Therapeutic hypothermia in neonatal hypoxic encephalopathy: A systematic review and meta-analysis

Abstract

Background Therapeutic hypothermia (TH) is regarded as the most efficacious therapy for neonatal hypoxic encephalopathy. However, limitations in previous systematic reviews and the publication of new data necessitate updating the evidence. We conducted this up-to-date systematic review to evaluate the effects of TH in neonatal encephalopathy on clinical outcomes. Methods In this systematic review and meta-analysis, we searched Medline, Cochrane Library, Embase, LIVIVO, Web of Science, Scopus, CINAHL, major trial registries, and grey literature (from inception to October 31, 2021), for randomized controlled trials (RCT) comparing TH vs normothermia in neonatal encephalopathy. We included RCTs enrolling neonates (gestation ≥35 weeks) with perinatal asphyxia and encephalopathy, who received either TH (temperature ≤34°C) initiated within 6 hours of birth for ≥48 hours, vs no cooling. We excluded non-RCTs, those with delayed cooling, or cooling to >34°C. Two authors independently appraised risk-of-bias and extracted data on mortality and neurologic disability at four time points: neonatal (from randomization to discharge/death), infancy (18-24 months), childhood (5-10 years), and long-term (>10 years). Other outcomes included seizures, EEG abnormalities, and MRI findings. Summary data from published RCTs were pooled through fixed-effect meta-analysis. Results We identified 36 863 citations and included 39 publications representing 29 RCTs with 2926 participants. Thirteen studies each had low, moderate, and high risk-of-bias. The pooled risk ratios (95% confidence interval, CI) were as follows: neonatal mortality: 0.87 (95% CI = 0.75, 1.00), n = 2434, I 2 = 38%; mortality at 18-24 months: 0.88 (95% CI = 0.78, 1.01), n = 2042, I 2 = 51%; mortality at 5-10 years: 0.81 (95% CI = 0.62, 1.04), n = 515, I 2 = 59%; disability at 18-24 months: 0.62 (95% CI = 0.52, 0.75), n = 1440, I 2 = 26%; disability at 5-10 years: 0.68 (95% CI = 0.52, 0.90), n = 442, I 2 = 3%; mortality or disability at 18-24 months: 0.78 (95% CI = 0.72, 0.86), n = 1914, I 2 = 54%; cerebral palsy at 18-24 months: 0.63 (95% CI = 0.50, 0.78), n = 1136, I 2 = 39%; and childhood cerebral palsy: 0.63 (95% CI = 0.46, 0.85), n = 449, I 2 = 0%. Some outcomes showed significant differences by study-setting; the risk ratio (95% CI) for mortality at 18-24 months was 0.79 (95% CI = 0.66,0.93), n = 1212, I 2 = 7% in high-income countries, 0.67 (95% CI = 0.41, 1.09), n = 276, I 2 = 0% in upper-middle-income countries, and 1.18 (95% CI = 0.94, 1.47), n = ...

Organizational factors associated with delayed therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: the LyTONEPAL cohort

“…Although the initiation of the LyTONEPAL cohort preceded the main publications on the impact of TH on mild HIE [21], our study identi ed an overall rate of 36.5%, 32.6%, 44.3% and 17.6% of neonates with a rst pH ≥ 7.0, rst lactate levels < 11.0 mMol/L, Apgar score ≥ 5 at 5 min, and resuscitation at birth with at least mask ventilation, respectively. This nding is in line with the actual concerns of the temporal change of recorded severity of HIE in cooled babies [20,22].…”

Therapeutic hypothermia for encephalopathic newborns with congenital heart defect: A cross-sectional survey on current practices and opinions in Germany

“…In contrast, practices and opinions vary widely regarding infants with severe CHD. Although only few cases of neonates with severe CHD treated with TH have been published, and infants with (major) congenital anomalies have been excluded in many randomized trials on TH, even neonates with severe CHD are offered TH in a variety of clinical scenarios in some centers ( 9 , 12 , 23 ). Almost one-third of departments offer TH after perinatal asphyxia in neonates with severe CHD, but when asked for their personal opinion, only 20.3% of the respondents opposed TH.…”

“…A 2018 survey of cooling centers in the United Kingdam found that a large number of centers offer TH to neonates with only mild HIE ( 28 ). It appears that TH is increasingly being used in neonates with indications other than those on which randomized trials of TH are based ( 2 , 9 ). This may be due to the fact that TH is the only therapeutic intervention for NE with beneficial neurologic outcomes to date, although this effect has been proven only in neonates with NE secondary to an intrapartum asphyxia event ( 2 , 29 ).…”

“…Most randomized controlled trials comparing TH vs. normothermia in NE have excluded newborns with major congenital malformations, including congenital heart defects (CHD) ( 9 ). The official guideline of the German-based Society for Neonatology and Pediatric Intensive Care Medicine (GNPI) recommends rejection of TH for perinatal asphyxial HIE in newborns with severe congenital malformations ( 10 ).…”

Characteristics and Outcomes of Neonates With Intrapartum Asphyxia Managed With Therapeutic Hypothermia in a Public Tertiary Hospital in South Africa

“…Matthew et al concluded that effects of TH on mortality are uncertain but that one cannot deny the protective effect on neurodevelopmental outcomes seen in survivors and recommend that further studies be conducted in diverse settings. (17) There are limited studies reporting on effect of TH in sub-Saharan Africa. A small randomized clinical trial from Uganda reported a high mortality in neonates managed with TH compared to those receiving standard care (33% vs 6.7%) (18).…”