Cerebral palsy: causes and prevention...Cerebral palsy (CP) is the most common cause of motor...
Transcript of Cerebral palsy: causes and prevention...Cerebral palsy (CP) is the most common cause of motor...
1 William Little Foundation
Cerebral palsy:causes and preventionA study of current knowledge and research funding
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Cerebral palsy: causes and prevention
A research review by the
William Little Foundation September 2020
William Little Foundation
The review of current knowledge was prepared for the William Little
Foundation by Dr AnnieBelle J Sassine, a medical researcher at Imperial
College London specialising in public health nutrition, epidemiology, statistics,
maternal health and pre-term birth.
Dr Sassine collaborated with WLF Chief Executive Jonathan Badger to produce
the report on research funding.
Designed and produced by Kasper de Graaf / Images&Co.
Copyright © 2020 William Little Foundation
Cerebral palsy: causes and prevention by the William Little Foundation is
licensed under a Creative Commons Attribution-NonCommercial 4.0
International License: http://creativecommons.org/licenses/by-nc/4.0/
William Little Foundation is a Charity registered in the UK No. 803551
William Little Foundation, Pinero House, 115A Harley Street,
London W1G 6AR, UK
www.williamlittlefoundation.org
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CONTENTS
Introduction .............................................................................................. 5Current Knowledge .................................................................................. 8
Definition of Cerebral Palsy .................................................................................................. 9Prevalence and Trends ......................................................................................................... 10Types of Cerebral Palsy ....................................................................................................... 11Causes .................................................................................................................................. 12
Obstetric mishaps and birth asphyxia .............................................................................. 12Gestational age at delivery .............................................................................................. 14Antenatal factors .............................................................................................................. 14Perinatal factors ............................................................................................................... 16Neonatal events ............................................................................................................... 17Nutrition .......................................................................................................................... 17
Prevention ............................................................................................................................ 20Summary .............................................................................................................................. 23Research Gaps ..................................................................................................................... 25
Prevalence and risk factor data from LMICs .................................................................. 25Maternal nutrition and infection ...................................................................................... 25Origins in early pregnancy .............................................................................................. 26Gestational diabetes and CP ............................................................................................ 26
Pioneers in CP Research ...................................................................................................... 27Key Organisations ............................................................................................................... 30
UK NGOs with CP Interest ............................................................................................. 30International NGOs with CP Interest .............................................................................. 32Interested Bodies – UK Research .................................................................................... 34Interested Bodies – International Research ..................................................................... 34Centres of Research – UK ............................................................................................... 35Centres of Research – International ................................................................................ 36
Research Funding .................................................................................. 45Global overview .................................................................................................................. 46Key Observations ................................................................................................................ 47Geographical Spread ........................................................................................................... 49
United Kingdom .............................................................................................................. 49Europe .............................................................................................................................. 59Australia .......................................................................................................................... 61United States of America ................................................................................................. 65Canada ............................................................................................................................. 71Globally ........................................................................................................................... 76
Conclusions ......................................................................................................................... 80
The cost of cerebral palsy .................................................................... 82
References ............................................................................................ 83
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Introduction
The William Little Foundation was established in 1990 (as “the Little
Foundation”) by Ian Dawson-Shepherd, the founder of Scope, to fund research
into the causes and prevention of cerebral palsy and other developmental
disorders. Named after Dr William John Little, the nineteenth century physician
who was the first to define the symptoms of infantile cerebral palsy (CP), the
Foundation has been fortunate to work with some of the world’s leading
researchers into CP and to enable some significant insights into both its causes
and its prevention.
While some progress has been made in reducing the onset of CP, the research
community is conscious that research has progressed very slowly in the last 20-
30 years: we still lack a robust understanding of its causes and only a few
therapeutic advances have been made in reducing risk or improving recovery.
While the Foundation has been able to contribute to greater understanding,
particularly through the work of Dr Martin Bax and Professor Michael Crawford,
it has also become clear to us that there is a lack of a central resource for those
with a professional interest or who have been directly affected by CP that defines
and describes the vital research that has been and is being undertaken globally.
This community has also emphasised the lack of accurate information for the
public on the risks of CP.
This review, prepared for the Foundation by Dr AnnieBelle Sassine of
Imperial College, London, is a first step towards establishing this resource –
highlighting nearly 150 important studies that have had a material impact on our
understanding of CP.
As well as identifying what research was either underway or had recently
reported, we also intended this review to help us identify the gaps in research
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activity based on what we now understand about CP. The second part of this
report also reviews the state of funding of CP-related research globally. Both
elements are based on publicly available information and data, and there are
therefore certain to be gaps. However, the report does provide a sufficient picture
to raise concerns for anyone with an interest in combatting CP.
At the heart of the concern is the oft-used observation that, as a comparatively
‘rare’ condition, CP does not merit the research investment of conditions with
higher incidence and prevalence. In truth, there is as yet no conclusive measure
of CP’s prevalence, not just in the developing world but in the developed world.
Moreover, as more babies survive preterm birth due to other medical advances,
the incidence of CP may rise in the future. This issue is highlighted by continuing
calls by fellow organisations like Action Cerebral Palsy for national CP registers:
a call to which the Little Foundation adds its voice. The rarity argument also
ignores the disproportionate social cost that is CP’s legacy: the condition is
lifelong and frequently involves 24-hour care for those affected. National social
and healthcare budgets and those of medical insurance companies for those not
supported by a national health service continue to be stretched by the need for
ever-increasing provision: CP costs the UK alone £1.6 billion every year. Yet
the amount spent annually on research is worryingly small: the figure for the UK
is less than £5 million. Our separate funding report looks in more detail at the
funding agencies (government and philanthropic) in more detail, revealing a
similar picture of cost vs investment disparity worldwide.
If the CP sector is unable to develop the mass of research activity, it is going
to need to take a more strategic approach: indeed, we have heard a clear message
from the professional community that there is a need for a strong, credible voice,
advocate and influencer for CP research into prevention. Our analysis has
identified four gaps in research focus where we feel attention could usefully be
given in the expectation of a high degree of impact:
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1. We need better data on CP prevalence and risk factors, particularly from
low- and middle-income countries
2. There is an urgent need for large-scale multi-site prospective
collaborative studies looking at maternal nutrition/infection and the risk
of CP
3. We need more evidence to show that the origins of CP trace back to the
early pregnancy period
4. There is a need for studies to test the relationship between gestational
diabetes and CP
This review and its analysis will inform the further evolution of the William
Little Foundation’s research strategy and spur our efforts to generate the funds to
enable this. We hope you find it similarly helpful.
Lord Hameed of Hampstead
Chair of Trustees
William Little Foundation
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Current Knowledge
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DEFINITION OF CEREBRAL PALSY
Cerebral palsy (CP) is the most common cause of motor disability in early
childhood (1). CP is a lifelong neurological disorder of movement and posture
secondary to non-progressive malformations in the developing fetal or infant
brain (2, 3). The brain injury may occur in utero (4-9), at birth (10, 11), during
the postnatal period (12) or in early childhood (13).
CP is often accompanied by intellectual deficits, disturbances of sensation,
perception, and coordination, epilepsy, and secondary musculoskeletal problems
(2). Children with CP can also be at risk of non-communicable diseases in
adulthood due to lack of physical activity and muscle weakness (14, 15). CP is a
very heterogeneous disorder presenting with different clinical types and brain
imaging patterns (16). Consequently, motor impairments can vary widely
between affected children; however, the poor quality of life and discrimination
faced by these children are often similar (17, 18).
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PREVALENCE AND TRENDS
The reported incidence of CP can range from 1.5 to more than 4 per 1,000 live
births or children of a defined age range based on studies from around the world
(1, 19-23). The estimated prevalence from registries has been static over the past
three decades with reported incidences ranging between 2-3 per 1,000 live births
for the developed world (24-31) and 2 per 1,000 live births for the UK (28, 32).
As for low and middle-income countries (LMIC), the data on CP prevalence
appear to be very scarce and systematic reviews seem to include data for high-
income countries (HIC) mostly (33), although the prevalence of CP in LMIC is
suspected to be higher than HIC (22, 23, 34-37).
Extremely preterm birth infants (born before 28 weeks of gestation) are greatly
affected by CP, with an estimated prevalence of 40-100 per 1000 live births (24).
The increase in the survival of very premature infants has resulted in a modestly
increased prevalence of cerebral palsy in developed countries from 1975-1999
that has now subsided (20).
Despite improvements in antenatal, delivery and postnatal care, CP incidence
in term infants has not notably changed over the last 30 years (38, 39). In fact,
term infants (>37 weeks of gestation) account for 50 to 65% of CP cases although
paradoxically preterm birth is a strong risk factor of CP (34, 40-42).
Data from European database (38, 43) in addition to USA (44), Australia (45),
and China (46) show that more than 50% of CP cases are among normal
birthweight babies (>2500 g). Research on CP has primarily focused on very
preterm infants due to the strong association between preterm birth and risk of
CP. However, infants born at or after 35 weeks of gestation contribute to two
thirds of CP cases and are considered the most under-researched group with the
majority of the literature fixating on birth asphyxia as the major cause of CP
among this group (45).
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TYPES OF CEREBRAL PALSY
CP is a heterogeneous disease presenting with different types. The most common
type is spastic CP accounting for 70% of cases and affects muscle control and
coordination. It is the result of injury to the motor cortex and the pyramidal
regions of the brain that link the motor cortex to the spinal cord, resulting in
muscle stiffness and tightness. It includes three subtypes depending on the body
area affected: hemiplegia, which affects one side of the body, with the upper body
usually more influenced; diplegia which affects the lower extremities of the body
(the legs); and quadriplegia which affects all four limbs.
Dyskinetic CP is the second type of CP prevailing in 10-20% of cases. It is
responsible for slow and uncontrollable movements of hands, feet, arms or legs
that can result in severe changes in muscle tone and posture and can be
accompanied by learning disabilities and frequent epilepsy (47, 48).
Ataxic CP (5-10%) is the least common and is characterised by difficulties in
balance and coordination and results in shaky movements that can affect writing
and speech.
Exhibiting one or more type of CP is classified under Mixed CP (10%).
Rosenbaum et al. in their ground-breaking report that altered the definition of
CP advised that classification of CP should be reliable and very specific to the
symptoms. Indeed, CP has varying degrees and can range from a minor limp to
severe incapability of movement and communication (2).
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CAUSES
The epidemiologic risk factors for CP have been substantially investigated with
research dating back to the 1970s and the risk pattern differs by CP subtype. The
most known risk factors to date are summarised below:
Obstetric mishaps and birth asphyxia
The earliest clinical identification of children with cerebral palsy established two
factors: preterm birth and oxygen deprivation during difficult birth.
For a long time, cerebral palsy was thought to happen at birth and was
considered a product of obstetric mishap, particularly birth asphyxia. Intrapartum
obstetric mishaps include nuchal cord, meconium in the amniotic fluid, mid or
high forceps, placental and cord abnormalities such as placental abruption and
cord prolapse, most of which are asphyxia-related due to their obstruction of
blood oxygen levels to the fetal brain (49). Birth asphyxia in most studies report
an attributable risk of less than 10%. Data from the National Collaborative
Perinatal Project (NCPP), which studied the relationship of pregnancy and labour
events to CP, concluded that pure asphyxial damage was in less than 10% of all
CP cases (50, 51). This is further supported by a study conducted in Australia
reporting 8% of cases of CP to be attributed to birth asphyxia (52). However, it
should be noted that this fraction is more elevated in developing countries with
limited access to healthcare. Birth asphyxia is still a major cause of mortality in
developing countries and 99% of deaths attributable to intra-partum hypoxia
occur in LMIC (53, 54), partly due to lack of access to healthcare or presence of
a skilled attendant. A study conducted in Zambia showed that 31% of those who
had birth asphyxia showed abnormal neurologic signs (55). Another study
from Nepal showed that 18% of birth asphyxia survivors had neonatal
encephalopathy (56). However, it would be hard to conclude whether the higher
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fraction of CP attributed to birth asphyxia in developing countries is actually true
or is an effect of the high prevalence of birth asphyxia reported.
Consequently, different methods to identify fetal hypoxia during labour were
introduced in the hope of reducing the incidence of CP, particularly electronic
monitoring of fetal heart rate. Although this widely used technique contributed to
an increase in surgical deliveries for fetal growth restriction, it failed to reduce
the incidence of cerebral palsy at birth over the past three decades (34).
Clark and Hankins stated in their CP trend analysis study, “Despite a five-fold
increase in the rate of Caesarean section based, in part, on the electronically
derived diagnosis of ‘fetal distress’ cerebral palsy prevalence has remained
stable”(39). This was further strengthened in 2004 by Bo Jacobsson and Gudrun
Harberg, pioneers in CP research, who concluded that “Evidence suggests that 70
to 80% of cerebral palsy cases are due to prenatal factors and that birth asphyxia
plays a relatively minor role (<10%)”(57). In 2007, Martin Bax published
ground-breaking results from the European Cerebral Palsy Study about Magnetic
Resonance Imaging (MRI) brain findings in 351 CP cases. Half of the CP cases
were born at term. The MRI scans showed significant white matter damage of
immaturity in 43% of the cases as well as lesions (22.2%) and malformations
(9.1%). White matter damage is thought to occur before 34 weeks of gestation
and malformations are indicative of earlier cerebral damage. This goes to show
that in infants who were born after 34 weeks of gestation, obstetric mishap or
perinatal processes couldn’t have caused CP (58). Although prematurity and birth
asphyxia are still significant contributors of CP (10, 59), recent evidence suggests
that the majority of CP cases are attributable to factors operating earlier in the
antenatal period (8, 9, 41, 42, 57, 60-62). The timing of the events and their
relationship to the onset of CP is still very complex and not fully understood;
nonetheless, intrapartum events are not likely the principal cause of CP, as
previously thought.
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Gestational age at delivery
Preterm birth has been considered the single largest risk factor for CP (63),
manifested by the increased prevalence of CP with declining gestational age at
delivery (64, 65). Recent studies show that late term pregnancies, with delivery
after 42 weeks may also be at increased risk of CP (66). However, the question
to be asked is whether gestation age at delivery is a direct cause for CP or only a
reflection of a common antenatal cause? For instance, infants who are born
prematurely as well as infants born with cerebral palsy are more likely to have
been exposed to fetal inflammation. Could inflammation in this case be the
underlying factor causing both preterm birth and CP?
Antenatal factors
Congenital anomalies and genetic variants, characterised by brain and cortical
malformations, have been strongly linked to certain types of CP (67-70), as
evidenced by birth defects occurring in 14-50% of CP children (70-72).
Consequently, genetic risk factors, particularly chromosomal abnormalities, have
been implicated in the aetiology of CP (16, 73-75), with the most recent evidence
identifying disease-causing mutant genes in 14% of CP cases (76).
Non-genetic antenatal factors also play a major role. Multiple pregnancies
(twin/triplets) (77, 78), untreated maternal hypothyroidism and thrombophilia
(79-82), advanced maternal age (>35 years) (83), high parity, obesity (84), and
preeclampsia ADDIN EN.CITE ( have been identified as potential risk factors
for CP, however further research is still required to confirm these relations.
The link between hypothyroidism as a risk factor for CP is becoming more
established. Three large studies (England, Netherlands, USA) conducted on
premature infants showed a strong association between low neonatal thyroid
levels and adverse neurodevelopment outcomes (85-89). However, the link
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between hypothyroidism and risk of CP may be mediated by iodine deficiency.
Iodine deficiency is a main contributor to hypothyroidism through its effect on
thyroid hormones (T3 and T4), which are necessary for normal brain and nervous
system development during pregnancy (90). There is increasing evidence for the
link between iodine deficiency and neurological impairment/brain damage,
which is thought to resemble CP (91-100).
Furthermore, a study conducted by Ahlin et al. showed that non-infectious risk
factors such as not living with the baby’s father and gestational diabetes were
strong independent predictors of CP, particularly spastic CP (101). A recent study
conducted in Israel showed an increased risk of neuropsychiatric disease
(including CP) in mothers who developed gestational diabetes during their
pregnancy (102). In a study from Pakistan, authors reported that lack of antenatal
care was associated with a high risk for spastic CP (103). Karen Nelson’s study
showed that fetal growth restriction was another potential risk factor associated
with the risk of CP in term babies born to mothers with normal blood pressure
(4).
There is increasing evidence about the role of infection and the onset of CP.
Intrauterine infection or inflammation has been strongly linked to CP (104). In
fact, a case-control study conducted on term babies found that mothers who were
exposed to severe infection during their pregnancy were 15 times more likely to
give birth to babies born with spastic CP. The latest systematic review published
by Cochrane reports that bacterial and viral infections during pregnancy may also
have a role, further backed up by studies showing that urinary tract infections can
impose a risk for CP (8, 105-107).
Other antenatal factors include placental vascular disorders and abnormalities,
which were also shown to be associated with CP (104).
Bax et al. in their European MRI study of cerebral palsy (EMCP) discussed
how nutritional, genetic, and inflammatory factors can lead to inadequate
placental development, which predisposes the fetus to increased risk of hypoxic
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ischemic events which in turn lead to white matter damage in the brain.
Intriguingly, they uncovered all lesions detectable by MRI scans originated well
before the time of birth. The authors emphasized that interventions around the
time of birth might not decrease the risk of CP as cerebral damage would have
already occurred (58).
Additionally, a recently published article (2019) explored associations
between fetal exposure to maternal infection and the risk of autism, depression,
and bipolar disorder in around 1,800,000 children followed up longitudinally up
to 41 years. Results of the study showed that exposure to maternal infection
during pregnancy increased the risk of autism and depression among children.
This study is particularly important, given that CP is also a neurodevelopment
disorder and often accompanied by co-morbidities such as behavioural and
cognitive difficulties. This further emphasizes the need to understand the role of
maternal infection in the onset of CP, particularly with increasing evidence
hinting that CP could be the product of an ischemic prenatal stroke (108, 109).
Stroke is the result of disrupted blood flow and inflammation resulting in a
hypoxic region and scarring. Infection and nutritional imbalances are known to
favour ischemia and inflammation (110-112).
This all plausibly suggests that CP may not be, as commonly perceived, a
product of obstetric mishap.
Perinatal factors
Perinatal factors include placental damage approaching labour, birth asphyxia,
and perinatal infection. Chorioamnionitis, defined as the inflammation of the fetal
membranes due to a bacterial infection, has been consistently associated with CP
in term infants (7, 8, 104, 113-115). In a recent meta-analysis, term/near-term
babies born to mothers who were diagnosed with histologic chorioamnionitis had
4.3 times the risk of CP compared to babies born to normal healthy controls (116).
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Placental abruption, characterized by the separation of the placenta from the inner
wall of the uterus prior to birth, has also been linked to CP, possibly due to the
loss of oxygen transfer to the fetus (7, 104). Factors related to the mode of
delivery have been also implicated, in particular emergency Caesarean section as
a risk factor for spastic CP (101).
Neonatal events
Events in the neonatal period have been also linked to the development of CP.
These include acute intrapartum hypoxia, intraventricular haemorrhage,
periventricular leukomalacia, meconium aspiration, neonatal stroke, seizures,
sepsis, fetal infection, and particular syndromes and chromosomal abnormalities
(57, 71, 103, 117, 118). Most neonatal events have been attributed to a higher risk
of dyskinetic CP such as admittance to NICU, Apgar score, and neonatal seizures
(101, 103) However, many cases of spastic CP have been also linked to neonatal
risk factors; small head circumference has been associated with hemiplegic
spastic CP (101) whilst neonatal infection in babies born at term was a strong and
independent predictor of spastic diplegia and quadriplegia (107).
Although these neonatal events may occur independently, recent evidence
shows that neonates who are exposed to an inadequate intrauterine environment
could be highly susceptible to such subsequent intrapartum events- a so-called
‘double-hit model’ (5, 119).
Nutrition
One of the first pioneers in cerebral palsy research was Professor Paul Polani at
Guy’s Hospital, he was an expert in medical genetics. His early works on CP
concluded the absence of a specific genetic cause, suggesting rhesus haemolytic
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disease as a potential risk factor, and leaving behind the possibility of infection
and inadequate nutrition as plausible culprits (120).
Studies investigating the role of maternal nutrition in CP development in the
offspring are very limited, despite considerable evidence linking maternal
nutrition to brain development in pregnancy. Crawford et al. discovered that the
brain is made up of essential omega-3 docosahexaenoic acid (DHA) and omega-
6 arachidonic acid (ARA) (121-123), a finding that triggered numerous
supplementation trials to assess the effect of essential fatty acids on preterm birth
and brain development (124-128). Results from the FOSS trial conducted at
Chelsea and Westminster Hospital showed that male infants born to mothers who
were supplemented with brain-specific fatty acids ARA, DHA, and EPA had
significantly larger total brain volumes, grey matter, corpus callosum and cortical
volumes compared to the placebo groups. These MRI findings suggest a
protective potential for essential fatty acids against hypoxic ischaemic injury,
which normally attacks the grey matter area (129).
The lack of information on the role of nutrition in the onset of CP is quite
surprising given that cerebral palsy is characterized by lesions in the developing
brain. A review of supplementary trials in nutritionally-deficient populations that
involved the supplementation of DHA, Vitamin D, folic acid, and/or iodine
concluded that these may prevent many brain and central nervous system
malfunctions (130).
One study in 1998 investigated the role of maternal diet during pregnancy in
the development of CP using a semi quantitative food-frequency questionnaire
administered by mothers of infants with CP (N=91) and matched controls
(N=246). Results showed that maternal diet rich in fish and modest meat intake
during pregnancy might reduce the risk of CP (131). The authors highlighted the
need for future large multi-center cohort studies to assess the relationship
between pregnancy diet and CP, which might be very difficult, as it would require
a birth cohort of 100,000 over a period of at least 4 years (131).
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In 2013, a study was published showing a link between impaired maternal
immune system within 5 years before pregnancy and risk of cerebral diseases in
the offspring (106).The authors stated that they were unable to account for the
possible confounding effect of dietary factors, which have been shown to affect
the immune system (106).
These studies, along with findings from the FOSS trial and Bax et al.’s study,
suggest a strong role for brain specific fatty acids in neuroprotection and possibly
preventive measures against neurodevelopmental disorders.
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PREVENTION
The identification of potential risk factors in the onset of CP has lead to the
development of many preventive strategies stretching from antenatal to postnatal
period (104, 132).
For antenatal and intrapartum interventions, treatment of pregnant women
with magnesium sulfate (MgSO4) for fetal neuroprotection significantly
decreased the risk of CP by 32% based on 5 randomized controlled trials (RCTs)
with a total of 6145 children (104). This intervention was considered of high-
quality evidence of effectiveness. In fact, Karin Nelson’s observational study in
1995 showed that exposure to MgSO4 was significantly lower in very low birth
weight (VLBW) born with CP compared to VLBW controls (133). In April 2020,
results from a multi-centre trial were published by a research group in Denmark
who studied the effect of antenatal magnesium sulphate on cerebral palsy in
infants born preterm. Findings showed that magnesium sulphate given to mothers
before 32 weeks of pregnancy decreased the risk of moderate to severe CP in
children (134).
There was medium-quality evidence for the harmful effect of giving
prophylactic antibiotics to women in preterm labour with intact membranes as
opposed to not giving antibiotics. Another ineffective and rather harmful
intervention was the immediate delivery of women with suspected fetal growth
restriction. They were at higher risk of CP than women whose birth was delayed
(104). There is not enough evidence on the effectiveness of giving antenatal
corticosteroids or antihypertensive drugs in the reduction of CP (104).
Very recently, a pre-clinical study in Australia supported by the Cerebral Palsy
Alliance Research Foundation (CPARF), showed that low platelet count might
weaken blood vessels in the brain and increase susceptibility to stroke and
subsequent CP. The authors suggest that platelet monitoring may be an effective
preventive measure against CP (135).
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Hartman et al. just published a study in Cell Reports showing that MRI with
hierarchal region splitting may help provide insight to selected newborns with
salvageable lesions that can be responsive to human neural stem cell transplant
and prevent cerebral infarct. Although these results are promising showing MRI
as an important biomarker tool, clinical trials are required to confirm the success
of stem cell interventions (136).
To our knowledge, there has been no study that tested the effect of nutritional
interventions during pregnancy on the prevention of CP. There has been however
a double blind RCT conducted by the University of Oxford (the DOLPHIN trial),
which investigated the role of a nutrition supplement in 40 children with
suspected CP in the UK (1 month-18 months). Based on the rationale that
phosphatidylcholine is the most abundant brain phospholipid that comprises
choline (uridine-5-monophosphate (UMP) and the long-chain polyunsaturated
fatty acid DHA, the treatment group received a supplement containing DHA,
choline and uridine. The trial did not find significant differences in cognitive and
language performances between the supplemented and placebo groups (137).
As part of her PhD thesis at Imperial College London, Dr. Xia Zheng
conducted a mice experiment to test the effect of DHA-enriched diet on
improving outcomes of hypoxic ischemic encephalopathy (HIE) brain damage.
Although her results showed improvement in DHA levels in pup brains of the
DHA-enriched diet group, there was no neuroprotective effect through reduction
of inflammation and apoptosis. However, she discusses that the lack of
neuroprotective effect could be attributed to the insufficient sample size and low
dose of DHA in the DHA enhanced diet in the study.
This further highlights the crucial need for studies investigating the role of
nutrition, specifically brain-specific fatty acids and key nutrients such as choline,
their dosage and the timing of interventions in the prevention of cerebral damage.
Importantly, a recently published review provided compelling evidence for the
synergistic role of DHA and choline in ensuring brain and eye health and authors
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suggested a prenatal screening for DHA (138) and choline status to ensure
maternal nutrient needs are met prior to pregnancy (139).
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SUMMARY
The current state of evidence on CP suggests a plausible role of prenatal infection
in the onset of CP. Preterm birth is still a powerful independent risk factor for CP,
but recent trend analysis for CP prevalence indicates that almost half of the cases
of CP occur in babies born at term. Despite improvements in fetal monitoring and
the consequent dramatic increase in the rates of Cesarean Sections, the rate of CP
among term babies has not decreased and the MRI scans on infants with CP
suggest that the timing of lesions traces back to the prenatal period. Consequently,
the long-term focus on obstetric mishap should be shifted to prenatal factors,
particularly fetal exposure to infection and/or inadequate maternal nutrition.
This brief review highlights important research gaps worth pursuing to
increase our understanding in CP, which the evidence now indicates is
preventable.
In view of the COVID-19 pandemic, children and adults living with cerebral
palsy are at higher risk for severe illness due to their susceptibility to chronic
diseases, compromised immune systems and their compromised mental well-
being. The Center for Disease Control has listed people with neurological
disorders such as cerebral palsy as vulnerable and advised that they should be
shielded and isolated. This is particularly dangerous, as people living with
cerebral palsy require special care and therapy and already feel neglected and
secluded from society. One could only imagine the toll of the COVID-19
pandemic on an already fragile group of people who are fighting a daily health,
mental, and social battle. The British Medical Journal recently published a
commentary on the socioeconomic gradient in health and the covid-19 outbreak,
in which the writers narrate the story of a 17 year old boy with cerebral palsy in
Hubei who was found dead after being left alone at home for 6 days because his
single father was quarantined in a health facility for suspected covid-19 infection
(140).
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Even before the COVID-19 crisis, people with cerebral palsy and their
families lead a very difficult life- the pandemic has further exposed the frailty and
disproportionate burden affecting those living with lifelong neurologic diseases.
Today, more than ever, our world necessitates human solidarity and strong
multidisciplinary collaboration to protect our most vulnerable not only from
diseases and viruses but also from the detrimental effects of suffering and
depression that accompany them.
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RESEARCH GAPS
Prevalence and risk factor data from LMICs
More research is required for LICs, which have different epidemiological features
of cerebral palsy. A study in Uganda showed that preterm birth was a minor
contributor to CP compared to postnatal infections (such as malarial infections)
that contributed to 25% of all cases of CP (36, 141). In India, the reported CP
prevalence is said to be 3 per 1,000 live births (142). This is particularly important
as some studies from low and middle-income countries show a prevalence of CP
ranging from 4.4 to 10 per 1,000 live births or children (143, 144).
Maternal nutrition and infection The role of nutrition in the development of cerebral diseases has not been clearly
investigated.
Large prospective studies with assessment of diet intake preconception up
until delivery are necessary. Studies looking at the potential relationship between
maternal lipid and micronutrient status (choline, iodine) in early pregnancy and
the risk of CP are also needed. However, these will require vast collaborations to
reach large sample sizes of more than 100,000 women due to the low incidence
rate of CP (2 per 1,000 live births) and the cost could be extortionately high.
Nutritional factors, as opposed to other risk factors such as age, BMI, parity,
obstetric history, cannot be accessed via medical records. Retrospective studies
tracing back the nutrition of mothers who gave birth to CP children is also rather
difficult, hence the need for prospective studies. Alternatively, the synergistic
effect of supplementation trials with brain-specific fatty acids and cofactors
(choline and B12) and iodine on the suppression on inflammation and the
prevention of cerebral damage should be the next steps. It would be worth starting
in LMICs where incidence rate is much higher and would require a smaller
26
sample size. Fish and marine sources are rich in DHA, choline and iodine,
deficiencies of which have been implicated in brain damage. The results will be
crucial to inform public health policy and could potentially help prevent
neurological impairment.
The cost of these trials, though prohibitively expensive, would be worth it if
brain damage can be avoided by a simple intervention such as increasing intake
of marine and fish sources or supplementation.
Origins in early pregnancy The timing of the brain lesions is still not fully elucidated and although many
studies show that the aetiology of CP has its origins in the prenatal period, it is
crucial to identify specific time periods after which cerebral damage might
become irreversible. This will be crucial for all preventive interventions.
Gestational diabetes and CP Many charity websites give strong claims linking gestational diabetes in
pregnancy to increased risk of CP; however, these claims are not backed up by
proper scientific studies that were powered to test this specific association.
Although some studies show an increased risk of CP with gestational diabetes in
certain populations such as mothers with obesity, the results cannot be
generalisable without the warrant of longitudinal or case/control studies to prove
the validity of these claims.
27
PIONEERS IN CP RESEARCH
There are many researchers who have been working on identifying causes of
cerebral palsy for more than 20 years:
¾ Allan Colver, Emeritus Professor Community Child Health at the Institute
of Health & Society at Newcastle University, UK. His research mainly
focuses on child health; he co-founded the North of England Collaborative
Cerebral Palsy Survey and established a database of children with Autism
Spectrum Disorder. He also coordinated a European Commission /
Wellcome Trust-funded study (SPARCLE) across Europe of children with
cerebral palsy (18, 145).
¾ Fiona Stanley, Distinguished Research Professor at the School of Paediatrics
and Child Health, University of Western Australia. An epidemiologist of
many years’ standing, she has specialised in public health, child and
maternal health and cerebral palsy. She has published many joint papers
with the other Australian scientists listed below, particularly around trends,
prevalence, and risk factors of CP in Australia (4, 31, 41, 45, 71, 118, 146,
147).
¾ Nadia Badawi, Professor in the Faculty of Medicine & Health, University
of Sydney and Chair of the Cerebral Palsy Alliance. With a research focus
into new-born encephalopathy as well as prevention, best intervention and
ultimately a cure for cerebral palsy, she is currently very much the public
face of the CP research community in Australia
¾ Sarah McIntyre, Senior Research Fellow at the Cerebral Palsy Alliance,
University of Sydney. Her research focus is population-based aetiology
research for cerebral palsy, neonatal encephalopathy and congenital
anomalies with the long-term aim of identifying avenues for prevention of
neurodisability.
28
¾ Hayley Smithers-Sheedy, NHMRC Early Career Fellow at the Sydney
Medical School, The University of Sydney. Her research focus is
epidemiology, congenital infection, neurodevelopmental disability and
consumer involvement in research.
¾ Eve Blair, Adjunct Associate Professor, Telethon Kids Institute, School of
Paediatrics and Child Health, University of Western Australia. Her research
on cerebral palsy has had a tangible effect on the approach of the Australian
courts and litigation compensation, providing a more evidence-based
pathway to assessing causation. Her research has included population-based
studies and cerebral palsy registers.
¾ Dinah Reddihough, Professor at the Murdoch Children’s Research Institute
in Victoria where she heads the Developmental Disability & Rehabilitation
Research Group. Her primary research interest is childhood disability,
particularly CP, and she was responsible for founding the Australasian
Academy of Cerebral Palsy & Developmental Medicine.
¾ Linda Watson and the Australian Cerebral Palsy Register Group. They are
all researchers from various universities and research institutes in Australia
and usually share authorship on most studies.
¾ Karin Nelson, Scientist Emeritus, Clinical Neurosciences Program at the
Division of Intramural Research, National Institute of Neurological
Disorders and Stroke (NINDS), the National Institutes of Health, USA (50,
62, 117, 133).
¾ Bo Jacobsson, Professor in the Department of Obstetrics and Gynecology,
Institute of Clinical Sciences, University of Gothenburg, who, with Kate
Himmelmann and Paul Uvebrant (below), is among the pioneers in research
on CP in Sweden. They have various joint papers focusing on aetiology, risk
factors, trends, and consequences in Sweden (27, 38, 57, 148, 149).
29
¾ Kate Himmelmann, Adjunct University Lecturer in the Department of
Pediatrics at the University of Gothenburg’s Institute of Clinical Sciences.
¾ Paul Uvebrant, Professor in the Department of Pediatrics, Institute of
Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg.
¾ Kerr Graham, Professor at the Murdoch Children’s Research Institute in
Victoria, Australia. He is an international leader in orthopaedic management
of cerebral palsy (10, 34).
¾ Martin Bax, Retired Consultant Paediatrician, Division of Paediatrics,
Obstetrics and Gynaecology, Imperial College, London. He is one of the
famous pioneers in CP who revised the definition and classification of CP
and conducted a study on MRI scans for children in CP which revealed brain
damage dating to prenatal period (3, 58, 150).
¾ Nigel Paneth, Professor of Epidemiology, Biostatistics and Pediatrics at
Michigan State University, USA. He is particularly interested in the causes
and prevention of childhood neurodevelopmental handicap, particularly CP.
His studies look at the epidemiology of CP (20).
¾ Peter Pharoah, Emeritus Professor at the Department of Public Health and
Policy at the University of Liverpool. His research has focused on
identifying risk factors for CP and epidemiology of CP in England and
Wales (12, 28, 78, 145, 151).
¾ Peter Rosenbaum, Professor of Pediatrics and co-founder of the CanChild
Centre for Childhood Disability Research at McMaster University in
Ontario Canada. His study on the definition and classification of CP has
been cited by 3,406 articles (2).
¾ Peter Uldall, Emeritus Professor of Child Neurology at the Department of
Pediatrics and Adolescent Medicine at The University of Copenhagen,
Denmark. His research interests focus on the causes and consequences of
cerebral palsy (29, 30, 82).
30
KEY ORGANISATIONS
UK NGOs with CP Interest
F: Family support
R: Research
¾ Aberdeen & District Cerebral Palsy Association [F]
¾ Action Cerebral Palsy [F, R]
¾ Action Medical Research [R]
¾ Adult Cerebral Palsy Hub [F]
¾ Bedford & District Cerebral Palsy Society [F]
¾ Bliss [F, R]
¾ Bobath Centre for Children with Cerebral Palsy [F, R]
¾ Boparan Charitable Trust [F]
¾ Brain Charity [F]
¾ Brain Injury Hub [F]
¾ Brain Injury Rehabilitation Trust / Disabilities Trust [F, R]
¾ Brainstars [F]
¾ Brainwave [F]
¾ British Institute for Brain-Injured Children [F]
¾ Castang Foundation [R]
¾ Caudwell Children [F]
¾ Cerebra [R]
¾ Cerebral Palsy Africa [F]
¾ Cerebral Palsy Midlands [F]
¾ Cerebral Palsy Northamptonshire [F]
31
¾ Cerebral Palsy Plus [F]
¾ Cerebral Palsy Scotland [F, R]
¾ Cerebralpalsy.org.uk / Bridge McFarland LLC [F]
¾ Chailey Heritage Foundation [F]
¾ Cheyne Charity [F]
¾ Child Brain Injury Trust [F]
¾ Children Today Charitable Trust [F]
¾ Contact (Contact-a-Family) [F]
¾ Council for Disabled Children [F]
¾ CP Sport [F]
¾ CPotential [F]
¾ Cumbria Cerebral Palsy [F]
¾ Dame Vera Lynn Children’s Charity [F]
¾ Dreams Come True [F]
¾ Elifar Foundation [F]
¾ Family Fund [F]
¾ Footsteps Centre [F]
¾ Freddie Farmer Foundation [F]
¾ Great Ormond Street Hospital [R]
¾ International Cerebral Palsy Society [R]
¾ Lincolnshire Cerebral Palsy Society [F]
¾ Liverpool Cerebral Palsy Society [F]
¾ Merlin's Magic Wand [F]
¾ National Network of Parent Carer Forums [F]
¾ NewLife [F, R]
¾ NICE [F]
¾ Paces [F]
¾ Rainbow Centre for Conductive Education [F]
32
¾ Roald Dahl's Marvellous Children's Charity [F]
¾ Scope [F]
¾ Sequal Trust [F]
¾ Shropshire Cerebral Palsy Society [F]
¾ Sky Badger [F]
¾ Starlight Children's Foundation [F]
¾ Sparks / GOSH Charity [R]
¾ Stars Foundation For Cerebral Palsy [F]
¾ Stick ’n Step [F]
¾ Stockport Cerebral Palsy Society [F]
¾ Tree of Hope [F]
¾ WellChild [F, R]
¾ Whoopsadaisy [F]
International NGOs with CP Interest
Australia Cerebral Palsy Alliance
Steptember
Australia/USA Cerebral Palsy Alliance Research Foundation
Canada Brain Canada
CanChild
CHILD-BRIGHT Network
Kids Brain Health Network
Ontario Federation for Cerebral Palsy Research
Fund
France Fondation Paralysie Cérébrale / Fondation Motrice
India ADAPT – India
33
Amrit Foundation of India
Indian Institute of Cerebral Palsy
Rehabilitation Council of India
Italy Cerebral Palsy European Community Association
S Africa Malamulele Onward
The Paige Project – South Africa
United Cerebral Palsy Association of South Africa
Singapore Cerebral Palsy Alliance of Singapore
Switzerland Naked Heart Foundation
USA Brain Injury Association of America
Brain Trauma Foundation
Cerebral Palsy Group
Cerebral Palsy Guidance
Cerebral Palsy Guide
Cure CP
Graham’s Foundation
Holton’s Heroes
Hope for HIE
March of Dimes
Reaching for the Stars
Save Babies Through Screening Foundation
The Baby Alex Foundation
The Cerebral Palsy Foundation
The Silverlining Brain Injury Charity
United Cerebral Palsy
34
Interested Bodies – UK Research
¾ Medical Research Council
¾ Wellcome Trust
¾ British Academy of Childhood Disability
¾ British Association of Perinatal Medicine
¾ British Maternal & Fetal Medicine Society
¾ Academic Paediatrics Association
¾ UK Child Health Research Collaboration
¾ Royal College of Paediatrics & Child Health
¾ Royal College of Obstetricians & Gynaecologists
¾ UK Clinical Research Collaboration
¾ Economic & Social Research Council
¾ UK Research & Innovation
¾ Innovate UK
¾ Research England
¾ British Academy of Childhood Disability
Interested Bodies – International Research
¾ Australasian Academy of Cerebral Palsy & Developmental Medicine
¾ American Academy for Cerebral Palsy & Developmental Medicine
¾ International Alliance of Academies of Childhood Disability
¾ European Academy of Childhood Disability
¾ International Alliance for Pediatric Stroke
¾ International Pediatric Stroke Study
35
¾ Cerebral Palsy Alliance Research Institute
¾ CP Quest
¾ IMPACT for CP
¾ International Cerebral Palsy Genomics Consortium
¾ Centre of Research Excellence in Cerebral Palsy
¾ European Academy of Childhood Disability
¾ National Organization for Rare Disorders
Centres of Research – UK
¾ Department of Public Health, University of Liverpool
¾ National Perinatal Epidemiology Unit, Radcliffe Infirmary, University of
Oxford
¾ Department of Public Health, University of Oxford
¾ Department of Community Child Health, Alder Hey Children's NHS
Foundation Trust, Liverpool
¾ Institute of Health & Society, Newcastle University
¾ Department of Paediatric Neurosciences, Evelina Children's Hospital, Guy's
& Saint Thomas' NHS Foundation Trust
¾ School of Nursing & Midwifery, Queen's University Belfast
¾ Centre for the Economics of Mental Health, Institute of Psychiatry
¾ Department of Clinical Sciences, Brunel University
¾ Division of Paediatrics, Obstetrics & Gynaecology, Imperial College
¾ FSID Unit of Paediatric & Perinatal Epidemiology, University of Liverpool
¾ Saving Newborn Lives / Save the Children, International Perinatal Care Unit,
Institute of Child Health, London
¾ Institute of Child Health, Royal Hospital for Children, Bristol
36
¾ Maternal & Infant Research Activities Group – Kathmandu and Nepal, UCL,
London
¾ Department of Paediatrics & Neonatal Medicine, Hammersmith Hospital,
London
¾ Institute of Nursing & Health Research, Ulster University, Belfast
¾ York District Hospital, York
¾ Academic Unit of Paediatrics, University of Leeds
¾ MRC Centre for Causal Analyses in Translational Epidemiology, University
of Bristol
¾ MRC-Dunn Human Nutrition Unit, University of Cambridge
Centres of Research – International
¾ National Institute of Neurological Disorders and Stroke
¾ Eunice Kennedy Shriver National Institute of Child Health and Human
Development
¾ Waisman Center, University of Wisconsin-Madison – USA
¾ University of Alabama at Birmingham – USA
¾ Division of Birth Defects & Developmental Disabilities, National Center on
Birth Defects & Developmental Disabilities, Centers for Disease Control &
Prevention – USA
¾ Institute of Allied Health Sciences, College of Medicine, National Cheng
Kung University – Taiwan
¾ Institute of Public Health, College of Medicine, National Cheng Kung
University – Taiwan
¾ College of Public Health, University of South Florida – USA
¾ Washington University in St. Louis – USA
37
¾ Department of Epidemiology, College of Human Medicine, Michigan State
University – USA
¾ Hackensack Meridian School of Medicine, Seton Hall University
¾ CanChild Centre for Childhood Disability Research, McMaster University
– Canada
¾ Developmental Disability & Rehabilitation Research, Murdoch Children’s’
Research Institute, The Royal Children's Hospital, Victoria – Australia
¾ College of Human Medicine, Michigan State University – USA
¾ Department of Neurology, Université Libre de Bruxelles – Belgium
¾ Department of Rehabilitation Medicine, VU University Medical Center,
Amsterdam – The Netherlands
¾ Department of Physical Medicine, Rehabilitation & Pediatrics, Feinberg
Northwestern School of Medicine, Rehabilitation Institute of Chicago –
USA
¾ Department of Rehabilitation Medicine, Erasmus MC, University Medical
Centre, Rotterdam – The Netherlands
¾ Department of Epidemiology & Biostatistics, Erasmus Medical Centre,
Rotterdam - The Netherlands
¾ Department of Pediatrics, Erasmus Medical Centre, Rotterdam – The
Netherlands
¾ RTI International, N Carolina – USA
¾ National Center on Birth Defects and Developmental Disabilities, Centers
for Disease Control & Prevention – USA
¾ Klinik für Kinder und Jugendmedizin, University of Lübeck – Germany
¾ INSERM, UMR 1027, Paul Sabatier University, Toulouse – France
¾ Department of Paediatrics, Queen Silvia Children's Hospital, Göteborg
University – Sweden
¾ Laboratory of Medical Biology, University Hospital of Grenoble – France
38
¾ AUSL Viterbo – Italy
¾ National Institute of Public Health, University of Southern Denmark,
Copenhagen – Denmark
¾ School of Public Health, Peking University Health Science Center, Beijing
– China
¾ School of Public Health, Fudan University, Shanghai – China
¾ Department of Community Health Sciences, University of Calgary – Canada
¾ Department of Neurology, Assiut University – Egypt
¾ Department of Neurology, El Azhr University – Egypt
¾ Department of Neurology, Sohag University, Solag – Egypt
¾ National Centre for Maternal & Infant Health, Beijing Medical University –
China
¾ Department of Pediatrics, Göteborg University – Sweden
¾ Robinson Research Institute, University of Adelaide – Australia
¾ Department of Paediatric Neurology, Adelaide Women’s & Children’s
Hospital, School of Pediatrics & Reproductive Health, University of
Adelaide – Australia
¾ School of Pediatrics & Reproductive Health, University of Adelaide –
Australia
¾ South Australian Clinical Genetics Service, SA Pathology (at Women’s and
Children’s Hospital), Adelaide – Australia
¾ School of Molecular & Biomedical Science, University of Adelaide –
Australia
¾ Department of Pediatric Rehabilitation, Women’s and Children’s Hospital,
Adelaide – Australia
¾ Department of Physical Medicine & Rehabilitation, Michigan Medicine,
University of Michigan – USA
39
¾ Department of Epidemiology & Public Health Medicine, Royal College of
Surgeons in Ireland – Ireland
¾ Department of Anthropology, University of Michigan – USA
¾ Department of Neurology, Boston University – USA
¾ Discipline of Paediatrics & Child Health, Children's Hospital Westmead and
Sydney Medical School, University of Sydney – Australia
¾ Division of Maternal-Fetal Medicine, Department of Gynecology-
Obstetrics, Johns Hopkins University School of Medicine – USA
¾ Department of Neurology, Children’s National Medical Center, Washington
– USA
¾ Departments of Neurology & Pediatrics, University of California, San
Francisco – USA
¾ Department of Global Public Health & Primary Care, University of Bergen
– Norway
¾ Department of Pediatrics, Haukeland University Hospital, Bergen – Norway
¾ Department of Public Health & Primary Health Care, University of Bergen
– Norway
¾ Medical Birth Registry of Norway, Norwegian Institute of Public Health,
Bergen – Norway
¾ Department of Clinical Medicine, Section for Pediatrics, University of
Bergen – Norway
¾ Department of Obstetrics & Gynaecology, Seoul National University
College of Medicine – South Korea
¾ Department of Obstetrics & Gynecology, Soroka University Medical Center,
Ben Gurion University of the Negev, Beer Sheva – Israel
¾ Center of Clinical Research, Faculty of Health Sciences, Ben Gurion
University of the Negev – Israel
¾ Telethon Kids Institute, University of Western Australia, Perth – Australia
40
¾ Department of Epidemiology, College of Human Medicine, Michigan State
University – USA
¾ National Center on Birth Defects & Developmental Disabilities, Centers for
Disease Control & Prevention, Atlanta, Georgia – USA
¾ Surveillance of Cerebral Palsy in Europe – Italy
¾ Department of Paediatrics & Child Psychiatry, University of Göteborg –
Sweden
¾ Western Australian Research Institute for Child Health, Princess Margaret
Hospital for Children, Perth – Australia
¾ Departments of Pediatric Neurology, Montreal Children’s Hospital, McGill
University – Canada
¾ Department of Human Development, Michigan State University – USA
¾ National Neurosciences Centre, Kolkata – India
¾ Department of Pediatrics & Child Health, Makerere University, Kampala –
Uganda
¾ School of Public Health, College of Health Sciences, Makerere University
– Uganda
¾ Department of Women's & Children's Health, Karolinska Institutet –
Sweden
¾ Department of Public Health, Karolinska Institutet – Sweden
¾ Department of Neuropaediatrics, Astrid Lindgren Children's Hospital,
Stockholm – Sweden
¾ IMC/ThEMAS-RHEOP, Grenoble University Hospital – France
¾ School of Medicine, LDS Hospital, University of Utah – USA
¾ Department of Paediatrics, University of Melbourne – Australia
¾ Grace Centre for Newborn Care, Sydney Children's Hospital Network,
Sydney – Australia
41
¾ Developmental Medicine, The Royal Children's Hospital, Melbourne –
Australia
¾ March of Dimes Birth Defects Foundation, California Birth Defects
Monitoring Program, Oakland – USA
¾ Department of Epidemiology, Institute of Public Health, University of
Aarhus – Demark
¾ National Health & Medical Research Council Research Unit in
Epidemiology & Preventive Medicine, University of Western Australia,
Nedlands – Australia
¾ Department of International Health, Johns Hopkins Bloomberg School of
Public Health, Baltimore – USA
¾ Neal Hodgson Woodruff School of Nursing and Rollins School of Public
Health, Emory University, Atlanta – USA
¾ Department of Pediatrics, All India Institute of Medical Sciences, New
Delhi – India
¾ MRC Maternal & Infant Health Care Strategies Research Unit, University
of Pretoria – South Africa
¾ Measurement & Health Information Systems, World Health Organisation,
Geneva – Switzerland
¾ Human Resources for Health, World Health Organisation, Geneva –
Switzerland
¾ Department of Pediatrics, Saint Louis University, Saint Louis – USA
¾ Department of Statistics & Epidemiology, RTI International, N Carolina –
USA
¾ University Teaching Hospital, Lusaka – Zambia
¾ Center for Research for Mothers & Children, National Institute of Child
Health & Human
¾ Development, Bethesda – USA
42
¾ Department of Pediatrics, University of Alabama at Birmingham,
Birmingham – USA
¾ Department of Paediatrics, Institute of Medicine, Kathmandu – Nepal
¾ Department of Paediatrics, Nepal Medical College, Kathmandu – Nepal
¾ Department of Obstetrics & Gynaecology, Institute for the Health of Women
& Children, Perinatal Centre, Sahlgrenska University Hospital, Göteborg –
Sweden
¾ Department of Neurology & Pediatrics, University of Vermont – USA
¾ Department of Pediatrics (Neonatology), Wake Forest University Health
Sciences, N Carolina – USA
¾ Neuroepidemiology Unit, Children’s Hospital of Boston – USA
¾ Department of Pediatrics (Newborn Medicine & Pediatric Neurology),
Floating Hospital for Children at Tufts Medical Center, Boston – USA
¾ Perinatal Neuroepidemiology Unit, Departments of Gynecology and
Pediatrics, Hannover Medical School – Germany
¾ INSERM U149 Research Unit on Perinatal Health & Women's Health,
Villejuif – France
¾ Hôpital Charles Nicolle, Rouen – France
¾ Research Unit on Epidemiology & Public Health, INSERM U558, Toulouse
– France
¾ Hôpital Jeanne de Flandre, Lille – France
¾ Hôpital Antoine Béclère, Paris – France
¾ Hôpital Mère-Enfant, Nantes – France
¾ Hôpital Hautepierre, Strasbourg – France
¾ Hôpital Saint-Jacques, Besançon – France
¾ CHU Montpellier, Montpellier – France
¾ Hôpital Universitaire, Nancy – France
43
¾ Department of Pediatrics, Izaak Walton Killam Health Centre, Halifax –
Canada
¾ Departments of Pediatrics, Obstetrics & Gynaecology, Perinatal
Epidemiology Research Unit, Dalhousie University, Halifax – Canada
¾ Department of Paediatric Rehabilitation, Medical University of Bialystok –
Poland
¾ Paediatric Department, Kolding Hospital, Kolding – Denmark
¾ Department of Child Neurology, University Children's Hospital, Tübingen
– Germany
¾ Registre des Handicaps de l’Enfant et Observatoire Périnatal, ThEMAS,
Technologies de l’Imagerie de la Modélisation et de la Cognition, Grenoble
– France
¾ Langley Porter Neuropsychiatric Institute, San Francisco – USA
¾ Department of Paediatrics, Monash University, Melbourne – Australia
¾ Oregon Institute of Occupational Health Sciences, Oregon Health & Science
University, Portland – USA
¾ Institute of Child Health, Neurology & Genetics, College of Medicine,
University of Arizona – USA
¾ Centre for Applied Genomics, The Hospital for Sick Children, Toronto –
Canada
¾ Department of Pediatrics, University of Alberta, Edmonton – Canada
¾ Holland Bloorview Kids Rehabilitation Hospital, Department of Paediatrics,
University of Toronto, Toronto – Canada
¾ Human Genome Sequencing Center, Baylor College of Medicine, Houston
– USA
¾ Center for Developmental Health, Curtin University of Technology, Perth –
Australia
44
¾ Department of Medicine, Pontifícia Universidade Católica de Goiás,
Goiânia – Brazil
¾ Departments of Pediatrics and Pediatric Neurology, Laboratory for
Molecular Biology, and Units of Pediatric Hematology, Human Genetics
and Child Development, HaEmek Medical Center, Afula – Israel
¾ Pediatric Department, Rigshospitalet, Copenhagen – Denmark
¾ Department of Pediatrics, Janeway Health Centre, St. John's – Canada
¾ Developmental Pediatrics, BC Children's Hospital, Vancouver – Canada
45
Research Funding
46
GLOBAL OVERVIEW
Medical research is a powerful tool as it informs public health policy and can
drive health, social, and economic benefits. The purpose of this analysis is to
assess the state of funding for CP research globally from key government and
charity health funders in countries where most of CP research is generated.
Cerebral palsy’s pooled prevalence is 2 to 3 per 1,000 live births (1, 19-22,
28). This prevalence is suggested to be higher in some low- and middle-income
countries (LMICs) (37, 141). As a lifelong problem with poor quality of life (2,
34, 145, 152-155). CP and its associated comorbidities place a huge economic
burden on families and the healthcare systems. In 2003, the United States’
Centers for Disease Control & Prevention (CDC) estimated the annual total
lifetime costs for CP in the USA to be $11.5 billion, with each CP case costing
$1.2 million (156).
The causes of CP are still not fully elucidated; obstetric mishaps were thought
to be the major contributors for CP for a long time, although recent studies now
show that prenatal factors such as maternal infection may contribute to the
cerebral damage in CP and that CP may in fact be preventable.
That there is now plausibility that CP may be preventable is as a result of the
ground-breaking study led by Professor Martin Bax and part-funded by the Little
Foundation, which found all lesions identifiable by MRI had been initiated well
before the time of birth (58).
This insight, alongside the low quality of life, extortionate costs of medical
and social care, and the healthcare economic burden attributed to CP, should
place it on the top priority list for medical research (18, 157-161). However, our
analysis demonstrates that this is not necessarily the case.
47
KEY OBSERVATIONS
¾ Most CP research is funded by high-income countries, and less so by low
and middle-income countries
¾ The countries that report the largest funding of CP-related research are the
USA (£17.9m), Canada (£5.5m), the UK (£4.6m) and Australia (£3.9m) –
2014 figures
¾ Australia spends the highest proportion of its annual health research budget
on CP research – 0.42%
¾ The CP-related research spend of £4.6m in the UK in 2014 represented
0.23% of all UK Health Research supported by government and charity. The
2018 CP-related research spend of £5.65m in the UK represented 0.22% of
total spend, representing a decrease in CP-related spending over the past 4
years.
¾ In 2014, 24% (£1.1m) of CP research in the UK was spent on understanding
the causes (aetiology) and only 0.3% was spent on prevention research
¾ Compared to 2014, the 2018 attributable research funding to aetiology of
CP decreased to 17% (£1m) of CP, whilst the prevention-related research
increased to 7 %.
48
Funding for CP-
related Research
GBP
Equivalent
% of total health
research spend
on CP
Australia AUS $7,100,0001 3,919,023 0.42%2
Canada CAN $8,870,281 5,474,815
0.24%
UK GBP £4,601,1293 4,603,129 0.23%
USA US $21,904,3634 17,979,320 0.07%5
Table 1 - Global leaders in CP-related research funding in 2014
1 Encompasses NHMRC, CPARF, and ARC total funding for CP research (government and charity spend) 2 Based on NHMRC 2013-2014 NHMRC research spending in National Health Priority Areas and NHMRC CP
funding for 2013 3 Based on UKCRC Health Research Analysis Data of 2014, which includes government and charity spend 4 Based on 2013 NIH funding -wide actual funding for Research, Condition and Disease Categories (RCDC),
CPARF, NSF funding in the USA 5 Based on the reported NIH total health expenditure (2013) of US$26,081.3 million from Viergever et al.
49
GEOGRAPHICAL SPREAD
United Kingdom
Health Research Analysis 2014 Every five years, the UK clinical research collaboration (UKCRC) releases a
dataset of all health research, including grants from charity and government
funders. We searched the term “cerebral palsy” in the abstract for recent research
grants included, and we retrieved 31 grants from different funding agencies; 9
from the Action Medical Research (AMR), 12 from the Department of Health
(DoH), 4 from the Medical Research Council (MRC), 3 from the Wellcome Trust
(9.7%) and the remaining 3 were from Sparks, the Engineering and Physical
Sciences Research Council (EPSRC) and Chief Scientist Office (CSO) in
Scotland.
Total funding between 2010-2015 was £16,197,600. The Department of
Health (DoH) contributed £5,797,433, followed by the Wellcome Trust with
£3,860,176 worth of funding, and £3,823,833 from the MRC. The latest UKHRA
report for funding data in 2014 estimated a total funding of £ 4.6 million in 2014
for CP research. The DoH in England and Wales contributed 37% of the total
expenditure on CP research, followed by the MRC (30%), Wellcome Trust (17%),
AMR (7%), EPRC (4%), SPARKS (3%), and CSO Scotland (3%).
50
Figure 1 - Funding amount and proportions for cerebral palsy research in UK (2014) according to the various funding organisations. Total funding is £4.6m. Graph generated based on data from the UKCRC Health Research Analysis Public Dataset 2014.
Figure 2 displays the distribution of funding according to area of research. The
largest amount was for aetiology, £1,122,402 (24.4%) followed by detection and
diagnosis £997,806 (21.7%), treatment evaluation £828,521 (18%), underpinning
£551,792 (12%), treatment and development £484,990 (10.5%), disease
management £336,915 (7.3%), health services £264,942 (5.8%), and prevention
£15,769 (0.3%).
51
Figure 2 - UK funding for cerebral palsy research in 2014, by area of research. CP, cerebral palsy. Total funding is £4.6m. Graph generated based on data from the UKCRC Health Research Analysis Public Dataset 2014.
The funding agencies discovered to date and described below are divided into
charitable and governmental according to their source of funding:
£551,792
£1,122,402
£15,769
£997,806
£484,990
£828,521
£336,915
£264,942
0
200000
400000
600000
800000
1000000
1200000
Underpinning Aetiology Prevention Detection anddiagnosis
Treatment anddevelopment
Treatmentevaluation
Diseasemanagement
Health services
Total amount spent (£) by CP research activity
52
Government
UK Research Councils – MRC / EPSRC / Innovate UK etc.
To obtain a complete picture of government funding for CP research, we accessed
the UK Research & Innovation (UKRI 6 ) portal (https://gtr.ukri.org/) and
identified 254 projects from the portal’s “cerebral palsy” keyword search. Of
these, 199 were found upon further review to be unrelated to CP but related to
other diseases such as Alzheimer’s. We excluded one Medical Research Council
(MRC) grant from 1997. Consequently, we identified 54 active and closed
projects (either directly related to CP or indirectly via risk factors such as pre-
term birth, low birthweight or stroke), with a collective value of £28.7 million,
funded between 2005-2019 by 5 research councils.
Of the funding bodies, the Medical Research Council (MRC) accounts for
more than half of the CP-related projects, followed by the Engineering & Physical
Sciences Research Council (EPSRC), and Innovate UK. The remaining 5.7% of
the projects were equally distributed between the Economic & Social Research
Council (ESRC), Biotechnology & Biological Sciences Research Council
(BBSRC), and the Arts & Humanities Research Council (AHRC) (Figure 3).
6 UKRI, a government-funded QUANGO, acts as the hub for UK research and innovation, administering the 7
national research councils
53
Figure 3 - Distribution of CP projects by UKRI institutions (n=54 projects).
Figure 4 shows the total funding for each of the UKRI institutions for the 2005-
2019 periods. The MRC was the biggest funder for CP research followed by the
EPSRC.
Figure 4 - Total funding for CP research by various UKRI institutions for 2005-2019. Pie chart compiled from data available via UKRI research council portal for government-funded projects.
54
Figure 5 represents the total funding for the 54 identified projects that are related
to CP. The funding received by UKRI institutions for CP research (2005-2019)
is sporadic and does not reflect a regular and general upward trend, although it
highlights boom years (2006, 2010, 2016). Except for 2008, where no grant was
awarded, the MRC seem to be consistently funding new projects annually.
Figure 5 - Total funding for cerebral palsy-related research by UK Research and Innovation (2005–2019): Medical Research Council (MRC), The Engineering and Physical Sciences Research Council (EPSRC), and Innovate UK.7
UK Department of Health / National Institute for Health Research The NIHR is the largest national clinical research funder in Europe, with a
reported 2015-2016 budget of over £1 billion. The advertised funding
opportunities through their website do not include cerebral palsy under their
specialties; however, they do include neurological disorders and mental health.
We identified 50 research projects using the term ‘cerebral palsy’ on the NIHR
database that stores the portfolio of studies funded by each of their research
programmes between 1997-2019 via the link:
https://www.journalslibrary.nihr.ac.uk/eme/#/.
7 The funding amounts are in British pounds and correspond to the amount allocated to each grant at the start
year. Chart was compiled from data available via UKRI research council portal for government-funded projects
(2005-2019).
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It should be noted that these projects are strictly restricted to academic
institutions and not to UK clinical research collaborations. Out of the 50, 20
projects were unrelated to CP (thyroid cancer, cardiac arrest, hyperacute stroke
system, oesophageal reflux, Alzheimer’s Disease, intracerebral haemorrhage,
dementia, cardiac disease, epilepsy, stenting) and 13 projects were indirectly
related to CP (preterm birth, neonatal health, seizures, neurodisability) and 17
research projects were related to CP. Furthermore, none of the NIHR-funded
projects were in the fields of aetiology or prevention research. Figure 6 shows the
total NIHR funding for the 30 research projects directly or indirectly related to
CP, which amounts to £25,036,579. Unlike research council funding, total NIHR
funding for CP research has increased from 2005 to 2019, peaking in 2014 and
2018. However, the number of projects specifically related to CP have decreased
since 2014 (Figure 6).
Figure 6 - Total funding for cerebral palsy-related research by NIHR (2005–2019), by specificity to CP research.
The funding amounts are in British pounds and correspond to the amount
allocated to each grant at the start year. Chart was compiled from data available
via journals library portal for portfolio of NIHR funded studies (2005-2019).
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Foundations / Charities
Action Medical Research Action Medical Research has funded a considerable number of studies related to
CP, mostly to studies exploring interventions for babies/children living with CP.
Current research interests focus on advancements in ultrasound scans for
identification of early hip problems for children with CP, technology-based
approaches for hand and arm rehabilitation and surgical interventions to improve
mobility. Their areas of interest include, but are not limited to, preterm birth (in
collaboration with Borne Charity), stillbirth, birth asphyxia, and autism. Data
from the UKCRC/HRA showed that AMR funded 9 CP research grants in 2014,
contributing a total of £342,736 for CP research, 40% of which was spent on
aetiology of CP (£136,620). Cerebra
Cerebra – For Brain Injured Children & Young People is a UK research charity
with a focus on research to improve life opportunities for children with brain
conditions, autism, ADHD, Down’s syndrome, learning disabilities, cerebral
palsy, epilepsy and developmental delay. One research priority is to “identify
women at risk of experiencing complications in pregnancy and preventing or
minimising the impact of those complications on mother and baby.” Annual
research expenditure is circa £660k, mainly supporting academic chairs in
UK/European universities. Their Thousand Women Study has collected over
2,000 blood samples from women during pregnancy, with associated
demographic and clinical information, creating an internationally unique resource
for research into the obstetric causes of preterm birth.
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Sparks Sparks is a children’s medical research charity that does not receive any
government funding and currently supporting over £5 million-worth of research,
with cerebral palsy being one of their historic priorities. The UKCRC report of
2015 shows one CP grant funded by Sparks in 2009 for £223k. In 2014, the total
estimated spend for CP research by Sparks was £114k, which accounted for 3%
of the total amount spent on CP research. 51% of this funding was spent on
aetiology (£57,696) and 6.5% on prevention of CP (£7,436). Their current
funding opportunities do not include CP, however, instead focusing on other
paediatric medical diseases.
Castang Foundation The Castang Foundation was established by a bequest in 1986 to fund research
for cerebral palsy, subsequently funded by private donations. The Foundation
funds research on cerebral palsy and other disability-causing neurological
conditions in partnership with other organisations – including The Little
Foundation. Primary research interests include basic science for the
understanding of the causes of disability, and effectiveness of interventions to
improve quality of life. Their latest grant scheme is in collaboration with BACD
(see below) and the award covers £60,000 funding for UK research projects
lasting 12-18 months that have the potential of changing the lives of children with
neurodisability.
British Academy of Childhood Disability
The BACD is an organisation for professionals working on childhood disability.
It is affiliated with the British Association of Community Child Health, part of
the Royal College of Paediatrics & Child Health, and is the UK branch for the
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European Academy of Childhood Disability. The academy offers two annual
awards for UK-based research, the Castang Award (see above) and the Paul
Polani Award (in association with the Royal College of Paediatrics & Child
Health) – amounting to £15,000 for research projects on paediatric neuro-
disability.
Wellcome Trust
The Wellcome Trust is a private research charity based in London, managing an
investment portfolio of £25.9 billion, which funds their work. They do not have
a specific funding scheme for cerebral palsy. We searched their database of grants
awarded using the keyword search term ‘cerebral palsy’ and only one grant was
retrieved. The grant was for the development of a neonatal brain health index
(DELPHI) with the aim of recognising patterns of brain activity to detect the
severity of brain injury- this was an Innovator Award for recognising brain injury
from babies’ brainwaves. Although not included in their database, the 10-year
SPARCLE study by Allan Colver about the quality of life of children with
cerebral palsy across Europe was partially funded by the Wellcome Trust. We
looked at Ethos Library to identify CP-related doctoral theses funded by the
Wellcome Trust and only one was retrieved. The UKHRA report of 2014 data
showed that the Wellcome Trust contributed to 17% of the total amount spent on
CP research, equivalent to £781,687, out of which £182,323 was spent on
aetiology (23.3%) and none on prevention.
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Europe
European Commission The European Commission, the executive of the European Union, is one of the
largest public funders of health research in the world. A search of their current
funding opportunities for research revealed no specifically CP-related schemes.
However, historically, the Commission has funded many CP-related projects.
Through their Erasmus+ Programme, which aims to increase awareness and
education, they have funded 59 CP-related projects, one of which was a multi-
country training programme for improving the wellbeing of persons with cerebral
palsy through inclusive feeding and physical activity (€255,489).
Our search through the Cordis database, of all EU-funded CP-related research
projects (via https://cordis.europa.eu) yielded 43 projects, 7 of which started
before 2005 and 2 of which did not have available budget information. The total
EU contribution for CP-related research between 2005 and 2019 was €62,624,825.
Figure 7 shows the total yearly spend for CP-research. Although there is more
consistent funding after 2013, with more money spent on CP-related research,
there is no evidence of an overall increasing trend. The peak year was 2015,
followed by 2017 and 2006.
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Figure 7 - Total funding for cerebral palsy-related research by European Commission (2005–2019).
Funding amounts are in Euros and correspond to the amount allocated to each
grant at the start year. Chart was compiled from data available via the Cordis
database of the European Commission.
We also searched the Horizon 2020 Framework Programme for current calls.
We did not find CP-specific calls; however, there were a few for
neurodegenerative diseases.
Nevertheless, the European Commission’s Joint Research Centre, having
invested over €1m in supporting its development, took on responsibility in 2016
for coordinating the work of the Surveillance of Cerebral Palsy in Europe8
network, managing its Central Registry, funding development of several CP
registries across Europe and ensuring European-level collaboration amongst
medical professionals, researchers and policy makers.
8 Surveillance of Cerebral Palsy in Europe (SCPE) was established in 1998 as a collaboration of professionals
and researchers working with cerebral palsy (CP) registries, bringing together paediatricians, paediatric
neurologists, epidemiologists and therapists from across Europe. The aim is to disseminate knowledge about
CP through epidemiological data, to develop best practice in monitoring trends in CP, to raise standards of care
for individuals with CP, to inform for service planning, and to provide a framework for collaborative research. It
is a non-profit NGO funded by the European Union Health Programme.
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Australia
Australia is at the forefront of global funders of research relating to cerebral palsy
in terms of commitment, with the highest reported proportion of annual national
health research budgets (0.42%) devoted to this area. There is a comparatively
thriving environment of scientific societies, research charities and government-
funded research councils prepared to invest in research both in and outside
Australia. Government National Health Medical Research Council
NHMRC is Australia’s primary distributor of federal medical research funding
and has an annual appropriation of AUS $829 million. It has increased its funding
for CP research over 2000 - 2014 (Figure 8) and sponsored 125 grants with circa
AUS $53 million over that period.
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Figure 8 - National Health and Medical Research Council Funding by Health Condition, 2000-2014.9
Australian Research Council
The ARC is the “is the primary source of advice to the Government on investment
in the national research effort” and is other major distributor of government
research funds, with a budget of c. AUS $800 million. It administers the National
Competitive Grants Programme and is responsible for the Excellence in Research
programme. Details could be found of only 6 grants relating to CP research,
making its total of AUS $1,542,000 the lowest of the 3 key funders of CP research
in Australia (162).
9 Image reproduced from Herbert et al. 162. Herbert DL, Barnett AG, White R, Novak I, Badawi N. Funding
for cerebral palsy research in Australia, 2000-2015: an observational study. BMJ Open. 2016;6:e012924. with
permission of the rights holder, BMJ Publishing Group Limited in accordance with Creative Commons
Attribution Non-Commercial (CC BY-NC 4.0) license.
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Australasian Academy of Cerebral Palsy & Developmental Medicine
The Academy was founded in 2002 to provide “multi-disciplinary scientific
education for health professionals and to promote excellence in research and best
practice clinical care for children and adults with cerebral palsy and
developmental conditions”. However, unlike its US counterpart, it does not have
a research grant programme although its members make up the bulk of grant
recipients from both government research councils and NGOs.
Foundations / Charities
Cerebral Palsy Alliance
The Cerebral Palsy Alliance was established 75 years ago and has a remit “to help
babies, children, teenagers and adults living with neurological and physical
disabilities lead the most comfortable, independent and inclusive lives possible.”
In addition to this focus on the quality of life of those affected by CP, and with
an annual income of c. AUS $110 million, it is one of the 3 main drivers of CP
research in Australia via its associated Cerebral Palsy Alliance Research
Foundation (see below).
The Alliance manages Australia’s National Cerebral Palsy Register, expected
to be one of the largest in the world and which has contributed significantly to
our current understanding of CP prevalence, trends and risk factors.
Cerebral Palsy Alliance Research Foundation
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Launched in Australia initially in 2005, subsequently in 2015 in the USA, by the
Cerebral Palsy Alliance, “to fund the best CP research around the world”. Total
funding from CPARF was close to AUS $22,000,000 covering 102 grants, with
32.3% allocated to the formation of Cerebral Palsy Alliance Research Institute at
the University of Sydney, 16.8% allocated to strategic grants for prevention and
cure, and 50.9% allocated to competitive grants to cover doctoral scholarships
and fellowships for CP research (162).
A recent review on the available funding for CP between 2005-2015
concluded that funding lacked consistency throughout the years and equivalence
across the three funding bodies; overall, competitive funding from NHMRC and
CPARF has improved. However, the NHMRC has sporadic annual awards,
resulting in an irregular pattern of funding. The review’s authors highlighted the
need for a consistent funding pattern from NHMRC and increased funding from
the federal government in order to meet its acknowledged research priorities of
prevention and cure of CP (162).
Following the review’s publication in 2016, the Federal Government‘s
Ministry of Health in June 2018 granted AUS $2 million in additional funding
for the Cerebral Palsy Alliance’s Research Institute to address issues related to
early diagnosis and treatment of CP, clinical trials in high risk infants, and new
therapies to prevent CP during pregnancy (163).
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United States of America
Government
National Institutes of Health
The main key funder for cerebral palsy research in the USA is the National
Institutes of Health (NIH), a national medical research agency that is part of the
U.S. Department of Health & Human Services. Although there are no specific
program announcements or requests for applications to address CP research gaps
particularly, the NIH has conducted workshops and set strategic plans to identify
gaps in CP research and prioritise specific areas.
A recently published review by Wu et al. assessed the state of NIH funding
for CP research from 2001 to 2013 (164). Results showed an increasing linear
trend of funding for NIH-sponsored CP research, amounting to a total of $392.8
million, with an annual average of $30 million. The grants were awarded to 188
organisations across 43 US states. The funding was provided by 20 different NIH
institutes, with 76% coming from the National Institute of Neurological Disorders
and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD). $1.4 million was spent on 80
scientific meetings, and the remaining amount was spent on different research
categories: 55% for clinical research ($215 million), 48% for basic research ($187
million), 11% for development of new technologies ($45 million) and 7% for
translational research ($26.3 million). The biggest area of research was attributed
to central nervous system development and mechanisms of injury (over $100
million) followed by research on muscle function and structure (around $90
million). In contrast, around $35 million was spent on basic and clinical research
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to identify risk factors for CP. The review highlighted the crucial need for
continued funding for the development of effective strategies for the prevention
and treatment of CP (164).
CP has gained remarkable visibility recently in N America. In 2017, both the
NICHD and NINDS put a 5-year strategic plan to tackle gaps in CP research.
Two workshops were held, and high priority recommendations were set to
increase advances in basic and translational research, clinical research, and
workforce development. The prenatal period was a particular focus area, with
particular focus given to improving the understanding of the fundamental
mechanisms of the brain-spine-muscle axis and molecular pathways of injury,
establishing biomarkers of genetic, structural, and functional basis that drive
impairment, and identifying critical periods of brain and motor development
(165). In 2013, according to the NIH’s review of funding for research condition
and diseases categories, the estimated worldwide total spend on CP research was
$18 million. National Science Foundation (NSF)
The NSF is an independent agency that accounts for 25% of federal support to
US academic institutions for research – their sole beneficiaries. Although there
are no specific research projects tailored to tackle the issue of CP, an analysis of
available funding via Grantome showed 115 grants granted by the NSF for CP-
related topics. Their range of funding is very wide, from thousands to millions,
and granted to US academic institutions only. Many of the grants support
workshops and conferences. In 2014, the estimated total funding by the NSF for
CP research was $3,354,363, none of which was spent on either prevention or
aetiology.
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American Academy for Cerebral Palsy & Developmental Medicine
As with the Australian Academy of Cerebral Palsy & Developmental Medicine
(above), the AACPDM’s mission is: “to provide multidisciplinary scientific
education for health professionals and promote excellence in research and
services for the benefit of people with and at risk for cerebral palsy and other
childhood-onset disabilities. Originating from the CP Advisory Medical Council,
it has a multi-disciplinary membership of over 1,000 health professionals
(paediatricians, neurologists, surgeons, rehabilitators, therapists, nurses, special
educators, engineers, and scientists). It accepts donations from the public and
companies (e.g. Amazon) and partners with medical research charities. It works
closely with the NIH and, together, have established the NINDS/AACPDM
Common Data Elements (CDEs) for Cerebral Palsy online resource to help
standardize data collection and assessment in research.
The Academy hosts annual conferences – in 2019 jointly with the International
Alliance of Academies of Childhood Disability – which includes the World CP
Register and Surveillance Congress It also collaborates with the Cerebral Palsy
Alliance with medium-scale research grant programmes:
¾ Transformative practice grants for its membership – focused on the
translation of evidence-based strategies into practice
¾ Clinical research grants up to $25,000 - open to non-members for high
impact projects on CP or childhood-onset disability
¾ International meeting development grants up to $50,000 – for newly-formed
organisations that aim to develop seminars related to early identification and
treatment of individuals with childhood-acquired disability (166).
¾ Junior investigator research grants up to $15,000 – aimed at fostering the
scientific development of the next generation of scientists.
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Foundations / Charities
Cerebral Palsy Alliance Research Foundation
The CPARF was recently (2015) founded in New York for US grants (2015) as
a complementing organisation to the CPARF in Australia, mentioned above, but
without its international funding remit. The grants cover up to $180,000 on
projects that fit into the foundation’s priorities for expanding CP research in the
US: aetiology, prevention, causal pathways, early identification and intervention,
and cure. The areas of research differ each year and the 2019-targeted areas are
technology innovations, regenerative medicine using stem cells, genetics and
reduction of pain (167). The money comes from private donations and, in some
instances, government agencies, such as the $2 million grant by the Australian
Ministry of Health. In 2014, the Foundation’s estimated annual research spend
was £550,000. Cerebral Palsy Foundation
Based in New Jersey, the CPF, formerly known as the United Cerebral Palsy
Research & Educational Foundation, was founded in 1955 and is the nation’s
principal non-government agency sponsoring research and education for cerebral
palsy. It is funded by private donors and corporate supporters such as Apple and
Microsoft.
The foundation has funded many research projects related to the cause, cure
of CP and evidence-based care for children affected by cerebral palsy and related
developmental disabilities. Currently, it has no grant schemes to offer; however,
it is funding animal trials conducted by researchers at the Kennedy Krieger
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Institute and John Hopkins which are looking at the effectiveness of anti-
inflammatory medication in reducing perinatal white matter inflammation. Cure CP
Cure CP is a non-profit organisation based in Atlanta, Georgia, founded by two
families who had children with CP. It pursues a unique approach, directing all
funding to support research focused on regenerative medicine. It secures its
funding through private donations and supporters such as investment banks
(Merrill Lynch/Goldman Sachs) and other private companies. CP Cure mainly
supports clinical trials and research studies related to regenerative medicine
(https://curecp.org/studies-we-support/) such as grants given to Duke University
School of Medicine for the use of cord blood stem cells to treat children with
spastic CP and University of Texas, also looking at stem cells from cord blood
for children with CP. It also contributed to other clinical trials and to the Cerebral
Palsy Summit annual meetings. There is no detail available on the scale of its
grant-making, while its annual income reported via GuideStar appears to be
below $200k.
Bill & Melinda Gates Foundation
Although there are no thematic grants for CP in particular, the foundation recently
awarded the University of San Diego a grant worth $219,675 for the testing of 3
new drug candidates for the potential to protect new-borns against brain injury
and cerebral palsy.
A notable facet of the Gates Foundation’s approach has been to seek resolution
to major issues by investing at scale on the basis of critical mass, such as with
their investment in the Global Polio Eradication Initiative. Based on the
accumulated knowledge of many years of research and the certainty of the
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required approach, the Foundation’s investment of circa $3 billion was designed
to improve and accelerate vaccination programmes globally – leading to polio’s
near eradication.
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Canada
RAND Europe’s 2008 report Health and Medical Research in Canada10 observes
that “one of the most interesting aspects of the Canadian health research system
is the use of endowment funding, a system more commonly associated with
university funding. The Canadian Health Services Research Foundation
(CHSRF) is mainly funded by endowments from the major federal funders of
health or services research: the then Medical Research Council of Canada
(MRCC, now the Canadian Institutes of Health Research [CIHR]); Health
Canada (the federal healthcare funder); and the Social Sciences & Humanities
Research Council (SSHRC).” Other funding agencies include the Canadian
Foundation for Innovation, Canadian Research Chairs, Networks of Centres of
Excellence and the Natural Science & Engineering Research Council.
They observe that “the higher education sector spends more than the federal
government, and nearly as much as industry, on health R&D.” Proportions of
investment in health research in 2005 were: 24% business enterprise, 25.6%
higher education and 25% government, with 62% of all research activity being
undertaken in the higher education sector and 34% in the business sector. The
NGO/charity sector was reported as contributing circa 8-9% of Canada’s R&D
funding.
Total health research expenditure in 2018 is reported as $4.13 billion11, an
increase from 2014’s $3.71 billion.
10 https://www.rand.org/content/dam/rand/pubs/documented_briefings/2008/RAND_DB532.pdf
11 https://www.statista.com/statistics/436571/total-health-research-spending-canada/
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Government
Canadian Institutes of Health Research
The CIHR is the largest single funder of health R&D in Canada, being responsible
for circa 60% of all federal spend and circa 12% of national R&D funding12. It
spends approximately $1 billion each year to support health research. There are
13 CIHR institutes that set the research priorities and offer grants. We conducted
a search of CIHR's public funding database, which comprises bilingual (English
and French) information on successful grant applications, studentships and
fellowships using the following keywords: “cerebral palsy” and
“la paralysie cérébrale” via: https://webapps.cihr-irsc.gc.ca/decisions/
Grants were included if their abstracts indicated specific focus on CP, its risk
factors, or its effects and implications. A total of 106 CP-related programs were
retrieved between 2008 and 2019, almost all for Canadian researchers. The total
amount spent by the CIHR between 2008-2018 on CP-related research was
$31,458,810. Research related to the aetiology of CP accounted for $6,192,529,
research for the prevention of CP amounted to $4,520,997, early detection and
diagnosis research, $719,566. The remaining $20 million was spent on muscle
rehabilitation, orthopaedic and mobility-related interventions, treatments to
improve quality of life and lifestyle of CP affected children, and social support. Canadian Foundation for Healthcare Improvement
The CFHI (formerly the Canadian Health Services Research Foundation) is a
federally funded organisation focused on the spread of innovative practices and
working “shoulder-to-shoulder with our partners to deliver better patient care
12 Health Canada is the country’s other main funder of medical research, but with a public health remit.
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more efficiently.” Its annual budget is c. $17 million CAN. It appears to fund no
explicitly CP-related programmes but does support others focused on obstetric
practice: i.e. taking a multi-institutional approach to maternal and foetal health.
Foundations / Charities
Ontario Federation for Cerebral Palsy Research Fund
The OFCP offers a CP-specific funding scheme for the support of high-quality
research in Canada. Projects with an estimated budget of $50,000.00 or less, per
year, over a three- year term are eligible for the award. Based on their research
inventory, they have previously funded 23 CP-related grants, 4 out of which were
related to aetiology of CP and 2 to prevention.
Kids Brain Health Network
KBHN (formerly NeuroDevNet) is part of the National Centres of Excellence
programme, part government/part philanthropy funded, “as a network of
researchers and clinicians seeking to understand brain development, with the
specific goal of mobilizing this knowledge to improve the lives of children living
with neurodevelopmental disabilities and their families.” It funds collaborative
research, with a focus on early diagnosis.
Current research funding opportunities include an open funding competition
to identify “an innovative approach to diagnosis, treatment or support for
caregivers raising children with neurodisabilities”. Recent grant awards vary
between $90k CAN and $200k CAN. The organisation also runs a programme
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of developmental neuroscience research training awards funded in association
with Brain Canada.
Importantly, the Network is also the originator and funder of the Canadian
Cerebral Palsy Register in 2007, which is already providing important
epidemiological data as a way to determine prevalence and describe CP in
Canada’s population. It is currently evolving to incorporate quality-of-life
questions. Brain Canada
Brain Canada describes itself as “ the national convenor of the community of
those who support and advance brain research” and drives the Canada Brain
Research Fund, a $260 million CAN initiative established in 2011 in
collaboration with Health Canada and a number of major philanthropic
institutions. To date this Fund has supported 6 CP-related research projects with
a collective value of $1.9 million CAN. CanChild
CanChild is a research organisation housed at McMaster University, with a focus
on children and youths with disabilities, with an annual income of circa $700k
CAN. Its recent Childhood Cerebral Palsy Integrated Neuroscience Discovery
Network (CP-NET) project seeks to connect families affected by CP to a national,
multi-disciplinary community of research scientists to improve the understanding
of CP with regard to causes, prevention and rehabilitation, with a particular focus
on hemiplegic CP.
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CHILD-BRIGHT Network
CHILD-BRIGHT Network is a research organisation hosted by McGill
University that, using a family- and child-focused approach, “creates novel
interventions to optimize development, promote health outcomes, and deliver
responsive and supportive services for children with brain-based developmental
disabilities”. Their research studies new diagnostic tests, therapies, service
models, and technologies “to optimize the physical and mental health of …
children”.
While one of its 3 research themes is early intervention, current projects do
not include a CP element. However, 3 historical CP-related projects (looking at
brain repair and improving early diagnosis) are reported, albeit without details of
the scale of their funding.
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Globally This section highlights other countries that have reported CP-related research and
funding.
India
The Indian Council of Medical Research (ICMR) is one of the biggest research
funding agencies, with a reported USD 140.3 million spent on health research in
2011 (168). However, there is no information available on CP specific grants or
previous awards, except for one grant. Other potential funding agencies are
Biotechnology Industry Research Assistance Council (BIRAC). A search through
their multiple institutional archived awards showed one grant related to CP
children. The Indian Department of Science and Technology (DST) is also a
major health research funder; however, there is little information about the
funding and grant schemes for all CP-research in India. Nevertheless, there is
evidence of CP- related research projects in India, albeit with no detail yet
available on focus, scale or institutions (169).
China
The main funder for CP research in China is the National Natural Science
Foundation of China (NSFC). A search for all CP-related articles showed that
most projects are supported by the NSFC. The Ministry of Health also contributes
to some CP research (46); however, neither organisation provides information
about the current and past state of funding for CP-related research.
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Japan
The Japan Society for Promotion of Science (JSPS) and Japan Science &
Technology Agency (JST) are the two main funding agencies for health research
in Japan, with an estimated spending in 2011 and 2012 of USD 472.5 million and
USD 338.5 million respectively (168). The Kaken Database of Grants-in-Aid for
Scientific Research reports on 11 CP-related research projects funded between
1985 and 2018 with a collected value of ¥32.9 million (£253,355 equivalent).
Although there is no website information on the amount and number of grants
spent on CP-related research, they have funded numerous studies, mostly on
rehabilitation and medical outcomes of children with CP.
The research/medical ‘interested parties’ community is served by the Japan
Cerebral Palsy Study Group, administered (and we assume funded) by UMIN,
Japan’s University/Hospital Medical Information Network, with an annual
conference. However, member/participants (and their institutions) are not
identifiable and, thus, it is difficult to define their research and the scale of its
funding.
South Korea
CP-related research in Korea is predominantly funded through governmental
agencies. The Korea National Institute of Health (KNIH) and the Korean
National Research Foundation (NRF) are the two main public funding
organisations for health research. While there is no information available on their
contribution to CP research, a search of the Korea Education & Research
Information’s Research Information Service System database reveals details of
775 CP-related research papers published between 1983 and 2019 – albeit with
no details of the scale of funding. Published studies from Korea report funding
from the NRF, Korea Centers for Disease Control & Prevention (KCDC) and
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Allergan Korea Ltd, a pharmaceutical company that supported the newly
introduced Korean Database of Cerebral Palsy.
Singapore
In Singapore, the main health funding agency is the Singapore National Medical
Research Council (NMRC). A search through Singapore government integrated
grant management system using the keyword “cerebral palsy” yielded two
awarded grants, one in 2010 and the other in 2016, with no information on the
amount of the award. The Cerebral Palsy Alliance of Singapore (CPAS), KK
Women's & Children's Hospital (KKH) and the National University
Hospital launched Singapore's first cerebral palsy registry in September 2017
(170).
South Africa
CP research in Africa overall is limited as little has been published. Although
there are quite a few studies generated from South Africa, there doesn’t seem to
be a clear funding scheme for CP. The South African Medical Research Council,
which is the main funder for health research, does not have available information
on funding for CP. In fact, a review on CP in Africa highlighted a crucial need
for studies on prevalence, spectrum of cerebral palsy, and main aetiologies in the
African context.
79
Brazil
The publicly funded13 São Paulo Research Foundation (FAPESP) is one of the
country’s leading funding agencies for health research (2012 estimate is USD
154.2 million, more recently over USD 500 million in support of c. 11k project
proposals) (168). We searched the grant and scholarship database using the
keyword “cerebral palsy”, which yielded a total of 81 CP-related research grants
and scholarships, without available data on the amount given.
It is worth noting that FAPESP has signed a bilateral agreement with UK
Research & Innovation (see above) “to welcome, encourage and support
applications that may cut across their national boundaries and involve
international collaborative teams”.
Argentina
The Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
(English: National Scientific and Technical Research Council) is one of the main
funding agencies for health research in Argentina. Cuts in government funding
means, however, that overall the Council is having to reduce the number of early-
stage researchers it has historically funded.
There is no explicit research policy around CP, but the term “cerebral palsy /
parálisis cerebral” yielded details of a total of 6 grants without available
information on the amount of funding given – none are focused on either
aetiology or prevention.
13 São Paulo State’s constitution mandates 1% of monthly revenue to the Foundation:
https://www.nature.com/articles/d42473-018-00281-z
80
CONCLUSIONS The results of the analysis of available funding for CP research shows that the
United States’ NIH is still the largest and most consistent contributor. The
funding for CP research in Australia has also increased, particularly due to the
founding of the CPARF, now one of the main funders for CP research. In the UK,
government-based funding for CP from the UKRI has not been increasing, whilst
funding from the NIHR has improved over the years, although not directly related
to CP.
Results of this review also show that only two philanthropically funded
organisations in the UK have a specific call for CP research, with The Little
Foundation being unique in focusing on CP prevention. Results of the health
research analysis report from the UKCRC show that, in general, the total estimate
for health relevant research in the UK was £2bn in 2014. Funding for
neurological research, which includes CP, appeared to have had the greatest
decrease, falling from 11.6% in 2004/05 to 9.0% per cent in 2014 (Figure 9) (171).
81
Figure9-Proportionofcombinedspendbyhealthcategoryfor2004/05,2009/10,and2014(HRAF,12funders).14
Among the reasons given for the lack of investment in CP research is the
condition’s comparative rarity. Two things militate against this: the inconsistent
nature and lack of CP registers globally in all probability masks the true
prevalence of CP – particularly in the less developed world; and the social cost
of caring for those affected by CP is growing, while incidence is not decreasing
among those not affected by pre-term birth.
The increasing evidence that CP may be preventable has not yet been
paralleled by an increase in funding for the prevention and identification of risk
factors for CP. There is a strong need for substantial future investment by
government and philanthropic agencies to prioritise and increase funding for CP-
related research projects and to increase funding for work on prevention.
14 Image reproduced from “UK Health Research Analysis 2014 (UK Clinical Research Collaboration, 2015)” in
accordance with Creative Commons Attribution 4.0 International (CC BY 4.0) License.
82
The cost of cerebral palsy As a lifelong condition with poor quality of life, CP and its associated co-
morbidities place a huge burden on families as well as the health and social care
systems. The high lifetime costs for a child born with the condition, combined
with the size of the CP-affected population, underline the case for prevention to
be a public health priority.
The average lifetime cost per person, based on research studies in the United
States in 2003 (172) and Denmark in 2009 (159), and an estimate reported by the
Chief Medical Officer of England in 2014 (173), is at least £690,595. These
estimates include health expenditure, educational needs, social services and lost
economic opportunity, but exclude legal claims and compensation pay-outs.
In the absence of a national CP register we cannot be precise about the life
expectancy of those affected by CP, nor about their overall number in the UK
population. The generally accepted lifespan is 30-70 years (159), while the CP
population is believed to be similar to those with multiple sclerosis and
Parkinson’s disease at between 100,000 and 120,000. Thus, assuming an average
lifespan of 50 years, the annual cost to the UK economy of mitigating CP is £1.4-
1.6 billion and may be significantly more.
Compensation payments arising from litigation against the NHS amounted to
a further liability of £390m between 2012 and 2015 (174).
If prevention research holds out a reasonable prospect of reducing the
incidence of CP, it is clear that significant and durable savings can be made.
83
References
1. Christensen D, Van Naarden Braun K, Doernberg NS, et al. Prevalence of cerebral palsy,
co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental
Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014;56:59-65.
https://onlinelibrary.wiley.com/doi/abs/10.1111/dmcn.12268
2. Rosenbaum P, Paneth N, Leviton A, et al. A report: the definition and classification of
cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8-14.
https://www.ncbi.nlm.nih.gov/pubmed/17370477
3. Bax M, Goldstein M, Rosenbaum P, et al. Proposed definition and classification of
cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47:571-6.
https://www.ncbi.nlm.nih.gov/pubmed/16108461
4. Blair EM, Nelson KB. Fetal growth restriction and risk of cerebral palsy in singletons
born after at least 35 weeks' gestation. Am J Obstet Gynecol. 2015;212:520 e1-7.
https://www.ncbi.nlm.nih.gov/pubmed/25448521
5. Mor O, Stavsky M, Yitshak-Sade M, et al. Early onset preeclampsia and cerebral palsy: a
double hit model? Am J Obstet Gynecol. 2016;214:105 e1-9.
https://www.ncbi.nlm.nih.gov/pubmed/26283455
6. Yoon BH, Park CW, Chaiworapongsa T. Intrauterine infection and the development of
cerebral palsy. BJOG. 2003;110 Suppl 20:124-7.
https://www.ncbi.nlm.nih.gov/pubmed/12763129
7. Tronnes H, Wilcox AJ, Lie RT, Markestad T, Moster D. Risk of cerebral palsy in relation
to pregnancy disorders and preterm birth: a national cohort study. Dev Med Child Neurol.
2014;56:779-85. https://www.ncbi.nlm.nih.gov/pubmed/24621110
8. Bear JJ, Wu YW. Maternal Infections During Pregnancy and Cerebral Palsy in the Child.
Pediatr Neurol. 2016;57:74-9. https://www.ncbi.nlm.nih.gov/pubmed/26857522
84
9. Nelson KB, Blair E. Prenatal Factors in Singletons with Cerebral Palsy Born at or near
Term. N Engl J Med. 2015;373:946-53.
https://www.nejm.org/doi/full/10.1056/NEJMra1505261
10. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of
the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J
Obstet Gynecol. 2008;199:587-95. https://www.ncbi.nlm.nih.gov/pubmed/19084096
11. Johnson SL, Blair E, Stanley FJ. Obstetric malpractice litigation and cerebral palsy in
term infants. J Forensic Leg Med. 2011;18:97-100.
https://www.ncbi.nlm.nih.gov/pubmed/21420644
12. Maudsley G, Hutton JL, Pharoah PO. Cause of death in cerebral palsy: a descriptive
study. Arch Dis Child. 1999;81:390-4. https://www.ncbi.nlm.nih.gov/pubmed/10519709
13. Saint Hilaire M, Burke R, Bressman S, Brin M, Fahn S. Delayed‐onset dystonia due to
perinatal or early childhood asphyxia. Neurology. 1991;41:216-.
https://www.ncbi.nlm.nih.gov/pubmed/1992364
14. Whitney DG, Hurvitz EA, Ryan JM, et al. Noncommunicable disease and multimorbidity
in young adults with cerebral palsy. Clin Epidemiol. 2018;10:511-9.
https://www.ncbi.nlm.nih.gov/pubmed/29750055
15. Cremer N, Hurvitz EA, Peterson MD. Multimorbidity in Middle-Aged Adults with
Cerebral Palsy. Am J Med. 2017;130:744 e9- e15.
https://pubmed.ncbi.nlm.nih.gov/28065772/
16. MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role
of genetic variants. Am J Obstet Gynecol. 2015;213:779-88.
https://www.ajog.org/article/S0002-9378(15)00510-4/abstract
17. Rosenbaum P. Cerebral palsy: what parents and doctors want to know. BMJ.
2003;326:970-4. https://www.ncbi.nlm.nih.gov/pubmed/12727772
18. Colver A, Rapp M, Eisemann N, et al. Self-reported quality of life of adolescents with
cerebral palsy: a cross-sectional and longitudinal analysis. Lancet. 2015;385:705-16.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61229-0/fulltext
85
19. Arneson CL, Durkin MS, Benedict RE, et al. Prevalence of cerebral palsy: Autism and
Developmental Disabilities Monitoring Network, three sites, United States, 2004. Disabil
Health J. 2009;2:45-8. https://www.ncbi.nlm.nih.gov/pubmed/21122742
20. Paneth N, Hong T, Korzeniewski S. The descriptive epidemiology of cerebral palsy. Clin
Perinatol. 2006;33:251-67. https://www.ncbi.nlm.nih.gov/pubmed/16765723
21. Van Naarden Braun K, Doernberg N, Schieve L, Christensen D, Goodman A, Yeargin-
Allsopp M. Birth Prevalence of Cerebral Palsy: A Population-Based Study. Pediatrics.
2016;137:1-9. https://www.ncbi.nlm.nih.gov/pubmed/26659459
22. Chang MJ, Ma HI, Lu TH. Estimating the prevalence of cerebral palsy in Taiwan: A
comparison of different case definitions. Res Dev Disabil. 2015;36C:207-12.
https://www.ncbi.nlm.nih.gov/pubmed/25462481
23. El-Tallawy HN, Farghaly WM, Shehata GA, et al. Cerebral palsy in Al-Quseir City,
Egypt: prevalence, subtypes, and risk factors. Neuropsychiatr Dis Treat. 2014;10:1267-72.
https://www.ncbi.nlm.nih.gov/pubmed/25045270
24. Surveillance of Cerebral Palsy in E. Surveillance of cerebral palsy in Europe: a
collaboration of cerebral palsy surveys and registers. Surveillance of Cerebral Palsy in
Europe (SCPE). Dev Med Child Neurol. 2000;42:816-24.
https://www.ncbi.nlm.nih.gov/pubmed/11132255
25. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden. VI.
Prevalence and origin during the birth year period 1983-1986. Acta Paediatr. 1993;82:387-
93. https://www.ncbi.nlm.nih.gov/pubmed/8318808
26. Hagberg B, Hagberg G, Olow I, von Wendt L. The changing panorama of cerebral palsy
in Sweden. VII. Prevalence and origin in the birth year period 1987-90. Acta Paediatr.
1996;85:954-60. https://www.ncbi.nlm.nih.gov/pubmed/8863878
27. Himmelmann K, Hagberg G, Uvebrant P. The changing panorama of cerebral palsy in
Sweden. X. Prevalence and origin in the birth-year period 1999-2002. Acta Paediatr.
2010;99:1337-43. https://pubmed.ncbi.nlm.nih.gov/20377538/
86
28. Pharoah PO, Cooke T, Johnson MA, King R, Mutch L. Epidemiology of cerebral palsy in
England and Scotland, 1984-9. Arch Dis Child Fetal Neonatal Ed. 1998;79:F21-5.
https://www.ncbi.nlm.nih.gov/pubmed/9797620
29. Topp M, Uldall P, Greisen G. Cerebral palsy births in eastern Denmark, 1987--90:
implications for neonatal care. Paediatr Perinat Epidemiol. 2001;15:271-7.
https://www.ncbi.nlm.nih.gov/pubmed/11489156
30. Topp M, Uldall P, Langhoff-Roos J. Trend in cerebral palsy birth prevalence in eastern
Denmark: birth-year period 1979-86. Paediatr Perinat Epidemiol. 1997;11:451-60.
https://www.ncbi.nlm.nih.gov/pubmed/9373867
31. Stanley FJ, Watson L. Trends in perinatal mortality and cerebral palsy in Western
Australia, 1967 to 1985. BMJ. 1992;304:1658-63.
https://www.ncbi.nlm.nih.gov/pubmed/1633518
32. Surman G, Bonellie S, Chalmers J, et al. UKCP: a collaborative network of cerebral
palsy registers in the United Kingdom. J Public Health (Oxf). 2006;28:148-56.
https://www.ncbi.nlm.nih.gov/pubmed/16556625
33. Oskoui M, Coutinho F, Dykeman J, Jette N, Pringsheim T. An update on the prevalence
of cerebral palsy: a systematic review and meta-analysis. Dev Med Child Neurol.
2013;55:509-19. https://www.ncbi.nlm.nih.gov/pubmed/23346889
34. Graham HK, Rosenbaum P, Paneth N, et al. Cerebral palsy. Nat Rev Dis Primers.
2016;2:15082. https://www.ncbi.nlm.nih.gov/pubmed/27188686
35. Banerjee TK, Hazra A, Biswas A, et al. Neurological disorders in children and
adolescents. Indian J Pediatr. 2009;76:139-46.
https://www.ncbi.nlm.nih.gov/pubmed/19082533
36. Kakooza-Mwesige A, Andrews C, Peterson S, Wabwire Mangen F, Eliasson AC,
Forssberg H. Prevalence of cerebral palsy in Uganda: a population-based study. Lancet Glob
Health. 2017;5:e1275-e82. https://www.thelancet.com/journals/langlo/article/PIIS2214-
109X(17)30374-1/fulltext
87
37. Gladstone M. A review of the incidence and prevalence, types and aetiology of childhood
cerebral palsy in resource-poor settings. Ann Trop Paediatr. 2010;30:181-96.
https://www.ncbi.nlm.nih.gov/pubmed/20828451
38. Sellier E, Surman G, Himmelmann K, et al. Trends in prevalence of cerebral palsy in
children born with a birthweight of 2,500 g or over in Europe from 1980 to 1998. Eur J
Epidemiol. 2010;25:635-42. https://www.ncbi.nlm.nih.gov/pubmed/20532622
39. Clark SL, Hankins GD. Temporal and demographic trends in cerebral palsy--fact and
fiction. Am J Obstet Gynecol. 2003;188:628-33.
https://www.ncbi.nlm.nih.gov/pubmed/12634632
40. Reid SM, Meehan E, McIntyre S, et al. Temporal trends in cerebral palsy by impairment
severity and birth gestation. Dev Med Child Neurol. 2016;58 Suppl 2:25-35.
https://www.ncbi.nlm.nih.gov/pubmed/26762733
41. McIntyre S, Taitz D, Keogh J, Goldsmith S, Badawi N, Blair E. A systematic review of
risk factors for cerebral palsy in children born at term in developed countries. Dev Med Child
Neurol. 2013;55:499-508. https://www.ncbi.nlm.nih.gov/pubmed/23181910
42. Croen LA, Grether JK, Curry CJ, Nelson KB. Congenital abnormalities among children
with cerebral palsy: More evidence for prenatal antecedents. J Pediatr. 2001;138:804-10.
https://www.ncbi.nlm.nih.gov/pubmed/11391320
43. Johnson A. Prevalence and characteristics of children with cerebral palsy in Europe. Dev
Med Child Neurol. 2002;44:633-40. https://www.ncbi.nlm.nih.gov/pubmed/12227618
44. Grether JK, Cummins SK, Nelson KB. The California Cerebral Palsy Project. Paediatr
Perinat Epidemiol. 1992;6:339-51.
45. Watson L, Blair E, Stanley FJ. Report of the Western Australian cerebral palsy register.
To birth year 1999. Perth: Institute for Child Health Research, 2006. Report:
https://www.kemh.health.wa.gov.au/~/media/Files/Hospitals/WNHS/Our-Services/State-
wide-Services/WARDA/Reports/2006_Report_of_the_WA_Cerebral_Palsy_Register.pdf
46. Liu JM, Li S, Lin Q, Li Z. Prevalence of cerebral palsy in China. Int J Epidemiol.
1999;28:949-54. https://www.ncbi.nlm.nih.gov/pubmed/10597996
88
47. Himmelmann K, Hagberg G, Wiklund LM, Eek MN, Uvebrant P. Dyskinetic cerebral
palsy: a population-based study of children born between 1991 and 1998. Dev Med Child
Neurol. 2007;49:246-51. https://doi.org/10.1111/j.1469-8749.2007.00246.x
48. Himmelmann K, McManus V, Hagberg G, et al. Dyskinetic cerebral palsy in Europe:
trends in prevalence and severity. Arch Dis Child. 2009;94:921-6.
https://www.ncbi.nlm.nih.gov/pubmed/19465585
49. Nielsen LF, Schendel D, Grove J, et al. Asphyxia-related risk factors and their timing in
spastic cerebral palsy. Bjog. 2008;115:1518-28.
https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/j.1471-0528.2008.01896.x
50. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. I. Univariate analysis of risks.
Am J Dis Child. 1985;139:1031-8. https://www.ncbi.nlm.nih.gov/pubmed/4036890
51. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. Multivariate analysis of risk. N
Engl J Med. 1986;315:81-6. https://pubmed.ncbi.nlm.nih.gov/3724803/
52. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr.
1988;112:515-9. https://www.jpeds.com/article/S0022-3476(88)80161-6/pdf
53. Lawn JE, Lee AC, Kinney M, et al. Two million intrapartum-related stillbirths and
neonatal deaths: where, why, and what can be done? Int J Gynaecol Obstet. 2009;107 Suppl
1:S5-18, S9. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1016/j.ijgo.2009.07.016
54. Lawn J, Shibuya K, Stein C. No cry at birth: global estimates of intrapartum stillbirths
and intrapartum-related neonatal deaths. Bull World Health Organ. 2005;83:409-17. https://
apps.who.int/iris/handle/10665/269418
55. Halloran DR, McClure E, Chakraborty H, Chomba E, Wright LL, Carlo WA. Birth
asphyxia survivors in a developing country. J Perinatol. 2009;29:243-9.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807866/pdf/nihms516634.pdf
56. Ellis M, Manandhar N, Shrestha PS, Shrestha L, Manandhar DS, Costello AM. Outcome
at 1 year of neonatal encephalopathy in Kathmandu, Nepal. Dev Med Child Neurol.
1999;41:689-95. https://onlinelibrary.wiley.com/doi/abs/10.1111/
j.1469-8749.1999.tb00524.x?sid=nlm%3Apubmed
89
57. Jacobsson B, Hagberg G. Antenatal risk factors for cerebral palsy. Best Pract Res Clin
Obstet Gynaecol. 2004;18:425-36.
https://www.sciencedirect.com/science/article/pii/S1521693404000379?via%3Dihub
58. Bax M, Tydeman C, Flodmark O. Clinical and MRI correlates of cerebral palsy: the
European Cerebral Palsy Study. JAMA. 2006;296:1602-8.
https://jamanetwork.com/journals/jama/fullarticle/203508
59. Okereafor A, Allsop J, Counsell SJ, et al. Patterns of brain injury in neonates exposed to
perinatal sentinel events. Pediatrics. 2008;121:906-14.
https://www.ncbi.nlm.nih.gov/pubmed/18450893
60. Durkin MV, Kaveggia EG, Pendleton E, Neuhauser G, Opitz JM. Analysis of etiologic
factors in cerebral palsy with severe mental retardation. I. Analysis of gestational,
parturitional and neonatal data. Eur J Pediatr. 1976;123:67-81.
https://www.ncbi.nlm.nih.gov/pubmed/976279
61. Grether JK, Nelson KB, Emery ES, 3rd, Cummins SK. Prenatal and perinatal factors and
cerebral palsy in very low birth weight infants. J Pediatr. 1996;128:407-14.
https://www.jpeds.com/article/S0022-3476(96)70292-5/fulltext
62. Nelson KB, Blair E. Prenatal Factors in Cerebral Palsy. N Engl J Med. 2015;373:2288-9.
https://www.nejm.org/doi/full/10.1056/NEJMra1505261
63. O'Shea TM, Allred EN, Dammann O, et al. The ELGAN study of the brain and related
disorders in extremely low gestational age newborns. Early Hum Dev. 2009;85:719-25.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801579/pdf/nihms-143272.pdf
64. Ancel PY, Livinec F, Larroque B, et al. Cerebral palsy among very preterm children in
relation to gestational age and neonatal ultrasound abnormalities: the EPIPAGE cohort study.
Pediatrics. 2006;117:828-35. https://pediatrics.aappublications.org/content/117/3/828
90
65. Vincer MJ, Allen AC, Joseph KS, Stinson DA, Scott H, Wood E. Increasing prevalence
of cerebral palsy among very preterm infants: a population-based study. Pediatrics.
2006;118:e1621-6.
https://pediatrics.aappublications.org/content/118/6/e1621.long?sso=1&sso_redirect_count=1
&nfstatus=401&nftoken=00000000-0000-0000-0000-
000000000000&nfstatusdescription=ERROR%3a+No+local+token
66. Moster D, Wilcox AJ, Vollset SE, Markestad T, Lie RT. Cerebral palsy among term and
postterm births. Jama. 2010;304:976-82.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711561/pdf/nihms-466639.pdf
67. Self L, Dagenais L, Shevell M. Congenital non-central nervous system malformations in
cerebral palsy: a distinct subset? Dev Med Child Neurol. 2012;54:748-52.
https://doi.org/10.1111/j.1469-8749.2012.04309.x
68. Kulak W, Sobaniec W, Goscik M, Olenski J, Okurowska-Zawada B. Clinical and
neuroimaging profile of congenital brain malformations in children with spastic cerebral
palsy. Adv Med Sci. 2008;53:42-8. https://www.semanticscholar.org/paper/Clinical-and-
neuroimaging-profile-of-congenital-in-Ku%C5%82ak-
Sobaniec/185d9d5a8533eb47d84cd26b5f2877e8bb90618e
69. Garne E, Dolk H, Krageloh-Mann I, Holst Ravn S, Cans C, Group SC. Cerebral palsy
and congenital malformations. Eur J Paediatr Neurol. 2008;12:82-8. https://www.ejpn-
journal.com/article/S1090-3798(07)00116-X/fulltext
70. Malamud N, Itabashi HH, Castormessinger HB. An Etiologic and Diagnostic Study of
Cerebral Palsy. A Preliminary Report. J Pediatr. 1964;65:270-93.
https://www.jpeds.com/article/S0022-3476(64)80530-8/fulltext
71. McIntyre S, Blair E, Badawi N, Keogh J, Nelson KB. Antecedents of cerebral palsy and
perinatal death in term and late preterm singletons. Obstet Gynecol. 2013;122:869-77.
https://research-repository.uwa.edu.au/en/publications/antecedents-of-cerebral-palsy-and-
perinatal-death-in-term-and-lat
91
72. Rankin J, Cans C, Garne E, et al. Congenital anomalies in children with cerebral palsy: a
population-based record linkage study. Dev Med Child Neurol. 2010;52:345-51.
https://doi.org/10.1111/j.1469-8749.2009.03415.x
73. van Eyk CL, Corbett MA, Maclennan AH. The emerging genetic landscape of cerebral
palsy. Handb Clin Neurol. 2018;147:331-42.
https://www.ncbi.nlm.nih.gov/pubmed/29325622
74. Fahey MC, Maclennan AH, Kretzschmar D, Gecz J, Kruer MC. The genetic basis of
cerebral palsy. Dev Med Child Neurol. 2017;59:462-9.
https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.13363
75. Oskoui M, Gazzellone MJ, Thiruvahindrapuram B, et al. Clinically relevant copy number
variations detected in cerebral palsy. Nat Commun. 2015;6:7949.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532872/
76. McMichael G, Bainbridge MN, Haan E, et al. Whole-exome sequencing points to
considerable genetic heterogeneity of cerebral palsy. Mol Psychiatry. 2015;20:176-82.
http://dx.doi.org/10.1038/mp.2014.189
77. Taylor CL, de Groot J, Blair EM, Stanley FJ. The risk of cerebral palsy in survivors of
multiple pregnancies with cofetal loss or death. Am J Obstet Gynecol. 2009;201:41 e1-6.
https://www.ajog.org/article/S0002-9378(09)00188-4/fulltext
78. Pharoah PO. Risk of cerebral palsy in multiple pregnancies. Clin Perinatol. 2006;33:301-
13. https://www.sciencedirect.com/science/article/pii/S0095510806000315?via%3Dihub
79. Torres VM, Saddi VA. Systematic review: hereditary thrombophilia associated to
pediatric strokes and cerebral palsy. J Pediatr (Rio J). 2015;91:22-9.
https://www.sciencedirect.com/science/article/pii/S0021755714001430
80. Yehezkely-Schildkraut V, Kutai M, Hugeirat Y, et al. Thrombophilia: a risk factor for
cerebral palsy? Isr Med Assoc J. 2005;7:808-11.
https://www.ima.org.il/MedicineIMAJ/viewarticle.aspx?year=2005&month=12&page=808
92
81. Smith RA, Skelton M, Howard M, Levene M. Is thrombophilia a factor in the
development of hemiplegic cerebral palsy? Dev Med Child Neurol. 2001;43:724-30.
https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0012-
1622&date=2001&volume=43&issue=11&spage=724
82. Petersen TG, Andersen AN, Uldall P, et al. Maternal thyroid disorder in pregnancy and
risk of cerebral palsy in the child: a population-based cohort study. BMC Pediatr.
2018;18:181. https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-018-1152-5
83. Schneider RE, Ng P, Zhang X, et al. The Association Between Maternal Age and
Cerebral Palsy Risk Factors. Pediatr Neurol. 2018;82:25-8.
https://www.sciencedirect.com/science/article/pii/S0887899416308360
84. Brion MJ, Zeegers M, Jaddoe V, et al. Intrauterine effects of maternal prepregnancy
overweight on child cognition and behavior in 2 cohorts. Pediatrics. 2011;127:e202-11.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605781/
85. Lucas A, Rennie J, Baker BA, Morley R. Low plasma triiodothyronine concentrations
and outcome in preterm infants. Arch Dis Child. 1988;63:1201-6.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779041/pdf/archdisch00681-0031.pdf
86. Meijer WJ, Verloove-Vanhorick SP, Brand R, van den Brande JL. Transient
hypothyroxinaemia associated with developmental delay in very preterm infants. Arch Dis
Child. 1992;67:944-7. https://www.ncbi.nlm.nih.gov/pubmed/2461683
87. Den Ouden AL, Kok JH, Verkerk PH, Brand R, Verloove-Vanhorick SP. The Relation
between Neonatal Thyroxine Levels and Neurodevelopmental Outcome at Age 5 and 9 Years
in a National Cohort of Very Preterm and/or Very Low Birth Weight Infants. Pediatric
Research. 1996;39:142-5. https://www.ncbi.nlm.nih.gov/pubmed/8825399
88. Reuss ML, Paneth N, Pinto-Martin JA, Lorenz JM, Susser M. The relation of transient
hypothyroxinemia in preterm infants to neurologic development at two years of age. N Engl J
Med. 1996;334:821-7.
https://www.nejm.org/doi/10.1056/NEJM199603283341303?url_ver=Z39.88-
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov
93
89. Hong T, Paneth N. Maternal and infant thyroid disorders and cerebral palsy. Semin
Perinatol. 2008;32:438-45.
https://www.sciencedirect.com/science/article/pii/S014600050800116X?via%3Dihub
90. Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. Lancet Diabetes
Endocrinol. 2015;3:286-95. https://www.thelancet.com/journals/landia/article/PIIS2213-
8587(14)70225-6/fulltext
91. Guo TW, Zhang FC, Yang MS, et al. Positive association of the DIO2 (deiodinase type
2) gene with mental retardation in the iodine-deficient areas of China. J Med Genet.
2004;41:585-90.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735866/pdf/v041p00585.pdf
92. Azizi F, Kalani H, Kimiagar M, et al. Physical, neuromotor and intellectual impairment
in non-cretinous schoolchildren with iodine deficiency. Int J Vitam Nutr Res. 1995;65:199-
205. https://www.ncbi.nlm.nih.gov/pubmed/8830000
93. Abel MH, Ystrom E, Caspersen IH, et al. Maternal Iodine Intake and Offspring
Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study.
Nutrients. 2017;9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707711/
94. Melse-Boonstra A, Jaiswal N. Iodine deficiency in pregnancy, infancy and childhood and
its consequences for brain development. Best Pract Res Clin Endocrinol Metab. 2010;24:29-
38. https://www.sciencedirect.com/science/article/pii/S1521690X09001092?via%3Dihub
95. de Escobar GM, Obregon MJ, del Rey FE. Iodine deficiency and brain development in
the first half of pregnancy. Public Health Nutr. 2007;10:1554-70.
https://www.cambridge.org/core/product/identifier/S1368980007360928/type/journal_article
96. Sethi V, Kapil U. Iodine deficiency and development of brain. Indian J Pediatr.
2004;71:325-9. https://www.ncbi.nlm.nih.gov/pubmed/15107513
97. Hetzel BS. Iodine Deficiency and the Brain. Nutr Neurosci. 1999;2:375-84.
https://www.ncbi.nlm.nih.gov/pubmed/27416050
94
98. Hetzel BS. Iodine deficiency and fetal brain damage. N Engl J Med. 1994;331:1770-1.
https://www.nejm.org/doi/full/10.1056/NEJM199412293312610?url_ver=Z39.88-
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
99. Hetzel BS, Chavadej J, Potter BJ. The brain in iodine deficiency. Neuropathol Appl
Neurobiol. 1988;14:93-104. https://www.ncbi.nlm.nih.gov/pubmed/27416050
100. Hetzel BS. Dietary iodine deficiency and brain development. Med J Aust. 1980;1:349.
https://pubmed.ncbi.nlm.nih.gov/7393068/
101. Ahlin K, Himmelmann K, Hagberg G, et al. Non-infectious risk factors for different
types of cerebral palsy in term-born babies: a population-based, case-control study. BJOG.
2013;120:724-31. https://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1111/1471-0528.12164
102. Nahum Sacks K, Friger M, Shoham-Vardi I, et al. Prenatal exposure to gestational
diabetes mellitus as an independent risk factor for long-term neuropsychiatric morbidity of
the offspring. Am J Obstet Gynecol. 2016;215:380 e1-7.
https://www.ncbi.nlm.nih.gov/pubmed/27018463
103. Bangash AS, Hanafi MZ, Idrees R, Zehra N. Risk factors and types of cerebral palsy.
J Pak Med Assoc. 2014;64:103-7. https://jpma.org.pk/article-details/5768?article_id=5768
104. Shepherd E, Salam RA, Middleton P, et al. Antenatal and intrapartum interventions
for preventing cerebral palsy: an overview of Cochrane systematic reviews. Cochrane
Database Syst Rev. 2017;8:Cd012077.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483544/
105. Polivka BJ, Nickel JT, Wilkins JR, 3rd. Urinary tract infection during pregnancy: a
risk factor for cerebral palsy? J Obstet Gynecol Neonatal Nurs. 1997;26:405-13.
https://www.ncbi.nlm.nih.gov/pubmed/9252888
106. Wu CS, Pedersen LH, Miller JE, et al. Risk of cerebral palsy and childhood epilepsy
related to infections before or during pregnancy. PLoS One. 2013;8:e57552.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057552
95
107. Ahlin K, Himmelmann K, Hagberg G, et al. Cerebral palsy and perinatal infection in
children born at term. Obstet Gynecol. 2013;122:41-9.
https://insights.ovid.com/pubmed?pmid=23743468
108. Kirton A, deVeber G. Cerebral palsy secondary to perinatal ischemic stroke. Clin
Perinatol. 2006;33:367-86.
https://www.sciencedirect.com/science/article/pii/S0095510806000224?via%3Dihub
109. Golomb MR, Garg BP, Saha C, Azzouz F, Williams LS. Cerebral palsy after perinatal
arterial ischemic stroke. J Child Neurol. 2008;23:279-86.
https://journals.sagepub.com/doi/abs/10.1177/0883073807309246
110. Bova IY, Bornstein NM, Korczyn AD. Acute infection as a risk factor for ischemic
stroke. Stroke. 1996;27:2204-6.
https://www.ahajournals.org/doi/full/10.1161/01.STR.27.12.2204
111. McColl BW, Allan SM, Rothwell NJ. Systemic infection, inflammation and acute
ischemic stroke. Neuroscience. 2009;158:1049-61.
https://www.sciencedirect.com/science/article/pii/S0306452208012001?via%3Dihub
112. Worthmann H, Tryc AB, Deb M, et al. Linking infection and inflammation in acute
ischemic stroke. Ann N Y Acad Sci. 2010;1207:116-22. https://doi.org/10.1111/j.1749-
6632.2010.05738.x
113. Zanardo V, Trevisanuto D, Cosmi E, Chiarelli S. Chorioamnionitis and cerebral
palsy: a meta-analysis. Obstet Gynecol. 2010;116:1454; author reply.
https://www.ncbi.nlm.nih.gov/pubmed/21099620
114. Shatrov JG, Birch SC, Lam LT, Quinlivan JA, McIntyre S, Mendz GL.
Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol. 2010;116:387-92.
https://insights.ovid.com/pubmed?pmid=20664400
115. Wu YW, Colford JM, Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-
analysis. JAMA. 2000;284:1417-24. https://jamanetwork.com/journals/jama/article-
abstract/193084
96
116. Shi Z, Ma L, Luo K, et al. Chorioamnionitis in the Development of Cerebral Palsy: A
Meta-analysis and Systematic Review. Pediatrics. 2017;139.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470507/
117. Nelson KB. Causative factors in cerebral palsy. Clin Obstet Gynecol. 2008;51:749-
62. https://insights.ovid.com/pubmed?pmid=18981800
118. Smithers-Sheedy H, Badawi N, Blair E, et al. What constitutes cerebral palsy in the
twenty-first century? Dev Med Child Neurol. 2014;56:323-8.
https://doi.org/10.1111/dmcn.12262
119. Korzeniewski SJ, Romero R, Cortez J, et al. A "multi-hit" model of neonatal white
matter injury: cumulative contributions of chronic placental inflammation, acute fetal
inflammation and postnatal inflammatory events. J Perinat Med. 2014;42:731-43.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987202/pdf/nihms956312.pdf
120. Evans PR, Polani PE. The neurological sequelae of Rh sensitization. Q J Med.
1950;19:129-49. https://www.ncbi.nlm.nih.gov/pubmed/24537667
121. Crawford MA, Hassam AG, Williams G. Essential fatty acids and fetal brain growth.
Lancet. 1976;1:452-3. http://www.thelancet.com/retrieve/pii/S0140673676914768
122. Crawford MA, Casperd NM, Sinclair AJ. The long chain metabolites of linoleic avid
linolenic acids in liver and brain in herbivores and carnivores. Comp Biochem Physiol B.
1976;54:395-401. https://www.sciencedirect.com/science/article/pii/0305049176902649
123. Crawford MA. Lipids and development of the human brain. Biochem Soc Trans.
1976;4:231-3. http://www.biochemsoctrans.org/content/4/2/231.long
124. Crawford MA, Golfetto I, Ghebremeskel K, et al. The potential role for arachidonic
and docosahexaenoic acids in protection against some central nervous system injuries in
preterm infants. Lipids. 2003;38:303-15. https://link.springer.com/article/10.1007/s11745-
003-1065-1
125. Dyall SC. Long-chain omega-3 fatty acids and the brain: a review of the independent
and shared effects of EPA, DPA and DHA. Front Aging Neurosci. 2015;7:52.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404917/
97
126. Dyall SC, Michael-Titus AT. Neurological benefits of omega-3 fatty acids.
Neuromolecular Med. 2008;10:219-35. https://link.springer.com/article/10.1007%2Fs12017-
008-8036-z
127. Rogers LK, Valentine CJ, Keim SA. DHA supplementation: current implications in
pregnancy and childhood. Pharmacol Res. 2013;70:13-9.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602397/pdf/nihms431150.pdf
128. Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE. Essential fatty acids in visual
and brain development. Lipids. 2001;36:885-95.
https://aocs.onlinelibrary.wiley.com/doi/abs/10.1007/s11745-001-0798-
1?sid=nlm%3Apubmed
129. Ogundipe E, Tusor N, Wang Y, Johnson MR, Edwards AD, Crawford MA.
Randomized controlled trial of brain specific fatty acid supplementation in pregnant women
increases brain volumes on MRI scans of their newborn infants. Prostaglandins Leukot
Essent Fatty Acids. 2018;138:6-13. https://www.plefa.com/article/S0952-3278(18)30129-
7/fulltext
130. Morse NL. Benefits of docosahexaenoic acid, folic acid, vitamin D and iodine on
foetal and infant brain development and function following maternal supplementation during
pregnancy and lactation. Nutrients. 2012;4:799-840.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407995/pdf/nutrients-04-00799.pdf
131. Petridou E, Koussouri M, Toupadaki N, et al. Diet during pregnancy and the risk of
cerebral palsy. Br J Nutr. 1998;79:407-12. https://www.cambridge.org/core/journals/british-
journal-of-nutrition/article/diet-during-pregnancy-and-the-risk-of-cerebral-
palsy/22CC47FB10313C9BF470C2690E007BF0
132. Shepherd E, Salam RA, Middleton P, et al. Neonatal interventions for preventing
cerebral palsy: an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev.
2018;6:Cd012409. Review:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513209/pdf/CD012409.pdf
98
133. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in
very low birthweight infants? Pediatrics. 1995;95:263-9.
https://pediatrics.aappublications.org/content/95/2/263.long?sso=1&sso_redirect_count=1&n
fstatus=401&nftoken=00000000-0000-0000-0000-
000000000000&nfstatusdescription=ERROR%3a+No+local+token
134. Wolf HT, Brok J, Henriksen TB, et al. Antenatal magnesium sulphate for the
prevention of cerebral palsy in infants born preterm: a double-blind, randomised, placebo-
controlled, multi-centre trial. BJOG. 2020. https://pubmed.ncbi.nlm.nih.gov/32237024/
135. Pena A. Monitoring Platelets Could Help Protect Babies Against Cerebral Palsy,
Early Research Finds Philadelphia: Bionews Feeds; 2019. Available from:
https://cerebralpalsynewstoday.com/2019/08/07/monitoring-platelets-protect-babies-against-
cerebral-palsy-research/?utm_source=CP+List&utm_campaign=da474476af-
RSS_WEEKLY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_13a5b79a46-
da474476af-73100285
136. Hartman RE, Nathan NH, Ghosh N, et al. A Biomarker for Predicting Responsiveness
to Stem Cell Therapy Based on Mechanism-of-Action: Evidence from Cerebral Injury. Cell
Rep. 2020;31:107622. https://pubmed.ncbi.nlm.nih.gov/32402283/
137. Andrew MJ, Parr JR, Montague-Johnson C, et al. Nutritional intervention and
neurodevelopmental outcome in infants with suspected cerebral palsy: the Dolphin infant
double-blind randomized controlled trial. Dev Med Child Neurol. 2018;60:906-13.
https://onlinelibrary.wiley.com/doi/abs/10.1111/dmcn.13586
138. Jackson KH, Harris WS. A Prenatal DHA Test to Help Identify Women at Increased
Risk for Early Preterm Birth: A Proposal. Nutrients. 2018;10.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316227/pdf/nutrients-10-01933.pdf
139. Mun JG, Legette LL, Ikonte CJ, Mitmesser SH. Choline and DHA in Maternal and
Infant Nutrition: Synergistic Implications in Brain and Eye Health. Nutrients. 2019;11.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566660/pdf/nutrients-11-01125.pdf
140. Chung RY, Dong D, Li MM. Socioeconomic gradient in health and the covid-19
outbreak. BMJ. 2020;369:m1329. Letter: https://www.bmj.com/content/369/bmj.m1329
99
141. Dan B, Paneth N. Making sense of cerebral palsy prevalence in low-income countries.
Lancet Glob Health. 2017;5:e1174-e5.
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(17)30420-5/fulltext
142. Torjesen I. NICE publishes guideline on diagnosing and managing cerebral palsy in
young people. BMJ. 2017;356:j462. https://www.bmj.com/content/356/bmj.j462
143. Durkin MS, Benedict RE, Christensen D, et al. Prevalence of Cerebral Palsy among
8-Year-Old Children in 2010 and Preliminary Evidence of Trends in Its Relationship to Low
Birthweight. Paediatr Perinat Epidemiol. 2016;30:496-510.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351288/pdf/nihms836607.pdf
144. Durkin MS, Maenner MJ, Benedict RE, et al. The role of socio-economic status and
perinatal factors in racial disparities in the risk of cerebral palsy. Dev Med Child Neurol.
2015;57:835-43.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529795/pdf/nihms669057.pdf
145. Colver A, Fairhurst C, Pharoah POD. Cerebral palsy. The Lancet. 2014;383:1240-9.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61835-8/fulltext
146. Smithers-Sheedy H, Raynes-Greenow C, Badawi N, McIntyre S, Jones CA,
Australian Cerebral Palsy Register G. Congenital cytomegalovirus is associated with severe
forms of cerebral palsy and female sex in a retrospective population-based study. Dev Med
Child Neurol. 2014;56:846-52. https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.12467
147. Smithers-Sheedy H, Raynes-Greenow C, Badawi N, et al. Neuroimaging findings in a
series of children with cerebral palsy and congenital cytomegalovirus infection. Infect Disord
Drug Targets. 2014;14:185-90. http://www.eurekaselect.com/129689/article
148. Ahlin K, Jacobsson B, Nilsson S, Himmelmann K. Antecedents and neuroimaging
patterns in cerebral palsy with epilepsy and cognitive impairment: a population-based study
in children born at term. Acta Obstet Gynecol Scand. 2017;96:828-36.
https://doi.org/10.1111/aogs.13128
100
149. Himmelmann K, Hagberg G, Beckung E, Hagberg B, Uvebrant P. The changing
panorama of cerebral palsy in Sweden. IX. Prevalence and origin in the birth-year period
1995-1998. Acta Paediatr. 2005;94:287-94.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1651-2227.2005.tb03071.x
150. Bax MC, Flodmark O, Tydeman C. Definition and classification of cerebral palsy.
From syndrome toward disease. Dev Med Child Neurol Suppl. 2007;109:39-41.
https://www.ncbi.nlm.nih.gov/pubmed/17370481
151. Pharoah PO. Risk of cerebral palsy in multiple pregnancies. Obstet Gynecol Clin
North Am. 2005;32:55-67, viii.
https://www.sciencedirect.com/science/article/pii/S0095510806000315?via%3Dihub
152. Maenner MJ, Benedict RE, Arneson CL, et al. Children with cerebral palsy: racial
disparities in functional limitations. Epidemiology. 2012;23:35-43.
https://pubmed.ncbi.nlm.nih.gov/22081059/
153. Morris C. Definition and classification of cerebral palsy: a historical perspective. Dev
Med Child Neurol Suppl. 2007;109:3-7. https://pubmed.ncbi.nlm.nih.gov/17370476/
154. Odding E, Roebroeck ME, Stam HJ. The epidemiology of cerebral palsy: incidence,
impairments and risk factors. Disabil Rehabil. 2006;28:183-91.
https://pubmed.ncbi.nlm.nih.gov/16467053/
155. Reddihough D. Cerebral palsy in childhood. Aust Fam Physician. 2011;40:192-6.
https://pubmed.ncbi.nlm.nih.gov/21597527/
156. Centers for Disease Control and Prevention. Economic costs associated with mental
retardation, cerebral palsy, hearing loss, and vision impairment- United States, 2003. MMWR
Morb Mortal Wkly Rep. 2004;53(3):57-59. https://pubmed.ncbi.nlm.nih.gov/14749614/
157. Rosenbaum P. Cerebral palsy: what parents and doctors want to know. BMJ (Clinical
research ed). 2003;326:970-4. https://pubmed.ncbi.nlm.nih.gov/12727772/
158. Beecham J, O'Neill T, Goodman R. Supporting young adults with hemiplegia:
services and costs. Health Soc Care Community. 2001;9:51-9.
https://pubmed.ncbi.nlm.nih.gov/11560721/
101
159. Kruse M, Michelsen SI, Flachs EM, Bronnum-Hansen H, Madsen M, Uldall P.
Lifetime costs of cerebral palsy. Dev Med Child Neurol. 2009;51:622-8.
https://pubmed.ncbi.nlm.nih.gov/19416329/
160. Wang B, Chen Y, Zhang J, Li J, Guo Y, Hailey D. A preliminary study into the
economic burden of cerebral palsy in China. Health Policy. 2008;87:223-34.
https://pubmed.ncbi.nlm.nih.gov/18282633/
161. Power R, King C, Muhit M, et al. Health-related quality of life of children and
adolescents with cerebral palsy in low- and middle-income countries: a systematic review.
Dev Med Child Neurol. 2018;60:469-79. https://pubmed.ncbi.nlm.nih.gov/29405292/
162. Herbert DL, Barnett AG, White R, Novak I, Badawi N. Funding for cerebral palsy
research in Australia, 2000-2015: an observational study. BMJ Open. 2016;6:e012924. https://
pubmed.ncbi.nlm.nih.gov/27798026/
163. Cerebral Palsy Alliance. Federal Government funds research into cerebral palsy 2018
[June 29, 2019]. Available from:
https://www.cerebralpalsy.org.au/sstposts/StoryId1529305994056
164. Wu YW, Mehravari AS, Numis AL, Gross P. Cerebral palsy research funding from
the National Institutes of Health, 2001 to 2013. Dev Med Child Neurol. 2015;57:936-41.
https://pubmed.ncbi.nlm.nih.gov/25951080/
165. NINDS and NICHD. NINDS/NICHD Strategic Plan for Cerebral Palsy Research.
2017. Available from:
https://www.ninds.nih.gov/sites/default/files/
NINDS_NICHD_2017_StrategicPlanCerebralPalsyResearch_508C.pdf
166. American Academy for Cerebral Palsy and Developmental Medicine (AACPDM).
AACPDM Grant Opportunities Milwaukee, WI: American Academy for Cerebral Palsy and
Developmental Medicine; 2019 Available from: http://www.aacpdm.org/awards/grants
167. Cerebral Palsy Alliance Research Foundation (CPARF). Apply for Funding New
York, NY2018. Available from: https://cparf.org/funding/how-to-apply/
102
168. Viergever RF, Hendriks TCC. The 10 largest public and philanthropic funders of
health research in the world: what they fund and how they distribute their funds. Health
Research Policy and Systems. 2016;14:12. https://pubmed.ncbi.nlm.nih.gov/26892771/
169. Singhi PD, Ray M, Suri G. Clinical spectrum of cerebral palsy in north India--an
analysis of 1,000 cases. J Trop Pediatr. 2002;48:162-6.
https://pubmed.ncbi.nlm.nih.gov/12164600/
170. Singapore CPA. Singapore Cerebral Palsy Registry 2019 [Available from :
https://cpas.org.sg/singapore-cerebral-palsy-registry/
171. UK Clinical Research Collaboration. UK Health Research Analysis 2014. London:
The Medical Research Council, 2015. Available from: http://hrcsonline.net/wp-
content/uploads/2017/09/UK_Health_Research_Analysis_Report_2014_WEB.pdf
172. Cdc.gov. (2019). Economic Costs Associated with Mental Retardation, Cerebral
Palsy, Hearing Loss, and Vision Impairment --- United States, 2003. [online] Available at:
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5303a4.htm
173. Annual Report of the Chief Medical Officer, 2014. Assets.publishing.service.gov.uk.
[online] Available at:
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data
/file/595439/CMO_annual_report_2014.pdf
174. Magro, M. (2017). Five years of cerebral palsy claims. A thematic review of NHS
Resolution data. Available at: https://resolution.nhs.uk/wp-content/uploads/2017/09/Five-
years-of-cerebral-palsy-claims_A-thematic-review-of-NHS-Resolution-data.pdf
102
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