Journal club on mild HIE and effect of therapeutic hypothermia on it. A topic from Neonatal Neurology.

1. Journal Club
By: Dr Inayat Ullah
Fellow Neonatology.
PEMH RWP.

2. Title/Authors
• Mild hypoxic ischemic encephalopathy and
long term neurodevelopmental outcome - A
systematic review
• J.M. Conwaya,⁎, B.H. Walshb, G.B. Boylana,
D.M. Murraya
• Irish Central for Fetal and Neonatal Translational Research-INFANT Centre, Department of
Pediatrics and Child Health, University College Cork, Cork University Hospital, Wilton, Cork,
Ireland
• Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA,
USA

3. Background
• Neonatal HIE occurs 3-5/1000 live birth.
• Leading cause of morbidity and mortality
• Severity graded according to Sarnat staging
system as mild, moderate and severe.
• Mild HIE is considered with excellent
prognosis without long term morbidity.
• That’s why many studies don’t follow long
term outcome of Neonates with mild HIE.

4. Background Cont’d
• RCT for therapeutic Hypothermia (TH) have been
designed such that mild HIE is not included in it.
• In very few cohorts mild grade HIE infants were
assessed at school age.
• Significant disabilities like learning and
neuropsychological difficulties, autism, epilepsy,
visual and sensory loss have been identified.
• Some studies have also found MRI changes
comparable to those in Moderate HIE.

5. Aim of the study
• The aim of this systematic review was to
identify the current available literature on
reported outcome in infants with mild HIE.

6. Methods
• Cochrane systematic review
• Search strategy was expanded to include all
papers reporting outcome in infants with mild
HIE.
• The RCT studies were analyzed using Review
Manager 5.3 and odds ratios using a fixed
effect model with 95% confidence intervals
are reported.

7. Search Strategy
• A search strategy adapted from the Cochrane
Neonatal Review Group via OVID of Medline
(1946–2017), Embase (1980–2017), Cochrane
Trials Database (1996–2017), previous
reviews including cross-references, abstracts,
conferences, symposia proceedings, expert
informants and journal hand searching as per
Cochrane Neonatal Review Group was
conducted on the 24th of March 2017

8. Inclusion Criteria
• Human studies of term infants ≥36 weeks GA
• All RCT’s quasi randomized trials and cohort
studies that described neuro developmental
outcome assessed using a standardized
assessment test in infants with mild HIE were
included
• Clearly defined HIE as per Sarnat Staging or EEG.
• Studies with standardized outcome assessment
with a minimal follow-up at 18 months of age.

9. Excluded
• In the meta-analysis infants with alternate
diagnoses, including congenital
malformations, were excluded.

10. Abnormal Outcome
I. Death
II. Major neurodisability ( CP, [Blindness vision <
6/60], SNHL requiring aids.
III. Developmental delay
IV. Intellectual impairment
• This was defined as formal cognitive assessment
more than one SD below the mean or intellectual
impairment (IQ more than one SD below mean).

11. Papers selection
• Papers selected using the online version of
MedNote™
• Duplicates deleted
• Extracted papers were filed into phase accept
or reject
• Due to large numbers of extracted papers
irrelevant studies were rejected.
• Second phase undertaken to check papers for
inclusion/exclusion.

12. Papers selection Cont’d
• Papers grouped according to country, centre
and cohort recruitment year
• Papers reporting the longest complete
outcome were chosen for analysis.
• Systematic reviews were also excluded but
kept for cross referencing.
• Once this process was complete and the
experts reached a consensus 20 papers
remained for analysis.

14. Methods
• Studies were critically appraised using the ten
question Quality Appraisal Checklist adopted
from CONSORT.
• Each of 10 appraisal questions were allocated 1
for yes and zero for No.
• Articles with a total score>75% were deemed
high quality; 50–74% medium quality and<50%,
low quality.
• Studies assessed by 2 independent researchers
and disagreement resolved with consensus.

15. Data Analysis
• RCT trials were analyzed using Review Manager
5.3
• Heterogeneity was assessed for appropriateness
of meta-analysis.
• Meta-analysis of neurodevelopmental outcomes
was performed in review manager reporting odds
ratios with a fixed effects model and 95%
confidence intervals.
• Abnormal outcome was defined as death,
cerebral palsy or a cognitive score more than 1
standard deviation below the mean.

16. Results
• Studies included 20
• 14 high rated article, 6 of medium quality with
none yielding a low score.
• 2 RCT’s multicenter, 8 in Europe, 7 in Asia 2 in
Australasia and 1 in North America.
• These 20 studies reported on total of 341
Neonates with Mild HIE.
• Studies included were those prospective cohort
studies that reported mild HIE with long term
outcome.

17. Results (Cont’d)
• In 16 non RCT studies outcome was reported in 250
mild HIE patients.
• Out of which 56 (22%) had abnormal outcome at 18
months or older.
• Studies reported since 1990 show 194 infants with mild
HIE with 50 (26%) having abnormal outcome.
• >25 years old studies may bias because of significant
improvement in Obstetric and Neonatal care, hence
omitted.
• However the Robertson paper 1989 was a large cohort
and a seminal paper and was included in overall
analysis.

18. Results (Cont’d)
• 4 RCT’s who reported mild HIE outcome as
part of therapeutic hypothermia (TH) trial.
• These trials were included in a meta-analysis
for effect of therapeutic hypothermia
treatment.

19. Results (Cont’d)
• RCT Studies enrolled 91 infants with mild HIE
• 45 cooled, 46 uncooled.
• Abnormal outcome: 29% in cooled vs. 37% in
uncooled with Odds ratio of 0.67 (95% CI:0.28
to1.61, p=0.59)
• Combination of RCT and Non-RCT
• Total 341 with 86(25%) having abnormal
outcome.

20. Results summarized
Study Type No of Studies Total Infant
enrolled mild HIE
Abnormal outcome
in Percent
RCT’s 04 91 Cooled 29%*
Uncooled 37%
Non-RCT’s 16 250 22 %
Total 20 341 25%**
*Cooled infant with Mild HIE having Favorable outcome
**Quarter of the infant with mild HIE having abnormal outcome

21. Results (Cont’d)
• Meta analysis was conducted for 4 RCT’s of TH
• Heterogeneity was found insignificant with
p=0.59 indicating similarities in studies fit for
meta-analysis.
• As described in previous slide data shown a
trend towards TH, but this trend was
insignificant and not strong enough to guide
the therapy for mild HIE.

22. Characteristics of RCTs

23. Characteristics of RCTs

24. Forest Plot

25. Discussion
• Combining both RCT and non-RCT studies,
outcome was reported in a total of 341 mild HIE
infants, with one quarter having abnormal
outcome
• It shows that outcome of babies outside cooling
criteria and mild HIE is not normal.
• Disability may appear to be less severe initially,
due to our difficulties in accurately measuring
cognitive ability at a young age.
• Difficulty may get severe as the child grows to
school age and beyond.

26. Discussion (Cont’d)
• Approximately 25% of infants with mild HIE
have mild to moderate disability at 2 years. By
5 years, 35% are having difficulties in one or
more areas
• A Swedish study also finds higher rates of
disability with 30% having CP and 70% non CP
having other disabilities impairing normal life.
• Thus unrecognized disabilities may be more
severe than what our limited study suggest.

27. Discussion (Cont’d)
• No trials of TH undertaken in mild HIE are there
• Some have inadvertently cooled mild HIE Term
Neonates with good outcome.
• However these studies were not powered to
determine this outcome and hence cannot be
used as evidence to change the practice.
• Before expanding the treatment there is need of
evidence suggesting the benefits outweighs the
risks associated with TH.
• Carefully well defined RCTs are needed to answer
this question.

28. Strength of the study
• Systematic and transparent result reporting
using guidance from Cochrane following
structured Protocol
• Aims and objectives were clear.
• Independent expert reviewer (Neonatologists,
Pediatricians)

29. Limitations
• All studies included were not studying mild HIE rather
have inadvertently included mild HIE.
• Each cohort have very small percent of mild HIE
despite of its increased incidence i.e. 50%.
• Timing of definition of HIE varied from day 1to 1 week.
• Identification of HIE assessor dependant and variable.
• Variable definition of mild HIE in literature.
• Abnormal neurodevelopmental outcome definitions
were also varied and complex.

30. Discussion (Cont’d)
• This study shows that infant with mild HIE are understudied
and underrepresented in available evidence.
• In Cochrane cooling review group 1505 infants were
included with moderate to severe HIE, data is available only
for 341 Neonates with Mild HIE of which only 91 included
in RCT.
• The rate and severity of disability is less common than that
associated with moderate HIE.
• Mild dev delay more common than CP or severe dev
disability.
• However the ones affected with mild HIE are greater in
number.

31. Conclusion
• This review shows that one quarter of infants
with Mild HIE have an abnormal outcome i.e.
Death, motor or dev delay at 18 month of age.
• There is insufficient evidence to recommend
therapeutic hypothermia in this mild category
of HIE.

32. Research directions
• A well-constructed RCT of TH in mild HIE is
urgently needed to give clinicians an evidence
base to guide therapy in this neglected group.

33. • How this review can change our Practice?

34. THANKYOU