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 earlyAccording 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 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 fi rst 7 days after birth. The proportion of babies who 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 the UK and Ireland.

“70% of premature infants born at 24 weeks survive without signifi cant 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 aff ects 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 fi rst 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 specifi c to the degree of development at the time of birth. “Being preterm exposes the developing brain to a range of stimuli radically diff erent 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 corti cocortical connections and this could explain also the reduced cortex volume and abnormalities in cortical organization observed in these 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 diffi cult. In the past decade, doctors have started to apply more sophisticated methods that off er new insights into tissue microstructure, and enable measurement of brain volume and the study of maturation of the brain. At the University of California San Francisco, Donna Ferriero and her team are developing the baby connectome, a map of the connectivity of the newborn brain at all stages of development starting with premature neonates.

Ferriero and her collaborators have implemented an automated technique based on diff usion 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 defi cits that are diffi cult to predict. Ferriero explains, “we have seen that severity of injury correlates to diff erent structural net work phenotypes in hypoxic–ischaemic encephalopathy babies. We observed a decline in brain network integration and segregation with increasing neuromotor defi cits.”

The study is the fi rst step towards understanding the large-scale baby connectome. This map will provide the knowledge of brain development that could guide eff orts 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 OnlineFebruary 21, 2013http://dx.doi.org/10.1016/S1474-4422(13)70041-3

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 effi cacy for decreasing the risk of death or disability in babies born at (or near) full term after asphyxia.

“The main eff ect 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 infl ammation” explains Michael Johnston, chief medical offi cer 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 eff ects 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 fi x all. Those who benefi t 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 off ered therapeutic hypothermia under clearly defi ned 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$15 000—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 effi ciency 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 specifi c 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 of testing.

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 fi ndings 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 diffi cult to demonstrate persisting long-term benefi ts. One current approach is to try to aff ect 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 fi nding 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 changing this 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 diffi cult 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%

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