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NEWS FEATURE

THE BR AIN,
INTERRUP TED
F
Babies are increasingly abienne never found out why she
went into labour three months too
The couple agreed that they did not want to
subject their child to that. We immediately told
ILLUSTRATION: PADDY MILLS

surviving premature early. But on a quiet afternoon in the doctors that we did not want fierce medical
June 2007, she was hit by accelerat- intervention to keep him alive and saw the
birth but researchers ing contractions and was rushed to relief on the doctors faces, recalls Fabienne,
the nearest hospital in rural Switzerland, near who requested that her surname not be used.
are only beginning to Lausanne. When her son, Hugo, was born at That night was the most tortured of her life.
26weeks of gestation rather than the typical 40, The next day, however, before any change
understand the lasting he weighed just 950 grams and was immedi- had been made to Hugos treatment, his doc-
ately placed in intensive care. Three days later, tors proposed a new option to confirm the
consequences for their doctors told Fabienne that ultrasound pictures diagnosis: a brain scan using magnetic reso-
mental development. of Hugos brain indicated that he had had a
severe haemorrhage from his immature blood
nance imaging (MRI). This technique, which
had been newly adapted for premature babies,
vessels. I just exploded into tears, she says. would allow the doctors to predict the risk of
Both she and her husband understood that cerebral palsy more accurately than with ultra-
BY ALISON ABBOTT the prognosis for Hugo was grim: he had a very sound alone, which has a high false-positive
high risk of cerebral palsy, a neurological con- rate. Hugos MRI scan showed that the damage
dition that can lead to a life of severe disability. caused by the brain haemorrhage was limited,

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FEATURE NEWS

and his risk of severe cerebral palsy was likely Hugos parents endured tense weeks during differences, too. They are less likely to take
to be relatively low. So just 24 hours after their which their son had a series of operations to risks, smoke, drink or have early sexual rela-
decision to let his life end, Hugos parents did fix damaged organs, and to create essential tionships, he says.
an about-turn. They agreed that the doctors connections between major blood vessels that Scientists are still struggling to understand
should try to save him. had not had time to develop before birth. They the physical changes in the brain that underlie
Thanks to medical advances since the knew he could still die at any time. But I felt all these differences. The brain is made up of
1970s, premature infants those born before like we were back on the TGV, says Fabienne, grey matter, which comprises densely packed
37weeks of gestation are increasingly able referring to the French high-speed trains. The cell bodies, and white matter, the long-reach
to survive. Some hospitals now try to save train goes fast and it rocks frighteningly but axons of cells that connect different brain
babies born as early as 22 weeks. But those we were on it again. regions. These axons are covered in a protective
developments are forcing doctors and parents But what happens after the immediate dan- coating called myelin during development, in a
to grapple with difficult decisions, because the ger has passed? Just a few studies have so far precise sequence that begins in the womb and
chances of severe disability increase with the followed up the long-term fate of premature continues for the first decade or so after birth.
extent of prematurity. Cerebral palsy, for exam- babies, because it is time-consuming and In the premature brain, immature, fragile
ple, affects 12% of babies born at term, 9% of blood vessels struggle to provide tissue with
those born earlier than 32 weeks and 18% of enough oxygen for normal development. When
those born at 26weeks.
That is just half the story. Neuroscientists
We were a vessel ruptures, crucial areas of white mat-
ter are destroyed and cerebral palsy can result.
are developing an increasingly sophisticated
picture of premature infants brains that could shocked to see But very little is known about what causes the
more subtle brain problems that cohort studies
help to inform medical decisions and treat-
ments. From some long-term studies, they are just how many of premature infants are revealing.

children had
learning that premature children face a higher TOO MUCH TOO SOON
risk than was previously thought of developing Scientists suspect that when the brain is forced
cognitive or behavioural problems according to carry out a crucial part of its development
to some studies, as many as half of them will.
Researchers are starting to ask why this
problems. while the child is in the outside world instead
of a warm, watery womb, it receives inap-
should be, whether it could be avoided and propriate signals from the environment that
what is the best way to provide educational expensive to track them with sophisticated cog- affect how its neurons are linked into net-
support for the affected children. We need to nitive and behavioural tests over many years. works. The premature brain gets subjected
gather a lot more data to understand what the One of the first studies to show the extent of to quite different sensory inputs like visual
best strategies are, says Petra Hppi, a neo- developmental problems was EPIPAGE, which stimulation and gravity effects which it is
natologist and developmental paediatrician at looked at a cohort of all live births between not supposed to be subject to, says Ghislaine
the University of Geneva in Switzerland, who 22 and 32 weeks of gestation from 9regions Dehaene-Lambertz of the INSERM-CEA Cog-
is following the brain development of children of France in 1997, and a reference group of nitive Neuroimaging Unit in Paris, who studies
who were born prematurely. 664full-term babies1. Up to half of the prema- language development in infants. They can
ture babies who survived to five years of age be sudden, intense but also unpredictable.
EARLY BIRTHDAY had some sort of neurodevelopmental prob- Some of these unnatural sensory signals are
Prematurity also called pre-term birth lem by then, and the impairments in cognitive inevitably provided by the intensive medical
is extremely common. According to World development grew more pronounced for each procedures that keep premature babies alive.
Health Organization statistics from 2012, extra week of prematurity. On a score of cogni- Pioneering brain-scanning studies support
more than one in 10 babies around 15 mil- tive ability, the team observed impairment in the idea that altered networks play a part in
lion in total are born prematurely each 44% of those born between 24 and 25 weeks of cognitive problems. Hppis Swiss collabora-
year. The great majority are born between 32 gestation and 26% of those born at 32 weeks, tion looked at 52 six-year-olds who had been
and 37weeks of gestation, but 1.6 million are compared with 12% of full-term controls. born prematurely, using MRI scans optimized
born between 28 and 32 weeks and 780,000 We were shocked to see just how many chil- to reveal tracts of neurons connecting brain
are born extremely pre-term, before 28 weeks dren had problems, says Hppi. Moderately regions4. Compared with children born at
(see Born too soon). premature babies may be at lower risk than term, the premature childrens neuronal tracts
In low-income countries, more than 90% extremely premature babies, she notes, but were organized less efficiently, often taking
of extremely pre-term babies born alive soon there are many more of them. a more meandering path. These changes in
die, which helps to explain why prematurity The effects seem to continue into adulthood. organization were correlated with reduced
is now the second biggest cause of death in Developmental psychologist Dieter Wolke social and cognitive skills.
children under five, after pneumonia. But in led an unusual study of hundreds of children In another study, neonatologist Jeffrey Neil,
richer countries, with sophisticated neonatal born between 26 and 31 weeks of gestation in then at St. Louis Childrens Hospital in Mis-
intensive-care facilities, more than 90% of these Bavaria in the mid-1980s. He assessed them souri, and his team used functional MRI to
extremely pre-term babies survive, and doctors at six years old2, and again at 26 years3. Last study the premature brain at rest. The low-
are continuing to push the age of survival even year, he reported3 that most of those who had level, idling activity of a resting brain gives a
earlier in development. Doctors in the United cognitive problems as children still had them read-out of its working connections, whose
States are debating a controversial recommen- as adults: one-quarter of them had moderate general topology is laid out before birth (see
dation to lower the gestational age at which a to severe cognitive deficits, and half had mild Nature 489, 356358; 2012). The team showed5
baby should be considered potentially viable cognitive deficits. Most of those who expe- that in babies born between 23 and 29 weeks
from 24 weeks to 23 weeks. In Japan, babies rienced problems had short attention spans, of gestation, this resting-state connectiv-
born at 22 weeks have been considered viable and as a group they tended to underachieve ity tends on average to be less complex and
since 1991. academically and career-wise. active at term-equivalent age than it is in full-
Parents of premature children face agoniz- Wolke, who is currently at the University term babies at birth. Another study on the
ing waits as their children fight for their lives. of Warwick, UK, observed subtler lifestyle 26-year-old Bavarians showed6 that this

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NEWS FEATURE

BORN TOO SOON


Just over 11% of live births worldwide are pre-term before 37 weeks of gestation and premature

SOURCE: H. BLENCOWE ET AL. LANCET 379, 21622172 (2012)


birth is the second largest cause of child deaths in under-fives. The medical risks increase with the extent
of prematurity; neuroscientists now think that some effects on brain development may last into adulthood.

Second trimester Third trimester

Completed weeks 16 20 24 28 32 36 40
of pregnancy Extremely pre-term Very pre-term Moderate or late pre-term Term Post-term
<28 weeks 2832 weeks 3237 weeks 3742 weeks >42 weeks

PRE-TERM BIRTH

22 WEEKS 2232 WEEKS 2339 WEEKS 24 WEEKS 26 WEEKS 34 WEEKS


Some hospitals One long-term study found that Brain-scanning studies point 50% chance of Cerebral palsy affects 50% chance of survival
now try to save up to half of children born in this to atypical structural and survival with neonatal around 10% of very with neonatal intensive
babies born as window have some neurodevelop- functional connections in the intensive care in most pre-term babies, but 18% care in many
early as 22 weeks. mental problem at age five. brains of premature infants. high-income countries. of those born at 26 weeks. low-income countries.

reduced complexity of resting-state connec- several associated with lipid metabolism, which other molecular and clinical data may eventu-
tivity stretches into adulthood. is crucial for white-matter development may ally lead to much greater precision. Should this
Researchers agree that the most revealing modify the risk of altered brain development. become possible, it will throw open a whole new
studies would monitor the brains of prema- Having a particular genetic profile might make debate about how best to ameliorate any future
ture babies and full-term comparison babies certain babies less vulnerable, he says. problems for premature children, through
from as early as possible after birth, with very specific social and educational support
follow-up scans and assessments throughout BRAIN PROTECTION something that neuroscientists and education
life. But such studies are difficult, and not only With scientists still working to identify the experts are only beginning to grapple with.
because it is hard to keep tabs on families who molecular, cellular and network differences Fabienne, like many parents of premature
may move house, lose interest or lose touch in the premature brain, finding treatments children, would like to have that information.
over the years. Parents are rarely keen for their seems a fond hope. But Hppi is attempting Hugo, who is now seven, occupies most of her
newborns whether premature or full-term to do it. She is conducting a clinical study of time. He has difficulties with fine movements,
to be whisked away into the loud and lonely erythropoietin, or EPO, a drug that stimulates and some visual problems; he also needs a
chamber of a distant MRI machine without a the production of red blood cells. It is already a lot of extra assistance at school. Fabienne is
burning medical reason. (In some countries, standard treatment to aid oxygenation of inter- deeply engaged with educational training
such as the Netherlands, it is illegal to do so.) nal organs not to mention being a favourite programmes, which she hopes will be helpful,
And not all obstetricians are comfortable with among endurance-sport cheats and it is also although she cannot know for sure. But Hugo
subjecting delicate premature babies to brain thought to protect and support neurons. is an unadulterated joy to her, and she is end-
scans at a medically and emotionally fraught Anecdotal reports had suggested that eryth- lessly grateful for the MRI scans that were so
time. Fabienne was happy for Hugo to be ropoietin might help long-term neurodevelop- crucial in the decision to save him. Neuro
scanned, but recalls how painfully long it took ment, and Hppis team is assessing this in a science was able to say that Hugo would be able
to get from the paediatric ward to the scanning prospective, randomized and controlled study to have a reasonable quality of life, she says.
suite in her hospital. I felt half-dazed walk- in nearly 500 very premature babies born in And she monitors from a distance the new
ing alongside Hugo in his incubator through Switzerland, who are being MRI scanned at wave of scientific interest in the brains of pre-
a long underground tunnel to get there, she term-equivalent age. The first results, pub- mature babies. Neuroscience is coming up
says. It looked like the tunnel you are sup- lished in 2014, showed9 that treated babies had with a lot of good information I really hope
posed to see when you are dying. fewer signs of neurological problems than did that they will soon translate what they are dis-
A small vanguard of scientists and clinicians children in a control group. But the acid test, covering into concrete actions that parents can
is pushing ahead, and several large long-term says Hppi, will come when they are assessed usefully undertake.
studies are under way around the world, col- at two years old, when neurodevelopment has
lecting neurological, cognitive, behavioural and proceeded further. Alison Abbott is Natures senior European
genetic data from birth, along with brain scans. Where does all this leave parents, who still correspondent.
In France, EPIPAGE 2 is now running, have to make decisions about their childrens
1. Larroque, B. et al. Lancet 371, 813820 (2008).
and has recruited more than 4,200 prema- treatment with only limited information about 2. Wolke, D. & Meyer, R. Dev. Med. Child Neurol. 41,
ture babies from all over the country7. In the the long-term prognosis? Some, such as Fabi- 94109 (1999).
United Kingdom, a team led by neonatologist enne, can be helped by MRI scans that can 3. Eryigit Madzwamuse, S., Baumann, N., Jaekel, J.,
David Edwards of Kings College London has detect damage in white and grey matter, and Bartmann, P. & Wolke, D. J. Child Psychol. Psychiatry
http://dx.doi.org/10.1111/jcpp.12358 (2014).
launched a study that will track children from make it possible to predict the risk of severe 4. Fischi-Gmez, E. et al. Cereb. Cortex http://dx.doi.
their time in utero until they are two years old, brain damage more precisely than in the past. org/10.1093/cercor/bhu073 (2014).
collecting brain scans and blood samples along Hppi says that the technology helps doctors to 5. Smyser, C. D. et al. Cereb. Cortex http://dx.doi.
the way. Some of these children will inevitably advise parents, and it is a terrible responsibility org/10.1093/cercor/bhu251 (2014).
6. Buml, J. G. et al. Cereb. Cortex http://dx.doi.
be born prematurely, and the plan is to identify if we are wrong. But this does little to identify org/10.1093/cercor/bhu133 (2014).
molecular signatures that might predict which which children will have milder developmental 7. Ancel, P.-Y., Goffinet, F. & EPIPAGE 2 Writing Group
of those infants are particularly vulnerable, or problems, or what those might be. BMC Pediatr. 14, 97 (2014).
8. Boardman, J. P. et al. Pediatrics 133, e1655e1663
resistant, to altered neurodevelopment. Edwards and others think that brain imaging (2014).
Edwards preliminary studies8 on premature alone can never provide that type of information 9. Leuchter, R. H.-V. et al. J. Am. Med. Assoc. 312,
babies suggest that some genes including but that combining scans with genetic and 817824 (2014).

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