EQUINE VETERINARY EDUCATION
Equine vet. Educ. (2015)  () -
doi: 10.1111/eve.12467
Review Article
Perinatal asphyxia syndrome
J. R. Gold
Department of Clinical Sciences, Washington State University, Pullman, USA.
Corresponding author email: golddvm@gmail.com
Keywords: horse; asphyxia; hypoxia; neonatal maladjustment
Summary
Hypoxic ischaemic encephalopathy (HIE) has been
described in foals for over 80 years. This condition has a
diversity of names including ‘dummy foals’, ‘wanderers’,
‘barkers’, neonatal encephalopathy, neonatal maladjustment
syndrome (NMS) and perinatal asphyxia syndrome (PAS). The
latter descriptive terms are all encompassing for a syndrome
that has varying degrees of multi-systemic effects rather than
just neurological disease. While foals with PAS are commonly
reported in the literature, the aetiology and underlying
pathophysiology are still very poorly understood, with a
majority of the information extrapolated from human and
animal models. Currently, no antemortem test exists and
diagnosis is made based on the history of the mare and foal
as well as reliance on clinical signs. Recent studies have
shown that neuroactive pregnanes may play a key role in
the syndrome; however, further research is needed to
clarify these findings. Another investigation compared
neurobiomarkers for brain injury in both sick and normal
neonatal foals. The mainstay of therapy for PAS is supportive
treatment. Specific therapies such as antioxidants and
neuroprotectants are used by some clinicians but little
scientific evidence exists that proves the therapeutic
protocols implemented improve overall outcome. Prevention
of PAS in foals revolves around the health of the mare
including, but not limited to, the prevention of placentitis or
other illnesses and observation and/or intervention during
parturition when necessary. More research is necessary to
fully comprehend this syndrome, its diagnosis and treatment
options.
Introduction
Reynolds (1930) first described hypoxic ischaemic
encephalopathy (HIE) as an alteration in behaviour of
neonatal Thoroughbreds. Symptoms noted included seizures,
central blindness, loss of suckle and loss of affinity for the dam
(Vaala 1999). In 1968, Rossdale described the condition as
‘neonatal maladjustment syndrome’ (NMS), which pertained
to foals with behavioural dysfunction and disruption of normal
adaptive responses needed for survival (Rossdale 1972;
Rossdale and Leadon 1975). Hypoxic ischaemic damage to
the brain was thought to be the cause of NMS.
Over the next 25 years, neurological dysfunction was
considered to be the hallmark clinical sign of this syndrome.
Pathological findings associated with this syndrome identified
a variety of central nervous system (CNS) lesions which
included subdural, epidural subarachnoid, parenchymal and
nerve root haemorrhage of the brain and spinal cord
(Rossdale and Leadon 1975). Central nervous system
oedema and necrosis were also noted as well as hepatic
1
and renal lesions (Rossdale and Leadon 1975; Clement 1985).
Survival rate for foals at this time was about 50% (Clement
1985; Vaala 1994).
It has become evident over the last 15–20 years that many
foals with HIE experience varying degrees of multi-systemic
effects due to hypoxia rather than just neurological disease.
Thus, perinatal asphyxia syndrome (PAS) has become a better
descriptive term because it recognises cardiopulmonary,
endocrine, gastrointestinal and renal abnormalities, along with
the neurological and behavioural disturbances that can
occur in these foals (Vaala 2009). The incidence of PAS is
reported to be 1–2% of all foals born (Bernard et al. 1995).
In contrast to neonatal foals, HIE or neonatal
encephalopathy in man affects 3.8 of every 1000 live infant
births (Badawi et al. 1998; Cowan et al. 2003; Kurinczuk et al.
2010) worldwide. About 60% of infants with HIE die and 25%
of survivors are left with a significant neurological disability
(Ballet 2010). The most significant lasting disability in infants is
the development of cerebral palsy (Vannucci and Hagberg
2004). Cerebral palsy is defined as multiple disorders of the
developing fetal or infant brain affecting movement, posture
and muscle disorders (Rosenbaum et al. 2007). Cerebral palsy
affects 3.6 per 1000 human infant births in the United States
(Yeargin-Allsopp et al. 2008). Severely affected foals tend to
die similarly to their human counterparts but the long-term
prognosis for foals is generally much better than for man. The
reason for the disparity in survival and clinical signs between
foals and man is likely multifaceted. Foals are precocious and
therefore brain development is further advanced than in
human infants, thus hypoxia/ischaemic events may not
manifest in a similar fashion.
Pathophysiology
The pathophysiology of HIE, brain damage simply stated,
occurs due to a decrease in cerebral blood flow and
oxygenation which leads to a cascade of deleterious
physiological and biochemical events during the ante-, peri-
or post partum period. Multiple different factors may
contribute to the clinical signs associated with HIE. It is
important to understand that HIE is a specific category of
neonatal encephalopathy and not all cases are caused by
hypoxic ischaemia (Dickey et al. 2011).
Evidence exists in human infants that inflammatory
mediators may play an important role in the cascade of
events leading to neonatal brain injury (Badawi et al. 1998;
Shalak et al. 2002). Therefore, especially with mares which are
ill during pregnancy or have placentitis (a known risk factor
for neurological deficits in foals), it is plausible but not
confirmed that a fetal inflammatory response may play a role
in the development of PAS in foals (Vaala 1999).
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2 Perinatal asphyxia syndrome

The pathogenesis of hypoxic-ischaemic damage is
extremely complex and not totally understood in the foal or
the human infant. It appears that the central nervous system
suffers the greatest damage from hypoxia and neuronal cell
death occurs in 2 phases (Volpe 1996; Inder and Volpe 2000;
Grow and Barks 2002) (Fig 1). The final outcome is ultimately
cell death (Volpe 1996; Grow and Barks 2002).
The second phase is called delayed neuronal cell death.
It is associated with reperfusion injury (oxidative stress),
excitotoxicity, excessive intracellular calcium, activation of
enzymes and multiple pathways, cytotoxic actions of
microglia, inflammation and apoptosis (Volpe 1996; Inder and
Volpe 2000). Many of the delayed cell death mechanisms
are initiated during an acute hypoxic ischaemic event;
however, the deleterious effects are seen hours to days after
initial injury (Calvert and Zhang 2005). Intracellular calcium is
extremely deleterious to neurons and other types of cells.
Calcium has been thought to be a contributor of neonatal
encephalopathy and ischaemic-reperfusion injury and is
associated with activation of calcium-dependent cellular
pathways, cell or neuronal swelling, injury and/or death
(Volpe 2001; Mishra et al. 2002).
Microglia are also involved in hypoxic ischaemic
encephalopathy and are believed to be derived from
haematogenous monocytes and reside in the brain (Chew
et al. 2006). They enter the fetal brain during development.
The cells are found in both the grey and white matter of the
brain and account for up to 10% of all cell types (Dickey
et al. 2011). Microglia are either in a resting state or are
activated (under pathological conditions) and expand in
response to stimuli. The predominant cell type allocated in
the production of inflammation-mediated neurodegeneration
is thought to be activated microglia (Chew et al. 2006).
Activated microglia are also believed to play a pivotal part
in neonatal hypoxic ischaemic damage (Chew et al. 2006).
The evidence for the pivotal role of microglia in neonatal
hypoxic injury is supported by findings that the antimicrobial
minocycline inhibits microglia and has been proven to
significantly decrease brain damage in response to injury in
various animal models (Zemke and Majiid 2004; Plane et al.
2010). It is unclear at this time whether microglia play the
same central role in neonatal foals.
Recently, Drs Aleman and Madigan (Aleman et al. 2013)
described what may be a subgroup of PAS foals. Parturition is
normal in these foals and they show few clinical signs (i.e.
lack of attachment to mare, not suckling effectively) and
recover very quickly with no observed neurological or
behavioural deficits. This is in contrast to other animal models,

Hypoxic or inflammatory event

Open ionophore channels

Extracellular space

NMDA
receptor
Membrane depolarisation Intracellular space

Time
Damage to Inflammatory
Excitotoxicity
mitochondria mediators

Oxididative
phosphorylation
TNF-α
IL-1β
ATP
IL-6

Alteration in Anaerobic Ubiquitination Cytosolic Ca2+ Xanthine

membrane glycolysis accumulation
ion pumps
Accumulation of
damaged protein Activation of
pH Activation of phospholipases Proteases
Reactive oxygen
protein kinases A and C activation
species
Protein synthesis
Loss of cell Chromatin DNA Lipid
integrity condensation Protein Cytoskeleton fragmentation peroxidation
inactivation disruption

Membrane damage Membrane permeability

Fig 1: A schematic diagram summarises the cellular and molecular events that are triggered after hypoxic-ischaemic or inflammatory
injury in the developing brain.

© 2015 EVJ Ltd

J. R. Gold
some human neonatal hypoxic encephalopathy cases and
other PAS foals require a significant amount of time devoted
to recovery and long-term neurological deficits are noted.
Therefore, not all foals suffering from PAS may have a hypoxic
event but have other factors contributing to their behavioural
abnormalities.
Several other publications (Holtan et al. 1991; Houghton
et al. 1991; Rossdale et al. 1995) have shown that neonatal
foals have high concentrations of pregnanes at parturition
which decrease rapidly over the first 48 h of life (Holtan et al.
1991; Houghton et al. 1991; Rossdale et al. 1995; Aleman
et al. 2013). Increased concentrations of pregnanes and a
correlation between decreasing concentrations and clinical
recovery have been previously reported (Holtan et al. 1991;
Houghton et al. 1991; Rossdale et al. 1995; Aleman et al.
2013). The elevated pregnanes may be responsible for some
of the behavioural modifications seen in foals with PAS. The
exact reason why plasma pregnane values are increased in
these foals remains unexplained at this time but may have to
do with persistence of in utero signals of being quiet and
nonambulatory (Aleman et al. 2013).
Consequently, it is likely that multiple factors (e.g.
pregnanes, hypoxia, inflammatory mediators) contribute to
PAS in foals and for numerous reasons it is important not to
label all neurologically abnormal foals as having perinatal
asphyxia. As an alternative, each foal should be individually
evaluated by obtaining a good history and performing a
thorough diagnostic work-up.
Risk factors
Numerous different influences can lead ultimately to hypoxia
and the abnormalities noted in PAS foals. Maternal diseases
can cause hypotension or decreased tissue perfusion such as
respiratory disease, endotoxaemia, haemorrhage/anaemia,
surgery or caesarean delivery (Galvin and Collins 2004).
Pathology of the placenta impairs uteroplacental
oxygenation/perfusion such as with placentitis (bacterial,
fungal, endophyte), chronic uteroplacental separation, which
leads to chronic hypoxia in the fetus, or acute/premature
uteroplacental separation (Galvin and Collins 2004).
Placentitis and other maternal diseases may cause
inflammation as well as leading to the clinical signs seen in
foals (LeBlanc et al. 2002, 2004, 2013; Cummin et al. 2008).
Problems that may lead to hypoxia in the fetus/foal may be
twinning, congenital abnormalities, dystocia, meconium
aspiration, umbilical cord compression, sepsis, prematurity
and dysmaturity (Galvin and Collins 2004). Twin fetuses lead
to reduced areas of placentation available for perfusion to
each individual fetus and tend to predispose the mare to
dystocia and its associated complications (Galvin and Collins
2004). Therefore, multiple different factors (maternal, fetal or
both) may contribute to the development of PAS in foals.
Clinical signs
Foals with PAS have a variety of clinical signs; generalised
weakness, lack of interest in the dam, lack of suckle reflex,
inability to lie down, recumbency and seizures (Rossdale
1972; Rossdale and Leadon 1975). Manifestations in other
body systems may also be seen such as ileus, enterocolitis,
decreased cardiac output or decreased renal output
(Mackay 2005). Abnormalities of one organ system may
3
prevail over others or all systems may be involved depending
upon the degree of hypoxia (Galvin and Collins 2004;
Mackay 2005).
Due to the continuum of clinical signs possible in foals
with PAS, they have also been characterised into two groups.
Category 1 foals are born with normal mentation and
develop clinical signs within the first 48 h (Galvin and Collins
2004; Mackay 2005). Category 2 foals typically have risk
factors associated with PAS and are abnormal at birth
(Galvin and Collins 2004; Mackay 2005). Typically prognosis
for Category 1 foals is excellent for survival (Vaala 1999;
Mackay 2005) and for Category 2 foals there is a tendency
towards a lower survival rate because abnormalities are
usually worse and foals deteriorate within the first 48 h of life
(Vaala 1999; Mackay 2005). However, due to the
improvement of neonatal care, survival for both categories of
foals is likely increased from previously reported data.
Human infants with HIE are also broken down into
different groups. Their categories depend upon the length
and severity of disease. For example, an infant with mild
hypoxic ischaemic encephalopathy may have slightly
increased muscle tone and deep tendon reflexes may be
brisk for the first few day of life (Zanelli 2014). These infants
also have behavioural abnormalities such as poor feeding,
irritability or excess crying or sleepiness (Zanelli 2014). This
degree of HIE typically resolves in less than 24 h (Zanelli 2014)
and clinical signs worsen depending on the degree of HIE.
Many of these infants also have multi-organ dysfunction.
Paediatricians depend upon history, clinical signs, blood
gases and APGAR scores in human neonates to assess the
extent of hypoxic injury. An APGAR score has been modified
for neonatal foals and this scoring system, along with blood
gases and a detailed history of the dam, may help with
diagnosis and prognosis for neonatal foals.
Diagnosis
Diagnosis of PAS in foals thus far is very limited. Many of the
clinical signs seen in foals can occur with other diseases such
as neonatal sepsis, hypoglycaemia and prematurity.
Therefore, PAS can be the only problem in the neonatal foal or
can be complicated by other conditions. Haematology and
biochemistry profile, blood culture, arterial blood gases and
IgG concentrations can help identify failure of passive transfer
of maternal antibodies and other clinical problems such as
sepsis or issues with other body systems. The diagnosis of PAS
typically relies on an accurate history and identification of
neurological deficits while excluding other causes of central
nervous system problems such as congenital malformation,
infectious, metabolic or developmental conditions. At this
time, no clinicopathological findings have been specific for
PAS; however, Bernard et al. (1995) found that 32% of foals
with PAS had an increase in serum creatinine concentrations
and 61% an increase in creatine kinase concentrations
(Bernard et al. 1995). Furthermore, increases in serum
creatinine (>309.4 lmol/l) and/or low blood glucose
concentrations before suckling (<1.94–2.5 mmol/l) have been
associated with placental insufficiency and an increase in PAS
(Vaala 1999). A study by Chaney et al. (2010) found that 20/
28 foals with elevated creatinine had clinical signs suggestive
of PAS. Abnormalities such as hyperlactaemia, hypoxaemia,
hypercapnoea, acidosis and hypocalcaemia have all been
noted in foals with PAS; however, these laboratory
© 2015 EVJ Ltd
4 Perinatal asphyxia syndrome
abnormalities also arise from other neonatal foal diseases
(Vaala 1994; Furr 1996; Borchers et al. 2012).
A study by Ringger et al. (2011) showed the potential for
use of neurobiomarkers; ubiquitin C-terminal hydrolase (UCHL-
1) and phosphorylated axonal forms of neurofilament H (PNF-
H) as an aid in the antemortem diagnosis of PAS in neonatal
foals. The study found that UCHL-1 was significantly better at
diagnosis of neonatal encephalopathy then PNF-H with a
sensitivity of UCHL-1 of 70% and specificity of 94% (Ringger
et al. 2011). Although promising, the study only included a
few cases and measurement of neurobiomarkers are not
readily available at this time.
The study by Aleman et al. (2013) of elevated pregnanes
in PAS foals is also promising as stated earlier. However, more
work is needed to clarify the role of pregnanes and the
measurement of these concentrations is also not readily
available at present.
In human infants, magnetic resonance imaging (MRI)
tends to be the modality of choice for diagnosis of HIE. The
conventional T1- and T2-weighted sequences provide very
accurate anatomical detail; however, when injury to the
brain occurs, these type sequences may remain normal for
several days (Volpe 2001). Therefore, the diffusion-weighted
imaging (DWI) appears to be better at early detection of
perinatal brain ischaemia (Chau et al. 2009).
Despite the increased use of MRI in equine patients, only
one previous study has been performed which looked at the
normal neonatal foal (Chaffin et al. 1997). Another project
described MRI findings of 12 neurological horses, one of
which was a 2-day-old foal with a high suspicion of PAS.
However, this foal had severe hydrocephalus not PAS (Ferrell
et al. 2002). With the larger magnets in MRI and
improvements in CT imaging techniques, perhaps more can
be gleaned from MRI and/or CT in the equine neonate.
Ambulatory electroencephalograpy (aEEG) is a modality
used for continuous monitoring of electrical activity of
critically ill human neonates (Volpe 2001). Another diagnostic
modality which is not utilised in neonatal foals is
electroencephalography (EEG). In a recent study by Toth
et al. (2012), the authors looked at neonatal consciousness
where they utilised EEG without sedation to study the effect
of squeeze-induced somnolence. Although used for other
types of research, EEG has not been used to identify seizures
in foals with PAS.
Ambulatory electroencephalography has be shown to be
sensitive for early prediction of outcome of HIE newborn
infants (Hellstro€ m-Westas et al. 2006). Because aEEG provides
constant appraisal of cerebral function, it can show
electrographic seizure activity when no obvious clinical signs
are present. Thus the aEEG may provide evidence that
further injury to the brain may occur despite no clinical signs
of seizures.
One study has looked at using aEEG in ambulatory horses
(Wingberg et al. 2013) and Aleman et al. (2006) has utilised
EEG for research on juvenile epilepsy in Arabian foals but no
studies have been performed in PAS foals. Seizures in neonatal
foals vary from very subtle such as lip smacking or mild
stretching to the severity of grand mal seizures. A question that
remains is whether foals, like human infants, have suspected
seizures or abnormal movements shows seizure activity with no
clinical notable seizures. An aEEG might answer the above
question and increase our understanding of seizure pattern
and the potential response to treatment. However, this
© 2015 EVJ Ltd
modality would not be available to all practitioners and ability
to perform it is limited to those with the equipment and who
understand the reading. Accurate determination of seizure
activity is important because neonatal seizures caused by
birth asphyxia in the human infant are associated with a worse
neurodevelopmental outcome regardless of the severity of
hypoxic ischaemic brain injury (Glass et al. 2009).
Treatment
For neonatal foals and infants alike, therapy for neonatal
encephalopathy tends to be supportive care and the various
therapies instituted depend upon the multiple organ systems
involved. Typical treatments revolve around maintenance of
glucose, oxygen supplementation, maintenance of blood
pressure and seizure control as well as a variety of
antioxidants and neuroprotectants.
It is important to be aware that, although many therapies
exist for neonatal foals with PAS, use of these therapies
remains entirely hypothetical. No specific information exists
regarding the outcome of foals treated with the variety of
therapies implemented. Most therapies are adjunct to
supportive care and do not harm the foal per se but whether
they actually help is unknown.
Treatment for human infants like those of equine neonatal
foals is supportive care, as well as the use of hypothermia.
Hypothermia has been documented as a protective
mechanism in multiple medical circumstances such as organ
transplants, cardiopulmonary bypass, spinal cord injury and
neonatal hypoxic ischaemia (Tang and Yenari 2010). The
mechanism of action of hypothermia appears to not just slow
metabolism but potentially has an effect on cell death and
cell survival pathways which leads to inhibition of inflammation
and apoptosis (Globus et al. 1995; Tang and Yenari 2010).
Human infants with HIE are now treated with hypothermia as
the major treatment modality. It involves reducing the normal
body temperature to 33°C within 6 h of delivery which is then
continued for a total of 72 h. The infant is then gradually
rewarmed to normal body temperature over 12 h. The goal is
to decrease the temperature of the susceptible deep brain
structures to 32–34°C. Multiple studies show that hypothermia
decreases the risk of the combined outcome of mortality and
moderate to severe neurodevelopmental disability in infants
and children (Jacobs et al. 2007; Gressans et al. 2008).
However, hypothermia does not provide complete protection
and is not successful in the most severely effected neonates,
although in combination with other therapies remains the
most promising (Cilio and Ferriero 2010).
Little data exists on the use of hypothermia in neonatal
foals and several studies have shown neonatal foals actually
have a worse prognosis if hypothermic (Furr et al. 1997;
Rohrback et al. 2006). However, the foals in these studies
were hypothermic due to disease and were not hypothermic
for therapeutic reasons. Thus, therapeutic hypothermia should
not be ruled out as a possible treatment and further
investigation into this topic is warranted. Other treatment
modalities that may merit study in foals are melatonin and
desferrioxamine. Research in animal models of HIE have used
melatonin and desferroxamine which were found to be
beneficial as free radical scavengers (Palmer et al. 1994;
Shadid et al. 1998; Sun et al. 2004; Welin et al. 2007; Carloni
et al. 2008; McPherson and Juul 2008; Hutton et al. 2009;
Elmahdy et al. 2010; Fan et al. 2010; Wong et al. 2011).
J. R. Gold
Hyperbaric oxygen therapy has been studied in rat models of
HIE and has been shown to reduce apoptosis, promote
neuronal stem cells, enhance oxygen radical scavengers and
increase oxygen delivery to the brain (Calvert and Zhang
2007; Wang et al. 2008; Feng et al. 2013). In human infants,
hyperbaric oxygen has been shown to increase superoxide
dismutase; decreased levels of malondialdehyde and nitric
oxide which lead to improved neurological assessment (Zhou
et al. 2008). A study by Slovis (2006) in neonatal foals with PAS
also had positive outcomes.
Prevention
Although risk factors for the development of PAS have been
identified in foals, preventative measures need to revolve
around the health of the mare.
Placentitis prevention and treatment, decreasing
inflammatory mediators if the mare is ill during pregnancy
and observation of foaling and assistance when needed, are
the goals of prevention. Preventive measures for the foal
revolve around recognition of distress and initiating
appropriate therapy (e.g. respiratory support or
cardiopulmonary resuscitation).
As stated earlier in treatment methods, neurosteroids may
also become a preventative treatment for neonatal foals.
Research has recently shown that the brain is able to form
neurosteroids which have a protective role and may possibly
prevent neonatal encephalopathy (Hirst et al. 2008; Tsutsui
2008). High allopregnanolone levels cause suppression of the
CNS and sleep-like behaviour in utero (Hirst et al. 2008).
However, after birth, neurosteroid concentrations decrease
and this may increase the susceptibility of neonates to brain
injury (Hirst et al. 2008). Therefore, neurosteroids may have a
protective effect on the fetal brain from hypoxic induced
injury, necessitating its potential usage as a preventive
therapy. Further research is needed to examine the possibilities.
Conclusion
Although PAS is thought to be the most common disorder
seen in neonatal foals, the understanding of this syndrome
remains unclear. Ample scientific publications exist on human
neonatal encephalopathy; however, limited literature exists
on neonatal foals with PAS. Therefore most of our knowledge
of the pathophysiology, risk factors, treatment and prevention
revolve around studies in man.
Maintaining the health of the mare, recognising equine
neonatal distress, treatment of multiple body systems, along
with supportive care are the key to successful management
of PAS.
Author’s declaration of interests
No conflicts of interest have been declared.
Acknowledgements
Special thanks to Drs C. Cable, A. Forbes and C. Ziegler.
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