A feature about latest research to improve premature babies' medical care. Published in The Lancet Neurology: http://www.lancet.com/journals/laneur/article/PIIS1474-4422%2813%2970041-3/fulltext

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

2. In Context
near full term with moderate to severe regeneration of the injured neonatal
hypoxic–ischaemic encephalopathy brain are urgently needed. Potential
caused by lack of oxygen should be neuroprotective treatments, such as
offered therapeutic hypothermia melatonin, erythropoietin and cell-
under clearly defined protocols at based therapies are also being touted
neonatal intensive care facilities that as potential treatments for preterm
provide multidisciplinary care and brain injuries, but all are in the early
Samuel Ashfield/Science Photo Library
follow-up. Although a simple idea, stages of testing.
the provision of such treatment is In parallel to neuroprotection,
more complicated in practice, and research is currently focused on identi-
requires clinical expertise in assessing fying more reliable biomarkers of brain
the neonate’s neurological status, development in preterm babies, as has
applying the treatment, monitoring been done in term babies. “Potential
Survival of babies born before week 25 of gestation is just 50% for complications, and providing candidates are being developed but the
long-term developmental follow-up. need to wait for children to grow up to
For Michael Johnston’s shown clinical efficacy for decreasing Another barrier to access is the validate findings tends to slow down
investigations see Review the risk of death or disability in babies high price of the equipment—costing the discovery process, particularly as
Lancet Neurol 2011; 10: 372–82
born at (or near) full term after about US$15 000—which makes reliable testing of cognitive function
For more on the low-cost,
low-power therapeutic asphyxia. hypothermia unviable as standard is relatively poor until [children are
hypothermia device see “The main effect of the absence of care in institutions in resource- aged] at least 4–5 years”, says Marlow.
Med Devices (Auckl) 2013; 6: 1–10 of oxygen at the moment of birth limited countries. Johnston’s team “Further interest is in trying to enhance
For more on hypothermia in is the release of the excitatory has produced a low-cost, low-power development in the infant after going
infants see Nat Rev Neurol 2011;
7: 485–94
neurotransmitter glutamate in the therapeutic hypothermia device for use home, but this is expensive and it is
brain. Glutamate activates several in resource-poor nations. The device is difficult to demonstrate persisting
cascades of injury that end up in cell composed of some simple electronics, long-term benefits. One current
apoptosis and necrosis and it also two clay pots, sand, and a urea-based approach is to try to affect the key
triggers inflammation” explains instant cold pack powder. The larger underlying executive processes that
Michael Johnston, chief medical officer pot, lined with 5 cm of sand, contains underpin the later learning problems
at the Kennedy Krieger Institute, the smaller pot, in which the baby that are seen in order to improve
Baltimore, USA. He has investigated is placed for treatment. The baby’s outcomes, but these studies are in their
treatments that reduce brain injury core body temperature is lowered by infancy.”
and promote recovery in infants evaporative and endothermic cooling. Over the past 40 years, advances
and children. “We know that, if “We have tested the device in piglet in neonatal medicine have enabled
administered early enough, drugs models and it mimics the results of more preterm babies to survive, but
that block the effects of glutamate on more expensive therapies but our researchers have had less success
one of its receptors, the NMDA, can device costs a maximum of $40”, in finding ways to protect the
totally prevent brain injury in infant concludes Johnston. developing brain in these infants. As
rodent models of perinatal hypoxia– However, hypothermia is not our understanding of the pathological
ischaemia.” suitable for infants born before mechanisms of brain injury advances,
“Babies treated with hypothermia 34–35 weeks. No preclinical studies of treatments and technologies for brain
show a reduction in severity and very preterm babies have been done, monitoring could improve, hopefully
extension of damage in about 60% and their organs are so immature changing this situation.
of cases. But it does not fix all. Those that cooling can kill them by reducing “To date, we have been able to push
who benefit more are the babies born the efficiency of lung surfactants down the barrier where 50% preterm
at term and those older than 35 weeks’ and increasing the risk of sepsis. And die and 50% survive with impairments
gestation who had a sentinel perinatal despite the results, cooling a baby’s from 26 weeks to 23 weeks. The
event that caused the injury, for entire body to spare its brain is a blunt question is: can we go any further?“
example that the mother’s placenta instrument. Neonatologists envision asks Marlow. “Trying to intervene
ruptured or the umbilical cord was more precise treatments targeted at earlier is, today, technically difficult
wrapped around the neck causing specific molecules that orchestrate because babies’ organs are very
asphyxia”, says Ferriero. neural development. Treatments that, immature. But what does the future
At present, the 2010 International alone or in conjunction with others, hold? We will see!”
Liaison Committee on Resuscitation provide long-lasting neuroprotection
guidelines state that infants born at or while also enhancing repair and Zuberoa Marcos
2 www.thelancet.com/neurology Published online February 21, 2013 http://dx.doi.org/10.1016/S1474-4422(13)70041-3