Original research

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2021-322906 on 15 April 2022. Downloaded from http://fn.bmj.com/ on October 28, 2022 at World Health
Availability of active therapeutic hypothermia at birth
for neonatal hypoxic ischaemic encephalopathy: a UK
population study from 2011 to 2018
Aarti Mistry  ‍ ‍,1 Lara Shipley  ‍ ‍,1 Shalini Ojha  ‍ ‍,1 Don Sharkey  ‍ ‍,1,2 UK
Neonatal Transport Research Collaborative (UK-­NTRC)

► Additional supplemental ABSTRACT

material is published online
only. To view, please visit the
journal online (http://d​ x.​doi.​
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2021-​322906).
1
Centre for Perinatal Research
(CePR), University of
Nottingham School of Medicine,
Nottingham, UK
2
Objective  Therapeutic hypothermia (TH) commenced What is already known on this topic?
soon after birth for neonatal hypoxic ischaemic
⇒ Active therapeutic hypothermia (TH) for
encephalopathy (HIE) improves survival and reduces
neonatal hypoxic ischaemic encephalopathy
neurodisability. Availability of active TH at the place of
(HIE) improves survival without neurodisability.
birth (Immediate-­TH) in the UK is unknown.
⇒ Infants with HIE achieving early therapeutic
Design  Population-­based observational study.
target temperature are less likely to have
Setting  UK maternity centres.
seizures and a poor neurological outcome.
Patients  5 975 056 births from 2011 to 2018.

Organisation (HINARI) - Group A. Protected by copyright.

UK Neonatal Transport
Research Collaborative (UK-­
NTRC), Neonatal Transport
Group, Nottingham, UK
Correspondence to
Professor Don Sharkey, Centre
for Perinatal Research (CePR),
University of Nottingham School
of Medicine, Nottingham, NG7
2UH, UK;
d​ on.​sharkey@n​ ottingham.​ac.​uk
Received 27 July 2021
Accepted 17 March 2022
Published Online First
15 April 2022
© Author(s) (or their
employer(s)) 2022. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Mistry A, Shipley L,
Ojha S, et al. Arch Dis Child
Fetal Neonatal Ed
2022;107:F597–F602.
Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F597–F602. doi:10.1136/archdischild-­2021-­322906
Intervention methods  For each maternity centre, the
year active Immediate-­TH was available and the annual
birth rates were established. Admission temperatures
of infants with HIE transferred from non-­tertiary centres
with and without Immediate-­TH were compared.
Main outcome measures  Quantify the annual
number of births with access to Immediate-­TH.
Secondary outcomes included temporal changes in
Immediate-­TH and admission temperatures for infants
requiring transfer to tertiary centres.
Results  In UK maternity centres, 75 of 194 (38.7%)
provided Immediate-­TH in 2011 rising to 95 of 192
(49.5%, p=0.003) in 2018 with marked regional
variations. In 2011, 394 842 (51.2%) of 771 176 births
had no access to Immediate-­TH compared with 276 258
(39.3%) of 702 794 births in 2018 (p<0.001). More
infants with HIE arrived in the therapeutic temperature
range (76.5% vs 67.3%; OR 1.58, 95% CI 1.25 to 2.0,
p<0.001) with less overcooling (10.6% vs 14.3%; OR
0.71, 95% CI 0.51 to 0.98, p=0.036) from centres with
Immediate-­TH compared with those without.
Conclusions  Availability of active Immediate-­TH has
slowly increased although many newborns still have no
access and rely on transport team arrival to commence
active TH. This is associated with delayed optimal
hypothermic management. Provision of Immediate-­TH
across all units, with appropriate training and support,
could improve care of infants with HIE.
INTRODUCTION
Globally, hypoxic ischaemic encephalopathy (HIE)
is the largest contributor of term newborn brain
injury with a UK incidence of 2.03 per 1000 live
births for moderate/severe HIE,1 and is associated
with significant costs from both a litigation and
healthcare provision perspective.2 Therapeutic
hypothermia (TH) is a well-­established, safe and
effective treatment for HIE if commenced within
6 hours of birth,3 increasing survival without
disability.4 5 In the UK, initiatives are underway to
halve birth-­related brain injury by 2025.6 7
What this study adds?
⇒ Between 2011 and 2018 in the UK, births with
access to active TH in their birthing centre have
marginally increased and marked regional
variability exists.
⇒ In 2018, 39% of UK births did not have
immediate access to active TH but almost all
infants had access once the transport team
arrived.
How this study might affect research,
practice or policy
⇒ Increasing access to active TH in all birthing
centres could improve the care infants with HIE
receive and reduce current disparities.
The diagnostic criteria used to commence TH in
the TOBY trial8 have been widely adopted including
in UK national guidance.9 These criteria include
early identification of risk factors and neurological
status supported with amplitude-­ integrated elec-
troencephalography (aEEG), which has become
a useful tool in the management of HIE and
supporting outcome prediction.10 Active TH using
a servo-­controlled device provides the optimal
method of administrating targeted hypothermia in
a controlled way.11 These devices are more effec-
tive in reaching and maintaining optimal thera-
peutic temperatures of 33°C–34°C8 9 compared
with passive cooling where the risk of overcooling
(<33°C) and potential harm is greater.12 13
In the UK, active TH was primarily adopted
by neonatal intensive care units, that are, tertiary
cooling centres; its recognition of benefit and the
technology’s relative simplicity and safety has led
to uptake by other maternity centres and transport
   F597
 Original research
teams.14–16 Both animal and human studies suggest that the
earlier the target temperature is achieved, the better the neuro-
logical outcome,17–20 hence access to active TH in all maternity
centres should be considered to ensure equitable provision.21
Study aims
The aim of the study was to quantify the proportion of births
in the UK who have access to active TH in their birth centre
(Immediate-­TH) and identify any temporal changes and regional
disparities. In addition, we aimed to compare the temperature
on admission to a tertiary cooling centre for infants with HIE
following transfer from non-­tertiary centres with and without
Immediate-­TH.
METHODS
Access to TH equipment
UK maternity centres with access to active TH between 2011
and 2018 were identified in two ways. First, using the TOBY
Register8 of UK cooling centres, we identified those under-
taking TH in 2011. Second, members of the UK-­ Neonatal
Transport Research Collaborative (UK-­ NTRC) completed a
survey identifying each maternity centre within their neonatal
network with access to active TH and the year commissioned.
The availability of aEEG was also established at the end of
2018 to allow population coverage costs to be estimated.
Each UK-­NTRC transport service also identified the year they
started active TH during transfer for infants with HIE. This
allowed every maternity centre, by year, to be assigned one of
three classifications:
1. Active TH available immediately at birth centre
(Immediate-­TH).
2. Active TH initiated on arrival of the transport team
(Transport-­TH).
3. Active TH initiated on arrival at a tertiary cooling centre
(Tertiary-­TH).
In the UK, tertiary centres are those providing neonatal inten-
sive care (level 3), non-­tertiary centres are local neonatal units
(level 2) and special care units (level 1) that do not routinely
care of infants with HIE requiring TH. For the purposes of the
analysis, active TH did not include passive cooling.
Maternity centre births and neonatal units
Total births from 2011 to 2018 (the latest year data were avail-
able) were obtained for each maternity centre using national
databases in England (National Health Service (NHS) Mater-
nity Statistics),22 Scotland (Scottish Morbidity Register),23 Wales
(National Community Child Health Database and NHS Wales
Informatics Service)24 and Northern Ireland (Northern Ireland
Statistics and Research Agency)25 (online supplemental table 1).
Births in England were reported as a maternity, each maternity
counting as one birth (live and stillbirths) irrespective of the
plurality (online supplemental table 2). Where centres in England
reported combined birth numbers within a healthcare Trust,
their births were differentiated using a ratio of each centre’s
known birth rate obtained from the Office for National Statis-
tics.26 Births in Scotland and Wales were reported as total births
(live and stillbirths), Northern Ireland births were reported as
live births. Freestanding midwifery-­led centres were excluded, as
they lack access to immediate neonatal care, and TH initiation is
not recommended from this setting21; they account for <2% of
the total UK births.27 28
F598 Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F597–F602. doi:10.1136/archdischild-­2021-­322906
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2021-322906 on 15 April 2022. Downloaded from http://fn.bmj.com/ on October 28, 2022 at World Health
Modelling ambulance journey times
For maternity centres without Immediate-­ TH, road journey
times were calculated between the transport service base to refer-
ring maternity centre and then to their nearest tertiary cooling
centre using online mapping software.29 Mean journey times
were calculated from three estimated hypothetical journeys over
a range of time points (midweek morning, weekday afternoon,
weekend morning). Initiating TH for HIE within 6 hours of
age is a benchmark agreed by neonatal transport services inter-
nationally,30 although HIE is not universally considered time-­
critical.30–32 As a proxy for timely dispatch, a 60-­minute dispatch
time was added to each journey to represent the quickest time-­
critical turnaround time. These journey times were used to
model estimates for the earliest potential time that active TH
could be commenced from the point of referral to a transport
service (the Isle of Wight centre was excluded as it combines
road and sea transfer).
Clinical database
Using data from a parallel study,1 infants 36–42 weeks’ gesta-
tional age, born in a UK non-­ tertiary centre between 2011
and 2016, with a diagnosis of moderate/severe HIE and were
Organisation (HINARI) - Group A. Protected by copyright.
transferred for TH were identified from the National Neonatal
Research Database (NNRD).33 Admission temperature following
transfer to the tertiary cooling centre was compared between
birth centres with and without Immediate-­TH, using specific
NNRD data fields (online supplemental table 3). The NNRD
collates prospective demographic and clinical data, which are
anonymised and cleaned by the Neonatal Data Analysis Unit
prior to its entry into the database. The NNRD is a designated
approved data set outlined by the National Neonatal Data Set
and validated by the Standardised Committee for Care Infor-
mation.33 34
Statistical analysis
Descriptive statistics were used to describe the provision of
Immediate-­ TH, Transport-­TH and Tertiary-­ TH for each year
and Χ2 test for trend (Cochran-­Armitage test) used to assess
significance of trends over time. Collating each centre’s data
into neonatal networks35 identified regional variations. Ambu-
lance journey times for each year were tested for normality and
Kruskal-­Wallis with Dunn’s correction used to assess significance.
Secondary outcomes were described using OR and Χ2 for trends.
A p value of <0.05 was considered statistically significant. All
analyses were performed in GraphPad Prism V.9.
RESULTS
From 2011 to 2018, there were a total of 5 975 056 births
included in the analysis. The total births across the UK declined
by 9% from 2011 to 2018 (online supplemental table 4).
Access to active TH
In 2011, there were 194 maternity centres with 75 (38.7%)
providing Immediate-­ TH, increasing in 2018 to 95 of 192
centres (49.5%, p=0.003, table 1). Expansion of Immediate-­TH
mostly occurred in local neonatal units. Proportionally, births
with Immediate-­TH access increased from 376 334 (48.8%) in
2011 to 426 536 (60.7%) in 2018 (p<0.001, online supple-
mental table 4).
Of the 394 842 (51.2.%) births occurring in centres without
Immediate-­ TH access in 2011, 171 775 (43.5%) had access
to Transport-­TH with 223 067 (56.5%) reliant on transfer for
Tertiary-­TH. In 2018, the number of births without access to
 Original research

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2021-322906 on 15 April 2022. Downloaded from http://fn.bmj.com/ on October 28, 2022 at World Health
Table 1  UK maternity centres and neonatal units with provision of therapeutic hypothermia (TH) from 2011 to 2018
Year 2011 2012 2013 2014 2015 2016 2017 2018
Number of UK maternity centres 194 195 195 194 194 193 193 192
 Immediate-T­ H, n (%) 75 (38.7) 77 (39.5) 78 (40.0) 80 (41.2) 85 (43.3) 87 (45.1) 93 (48.2) 95* (49.5)
 Transport-­TH, n (%) 52 (26.8) 63 (32.3) 81 (41.5) 80 (41.2) 105 (54.1) 103 (53.4) 98 (50.8) 95** (49.5)
 Tertiary-­TH, n (%) 67 (34.5) 55 (28.2) 36 (18.5) 34 (17.6) 11 (5.7) 3 (1.6) 2 (1.0) 2 (1.0)
Neonatal units with Immediate-­TH
 NICU (level 3), n (%)† 53 (92.9) 55 (96.4) 55 (96.4) 56 (98.2) 56 (98.2) 56 (98.2) 56 (98.2) 55 (98.2)
 LNU (level 2), n (%)† 22 (24.2) 22 (24.4) 23 (25.3) 24 (26.4) 24 (31.9) 31 (34.1) 32 (35.2) 35 (38.5)
 SCU (level 1), n (%)† 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 5 (11.1) 5 (11.1)
*P=0.003 and **p<0.001 Χ2 test for trend.
†Percentage based on total number of units within each level.
LNU, local neonatal unit; NICU, neonatal intensive care unit; SCU, special care unit.

Immediate-­TH was 276 258 (39.3%) with significantly more able
to access Transport-­TH (273 382, 98.9%) compared with 2011
(p<0.001, online supplemental table 4). By 2016, over 99%
of births had access to either Immediate-­TH or Transport-­TH
(figure 1). By 2019, the UK-­NTRC reported 129 of 192 mater-
Admission temperatures
Between 2011 and 2016, 2573 infants were born in non-­tertiary
centres with moderate/severe HIE and were transferred to a
tertiary cooling centre for TH. Of these infants, 475 (18.5%)
had access to Immediate-­TH and the remaining 2098 (81.5%)

Organisation (HINARI) - Group A. Protected by copyright.

nity centres had aEEG equipment.
Regional differences
The median percentage of births in regions with Immediate-­TH
was 52.6% in 2011 and 64.9% in 2018 (online supplemental
table 4). Over the study period, only 8 of 14 networks increased
the number of maternity centres with Immediate-­ TH provi-
sion. The South East Coast Neonatal Network had the greatest
increase in the percentage of births with Immediate-­TH from
32.2% in 2011 to 95.4% in 2018 (figure 2).
Earliest potential time to commence active TH
In the UK, neonatal transport services underwent reconfigura-
tion reducing from 20 to 15 transport services over the study
period. By 2017, 14 of the 15 transport services provided active
TH in transit for infants with HIE. For maternity centres without
Immediate-­TH, the earliest potential time to start active TH by
either Transport/Tertiary-­TH from the point of referral was esti-
mated (figure 3). In 2011, those without Immediate-­TH had a
median time of 122 min (IQR 105–146), with maximum time
of 328 min to commence active TH; by 2018, the median time
reduced to 104 min (IQR 92–129, p<0.001), with maximum
time of 243 min.
Figure 1  Provision of Immediate-­TH, Transport-­TH and Tertiary-­TH in
relation to percentage of total UK births from 2011 to 2018. **P<0.001
Χ2 for trend Immediate-­TH compared with those without Immediate-­TH.
TH, therapeutic hypothermia.
Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F597–F602. doi:10.1136/archdischild-­2021-­322906
required Transport-­TH or Tertiary-­ TH (online supplemental
table 5). A total of 2466 infants had admission temperatures
recorded following transfer (online supplemental table 6). In
2011, there was no difference between infants achieving optimal
therapeutic temperatures (33°C–34°C) with or without Immedi-
ate-­TH (64.3% vs 60.4%, respectively; OR 1.18, 95% CI 0.61
to 2.25, p=0.63, figure 4). In 2016, infants with Immediate-­TH
were more likely to arrive within therapeutic range (83.5% vs
73.7%; OR 1.81, 95% CI 1.05 to 3.16, p<0.036, figure 4).
Overall, infants without Immediate-­ TH (n=2011), compared
with Immediate-­TH (n=455), were more likely to arrive outside
the optimal therapeutic temperature range (32.7% vs 23.5%;
OR 1.58, 95% CI 1.25 to 2.0, p<0.001) and have an admission
temperature <33°C (14.3% vs 10.5%; OR 1.41, 95% CI 1.02 to
1.95, p=0.036, online supplemental table 6).
DISCUSSION
Neonatal HIE is the leading cause of brain injury in term
infants, and treatment within 6 hours of birth reduces death and
disability,4 5 with some evidence stating that the earlier thera-
peutic temperature is reached, the better the outcome.17 19 20 This
is the first national study to describe the temporal changes and
regional variations in access to active Immediate-­TH in maternity
centres. During the study period, there has been a small increase
in availability of TH, mostly in local neonatal units, with 50 000
more births in 2018 having access to Immediate-­TH if needed.
Despite this, approximately 275 000 (39%) of UK births in 2018
still occurred in centres without Immediate-­TH.
Using 6 years’ worth of national data, we identified 2098
infants with HIE who were transferred to a tertiary cooling
centre from a maternity centre without Immediate-­ TH. This
equates to approximately 350 babies per year who poten-
tially receive suboptimal TH with passive cooling. The delay
achieving therapeutic temperatures and the risk of overcooling
may adversely impact their outcome.12 13 The adoption of active
TH by neonatal transport teams has partly compensated this,
with over 98% of births without Immediate-­TH now able to
access TH at their birth centre on the arrival of the transport
team. Infants with HIE born in centres with active TH were
more likely to be in the therapeutic temperature range following
transfer to the tertiary centre36 and, importantly, less were over-
cooled, which is associated with adverse effects.12 13
F599
 Original research
Figure 2  Heat map showing the percentage of births within UK regions, based on neonatal networks, with Immediate-­TH access in 2011 and
2018. The scale is presented as quintiles of the percentage of regional births with Immediate-­TH access. Powered by Bing DSAT for MSFT, Geonames,
Microsoft, Navteq. TH, therapeutic hypothermia.
We observed inequalities in UK availability of Immedi-
ate-­
TH with access varying from 31% to 95% of regional
network births. The significant improvement in the South East
Coast Network reflects work from their network-­wide quality
improvement project ‘Time=Brain’ consisting of education,
outreach training and provision of TH equipment.37 To imple-
ment similar initiatives nationwide would require an estimated
Figure 3  Violin plot of earliest estimated time to start active TH from
the point of referral for births in centres without Immediate-­TH from
2011 to 2018. Statistical significance comparing 2011 with 2018 using
Kruskal-­Wallis and Dunn’s correction test, **p<0.001. TH, therapeutic
hypothermia.
F600 Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F597–F602. doi:10.1136/archdischild-­2021-­322906
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2021-322906 on 15 April 2022. Downloaded from http://fn.bmj.com/ on October 28, 2022 at World Health
Organisation (HINARI) - Group A. Protected by copyright.
£2.5 million to provide active Immediate-­TH and aEEG equip-
ment for those centres without these resources. These costs seem
small compared with the £1.9 billion incurred annually in the
UK around litigation claims for birth-­related brain injury,2 38
not including the additional healthcare expenses for disability.2
Based on this analysis, the current rate at which Immediate-­TH
provision is increasing, approximately 6300 more births per
year, it could take a further 40 years without additional resource
for the remaining birth population to gain access.
Expansion of Transport-­TH over the study period was linked
with benchmarking and reporting by the UK-­Neonatal Transport
Group (UK-­NTG) against national transport targets.32 In addi-
tion, neonatal transfer studies have found servo-­controlled TH
to be safe and effective.14–16 39 Consequently, there was a rapid
increase in Transport-­TH, effectively reducing the potential time
to initiate active TH by almost 2 hours.10 16
Animal studies support early TH (<3 hours of age) with less
neuronal loss and better neuroprotection compared with late
(3–6 hours) or delayed (>6 hours) treatment.17 18 20 40 This is
supported by observational human data showing better motor
development19 and less occurrence of seizures.41 42 Seizures
associated with HIE can increase the long-­term risk of a poor
neurodevelopmental outcome.43–45 For some infants with HIE
requiring transfer, achieving therapeutic temperatures within
6 hours of age, even with Transport-­ TH, is still challenging.
The UK-­ NTG 2019 data reported only 76% of 279 infants
with HIE transferred with active TH reached the therapeutic
temperature target by 6 hours of age.31 We demonstrate nation-
ally, more infants in non-­tertiary centres with Immediate-­TH
 Original research

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2021-322906 on 15 April 2022. Downloaded from http://fn.bmj.com/ on October 28, 2022 at World Health
achieve therapeutic temperatures, with less overcooling on
arrival to their tertiary cooling centre than those without Imme-
diate-­
TH. Similar benefits have been reported where infants
reach therapeutic temperatures 2 hours earlier if active TH was
commenced prior to the arrival of the transport team compared
with infants passively cooled.13 36 Access to Immediate-­TH could
help alleviate the time pressure faced by transport teams30–32 and
potentially improve outcomes for at-­risk infants, through early
TH initiation, a recommendation incorporated into a new UK
national framework.21

Strengths and limitations

The strengths of this study include the utilisation of national
data to quantify changes over time across an entire healthcare
system in the UK. We also used nationally collected data on
infants transferred for TH from non-­tertiary centres providing
insights into the temporal changes on temperature control.
The main limitation of our study is the birth denominators
varied by country, potentially underestimating by 20 000–25
000 each year due to English births being reported as materni-
ties, equating to approximately 3% of the population.

Organisation (HINARI) - Group A. Protected by copyright.

Additional limitations include the model estimates on the
earliest potential time to start TH do not factor in real-­time
delays of road-­traffic conditions, variable dispatch time or the
age at which a referral is made.14 31 The use of NNRD for HIE
does have limitations1 but the large cohort of infants analysed
partly mitigates this. We have not adjusted for differing clinical
variables, which may influence temperature data. Addition-
ally, varying practices between maternity centres and transport
services could not be accounted for. Finally, there could be recall
bias with healthcare professionals identifying the year TH was
commissioned.
CONCLUSION
Availability of Immediate-­TH for HIE has gradually increased
across maternity centres in the UK, however, there remains
significant variability between regions resulting in disparities
with access to optimal care. To reduce birth-­related brain injury
and implement new UK frameworks, investment is needed now
to expand the provision of active TH and aEEG to all maternity
centres, alongside training, education and support by tertiary
centres. This cost-­effective solution could address the inequali-
ties in delivery of TH, alleviate pressures on transport teams and
help improve outcomes through earlier initiation of TH.
Twitter Aarti Mistry @AartiMistry5, Lara Shipley @DrLTurner, Shalini Ojha @
shaliniojha7 and Don Sharkey @DrDonSharkey
Figure 4  The percentage distribution of admission temperatures on
arrival to the tertiary cooling centre of infants ≥36 weeks’ gestational
age with moderate or severe HIE born in non-­tertiary centres without
Immediate-­TH (n=2011, (A)) and with Immediate-­TH (n=455, (B)) from
2011 to 2016. Χ2 for trend for temperature within therapeutic range
(33°C–34°C), infants without Immediate-­TH, p<0.001 and infants with
Immediate-­TH p<0.01. HIE, hypoxic ischaemic encephalopathy; TH,
therapeutic hypothermia.
Foundation Trust; Scottish Specialist Transport and Retrieval Service, Princess Royal
Maternity, Glasgow; Kent Neonatal Transport Service, Medway NHS Foundation
Trust, Kent; KIDS-­Neonatal Transfer Service; London Neonatal Transport Service, Royal
London Hospital, Whitechapel, London; Acute Neonatal Transfer Service, East of
England; Newborn Emergency Stabilisation and Transport Team, University Hospitals
Bristol and Weston Foundation NHS Trust; Northern Neonatal Transport Service;
The Grange University Hospital, Cwmbran; London Neonatal Transfer Service, Barts
Health NHS Trust, London; Northern Ireland Specialist Transport and Retrieval and
University Hospitals Sussex NHS Foundation Trust.

Acknowledgements  To the UK-­Neonatal Transport Research Collaborative
(UK-­NTRC) and UK-­Neonatal Transport Group (UK-­NTG) for their support in this
study. Professor D McNally, University of Nottingham and chief investigator on i4i
NIHR project below. Electronic patient data recorded at participating neonatal units
that collectively form the UK Neonatal Collaborative (UKNC) are transmitted to
the Neonatal Data Analysis Unit (NDAU) to form the National Neonatal Research
Database (NNRD). DS had full access to all the data in the study and takes full
responsibility for the integrity of the data and accuracy of the data analysis. We are
grateful to all the families who agreed to the inclusion of their baby’s data in the
NNRD, the health professionals who recorded data and the NDAU team.
Collaborators  On behalf of the UK-­NTRC, an affiliated group of the UK-­NTG: E
Adams, I M Dady, H Darby, S J Davidson, N Davey, N Fowler, C H Harrison, A Jackson,
J Madar, A Leslie, S Pattnayak, A Philpott, N Ratnavel, S Rattigan, J Tooley, P Turton,
M S Reddy, P Sakhuja, R Tinnion, A Walker and L Watts. Collaborators’ affiliations
are as follows: Oxford University Hospitals NHS Foundation Trust; Connect North
West Neonatal Transport Service, Manchester University NHS Foundation; University
Hospitals Plymouth NHS Trust, Plymouth, UK; University Hospitals Southampton NHS
Foundation Trust; CenTre Neonatal Transport Service, University Hospitals of Leicester;
Embrace Transport service, Sheffield Children’s NHS Trust; Manchester University NHS
Contributors  DS is the guarantor of this study. AM and DS made substantial
contributions to the concept, planning, design of the study and acquisition of data.
LS and DS collated the secondary outcome data from the NNRD. The UK Neonatal
Transport Research Collaborative (UK-­NTRC) helped identify centre equipment access
and revised the final manuscript. AM, LS, SO and DS assisted in drafting and editing
the manuscript. All authors approved the final version for publication.
Funding  AM was part of the project funded by the National Institute for Health
Research (NIHR) i4i programme (II-­LA-­0715-­20003) and DS was a co-­investigator on
the same award.
Disclaimer  The views expressed are those of the author(s) and not necessarily
those of the NIHR or the Department of Health and Social Care.
Map disclaimer  The inclusion of any map (including the depiction of any
boundaries therein), or of any geographic or locational reference, does not imply the
expression of any opinion whatsoever on the part of BMJ concerning the legal status
of any country, territory, jurisdiction or area or of its authorities. Any such expression
remains solely that of the relevant source and is not endorsed by BMJ. Maps are
provided without any warranty of any kind, either express or implied.
Competing interests  None declared.

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;107:F597–F602. doi:10.1136/archdischild-­2021-­322906 F601
 Original research
Patient consent for publication  Not required.
Ethics approval  The study was performed in line with the principles of the
Declaration of Helsinki. Ethical approval was granted by London–City and East
Research Ethics Committee (REC: 17/LO/1822). National Neonatal Research
Database (NNRD) data extracted and supplied by the Neonatal Data Analysis
(NDAU) are anonymised data and therefore did not require informed consent.
Provenance and peer review  Not commissioned; externally peer reviewed.
All data relevant to the study are included in the article or uploaded as
supplementary information. All National Birth statistics were obtained from publicly
available databases. All survey data from UK-­NTRC was contributed freely and under
consent of each UK Neonatal Transport service. NNRD data extracted and supplied
by the Neonatal Data Analysis (NDAU) were available from the corresponding author
on reasonable request and with permission of the study team and NDAU.
Supplemental material  This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
ORCID iDs
Aarti Mistry http://orcid.org/0000-0003-0338-1833
Lara Shipley http://orcid.org/0000-0002-8538-9531
Shalini Ojha http://orcid.org/0000-0001-5668-4227
Don Sharkey http://orcid.org/0000-0002-4989-8697
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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Fetal Neonatal Ed

Availability of active therapeutic hypothermia at birth for neonatal hypoxic ischaemic

encephalopathy: A UK population study from 2011 to 2018
Authors: Dr Aarti Mistry1, Dr Lara Shipley1, Dr Shalini Ojha1, Professor Don Sharkey1,2, UK Neonatal
Transport Research Collaborative (UK-NTRC)2
Corresponding Author: Professor Don Sharkey, Centre for Perinatal Research (CePR), E floor, East
Block, University Hospital, Derby Rd, Nottingham, NG72UH, UK. Don.Sharkey@nottingham.ac.uk. Tel
no. 44 1158230611.
1
Centre for Perinatal Research, School of Medicine, University of Nottingham, 2 UK Neonatal Transport
Research Collaborative (UK-NTRC), UK Neonatal Transport Group

Supplementary Tables
Supplementary Table 1. UK Regional birth denominators and source of data(1-4)

Year covered,
Region Denominators Source of Data Additional notes of the data
any changes
Scotland Total Births Scottish Morbidity 2011 to 2018 Total births used
(Still and Live) Register live and stillborn data available
(SMSR)(1)

Northern All Live Births Northern Ireland 2011 to 2018 1. This table includes resident births
Ireland Statistics and only. There are around 200 births
Research each year to non-residents and most
Agency(2) of these births occur in Altnagelvin
and Daisy Hill Hospitals.

2. This includes births in hospitals

where the count was less than 5 births
per year.

* Please note: A small number of

births registered each year are of
people who were born many years
earlier (approx. 60 years) and had not
had their birth officially registered.
Wales Total Births National 2011-2018
(Still and live) Community Child
Health Database
(NCCHD), NHS
Wales Informatics
Service (NWIS)(3)
England Maternity HES, NHS 2011-2018 Trusts having fewer than 6 delivery
episodes. Maternity Trust episodes in total have been excluded;
(Still and live Statistics(4) reconfigurations because of this column totals may not
births) over time. agree with the sum of the figures
Shown in below them.
Each Maternity numerical data
account for submitted. Numbers are organised into Trusts
one birth which can include multiple maternity
irrespective of centre sites therefore birth ratios have
plurality. been used to split the data. Data from
Office of National Statistics (5)

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-322906
 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Fetal Neonatal Ed

Supplementary Table 2. 2011 to 2018 English birth data (number of maternities vs total births, live
births) (4)

Years No Maternities Total Births Live Births Stillbirths

2011 668,936 - 688,120 -

2012 671,255 - 694,241 -

2013 646,904 - 664,517 -

2014 636,643 - 661,496 -

2015 648,107 667,351 664,399 2,952

2016 636,401 666,052 663,157 2,895

2017 626,203 649,473 646,794 2,679

2018 603,766 628,171 625,651 2,520

Supplementary Table 3. Description of data fields used for identifying infants 36 to 42 weeks gestation
with moderate/severe HIE born in non-tertiary centres and their clinical variables and the studies
secondary outcomes from the National Neonatal Research Database (6-8)

Principle Diagnosis at Discharge database entries for HIE Grading

Severe HIE:
- HIE Grade 3 - Severe Neonatal Encephalopathy
- Hypoxic ischaemic brain damage; Severe
- Severe perinatal asphyxia (with 1-minute Apgar <4)
- Severe Neonatal Encephalopathy - Gr.3
- Hypoxic Ischaemic Encephalopathy (Gr 3)
- Severe Neonatal Encephalopathy – Grade 3 HIE
Moderate HIE:
- HIE Grade 2 - Moderate Neonatal Encephalopathy
- Hypoxic ischaemic brain damage; Moderate
- Moderate perinatal asphyxia (with 1-minute Apgar 4-7)
- Moderate Neonatal Encephalopathy - Gr.2
- Hypoxic Ischaemic Encephalopathy (Gr 2)
- Moderate Neonatal Encephalopathy - Grade 2 HIE
Unspecified
- Birth Asphyxia
- Anoxic Brain Damage
Therapeutic Hypothermia
- Therapeutic Hypothermia
- Therapeutic Hypothermia (whole body cooling)
- Hypothermia Therapeutic
Principle procedures during stay entries for identification of Therapeutic Hypothermia
Therapeutic Hypothermia
- Therapeutic Hypothermia
- Therapeutic Hypothermia (whole body cooling)
- Hypothermia Therapeutic

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-322906
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Demographic and Clinical Variables

- Gender
- Birthweight
- Gestation in weeks
- Year of Birth
- Presentation of fetus
- Mode of Delivery
- Methods of resuscitation
- Apgar score at 1 minutes
- Apgar score at 5 minutes
- Cord Venous pH
- Maternal Infection determined from data fields “Maternal pyrexia in labour” and
“Problems during pregnancy with mother” (maternal UTI/chorioamnionitis/prolonged
rupture of membranes)
- Place of birth NHS hospital code
- Place of birth NHS hospital level
- Pre-eclampsia determined from data field problems during pregnancy with mother
- Gestational Diabetes determined from data field “Problems during pregnancy with
mother”
- Acute intrapartum events determined from data fields “Problems (obstetric) during
pregnancy with mother” (Reduced fetal movements/placental abruption/cord
problems/shoulder dystocia) and “Principle diagnosis on discharge”
- Significant resuscitation determined from data field “Methods of resuscitation” (cardiac
compressions/intubation/adrenaline/other drugs)
- Respiratory Support device (No support/CPAP/Ventilated/HFOV)

Outcome Variables
- Transferred infants were identified through the discharge destination data field.
- Admission temperature (on arrival to Tertiary cooling centre)

(HIE) Hypoxic Ischaemic Encephalopathy; (UTI), Urinary Tract Infection; (NHS), National Health Service;
(CPAP), Continuous positive airway pressure; (HFOV), High frequency oscillatory ventilation

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-322906
 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Fetal Neonatal Ed

Supplementary Table 4. UK total births with provision of therapeutic hypothermia (TH) and neonatal network regions from 2011 to 2018

Year 2011 2012 2013 2014 2015 2016 2017 2018

Total births 771,176 776,375 750,807 742,861 756,217 746,666 728,160 702,794

Births with Immediate-TH, n (%) 376,334 389,799 383,533 392,239 420,790 415,395 432,609 426,536**
(48.8) (50.2) (51.1) (52.8) (55.6) (55.6) (59.4) (60.7)

Reliant on Transport-TH, n (%) a 171,775 221,950 275,172 270,606 311,739 326,233 292,573 273,382**
(43.5) (57.4) (74.9) (77.2) (92.9) (98.5) (98.9) (98.9)

Reliant on Tertiary-TH, n (%) a 223,067 164,626 92,102 80,016 23,688 5,038 2,978 2,876
(56.5) (42.6) (25.1) (22.8) (7.1) (1.5) (1.1) (1.1)

Births within neonatal networks

with Immediate-TH (%)
Median
52.6 50.2 52.0 56.9 59.4 61.2 63.3 64.9
Minimum
24.6 23.9 23.9 24.1 24.2 24.1 30.9 31.4
Maximum
77.8 76.9 76.5 76.7 89.2 89.5 95.5 95.4

a=Percentage based on number of births without Immediate-TH, **p<0.001 Chi squared test for trend

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-322906
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Supplementary Table 5. Clinical variables of infants with HIE born in non-tertiary centres with or
without Immediate-TH, identified in the National Neonatal research database (NNRD) (6-8)

Born in non-tertiary Born in non-tertiary

centre without centre with
Variables Missing p value**
Immediate-TH Immediate-TH
n = 2098* n = 475*
Gender (Male) 1202 (57.3) 252 (53.1) 0 0.09
Birthweight (grams) 3350 3370 0 0.78
(2960-3770) (2980-3750)
Gestation (weeks) 40 40 0 0.73
(38-41) (38-41)
Pre-eclampsia 100 (4.8) 22 (4.7) 0 0.90
Risk factors for early 503 (24.0) 129 (27.2) 0 0.15
sepsisa
Gestational diabetes 84 (4.0) 18 (3.8) 0 0.83
Smoking in pregnancy 262 (12.5) 45 (9.5) 353 (13.7) <0.01
Mode of Delivery:
Normal vaginal delivery 688 (32.8) 140 (29.5) 102 (4.0) 0.14
Em-LSCS not in labour 359 (17.1) 87 (18.3)
Em-LSCS in labour 619 (29.5) 138 (29.1)
El-LSCS not in labour 17 (0.8) 5 (1.1)
El-LSCS in labour 6 (0.3) 3 (0.6)
Instrumental 319 (15.2) 90 (11.0)
Missing 90 (4.3) 12 (2.5)
Presentation:
Cephalic 1631 (77.7) 401 (84.4) 351 (13.6) <0.01
Breech 130 (6.2) 29 (6.1)
Transverse lie 10 (0.5) 2 (0.4)
Other 17 (0.8) 2 (0.4)
Missing 310 (14.8) 41 (0.6)
Intrapartum eventsb 255 (12.1) 60 (12.6) 0 0.78
Significant resuscitationc 1250 (59.6) 311 (65.5) 0 0.02
Apgar 1 minute 1 (1-3) 2 (1-3) 173 (6.7) 0.64
Apgar 5 minutes 4 (2-5) 4 (2-6) 149 (5.8) 0.18
Cord pH venous 7.12 7.13 736 (28.6) 0.11
(6.95-7.25) (6.99-7.25)
Grade of HIE
Grade 2 754 (35.9) 175 (36.8) 0 0.71
Grade 3 1344 (64.1) 300 (63.1)
Respiratory:
None/Oxygen 179 (8.5) 26 (5.5) 1 (0.04) <0.01
Ventilated 1455 (69.4) 329 (69.3)
HFOV 388 (18.5) 109 (23.0)
CPAP 76 (3.6) 10 (2.1)
Em-LSCS, Emergency caesarean section; El-LSCS, Elective caesarean section; HFOV, High Frequency
Oscillation Ventilation; CPAP, Continuous Positive Airway Pressure
* Data are n (%) or median (interquartile range); ** Categorical data analysed using chi squared test; non
normally distributed continuous data analysed using Mann-Whitney U test
Gestational diabetes, preeclampsia, risk factors for early sepsis, intrapartum events and significant
resuscitation variables are tick box items, so not possible to accurately determine missing data.
a
Maternal pyrexia, chorioamnionitis, prolonged rupture of membranes, urinary tract infection
b
Cord prolapse, shoulder dystocia, abruption, reduced fetal movements
c
Chest compressions, intubation, drugs

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-322906
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Supplementary Table 6. Infants ≥36 weeks gestation with HIE born in a non-tertiary centre and transferred to a tertiary centre for therapeutic
hypothermia (TH) from 2011 to 2016. Admission temperatures on arrival based on their access to Immediate-TH are presented.

Year 2011 2012 2013 2014 2015 2016 Total

n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Infants with HIE 376 351 423 460 477 486 2573

No Immediate-TH 334 (88.8) 298 (84.9) 354 (83.7) 383 (83.3) 358 (75.1) 371 (76.3) 2098 (81.5)
Immediate-TH 42 (11.2) 53 (15.1) 69 (16.3) 77 (16.7) 119 (24.9) 115 (23.7) 475 (18.5)
Admission temperature
All infants 365 341 403 437 450 470 2466

>340C 94 (25.8) 76 (22.3) 61 (15.1) 77 (17.6) 58 (12.9) 64 (13.6) 430 (17.5)

33-340C 222 (60.8) 214 (62.8) 271 (67.3) 314 (71.9) 323 (71.8) 357 (76.0)*** 1701 (69.0)
<330C 49 (13.4) 51 (14.9) 71 (17.6) 46 (10.5) 69 (15.3) 49 (10.4) 333 (13.5)

Admission temperature
No Immediate-TH 323 290 336 365 336 361 2011

>340C 83 (25.7) 65 (22.4) 52 (15.5) 68 (18.6) 48 (14.3) 55 (15.2) 371 (18.4)

33-340C 195 (60.4) 178 (61.4) 222 (66.1) 261 (71.5) 231 (68.7) 266 (73.7)*** 1353 (67.3)***
<330C 45 (13.9) 47 (16.2) 62 (18.4) 36 (9.9) 57 (17.0) 40 (11.1) 287 (14.3)
Admission temperature
With Immediate-TH 42 51 67 72 114 109 455

>340C 11 (26.2) 11 (21.6) 9 (13.4) 9 (12.5) 10 (8.8) 9 (8.3) 59 (13.0)

33-340C 27 (64.3) 36 (70.6) 49 (73.2) 53 (73.6) 92 (80.7) 91 (83.4)** 348 (76.5)
<330C 4 (9.5) 4 (7.8) 9 (13.4) 10 (13.9) 12 (10.5) 9 (8.3) 46 (10.5)

Chi squared test for trend **p=0.003, *** p<0.001

Chi squared test comparing target temperature within range (33-340C) on arrival for total number of infants with and without Immediate-TH *** p<0.001

Mistry A, et al. Arch Dis Child Fetal Neonatal Ed 2022;0:1–6. doi: 10.1136/archdischild-2021-322906
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