Table 1.

Characteristics of the included studies

No.	Trials (n = 29)	Publications (n = 39)	Country	Inclusion criteria	Exclusion criteria	Number randomized		Type of cooling and method	Site of temperature measurement	Target temperature (°C)
						TH	Control			TH	Control
1	Akisu	Akisu 2003 [32]	Turkey	5 min AS<6; cord blood or arterial pH 7.1 or BD>10 mmol/l; encephalopathy (stupor, hypotonia, abnormal neonatal reflexes)	Metabolic disorders, congenital malformations, chromosomal abnormalities, congenital infection, transitory drug depression	11	10	SHC (cooling caps)	EAC; rectal	33.0-33.5	36.0-36.5
2	Battin	Battin 2001 [34]*, Battin 2003 [63]†	New Zealand	GA≥37 wk; 5 min AS≤6 or cord/first arterial pH≤7.09; encephalopathy (lethargy/stupor, hypotonia, abnormal reflexes)	Major congenital abnormalities	25	15	SHC (cooling caps)	rectal	36.5-36 (n = 6); 35.9-35.5 (n = 6); 35.0 ± 0.5 (n = 6); 34.5 ± 0.5 (n = 7)	37.0 ± 0.2
3	Bharadwaj	Bharadwaj 2012 [35]	India	GA>37 wk with HIE; ABG pH≤7 or BE≥-12 meq within 1st h and also fulfilling any two of, AS≤6 at 10 min; evidence of fetal distress; assisted ventilation for at least 10 min after birth; evidence of any organ dysfunction; and history of acute perinatal event with evidence of encephalopathy	Age >6 h, major congenital anomalies, if the infant did not establish spontaneous respiration by 20 min after birth, out-born babies	65	65	WBC (gel packs)	rectal	33.0-34.0	36.5
4	Bhat	Bhat 2006 [36]	India	NA	NA	20	15	WBC (not mentioned)	rectal, skin	33.5	NA
5	Catherine	Catherine 2020 [38]	India	pH≤7 or BD≤12 meq in cord blood; AS≤6 at 10 min, any clinical evidence of fetal distress, requiring assisted ventilation for at least 10 min after delivery, and any evidence of one or more organ dysfunction	Age >6 h, out-born babies, major congenital abnormalities, no spontaneous respiratory efforts by 20 min following delivery	78	84	WBC (phase changing material)	rectal	33.5 ± 0.5	36.5
6	Chen	Chen 2018 [39]	China	NA	NA	20	20	SHC (not mentioned)	rectal	34.5-35.0	NA
7	CoolCap Trial	Gluckman 2005 [29]	USA	AS≤5 at 10 min after birth; need for resuscitation at 10 min after birth; or severe acidosis (pH<7.00 or BD≥16 mmol/l in cord, arterial or venous sample within 60min of birth)	Age >5.5 h, prophylactic high-dose anticonvulsants, major congenital abnormalities, head trauma causing major intracranial hemorrhage, severe growth restriction, BW<1800 g, infants judged critically ill, unavailability of essential equipment, planned concurrent participation in other experimental treatments	116	118	SHC (cooling caps)	rectal	34.0-35.0	36.8-37.2
8	Eicher	Eicher 2005 [41]	USA	GA≥35 wk, BW 2000 g, hypoxic-ischemic insult, with one clinical sign & two neurologic findings of hypoxia-ischemia, cord pH 7.0 or BD 13, initial infant pH 7.1, AS 5 at 10 min, continued resuscitation after 5 min, fetal bradycardia with HR 80/min lasting 15 min, or postnatal hypoxic ischemic event with oxygen desaturation 70% or arterial oxygen tension 35 mm Hg for 20 min with evidence of ischemia	Clinical sepsis, maternal chorioamnionitis, weight or head circumference <10th percentile for gestation age, or congenital abnormalities	32	33	WBC (cooling blanket)	rectal	33.0 ± 0.5	37.0 ± 0.5
9	El Shimi	El Shimi 2014 [57]	Egypt	pH≤7.0 or BD≥16 mmol/l in cord or any blood during 1st h after birth. If pH 7.01-7.15, BD 10.0-15.9 mmol/l, or blood gas unavailable, additional criteria viz. acute perinatal event (late or variable decelerations, cord prolapse, cord rupture, uterine rupture, maternal trauma, hemorrhage, or cardiorespiratory arrest) and either 10 min AS≤5 or assisted ventilation initiated at birth and continued for >10 min	Major congenital anomalies, severe growth restriction (BW 1800g), presence of an infectious cause, suspected inborn error of metabolism, age >6 h	10	10	WBC (cool packs)	rectal	33.0-34.0	NA
10	HELIX trial	Thayyil 2021 [10]	India, Sri Lanka, Bangladesh	GA≥37 wk, BW≥1kg, need for resuscitation at 5 min of age or AS<6 at 5 min of age (for babies born in hospital), or both, or absence of crying by 5 min of age (for babies born at home); and evidence of moderate or severe encephalopathy between 1-6 h of age	No heart rate at 10 min of age despite adequate resuscitation, with major life-threatening congenital malformations	202	206	WBC (servo-controlled cooling device)	rectal	33.5 ± 0.10	36.7 ± 0.06
11	ICE trial	Jacobs 2011 [26], Cheong 2012 [40]	Australia, New Zealand, Canada, USA	GA≥35 wk, age <6 h, moderate or severe encephalopathy and indicators of peripartum hypoxia-ischemia (≥2 of the following, AS≤5 at 10 min, continued need for mechanical ventilation at 10 min, and/or metabolic acidosis (cord, arterial or venous pH<7.00; or BD≥12 within 60 min of birth)	Age >6 h, BW<2 kg, major congenital abnormalities, bleeding, >80% inspired oxygen, imminent death, TH before assessment	110	111	WBC (gel packs)	rectal	33.0-34.0	37.0
12	Inder	Inder 2004 [43]	Australia	GA≥35 with intrapartum hypoxia-ischemia comprising at least two of, AS≤5 at 10 min; ongoing resuscitation at 10 min; and metabolic acidosis (cord pH≤7 or BD≥12 mmol/l or more within 60 min of life) combined with clinical evidence of encephalopathy	NA	13	14	WBC (cool packs)	rectal	33.0-34.0	36.8-37.3
13	Jose	Jose 2018 [44]	India	Moderate or severe encephalopathy within 6 h after birth after an acute perinatal event, with acidosis or resuscitation	NA	77	79	WBC (not mentioned)	NA	33.0	NA
14	Joy	Joy 2012 [45]	India	GA≥37 wk with cord or peripheral blood pH≤7 or BD≥12 mEq within 1 h with evidence of encephalopathy and with any two of, AS at 10 min ≤5; assisted ventilation for at least ≥10 min after birth; evidence of any organ dysfunction; history of acute perinatal event (intrapartum fetal distress, cord prolapse, placental abruption, uterine rupture, maternal trauma, or cardiac arrest)	Age >6 h, major congenital abnormalities; no spontaneous respiration by 20 min, out-born babies	58	58	WBC (gel packs)	rectal	33.0-34.0	36.5
15	Li	Li 2009 [46]	China	GA≥37 wk; BW>2500 g, admitted to NICU within 10 h$$ history of asphyxia (AS at 5 min ≤5 with ABG pH<7.1 or BD>16 mmol/l within 1h birth); clinical evidence of encephalopathy	Major congenital abnormalities; head trauma; skull fracture; enrollment >10 h after birth	46	47	WBC (cooling mattress)	rectal	33.0-34.5	37.0
16	Lin	Lin 2006 [47]	China	GA≥37 wk; AS at 5 min <6 with postnatal ABG pH<7.1 or BD>15 mEq/l; signs of postpartum encephalopathy (decreased muscle tone, lethargy, coma, or seizures within 6 h after birth)	Major congenital abnormalities; prolonged hypoxemia due to severe persistent fetal circulation	32	30	SHC (cooling caps)	rectal; NP	34.5 ± 0.5 (rectal); 34.4 ± 0.5 (NP)	37.1 ± 0.5 (rectal); 36.8 ± 0.5 (NP)
17	neo.nEURO.network trial	Simbruner 2010 [58]	Germany	AS 5, or continued need for resuscitation at 10 min after birth, cord or any arterial pH 7.00 within 1 h after birth, BD 16 mmol/l, encephalopathy (lethargy, stupor, or coma and one of the following, hypotonia, abnormal reflexes, absent or weak suck), clinical seizures and abnormal standard EEG or aEEG findings	Age >5.5 h, high-dose anticonvulsant therapy, BW 1800 g or GA 36 wk, head circumference <3rd percentile, major congenital malformations with poor developmental prognosis, Imperforate anus gross hemorrhage, infant “in extremis”	64	65	WBC (cooling blanket)	rectal	33.0-34.0	36.5-37.5
18	NEST study	Field 2013 [42]	UK	Standard criteria for ECMO eligibility based on the clinical decision of the local ECMO team	Congenital diaphragmatic hernia, post-cardiac surgery, any therapeutic cooling before randomization	56	55	WBC (heat exchanger in the ECMO circuit)	rectal	34.0	37.0
19	NICHD trial	Shankaran 2005 [27],Shankaran 2008 [54], Shankaran 2012 [55], Shankaran 2012a [56],	USA	Cord or any blood pH≤7.0 or BD≥16 mmol/l during 1st h after birth. If pH 7.01-7.15, BD 10.0-15.9 mmol/l, or blood gas unavailable, additional criteria applied viz. acute perinatal event (late or variable decelerations, cord prolapse, cord rupture, uterine rupture, maternal trauma, hemorrhage, or cardiorespiratory arrest) and either 10 min AS≤5 or assisted ventilation initiated at birth and continued for at least 10 min	Age >6 h, major congenital abnormality, severe growth restriction (BW≤1800 g), refusal of consent by a parent or attending neonatologist; moribund infants	102	106	WBC (cooling blanket)	esophageal	33.5	36.0-37.0
20	Rakesh	Rakesh 2017 [49]	India	GA≥37 wk, cord or arterial blood pH≤7 or BD≥12 meq within 1st h, encephalopathy (Sarnat and Sarnat staging)	Age >6 h; major congenital abnormalities, absent spontaneous respiratory efforts by 20min after birth; out-born babies	60	60	WBC (phase) changing material)	rectal	33.0-34.0	NA
21	Robertson	Robertson 2008 [50]	Uganda	GA≥37 wk, need for resuscitation, and/or AS<6 at 5 min plus abnormal neurological assessment (>5 on Thompson score) from 30 min to 3 h after birth	Apnea or cyanosis, absent cardiac output for >10 min after birth, BW<2 kg	21	15	WBC (cooling mattress)	rectal	33.0-34.0	36.5
22	Shankaran	Shankaran 2002 [53]	USA	Cord or any blood pH within 1st h 7.0 or BD 16 mEq/l. If blood gas unavailable or pH at 1h 7.01-7.15 or BD 10.0-15.9 mEq/l, additional history of acute perinatal event and either AS = 5 at 10 min or continued need for ventilation initiated at birth and continued for at least 10 min	Age >6 h, chromosomal abnormality, major congenital anomaly, severe growth restriction (BW 1800 g), infant unlikely to survive, and parent or attending neonatologist refusal of consent	9	10	WBC (cooling blanket)	oesophageal	34.5	36.5
23	Sun	Sun 2012 [59]	China	AS<3 at 1 min and <5 at 5 min; pH<7; BD≤16 mmol/l; HIE	Major congenital abnormalities, infection on admission, severe anemia, other encephalopathy	23	28	SHC (cooling caps)	rectal	34.5-35.0	36-37.5
24	Tanigasalam	Tanigasalam 2015 [60]	India	Encephalopathy, pH 7 or BD 12meq in cord blood and fulfilling any two of, AS≤5 at 10 min of life, evidence of fetal distress, assisted ventilation for at least 10 min after birth, evidence of any organ dysfunction	Age >6 h, out-born babies, major congenital abnormalities, no spontaneous respiratory efforts by 20 min after birth or history of maternal renal failure	60	60	WBC (gel packs)	rectal	33.0-34.0	36.5
25	Thayyil	Thayyil 2013 [28]	India	Age ≤6 h, NE with Thompsons encephalopathy score >5	NA	17	16	WBC (phase changing material)	rectal	33.5	36.4
26	THIN study	Aker 2019 [31]	India	GA≥36 wk, BW>1800 g, age <5 h, perinatal asphyxia (umbilical cord or 1st h pH<7.0 or BD≥12), 5 min AS≤5, or need of PPV≥10 min at birth	Major congenital anomalies or imminent death anticipated	25	25	WBC (phase changing material)	rectal	33.5 ± 0.5	37.0 ± 0.5
27	TOBY trial	Azzopardi 2009 [30], Azzopardi 2014 [33], Campbell 2018 [37], Perrone 2010 [48], Roka 2011 [51], Rutherford 2010 [52]	UK	GA≥36 wk, at 10 min after birth, either AS≤5 or continued need for resuscitation or, within 60 min after birth, acidosis (umbilical-cord, arterial, or capillary pH<7.00 or BD≥16mmol/l); moderate-to-severe encephalopathy (lethargy, stupor, or coma) and either hypotonia, abnormal reflexes, absent or weak suck, or clinical seizures; abnormal background activity for ≥30 min or seizures (on aEEG)	Age >6 h, major congenital abnormalities that required surgery or were suggestive of chromosomal anomaly or syndromes that involve brain dysgenesis	163	162	WBC (cooling blanket)	rectal	33.0-34.0	37.0 ± 0.2
28	Yang	Yang 2020 [61]	China	Age <6 h; GA 37 wk and BW 2500 g; 1 min AS 3 and 5 min AS 5	Convulsions caused by electrolyte disorder, intracranial hemorrhage, brain injury caused by intrauterine infection, genetic and metabolic diseases, other congenital diseases; congenital malformation or congenital metabolic abnormality; suspicion of prenatal and intrapartum infection	62	30	SHC (cooling caps)	NA	28.0-30.0 (head skin temp); 34.5 ± 0.5 (body surface skin); 35.5 ± 0.5 (anal temp)	NA
29	Zhou	Zhou 2010 [62]	China	Age <6 h, GA 37 wk, BW 2500 g, with clinical evidence of perinatal hypoxia-ischemia or diagnosis of encephalopathy. AS≤3 at 1 min and ≤5 at 5 min; cord blood pH<7.0 or BD≤16 mmol/l; and need for resuscitation or ventilation at 5 min of age	Major congenital abnormalities; infection; other encephalopathy, severe anemia	138	118	SHC (cooling caps)	NP; rectal	34.0 ± 0.2 (NP); 34.5-35.0 (rectal)	36.0-37.5 (rectal)

EAC – external auditory canal, ECMO – extracorporeal membrane oxygenation, HELIX – hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries, HIE – hypoxic ischemic encephalopathy, HT – hypothermia, ICE – The Infant Cooling Evaluation, NA – not reported, NE – neonatal encephalopathy, NEST – neonatal ECMO Study of Temperature, NICHD – National Institute of Child Health and Human Development, NP – nasopharyngeal, SHC – selective head cooling, WBC – Whole body cooling, THIN – Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy in India, TOBY – Total Body Hypothermia for Neonatal Encephalopathy Trial, wk – weeks

*In this trial, TH group had 4 subgroups with cooling to 36.5-36°C (n = 6): 35.9-35.5°C (n = 6): 35 ± 0.5°C (n = 6): 34.5 ± 0.5°C (n = 7). Only those with cooling to 34.5 ± 0.5°C were eligible for inclusion in this systematic review. The median time of initiation of intervention was within 4 hours of birth in the TH group; and 4.5 hours after birth in the control group.

†This study is the same as the Battin 2001 trial, however in this study data for TH group included participants cooled to temperature 35.0 ± 0.5°C (n = 6); or 34.5 ± 0.5°C (n = 7). Although, the latter conformed to the inclusion criteria of this review, outcome data could not be extracted separately for this group. Therefore, data from this study was unusable for meta-analysis.