One of the most challenging parts of navigating an HIE diagnosis is that there are many possible causes—and often, there aren’t clear answers about what caused it or how it will affect a baby or child.
Dr. Monica Arroyo, a pediatric neurologist at Joe DiMaggio Children’s Hospital in Florida, shares that clinicians deeply understand how painful that uncertainty can be. In many cases, the care team will walk through every possible avenue—placental pathology, birth records, imaging, genetic testing—not just to gather information, but to try and understand why.
While not every family receives definitive answers, there are many clear-cut and known causes of HIE. Understanding them is often a key part of supporting families, guiding treatment decisions, and planning for the future.
Dr. Arroyo recently met with Hope for HIE to walk through the range of causes—from those that occur during pregnancy or delivery and into childhood—to help provide families with clarity, context, and a deeper understanding of what may have happened and why.
Missed the live Q&A? No worries. Like any good partner, we took notes and are willing to share!
And to understand neonatal encephalopathy, we should start with encephalopathy itself. It’s one of those terms that might sound intimidating, but at its core, it simply refers to a type of dysfunction in the brain.
Think of it like this: if you’ve ever heard someone talk about an adult who’s confused, lethargic, or having trouble walking, that might be an example of encephalopathy. It’s a term used to describe when the brain isn’t functioning as it should. Now, with babies – or neonatal encephalopathy – it may look like any behavior unlike that seen in a typical newborn, whether in how they’re moving, reacting to stimuli, or their overall level of alertness.
Now, here’s where things can get tricky: while HIE falls under the umbrella of neonatal encephalopathy, they aren’t the same thing.
Neonatal encephalopathy is a broad term that refers to a range of conditions that can cause brain dysfunction in newborns. HIE is the most common cause, but it’s far from the only one.
Sometimes, for instance, a baby’s presentation might look like HIE, but it’s actually due to a genetic condition affecting brain function, especially since genetics can influence things like alertness and movement and can even cause seizures. (If you’re intrigued and want to go down the genetics rabbit hole, here’s your ‘Pass Go’ card to head straight to Key Takeaway 4!)
Infections are another potential cause. A baby may acquire an infection in utero from the mother or after birth, and severe infections can lead to encephalopathy-like symptoms.
Then, there are cases of stroke, where a blockage of blood flow to part of the brain leads to similar signs of encephalopathy. The difference between a stroke and HIE? A stroke is a localized, vascular blockage. HIE is a global block of oxygen and blood flow that can impact different parts of the brain.
The list of potential causes can go on, and while it’s not a truth we particularly enjoy, we know that many things can go wrong when it comes to childbirth. After all, as Dr. Arroyo points out, giving birth is hard, and being born is hard. So, it makes sense that the list of potential causes can get a bit muddled when things don’t go as expected.
So, if HIE is under the umbrella of neonatal encephalopathy, then why does this distinction matter?
It matters – and for so many reasons. Primarily? It directly impacts treatment decisions. When clinical stories, signs, and data—like blood gases showing hypoxia (low oxygen levels) and acidosis (excess acid in the blood)—point to HIE, it opens the door for therapeutic hypothermia (known as cooling.)
If it’s not HIE, then cooling may not be the most appropriate treatment. That said, there are moments when providers might still recommend cooling as a precautionary measure, especially when they’re uncertain. As Dr. Arroyo points out, the potential benefits of therapeutic hypothermia could still help reduce brain damage, even if the root cause of the encephalopathy isn’t definitively HIE.
But here’s why this distinction really matters: every family deserves clarity. Getting a clear diagnosis makes all the difference—not just for making informed decisions, but also for the emotional journey of navigating this experience.
In cases where we don’t have a clear clinical picture, there’s no obvious sentinel event—defined as a situation where there’s a clear clinical picture before the event (everything seems normal) and a clinical picture after the event (suddenly, something is wrong)—or when the signs don’t add up, this is where providers go on a mystery hunt. And more often than not, that hunt leads us toward genetics for answers. As Dr. Arroyo aptly calls it, genetics is the next frontier in medicine—it can help us understand what we don’t yet fully grasp.
(And sometimes, even when a sentinel event is present or if the presentation doesn’t seem to fit the typical HIE profile, genetic testing can offer new insights!)
In fact, genetic testing has become more routine in cases of suspected HIE. Many research centers and clinical hubs are now incorporating it into their practice. For instance, some families participate in the Neonatal Seizure Registry (NSR) and its genetic study, NSR-Gene, where researchers explore genetic factors that could contribute to neonatal brain dysfunction.
There’s been growing interest in expanding genetic testing to all consenting babies, as seen in clinical trials like the HEAL study. This study found that about 5% of cases previously suspected to be HIE actually had a genetic component. A smaller cohort analyzed by Dr. Christian Parobek revealed an even higher percentage—up to 20%—of babies with suspected HIE who had a genetic cause.
So, who is Dr. Parobek, and what is his research about? Super glad you asked. We’ve hosted a Q&A with him before, but here’s a quick breakdown: Dr. Parobek’s research focuses on genetic expression—not necessarily in terms of “bad” genetics or conditions, but on how the genes interact and work together during a baby’s development.
He hypothesizes that some babies may have a genetic predisposition that makes them more vulnerable to complications during labor and delivery, like HIE. What’s particularly exciting is that Dr. Parobek believes we could identify these genetic markers through prenatal testing, allowing us to recognize babies who are most at risk of HIE early on and provide an opportunity for tailored interventions during labor to potentially prevent brain injury before it happens.
Okay, let’s do a quick progress check. We’ve covered neonatal encephalopathy versus HIE and why understanding the difference is so important. Now, let’s get into where HIE might begin—in utero.
Now, to make sense of this, we need to talk about the lifeline of a developing baby: the placenta. The placenta is responsible for providing oxygen and nutrients to the baby, but many things can affect how well it functions. There could be a genetic abnormality with the placenta, or an infection could interfere with its ability to do its job. Stress, diabetes, and high blood pressure can also affect how the placenta grows and works.
Here’s one of the frustrating realities about the placenta: it’s often working behind the scenes, and during routine checkups, it’s not always easy to tell if it’s functioning perfectly. In fact, for some babies, it’s only after an HIE presentation that it becomes clear that the placenta wasn’t working as it should have been.
And then there’s the umbilical cord, another critical part of that lifeline. The cord can become compressed or tangled, and some uteruses are shaped in ways that increase the risk of cord compression. The baby’s movements might temporarily relieve the pressure, but intermittent compression can still affect blood flow to the baby. While this may not be enough to cause a long-term problem, it could be enough to lead to HIE in certain situations.
We often hear from families who say, “Everything seemed fine during pregnancy until it wasn’t,” and that’s because, in many cases, these issues simply can’t be predicted. We can’t always pinpoint what went wrong, and that uncertainty can be incredibly frustrating. For us, it means doing the work —through research, advocacy, and more—to reduce future incidences of HIE and provide families with the answers and support they deserve.
But we’re not the only ones. The NIH Human Placenta Project is also making strides in this area. For those who may not know, this research initiative aims to better understand how the placenta develops and functions in real time during pregnancy. The goal? To identify early markers of placental dysfunction that could contribute to complications like HIE, preeclampsia, preterm birth, and more.
This project uses advanced imaging tools, including high-resolution MRIs and biomarkers, to track the placenta’s health and performance throughout gestation.
One particularly exciting development is that some families involved in the NIH Placenta Project are participating in MRI scans during subsequent pregnancies, which may provide valuable insights into how to track and manage high-risk pregnancies more effectively, potentially preventing HIE before it even has a chance to occur.
… More often, it’s a combination of factors that we’re only just beginning to understand.
Childbirth is incredibly complex, and even with the best preparation and care, things can still go wrong. Dr. Marc Scher has spoken to us about the idea of fetal reserves—the baby’s ability to tolerate the natural stress of birth, which is inherently a hypoxic process. Birth is supposed to be stressful, physiologically. But at what point does that stress cross a line into HIE? That line isn’t always clear, and it’s often not one single event. More often, it’s a combination of factors that gradually increase the risk and overwhelm a baby’s ability to recover.
Let’s start with the birthing parent. Several medical situations that impact both parent and baby can develop during labor or delivery. These include:
Now, shifting focus to the baby—there are also several ways things can go wrong during labor and delivery:
Dr. Arroyo also says that labor duration is another factor, as prolonged labor can create additional stress on the baby. Neurologists, who are often consulted after the fact, she says, may not have access to every detail of what unfolded during delivery—how long the baby was in distress, what the heart rate tracings looked like, or exactly when things began to turn. But we hear similar stories over and over from families, most with the recurring theme that everything was fine —right until the finish line.
That’s why collaboration between specialists—obstetricians, neurologists, neonatologists—is so important. Each birth story is an opportunity to learn more. It’s why ongoing research is so vital. The more we understand about the timing, the causes, and the interplay of different risk factors, the better chance we have to prevent HIE from happening in the first place.
One of the most distressing situations clinicians and families can face is when a baby seems perfectly healthy at birth—good Apgar scores, reassuring blood gases—and then, out of nowhere, has a seizure 12 to 24 hours later. These cases fall under what’s called SUPC, or Sudden Unexpected Postnatal Collapse, and they account for about 5% of neonatal HIE cases.
These are the babies who didn’t show any apparent signs of distress during delivery. And because of that, it’s unsettling for everyone involved when something goes wrong hours later. Clinicians ask themselves: Did we miss something? Could this have been prevented? And parents are often left wondering the same.
In these cases, the investigation begins. A full workup is done to rule out every possibility. Genetics often becomes a key part of that process (and referrals to genetics are strongly recommended, especially by Dr. Arroyo). But even with everything modern medicine has to offer, the truth is, sometimes we don’t get clear answers.
Another obstacle in these situations is that the placenta— which, if you recall, is a great resource of potential clues—is sometimes discarded before anyone realizes it might be needed. That leaves families and care teams stuck, trying to piece together what happened without one of the most important parts of the puzzle.
Sometimes, it’s not until the baby has an MRI that we even start to see a clearer picture. We might find signs of inflammation, but that still raises more questions: Is this from the seizures? Was it already there? Without the full clinical story, connecting the dots becomes incredibly difficult—and it can take months to sort out.
Studies like the CoolPrime study, which explores the effectiveness of cooling for mild HIE, are helping push the field forward.
We’re also beginning to look more critically at how newborns are screened. At birth, we check every system—heart, lungs, reflexes—but not the brain. As more data comes out, there’s hope that screening practices might evolve to help us catch more subtle cases earlier, giving more babies the chance to receive therapeutic hypothermia when it could still help.
While most conversations around HIE focus on what happens during or shortly after birth, there’s another side to this diagnosis—pediatric-acquired HIE. In these cases, the brain injury occurs after the newborn period, many times in a child who was previously healthy.
These events can stem from a variety of causes: cardiac arrest, severe respiratory illness like pneumonia, choking or near-choking, and one of the most common—near-drowning. The term “near-drowning” refers to situations where a child was submerged under water and survived, but the brain may have been without adequate oxygen for a significant period.
Encouragingly, there’s new momentum in the research world to better understand this population. A new Pediatric Neurocritical Care Workgroup is coming together to build a research agenda for pediatric-acquired HIE by bringing together multidisciplinary experts in neurology, critical care, rehabilitation, and beyond to identify priorities, share data, and drive innovation in care and outcomes. Until now, most research and resources have focused on neonatal cases—but these children and their families deserve just as much attention, support, and study. This shift is long overdue.
We’re excited to be connected with researchers who are finally giving this group the focus it deserves—and if you’re part of this community and want to get involved, we’d love to hear from you.
We’re human. We want definitive answers. Families want—and deserve—them, too. Understanding the cause can impact healing, closure, and decisions around future pregnancies.
Depending on the reason for the HIE, a family might be considered at higher risk—or, reassuringly, not at all. That’s why conversations with Maternal-Fetal Medicine (MFM) specialists can be so valuable. These high-risk obstetricians can review placental pathology, birth records, and your unique medical history to help create a plan for the future. They often spot patterns or clues that others may have missed.
We’ve seen many families go on to have healthy pregnancies after an HIE diagnosis—and we want that for anyone who desires it. A preconception consult with an MFM provider can be the next step to consider! They can walk you through what’s known and possible and what might need closer monitoring. It’s about building a plan that reflects your physiology and history—with the best information we have today to give you more clarity in the future.
Dr. Arroyo recommends the following resources to learn more about HIE, including its potential causes, impacts, and outcomes, as well as support options for families navigating diagnosis, care, and life after HIE.
A final note from Dr. Arroyo:
The truth is, the literature isn’t always caught up to what families are experiencing on the ground. Sometimes, families find research studies or articles before the medical community does—so share what you’re reading and learning. If it’s within the scope of what can be explored, the team will dive into it together.
And that’s what Hope in Action is all about — community and advocacy coming together to drive progress.
To watch the full Q&A, visit our 2025 Awareness Month Playlist on YouTube, and click the button below for our key takeaways at a glance!
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