**4. Discussion**

In the present study, we described the association between body temperature and regional tissue oxygenation, HR, and SpO2 of term and preterm neonates born by Caesarean Section 15 min after birth. The main findings can be summarized as follows: (i) no association between body temperature and cerebral tissue oxygenation in term and preterm infants, (ii) no association between body temperature and peripheral tissue oxygenation in term infants, (iii) a weak negative correlation between body temperature and peripheral tissue oxygenation in preterm infants, (iv) a weak positive correlation between body temperature and HR in term and preterm infants, and (v) no association between body temperature and SpO2 in term and preterm infants.

The absent association between body temperature and cerebral tissue oxygenation may be explained by the neonatal brain's autoregulation ability and by the only mild deviation of body temperature in our cohort. This assumption is supported by a recently published porcine model study, investigating the changes of cerebral autoregulation during induction of deep hypothermia [15]. A rapid induction of deep hypothermia was performed to simulate the clinical scenario of accidental hypothermia. It was demonstrated that the analyzed autoregulation indices (pressure reactivity index, oxygen reactivity index, brain tissue oxygen tension, and the cerebral oximetry index) reflected normal cerebral autoregulation and did not change until a brain temperature of 34 ◦C. Cerebral tissue oxygen saturation increased not before a brain temperature of 29 ◦C [15]. However, cerebrovascular autoregulation varies between term and preterm neonates. Pressure reactivity and autoregulation to systolic and MABP are not observed until 26 to 28 weeks of gestation due to the on-going vascular development and anatomical features of the premature cerebral vasculature [16]. The very small number of EPI in our cohort may explain the absent association between body temperature and cerebral tissue oxygen saturation.

We found a weak, but significantly negative correlation between peripheral tissue oxygen saturation and central body temperature only in preterm neonates. However, as cardiac function, blood gases (e.g., carbon dioxide), hemoglobin levels, and especially peripheral temperature all influence peripheral blood flow, tissue oxygenation, and oxygen extraction, interpretation of this finding is challenging [17]. The weak negative correlation may be explained by the fact that hyperthermia causes a higher metabolic rate, resulting in higher tissue oxygen extraction and a consequent decrease in peripheral tissue oxygen saturation. Furthermore, microvascular perfusion in preterm infants may be more affected by temperature variations than peripheral perfusion in term neonates, due to their higher body surface to weight ratio, higher heat loss by evaporation due to skin immaturity, deficiency of subcutaneous adipose tissue, and limited ability to regulate cutaneous blood flow [18,19].

Physiologically, the HR of neonates should decrease when suffering from hypothermia, at least initially [20]. Thereafter, norepinephrine gets released and the HR increases [20]. This matches our finding of a significantly positive correlation between body temperature and HR for the whole cohort as well as in preterm and term neonates individually. This was also observed in other studies [2,21], whereby Davies et al. reported the increase in HR per added degree of temperature is approximately 10 bpm based on observations in 31851 children, attending the pediatric emergency department [21]. On the other hand, we did not find a correlation between body temperature and SpO2, which was independent from gestational age. Literature about the association between body temperature and SpO2 in neonates is scarce. Mitra et al. demonstrated that SpO2 dropped briefly at the start of induced therapeutic hypothermia in neonates, but it was mostly above 95% [22]. When the body temperature was raised to 37 ◦C, SpO2 remained stable [22], suggesting no clinically relevant association between body temperature and SpO2. This was confirmed in a recent study by Wu et al., where SpO2 remained stable during the rewarming phase after induced hypothermia in neonates with hypoxic-ischemic encephalopathy [23].

Regarding our secondary aim, we observed statistically lower body temperature in preterm neonates; however, the difference was small (mean of 0.1 ◦C) and we expect that its clinical relevance is negligible. Nevertheless, preterm neonates suffered from hypothermia significantly more often compared to term neonates. There are only limited data about hypothermia in term neonates. We reported hypothermia only in 12% of term born infants, whereas Takayama et al. observed that 17% of the included healthy term born infants suffered from hypothermia 34 min after birth [6]. In contrast to term born infants, several studies have investigated body temperature in large cohorts of preterm infants. The incidence of hypothermia in preterm neonates ranged between 38–53% [9,24,25], and in EPI the incidence of hypothermia below 35.0 ◦C was found in a worrying 9.6% [25]. In contrast, Lyu et al. reported that only 12% of the investigated preterm infants had an admission temperature of below 36.0 ◦C, and only 2% had an admission temperature lower than 35.0 ◦C [3]. This suggests that temperature managemen<sup>t</sup> varies between institutions and may have a profound impact on postnatal body temperature.

We observed a distinctly lower rate of hypothermia in our cohort compared to the results of the abovementioned studies, as a body temperature of below 36.0 ◦C was only found in 4.1% of preterm infants. The highest rate of hypothermia occurred in VPI (7.9%), but even this rate is considerably lower than in other studies. Interestingly, none of the EPI had a body temperature of below 36.0 ◦C. We speculate that attention to body temperature managemen<sup>t</sup> was paid mostly to EPI and to a lesser extent to more mature preterm neonates. Only Lyu et al. published an incidence of hypothermia in preterm infants similar to our results, but it has to be acknowledged that their hypothermia thresholds were lower than ours [3]. The number of included infants, the earlier body temperature measurement, and the fact that this is a mono-centric study may explain the differences between our results and those of other studies. In the present study, all included infants were born by Caesarean section. The birth mode may have an impact on vascular reactivity, peripheral oxygenation, and thermal homeostatic mechanism. Additionally, vaginally delivered newborns often benefit from postnatal skin-to-skin contact, whereas infants born by Caesarean section are regularly placed on a resuscitation table after birth, resulting in a different body temperature management. Additionally, in all included infants, early cord clamping (<30 s) was performed. Timing of umbilical cord clamping has an impact on neonatal hemodynamics and may affect both body temperature and cerebral tissue oxygenation. Whereas studies reported no differences in cerebral tissue oxygenation six to 12 h after birth when comparing immediate and delayed cord clamping [26], Pichler et al. demonstrated that delayed cord clamping caused lower initial cerebral tissue oxygen saturation in spontaneously breathing preterm neonates compared to preterm neonates without immediate cord clamping [27,28]. Furthermore, we observed a high rate of normothermic infants and, therefore, temperature differences may have been more pronounced in other studies.

Several studies demonstrated that the number of preterm infants suffering from hypothermia could be decreased (without increasing hyperthermia rates) by using a practice plan including consistent head and torso wrapping, warmed blankets, a transwarmer mattress, and maintaining a consistent operating room temperature (between 21 ◦C and 23 ◦C) [29,30]. In consideration of our observations, we assume that our standardized postnatal temperature managemen<sup>t</sup> concept seems to be beneficial for body temperature preservation in preterm infants.

Besides hypothermia, also iatrogenic hyperthermia is a complication with detrimental neonatal outcomes [3]. Overheating can be caused by the use of plastic wraps, radiant warmers, incubators, or excessive environment heating [10,31]. Studies described hyperthermia incidences in preterm infants at admission between 1–2% [3,7,25]. In comparison to these studies, the prevalence of hyperthermia was higher in our study, ye<sup>t</sup> the difference was small. According to the WHO, we defined hyperthermia as a body temperature of above 37.5 ◦C, which is in contrast to the abovementioned studies, defining hyperthermia mostly ≥38.0 ◦C. This different definition may explain the higher rate of hyperthermia in our cohort. Nevertheless, it has to be considered that two of the included ten EPI suffered from hyperthermia. This may have been caused by the use of polyethylene bags [32,33]. However, Lenclen et al. demonstrated that a higher admission body temperature may be achieved in preterm neonates without increasing the risk for hyperthermia by using polyethylene bags [34]. Additionally, maternal fever and/or infections such as chorioamnionitis may have contributed to the rate of neonatal hyperthermia, but these data were not available in our database. Nonetheless, it should be kept in mind that excluding neonates from mothers with signs of infection would have increased the incidence of neonates suffering from hypothermia.

The use of heated humidified gases for respiratory support to avoid hypothermia in newborn infants is an important concept. A recent meta-analysis investigating heated humidified gases for respiratory support in preterm neonates during resuscitation could only include two studies [35]. Still, the authors concluded that heating and humidification of inspired gases immediately after birth improves admission temperature in preterm infants [35]. In the present study, we did not find any differences between newborn infants without respiratory support and those who received respiratory support using non-heated unconditioned gases. This raises the question whether the use of heated humidified gases offers a substantial advantage during immediate postnatal stabilization and resuscitation in a cohort of newborn infants in whom the hypothermia rate was generally low.
