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Blood test could determine cause of brain injury in newborns and aid treatment decisions

Patterns of gene expression that are detectable in the blood could determine the cause of hypoxic-ischemic encephalopathy (HIE) in babies, according to a new study.

This means that a simple blood test could show doctors whether a newborn is likely to respond to whole-body hypothermia – the standard treatment used in high-income countries.

The study, published in the journal JAMA Network Open and led by Imperial College London and its South Asian partners, considered whether genome expression profiles at birth in neonates with HIE in a high-income country differed from those of their counterparts in low-income countries.

It also sought to determine why babies with HIE in low-income countries appear to have worse outcomes and increased mortality risk when treated with therapeutic hypothermia when compared to those in high-income countries.

The researchers found that the disease mechanisms underlying HIE were primarily associated with acute hypoxia in the Italian cohort and nonacute hypoxia in the South Asia cohort.

This finding might explain the lack of hypothermic neuroprotection, they concluded.

Study co-author Professor Swati Manerkar, from Lokmanya Tilak Municipal Medical College in Mumbai, India, said: ‘We were expecting to see some differences in gene expression between babies in the cohorts – but not such a dramatic divergence.

‘It clearly shows that we are seeing are very different causes of brain injury between the two groups, with different characteristics which also helps to explain why some babies respond to cooling and others are harmed by it.’

Differing gene expression patterns

Blood samples were taken shortly after birth from 35 babies born with moderate or severe HIE in Italy (high-income country) and 99 babies born in India, Sri Lanka and Bangladesh (low-income countries).

A total of 14 babies from Italy were also included as healthy controls, and all cohorts were medically assessed at 18 months of age.

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Half the babies in the South Asian cohort died or developed severe disabilities (51 of 99), as did a quarter of the Italian cohort (9 of 35).

A total of 1,793 significant genes in the Italian cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05).

Only 11 of these genes were in common, and all had opposite direction in fold change.

The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signalling in the Italian cohort (z score = −4.56; P < .001) and aldosterone signalling in epithelial cells in the South Asia cohort (z score = null; P < .001).

The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14).

Brain injury and socioeconomic factors

Lead investigator, Professor Sudhin Thayyil, professor of perinatal neuroscience and director of the Centre for Perinatal Neuroscience at Imperial College London, said: ‘The gene expression patterns we saw in babies from [low-income countries] were similar to what you would see in people with sleep apnoea, suggesting that they experienced intermittent hypoxia in the womb and at birth.

‘We believe this is brought on by multiple chronic stresses during pregnancy such as poor nutrition or infection, as well as the normal labour process and uterine contractions, which leads to further hypoxia and ultimately injury to the baby’s brain.’

He added: ‘On the other hand, gene expression patterns in babies from [high-income countries] suggested a single, acute cause of brain injury, for example complications during birth like maternal bleeding, leading to a sudden drop in blood oxygen levels in the foetus.’

The differences between the cohorts are not related to ethnicity, but rather socioeconomic factors, the researchers stressed.

As such, the type of chronic brain injury commonly seen in low-income countries is also likely to be present in deprived areas in high-income countries, they said.

Professor Thayyil concluded: ‘The key for clinicians, anywhere in the world, is to be able to identify which type of brain injury they are dealing with as soon as possible – and that’s something we’re currently working on.’

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