Letter in response to the article: “Therapeutic hypothermia for neonatal encephalopathy in developing countries: Current evidence”

We read with interest the paper "Therapeutic hypothermia for neonatal encephalopathy in developing countries: Current evidence" by Deepak Chawla.1Chawla D. Therapeutic hypothermia for neonatal encephalopathy in developing countries: current evidence.Clin Epidemiol Global Health. 2024/03/01/2024; 26101507https://doi.org/10.1016/j.cegh.2024.101507Abstract Full Text Full Text PDF Scopus (0) Google Scholar However, we have some critical observations. First, we were worried to see that data on mortality before discharge reported in the THIN study were misinterpreted. This was especially disappointing as the review that this paper relies on, has quoted the THIN study data correctly.2Mathew J.L. Kaur N. Dsouza J.M. Therapeutic hypothermia in neonatal hypoxic encephalopathy: a systematic review and meta-analysis.J Glob Health. 2022; 1204030https://doi.org/10.7189/jogh.12.04030Crossref Google Scholar The number of deaths before discharge was five in the control group and not one as reported in the forest plots.1Chawla D. Therapeutic hypothermia for neonatal encephalopathy in developing countries: current evidence.Clin Epidemiol Global Health. 2024/03/01/2024; 26101507https://doi.org/10.1016/j.cegh.2024.101507Abstract Full Text Full Text PDF Scopus (0) Google Scholar,3Aker K. Stoen R. Eikenes L. et al.Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN study): a randomised controlled trial.Arch Dis Child Fetal Neonatal Ed. Jul 2020; 105: 405-411https://doi.org/10.1136/archdischild-2019-317311Crossref Scopus (26) Google Scholar Though we report outcomes at 18–24 months of age in the second paper of the THIN study, this has not been included in the article by Chawla. We request the author to correct the forest plots using the correct published data from the THIN study. Second, the motivation for the publication of this paper is unclear. The author states: "We planned to update the most recent systematic review by including the newly published studies". However, no recent randomized controlled trials are included compared to the review by Mathew et al.2Mathew J.L. Kaur N. Dsouza J.M. Therapeutic hypothermia in neonatal hypoxic encephalopathy: a systematic review and meta-analysis.J Glob Health. 2022; 1204030https://doi.org/10.7189/jogh.12.04030Crossref Google Scholar Two additional studies are included, one (Gane, 2014) from the same center in India as four other trials with partly overlapping recruitment periods, though reported as separate cohorts. The other (Gunn, 1998) is a safety study with randomization of 22 infants to normothermia or cooling to 36.0–36.5 °C or 35.5–35.9 °C and hardly relevant for the current discussion about cooling in low- and middle-income countries (LMIC). Ten studies included in the same review2Mathew J.L. Kaur N. Dsouza J.M. Therapeutic hypothermia in neonatal hypoxic encephalopathy: a systematic review and meta-analysis.J Glob Health. 2022; 1204030https://doi.org/10.7189/jogh.12.04030Crossref Google Scholar are not included in the present paper with no explanation as to why. Thirdly, the author has tried to look at some factors (cord pH, proportion of outborns, severity of HIE and admission temperature) that could explain why results from LMIC differ from high-income countries (HIC) by performing sub-group analysis. However, while Chawla has divided the studies into LMIC vs HIC for the inclusion of outborns, HIC and LMIC are combined when looking at cord pH. As stated, the increased mortality with admission temperature <36 °C was due to the HELIX trial contributing to 92.6% of the pooled data and does not truly reflect that admission temperature impacts mortality. Also, it should not come as a surprise that a higher proportion of severe HIE will be associated with more poor outcomes, and it is unclear why the author looked at the correlation of the severity of HIE with mortality. The study by Chawla only adds confusion to the very important discussion about how infants with HIE in LMIC can benefit from cooling. We support the conclusion by Mathew et al.2Mathew J.L. Kaur N. Dsouza J.M. Therapeutic hypothermia in neonatal hypoxic encephalopathy: a systematic review and meta-analysis.J Glob Health. 2022; 1204030https://doi.org/10.7189/jogh.12.04030Crossref Google Scholar that more large-scale trials on cooling would be expensive in both time and resources, and we suggest that it may even be unethical. Selection of patients for optimal safety as well as efficacy of cooling is a challenge in all settings and needs to be further studied. The important question is what level of supportive care is needed for cooling to be safe and effective so that guidelines for facilities providing cooling can be developed. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Niranjan Thomas has patent #1796/DEL/2013 Life cradle device for inducing neonatal hypothermia issued issued to Niranjan Thomas. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.