Brain injury and its consequences in
extremely premature babies
John Wyatt
Perinatal Brain Protection and Repair Group
University College London
Survival of babies 23-25 weeks gestation
UCLH 1981-2000
(as percentage of admissions to NICU)
Riley et al. Acta Paediatrica 2008; 97:159-65
Percentage of surviving extremely preterm infants
with neurodevelopmental impairment
at 1 year of age, UCLH 1981-2000
Riley et al. Acta Paediatrica 2008; 97:159-65
Neurodevelopmental outcome
at 8 years of age
< 28 weeks
(n = 137)
28 – 32 weeks
(n = 445)
Disability
23%
12%
Brain lesion detected
by ultrasound
48%
22%
Vollmer et al, Pediatrics 2003, 112, 1108-1114
EPICURE nationwide study of all babies in UK and
Ireland, born 22-25 weeks gestation in 1995.
Assessment at 6 years of age
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Out of 241 survivors:
15 were unable to walk due to cerebral palsy
27 had severe learning difficulties
4 blind and 7 severe hearing loss
Total of 32 had any severe disability
Marlow et al. NEJM 2005; 325: 9-19
Cognitive (IQ) scores for ex-premature infants
at 6 years of age compared with class mates
White matter loss in the ex-preterm brain
Thinning of corpus callosum
Rate of cortical development is maximal between
22 weeks and term
25 wks GA
27 wks GA
32 wks GA
Rate of synaptic development
• ~ 1011 neurons in CNS
• Each neuron develops ~ 103 synapses
• Therefore total of ~ 1014 synapses created –
majority are formed between 22 and 40 weeks of
gestation
= ~ 5 x 1011 synapses per day
= ~ 3 x 108 synapses per minute!
Cranial MRI scans at 14 years in a cohort
of ex-preterm infants
MRI
Ex-preterm
Normal
Equivocal
Abnormal
23%
21%
56%
Term controls
71%
24%
5%
Stewart et al, Lancet 1999, 353: 1653-1657
MRI abnormalities in ex-preterm
adolescents at 14 years
• MRI abnormalities correlated with abnormal
behaviour scores.
• MRI abnormalities did not correlate with IQ, with
neurological signs or with need for extra
educational help.
Grey matter changes in ex-preterm adolescents
Nosarti et al, Brain 2002, 125, 1616-1623
White matter changes in ex-preterm adolescents
Nosarti et al, Brain 2002, 125, 1616-1623
Changed brain microstructure following
developmental care programme
Als et al. Pediatrics 2004, 113, 846-857
Possible mechanisms of improved outcome
following perinatal brain injury
• Cell differentiation and replacement from
neuronal and glial precursor stem cells
• Refinement and selection of dendritic synaptic
connections
• Rerouting of white matter connections
• Development of alternative cortical processing
strategies
Conclusions
• White matter injury in extremely premature infants is
the most important cause of long term
neurodevelopmental disability.
• The developing central nervous system has
remarkable potential for repair and compensation
following perinatal injury
• New therapeutic approaches are required to translate
experimental findings into practical therapies whilst
babies are undergoing intensive care and following
discharge from hospital
Acknowledgements
Ann Stewart
Osmund Reynolds
Matt Allin
Topun Austin
Jenny Baudin
Alan Connolly
David Edwards
Michelle de Haan
Angela HuertasCeballos
David Gadian
Robin Murray
Brian Neville
Chiara Nosarti
Fran O'Brien
Claire Price
Larry Rifkin
Kate Riley
Nikki Robertson
Maeve Rooney
Simon Roth
Teresa Rushe
Al Santhouse
Alison Skinner
Faraneh Vargha-Khadem
Brigitte Vollmer
UCL NHS Trust
Centre for Perinatal Brain Protection & Repair
Obstetrics & Gynaecology, Paediatrics & Child Health
Medical Physics & Bioengineering