#336 - Building a World Without NEC – A Conversation with Dr. Mark Underwood

Hello friends 👋

In this special collaboration with the NEC Society, Dr. Mark Underwood joins the podcast to discuss the evolving science and clinical approach to necrotizing enterocolitis (NEC). A long-time leader in neonatal nutrition and NEC prevention, Dr. Underwood shares his perspective on why prevention remains the most effective lever in tackling this devastating disease — from the irreplaceable role of maternal milk to the complex regulatory barriers around probiotics.

The conversation covers his recent articles unpacking the risks and benefits of formula, donor milk, and the current probiotic landscape in U.S. NICUs. Dr. Underwood also previews highlights from the upcoming NEC Symposium and shares his hopes for the future of NEC care, including earlier biomarker-driven interventions and smarter pasteurization of donor milk.

Whether you’re a clinician, researcher, or parent advocate, this episode offers pragmatic insights into the current NEC landscape and the road ahead.

Listeners can register for the 2025 NEC Symposium at https://necsociety.org/nec-symposium/ and use promo code incubator for 10% off. 

Link to episode on youtube: https://youtu.be/_pjEYQW_gjo

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Short Bio:  Dr. Underwood received his undergraduate degree in Italian from Brigham Young University and then attended the University of Texas Southwestern Medical School in Dallas followed by pediatric residency at UCLA.  After 13 years as a general pediatrician in Montana and New Zealand, he completed a fellowship in neonatology at UC Davis and then joined the faculty there in 2006 and became the division chief in 2014.  He retired from UC Davis in 2021 and moved to Spokane to be closer to family. His research focuses predominantly on necrotizing enterocolitis, human milk oligosaccharides, the intestinal microbiome and probiotics.  He also enjoys international collaborations and has taught and provided care across Africa, Central and Eastern Asia, Eastern Europe, South America and the Middle East.  

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

The fifty billion dollar question: does formula cause necrotizing enterocolitis?

Underwood MA.J Perinatol. 2025 May;45(5):565-571. doi: 10.1038/s41372-025-02277-2. Epub 2025 Mar 26.PMID: 40133659 Free PMC article. Review.

Probiotics and the prevention of necrotizing enterocolitis.

Underwood MA.J Pediatr Surg. 2019 Mar;54(3):405-412. doi: 10.1016/j.jpedsurg.2018.08.055. Epub 2018 Sep 6.PMID: 30241961 Review.

https://www.the-microbiologist.com/opinion/catch-22-the-fda-probiotics-and-preterm-infants/2079.article 

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

Ben Courchia, MD: Hello everybody. Welcome back to The Incubator Podcast. Today we are thrilled to bring you a special episode in collaboration with the NEC Society, an organization dedicated to building a world without NEC. Our guest is someone whose research and advocacy have shaped how we think about neonatal nutrition and NEC prevention. Dr. Mark Underwood is an emeritus professor of pediatrics at UC Davis School of Medicine. You’re the former chief of neonatology at UC Davis Children’s Hospital and a founding contributor to the NEC Society’s efforts. Your research has focused on necrotizing enterocolitis, human milk oligosaccharides, the intestinal microbiome, and probiotics. After years in clinical practice and leadership. You now live in Spokane and continue to collaborate internationally, teaching and providing neonatal care across five continents. Mark, welcome to the podcast.

Mark Underwood: Thank you very much. Pleasure to be with you.

Ben Courchia, MD: As we just mentioned, the episode is also a preview of the upcoming NEC Symposium taking place September 7 through 10 in Chicago at the Renaissance Chicago Hotel. Listeners of The Incubator can get 10% off their registration using the promo code incubator. Visit NECSociety.org to learn more and register.

Dr. Underwood, I wanted to start again by thanking you for joining us and by asking what initially drew you to necrotizing enterocolitis as an area of focus? What was it about this particular disease that convinced you it was where you wanted to dedicate a significant amount of your time and work?

Mark Underwood: I think it’s the devastating nature and rapid progression of necrotizing enterocolitis. The hardest thing about NEC is that a premature baby can be quite stable, progressing toward growth and discharge home, and then seemingly in a matter of hours can deteriorate rapidly—sometimes to death or to severe disease that requires surgery and has lifelong consequences. My first attempts to research NEC were more than 20 years ago. At that point I had seen so many babies develop this disease, yet we knew very little about what caused it and why it progresses so quickly in babies compared to other diseases.

Ben Courchia, MD: For those working in this space, NEC research presents multiple avenues. You have therapeutics, surgical management, prevention, and studying the microbiome. But you seem to emphasize prevention as the most impactful lever. Is that a fair characterization of your work? And if so, why do you see prevention as such a hopeful and critical piece of the NEC puzzle?

Mark Underwood: Yes, that’s a fair characterization. Prevention really has been the focus of my interest and research, because once NEC starts, there’s so little available to us to make it stop. Trying to find out what triggers it, what risk factors are involved, and how to recognize it early are all of great value. In particular, one of the striking things that led me to focus on prevention was mounting evidence 20 years ago that human milk is protective against NEC. The composition of the intestinal microbiota—the bacteria and viruses that live inside the intestine—is a significant risk factor, and potentially one we could manipulate to decrease risk.

Ben Courchia, MD: Earlier this year, you published a beautiful article in the Journal of Perinatology called The $50 Billion Question: Does Formula Cause NEC? In it, you performed a nuanced and rigorous review of the evidence on NEC risk factors and the biological components of human milk. Your conclusion was very eloquent: you state clearly that a human milk diet is best, especially for our most vulnerable population. But you also warn against oversimplified narratives that could lead us to say, “Formula causes NEC,” calling instead for more clarity and transparency with families.

How do you interpret the current moment we’re in with legal cases in the news? Some hospitals I’m aware of are even requiring parents to sign special forms if they choose formula, based on recent litigation. How should we be counseling families at the bedside, and how do we distinguish facts from disinformation?

Mark Underwood: I’d start with how we counsel parents and build from there. Ideally—and it’s not always possible—it helps to have a conversation with families anticipating the birth of a very preterm baby even before delivery. When a mother is admitted in preterm labor and her baby may be born very early, it’s valuable to sit down and talk about the difficult journey ahead. That conversation should include NEC. As you know, NEC affects 5–10% of very premature babies, and the more preterm the infant, the higher the risk. Sometimes parents say, “If the chance is 5–10%, that means my baby has a 90–95% chance of not getting NEC. Why worry me about it?” My answer is that when it does happen, it’s devastating. And we do know of strategies that reduce risk. If parents are prepared and understand this disease—even before birth—it’s extremely valuable. That prenatal discussion helps us emphasize the importance of mother’s milk.

Years of data show that mother’s milk protects against infections in general and necrotizing enterocolitis in particular. It contains hundreds of fascinating molecules and cells that protect against infection, encourage organ development, and prepare the baby for microbial exposures. When parents understand the power of mother’s milk, it empowers mothers to do the hard work of providing it. They also better understand the differences between: mother’s milk, with its unique protective components; donor human milk, which has some advantages but is not equivalent; and formula, which while valuable, lacks many protective components. If we can have these discussions prenatally, wonderful. If not, then we revisit them in the NICU—though parents often say those first days are a blur, so repetition is key.

As for litigation, we live in a time, particularly in the U.S., when poor outcomes often lead to the question: “Whose fault is this?” Studies have consistently shown higher NEC incidence in babies fed formula—especially in the first two weeks—compared to those fed mother’s milk. That has led researchers to study not only protective factors in breast milk but also potential toxic components of formula. My article was an attempt to summarize that evidence. The conclusion is that mother’s milk contains many protective molecules, bacteria, and cells. Pasteurization, which is necessary for donor milk, destroys some of these. These protective factors are not present in formula. What we have not found, despite 20 years of searching, is any specific toxic component in preterm formulas that directly causes NEC.

Ben Courchia, MD: In that paper, it’s almost depressing to see the table of protective factors in milk that are degraded by pasteurization—it feels like almost every row is marked with an “X.”

Mark Underwood: Yes. That’s not to say donor milk isn’t a valuable resource—it is. But thinking it’s equivalent to mother’s own milk would be a big mistake.

Ben Courchia, MD: Exactly—and that’s what your paper highlights so well. Especially in centers where all three feeding options exist, it’s important to present them honestly as distinct choices, not equivalents. There is a hierarchy, and mother’s milk is unequivocally the best.

I also want to take some time to talk about probiotics. You’ve written extensively about them, and the data are so compelling. The most recent meta-analyses show a 46% relative risk reduction in NEC, with a number needed to treat of 33. And yet, in the U.S., we’re facing a memo from the FDA that has essentially stalled probiotic use across the country. You’ve written an excellent piece called Catch-22: The FDA, Probiotics, and Preterm Infants, where you describe this frustrating paradox: these agents can prevent NEC and save lives, yet we can’t use them because they’re not FDA-approved—and they’re not FDA-approved because we’re not using them in trials.

Can you unpack this? Why did you call it a catch-22, and what is the situation now?

Mark Underwood: A good starting point is that the FDA has never approved probiotics for NEC prevention. And it’s important to understand their mission and the guidelines that Congress has set for them. My intent has not been to criticize the FDA. I respect their mission to ensure food and drug safety, but their role is not to regulate the practice of medicine. The FDA currently classifies probiotics as dietary supplements, generally regarded as safe, but not designed to prevent, mitigate, or treat disease. If I tell a family, “I want to give your baby probiotics to improve intestinal health,” that’s acceptable. But if I say, “I want to give probiotics because dozens of studies show they reduce NEC and death,” then by FDA definition, I’ve crossed into the realm of a drug claim. In September and October 2023, the FDA issued a warning, emphasizing two points: (1) Probiotics in the U.S. are not manufactured or tested to the standards required for drugs. (2) A case of probiotic sepsis occurred in a premature infant who later died. They haven’t released the details of the case. But we know that probiotic sepsis—where bacteria or fungus from the probiotic translocate from the intestinal lumen into the bloodstream—is a known but rare complication. Rates have been monitored for years, especially in Scandinavia where probiotics have been used for a long time. Rates are estimated at 1 in 1,000 to 1 in 10,000 (maybe slightly higher in preterm infants). Meanwhile, studies consistently show lower rates of sepsis, death, and NEC in babies who receive probiotics versus those who don’t. Yet, based on that one case, the FDA pulled two products from the market—not because they failed standards, but because manufacturers had shared NEC reduction data, which the FDA viewed as marketing them as drugs. The effect has been that across the U.S., most hospitals have stopped using probiotics, and many physicians can’t even offer them “off label.” Meanwhile, probiotic use remains common in Europe, Canada, Japan, China, Australia, and elsewhere, in spite of the FDA. The Canadians are so good at sharing their data, and they just recently shared data across their entire neonatal network about their use of probiotics. In Canada, probably half of the very small premature babies get probiotics.

Ben Courchia MD: Something like of like 40%, which is quite impressive.

I want to go to a more exciting, optimistic topic. Obviously, there's been a lot of incredible research done in the field of necrotizing enterocolitis. Is there anything getting you excited right now, something coming down the pipe that could revolutionize our understanding or our approach to managing or preventing this terrible disease?

Mark Underwood: Two things come to mind. Number one, I think there's some evidence that we can do a better job of pasteurizing donor milk. Our current method is to heat it up to 63 degrees Celsius for 30 minutes, which kills all the bacteria and viruses in donor milk, but also wipes out so many of the beneficial components we talked about earlier. People have been working for years to develop better methods—ways to kill pathogens without doing such harm. Some groups in Europe are making real headway, and I’m hopeful those processes will be helpful.

The other thing that excites me is our growing understanding of the very aggressive inflammatory nature of NEC. Uncontrolled inflammation is why it progresses so quickly. In adult medicine, anti-inflammatory agents are used in diseases like Crohn’s disease or ulcerative colitis, and many of those mechanisms are similar to what we see in NEC. The idea that we might be able to test these products in premature babies with NEC is exciting. It could be a paradigm shift, because our current treatment approach hasn’t changed much since the 1970’s: we stop feedings, empty the stomach, give antibiotics, and monitor progression with x-rays. But we don’t have proven tools beyond antibiotics—and many cases are triggered by viruses, making antibiotics less helpful. So the idea of rapid-acting anti-inflammatory agents to prevent or stop the spread of NEC is, for me, hopeful and exciting.

Ben Courchia MD: That truly is exciting. I want to turn our attention to the NEC Society and the NEC Symposium. You're part of the planning committee of the upcoming symposium. What can attendees expect from this year's event?

Mark Underwood: This conference is really unique among medical conferences. I've never been to anything quite like the NEC Symposium. Part of that is because it’s so focused on a single disease. There’s a lot of passion and urgency, because this disease is so common and devastating. Another unique aspect is the importance and involvement of patient families. At most medical conferences, you hear researchers present their work—some talks grab your attention, others less so. At the NEC Society Symposium, multiple sessions will be introduced by patient-family advocates. That keeps us grounded in the personal nature of this disease and the urgency of finding answers. Imagine a family who has lived through NEC introducing a scientist and sharing their story—those presentations are powerful. The community of NEC researchers and families comes together in a unique and meaningful way.

Ben Courchia MD: Is there a specific presenter or topic you’re especially excited about this year? It’s quite an international panel.

Mark Underwood: I’d have to go with the session on human milk. As exciting as the other sessions are, the study of human milk and its components is still in its infancy. Some really talented scientists will be presenting, and the list of discoveries is long. We could hold a three-day conference on human milk alone and still not cover everything. For me, that will be one of the most exciting sessions.

Ben Courchia MD: Let me ask you a mentoring question. Many of our listeners are trainees or young career neonatologists. They might look at the NEC Symposium and think, “Should I go? It’s just one disease. Maybe I’d get more bang for my buck out of a broader conference.” Why, in your opinion, should early-career neonatologists come to this event?

Mark Underwood: Maybe I’ll share my own experience. Early in my career, when I was first learning about NEC, my mentor Francis Poulain told me: pick a topic and learn everything you can about it. It’s hard, but if you choose something specific enough, you can actually read most of the world’s literature in a few months. That was fascinating—to realize you could really immerse yourself and come to understand how people think about a disease.

At big meetings like the Pediatric Academic Societies, there might be one or two NEC sessions, maybe eight speakers total. That was valuable, but limited. The NEC Society Symposium brings many of the leaders in the field together for three days. It’s not just the talks—it’s the conversations during breaks and in the evenings, where you learn what people are really working on and thinking about.

For example, in the past decade, organoid technology has allowed us to model the intestine in the lab in ways we couldn’t before. Those discoveries are possible because of collaborations and idea-sharing at meetings like this. Meeting people, like when I first met Mickey Kaplan 20 years ago, can change your research direction and open new doors. Every discovery raises 10 more questions, and that energy is contagious at NEC meetings.

Ben Courchia MD: I’ll add my perspective too. If you’re passionate about NEC research, it’s a no-brainer. But even if you’re not directly in the NEC space, the scale of the meeting makes it unique. It’s not too crowded, you get to interact with both speakers and attendees, and the faculty list is carefully curated. Last year, I met Mark Del Monte, CEO of the American Academy of Pediatrics, who’s returning this year. I think these conferences are very unique and provide a huge value in potentially engaging with people like yourself, with Martin Blakely, Cami Martin, Ravi Patel, with so many amazing, amazing physicians and researchers. Sometimes these relationships can be career defining. Even if your interest is, say, transfusion medicine or neurology, there are connection points—because NEC touches so many outcomes. These meetings create opportunities for collaboration and mentorship that can be career-defining.

Mark Underwood: I agree. NEC affects so many organ systems. For example, neurologists are very interested in what happens to the brain during NEC, and nephrologists study the kidney injury that often accompanies it. It’s hard to think of a pediatric subspecialty not impacted by NEC.

Ben Courchia MD: Dr. Underwood, my last question comes from something you wrote about probiotics: “Every day we wait for a paradigm shift, more babies develop and die from NEC.” What do you think that paradigm shift will be? Is it family involvement, as the NEC Society promotes, or something else?

Mark Underwood: What we know is that empowered families advocating for their baby improve outcomes. Parents often notice subtle changes before the care team does, and their presence makes a difference—not just for NEC, but for many outcomes in the NICU. I also think shaping the intestinal microbiota early is an exciting paradigm shift. I’m confident we’ll develop rapid tools to assess a baby’s gut bacteria and make timely adjustments. I sometimes think about what physicians 20 years from now will say about what I’m doing today—I suspect half of it will be wrong, I just don’t know which half.

In the 1980s, people tried giving oral antibiotics that stayed in the gut, and it worked, but we stopped because of the risks of overexposure. The idea of identifying a baby heading toward NEC before symptoms appear is compelling. Biomarker research, which will be featured at this year’s symposium, is another exciting step in that direction.

Ben Courchia MD: Dr. Underwood, thank you so much for your time, your insights, and your tireless work to prevent NEC. To our listeners, please consider joining us at the NEC Symposium in Chicago. Visit necsociety.org, and don’t forget to use the code incubator for a discount. Together, let’s keep building a world without NEC.

Mark Underwood: Thank you, Ben.