Association between admission hypothermia and outcomes in very low birth weight infants in China: a multicentre prospective study

Preterm infants have difficulty maintaining body temperature after birth due to a high surface area-to-mass ratio, little subcutaneous adipose tissue, a thin stratum corneum and inadequate brown fat, especially among very low-birth weight (VLBW) infants [1, 2].

Neonatal hypothermia (temperature below 36.5 °C) is a vital risk factor for neonatal mortality and morbidity in preterm infants [3‐5]. Laptook et al. [6] reported that hypothermia increased the risk of mortality by 28% for every 1 °C drop in body temperature. In a multicentre study, Caldas et al. [7] reported that admission hypothermia (AH) was significantly associated with early neonatal death regardless of hospital performance. In Korea, Lee et al. [8] reported that 74.1% of 5860 VLBW preterm infants with a gestational age (GA) < 33 weeks and hypothermia were admitted to neonatal intensive care units (NICUs), which was associated with high mortality and several important morbidities. Wilson et al. [9] reported that hypothermia occurred in 53.4% of 5697 infants born at a GA < 32 weeks in a population-based study with samples from 11 European countries and that admission hypothermia (AH) after very preterm birth was a significant problem associated with an increased risk of early and late neonatal death. In an analysis of risks associated with AH in preterm infants in the Canadian Neonatal Network, Lyu et al. [10] showed that both hypothermia and hyperthermia were associated with increased risks of adverse outcomes. However, in China, clinical data on AH in premature infants are scarce, and most of the studies include small samples from a single centre [11].

The aim of this study was to examine the association between AH and neonatal outcomes in VLBW infants in multiple NICUs in China.

This prospective, multicentre, observational cohort study was carried out over a period of 12 months, from January 1, 2018, to December 31, 2018, in 28 NICUs in Shandong Province, China. The 28 recruited hospitals included 14 teaching hospitals and 14 non-teaching hospitals, with averages of 59 and 40 beds in the neonatology departments and NICUs, respectively.

A total of 1582 in-born infants with a BW < 1500 g and GA < 34 weeks were enrolled in the study on their day of birth; 93 infants were excluded because they were out-born. Additionally, 150 infants with redirection of intensive care and 92 infants with missing temperature data were excluded. The remaining 1247 infants were included in this analysis (Fig. 1). The final cohort had a median BW and GA of 1250 (480–1499) g and 29 (24.1–33.9) weeks, respectively.

This is the first prospective, multicentre, observational cohort study with a large sample size to investigate the association between mortality and major morbidity with hypothermia in China. Our study demonstrated that infants with hypothermia, particularly moderate/severe hypothermia, had adverse outcomes with relatively high rates of death; these findings are consistent with previous reports [20, 21]. The multivariate analysis showed that the OR of death was 4.148 for VLBW infants with moderate/severe hypothermia at NICU admission in our study. Sindhu et al. [22] reported that a reduction in an infants’ body temperature is the primary cause of 18–42% of annual infant mortality worldwide. A recent study by Tay et al. [23] reported that hypothermia at NICU admission in extremely preterm infants was independently associated with mortality. Our study showed that mortality was inversely related to admission temperature, although the relationship was not linear but rather a quadratic curve. A quadratic curve indicated that there was an admission temperature range with the lowest death rate, and hypothermia should be avoided in vulnerable VLBW infants.

The univariate and multivariate analyses showed that adverse outcomes in VLBW infants, including RDS, IVH and LOS, were associated with AH. This is consistent with the results of previous studies [24, 25]. Laptook et al. [6] reported that hypothermia increased the risk of sepsis by 11% for every 1 °C drop in body temperature. Miller et al. [26] reported that moderate/severe hypothermia significantly increased the incidence of several morbidities, including death, high-grade IVH and late-onset sepsis. Chang H-Y et al. [27] reported that hypothermia was associated with IVH and RDS. Hypothermia leads to increased oxygen consumption, which leads to hypoxemia, which in turn leads to pulmonary vasoconstriction, the reduced release of pulmonary surfactant and decreased work by respiratory muscles, increasing respiratory distress in these vulnerable preterm infants [28].

In this study, we found that the incidence of hypothermia was 88.2%. The incidence of hypothermia at admission to the NICU in VLBW preterm infants was 31–78% in previous studies [29, 30]. In a retrospective observational study, Lyu et al. [10] showed that the incidence of hypothermia was 35.6%. In Taiwan, Chang H-Y [27] reported that the incidence of hypothermia was 76.8%. Compared with the above international data, the incidence of AH in China is significantly higher. A retrospective analysis was conducted on infants born between January 1 and December 31, 2017 to determine key causes of hypothermia [14]. This study found that inadequate measures were taken to keep warm in the process of neonatal resuscitation and in-hospital transportation. In addition, medical personnel are not aware of the harm of hypothermia in preterm infants.

The results showed that AH was associated with SGA, caesarean section, intubation at DR, and a low 5-min Apgar score. Caesarean delivery may contribute to hypothermia, as operating rooms are often kept at cool temperatures to maintain a comfortable operating environment. Johannsen et al. [31] showed that a relatively high ambient temperature in the DR may also prevent hypothermia in preterm infants in addition to the above mentioned methods to stabilize body temperatures of VLBW infants. The WHO has recommended that delivery or resuscitation room temperatures be set at a minimum of 25 °C, with a suggested range of 25 ~ 28 °C [3], which, anecdotally, is not often the case. SGA is associated with a large surface area-to-body mass ratio, decreased subcutaneous fat, high body water content, and immature skin, leading to increased evaporative water and heat losses [32]; therefore, SGA was also a risk factor for AH. A low 5-min Apgar score and intubation at DR may be associated with increased resuscitation efforts, an increased resuscitation time and inadequate thermal measures [8, 33]. Therefore, heat preservation measures should be included in the management of premature infant resuscitation and the “golden hour” after birth [34].

AH was also associated with antenatal steroids. The interpretation of this variable requires special care. During the study period, prenatal use of glucocorticoids is only considered complete prenatal steroid therapy. Pregnant women at risk for preterm delivery are often associated with serious complications, for example maternal hypertension, unexplained uterus contraction. The mothers with hypertensive disorders of pregnancy may be monitored more closely and was higher rates of antenatal corticosteroid use [35]. These risk factors cause a higher incidence of asphyxia in preterm infants, leading to a statistical analysis that affected this variable. Therefore, the statistical significance of antenatal steroids has no clinical significance.

Our study had several limitations. We investigated only the incidence of hypothermia and studied the association between hypothermia and poor outcomes; we still have not conducted a quality improvement project considering VLBW infants. Based on the results of this study, our next research project will be to carry out a multicentre quality improvement project to reduce the incidence of hypothermia according to international evidence-based practices for improving quality (EPIQs).

AH is still very high in VLBW infants in NICUs in China. SGA, caesarean section, a low Apgar score at 5 min and intubation in the DR were associated with increased odds of hypothermia. Moderate/severe hypothermia was associated with mortality and poor outcomes, such as RDS, IVH, LOS.