# Background on NE and hypoxic ischaemic encephalopathy (HIE)

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:caption: Neonatal encephalopathy (NE)

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:caption: Identifying HIE

summary
neo_out_cooling
neo_out_hie_diagnosis
neo_out_blood
neo_out_sentinel
neo_out_resus
neo_out_meconium
neo_out_care
neo_out_cp
neo_out_mri
neo_out_enceph_symptoms
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`````{admonition} Executive summary
:class: info

**Neonatal encephalopthy (NE)**:
* NE refers to neurological dysfunction in late pre-term or term infants, characterised by seizures, impaired consciousness, respiratory difficulties and reduced tone.
* Causes include hypoxia-ischemia, stroke, infection, intracranial hemorrhage, congenital anomalies, neurometabolic and genetic factors. NE can have a single or multiple causes.
* Approximately 1 to 6 per 1000 term births have NE. In more than half, the cause is unknown. The most common cause is hypoxia ischaemia (referred to as hypoxic-ischemic encephalopathy).
`````

## Broad definition of NE

Neonatal encephalopathy (NE) refers to brain disease, damage or malfunction in infants, with the broad clinical definition of NE being that it is:
* A neurological syndrome
* In infants born at or beyond 35 weeks of gestation (late pre-term or term)
* Characterised by:
  * Seizures
  * Impaired levels of consciousness
  * Difficulties initiating and maintaining respiration
  * Reduced tone and reflexes[[DEFiNE - Molloy et al. 2023]](https://doi.org/10.1038/s41390-023-02775-z)[[COHESION - Quirke et al. 2013]](https://doi.org/10.1038/s41390-023-02938-y)

## Causes of NE

Possible causes of NE include:
* **Hypoxia ischaemia** (most common cause, "hypoxia" means low levels of oxygen in blood flowing to tissues, and "ischaemia" means blood flow (and therefore oxygen) is restricted/reduced to tissues) (this has sometimes been referred to as asphyxia, perinatal asphyxia, or birth asphyxia - but these terminology are not recommended) (when this is the case, it is referred to as **hypoxic-ischemic encephalopathy**)
* **Perinatal/neonatal stroke** (ischemic perinatal stroke (IPS) is the leading known cause of hemiplegic CP [[source]](https://doi.org/10.1016/j.gpeds.2022.100025))
* **Infection** (chorioamnionitis)
* **Intracranial haemorrhage** (bleed in the skull/brain)
* **Congenital brain anomalies/malformations** (brain 'abnormalities present at birth that can result from developmental disruptions at various embryonic or fetal stages'[[source]](https://doi.org/10.1016/j.spen.2022.100973))
* **Neurometabolic** (extensive and diverse set of neurometabolic disorders that can impact the neonatal prain, presentation is non-specific and can mimic acquired things like HIE and sepsis. They are rare, and are primarily genetic disorders leading to disruption of enzyme activity, cellular transport, or energy production [[source]](https://journals.lww.com/topicsinmri/fulltext/2018/08000/neurometabolic_disorders_of_the_newborn.1.aspx))
* **Genetic and epigenetics factors**[[COHESION - Quirke et al. 2013]](https://doi.org/10.1038/s41390-023-02938-y)[[Source - NHS East of England Guidelines for Management of Infants with Suspected HIE]](https://www.eoeneonatalpccsicnetwork.nhs.uk/wp-content/uploads/2021/10/HIE-Guideline.pdf)

NE **does not have to have a single cause** - for example, you could distinguish between hypoxia-ischaemia alone, a combination of other etiologies with hypoxia ischaemia, or non-HI-related etiology.[[DEFiNE - Molloy et al. 2023]](https://doi.org/10.1038/s41390-023-02775-z) 'Sentinel events such as cord prolapse, uterine rupture, or abruptio placentae may be clearly associated with HIE but often HIE is a **secondary** event. Therefore although hypoxia-ischemia may be involved, the exact cause of HIE is often not identified. Causes include cord prolapse, uterine rupture, abruptio placenta, placenta previa, maternal hypotension, breech presentation, shoulder dystocia'[[source]](https://doi.org/10.1053%2Fj.nainr.2011.07.004)

As commented by Steve Thornton, we need to consider both **infection** (chorioamnionitis) and hypoxia. Infection will make the effect of hypoxia worse. We may not be able to seperate them completely.

There have been several medical malpractice claims related to HIE. This list of causes from [Michigan Cerbral Palsy Attornerys](https://www.michigancerebralpalsyattorneys.com/causes-and-risk-factors-of-cerebral-palsy/labor-and-delivery-problems/hypoxic-ischemic-encephalopathy-hie/hypoxic-ischemic-encephalopathy-hie-infographic/) includes some examples that relate to that.
* Birth trauma - delayed emergency C-section, prolonged and arrested labour, post-term pregnancy, anaesthesia mistakes, intracrainal haemmhorage, fetal monitoring errors
* Abnormal size and presentation - cephalopelvic disproportion (CPD), breech presentation, face presentation, macrosomia
* Labour and delivery problems - miuse of oxytocin or cytotec, uterine rupture, placental abruption, umbilical cord problems (prolapse, compression, nuchal and short), placenta previa, uteroplacental insufficiency, premature rupture of membranes
* Maternal health problems - pre-eclampsia, polyhydramnios, oligohydramnios
* Infant health problems - fetal stroke, mismanagement of fetal respiration after delivery, mismanaged of fetal anemia after delivery

Note: Haven't checked all these - but for example of fetal stroke, from a quick google, it appears that HIE and neonatal stroke can often occur together, and that it seems more that the asphyxia is then a risk factor for stroke. Steve Thornton confirmed that HIE and stroke are related.

## Risks for and signs of HIE

Risk of HIE before birth is increased with observation of: 'decreased fetal movement, severe maternal cramping (often accompanied by severe back pain), abnormal fetal heart rate, abnormal contraction pattern, vaginal bleeding, abnormally low or high maternal weight gain, maternal high blood pressure'.

Signs and symptoms of HIE shortly after birth (in neonates) include: 'low Apgar scores at five or 10 minutes, seizures, difficulty feeding, breathing problems, hypotonia (low muscle tone), organ problems (failure, damage), acidemia (low pH in umbilical cord blood gas tests), abnormal response to light, state of abnormal consciousness (hyperalert or lethargic), coma'

'**In some children with HIE, especially those with mild to moderate HIE, obvious signs and symptoms of an oxygen-depriving event may not be present at the time of birth**... HIE may beconme more evident later in infancy.' Signs and symptoms of HIE during infancy and early childhood include: 'impaired motor function, delayed developmental milestones, seizure disorder, delayed growth, hearing and visual impairments'. [[Source]](https://hiehelpcenter.org/medical/identifying-hie/sign-symptoms/)

## Incidence

Below are some incidence estimates from a few difference sources.

NE:
* 'The reported incidence of NE from different studies ranges from about 2.0 to 6.0 per 1000 live births. The incidence of HIE ranges from about 1.0 to 8.0, excluding the estimate from Nigeria. There are, however, several difficulties in interpreting these figures. With the exception of the data from Derby, UK where three retrospective analyses were conducted using similar methods over a 20 year period no two sets of investigators used the same case definition for either NE or HIE. Furthermore, only two of the estimates of NE incidence and three of the HIE estimates come from studies which were population-based'.[[Kurinczuk et a. 2010]](https://doi.org/10.1016/j.earlhumdev.2010.05.010)
* 1.15 million infants per annum.[[COHESION - Quirke et al. 2013]](https://doi.org/10.1038/s41390-023-02938-y)
* Affects 2 to 6 per 1000 term births.[[Russ et al. 2021]](https://doi.org/10.1542/neo.22-3-e148), or in 1-3 per 1000 term births[[Hagberg et al. 2016]](https://doi.org/10.1016%2Fj.nbd.2015.09.011)

Unknown cause:
* In more than half of cases of encephalopathy, the cause is **unidentified**.[[Molloy et al. 2018]](https://doi.org/10.1038/s41390-018-0169-7)

Hypoxia ischaemia as cause of NE:
* Hypoxia ischaemia contributes to approximately 29% of neonatal encephalopathy.[[COHESION - Quirke et al. 2013]](https://doi.org/10.1038/s41390-023-02938-y)
* Hypoxic ischaemic encephalopathy accounts for 1.5 per 1000 term births.[[Russ et al. 2021]](https://doi.org/10.1542/neo.22-3-e148)
* Hypoxia ischaemia is known to be 'the sole instigator of encephalopathy in an estimated 7% of infants with NE. The Vermont Oxford Network Neonatal Encephalopathy Registry found that an asphyxia event accounted for 15% and inflammation 24% of cases of NE with other maternal etiologies also implicated'.[[Molloy and Bearer 2018]](https://doi.org/10.1038/s41390-018-0169-7)
* 'Some authors state that HIE is the cause of NE in 50%–80% of cases based on clinical, EEG, and MRI criteria.'[[Molloy and Bearer 2018]](https://doi.org/10.1038/s41390-018-0169-7)
* 'The incidence of HIE has not declined even with advances in obstetric care (i.e. fetal monitoring) aimed at preventing the hypoxic-ischemic event.'[[source]](https://doi.org/10.1053%2Fj.nainr.2011.07.004) Rapid recognition of and response to hypoxic ischaemia is extremely challenging for obstetricians.[[source]](https://doi.org/10.1576/toag.13.3.169.27669)
* The greatest burden of NE is in **low-middle-income** countries.[[COHESION - Quirke et al. 2013]](https://doi.org/10.1038/s41390-023-02938-y)

This section is in no way comprehensive - these are just a couple of random statistics from various sources in varying cohorts - on outcomes of infants with HIE:
* 'Around 20%–50% of infants with HIE die early in infancy, and 25%–60% of surviving infants have long-term neurological disorders such as cerebral palsy, epilepsy, intellectual disability, and learning disabilities'.[[source]](https://doi.org/10.3345/cep.2020.01459)
* In a study of mild HIE, 4.1% (17/414) infants had the composite outcome, whilst 0.9% (4786/504661) without HIE had it. Infants with mild HIE are four times as likely to be diagnosed with the composite outcome (HR 4.42, 95% CI 2.75–7.12) compared with infants without HIE (outcome was composite of cerebral palsy, epilepsy, intellectual disability and death up to 6 years of age)[[source]](https://doi.org/10.1111/1471-0528.17533)
* By the age of 2, 40 to 60% of infants with HIE will either die or have severe disabilities.[[source]](https://doi.org/10.1053%2Fj.nainr.2011.07.004) These include:
    * **Intellectual disability**
    * **Epilepsy**
    * **Cerebral palsy (CP)**

## Interventions

Used widely: **therapeutic hypothermia** - see more [on this page](../outcomes/neo_out_cooling.md)

Being investigated: **Magnesium sulfate** (MgSO<sub>4</sub>) -
* Recent systematic review and meta-analysis of MgSO<sub>4</sub> randomised trials concluded that there was minimal evidence on long-term outcomes, but that it may improve short-term (in-hospital) outcomes without affecting mortality
* Majority of trials gave 3 doses of MgSO<sub>4</sub> within 6 hours of birth [[Gowda et al. 2023]](https://doi.org/10.1016/j.jpeds.2023.113610)

## Economic burden and medical malpractice

* 'HIE is the leading neonatal condition referred to pediatric neurologists, accounting for approximately 38% of new consultations.'
* 'The economic burden of the long-term effects of HIE is estimated to be $1.2 million over the lifetime of a child with' cerebral palsy
* 'When a diagnosis of HIE is potentially associated with the medical care provided during birth, it may result in a civil lawsuit alleging negligence. One-third of obstetrical malpractice claims are associated with neonatal neurological injuries. The primary factors leading to malpractice claims include failing to 1. account for poor obstetrical history (e.g. history of miscarriage or stillbirth); 2. predict fetopelvic or other disproportion; 3. act when admission findings, such as abnormal fetal heart rate, suggest a distressed or compromised fetus; 4. recognize when labor is not progressing; 5. diagnose a malpresentation or malposition; and injudicious use of oxytocin, delay or failure to diagnose fetal distress, delay in cesarean or operative delivery, and substandard operative delivery technique. These factors indicate that a fundamental issue in preventing HIE is the recognition of magnitude of individual risk factors, and how risk may accumulate when multiple risk factors are present.'[[Leith et al. 2024]](https://doi.org/10.1016/j.annepidem.2023.11.011)