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Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy
  1. Peter J Lally1,
  2. Paolo Montaldo1,
  3. Vânia Oliveira1,
  4. Ravi Shankar Swamy1,
  5. Aung Soe2,
  6. Seetha Shankaran3,
  7. Sudhin Thayyil1
  1. 1 Centre for Perinatal Neuroscience, Imperial College London, London, UK
  2. 2 Oliver Fisher Neonatal Unit, Medway Maritime Hospital, Kent, UK
  3. 3 Department of Neonatal Perinatal Medicine, Wayne State University, Detroit, Michigan, USA
  1. Correspondence to Peter J Lally, Centre for Perinatal Neuroscience, Imperial College London, Level 5, Hammersmith House, Du Cane Road, London, W12 0HS, UK; p.lally{at}


We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5–13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage).

  • encephalopathy
  • therapeutic hypothermia
  • newborn
  • magnetic resonance
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What is already known on this topic?

Anecdotal evidence suggests that many cooling centres offer therapeutic hypothermia to babies with mild encephalopathy and often discontinue this prior to 72 hours, deviating from the National Institute of Clinical Excellence guidelines.

What this study adds?

Brain injury and adverse neurodevelopmental outcomes are observed in babies with mild neonatal encephalopathy who have had premature cessation of cooling therapy.


Although therapeutic hypothermia is the standard therapy for moderate and severe neonatal encephalopathy, cooling therapy is increasingly offered to babies with mild encephalopathy.1 This may be partly due to ‘therapeutic creep’, the expectation that perhaps these babies could also benefit from cooling, the reassurance of the safety profile of cooling in moderate and severe encephalopathy or due to the difficulties in accurately measuring the severity of encephalopathy within 6 hours of birth. Hence, clinicians may err on the side of caution and offer cooling therapy to babies with mild encephalopathy, and then subsequently discontinue cooling if a baby shows rapid clinical recovery.

We examined brain injury and neurological outcomes in babies with mild neonatal encephalopathy, who had early cessation of cooling therapy.


We retrospectively identified all babies with mild encephalopathy who were cooled as part of clinical care and who had premature cessation of cooling due to clinical improvement,2 from the study database of the Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) study. All recruited babies had: (A) their encephalopathy grade assessed before 6 hours of age using a previously validated neurological examination3; (B) MRI and single voxel thalamic proton spectroscopy (3 Tesla) between 4 and 14 days after birth; and (A) a detailed neurological examination at 2 years of age using Bayley-III2or British Association of Perinatal Medicine (BAPM)/Royal College of Paediatrics and Child Health (RCPCH) working group classification, if Bayley-III was not available.4

An MR physicist (PJL) analysed the spectroscopy data using LCModel (v6.3–1J, LCModel, Oakville, Ontario, Canada), and a neonatal neurology consultant (ST) with 8 years of neuroimaging experience reported conventional MRI, masked to the clinical details. The North London Research Ethics Committee and clinical sites approved the MARBLE study (11/H0717/6), and informed parental consent was obtained from parents or legal representatives of the infants.


From a subgroup of 42 babies with mild encephalopathy who were offered cooling as part of clinical care, therapy was prematurely discontinued in 10 (24%) infants (5% of the first 200 babies recruited into the MARBLE study). Clinical characteristics, MRI abnormalities and neurodevelopmental outcomes of these 10 babies are given in table 1. All babies had a normal amplitude integrated electroencephalography at the time of initiation of cooling therapy, which remained normal throughout the cooling period, and had a normal neurological examination at the time of rewarming.

Table 1

Clinical characteristics, MRI and neurodevelopmental outcomes following premature cessation of cooling therapy

MRI was performed at a median age of 6 days (IQR: 5–7 days). Five (50%) infants had MRI abnormalities: periventricular white matter injury alone (two babies); subcortical and focal white matter injury (one baby); severe wide spread white matter injury (one baby); and abnormal signal intensity in thalami and equivocal loss of T1 high signal abnormality in the posterior limb of internal capsule (one baby).

  • Three babies (cases 3, 5 and 6) had white matter injury, of which one baby later had proven sepsis with group B streptococcus. All of these babies had normal neurodevelopmental outcomes at 2 years of age.

  • One baby (case 4) had white matter injury as well as an elevated thalamic lactate/N-acetyl aspartate ratio (0.35). Additional MR scans at 45 days and 22 months showed persistence of the white matter injury (figure 1).

  • Another baby (case 8) had white matter injury plus signal abnormalities in the basal ganglia (figure 1).

  • None of the babies had reported hypoglycaemic episodes.

Figure 1

MRI in babies with an abnormal neurodevelopmental outcome at 2 years. Images 1a–3a: normal basal ganglia at different timepoints, on T1-weighted axial MR; images 1b–3b: periventricular white matter injury (white arrows) at different timepoints, on T1-weighted axial MR. Case 4: image 1c: white matter injury (white arrows) at 6 days, on axial diffusion-weighted imaging; images 2c–3c: T2-weighted axial MR at 45 days and 22 months. Case 8: image 4a: focal high signal intensity in left caudate (black arrow), on T1-weighted axial MR. Image 4b–4c: white matter injury in the occipital region on T2-weighted and diffusion-weighted axial MR, respectively.

A detailed neurological examination was performed at a median age of 22 months (IQR: 20–24 months) and was abnormal for two (20%) of the babies (figure 1).

  • None of the babies had cerebral palsy (Gross Motor Function Classification System=0).

  • At 21 months of age, case 4 had a cognitive composite score of 80 (equivalent developmental age: 16 months), a language composite score of 74 (receptive communication equivalent developmental age: 16 months; expressive communication equivalent developmental age: 15 months) and a motor composite score of 82 (fine motor equivalent developmental age: 17 months; gross motor equivalent developmental age: 16 months). Her gait was not fluent, and she had a persistent adduction of her right thumb.

  • At 22 months of age, case 8 had language delays in expression and receptive communication. He could speak only two words and did not follow simple instructions or respond to social requests. His neurological examination was normal, except for a poor pincer grasp.


Here we report the brain injury and neurodevelopmental outcomes after premature cessation of cooling therapy in a small series of babies with mild encephalopathy.

Discontinuation of cooling therapy due to adverse events or for palliative care is a well-accepted clinical practice, hence we specifically excluded such cases. Discontinuation of cooling in our cohort was driven by a view that therapeutic hypothermia was no longer needed as the baby had already recovered clinically. Uncertainty also existed about whether the infant had fulfilled the cooling criteria in first place (moderate or severe encephalopathy). This often occurs when passive cooling therapy is initiated at a local hospital prior to the referral, followed by a detailed neurological evaluation at the cooling centre, during which the baby no longer exhibits signs of encephalopathy.

It is unclear if brain injury might have been averted if cooling therapy was given up to 72 hours. Walsh and colleagues from Boston Children Hospital have recently reported brain injury on MRI in 54% of the babies with mild neonatal encephalopathy, despite complete cooling therapy.5 Nevertheless, in preclinical models, brief hypothermia after hypoxia-ischaemia only postpones brain injury and does not provide any long-lasting neuroprotection.6 Furthermore, short cooling therapy (48 hours) offers less neuroprotection than standard cooling (72 hours) in a fetal sheep model of perinatal encephalopathy.7

Inflammatory markers are commonly elevated in neonatal encephalopathy even without coexistent infection,8 and only one baby in our series had proven blood stream positive sepsis (group B streptococci). Preclinical data suggest that hypothermic neuroprotection may be lost with coexistent Gram-negative infections, but not with Gram-positive infections.9 Hence, any lack of neuroprotection in our cohort is unlikely to be due to coexistent perinatal infection.

There are three major limitations of our study. First, the reported incidence of premature cessation of cooling in our study (24%) is likely to be an underestimate, when compared with actual clinical practice. Our babies were part of a multicentre study, and hence may have had closer monitoring. A recent survey in Australia reported a 20% (21/104) incidence of premature cessation of cooling therapy (due to clinical improvement (n=16) or lack of qualification (n=5) in retrospect) in 104 babies who were cooled despite not meeting the cooling criteria.1 Cooling therapy was also prematurely discontinued in 2% (2/103) of the babies who had originally met the cooling criteria (moderate or severe encephalopathy), due to an apparent clinical improvement. Neuroimaging or neurodevelopmental outcome data were not available in this cohort, nevertheless the authors do raise concerns about such practices. Second, although none of our cases seemed to have met the original cooling criteria and had a rapid clinical recovery, the high incidence of brain injury and the adverse neurodevelopmental outcomes in these babies is worrying. This questions whether these babies may have in fact suffered moderate (not mild) injury, and reflects the practical challenges in accurately identifying the severity of encephalopathy within 6 hours of birth. Finally, we have not compared the outcomes of complete versus incomplete cooling therapy in babies with mild encephalopathy.

The long-held view of uniformly good outcomes in mild encephalopathy is being increasingly challenged in more recent studies. Growing evidence suggests that cognitive impairments and behavioural problems during childhood following mild neonatal encephalopathy are closer than previously thought to those of children with moderate encephalopathy.10 Although in three cases the MRI abnormalities did not correlate with 2-year outcomes in our series, they could be associated with adverse outcomes during childhood.

Although classical secondary energy failure may not occur in mild encephalopathy, it is possible that perinatal hypoxic injury is a continuum. For example, perinatal asphyxia without encephalopathy leads to a reduction in IQ compared with healthy peers, and mild, moderate and severe encephalopathy results in increasing severity of long-term adverse outcomes. Hypothermia is reported to have a marked neuroprotective effect in a recently described preclinical model of mild encephalopathy, where the predominant injury was in the white matter.11 Preclinical studies also report that brain cooling in the absence of perinatal asphyxia may increase apoptosis.12

The data presented in this case series suggest that despite clinician perception of clinical recovery, the premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. The creeping introduction of non-standard cooling practices, constantly challenged by residual safety concerns, can only be resolved by large pragmatic trials of cooling in mild encephalopathy. In addition to neurodevelopmental outcome assessments, these studies should also examine the cost–benefit implications, as cooling therapy is expensive and may prolong hospital stay. Such trials are currently in development in the UK and USA.


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  • PJL and PM contributed equally.

  • Contributors The first two authors PL and PM contributed equally to this manuscript. ST conceived the idea for this study. PJL, PM, VO, RSS and ST facilitated MRI scanning, data acquisition and analysis. ST and PJL analysed the magnetic resonance imaging and spectroscopy data, respectively. PM conducted neurodevelopmental assessments. PM and PJL wrote the first manuscript draft. AS and SS contributed to data analysis and advised on important intellectual content. All authors contributed to the manuscript revision and approved the final version.

  • Funding PL and VO are funded by National Institute for Health Research (NIHR) doctoral fellowships, and PM is funded by a Medical Research Council doctoral fellowship. ST is funded by a Weston endowment chair at Imperial College London. This research was supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests None declared.

  • Patient consent Obtained from the parents/guardian.

  • Ethics approval North London Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This paper has been amended since it was published Online First. The contributors statement has been updated.

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