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Complex medical intervention does not imply effectiveness: contrasting results of two recent multi-country intervention trials WHO immediate kangaroo mother care and HELIX therapeutic hypothermia

Nearly half of all the global underfive deaths take place during the neonatal period and 99% of them are in lowincome and middleincome countries (LMICs). Preterm birth complications and neonatal encephalopathy account for majority of these deaths. Two recent multicountry randomised clinical trials to evaluate interventions to reduce these deaths have major implications on neonatal care in LMICs. First, a WHO study investigated the impact of immediate kangaroo mother care (iKMC) on survival of low birth weight neonates weighing 1000–1799 g. In the intervention arm, neonatal intensive care units (NICUs) were redesigned for a familycentred care allowing treatment of neonates in zero separation from mother or a surrogate during the NICU stay. In the control arm, neonates received care as usual in an incubator with mothers giving brief KMC sessions at earliest 24 hours from birth. Neonates from both groups were moved to a usual KMC ward once deemed sufficiently stable for at least 24 hours. Median duration of the NICU stay was 6.4 days in both groups and during this time median daily skintoskin contact in the iKMC group was 16.9 hours and in the usual care group 1.5 hours. Neonates in the iKMC group had 25% reduction in the risk of 28day (neonatal death) compared with the control arm (12.0% vs 15.7%, risk ratio (RR) 0.75; 95% CI 0.64 to 0.89). Cochrane’s systematic review has shown that low birth weight neonates cared with KMC after stabilisation of some days to weeks have better survival and lower rates of sepsis and hypothermia compared with usual care in incubators. WHO iKMC trial found that even lower rate of suspected sepsis (RR 0.82; 95% CI 0.73 to 0.93) and episodes of hypothermia (RR 0.65; 95% CI 0.51 to 0.83) can be achieved with iKMC compared with the usual care. The second trial, HELIX, investigated the effect of therapeutic hypothermia in term or nearterm postasphyxiated neonates with neonatal encephalopathy comparing it with usual NICU care with normothermia. The study showed that cooling was potentially dangerous with 1.35 times higher risk of death during the first 18 months of life in the intervention group compared with usual care group (RR 1.35; 95% CI 1.04 to 1.76) and found that cooling was inefficient for neuroprotection (RR 1.06; 95% CI 0.87 to 1.30; p=0.55 for the main outcome of death or moderate to severe disability at 18–22 months). The HELIX study aimed to provide definitive evidence on a technologybased intervention in LMIC setting with highest burden of disease. Therapeutic hypothermia was provided using state of the art servocontrolled whole body cooling device with excellent safety record in highincome trials. All participating centres had consultants with previous experience in cooling and protocol violations were exceptionally few. Only major difference from highincome practice was not requiring a blood sample to confirm acidosis. However, cord blood samples in those 10% of neonates that did undergo testing indicated severe acidosis and all neonates were moderately or severely encephalopathic in a clinical examination performed by certified evaluators. Most neonates underwent MRI during hospitalisation and the followup using Bayley III test achieved 97% coverage. Cooled neonates fared worse across all sites and in several secondary outcomes. Importantly, they also had no better disabilityfree survival than the usual care group. The HELIX results are likely to be contested as cooling has become the standard of care in many LMIC NICUs with majority of previous randomised controlled trials and observational studies showing good safety record. Even the International Liaison Committee on Resuscitation guidelines 2020 had cautiously recommend cooling in LMICs. However, few of the previous trials were powered to detect differences in death and neurodevelopmental disability. Nor were they conducted with the same rigour as the HELIX trial. The reported results of the HELIX study give little information as to why cooling did not work as expected. The two groups were similar at baseline except somewhat higher rate of sentinel events and lower rate of caesarean sections in the control group. The proportion of infants with cultureconfirmed sepsis was no higher than in the highincome trials, whereby the mechanism of inflammation is unlikely to explain the observed lack of neuroprotection. Sentinel events were quite rare overall, most neonates had seizures within 6 hours of birth and white matter injury was much more prevalent than basal ganglia injury on MRI. All these findings suggest a prolonged hypoxia that could have been compounded by a poor intrapartum care during difficult deliveries. As therapeutic hypothermia is based on slowing down brain metabolism during latent phase 6 to 72 hours after a hypoxicischaemic event, it will be less effective for subacute injuries. More than twothirds of the neonates were born outside the cooling centres. Cooling was started at median age of 4.3 hours and while time to achieving target temperature was not reported, in figure 2B it appears that this took place at around 5 to 6 hours from randomisation and thus beyond the optimal window of opportunity. Lastly, it is also possible that supportive care provided in these public hospitals was not up to the standard required for safe management of hypothermia. Further research is needed to clarify any populationlevel differences in cooling outcomes and centres already practicing therapeutic hypothermia should evaluate their practices. Prevention of intrapartumrelated neonatal encephalopathy by improving delivery care and optimising neonatal resuscitation are currently the best ways of helping term and nearterm neonates at risk of brain injury in LMICs. Department of Women’s and Children’s Health, Uppsala Universitet, Uppsala, Sweden