a very simple and kid-friendly way. It’s a high-quality picture board book with bright and colorful illustrations. It's also a wonderful resource for hospitals to give to NICU families. Reading to your baby has so many benefits—bonding, stress relief, and early brain development.

You can purchase the book at www.nic-zoobook.com, and use the code NICZOO25 to get a 25% discount. For hospitals or NICU workers interested in bulk orders for family libraries, you can reach out to niczoobook@gmail.com, or message Paige on Instagram at @nicu_childrensbook. A great initiative and a great book—check it out. All right, I think that’s all the announcements I had for today. See you next week.

Daphna:

Yeah, we filled the hour! No, you promised us some contentious topics.

Ben:

Yeah, today we're going to talk about the PDA. There are a few articles we wanted to review. The most important one is the article published a few weeks ago in Pediatrics called “Patent Ductus Arteriosus in Preterm Infants.” It’s a report from the American Academy of Pediatrics, from the Committee on the Fetus and the Newborn. It’s a very interesting article. The background, of course, is that despite decades of research—and thousands of infants enrolled—there’s still so much uncertainty around PDA management. There’s so much variation in practice. The goal of the article, which is structured like a report (not a study or meta-analysis), is to walk through specific topics and review the literature on each subject. If you’re a trainee, it’s a great paper to review. So much has been published on the PDA that when you search PubMed, it’s easy to get lost in the weeds. This AAP paper does a great job highlighting the studies that are most impactful and should be considered when making recommendations.

I’ll go over some of the review, and then we’ll cover the AAP recommendations at the end. Let’s start with the scope of the problem. For term infants, 90% of PDAs close by 48 hours of life, and nearly all by 96 hours. But as gestational age decreases, the story changes dramatically. At 30–37 weeks, about 10% remain open at four days. At 25–28 weeks, 80% remain open at four days. At 24 weeks, 90% remain open at four days. Spontaneous closure rates also vary. For example, 73% of infants born at 28 weeks will close spontaneously, as well as 94% of infants over 1,000 grams. What’s interesting about the variation in closure rates is obviously the timing. By day seven after birth, the rates of closure fall to 2%, 65%, and 87%, depending on whether the baby was born at 30–37, 25–28, or 24 weeks and less gestation.

Conservative management shows that 50% of infants discharged with a persistent PDA will have spontaneous closure within nine months. By two years, that number increases to 80%. The challenge is: do we have two years to wait for closure without risking the negative effects of the PDA?

Then comes the issue of treatment. The paper begins with prophylactic treatment. The big question it addresses is: which PDAs need treatment? That’s why I want to start with prophylaxis.

There are three medications: indomethacin, ibuprofen, and acetaminophen. Regarding indomethacin, the review covers 19 trials including 2,872 infants. It reduces symptomatic PDA and severe IVH but doesn’t affect mortality, BPD, or neurodevelopmental outcomes. There are concerns about intestinal complications.

Prophylactic ibuprofen has been studied in nine trials with about 1,000 infants. It reduces the incidence of PDA by day 3–4 and reduces the need for rescue treatment. However, there's some significant concern with the use of ibuprofen, including the increased risk of oliguria. And again, no effect on mortality or BPD. I know some people might be thinking, “What about some of the other trials?” We're talking about prophylactic use—meaning not even trying, just giving it wholesale to everybody. That's what we're talking about right now.

And lastly, we have prophylactic acetaminophen, which has been looked at in about 27 studies, including approximately 2,278 infants. While it is more effective than placebo, it hasn't really been shown to influence mortality. So there's a level of evidence 1A, which is one of the highest levels of evidence we can get, that shows—taking all this into account—all prophylactic agents can close the PDA but provide no meaningful clinical benefit. That means we can’t actually recommend their use. And that concludes the discussion on prophylactic treatment.

Now, in terms of the evidence for early treatment of the PDA, the big question is: we want to treat the PDA because we think it's compelling to do so. But the secondary question is, are we dealing with just any PDA, or are we dealing with what's known as a hemodynamically significant PDA? The AAP does mention that, to date, an accurate and precise definition of a hemodynamically significant PDA remains elusive. The hemodynamic effects of a large left-to-right shunt associated with the PDA may be evident by physical examination, echocardiography, or serum biomarkers. One of the big contributions of this paper is that it ventures a definition of a hemodynamically significant PDA. Hopefully, that can set the standard for what should be considered a hemodynamically significant PDA, and future research can use that as a benchmark to assess babies consistently.

Neonatal echocardiography has a critical role to play in PDA diagnosis and evaluation of therapeutic response. Defining a hemodynamically significant PDA involves careful assessment of the PDA shunt and its impact on systemic and pulmonary circulation. It also involves evaluating myocardial and mitral valve function—especially in the context of potential myocardial ischemia—secondary to impaired coronary artery perfusion. A third consideration is identifying clinically relevant characteristics that modify the effect of a shunt on an already compromised milieu.

Echocardiography and color Doppler ultrasonography can be used to assess the effects of a hemodynamically significant PDA on end-organ perfusion and function. They include a very helpful figure that breaks down the effects of a PDA into four categories: shunt size, volume overload, pulmonary overflow, and systemic hypoperfusion. It shows how echocardiography can assess these aspects using specific measurements.

For example, shunt size is measured by the PDA diameter and flow pattern through the PDA. Volume overload can be assessed using the left atrium to aortic ratio (LA:AO) or the left ventricular output. Pulmonary overflow uses similar indicators as volume overload but also includes pulmonary artery end-diastolic velocity in the left pulmonary artery (LPA). For systemic hypoperfusion, we can evaluate organ flow, particularly flow through the descending aorta. This framework is helpful in understanding why we measure certain parameters and not others—it summarizes it quite well.

To further understand the definition, let’s look at Table 1 of the paper, which offers a suggested definition of a hemodynamically significant PDA. There are two domains: clinical criteria and echocardiographic criteria. You need criteria from both domains to make a diagnosis. From a clinical standpoint, two of the following four criteria must be met:

1. High CPAP or NIMV with high FiO2, or moderate/high ventilator settings at any FiO2. For instance, a baby on an oscillator at 50% FiO2 fits this criterion

2. Presence of hypotension requiring vasopressors

3. Persistent oliguria or renal dysfunction, likely due to poor kidney perfusion

4. Abdominal distension, feeding intolerance, poor growth, NEC, or similar findings

In addition, at least one of the following four echocardiographic criteria must be met:

1. PDA size ≥ 1.5 mm

2. Unrestrictive left-to-right transductal flow

3. Evidence of left-sided volume overload

4. Decreased, absent, or reversed end-diastolic flow in the abdominal descending aorta

If any one of these is present, the echocardiographic criteria are fulfilled.

This is quite interesting. While the components have likely been discussed before, this may be the first time they are summarized in a table that clinicians can refer to and potentially adopt as a standard.

Daphna:

I think that was always the debate—are people using different criteria? So at least if we can decide on a standard, then we can go from there. This was useful.

Ben:Absolutely. Now, in terms of early treatment and evaluating the evidence and risks, they reference an overview of 16 Cochrane systematic reviews that compiled data from 138 randomized clinical trials and nearly 12,000 preterm infants. When we talk about pharmacologic therapy for symptomatic PDA, they mention that all available prostaglandin inhibitor drugs are very effective in PDA closure compared to no therapy. This evidence is rated as level 1A.

Intravenous ibuprofen, used at a standard dose—10 mg/kg for two doses followed by 5 mg/kg every 24 hours for the rest of the course—may be preferred. It is as effective as indomethacin for PDA closure and has a significantly better safety profile, with a lower risk of NEC, a trend toward less intestinal perforation, and less oliguria. Just to clarify, while one medication may show relative benefits over another, that doesn’t automatically make it the recommended choice. It's important to follow the discussion through to the formal recommendation.

A systematic review and meta-analysis evaluating placebo, indomethacin, ibuprofen, and acetaminophen for closure of hemodynamically significant PDA looked at 68 randomized controlled trials involving 4,802 infants, comparing 14 variations of these drugs.

The overall PDA closure rate was 67.4%. A high dose of oral ibuprofen—15 to 20 mg/kg followed by 7.5 to 10 mg/kg every 24 hours—was associated with higher odds of closure compared to standard doses of IV ibuprofen or standard indomethacin. However, this high-dose regimen has not been adequately evaluated in extremely preterm infants, and the sample size in this subgroup has been very limited. Therefore, its efficacy and safety in that population remain unknown. A recent Cochrane review assessed the effectiveness and safety of early treatment—which is defined as treatment initiated by seven days of age, or very early treatment initiated by 72 hours of age—compared to a more expectant management approach for a hemodynamically significant PDA. The timing of treatment is very important. What the review found was that early or very early treatment did not decrease mortality and did not impact the rates of BPD, severe IVH, NEC, or surgical ligation. However, it did increase exposure to NSAIDs.

So, then the next question they address is: what about repeat courses? We know that sometimes we administer a single course, and the ductus arteriosus remains patent. In those cases, we often consider another course. However, the efficacy and safety of repeat courses of medication—if the initial course fails to close the PDA—have not been adequately investigated in randomized controlled trials. Observational studies suggest that a second course may increase the closure rate, but a third course is less likely to be effective. Adverse effects are rare with additional courses. There is no evidence to suggest that dual medication therapy—combining drugs—improves the rate of successful PDA closure or clinical outcomes. While medical therapies are often effective in closing the PDA, improvements in hospital and longer-term outcomes, including all-cause mortality, BPD, NEC, or moderate to severe neurodevelopmental impairment, have not been demonstrated. So, although it’s not entirely clear, the authors suggest that the hemodynamic benefits of a closed PDA may be counterbalanced by the adverse effects of NSAIDs on the lungs.

They go on to present some single-center data after that. Obviously, the next step is expectant management. So what about not doing anything? With increasing concern over medication exposure without clear benefit, conservative/expectant management is defined as tolerating the presence of a PDA that does not appear hemodynamically significant and allowing for delayed spontaneous closure. This approach has become quite common. They mention a retrospective review from the CPQCC (the California Perinatal Quality Care Collaborative) that found reduced use of COX inhibitors in NICUs was associated with lower rates of BPD in infants weighing more than 1,000 grams, but not in those under 715 grams. In that lower weight group, reduced COX inhibitor use was actually associated with increased mortality.

A similar retrospective, multi-center study from the Pediatrix Clinical Data Warehouse looked at data from 259 NICUs and nearly 80,000 infants. It found that reduced use of indomethacin, ibuprofen, or ligation was associated with a concurrent increase in local mortality, but also a decrease in BPD among babies weighing 400–749 grams, and decreased pulmonary hemorrhage in larger infants.

Additionally, a recent systematic review by Hundscheid and colleagues—which we reviewed on the podcast and was one of the EB-NEO Impact Articles of the Year—compared conservative management with other treatment approaches (prophylactic, non-prophylactic, or surgical). It included 12 cohort studies and 4 RCTs encompassing about 41,720 patients. Cohort studies showed higher mortality but lower BPD and ROP with conservative management, while the meta-analysis of the RCTs found no significant differences between conservative and active treatment.

To address this prospectively, there's the PDA-Tolerate Trial—one of the most important trials on the subject. It looked at 202 preterm infants born before 28 weeks gestation with a moderate-to-large PDA, between 6 and 14 days of age. Infants were assigned either to early routine treatment with indomethacin, ibuprofen, or acetaminophen, or to a conservative approach, with open-label rescue treatment for hemodynamically significant PDA in either group. Infants in the conservative management arm were more likely to receive open-label therapy, especially those born before 26 weeks gestation. However, there were no significant differences in the primary outcome of ligation or presence of a PDA at discharge. No differences were found in secondary outcomes like BPD or BPD/death. Interestingly, there was a trend toward higher death in the early routine therapy group. Among infants born after 26 weeks, those who received early treatment took significantly longer to achieve full enteral feeds and had a significantly higher incidence of late-onset sepsis and death, likely due to the need for prolonged invasive catheters, etc.

The review also mentions the BeNeDuctus Trial, which included 273 infants born before 28 weeks with a large PDA, randomized to either expectant management or early ibuprofen therapy. The primary outcome was NEC, moderate-to-severe BPD, and/or death at 36 weeks. Open-label treatment was allowed for heart failure or clinically significant shunt. The primary outcome occurred in 46% of the expectant group versus 63% in the ibuprofen group. No significant differences were found in rates of NEC or death, although BPD was increased in the ibuprofen group—again, not favoring early intervention.

Another study mentioned is the Baby-OSCAR Trial, which evaluated early ibuprofen treatment for a large PDA in extremely preterm infants (23–28 weeks). It included 326 infants in the ibuprofen group and 327 in the placebo group. Death or moderate/severe BPD occurred in 69% of the ibuprofen group versus 63% of the placebo group. Death occurred in 13% of the ibuprofen group and 10% of the placebo group—again, showing no reduction in death or BPD.

So, ongoing trials continue. The conclusion of this literature review is that selective treatment of infants born at or before 28 weeks who are at high risk of PDA may remain an option beyond two weeks of age. Deferral of early treatment in infants without hemodynamic compromise may allow for spontaneous closure without affecting the efficacy of future medical treatment. Similarly, deferring early procedural closure for non-hemodynamically significant PDA may help avoid unnecessary interventions. However, the optimal duration of watchful expectancy still needs to be defined, and more evidence is needed.

The first two weeks of life have the most available data. While no intervention is recommended during this period, there may be room for symptom-based intervention after two weeks. This is the part of the paper that everyone had questions about, which is why I spent so much time on it.

The paper also discusses procedural closure—surgical and transcatheter. Surgical closure is very effective but carries significant risks: pneumothorax, vocal cord paralysis, chylothorax, and it's associated with increased BPD, ROP, and neurodevelopmental impairment. It's usually reserved for failed medical therapy. Transcatheter closure is rapidly evolving with a very high success rate—95.5% recently, and 99.4% at six months. Registry data shows excellent outcomes with lower morbidity than surgery, but there are no randomized trials yet to formally support its use.

The paper also mentions adjunctive and non-pharmacological therapies. For example, fluid restriction: restricted water intake in preterm infants has been shown to increase postnatal weight loss and reduce the risk of PDA and NEC, with trends toward reduced BPD and death. But the AAP notes that this data is based on trials from decades ago and may not apply to today’s more immature patients. After diagnosis, fluid restriction may negatively affect energy intake and growth. A reduction from 145 to 108 mL/kg/day didn’t change respiratory variables or PDA characteristics. A more reasonable restriction might be 120–130 mL/kg/day after the first week to avoid adverse effects.

Diuretics are another consideration. Loop diuretics like furosemide increase renal prostaglandin E2 production and may dilate the PDA. Early use of furosemide in small trials led to faster postnatal weight loss and higher heart rate, but also a trend toward more PDA. There's concern over their use in PDA and no consensus.

Let me finish this long review with the final AAP clinical practice recommendations. These are key takeaways:

1. Prophylactic medical interventions are not recommended at any age or birth weight to reduce symptomatic PDA. They show no benefit on mortality, BPD, or neurodevelopmental outcomes. (Level of evidence: 1A)

2. Early fluid restriction may reduce PDA incidence, but the supporting data is outdated. There is no evidence that fluid restriction or loop diuretics help after diagnosis of a hemodynamically significant PDA. (Level of evidence: 2B)

3. Very early (<72 hours) or early (7–14 days) routine treatment—medical, transcatheter, or surgical—closes the ductus but does not improve outcomes and is therefore not recommended. Conservative management in this age group may let infants avoid medical therapy, procedural exposure, allowing spontaneous delayed closure without risk of increased adverse outcomes. It is likely that the presence of a PDA is a marker for more extreme immaturity and a biomarker for worse outcome, but treatment to close the PDA may not significantly impact such outcomes. (Level of evidence: 1A)

4. Insufficient data exists to guide management of PDA beyond two weeks of age. Duration of watchful expectancy and timing of medical closure, transcatheter, or surgical approaches need further study.

5. Pharmacologic closure beyond two weeks for hemodynamically significant PDA is considered reasonable. Ibuprofen is preferred, though acetaminophen or indomethacin are alternatives. (Level of evidence: 5 — expert consensus, lowest level of evidence)

6. If PDA persists despite up to two pharmacologic courses, transcatheter or surgical closure may be considered.

Daphna:

Yeah, I think it's so important that everybody knows this is out there. Definitely take a look at it.

Ben:Absolutely. It’s such a controversial topic. The AAP is walking on eggshells, trying not to make any premature recommendations. But they did a good job reviewing the evidence. It’s clear that PDA is likely a marker of extreme immaturity, and its presence may reflect poor outcomes—but that doesn’t mean treating it changes those outcomes. What I’m taking away is that your PDA will probably show up in the first week of life, and the data doesn’t support doing much about it then. But you should not attempt to treat it, I think, until two weeks have elapsed. That’s something I’m taking home right away. It seems that there's not strong evidence to suggest one medication over the other, but ibuprofen is probably the one being recommended. I still have a lot of reservations about ibuprofen, and considering the level of evidence, I might still favor acetaminophen, if you ask me.

And then all these adjunct therapies like Lasix and fluid restriction—we have to be very cautious not to be too aggressive. If you want to use one or two doses of Lasix, maybe, but don’t be too aggressive with it. Fluid restriction should be held at a minimum. I’d say if you're capping your babies at 145-150, you're probably okay, but I wouldn't start playing with much more restriction than that. I think they’re also highlighting that transcatheter closure has not been as thoroughly tested as we’d like. Don’t ship every kid for transcatheter closure unless you have a good reason.

Daphna:That was a great overview, thank you. Well, then I’ll give you a break. I know you still have PDA papers you want to carry out.

Ben:

No, actually, I don’t want to take a break—I just want to carry on quickly since the topic is the same. Obviously, one of the reasons we wanted to focus on the PDA paper today. There was an article in JAMA Pediatrics published recently looking at “Active Treatment vs Expectant Management of Patent Ductus Arteriosus in Preterm Infants: A Meta-Analysis.” So it’s interesting that as we’re reviewing this evidence, this meta-analysis comes out a few weeks later. But surprisingly, it's not going to create controversy—I think it aligns with what we just reviewed.

The goal was to assess the clinical outcomes of active versus expectant management of hemodynamically significant PDA. The primary outcome was a composite of death at 36 weeks post-menstrual age or at discharge, or moderate to severe BPD. This meta-analysis included 10 randomized controlled trials involving about 2,000 infants—about 1,000 in the active treatment group and 1,000 in the expectant management group. These were relatively immature populations, with a mean gestational age of 26 weeks and a mean birth weight of 874 grams. The incidence of the composite outcome (death at 36 weeks or discharge, or moderate to severe BPD) was higher in the active treatment group compared to the expectant management group: 56% vs. 50%, with a p-value of 0.02. Death at 36 weeks was also higher in the active treatment group—14% vs. 11%. There was a non-significant increase in moderate to severe BPD (47.4% vs. 43.3%), and for PVL, 5.7% vs. 3.5% in active vs. expectant management.

I’ll let you all review this paper. The interventions here were initiated in the first two weeks of life, which led the authors to conclude that active treatment of a hemodynamically significant PDA during that time was associated with a significantly higher incidence of death or moderate to severe BPD—and with increased mortality—compared to expectant management. So again, within the first two weeks, maybe back off a little. Because it's a meta-analysis, it uses some of the same data the AAP report used. And now I can get a break.

Daphna:

Okay, well, I’m happy to carry on then. I’m actually going to do a little bit of a review paper myself. This one is from Pediatric Neurology. It’s a “Consensus Approach for Standardization of the Timing of Brain Magnetic Resonance Imaging and Classification of Brain Injury in Neonates With Neonatal Encephalopathy/Hypoxic-Ischemic Encephalopathy: A Canadian Perspective.”

This is on behalf of the Newborn Brain Health Working Group of the Canadian Neonatal Network. Many of the authors are closely connected to the Newborn Brain Society. They are trying to standardize their approach across Canada. The working group represents 26 NICUs across Canada that offer therapeutic hypothermia for babies with neonatal encephalopathy. They created a task force with neonatologists, radiologists, neuroradiologists, and pediatric neurologists to develop these consensus guidelines using literature review and expert opinion. The goals were to:

1. Develop a clinical classification of brain injury patterns

2. Establish a standardized MRI protocol

3. Adapt or modify existing scoring systems

4. Achieve consensus on the timing of the first brain MRI

This began with a set of surveys previously published in Pediatric Research in 2023. They examined the variation in care for neonates undergoing therapeutic hypothermia across their network. Twenty-four of the 26 centers responded. At that time, they already had national guidelines about who qualifies for therapeutic hypothermia. In general, centers were following the national guidelines, using the modified Sarnat score to assess severity, initiating hypothermia within six hours, and emphasizing follow-up. But they found significant variation in other practices—ventilation, hypotension treatment, echocardiography, sedation, EEGs, MRIs, placental analysis, and follow-up.

This paper is an excellent review and overview of HIE, therapeutic hypothermia, and how we evaluate it. Their recommendations begin with standardizing MRI protocols. They recognize the challenge—different facilities have different capabilities—but by standardizing, maybe everyone can get comparable results. They recommend using specialized neonatal or pediatric brain coils (12 to 15 cm) to improve image resolution and signal quality. Adjustments to MRI parameters like longer T2-weighted imaging times and longer repetition times for T1-weighted imaging are also advised. While a 3T MRI provides higher resolution, excellent results can also be achieved with a 1.5T MRI using the proper settings.

Recommended MRI sequences include:

• T1 and T2 weighted images to examine anatomy

• Diffusion-weighted imaging (DWI) for ischemic injury

• Gradient echo T2 or susceptibility-weighted imaging for hemorrhages and microbleeds

• 3D T1-weighted images for detailed anatomy (high-quality 2D T1 acceptable if needed)

They also talk about magnetic resonance spectroscopy (MRS), which evaluates brain metabolism. We know babies with asphyxia may have elevated lactate-to-creatinine ratios and reduced NAA levels in the basal ganglia—strong indicators of poor long-term outcomes. This could help with prognosis, but interpretation is tricky in neonates, especially preterms, since healthy ones can also have low NAA and, especially in preterm “normal” neonates, moderate lactate levels.

Then there's the timing of MRI, which is a big one. Most centers across Canada perform brain MRIs in neonates within the first week of life. A few follow the timing recommended by the task force. One center does an MRI on day 4 and repeats on day 15. Another does it around day 10. Some centers do early MRIs during therapeutic hypothermia for research or family discussions around care withdrawal. Two centers didn’t use a standard day but stayed between days 4 and 10.

After much discussion, the task force recommended performing the MRI consistently either on days 3–5 (right after cooling), or days 10–14, if the baby is still in the NICU. They suggest repeating the MRI if the initial one doesn’t align with the baby’s clinical picture—whether things look worse or surprisingly better than expected.

Following MRI timing, they also worked on a more robust radiologic classification for brain injury patterns. It's a long section, so I won’t read it all, but anyone new to HIE or therapeutic hypothermia should read it. It gives a great explanation of common presentations and includes findings like intracranial hemorrhage, cerebellar injury, and brainstem injury—things we often overlook.

They also reviewed the available MRI scoring systems. Ultimately, the working group chose to use the modified Weeke score combined with the Wisnowski classification for their database. They kept the Barkovich score as well, since many centers still use it. They listed 3 major modifications to this combined scoring system to help standardize how brain injuries are described, allowing for better comparison across centers.

I thought that was really interesting—worth a read. I think we're all still debating the timing, but this offers more guidance. Thoughts?

Ben:

I think this is almost like a book chapter. It has so much information, and the sections are very well-crafted. There are lots of pictures, which is good, because if you want to see what certain things look like on MRI, they’re right there. Each section is short, so even though it’s a long paper, it's broken down nicely. I think the most debated topic is going to be the timing of the MRI. I don’t know what your thoughts are on that in terms of what do you think is the most practical? Taking into account the Canadian practice model, what’s your take?

Daphna:

Yeah, I think it’s consistent with the data we have about how MRI findings evolve. They discuss this—as do many other papers. Early on, you rely more on diffusion-weighted imaging and MR spectroscopy. Later, you see more changes on T1 and T2. A good take-home message is that we’re all trying to identify the optimal time that gives us the best prognostic information—what this baby will be like as a child. Several studies have shown pretty good agreement between early and late MRI scans in large populations and meta-analyses. But is it different for individual babies? Yes, especially depending on the type of injury and the preceding event. In the States, major institutions have largely adopted the same kind of timing approach. Getting the early MRI is especially helpful because some of our babies are ready to go home before day 10–14.

So it's nice to have that information. I think it’s especially helpful that—even if the MRI looks great—but the baby doesn't clinically look great, that’s definitely an indication to follow up with imaging and make sure nothing was missed.

There was another review I want to highlight in Pediatric Research, though I won’t go into all the details. It’s called “Shifting outlooks after neonatal encephalopathy in the era of therapeutic hypothermia.” It’s a valuable reminder, especially when we see MRIs that are better than expected or even normal. “[Children with a history of HIE can face challenges in motor skills, emotional regulation, behavior, language, communication, cognition, learning, and academic achievement. All children with a history of HIE benefit from close neurodevelopmental surveillance—even when their MRI is reassuring.]” The review discusses long-term outcomes, and I want to share this impact statement: “[Children with moderate to severe hypoxic-ischemic encephalopathy, even without significant brain injury on post-cooling neonatal MRI, are still at risk for a range of neurodevelopmental challenges at school age and beyond. Neonatal neuroimaging and early developmental evaluations don’t reliably predict school-age outcomes, making prognostication and counseling difficult in the NICU and follow-up clinics. All children with perinatal HIE should have long-term follow-up and support through school age].”

Ben:

Yeah, I agree—but I also want to moderate that statement a bit. I mean, I’m not the expert, but I agree with the premise: a good-looking MRI doesn’t mean everything’s behind us. But at the same time, we shouldn't overlook a positive result either. For families, it's important that [they have hope]. I know that a negative MRI doesn’t guarantee there won’t be anything concerning later, but it’s definitely better than a terrible-looking MRI. We just have to balance that. Otherwise, our tone with families can become too negative: “This bad thing happened, now we’re doing this invasive thing, the MRI looks normal—but it still doesn’t mean anything.” Let’s make sure we keep giving parents the right guidance while still celebrating the small wins.

Daphna:

Yeah, I totally agree with you.

Ben:

I knew I wasn’t going to say anything too controversial—so I’m okay.

Daphna:

I totally agree. It’s about balancing hope while making sure kids don’t fall through the cracks. So we say, “We’re thrilled this looks good, and now we want to connect you to early intervention.” That’s another reason why connecting families with organizations like Hope for HIE is so valuable. They can find support from other parents and access resources—even if they don’t realize they need them until years later. I know Betsy has so many stories about that.

Ben:

We tend to be a little egotistic as neonatologists—looking at our own little backyard. If we resuscitate a baby, cool them, and get a normal MRI, we feel we’ve done pretty well. And in a way, it’s true, but that’s the extent of our oversight. But we have to make sure our optimism is well conveyed. Okay, we’re way over time, but I wanted to mention one last article.

There’s one article I have to mention. It’s published in Archives of Disease in Childhood and it’s called “Treatment of Hypotension of Prematurity: A Randomized Trial.” The first author is Thomas Alderliesten. It’s very interesting. We all know hypotension in preterm infants is common, but management remains controversial—we’ve talked about this a lot. Traditionally, we use a rule: when the mean arterial pressure (MAP) in mmHg falls below the infant’s gestational age in weeks, that’s hypotension. So for a 26-week infant, we intervene if the MAP drops below 26. But the evidence supporting this is not as solid as we might think. The literature is inconclusive about whether low blood pressure directly contributes to brain injury. Some studies link low MAP in the first 24 hours to short-term outcomes; others question whether treatment even helps. Recent work suggests that low MAP might just reflect a bigger issue—like low cerebral oxygenation—and that is linked to worse outcomes. That’s the basis of this trial: the TOHOP trial (Treatment of Hypotension of Prematurity). They hypothesized that a perfusion-based approach—what they call “permissive hypotension”—might be safe and reduce unnecessary inotrope use. The term alone raises my blood pressure! It’s like saying “acceptable death.” It’s not acceptable.

Daphna:

Well, we use permissive hypercapnia, don’t we? You like that one.

Ben:

Yeah, CO₂ feels less scary than hypotension. Anyway, they argue permissive hypotension may be safe as standard treatment. It was a single-center randomized controlled trial conducted at Wilhelmina Children's Hospital in Utrecht, Netherlands, between 2011–2018. They included infants born between 24 and 29+6 weeks with idiopathic hypotension (MAP below gestational age). They excluded babies with congenital anomalies, signs of sepsis, or no arterial line, among others. When infants met hypotension criteria (MAP below gestational age for at least 15 minutes), they were randomized to two groups: standard treatment, which treated based on MAP/gestational age, or permissive hypotension, which used a more nuanced approach. You needed one of several criteria in addition to low MAP:

• Regional cerebral oxygen saturation <50% for 30 minutes

• Urine output <0.6 mL/kg/hr

• Cap refill >3 seconds (x2)

• Lactate ≥6

• MAP 5 mmHg below gestational age (as a safety net)

In the end, if MAP was 5 below gestational age, that was enough to qualify as hypotensive. Their treatment approach was:

1. Fluid bolus

2. Dopamine

3. Dobutamine

4. Epinephrine (with or without hydrocortisone)

I’m not going to get into the dopamine-first debate here—don’t send hate mail.

Daphna:

Just know dopamine is falling out of favor.

Ben:

Primary outcome: neurodevelopmental assessment at 24 months using Bayley Scales. Secondary outcomes included mortality, Bayley composite scores, and IVH in the first seven days. They enrolled 86 infants—only 57% of projected due to recruitment challenges. Median age at randomization was  ~5 hours after birth. Primary outcome was that there was no significant difference between groups. Cognitive scores were 90.9 (standard) vs 91.7 (permissive); motor scores 90.4 (standard) vs 94.1 (permissive). Secondary outcomes showed mortality similar—7.5% (standard) vs 13% (permissive). Adverse composite outcome of death or significant neurodevelopmental impairment were 54% (standard) vs 44% (permissive).

Blood pressure outcomes were striking: despite different thresholds, the actual MAPs were very similar. Permissive group spent slightly more time below gestational age MAP (11% vs 7.7%), but used far fewer inotropes—15% (permissive) vs 43% (standard). And when inotropes were used, duration was shorter: 17 hours (permissive) vs 48 hours (standard).

Cerebral oxygenation: permissive group spent more time <50%, especially from 36–42 hours and over 72 hours. However, no difference was seen in time <55%. And importantly, no group effect could be demonstrated in the mixed model analysis.

In terms of clinical events, four infants in the permissive hypotension group developed severe late-onset sepsis after the initial 72-hour intervention period, compared to none in the standard treatment group. These infants were then treated for these particular instances. The timing of severe IVH was similar between the groups—again, usually between day three and four of life. In terms of IVH, for grade three or more, the rates were 7.5% (standard) versus 13% (permissive).

What’s interesting is that the authors are showing that if you're less strict with the blood pressure, it might be feasible, and you might have much less inotrope use without major adverse effects. One of the things that was interesting, as I mentioned earlier, is that they never really reached their recruitment goals. The study was quite underpowered, achieving only 57% of projected enrollment. They note that multiple factors contributed to this: number one, the declining incidence of hypotension in their unit; a spillover effect where staff began favoring the more personalized approach even outside the study; and most significantly, challenges with the consent process.

So I thought this was interesting. The authors, in the conclusion, state that a more individualized and less strict BP-driven strategy for low BP in premature infants with a gestational age of less than 30 weeks and no signs of sepsis during the first three days after birth leads to lower usage of inotropes while maintaining similar BP levels and without signs of impaired systemic perfusion. Although the study is underpowered, they say they did not see any major negative effects of an individualized approach in terms of risk of death, NEC, grade III IVH/periventricular hemorrhage, or neurodevelopmental outcomes at two years. I thought it was interesting.

It’s an interesting study because some of these shorter outcomes can give you a bit of pause, but the change is not that significant. I kind of like this idea of an individualized approach. I don't know if the data is there yet to roll this out and make it broadly generalizable.

Daphna:

Yeah, I think it's complicated by the fact that not everybody believes we should be using gestational age. So might those babies that you allowed permissive hypotension for—with another set of criteria—fall into the same group? Maybe they're not so different. Especially since we reviewed just a few weeks ago those beautiful graphs about blood pressure ranges in babies, which I think challenge the use of gestational age criteria—not at every gestational age, but at some especially so. And then, what is the right agent for helping with blood pressure? That’s up for debate. So I think those are the complicating factors with this study. But I think it shows that, again, the individualized approach—taking a look at the baby and understanding perfusion—helps us make those treatment decisions.

Ben:

Yeah, and right away it makes more physiologic sense. I thought this was an interesting paper. I don't know if it has tons of practical implications, but I think it makes us think about blood pressure and about looking beyond just the number.

Daphna:

Yeah, and reminding us to go back to the bedside. So many of our clinical skills—they teach us they’re not just for adults—all those markers of the different types of shock, we can see them in babies, and they help us make decisions. Of course, point-of-care ultrasound and hemodynamic echo will be a supporting feature, but we can see a lot of those findings on a clinical exam, you know?

Ben:

For sure. Especially when you have arterial lines. One of the things I’m taking away is how variable it all is. You come by the bedside and the blood pressure is 23, and you're like, ugh. Then you come back and it’s bumped up a little to 26, and you wonder, okay, what do I do? Maybe that’s when we put something on the head (NIRS) and look at the cerebral oxygenation. Then let’s try to think a little more proactively about perfusion status. I think that’s very helpful.

Daphna:

Yeah, and I think to your point, even if we agreed on what numbers to start medications and which medications to start, what are the right numbers to wean medications? What are the parameters?

Ben:

For sure. And maybe the MAP is good, but you see the diastolic is going down slowly and you're like, well, technically the MAP is still equal to or above the gestational age, but what else is happening? All these things are the aspects of care that get me excited because it’s more intelligent, in my opinion.

Daphna:

For sure. We’ve been talking about this in our unit—is that what is hypotensive for one baby, even at the same gestational age, may not be hypotensive for another baby. When you're saying, "This blood pressure is low for this baby," and everyone else says, "It’s fine," you're like, "But I know this baby, and this isn’t right for them." Again, being at the bedside, continuity of care, helps us make those decisions for kids.

Well, I have some more papers, but I just don't know that we have the time today.

Ben:

Yeah, same for me. But I think we overstayed our time. I guess we’re going to wrap up. Everybody, thank you for staying with us today. Again, remember to fill out the survey and enter the giveaway. And check out the website for tickets to the Delphi Conference this coming January 26, 27, and 28, 2026 in Fort Lauderdale. It was a pleasure doing Journal Club today, Daphna. I’ll see you next time.