Early Human Development 86 (2010) 329338

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Early Human Development

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev

Best Practice Guideline article

Epidemiology of neonatal encephalopathy and hypoxicischaemic encephalopathy

Jennifer J. Kurinczuk a,, Melanie White-Koning b,1, Nadia Badawi c,d,2
a

National Perinatal Epidemiology Unit, University of Oxford Old Road Campus, Headington, Oxford OX3 7LF, UK
Universit Paul Sabatier Toulouse III, Facult des Sciences Pharmaceutiques, 31962 Toulouse Cedex 09, France
c
The Cerebral Palsy Institute, The Spastic Centre and the University of Notre Dame, Australia
d
Grace Centre for Newborn Care, The Childrens Hospital at Westmead, the University of Sydney, Australia
b

a r t i c l e

i n f o

a b s t r a c t

Article history:
Accepted 7 May 2010

Neonatal encephalopathy (NE) is the clinical manifestation of disordered neonatal brain function. Lack of
universal agreed denitions of NE and the sub-group with hypoxic-ischaemia (HIE) makes the estimation of
incidence and the identication of risk factors problematic. NE incidence is estimated as 3.0 per 1000 live
births (95%CI 2.7 to 3.3) and for HIE is 1.5 (95%CI 1.3 to 1.7). The risk factors for NE vary between developed
and developing countries with growth restriction the strongest in the former and twin pregnancy in the
latter. Potentially modiable risk factors include maternal thyroid disease, receipt of antenatal care, infection
and aspects of the management of labour and delivery, although indications for some interventions were not
reported and may represent a response to fetal compromise rather than the cause. It is estimated that 30% of
cases of NE in developed populations and 60% in developing populations have some evidence of intrapartum
hypoxic-ischaemia.
2010 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Neonatal encephalopathy
Hypoxicischaemic encephalopathy
Incidence
Risk factors
Epidemiology

Contents
1.
Introduction . . .
2.
Denitions. . . .
3.
Incidence . . . .
4.
Risk factors . . .
5.
Future directions .
Acknowledgements . .
References . . . . . .

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1. Introduction
Neonatal encephalopathy (NE) is the clinical manifestation of
disordered neonatal brain function. It is a relatively common clinical
condition which results in serious consequences for many of the infants
including death, cerebral palsy, epilepsy and other signicant cognitive,
developmental and behavioural problems. The nancial and human
costs to infants affected, their parents, professionals and wider society
are enormous. Some, but by no means all, of these costs are reected in
awards following medical litigation. In the UK about half of the cases

Corresponding author. Tel.: + 44 1865 289700; fax: + 44 1865 289701.

E-mail addresses: jenny.kurinczuk@npeu.ox.ac.uk (J.J. Kurinczuk), koning@cict.fr
(M. White-Koning), NadiaB@chw.edu.au (N. Badawi).
1
Tel.: + 33 567 22 25 51; fax: + 33 561 42 46 31.
2
Tel.: + 61 2 98452715; fax: + 61 2 98452251.
0378-3782/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2010.05.010

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329
330
330
334
337
337
337

dealt with by the National Health Service Litigation Authority (NHSLA)

concern birth related adverse events; cases of NE and cerebral palsy
feature heavily. In 2008 the outstanding liability of the NHSLA stood at
11.9 billion [1]. An expert group led by the Chief Medical Ofcer for
England reported in 2000 estimating that preventing 10% of birth
related adverse events would save about 20 million per year [2].
Important initial considerations in trying to describe the epidemiology of NE and hypoxic ischaemic encephalopathy (HIE) are the lack of
a universally agreed denition of both these terms [3] and the need for a
clear consensus in understanding of the relationship between the two
that is reected in common medical parlance. In this article we aim to
provide an epidemiological background to the related papers in this
edition and start by considering issues surrounding the denition of NE
and HIE, how these affect incidence estimates and the identication of
risk factors. Finally we consider current research needs to further our
understanding of the aetiology of NE and HIE.

330

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

2. Denitions
Nelson and Leviton described NE as a clinically dened syndrome of
disturbed neurologic function in the earliest days of life in the term
infant, manifested by difculty with initiating and maintaining respiration, depression of tone and reexes, subnormal level of consciousness,
and often by seizures [4].
Volpe denes hypoxaemia as the diminished amount of oxygen in
the blood supply and cerebral ischaemia as the diminished amount
of blood perfusing the brain with the latter being the more important
of the two forms of oxygen deprivation since it also results in
deprivation of glucose which is also crucial in the genesis of neuronal
injury [5]. Asphyxia is the result of the impairment of exchange of the
respiratory gases oxygen and carbon dioxide. Thus, in addition to
hypoxia, asphyxia has the important additional feature of producing
elevated levels of carbon dioxide which result in a number of
additional metabolic and physiological features which include
acidosis and increased cerebral blood ow [5].
Levels of cerebral oxygen, glucose and carbon dioxide are not
directly, routinely measurable in humans in vivo, although fetal venous
scalp samples may be taken during labour when clinically indicated.
This has led to the use of indirect clinical markers, such as low Apgar
scores, peripheral blood pH and acid-base parameters, which if present
in combination with features of encephalopathy, are taken to imply the
occurrence of hypoxic-ischaemia which is termed HIE [3].
In the past it was largely assumed that most cases of NE were due to
adverse intrapartum events and a number of terms have been used to
describe the condition of affected neonates which include: HIE, postasphyxial encephalopathy, perinatal asphyxia and birth asphyxia [3].
One consequence of this aetiological assumption is that the range of
clinical features used to dene the presence of encephalopathy in many
studies included markers of the purported causal insults, e.g. intrapartum complications. As a consequence these purported insults were then
found to be associated with HIE and deemed to be causal. However, this
is not a surprising nding since the features had by denition to be
present for the cases to be included in the study population and to be
absent in the controls; a tautology indeed. A further complication is the
fact that in the absence of a single agreed set of dening criteria a varying
number of features have been used by different investigators with about
12 different sets of criteria being fairly consistently used [6], although
many of these sets are modications of the criteria Sarnat and Sarnat
used to characterise the 21 cases of neonatal encephalopathy following
fetal distress they originally described [7].
The term HIE is often used synonymously with NE which implicitly
suggests that all cases of NE are due to HIE that is, a recent hypoxic
ischaemic episode usually occurring during labour and delivery, and
implies that in all encephalopathic cases the cause of the encephalopathy is known. Whereas in fact, the term NE is simply a clinical
description of disordered neurological function that does not require
assumptions about either the pathogenesis or the aetiology. Since use of
the term NE also avoids use of terms such as birth asphyxia or perinatal
asphyxia, with their heavily pejorative connotations for parents, we
suggest that NE be used as the general term to describe the clinical
dened condition of disordered newborn brain function for which there
may be many causes, many risk factors and a number of potential routes
to prevention and treatment. In this article we reserve the term HIE for
the sub-set of cases of NE where there is evidence of a recent, and usually
an intrapartum, hypoxicischaemic cause for the NE [3].
3. Incidence
The reported incidence of NE from different studies ranges from
about 2.0 to 6.0 per 1000 live births (Table 1) [811]. The incidence of
HIE ranges from about 1.0 to 8.0, excluding the estimate from Nigeria
[16] based on a single hospital series which was 26.2 per 1000 live
births (Table 2) [1220]. There are, however, several difculties in

interpreting these gures. With the exception of the data from Derby,
UK where three retrospective analyses were conducted using similar
methods over a 20 year period [12,17], no two sets of investigators
used the same case denition 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 [8,9,1214]. The
difference between hospital and population-based estimates is
illustrated in Figs. 1 and 2; in general, hospital-based incidence
gures tend to be higher than population-based results. This
difference is probably mainly due to referral bias since hospitalbased studies tend to be conducted in referral centres. Whilst some
authors specically excluded out-born cases in the calculation of
incidence [11,19], referral bias is, however, still likely to be present to
some extent because of antenatal referral of complicated pregnancies
which are at greater risk of the outcome.
The comparison between the population and hospital-based data
is also compounded by a further problem which is the time period of
study. With the exception of the studies from Nepal [10] and Saudi
Arabia [15] the hospital studies tend to be older than the populationbased studies. One might anticipate that with improvements in
clinical practice the incidence of NE and HIE would have decreased
over time. The only three estimates of HIE incidence overtime which
are comparable in terms of case denition and study methodology
again come from Derby, UK where there is evidence of a reduction in
the incidence from the late 1970s (7.6 per 1000 live births) [17],
through the late 1980s (4.6) [17], to the early 1990s (1.9) [12]. Thus,
the interpretation of older data in relation to the current situation is
highly problematic.
Two further methodological problems are rst the differences in
case ascertainment and second the selection of an appropriate
denominator. Case ascertainment is the more important issue and
this varies from retrospective identication of cases through routine
hospital data collection systems using an imprecise or undened set of
criteria, for example, in the studies from Pittsburgh [20] and Edinburgh
[11] through to an active, prospective method of case identication
from a clearly dened population, based on a tight case denition [8
10,19]. These differences in study design also have implications for the
investigation of risk factors since the former types of studies tend to
rely wholly on medical case notes for data collection whereas the latter
often have access to other sources of contemporaneous data including,
in some studies, maternal interview which can provide more extensive
and detailed information about potentially important exposures and
events.
Care should always be taken when comparing incidence estimates to
ensure that the same denominator has been used to calculate the rates.
For NE and HIE, as these are conditions of term infants, the correct
denominator should include only those infants at risk of being in the
numerator i.e. at risk of being a case, which by denition for NE and HIE
means that they should all be term infants. However, not all
investigators have access to population data by gestational age, and
the rates of NE and HIE are commonly quoted per 1000 live births rather
than 1000 term live births. In reality the difference in the estimates
produced is relatively small since the majority of live births deliver at
term and the importance of this issue at present is largely out-weighed
by the other problems outlined above.
In addition to methodological differences in measuring incidence
using data from around the world to estimate incidence assumes that
the true underlying rate of NE and HIE is the same in different places;
this is unlikely to be so. The contribution of intrapartum causes in
particular is likely to vary, especially between developed and developing
countries, thus leading to a variation in the proportion of NE cases
attributable to the HIE sub-group. This has important implications at
different levels in particular for immediate clinical decision-making, for
example, the proportion of cases that are likely to benet from therapies
such as cooling will vary depending upon the relative proportion of NE
cases which fall into the HIE sub-group.

Table 1
Studies estimating the incidence of neonatal encephalopathy (NE) in terms infants from population and hospital-based studies.
Denition and case identication

Number of cases/live birthsa

Incidence per 1000

live births (95%CI)b

Population-based studies
Evans et al. [8]
SW Thames Region,
London, UK

1993 to 1995

150/57,062

2.63 (2.22 to 3.08)

Badawi et al. [9]

1993 to 1995

Prospective identication of infants born at 37 weeks gestation with one or more of

the following features presenting in the rst 4 days (96 h) after birth, regardless of other
diagnoses:
Denite or probable ts, including apnoeic episodes and cyanotic spells
Increased muscle tone
Decreased muscle tone
Abnormal neurological behaviour such as reduced responsiveness, coma, hyper-alertness, jitteriness
Unable to feed orally for at least 24 h (unless caused by respiratory problems, structural lesions or
by the need for neonatal surgery)
Exclusions: Down's syndrome unless the baby has one or more of the features which cannot be attributed
to Down's syndrome alone
Prospective identication of infants born at 37 weeks gestation who during the rst seven days after
delivery presented with:
Either seizures alone
Or
Any two of the following lasting for longer than 24 h:
Abnormal consciousness
Difculty maintaining respiration (of presumed central origin)
Difculty feeding (of presumed central origin)
Abnormal tone and reexes
Exclusions: Down's Syndrome or neural tube defects (no cases actually excluded)

164/43,158 term live births

164/48,235 all live births

3.80 (3.24 to 4.43)

3.40 (2.90 to 3.96)

131/21,609

6.06 (5.07 to 7.19)

83 (inborn)/14,020
[11 additional cases referred]

5.92 (4.72 to 7.33)

Location

Western Australia

Hospital-based studies
Ellis et al. [10]
Prasuti Griha Hospital,
Kathmandu, Nepal

Brown et al. [11]

a
b

Simpson Memorial
Maternity Pavilion,
Edinburgh, UK

1995 to 1996
(18 months)

Unspecied
period of time.
Published in 1974

Prospective identication of infants born at 37 weeks gestation presenting at 624 h after birth with:
Altered conscious level with abnormalities of neuromuscular tone or sucking behaviour (based on
Fenichel [21]). In addition there may be seizures or abnormalities of respiratory control, primitive
reexes and brainstem reexes.
Exclusions: Severely dysmorphic infants or infants with at least one major congenital anomaly;
indications of intra-uterine infection; neonatal infections; and hypoglycaemia when corrected resulted
in normal neurology.
No indication of how the cases were identied. Gestational age ranged from 29 to 42 weeks
Severe degree of asphyxia indicated by the presence of:
Feeding difculty necessitating tube feeding
Apnoeic or cyanotic attacks
Apathy
Convulsions
Hypothermia
Cerebral cry
Persistent vomiting

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

Year of birth

Author

Live births of all gestations unless indicated otherwise.

Where 95% condence intervals were not quotes by the authors we calculated them for the purposes of this paper using the exact binomial distribution.

331

332

Table 2
Studies estimating the incidence of hypoxicischaemic encephalopathy (HIE) in terms infants from population-based studies.
Author

Location

Denition and case identication

Number of cases/live birthsa

Incidence per 1000

live births (95%CI)b

1992 to
1996

Retrospective medical records review to identify infants N37 weeks gestation where the infants had features of
hypoxicischaemic encephalopathy as dened by Levene et al. [18]. The severity was graded according to the
Levene criteria [18]:
Grade 1 (mild): irritability, hyper-alert, mild hypotonia, poor sucking
Grade 2 (moderate): lethargic, seizures, marked abnormality of tone, required tube feeding
Grade 3 (severe): comatose, prolonged seizures, severe hypotonia, failure to maintain spontaneous respiration
Exclusions: Infants with encephalopathy clearly attributable to a cause other than asphyxia were excluded
Cases of neonatal encephalopathy included in the study as per details in Table 1.
The following criteria were used to identify the sub-set of cases with possible intrapartum hypoxia (criteria
modied from ACP [22]): presence of an abnormal cardiotocogram or abnormal fetal heart rate on auscultation
or fresh meconium in labour, or both, together with a 1 minute Apgar score of less than 3 and a 5 minute Apgar
score of less than 7. Results of cord pH measurements were not included as they were performed so infrequently.
Further cases which did not strictly full the denition were added where there was evidence that they had
experienced a signicant intrapartum event which may have been associated with intrapartum hypoxia, for example a
case of breech presentation with head stuck who was born before arrival (no Apgar measurement as no accoucher
present at the birth)
Retrospectively identied cases recorded on the Swedish Medical Birth Register born at 37 weeks gestation with an
Apgar score of b 7 at 5 min excluding infants with the following which were considered the cause of their low Apgar
score: opioid/anaesthesia related, congenital malformations and chromosomal disorders, congenital neuromuscular
disorder and subarachnoid haemorrhage. The remaining group were considered to have birth asphyxia (BA).
A retrospective HIE classication was performed using the criteria of Sarnat and Sarnat [7] as modied by Fenichel [21].
This group was called birth asphyxia-HIE group (BA-HIE)

48/24,700

1.94 (1.43 to 2.58)

47/43,158 term live births

47/48,235 all live births

1.09 (0.80 to 1.45)

0.97 (0.72 to 1.30)

227 BA/42,203
74 BA-HIE/42,203

5.38 (4.70 to 6.12)

1.75 (1.38 to 2.20)

70/12,730 term live births

70/15,005 all live births

5.50 (4.29 to 6.94)

4.67 (3.64 to 5.89)

166/6261

26.2 (22.7 to 30.8)

Badawi et al. [13]

Western Australia

1993 to
1995

Thornberg [14]
et al.

City of Gteborg,
Sweden served by
three hospitals

1985 to
1991

Hospital-based studies
Itoo et al. [15]
Madina Maternity
and Children's
Hospital,
Madina-Al-Manawara,
Kingdom of
Saudi Arabia
Airede [16]

Jos University
Teaching Hospital,
Nigeria

1995 to
1996

1987 to
1989

Babies with a gestational age of 37 that were admitted with the clinical picture of HIE at birth on the basis
of changes in the level of consciousness, muscle tone, neonatal and deep tendon reexes and development of
seizures were included.
The cases were assessed and followed to assign a stage of HIE according to the criteria of Sarnat and Sarnat [7]
without electroencephalogram.
Exclusions: babies with major congenital malformations and those born outside the hospital were excluded.
Note: It is not clear if the data were collected prospectively or retrospectively.
Retrospective identication from case notes of infants born between 37 and 42 weeks gestation presenting with
birth asphyxia and signs related to birth asphyxia (irritability, hypotonia, convulsions, cerebral cry or poor feeding).
Post-asphyxial hypoxicischaemic encephalopathy severity grading (modied from Fenichel [21]) used:
Grade I (mild):
Irritability, hyper-alert
Mild hypotonia
Poor sucking
Grade II (moderate):
Lethargic
Seizures
Marked abnormalities of tone
Requiring tube feeding

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

Population-based studies
Smith et al. [12]
Derby Health
Authority,
Derbyshire, UK
served by
single hospital

Year of
birth

Table 2 (continued)
Author

Location

Year of
birth

1984 to
1988

Derby City
Hospital,
Derbyshire, UK

Levene et al. [18]

1980 to
Leicester Royal
1983
Inrmary Maternity
Hospital, Leicester, UK

Hull and Dodd [17]

Derby City Hospital,

Derbyshire, UK

1976 to
1980

Finer et al. [19]

Royal Alexandra
Hospital, Alberta,
Canada

1974 to
1978

MacDonald et al. Magee-Womens

[20]
Hospital, University
of Pittsburgh, USA
a
b

1970 to
1975

Grade III (severe):

Comatose
Prolonged and persistent seizures
Severe hypotonia
Failure to maintain spontaneous respiration
Exclusions: Cases where there was no good evidence that asphyxia was the cause of their neurological
disturbance. Metabolic screening also excluded other causes of irritability.
Noteno period of presentation given
Retrospective case note review; those records where the infant was described as having the features
of hypoxicischaemic encephalopathy were included.
The cases were graded according to the criteria of Levene et al. [18]:
Grade I (mild): irritability, hyper-alert, mild hypotonia, poor sucking
Grade II (moderate): lethargic, seizures, marked abnormalities of tone, required tube feeding
Grade III (severe): comatose, prolonged seizures, severe hypotonia, failure to maintain spontaneous respiration
Retrospective identication from computer system of infants born 37 to 42 weeks gestation who had a
primary or secondary diagnosis of birth asphyxia.
The severity was graded according to the criteria modied from Fenichel [21]:
Grade 1 (mild): irritability, hyper-alert, mild hypotonia, poor sucking
Grade 2 (moderate): lethargic, seizures, marked abnormality of tone, required tube feeding
Grade 3 (severe): comatose, prolonged seizures, severe hypotonia, failure to maintain spontaneous respiration
Exclusions: cases were excluded if there was not good evidence that intrapartum asphyxia was the cause of their
neurological disturbance.
Retrospective case note review; those records where the infant was described as having the features of
hypoxicischaemic encephalopathy were included.
The cases were graded according to the Levene criteria [18]:
Grade I (mild): irritability, hyper-alert, mild hypotonia, poor sucking
Grade II (moderate): lethargic, seizures, marked abnormalities of tone, required tube feeding
Grade III (severe): comatose, prolonged seizures, severe hypotonia, failure to maintain spontaneous respiration
Prospective identication of term singleton infants with an abnormal neurologic examination in the rst week after
birth and one or more of the following:
Documented intrapartum fetal distress through the recognition of abnormal heart rate patterns with or without meconium
Presence of immediate neonatal distress as evidenced by a low (b5) one-minute or ve-minute Apgar score
The need for immediate resuscitation with or without prolonged ventilation for greater than 5 min
An abnormal neurological examination included the presence of any two or more of the following:
Alterations of consciousness assessed following vigorous stimulation to attempt the arouse the infant
Alterations of muscle tone categorized as global hypotonia or hypertonia, as well as localized tone disturbances
Abnormal primitive reexes
The Sarnat [7] classication was used to dene the clinical stage:
Stage I: hyper-alertness, hyper-reexia, dilated pupils, tachycardia, absence of seizures
Stage II: presence of lethargy, hyper-reexia, miosis, bradycardia, seizures, hypotonia, weak suck, weak Moro response
Stage III: stupor, accidity, poor pupil response, decreased stretch reexes, hypothermia, absent Moro, absent suck
Exclusions: Infants with conrmed central nervous system malformation, chromosomal abnormality, familial illness or
intra-uterine infection were excluded.
Retrospective identication from computer system of infants of all gestations, only those born 37 weeks given here,
with neonatal asphyxia dened as:
Infant requiring N 1 min of positive pressure ventilation before sustained respiration occurred

Number of cases/live birthsa

Incidence per 1000

live births (95%CI)b

112/24,265

4.62 (3.80 to 5.55)

126/20,975

6.01 (5.01 to 7.15)

189/24,824

7.61 (6.57 to 8.77)

67 inborn/20,155
3.32 (2.58 to 4.22)
[18 additional cases referred]

149/30,621 term live births

149/38,405 all live births

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

Hull and Dodd [17]

Denition and case identication

4.87 (4.12 to 5.71)

3.88 (3.28 to 4.55)

Live births of all gestations unless indicated otherwise.

Where 95% condence intervals were not quotes by the authors we calculated them for the purposes of this paper using the exact binomial distribution.

333

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J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

4. Risk factors

Fig. 1. Estimates of the incidence of neonatal encephalopathy in term infants from

population and hospital-based studies. *Population-based studies; Hospital-based
studies.

Thus, given all these difculties the question is whether with the
data available it is possible to reach a reasonable estimate of the
current incidence of NE and HIE. In their review of the relationship
between NE and cerebral palsy in 2003, the American College of
Obstetricians and Gynecologists and the Academy of Pediatrics
concluded that the best estimate of the incidence of NE comes from
population data and was 1.9 to 3.8 per 1000 [3,23]. This estimate
included data from the neonatal audit in the Trent Region of the UK
which, given the inclusion criteria, probably more closely reects the
incidence of the HIE sub-group of NE than NE incidence overall.
Excluding the Trent data and taking in combination just the gures
from the South West Thames area of London and Western Australia,
and using all live births as the denominator, we arrived at an estimate
of 3.0 per 1000 live births with a 95% condence interval of 2.7 to 3.3
[8,9].
An estimate of the incidence of HIE derived by the combination of
data from the three population-based studies carried out since 1980
gives a gure of 1.5 per 1000 live births with a 95% condence interval
of 1.3 to 1.7 [1214]. This is a much lower estimate than the older,
hospital-derived rates illustrated in Fig. 2.
For the reasons discussed above, the estimates of the incidence of
NE of 3.0 per 1000 and of HIE of 1.5 per 1000 should be used with
caution. The age of many of the studies and the difculties outlined in
relation to case denition and other aspects of study design all serve
to illustrate the need for new up-to-date estimates of the incidence of
this enigmatic condition.

As with any condition, identifying the risk factors for NE and HIE is
key to understanding the causal pathways and developing preventive
strategies [24]. Progress has been hindered by the absence of a
universally accepted case denition and a paucity of appropriately
designed unbiased studies. Although clinically NE is a relatively
common condition, in population terms it is relatively rare. As a
consequence the casecontrol study design is the only realistic approach
to aetiological investigation. When poorly designed, casecontrol
studies can be subject to a number of biases which can seriously affect
the validity of the results and the reputation of casecontrol studies has
suffered as a consequence of poorly designed studies in the past. For
example, in studies in which cases and controls are identied solely
from tertiary care centres referral biases tend to lead to identication of
more severely affected cases and controls born to mothers with on
average poorer obstetric histories and other medical problems, leading
to biased estimates of the effects of risk factors and results which cannot
be generalised.
One of the inherent problems with trying to identify risk factors for
NE and quantify their impact is the implicit assumption that the risk
factors for NE will be universally applicable in different populations and
at different times. NE is a multifactorial disease and the distribution of
different causes and causal agents is likely to vary from place to place
and over time. If, for example, a causal agent is eliminated, then not only
will the incidence of the disease decrease, but the distribution and
impact of the remaining risk factors will also change. This effect has
clearly been seen in the changing epidemiology and risk factor prole of
sudden infant death syndrome following the introduction of the Back
to sleep campaign [25].
It is likely, however, that some risk factors are universal, although
it is not clear which ones these are. Nevertheless, the relative
importance of even universal risk factors is likely to be different in
different populations and at different times as other factors come into
play. Furthermore, our capacity to identify particular risk factors is
also affected by the relative frequency in the at-risk population at
large. For example, it is salutary to consider that if everyone in the
population smoked cigarettes, smoking, which is the single largest
cause of lung cancer, would never have been identied as a risk factor.
Expressed less dramatically, the frequency of exposure to a particular
risk factor in the general population has an impact on the likelihood
that it is identied as having a statistically signicant effect even if in
reality such an effect exists. Unless they have overwhelmingly
catastrophic effects both very uncommon and very common exposures require larger studies than moderately common exposures in

Fig. 2. Estimates of the incidence of hypoxicischaemic encephalopathy in term infants from population and hospital-based studies (excludes Airede [16] as estimate too high to be
included on the chart). *Population-based studies. Hospital-based studies.

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

Table 3
Pre-conception and antepartum risk factors for neonatal encephalopathy (NE) in term
infants based on two recent casecontrol studies [9,10,13].
Risk factors

Maternal age (years)

b20
2024
2529
3034
35
Parity: Primiparity

Western Australian
Cases=164; Controls=400
Adjusteda odds ratio
(95% condence interval)

1c
4.21 (1.01 to 17.5)
5.91 (1.42 to 25.5)
6.71 (1.53 to 29.4)
6.01 (1.28 to 28.2)
vs para 2+: 1.81
(0.87 to 3.73)
Measure of socio-economic status
Maternal employment
Professional
1c
Trade or clerical
1.26 (0.63 to 2.50)
Unskilled manual
3.84 (1.43 to 10.3)
Housewife
2.48 (1.14 to 5.39)
Unemployed
3.60 (1.10 to 11.8)
Missing
0.93 (0.33 to 2.60)
Maternal
Variable not reported
education (years)
N5
15
None
Health insurance
Private
1c
Public
3.46 (1.25 to 9.59)

Nepal
Cases=129; Controls=633
Adjustedb odds ratio
(95% condence interval)
1c
1.82 (0.95 to 3.51)
1.87 (0.81 to 4.34)
2.75 (0.98 to 7.76)
4.35 (1.04 to 18.2)
vs para 1+: 2.00
(1.10 to 3.61)

Variable not reported

1c
1.81 (0.88 to 3.73)
1.48 (0.83 to 2.67)
Not applicable in a
publicly funded
hospital with a modest
user charge
Variable not reported

Family history of seizures 2.55 (1.31 to 4.94)

(recurrent, non-febrile)
2.73 (1.16 to 6.41)
Variable not reported
Family history of
neurological disorders
excluding seizures
Infertility treatment
4.43 (1.12 to 17.6)
Variable not reported
Maternal height (cm)
b160
0.98 (0.57 to 1.70)
160164
1c
N164
0.79 (0.43 to 1.43)
b145
3.16 (1.50 to 6.66)
145154
1.07 (0.57 to 2.01)
N154
1c
Maternal thyroid disease 9.70 (1.97 to 47.9)
2.14 (1.19 to 3.82)d
Pre-eclampsia vs none
Severe: 6.30 (2.25 to 17.6) Any: 1.86 (0.82 to 4.22)
Bleeding: moderate or
3.57 (1.30 to 9.85)
Variable not reported
severe vs none
Documented viral illness 2.97 (1.52 to 5.80)
Variable not reported
Alcohol consumption
Some
1c
Variable not reported
None
2.91 (1.70 to 5.00)
Missing
6.38 (2.33 to 17.5)
Gestational age
at delivery (weeks)
37
2.35 (1.11 to 4.97)
Variable not reported
38
1.18 (0.90 to 1.56)
39
1c
40
1.41 (1.17 to 1.70)
41
3.34 (2.09 to 5.35)
42
13.2 (5.03 to 34.8)
Centile birth weight (adjusted for gestation, parity, maternal height and infant sex)
N90th
1c
10th90th
1.54 (0.66 to 3.62)
3rd9th
4.37 (1.43 to 13.4)
b3rd
38.2 (9.44 to 155)
Birth weight (g)
N2999
1c
25002999
1.36 (0.78 to 2.37)
b2500
0.73 (0.35 to 1.51)
Maternal haemoglobine (g/dL)
12.00
Not reported
1c
1011.99
1.58 (0.91 to 2.77)
89.99
1.45 (0.73 to 2.90)
b8.00
2.64 (1.00 to 9.01)
(continued on next page)

335

Table 3 (continued)
Risk factors

Western Australian
Cases=164; Controls=400
Adjusteda odds ratio
(95% condence interval)

Plurality
Singleton
1c
Twins
1.04 (0.11 to 9.55)
Abnormal appearance
2.07 (1.15 to 3.73)
of placenta
Number of antenatal care visits
Normal care
1c
Late or no
5.45 (0.47 to 63.0)
antenatal care
3
12
None
`

Nepal
Cases=129; Controls=633
Adjustedb odds ratio
(95% condence interval)
1c
22.1 (3.45 to 141)
Variable not reported

1c
0.68 (0.30 to 1.55)
2.05 (1.16 to 3.66)

a
Adjusted for all other variables listed and also: maternal race, maternal hypertension,
infant sex and level of hospital of delivery.
b
Adjusted for all other variables listed and also: previous neonatal death and infant
sex.
c
Baseline comparison group.
d
Based on increased concentration of thyroid stimulating hormone measured during
the puerperium.
e
Measured during the puerperium.

order to be identied; study power and consequently study size and

cost, are therefore important considerations.
We have tabulated the pre-conceptional, antepartum and peripartum risk factors for NE which were identied in the two most recently
published casecontrol studies (Tables 3 and 4) [9,10,13]. These tables
only include those variables found to be statistically signicant in one or
both studies; only adjusted odds ratios are quoted.
Growth restriction was the strongest risk factor for NE found in the
Western Australian (WA) study. As birth weight for gestation was not
reported from the study in Nepal its impact there was not known,
although low birth weight did not increase the risk of NE and indeed the
point estimate indicated a non-signicant protective effect. The causes
of the growth restriction in the WA cases were not reported but were
likely to be numerous; however, the presence of growth restriction in
13% of cases suggests a pre-existing potential vulnerability prior to the
onset of labour for this group. The risk of NE also increased for every
completed week of gestation after 39 weeks in a curvilinear J-Shaped
pattern to 42 weeks. The strongest risk factor in the Nepalese data was
twin pregnancy which was not associated with an increase in the odds
of NE in the WA despite there being a similar proportion of twins in the
controls which suggests that twining is equally common in the two
populations, although diagnosis, management and the overall prospective for twins may have differed.
Socio-demographic and obstetric risk factors present prior to
conception included older maternal age, parity (only in Nepal), socioeconomic status to some extent, alcohol consumption (only in WA)
and maternal height in Nepal. There was a doseresponse relationship
between the odds of NE and increasing maternal age in both studies.
The strong correlation between maternal age and parity makes the
independent effects of these two factors difcult to disentangle and a
signicant effect of parity having adjusted for maternal age was only
evident in Nepal with primiparity having a protective effect.
The known risk factors for neonatal seizures and cerebral palsy of a
family history of seizures and other neurological disorders [26] were
found in the WA data but not reported in the results from Nepal.
However, since both studies only reported statistically signicant
ndings it is not clear whether this was because these effects were not
found or the data were not collected in Nepal, although because antenatal
notes were not available to the investigators in Nepal who had to reply
solely on maternal interview and intrapartum records, the latter seems
more likely. A history of infertility treatment and thyroid disease which

336

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

Table 4
Peripartum risk factors for neonatal encephalopathy (NE) in term infants based on two recent casecontrol studies [9,10,13].
Risk factors

Presentation
Occipitoanterior and non-cephalic
Occipitoposterior
Cephalic
Non-cephalic
Onset of labour
Spontaneous
Induced
None
Syntocinon
None
Induction
Augmentation
Maternal pyrexia during labour ( 37.5 C)
Intrapartum complications and events
None
Acute intrapartum eventd
None
Clinically obstructed labour
Othere
Membrane to rupture delivery interval
12 h
N12 h
24 h
N24 h
Meconium
None
Thin
Thick
Mode of delivery
Spontaneous vaginal
Induced vaginal
Instrumental vaginal
Elective caesarean section
Emergency caesarean section
Breech manoeuver
General anaesthesia

Western Australian
Cases = 164; Controls = 400
Adjusteda odds ratio
(95% condence interval)

Nepal
Cases = 129; Controls = 633
Adjustedb odds ratio
(95% condence interval)

1c
4.29 (1.74 to 10.5)
1c
3.35 (1.38 to 8.11)
1c
0.97 (0.57 to 1.68)
0.17 (0.04 to 0.49)

1c
5.28 (2.03 to 13.8)
None reported

Not reported

1c
9.09 (3.32 to 24.8)
3.51 (2.04 to 6.07)
Not reported

3.82 (1.44 to 10.1)

1c
4.44 (1.30 to 15.2)

1c
5.73 (2.30 to 14.2)
28.2 (2.88 to 275)
1c
1.31 (0.69 to 2.47)
1c
3.84 (1.56 to 9.47)
Unadjusted resultf
1c

[16.7 (5.76 to 50.0)]

1c
1.10 (0.55 to 2.18)
2.34 (1.16 to 4.70)
0.17
2.17
1.54
3.08

(0.05
(1.10
(0.10
(1.16

to.056)
to 4.64)
to 25.1)
to 8.17)

1c
6.04 (2.56 to 14.3)
18.2 (8.05 to 41.2)
1c
Vacuum: 7.93 (3.02 to 20.8)
Forceps: 6.11 (1.01 to 37.2)
Not estimated as no cases in this group
3.91 (1.96 to 7.84)
Not reported

Adjusted for factors before conception and antepartum: maternal age, parity, employment status, health insurance, race, family history of seizures and other neurological
disease, infertility treatment, hypertension, height, thyroid disease, pre-eclampsia, moderate or severe antepartum bleeding, viral illness, alcohol consumption, gestational age at
delivery, centile birth weight, infant sex, placental appearance, late or no antenatal care, level of hospital of delivery and plurality. Not adjusted for the factors listed in the table.
b
Adjusted for factors before conception and antepartum: maternal age, parity, education, height, previous neonatal death, antenatal care, pre-eclampsia, birth weight, infant sex
and plurality. Not adjusted for the factors listed in the table.
c
Baseline comparison group.
d
Haemorrhage, maternal convulsions, uterine rupture, snapped cord and birth of baby before arrival at obstetric facility.
e
Haemorrhage, maternal convulsions, uterine rupture and cord prolapse.
f
Meconium, abnormal intrapartum CTG and fetal distress which are normally considered to reect intrapartum hypoxia were not included in the adjusted analysis as they were
thought likely to be along the causal pathway for, or the rst signs of, NE or were markers of encephalopathy. Inclusion of these markers would have masked the effects of other
variables working through them.

have been implicated in cerebral palsy [2628] had not been previously
described in relation to NE; both were identied as risk factors in the WA
data and the latter but not the former was also found in Nepal.
A history of antepartum bleeding in association with NE was described
by Finer et al. [19] and was found in the WA but not the Nepalese data.
Severe pre-eclampsia increased the odds of NE in the WA study but not
the study from Nepal. Interestingly the incidence of any grade of severity
of pre-eclampsia was over 14% in the controls from WA compared with
only 5.4% of controls in Nepal. This may represent either a natural
variation in the incidence of pre-eclampsia, even though primiparity was
more common in Nepal, or a difference in diagnosis. Of note 16% of the
control women in Nepal did not receive any antenatal care compared with
only 0.2% (1 woman who booked late) of controls in WA which may have
led to under diagnosis of conditions such as pre-eclampsia in Nepal. There
was a much higher odds of NE associated with late or no antenatal care in
WA than no care in Nepal, but only the latter was statistically signicant
probably because of the small number of cases and control in WA who

received no antenatal care or booked late: only 0.2% of controls and 3.7% of
cases in WA compared with 16% and 28% respectively in Nepal.
The potential role of infection was hinted at in the results from
both WA and Nepal. A history of viral illness documented in the
obstetric notes and maternal pyrexia in labour were both statistically
signicantly associated with NE in WA and prolonged membrane
rupture to delivery interval was a risk factor in Nepal (but not WA).
Non-cephalic presentation, induction and augmentation of labour
were risk factors in the study from Nepal although indication information
was not reported and it is possible that these interventions represent a
response to fetal compromise rather than the cause. In WA only
presentation in an occipitoposterior position was a risk factor. A similar
rate of catastrophic intrapartum events including haemorrhage, maternal
convulsions, uterine rupture and cord accidents was described in both
studies with a similar frequency of 78% in the cases. In addition clinically
obstructed labour was present in 15% of the cases in Nepal; this condition
was not reported from the WA data. Evidence of fetal distress in the form

J.J. Kurinczuk et al. / Early Human Development 86 (2010) 329338

of meconium stained liquor was a risk factor in both datasets. Nonspontaneous vaginal modes of delivery were important risk factors
particularly in Nepal. It was possible to quantify the protective effect of
elective caesarean section in the WA data but not the data from Nepal
because no Nepalese cases had an elective section. Again variations in
clinical practice in the developing compared with the developed country
were evident from the controls where the elective caesarean section rate
was only 2.5% versus 14.5% respectively and the emergency caesarean
section rates were 6.7% and 9.5% respectively.
The data from both studies were used to attempt an estimation of
the contribution of intrapartum hypoxia to the cases overall. Less than
a third (29%) of the WA cases had evidence of intrapartum hypoxia
based on relatively non-specic criteria which have a high false
positive predictive value [22] and including cases in which a
signicant intrapartum event is likely to have been associated with
recent acute hypoxia; furthermore, of these cases only 4% had no
antenatal risk factors identied whereas 25% did. In the study from
Nepal overall 43% of cases met similar criteria used to identify
evidence of intrapartum hypoxia with a further 17% of cases with
evidence of a signicant intrapartum event which was probably
associated with fetal hypoxia giving a total of 60%.

337

There are numerous risk factors for NE some of which are common
to both developing and developed country settings. Potentially
modiable risk factors include the management of maternal thyroid
disease, the role of infection and aspects of the management of
labour including particularly the management of labour induction
and provision of better antenatal care in the developing country
setting.
Research directions:
Work is under way to try to reach consensus on the denitions of NE
and HIE.
Up-to-date studies are needed to test hypotheses about potentially
modiable risk factors raised in the most recently conducted studies
which are now over a decade old. These should include the collection
of data from cases and appropriately selected unbiased controls.
Data collection should include detailed clinical data, information from
maternal interview, neonatal brain imaging and aEEG recording on all
cases, genetic and metabolic analysis, sensitive measures of the
presence of infection and condential evaluation of the care provided
before, during and after delivery.

5. Future directions

Acknowledgements

The causal chain of events resulting in NE is complex, multifactorial

and far from completely understood. Several promising lines of enquiry
and hypotheses relating to potentially modiable risk factors were
generated by previous epidemiological studies although these studies
are now well over a decade old and there have been substantial changes
in clinical practice and clinical governance since their publication. Even
the most recent population-based studies were carried out before
improved cerebral imaging techniques were commonly available.
Advances in cranial ultrasound and magnetic resonance (MR) brain
imaging have led to a much better understanding of the relationship
between brain injury and the likely timing of the causal insult in the
antepartum and peripartum periods [29,30]. Amplitude integrated EEG
(aEEG) is becoming routine in clinical practice. There have also been
promising developments in understanding the effects on hypoxic injury
of variations in genetic susceptibility and metabolic phenotypes, and the
presence of infection [3133]. All of these developments merit further
investigation in appropriately sized population-based casecontrol
studies which would also benet from the incorporation of an
evaluation of the quality of care provided before, during and after
labour using condential enquiry methods [34,35]. Reaching agreement
on the case denitions of both NE and HIE is a vital rst step and a project
is currently underway to try to achieve this using a similar consensus
method to that used by MacLennan and the International Cerebral Palsy
Task Force [36].
Key guidelines:

This paper reports on independent work which is part-funded by

the Policy Research Programme in the Department of Health, England.
The views expressed are not necessarily those of the Department.

Neonatal encephalopathy (NE) is a clinical dened syndrome of

disordered neonatal brain function for which there is, as yet, no
universally accepted denition.
The term hypoxic ischaemic encephalopathy (HIE) should be
reserved for the sub-set of cases of NE where there is good evidence
of a recent, and usually an intrapartum, hypoxicischaemic cause of
the encephalopathy. The use in clinical practice of terms, which in
common usage have pejorative connotations including birth
asphyxia and perinatal asphyxia, should be discouraged.
The incidence of NE is estimated to be between 2.5 and 3.5 per 1000
live births with a combined point estimate of 3.0 per 1000 live births.
The incidence of HIE is estimated to be between 1.3 and 1.7 per 1000
live births with a combined point estimate of 1.5 per 1000 live births.
An estimated 30% of cases of NE in developed countries and 60% of cases
in developing countries are associated with evidence of intrapartum
hypoxic-ischaemia.

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