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Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis

Presented at the Neonatal Society 2012 Autumn Meeting.

Pauliah S1, Wade A2, Shankaran S3, Thayyil S1

1 Institute for Women’s Health, University College London, UK
2 Paediatric epidemiology and biostatistics, University College London, UK;
3 Children’s Hospital of Michigan and Hutzel Women’s Hospital; Wayne State University School of Medicine, USA

Background: Meta-analysis of cooling trials suggests that therapeutic hypothermia alongside optimal neonatal intensive care treatment reduces mortality and long-term neurodisability after neonatal encephalopathy in high-income countries (1). Encephalopathy related to perinatal asphyxia is about 10–20 times more common in low- and middle-income countries (LMIC) than in high-income countries. Annually, approximately 1 million neonatal deaths are caused by perinatal asphyxia in LMIC (2). However, higher incidence of perinatal sepsis, different co-morbidities, sub optimal neonatal intensive care, and lack of effective low technology cooling devices raise concerns about the use of therapeutic hypothermia in LMIC. We performed a systematic review and meta-analysis of safety and efficacy of therapeutic hypothermia after neonatal encephalopathy in LMIC.

Methods: We examined all randomised or quasi-randomised controlled trials comparing selective head or whole body cooling (initiated within six hours of birth, and continued for at least 48 hours), with standard care, in term or near term infants with neonatal encephalopathy, conducted in a LMIC. Primary outcomes were neonatal mortality and moderate or severe disability at ≥ 18 months of age. Secondary outcomes were blood stream infections, coagulopathy or thrombocytopenia requiring blood products, respiratory failure, and hypotension requiring intervention. We used standard Cochrane methodology for literature search (1995 to 2012), data extraction and analysis. Studies without a standard arm were excluded. We used random effects model for meta-analysis, and examined heterogeneity using the I2 test (RevMan version 5.1.4; Copenhagen).

Results: 12 studies (4 selective head cooling, 8 whole body cooling) were identified, 5 were excluded due to lack of control arm; thus a total of 546 babies were included in the meta-analysis. A variety of cooling devices, including ice, frozen gel packs, fans, water bottles, water circulating caps or phase changing materials were used to administer hypothermia. The neonatal mortality was similar in the cooled and standard care infants, risk ratio (RR) 0.74 (95% confidence interval (CI) 0.44 to 1.25) (Figure).

No difference in blood stream positive infections was seen RR 0.98 (95% CI 0.26 to 3.6). Data were inadequate to examine the long-term neurodevelopmental outcome or other secondary outcomes. Unlike high-income country cooling trials, most ‘in-trial’ infants had mild or moderate encephalopathy, and were not ventilated. Of note, infants were hypothermic in the standard arm for several hours after birth; conversely hyperthermia was not seen in standard care infants.

Conclusion: Therapeutic hypothermia can be effectively administered using low technology cooling devices outside the setting of a well-equipped neonatal intensive care unit. Although point estimates suggested a reduction in the neonatal mortality following selective head or whole body cooling in LMIC, this was not statistically significant. No data were available on the long-term neurodevelopmental outcomes. The differences in population co-morbidities of LMIC encephalopathic infants may have influenced the treatment effects of hypothermia. Adequately powered clinical trials are required before cooling can be considered as a therapeutic option in LMIC. One such multi-country LMIC clinical trial – HELIX (Hypothermia for Encephalopathy in Low- Income countries) is expected to start recruitment in the near future.

Corresponding author: s.thayyil@ucl.ac.uk

1. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. Edward et al: BMJ 2010;340:c363 doi:10.1136/bmj.c363
2. 4 million neonatal deaths: When? Where? Why? Joy E Lawn et al. Lancet 2005; 365: 891–900

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