Early Human Development 86 (2010) 339–344

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Early Human Development

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Best Practice Guideline article

Obstetric aspects of hypoxic ischemic encephalopathy

Sailesh Kumar 1, Sara Paterson-Brown ⁎Queen Charlotte's and Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, United Kingdom

⁎ Corresponding author. Tel.: +44 208 3833998; fax:E-mail addresses: sailesh.kumar@imperial.ac.uk (S. K

sara.paterson-brown@imperial.nhs.uk (S. Paterson-Brow1 Tel.: +44 208 3833998; fax: +44 208 3833507.

0378-3782/$ – see front matter © 2010 Elsevier Irelanddoi:10.1016/j.earlhumdev.2010.05.009

a b s t r a c t

a r t i c l e i n f o

Keywords:

Hypoxic ischemic encephalopathyNeonatal encephalopathyIntrapartum asphyxiaCerebral palsyFetal heart monitoring

Hypoxic ischemic encephalopathy (HIE) describes neonatal encephalopathy that is caused by intrapartumasphyxia and it can result in the long term sequelae of cerebral palsy which is a major cause of disability. Theincidence of cerebral palsy has not changed over the last few decades and the challenge to obstetriciansremains how best to recognise those babies at risk of this intrapartum insult both before and during labour.Many associations and risk factors are unavoidable or unrecognisable, and others are fairly common andassociated with poor predictive value. Intrapartum fetal heart monitoring remains the main focus ofattention but how this is best achieved is still the subject of research. Computerised decision support systemsbuilt into fetal heart rate monitoring and non-invasive fetal ECG signal pick-up are currently being explored.

+44 208 3833507.umar),n).

Ltd. All rights reserved.

© 2010 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3392. Diagnosis of hypoxic ischemic encephalopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3403. Patterns of brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3404. Risk factors for perinatal hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3415. Prevention of hypoxic ischemic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

5.1. Antenatal detection of fetal growth restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3415.2. Intrapartum care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

5.2.1. Minimising intrauterine infection/inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3415.2.2. Fetal heart rate monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3425.2.3. More liberal use of caesarean section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3425.2.4. Staff training, intrapartum guidelines and clinical governance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

1. Introduction

Hypoxic ischemic encephalopathy (HIE) and neonatal encepha-lopathy and their long term sequelae of cerebral palsy aremajor causesof disability in term and near term infants. They feature prominentlyin medico-legal claims against the health service both in terms oftheir quantum but also for the length of time taken to resolve. Theirprevalence is estimated at 1–6 per 1000 live full-term births [1].

Neonatal encephalopathy is a clinical syndrome of disturbed neu-rologic function of the term and near term infant in the early neonatal

period, manifested by respiratory difficulties, depression of tone andreflexes, obtundation, and frequently by seizures [2]. It is classified asmild, moderate or severe (or stage 1, 2 or 3) according to the criteriaby Sarnat and Sarnat (1976) [3] and is based on the baby's response tohandling, consciousness level, abnormalities of tone or reflexes, pres-ence of seizures and the duration of the symptoms after birth. Theetiology of neonatal encephalopathy is varied, with many genetic andmetabolic conditions presenting with similar clinical signs [4]. Thedisorder is only called hypoxic ischemic encephalopathy if there isevidence that intrapartum asphyxia is the cause of the encephalop-athy resulting in neurologic depression or seizures. However, thereis often confusion between the two conditions as they are frequentlyused interchangeably in the literature.

Although it was previously believed that intrapartum asphyxiawas the main causative factor for the development of cerebral palsy,

340 S. Kumar, S. Paterson-Brown / Early Human Development 86 (2010) 339–344

more recentpopulationbased studies have shown intrapartumhypoxia/ischemia to be present in only 8–28%of cases [5,6]. Themajority (65%)ofchildrenwith cerebral palsy arebornat term [7]. Despite thewidespreaduse of electronic fetal monitoring and increased caesarean section ratesthe incidence of cerebral palsy has not decreased in developed countriesover the past 30 years [8].

2. Diagnosis of hypoxic ischemic encephalopathy

There have been three consensus statements from various bodiesaddressing the diagnosis of intrapartum asphyxia [9–11] (Table 1).These consensus statements emphasise the use of multiple markersfor the diagnosis, with both essential criteria and supportive evidencerequired before the diagnosis can be made. Some markers are used todiagnose the presence of asphyxia and some the timing of asphyxia.

When intrapartum asphyxia was defined as an umbilical arterialpHb7.0 the incidence at termwas3.7per 1000 live births. The incidenceof HIE at term was 2.5 per 1000 live births and the proportion of casesof cerebral palsy associated with intrapartum asphyxia was 14.5% (seesystematic review by Graham et al. 2008) [12].

The most objective assessment of the presence of intrapartumhypoxia–ischemia is metabolic acidosis in umbilical arterial blood atthe time of delivery [9–11]. Term infants have a mean (SD) umbilicalarterial pH of 7.27±0.07 and base excess of −2.7±2.8 mM [13]. Innormal labour, umbilical arterial pH decreases and the base deficitincreases. Although respiratory acidosis can be quickly corrected bythe neonate, the fetus is unable to tolerate metabolic acidosis for aprolonged period of time. An increased risk of neurologic morbidityis usually seen when the umbilical arterial pH is b7.0 [14] or if thebase deficit is N12 mM [15]. Furthermore, neonatal seizures, otherneurologic abnormalities, and death are significantly more commonin neonates with a pHb7.0 [14,16]. Paradoxically, in some studies,more than two-thirds of newborn infants with an umbilical arterypHb7.0 were classified as normal on discharge from the hospital[14,17]. Of neonates with this degree of acidosis, 23.1% had neonatalneurologic morbidity or mortality [12].

Defining intrapartum hypoxia–ischemia as a cord pHb7.0 is notuniversally agreed on, and some investigators have reported cases ofintrapartum hypoxic ischemic injury occurring in neonates with cordpHN7.0 [12]. Indeed it can be argued that there is no single umbilicalarterial pH value that clearly distinguishes between cases that haveintrapartum hypoxia/ischemia and those that do not. Nevertheless, itis generally agreed that the risk for neonatal complications increasesas the pH at birth decreases.

Other parameters used to diagnose intrapartum hypoxia/HIE in-clude a low Apgar score, the presence of meconium stained liquor,fetal heart rate abnormalities from electronic monitoring or the needfor immediate neonatal resuscitation. These parameters are not spe-cific or sensitive enough for the diagnosis of either fetal hypoxia or

Table 1Consensus statements for the diagnosis of intrapartum hypoxia as the etiology for cerebral

American Academy of Paediatrics/American Collegeof Obstetrics and Gynaecology (1996) [10]

International Cerebral Palsy Task F

Essential criteria Essential criteria• Profound metabolic acidosis (pHb7.0) in anumbilical artery sample

• Metabolic acidosis in early neonaand base deficit N 12 mmol/L)

• Apgar scoreb3 after 5 min • Moderate or severe encephalopat• Neonatal encephalopathy • Cerebral palsy of spastic quadripl• Multi-organ system dysfunction

Criteria suggestive of intrapartum tim• Sentinel event• Abrupt change in fetal heart rate• Apgar score b6 beyond 5 min• Multi-system involvement• Imaging evidence

acidemia as they can be influenced by many other factors. For ex-ample, the Apgar score can be low because of intrapartum maternalsedation or anaesthesia, congenital malformations (e.g. neuromus-cular disorders), objectivity of the individual assigning the score,resuscitative efforts, and the presence of infection [12].

Although objective grading systems now exist for neonatalencephalopathy, older studies have used numerous definitions forintrapartum hypoxia/ischemia, which have contributed to inconsis-tencies in outcome and proposed etiology. Regardless of the specificdefinition used, the majority of cases of cerebral palsy are not asso-ciated with intrapartum hypoxia/ischemia.

3. Patterns of brain injury

Despite a similar etiology, the preterm and term brains respondvery differently to hypoxia/ischemia. Although these differences arenot absolute, the preterm brain is more susceptible to white matterabnormalities while the term brain exhibits primarily grey matterinjury. These differences cause the development of periventricularleukomalacia (PVL) in the preterm infant and that of hypoxic enceph-alopathy, seizures, and stroke in the term infant. The gestation ofgreatest susceptibility to PVL is between 24 and 32 weeks when thewhite matter is predominantly populated by oligodendrocyte pre-cursors and immature oligodendrocytes (preoligodendrocytes) [18].This lesion occurs almost exclusively in neonates b34 weeks, and 60–100% of survivors develop cerebral palsy [19]. PVL represents thetypical response of the preterm brain to an insult, either a hypoxic/ischemic injury (from reduced cerebral blood flow) or one caused bydamage from cytokines associated with infection. In preterm infantsthe cerebral white matter is particularly vulnerable because of itsdecreased blood flow (it receives only 25% of the blood flow of corticalgray matter), its inability to autoregulate perfusion, and a decreasednumber of anastomoses between the short and long penetrating ar-teries that provide its blood supply. The vascular end zones in thewhite matter are the sites for focal necroses of periventricularleukomalacia and white matter atrophy producing ventriculomegaly.MRI features include a reduced bulk of white matter with scallopedventricular margins and gliosis in the periventricular region. Preterminfants develop spastic diplegic cerebral palsy as a consequence ofthese cerebral injuries.

Term infants can develop athetoid (dyskinetic) cerebral palsy orspastic quadriplegic cerebral palsy as a consequence of intrapartumhypoxia. In the term or near term brain, a short period of profoundhypoxic ischemia causes injury to parts of the brain with a highmetabolic rate, high blood supply, high glucose metabolism and alarge number of excitatory glutaminergic neurons [20,21]. Theseregions include the posterior putamina of the lentiform nuclei, theventro-lateral nuclei of the thalami, the hippocampus and the peri-Rolandic cortex [22,23]. The precise pattern and extent of injury

palsy [9–11].

orce (1999) [9] American College of Obstetrics and Gynaecology(2003) [11]

Essential criteriatal blood sample (pHb7.0 •Metabolic acidosis (pHb7.0 andbasedeficitN12 mmol/L)

in umbilical artery samplehy • Moderate or severe encephalopathyegia or dyskinetic type • Cerebral palsy of spastic quadriplegia or dyskinetic type

• Exclusion of other pathologies of cerebral palsying

Criteria suggestive of intrapartum timing• Sentinel event• Abrupt change in fetal heart rate• Apgar score b6 beyond 5 min• Multi-system failure within 72 h of life• Imaging evidence

341S. Kumar, S. Paterson-Brown / Early Human Development 86 (2010) 339–344

depends on the severity and duration of the insult. Sometimes thewhitematter of the corona radiata and the optic radiations are damaged, andon occasion, there is involvement of the hippocampus [24,25].

In spastic quadriplegic cerebral palsy, parasagittal cerebral injuryor damage to the deep greymatterwithwhitematter involvement andcerebral atrophy is seen. Some children occasionally show changesconsistent with periventricular leukomalacia (PVL). Parasagittalcerebral injury occurs because of systemic and cerebral hypotensionand hypoperfusion. A prolonged period of mild to moderate hy-potension can cause damage to the brain in the parasagittal zones(watershed areas) that are supplied by the anterior, middle andposterior cerebral arteries. This pattern of injury is characterised bynecrosis of the cortex and adjacent whitematter and involves both theanterior and parieto-occipital regions. Under perfusion of the gyrileads to shrinkage at the bases and the development of ulegyria areaction that is specific to the term or near term brain [26]. There isconsiderable overlap between these two types of termbrain injury andthe clinical features may be similarly consistent.

In addition to the above, both preterm and term infants can de-velop hemiplegic cerebral palsy. However unlike athetoid or spasticcerebral palsy, hemiplegic cerebral palsy is not considered to be dueto intrapartum asphyxia. A common cause is infarction of the regionusually supplied by the left middle cerebral artery. The incidenceof neonatal stroke in term infants is estimated at 1 in 4000 cases [27].Symptoms may be mild in some infants and not recognized, althoughfocal seizures may often be present. Babies with more extensiveinfarcts may develop encephalopathy [28,29]. Risk factors for anarterial stroke in the newborn period include a prolonged labour withan occipito-posterior position, umbilical cord occlusion and inheritedthrombophilias [27,30,31].

4. Risk factors for perinatal hypoxia

Although there has been much optimism that the incidence ofcerebral palsy was likely to decrease with improvements in obstetricand neonatal care, there has been no consistent decrease in its fre-quency in the last 30 years [8] and the incidence of dyskinetic cerebralpalsy usually caused by birth asphyxia has not declined [32]. Thisdisappointment may be partially explained by the multifactorial riskfactors associated with this condition and the fact that many areunavoidable and others difficult to detect or treat (Table 2).

One of the aims of antenatal care is to screen women early in theirpregnancy to detect risk factors for adverse outcomes and then tominimise their effects with appropriate monitoring and intervention.Examples of such an approach include: Blood Pressure (BP) measure-ment and urinalysis to detect pre-eclampsia with subsequent blood

Table 2Risk factors for neonatal encephalopathy [4,25,33].

Pre-pregnancy factors Antenatalfactors

Fetal factors Intrapartum factors

Socioeconomic status Bleeding Multiplepregnancy

Infection

Family history of seizures Hypertensivedisorders

Chromosomalanomaly

Placental bleeding

Family history ofneurological disease

Abnormalplacentation

Congenitalabnormality

Feto-maternalhemorrhage

Fertility treatment Viral illness Fetal growthrestriction

Bleeding fromvasa praevia

Maternal thyroid disease Bacterialinfection

Prematurity Uterine rupture

Maternal obesity Coagulationdisorders

Coagulationdisorders

Cord accident

Postmaturity Maternal collapseBreechpresentation

Prolonged labour

Male sex Oxytocin abuse

pressure control and timely delivery; and abdominal palpation withsymphysio-fundal height measurement to detect fetal growth re-striction. While the former is reasonably straightforward the latter isvery much an inexact science (made harder by increasing maternalobesity) and therefore although severe growth restriction is a strongrisk factor for neonatal encephalopathy [33] it often goes undetected.

The importance of intrapartum factors on cerebral palsy remainsuncertain. Blair and Stanley [5] considered that only 8% of all ofthe children with spastic cerebral palsy had intrapartum asphyxia as apossible cause of their brain injury. More recently Badawi et al. (1998)[33,34] showed in a case–control study from Western Australia thatthe causes of moderate or severe neonatal encephalopathy wereheterogeneous and many etiological pathways start either pre-conception or in the antepartum period (see review by Kurinczuk inthis issue). Intrapartum events may also be responsible and a recentstudy [25] found no evidence of long-standing brain damage in acohort of babies imaged after suffering a sentinel intrapartum eventsuggesting that brain injury occurred as a result of such an eventrather than from a pre-existing cause.

The wide variation in the effect of hypoxia/ischemia on thenewborn brain suggests the possibility that genetic factors may alsoplay a significant role. Animal models of HIE show wide inter-strainvariability in the severity of injury after an identical insult [35,36].Gender differences of response to HIE have also been observed [37].There is enough evidence now to support the view that a variety ofgenetic factors may interplay in the perinatal period to increase thevulnerability of the developing brain to hypoxic/ischemic injury.

5. Prevention of hypoxic ischemic encephalopathy

5.1. Antenatal detection of fetal growth restriction

Detecting risk factors in the antenatal period can enable closefollow-up of women whose babies are at risk and this in turn canallow appropriate decisions about timing, mode and place of deliveryto bemade. Improving the clinical diagnosis of fetal growth restrictionwould be a step forward in this context, but routine late pregnancygrowth scans are not cost effective [38] and routine Doppler studiesare not beneficial [39]. Furthermore, late scans in pregnancy are as-sociated with a small increase in caesarean section rates [39]. Thedetection of the small baby remains very much a clinical skill. Agrowth restricted baby at term is more at risk of intrapartum hypoxic/ischemic injury and therefore if the diagnosis has been made thethreshold for operative delivery may be lower, but many small babiesare delivered safely vaginally and there is constant pressure on ob-stetricians to avoid ‘unnecessary’ caesarean sections.

5.2. Intrapartum care

Although the majority of fetal neurological injuries predate labour,the intrapartum period is a time of risk for asphyxia and asphyxia-related morbidity and mortality. Intrapartum care aims to identifythose babies at risk of hypoxia to recognise when signs develop andthen to intervene in a timely way.

5.2.1. Minimising intrauterine infection/inflammationIt has been proposed that cytokines may be the final common

mediators of brain injury that is initiated by hypoxia/ischemia, re-perfusion, and infection [40]. Furthermore there have been manypublications linking the presence of maternal fever or placental in-flammation (chorioamnionitis)with adverse neurologic outcome [41].The fetal inflammatory response and cytokine mediated injury effecton oligodendrocytes, has been implicated in the white matter damagethat occurs in preterm infants. A similar association is also present interm infants. The effect of any intrapartumhypoxia/ischemia is greaterif maternal pyrexia is present in labour.

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Adequate precautions to reduce an abnormally elevated maternaltemperature and to treat suspected infection are required to reducethe vulnerability of both the preterm and term brain from hypoxicinjury. On a practical level this has been made more difficult by therelatively common increase in body temperature associated withepidural analgesia. A temperature of 37.5 °C is commonplace in suchlabours and rather than promotewidespread use of antibiotics (whichis not recommended), a pyrexia needs to approach 38 °C beforetreatment is started unless other signs of sepsis exist. Thus para-cetamol is commonly used to keep temperatures down and this canthen mask what might otherwise have become a ‘clinical’ pyrexia.

5.2.2. Fetal heart rate monitoringMonitoring the fetal heart rate during labour is well established

but how best to do it remains the subject of research. When inter-mittent auscultation is used for low risk pregnancies twice as manybabies will require admission to neonatal intensive care with en-cephalopathy than if electronic monitoring is used [42] and yet thisis the practice supported by the Cochrane review and the NICEintrapartum guidelines [43] as there is no difference in mortality or incerebral palsy rates while operative intervention rates are higher withelectronic monitoring. The evidence to date is therefore confusingand often contradictory.

There have been some studies that suggest electronic fetal mon-itoring correlates well with metabolic acidosis and neurologic injury[44,45]. Williams and Galerneau [45] found that the best intrapartumfetal heart rate parameter to predict the development of significantacidemia was minimal/absent variability for at least 1 h as a solitaryabnormal finding or in conjunction with late decelerations in theabsence of accelerations. Although the sensitivity of these electronicfetal monitoring abnormalities for the identification of intrapartumasphyxia was 93% the positive predictive value was only 3%–18%.Studies on monkey fetuses [46] have shown that during the courseof progressive hypoxia that led to death, fetal heart rate variabilitydecreased and then disappeared, and late decelerations preceded fetalacidemia. It is generally believed that decreased short-term variabilityis the single most reliable sign of fetal compromise and normal short-term variability is a good indicator of normoxia. Computerised ante-natal fetal heart rate monitors are now available that identify ab-normalities in the short term variability of the fetal heart rate pattern.Their use in the intrapartum setting remains unclear and clinical trialsare underway.

Other studies have not found electronic fetal monitoring to beclinically helpful in the identification of fetal acidosis or neurologicinjury [47–50]. It has been suggested that given the low incidence ofneonatal encephalopathy the predictive value of an abnormal fetalheart rate tracing is poor. Other critics of electronic fetal monitoringpoint out that although fetuses with metabolic acidosis have sig-nificant episodes of bradycardia, decreased variability, nonreactivityand late decelerations the predictive power for HIE is not high.

There is evidence that changes in the ST segment of the electro-cardiogram (ECG) are related to fetal acidemia and that detection ofthese changes in combination with the cardiotocograph (CTG) canreduce the incidence of intrapartum asphyxia and/or neonatal en-cephalopathy [51–53]. Despite this initial optimism there remainreservations about this method of intrapartum monitoring [54] and anumber of problems have been raised since it was introduced intoroutine clinical practice in some units [55–57]. Other intrapartummonitoring techniques which have explored over the years includepulse oximetry and near-infrared spectroscopy, but neither have beenshown to have a place in clinical care [58,59].

On a practical level, the secret of intrapartum fetal monitoringremains one of vigilance with the midwife being present with thewoman throughout her labour to support her whilst midwife plus/minus obstetrician maintain a critical assimilation of signs and symp-toms in conjunction with an analysis of the fetal heart rate. Expecting

the fetal heart rate alone to give an answer is not logical and can helpexplain why the most complex methods of monitoring sometimesfail, as it can distract from other signs.

5.2.3. More liberal use of caesarean sectionThis is a very contentious suggestion because of the risks to both

mother and baby. Infants delivered by caesarean section have in-creased rates of respiratory problems compared to normally deliveredbabies. In addition, the surgical risks to the mother, particularly withrepeat caesarean sections are not inconsequential. Certainly in thepreterm situation the available evidence suggests that there is noreduction in neonatal mortality or incidence of cerebral abnormalitiesin babies delivered by caesarean section [60,61]. In the term infant thebest evidence for improved perinatal outcome is the term breech trial[62,63]. Perinatal mortality, neonatal mortality, or serious neonatalmorbidity was significantly lower for the planned caesarean sectiongroup (1.6%) than for the planned vaginal birth group (5%) (RelativeRisk 0·33 (95% CI 0·19–0·56)) but this benefit was no longer ap-parent at the two year follow-up [64].

5.2.4. Staff training, intrapartum guidelines and clinical governanceThe extent to which intrapartum asphyxia can be prevented by

improved care is controversial, but several investigations and malprac-tice claims analyses suggest that a significant proportion is preventable[65–69]. It often appears that substandard care is attributable to systemfailures frequently caused by poor communication between providers.

A recent study [70] suggested that suboptimal intrapartum careoccurred in 40–50% of cases with metabolic acidosis at birth. Mostcases of suboptimal care consisted of injudicious use of oxytocin or afailure to act on an abnormal fetal heart rate trace. The authors notedthat in many cases there appeared to be a gap between knowledgeand clinical practice and that availability of clinical intrapartum guide-lines did not reduce the incidence of adverse outcome. This trendis also supported by various national surveys in the United Kingdomsuggesting that suboptimal care was present in almost 70% of intra-partum fetal deaths.

Intrapartum care protocols for oxytocin usage, operative vaginaldelivery, shoulder dystocia, the use of magnesium sulphate, andcombined certification of physicians and nurses of training in fetalmonitoring can reduce malpractice claims paid, decrease caesareansection rates, and result in fewer adverse outcomes [71]. These are allnow included in standards of safety within maternity units and areaudited for CNST compliance.

In the United Kingdom, the Royal College of Obstetricians andGynaecologists recommend that any obstetric service delivery orga-nisation has a robust and transparent clinical governance frameworkwhich is applicable to each birth setting. Within this setting effectivemultidisciplinary care and good communication should be key factorsfor good practice. Furthermore, adequate staffing levels of all clinicaland support staff is required and this must be reviewed and auditedannually. Clinical leadership in promoting good practice and coordi-nating care is vital. Protocols based on clinical, organisational andsystem needs should also be available.

Professional staff should have the opportunity and support forcontinuing professional development, including agreed mandatorymultidisciplinary education and training sessions. Ongoing audit ofrelevant outcomes, with attention to any changes or trends is alsomandatory. These administrative factors are as important as clinicalinterventions in reducing the risk of hypoxic ischemic injury in thepreterm or term infant.

6. Conclusions

The initiation and evolution of brain injury in the term infant aftera hypoxic/ischemic insult is a very complex process with excitotoxi-city, oxidative stress and inflammation playing different roles within

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an environment of cerebral energy failure. Although there is now aneffective treatment in the form of neonatal brain cooling [72], manyaffected infants do not receive this intervention in time and for thosethat do receive it the response may not always be satisfactory. It isunlikely that, given the heterogeneity of risk factors, neonatal en-cephalopathy or hypoxic ischemic encephalopathy will be eradicated.The onus on obstetricians is therefore to minimise its occurrence withboth effective antenatal and preventative intrapartum strategieswhile refinements in neonatal treatment may optimise outcomes.Long-term follow-up of these infants is important to identify moresubtle disabilities such as learning difficulties or perceptual-motorproblems later in their life.

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