1. In Context
www.thelancet.com/neurology Published online February 21, 2013 http://dx.doi.org/10.1016/S1474-4422(13)70041-3 1
Arriving too early
According toWHO, 13 million babies are born prematurely worldwide every year and many will
be left with serious neurodevelopmental disabilities. Zuberoa Marcos reports.
Over the past 20 years, the prevalence
of premature birth has risen
worldwide. In high-income countries,
such as Australia, Canada, Spain, and
the UK, prevalence is about 4–8%,
whereas South America and Asia have
prevalences of 15%, increasing to
20–25% in rural areas. In the USA, 12%
of births are preterm partly because of
the population of African-American
women, in whom premature births
are 3–4 times more common than in
white women. Increasing maternal
age, increasing number of multiple
pregnancies made possible by
assisted-reproduction techniques, and
maternal stress could partly explain
the worldwide upturn.
“The number of babies born before
27 weeks of gestation who survive
and leave hospital is higher than ever
because we have become better at
anticipating the problems of preterm
babies”, says Neil Marlow, a researcher
at University College London Institute
for Women’s Health. “We now are
better at giving steroids before birth,
intervening at delivery with surfactant,
keeping these babies warm…but these
improvements have an impact in the
first 7 days after birth. The proportion
of babieswho experience serious health
problems into childhood and later life
remains largely unchanged.” Since
1995, he has been leading EPICure, a
large study that has analysed survival
and later health status in infants born
as early as 22–25 weeks of gestation in
theUK and Ireland.
“70% of premature infants born at
24 weeks survive without significant
disabilities. Among babies born prior
to week 24, survival is 50%; and just
25% will have no major problems as
they grow” Marlow told The Lancet
Neurology.
Brain injury in premature infants is of
enormous public health importance;
many such infants survive, but with
serious neurodevelopmental disabil-
ities. “Cerebral palsy is the most well-
known neurological consequence of
premature birth but it is not the most
common. It affects about 4–5% of
very premature babies, while cognitive
impairments can occur in up to 50%.
Many studies have shown that preterm
infants can have intellectual quotients
up to 17 points lower than term babies
and most importantly they have more
problems in academic achievement
and school performance”, explains
Thais Agut, who is responsible for the
follow-up care of neonates at risk for
neurological impairment at Sant Joan
de Deu Hospital, Barcelona, Spain.
“There are two things that we need
to understand to repair this sort of
damage: the first one is how babies’
brains grow, and the second is the
impact of the treatments currently
available on the developing brain”,
explains Marlow. Research into
brain maturation has shown that
responses to injury are specific to the
degree of development at the time
of birth. “Being preterm exposes the
developing brain to a range of stimuli
radically different to those it has in
utero. Oligodendrocyte precursors,
the cells that develop to form myelin
sheaths,the white matter, and subplate
neurons, play a critical role in cerebral
development in the third trimester of
pregnancy. These cells are extremely
vulnerable to this stress but also to
hypoxia–ischaemia, infection, and
the impaired nutrition so frequently
seen in these premature babies”, Agut
explains. “This could explain why we
see so many cases of injuries involving
malfunctioning oligodendrocytes, such
as hypoxic–ischaemic encephalopathy
in full term babies and periventricular
leukomalacia in preterm babies. The
white matter and suplate injury may
interrupt the thalamocortical and
corticocortical connections and this
could explain also the reduced cortex
volume and abnormalities in cortical
organizationobserved inthese infants.”
Conventional neuroimaging tech-
niques have made diagnosis of brain
lesions easier, but predicting which
babies are at risk of injury or how
an existing brain injury will develop
is still difficult. In the past decade,
doctors have started to apply more
sophisticated methods that offer new
insights into tissue microstructure, and
enable measurement of brain volume
and the study of maturation of the
brain.AttheUniversityofCalifornia San
Francisco, Donna Ferriero and her team
are developing the baby connectome, a
mapofthe connectivityofthe newborn
brain at all stages of development
startingwith premature neonates.
Ferriero and her collaborators
have implemented an automated
technique based on diffusion MRI
and have used it to characterise
large-scale connectivity of the cortex
in a cohort (n=17) of 6-month-old
term babies with hypoxic–ischaemic
encephalopathy. Such babies have
a high risk of neurological and
developmental deficits that are
difficult to predict. Ferriero explains,
“we have seen that severity of injury
correlates to different structural
network phenotypes in hypoxic–
ischaemic encephalopathy babies. We
observed a decline in brain network
integration and segregation with
increasing neuromotor deficits.”
The study is the first step towards
understanding the large-scale baby
connectome. This map will provide
the knowledge of brain development
that could guide efforts to prevent
brain damage. However, therapeutic
strategies to repair injuries will still be
needed. To date, only hypothermia has
For more on EPICure see BMJ
2012; 345: e7961
For more on the baby
connectome see PLoS ONE 2012;
7: e31029
Published Online
February 21, 2013
http://dx.doi.org/10.1016/
S1474-4422(13)70041-3

2. In Context
2 www.thelancet.com/neurology Published online February 21, 2013 http://dx.doi.org/10.1016/S1474-4422(13)70041-3
For Michael Johnston’s
investigations see Review
Lancet Neurol 2011; 10: 372–82
For more on the low-cost,
low-power therapeutic
hypothermia device see
Med Devices (Auckl) 2013; 6: 1–10
For more on hypothermia in
infants see Nat Rev Neurol 2011;
7: 485–94
shown clinical efficacy for decreasing
the risk of death or disability in babies
born at (or near) full term after
asphyxia.
“The main effect of the absence
of oxygen at the moment of birth
is the release of the excitatory
neurotransmitter glutamate in the
brain. Glutamate activates several
cascades of injury that end up in cell
apoptosis and necrosis and it also
triggers inflammation” explains
Michael Johnston, chief medical officer
at the Kennedy Krieger Institute,
Baltimore, USA. He has investigated
treatments that reduce brain injury
and promote recovery in infants
and children. “We know that, if
administered early enough, drugs
that block the effects of glutamate on
one of its receptors, the NMDA, can
totally prevent brain injury in infant
rodent models of perinatal hypoxia–
ischaemia.”
“Babies treated with hypothermia
show a reduction in severity and
extension of damage in about 60%
of cases. But it does not fix all. Those
who benefit more are the babies born
at term and those older than 35 weeks’
gestation who had a sentinel perinatal
event that caused the injury, for
example that the mother’s placenta
ruptured or the umbilical cord was
wrapped around the neck causing
asphyxia”, says Ferriero.
At present, the 2010 International
Liaison Committee on Resuscitation
guidelines state that infants born at or
near full term with moderate to severe
hypoxic–ischaemic encephalopathy
caused by lack of oxygen should be
offered therapeutic hypothermia
under clearly defined protocols at
neonatal intensive care facilities that
provide multidisciplinary care and
follow-up. Although a simple idea,
the provision of such treatment is
more complicated in practice, and
requires clinical expertise in assessing
the neonate’s neurological status,
applying the treatment, monitoring
for complications, and providing
long-term developmental follow-up.
Another barrier to access is the
high price of the equipment—costing
about US$15000—which makes
hypothermia unviable as standard
of care in institutions in resource-
limited countries. Johnston’s team
has produced a low-cost, low-power
therapeutic hypothermia device for use
in resource-poor nations. The device is
composed of some simple electronics,
two clay pots, sand, and a urea-based
instant cold pack powder. The larger
pot, lined with 5 cm of sand, contains
the smaller pot, in which the baby
is placed for treatment. The baby’s
core body temperature is lowered by
evaporative and endothermic cooling.
“We have tested the device in piglet
models and it mimics the results of
more expensive therapies but our
device costs a maximum of $40”,
concludes Johnston.
However, hypothermia is not
suitable for infants born before
34–35 weeks. No preclinical studies of
very preterm babies have been done,
and their organs are so immature
that cooling can kill them by reducing
the efficiency of lung surfactants
and increasing the risk of sepsis. And
despite the results, cooling a baby’s
entire body to spare its brain is a blunt
instrument. Neonatologists envision
more precise treatments targeted at
specific molecules that orchestrate
neural development. Treatments that,
alone or in conjunction with others,
provide long-lasting neuroprotection
while also enhancing repair and
regeneration of the injured neonatal
brain are urgently needed. Potential
neuroprotective treatments, such as
melatonin, erythropoietin and cell-
based therapies are also being touted
as potential treatments for preterm
brain injuries, but all are in the early
stages oftesting.
In parallel to neuroprotection,
research is currently focused on identi-
fying more reliable biomarkers of brain
development in preterm babies, as has
been done in term babies. “Potential
candidates are being developed but the
need to wait for children to grow up to
validate findings tends to slow down
the discovery process, particularly as
reliable testing of cognitive function
is relatively poor until [children are
aged] at least 4–5 years”, says Marlow.
“Further interest is in trying to enhance
development in the infant after going
home, but this is expensive and it is
difficult to demonstrate persisting
long-term benefits. One current
approach is to try to affect the key
underlying executive processes that
underpin the later learning problems
that are seen in order to improve
outcomes, but these studies are in their
infancy.”
Over the past 40 years, advances
in neonatal medicine have enabled
more preterm babies to survive, but
researchers have had less success
in finding ways to protect the
developing brain in these infants. As
our understanding of the pathological
mechanisms of brain injury advances,
treatments and technologies for brain
monitoring could improve, hopefully
changingthis situation.
“To date, we have been able to push
down the barrier where 50% preterm
die and 50% survive with impairments
from 26 weeks to 23 weeks. The
question is: can we go any further?“
asks Marlow. “Trying to intervene
earlier is, today, technically difficult
because babies’ organs are very
immature. But what does the future
hold?We will see!”
Zuberoa Marcos
Survival of babies born before week 25 of gestation is just 50%
SamuelAshfield/SciencePhotoLibrary