New Study Explains Why it is Sometimes Difficult to Pinpoint Oxygen Deprivation-Related Brain Injuries Such as HIE in Preterm Babies

Summary: New research in Clinical Perinatology explains the difficulty of diagnosing hypoxic-ischemic encephalopathy (HIE) injuries in premature babies. The study describes differences in the causes, mechanisms, signs and symptoms of brain injuries in babies of different gestational ages, and points out similarities and differences in babies that are full-term, more mature preterm babies, and extremely preterm babies.

Why is this important? We know that babies’ brains develop in different ways as they grow, and that very premature babies are at a much higher risk of brain injury because their brains are still in the process of developing and are very fragile. Understanding the underlying mechanisms of different types of brain injuries in premature babies is a very technical and complex feat, but it allows us to better identify infants that are at risk of hypoxic-ischemic encephalopathy, and – critically – helps clinicians determine whether certain treatments (such as hypothermia therapy, or brain cooling) will be effective in helping premature babies.

What Do we Know about Hypoxic-Ischemic Encephalopathy (HIE) Already?

Much of the information we know regarding hypoxic-ischemic encephalopathy (HIE) comes from studies done on infants that are 36 weeks or older (babies that are at term or near term). We know that hypothermia therapy is effective in helping babies that are 36 weeks or older to recover from hypoxic-ischemic injuries. These injuries are typically severe, and can impact a baby’s cognitive, motor or sensory development permanently. The importance of existing hypothermia therapy studies do two things: (1) they demonstrate the efficacy of the treatment, and (2) they show that the severity of oxygen deprivation injuries in babies can be muted. This has resulted in more funding and testing of other ‘neuroprotective’ therapies that researchers hope will be able to heal and/or prevent oxygen deprivation injuries in the future. This is exceptionally important, as studies show that 63% of infants that do not get hypothermia therapy either die or show signs of disability.

To ensure that hypothermia therapy is being given to infants correctly, there are certain guidelines (‘standards of care’) that medical staff have to follow when it comes to prescribing hypothermia therapy to a baby. Current guidelines state that the only babies that should be getting hypothermia therapy (brain cooling) are those that are 36 weeks or older. However, 2.8% of infants under 36 weeks received hypothermia therapy in the TOBY registry, while 5.8% of infants in the Vermont Oxford registry (2006-2011) received brain cooling. Although the treatment was provided to this portion of babies, no data was collected determining whether or not treatment was effective. In the absence of hard evidence, it is likely that some portion of premature babies will be getting brain cooling.

This particular study is an overview of HIE injuries in preterm babies, ranging from extremely preterm babies to late preterm babies.

How is HIE Diagnosed?

HIE is a very complex diagnosis, and there are many factors that are taken into account before a baby can be diagnosed with HIE. First, medical staff must identify an event that could cause reduced fetal gas exchange (changes in oxygen and carbon dioxide levels), and the baby has to show physiological signs of that event. Functionally, this means that the baby must demonstrate signs of encephalopathy, a condition that indicates abnormal or disturbed brain function. Babies with HIE are diagnosed when they demonstrate clinical or biochemical indicators of lowered gas exchange between the placenta and baby; if the baby shows biochemical indicators, hypothermia therapy is only given when the baby has moderate or severe encephalopathy. These criteria add up to a ‘tiered’ approach to diagnosis.

The Difficulties of Diagnosing HIE in Preterm Babies vs. Term Babies

Preterm_infant_with_ventilatorThere are some issues with having a tiered diagnostic approach, however, especially when it comes to preterm babies (‘preemies’). The younger these premature babies are, the more problematic the diagnostic criteria for HIE. The difficulty with diagnosing hypoxic-ischemic encephalopathy in preterm babies is that factors that doctors use to diagnose HIE in term babies might not necessary apply the same way to preterm babies. Signs that research demonstrates is a definite result of HIE in term babies are sometimes just a result of prematurity in preemies who show the same clinical issues. For example, low Apgar scores and/or a need for resuscitation or intubation at birth is commonly a sign of HIE in a term baby, but preterm babies tend to have generally lower Apgar scores already due to prematurity. Extremely premature and moderately premature babies commonly need intubation and mechanical ventilation. In term babies, these are often signs of HIE, but in preterm babies, this can be simply a result of physiological immaturity: these babies often don’t have lungs that are developed enough to be able to breathe on their own. This means that it can be very difficult to tell if certain negative events (like the need for breathing help) in a preterm baby are due to hypoxic-ischemic encephalopathy or are simply a result of preterm disease or transitional physiology. This is a crucial distinction to make, because different root causes of particular events can require different interventions. Properly selecting an intervention is dependent on understanding the underlying cause of a particular issue.

There Are Different Types of Encephalopathy, and They Can Have Different Root Causes in Term vs. Preterm Babies

In term babies, the presence of encephalopathy (characterized by lethargy, stupor, coma, hypotonia or flaccidity, decreased movement, loss of primitive reflexes, or breathing difficulties) indicates that there was hypoxia-ischemia (low oxygen and compromised blood flow) that leads to HIE. Examinations of preterm babies without hypoxia-ischemia shows that preterm babies can have these clinical signs even if hypoxic-ischemic encephalopathy isn’t present. This makes evaluating HIE somewhat difficult in preterm babies. Neurological evaluations show that there is a spectrum of maturation in preterm babies, so it is potentially possible to extend the diagnosis of HIE to more mature preterm babies that have umbilical cord metabolic acidosis (a sign of hypoxia-ischemia), but this evaluation criteria gets murkier the more premature the baby is. Extremely premature babies can have ‘encephalopathy of prematurity,’ which is marked by periventricular leukomalacia (PVL) and resulting injury to the cerebral cortex, thalamus, basal ganglia and white matter.

We know that preterm babies are more susceptible to hypoxia-ischemia, but the way hypoxic-ischemic events occur are different in full-term babies and preterm babies. In term babies, hypoxia-ischemia happens before or during birth as a result of impaired gas exchange that can occur due to a variety of factors (either a combination of uterine environment and fetal characteristics, or serious birth-related emergencies like placental abruption, umbilical cord prolapse or cord compression). In preterm babies, the risk for hypoxia-ischemia can stem from these factors, but can also stem from prematurity-related breathing issues that tend to be most severe in the first few days after birth. Because preterm babies are at a far greater risk of hypoxia-ischemia from events resulting both before, during and after birth, this can make pinpointing the exact time of a hypoxic-ischemic event much harder. Furthermore, preterm babies can suffer hypoxia-ischemic from non-birth-related health issues like sepsis, necrotizing enterocolitis, infections, apnea and bradycardia, or anemia. These risk factors increase the chances that a preterm baby will have multiple hypoxic-ischemic events compared to a term baby.

Identifying Encephalopathy in Preterm Infants Is Difficult; Alternate Tools Are Being Investigated

Because the presence of encephalopathy in a preterm baby by itself is not enough to demonstrate that a baby has HIE, researchers are investigating other ways of pinpointing whether a baby has HIE or not. One potential method is called amplitude-integrated electroencephalography (aEEG), thought this method also has its limitations: premature babies have different aEEG tracings and defining what an abnormality looks like in these tracings can be difficult, because the aEEG patterns of premature infants look similar to those of abnormal tracings of term infants. It can also be difficult to use aEEG as a diagnostic tool for premature babies because preterm babies of the same gestational age have very similar aEEG readings. Researchers have identified new ways of evaluating preterm babies’ neurological dysfunction as an important area of study, including serum biomarkers that indicate neurovascular issues and the presence of generalized inflammation in the baby’s brain.

What does HIE look like in an infant at term vs. a preterm infant?

HIE can look very different in a term baby vs. a preterm baby, as different parts of the brain are more likely to be injured at different stages of the developmental process. The following signs indicate the presence of HIE in infants:

Signs of HIE in an Infant at Term

At term, HIE primarily manifests itself in three ways:

  • Selective neuronal necrosis
  • Parasagittal cerebral injury
  • Focal ischemic necrosis in a vascular distribution

The pattern of injury depends heavily on the extent and duration of the asphyxia as well:

  • In total or complete asphyxia, the areas primarily injured are the thalamus and brainstem
  • In partial, prolonged asphyxia, the injury is spread out across a larger area, including:
    • The basal ganglia
    • Parasagittal aspects of the cerebrum (paracentral cerebral cortex and associated white matter) representing watershed injury between major vascular arteries
    • Cerebral white matter (In milder asphyxia)

Of course, the severity of the injury depends on numerous factors, including the duration, severity and number of times a hypoxic-ischemic event occurred, as well as the susceptibility of the fetus to hypoxia-ischemia. Because the severity of HIE depends on so many different factors, the injuries can range from isolated focal white matter injury to complete hemispheric devastation.

Signs of HIE in a Preterm Infant

In a preterm infant, HIE manifests itself very differently than in a term infant, with most of the injury being periventricular leukomalacia (PVL), an injury to the brain’s white matter. This is especially common in infants 23-32 weeks old. There are different kinds of PVL, but the one seen most commonly in current practice is diffuse PVL that can be detected by MRI but not by ultrasound. The PVL injury is caused  by interrupted growth of oligodendrocytes at the pre-oligodendrocyte stage, resulting in decreased brain myelination. In the brains of extremely preterm infants under 29 weeks, the vast majority of the oligodendrocytes are at this stage; these cells are extremely sensitive to hypoxia-ischemia and inflammation, both of which are triggers of white matter injury. With extensive injury, all cell types (oligodendrocytes, glia and axons) are impacted, causing cysts to form. One particular researcher by the name of Volpe dubbed this specific kind of encephalopathy “encephalopathy of prematurity,” characterized by both gray matter lesions and diffuse white matter injury.

Signs of HIE in Extremely Preterm Infants

Extremely preterm infants are not only susceptible to PVL, but also to intracranial hemorrhages (ICH). Extremely preterm babies have more limited ability to autoregulate their blood pressure, and the amount of autoregulation decreases the younger the preterm baby is. The factors that combine to make blood pressure a problem for preterm babies are most dangerous in the first few days after birth when morbidities of prematurity are most severe. This reduced ability makes the brain more vulnerable to changes in systemic blood pressure, venous pressure and blood gases, which in turn make the brain more prone to bleeding.

What We Don’t Know About Brain Injury in HIE as It Relates to Prematurity

While we do have some knowledge regarding what HIE looks like in preterm infant, there are several unanswered questions about moderate to late preterm babies.. Specifically, we do not know whether the pattern of brain injury in moderate to late preterm infants exactly resembles that of term infants (selective neuronal necrosis) or preterm infants (arrest of pre-oligodendrocyte maturation and PVL). We know that PVL can occur in late preterm babies as well as in term babies.

Imaging Hypoxic-Ischemic Brain Injury in Term vs. Preterm Babies

Imaging Term Babies with HIE

Term babies with HIE are usually imaged using MRI to detect selective neuronal necrosis caused by HIE. Studies show that one of the signature injury patterns occur in the basal ganglia-thalamic region (with or without white matter damage), and that brainstem involvement is less commonly imaged because brainstem injuries usually result in a high mortality. Depending on the severity of the injury, there is a hierarchy of injury, ranging from (milder) isolated cerebral lesions to abnormalities in the basal ganglia-thalamic regions to the most severe hemispheric devastation.

Imaging Preterm Babies with HIE

With preterm infants, medical staff also use MRI for imaging, though this imaging is done at term age equivalent. This allows physicians to determine whether a baby’s brain has signs of white matter signal abnormalities  or other features of diffuse PVL, such as:

  • Loss of volume
  • Cysts
  • Enlarged ventricles
  • Thinned corpus callosum
  • Delayed myelination

Because this imaging is done at term age equivalent, the imaging shows a brain injury that is no longer evolving. Studies of serial MRIs show different results at different times: early imaging shows a predominance of destructive lesions such as brain bleeds, while imaging at or after 36 weeks shows diffuse excessive high signal intensity in white matter. This is typically a marker of the existence of injuries in other parts of the brain. Diffuse white matter injury is also associated with reduced volume of cerebral gray matter and myelinated white matter, and an increase in cerebral volume. Thus far, the differences between what these injuries look like in moderate to late preterm babies is still somewhat unclear. Some evidence indicates that diffuse PVL is common in this population, while other evidence fails to confirm this. Some studies indicate that moderate and late preterm babies have white matter abnormalities, smaller brains and an immature gyral pattern in comparison to term babies, but the clinical significance of these findings is unclear.

Imaging Preterm Babies with Clear HIE Sentinel Events

There is less  information available regarding imaging for preterm infants with well-known and well-described HIE. One study found that major locations of injury included the thalami, basal ganglia, and cerebellum (with a relatively spared cortex). Along with this injury there was evidence of reduced cerebral hemispheric white matter and shrunken basal ganglia, thalami, brainstem, and cerebellum. A different study found that major injury sites included severe injury to the basal ganglia and thalami, and mostly mild and diffuse injury of the white matter, brainstem and cortex. Severe white matter injury was uncommon, but (when present) was associated with basal ganglia/thalamic lesions. Overall, preterm babies with a clinical diagnosis of hypoxia-ischemia at birth may have altered brainstem function, suggesting that profound asphyxia in a preterm baby leads to abnormalities that may differ from PVL and approximate the term brain injury pattern. Less severe hypoxic-ischemic events may trigger noncystic PVL.

How Common Is HIE in Preterm Babies?

Overall, it is more difficult to determine precisely how common HIE is among preterm babies. Firstly, most of the available data looks at more mature gestational ages. Second, existing studies are mostly retrospective and focus mostly on moderate to severe encephalopathy; there is little to no data available on extremely preterm infants. These studies also stipulate inclusion criteria differently so there may be some uncertainty in terms of how different criteria are defined. One study placed the incidence of moderate to severe encephalopathy at 1.4 incidents per 1000 live births, while other studies place the numbers closer to 9/1000 or 5/1000 live births. Over, the incidence of HIE in preterm babies is more difficult to assess.

The Most Important Question: Can Hypothermia Therapy Help Preterm Babies?

We know that hypothermia therapy is useful in protecting the brains of term infants older than 36 weeks who have shown signs of hypoxic-ischemic encephalopathy, and is indeed the only therapy available to treat the effects of HIE. There have been very few trials that collected data on hypothermia therapy’s effect specifically on preterm infants. Data is thus far lacking about the treatment’s efficacy for premature babies, but further study is definitely justified.

Existing animal studies on the effects of head cooling on preterm birth demonstrated that hypothermia was associated with less neuronal loss in the basal ganglia and hippocampus, less loss of immature oligodendrocytes in the periventricular white matter, and less programmed cell death and inflammation compared with subjects that did not get hypothermia therapy. These studies mean that hypothermia therapy may provide neuroprotection to the oligodendrocytes, which are most susceptible to injury in extremely preterm infants. Some researchers suggest that hypothermia therapy should be extended to babies with HIE as young as 33 weeks.

Two studies have been done on hypothermia therapy in preterm infants; one study did not fulfill cooling criteria as used in randomized trials while another demonstrated poor outcomes and concluded that hypothermia should only be provided to preterm infants in the clinical trial setting.

Given the general absence of conclusive evidence, it is likely that hypothermia therapy will be extended to preterm babies as is; in light of this, the National Institute of Child Health and Development Neonatal Research Network is beginning studies of whole-body hypothermia therapy’s effect on moderate to late preterm infants between 33 and 36 weeks.

The key consideration in studying hypothermia in the context is preterm birth is safety. Babies nursed in cooler vs. warmer environments in the first 5 days after birth had a higher mortality and this principle was extended, resulting in the recommendation that babies not be given hypothermia therapy. Because preterm babies are known to be more susceptible to intracranial hemorrhages (though they are uncommon in more mature moderate to late preterm babies), and because hypothermia can change the way that coagulation and blood platelets work, there is a possibility that hypothermia therapy could increase brain bleeds. Other concerns include impaired oxygenation in preterm babies with severe respiratory difficulties, increased blood drug concentrations due to decreased metabolism, and immune system suppression which could result in greater infection risk.

Other Neuroprotective Strategies for Use in Extreme Preterm Babies

The methods for protecting the brains of extremely premature babies will be very different from moderate to late preterm babies because diagnosing and identifying the timing of hypoxic-ischemic injury remains very difficult, and because many of the injuries that premature babies are sensitive to are not necessarily a result of hypoxia-ischemia (such as infection, inflammation, drug toxicity, or nutritional issues). Furthermore, preterm babies are often hospitalized for long time periods, which make them vulnerable to NICU-related injuries such as late-onset sepsis, necrotizing enterocolitis, apnea and bradycardia, evolving bronchopulmonary dysplasia, or poor nutrition.

There are, however, certain therapies being used for very preterm babies of specific gestational ages other than hypothermia therapy. Extremely preterm infants may have a  higher rate of neurodevelopmental impairment, which means that there is a strong rationale from providing neuroprotection to all or the highest-risk infants within a specific gestational age range. Examples of such therapies include caffeine therapy for babies between 500-1250 grams whose clinicians considered them to be candidates for treatment, delayed cord clamping, and prophylactic indomethacin. One ongoing trial, the PENUT trial, is examining the use of EPO for infants ages 24-27 weeks in trial centers across the United States. These trials seek to determine whether there are other neuroprotective strategies for preterm infants that will reduce the rate of death or disability in this highly vulnerable population.

[Note: To read more about studies dealing with neuroprotection in babies with HIE, please see the following articles: Combination EPO/Hypothermia Therapy, Future Directions in HIE Treatment, Magnesium Sulfate Treatment for Neuroprotection, and Betamethasone Treatment for Premature Babies.]  

Summary: It is sometimes difficult to diagnose HIE in preterm babies because of numerous confounding factors and limitations in our current diagnostic capabilities. Researchers are currently investigating diagnostic methods and treatments to help clinicians identify and treat hypoxic-ischemic encephalopathy in preterm babies, but there are many factors that still require further investigation. Neuroprotective therapies provided over a longer timeframe might be appropriate for very preterm infants. When it comes to moderate to late preterm infants, questions remain regarding whether their brain injuries are closer in neuropathology to those of extremely preterm infants (diffuse white matter injury) or term infants (selective neuronal necrosis), which has implications for the kind of neuroprotective strategies that may be recommended. It is also still unclear whether the incidence of brain bleeds (intracranial hemorrhages) is higher in preterm infants with HIE. It is possible that hypothermia therapy may be useful for helping moderate to late preterm babies, but is very unlikely to be of use in extremely premature babies. Whatever neuroprotective strategies end up being used, safety will be a critical factor.

Legal Help for Preterm Babies with Oxygen Deprivation Injuries

If your baby was born prematurely and sustained a birth injury as a result, the birth injury attorneys at Reiter & Walsh ABC Law Centers may be able to help. We would be happy to speak with you about legal options for securing your child’s future care. Please reach out to us for a free and confidential case evaluation. If you choose to pursue a case with us, you will never pay fees out-of-pocket (we are paid on a contingency basis).

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Abbot R. Laptook, Birth Asphyxia and Hypoxic-Ischemic Brain Injury in the Preterm Infant, Clinics in Perinatology, Volume 43, Issue 3, September 2016, Pages 529-545, ISSN 0095-5108,

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Brain research is an ongoing process, and, at the moment, hypothermia therapy is the standard of care when it comes to hypoxic ischemic encephalopathy. Additive or supplemental measures in addition to hypothermia are still in preclinical or clinical trials, so it is too early to say whether any of these supplemental measures will be adopted as standards of care. Because these are highly experimental findings, we caution readers that we are merely providing this information as an update on findings in the field of HIE research, rather than as a potential source of treatment information. 

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