Thermoregulation: Advances in Preterm Infants

1. Thermoregulation of preterm infants is often overlooked, precipitating hypothermia.

2. Clinicians should understand the morbidities and the mortality associated with hypothermia in preterm infants.

3. Clinicians should be able to plan appropriate management to prevent hypothermia after birth and beyond.

After completing this article, readers should be able to:

1. Describe the mechanisms of heat production and heat loss in neonates, and why preterm infants are more susceptible.

2. Identify the conditions leading to hypothermia in preterm infants and its consequences.

3. Recognize the different ways of preventing hypothermia in preterm neonates.

Newborns must undergo many adaptations after delivery to adjust to extrauterine life. One of the paramount adjustments is the need to rapidly increase body temperature, and strive to accommodate to an environment colder than that of the prenatal milieu. The temperature of a fetus is 0.9°F (0.5°C) above the maternal temperature but within a few minutes after birth, the neonatal core temperature begins to fall. (1) Keeping newborns warm, especially preterm infants, can be challenging. Preterm infants can be characterized as inefficient homeotherms. Although they do have an initial appropriate response to a decrease in environmental temperatures, the effect is limited, placing the preterm infant at high risk for hypothermia with all of its associated complications.

Budin (2) and Silverman, pioneers in the field of neonatology, had observed significant mortality among low-birthweight infants who were hypothermic on admission to the nursery and in the first few days after birth. (3) They noted a striking improvement in survival rates if infants were cared for in warm environments, especially in the first 5 days after birth. Budin found a significant difference in mortality based on the temperature of newborns at the time of admission to the NICU. In this study, the mortality rate in neonates weighing less than 2,000 g was as high as 98% if their admission temperature was less than 89.6°F (32°C); 90% if the admission temperatures were between 89.6°F and 95°F (between 32°C and 35°C); and decreased to 23% if temperatures were maintained above 95°F (35°C). More recent studies have reported that each decrease in admission temperature by 1°C below 36°C is associated with a mortality increase of 28%. (4) As a result of this association, admission temperatures have become an integral component of the mortality prediction scores, such as the Clinical Risk Index for Babies and Score for Neonatal Acute Physiology. Hypothermia after delivery is also associated with an increased risk of respiratory distress syndrome, hypoglycemia, pulmonary hemorrhage, and sepsis.

The World Health Organization and other scientific organizations have recommended that axillary temperature be maintained between 97.7°F and 99.5°F (between 36.5°C and 37.5°C) among newborns. (5)(6) The American Academy of Pediatrics advocates for a goal temperature of 97.7°F (36.5°C) for preterm infants during resuscitation because they are prone to both hypothermia (while being dried) and hyperthermia (when resuscitated in plastic wraps along with exothermic mattresses). (7) However, despite recent advances and breakthroughs, neonatal hypothermia continues to be a significant challenge, especially in the extremely preterm population. Extreme preterm births constitute about 1% of all live births but comprise almost half of all infant deaths. (8) At the turn of the century, landmark studies revealed that as many as 40% of extremely preterm infants had temperatures less than 95°F (35°C) at the time of NICU admission. (9)(10) Recent innovations notwithstanding, an organized approach needs to be taken to reduce the burden of hypothermia.

The fetus has limited capability of regulating its own temperature. The fetus has an elevated metabolic rate, almost twice that of the pregnant woman. At equilibrium, the fetus’ temperature is 0.9°F (0.5°C) higher than that of its mother. Thus, the net flow of heat is from the fetus to the pregnant woman, mostly through the placenta, and to some extent, through the skin. (11)

Newborns of most mammalian species are unique. They are unable to shiver in cold environments, though they show an increase in oxygen consumption as well as heat production. After birth, with the rapid fall in surrounding temperatures, a newborn must rely primarily on nonshivering mechanisms to maintain body temperature. This contrasts with adults, in whom shivering provides a mode of heat production. Nonshivering mechanisms involve chemical thermogenesis, which depends on brown fat.

During the initial neonatal response to cool external temperatures, thermoreceptors on the newborn’s skin are stimulated, initiating nonshivering thermogenesis. Norepinephrine is released from the abundant nerves of the brown fat, resulting in vasoconstriction and increased metabolism. Simultaneously, stimulation of sympathetic pathways induces a surge in thyrotropin that leads to release of thyroxine (T4) and triiodothyronine (T3). T3 causes upregulation of the uncoupling protein called thermogenin that causes the uncoupling of mitochondrial oxidation and phosphorylation. Thermogenin, similar to norepinephrine, acts on brown fat to initiate chemical thermogenesis, and heat is produced by fatty acid oxidation and uncoupling of adenosine triphosphate formation. Thus, in contrast to white fat, the energy that is generated by brown fat cannot be stored but instead is used to increase the newborn’s body temperature.

Brown fat is highly vascularized, almost 4 to 6 times more than white fat, with many mitochondria, lipid molecules, and numerous capillaries that lead to the characteristic “brown” color. Brown fat is found in the neck, axilla, intrascapular regions, and the mediastinum surrounding the vasculature and major organs, as well as near the kidneys and adrenal glands. Brown fat may be present as early as 25 weeks of gestation and disappears by 9 months of age. Brown fat constitutes about 1% to 2% of body weight in a preterm infant and term infants have the most amount of brown fat, constituting 4% of their body weight. When brown fat is metabolized, the heat that is produced warms the organs and blood directly, leading to an elevation in body temperature. Brown fat is ultimately converted to glucose and oxygen. Once brown fat is depleted, it cannot be replaced. (11)(12)(13)(14)(15)(16)

Compared with term infants, preterm infants are at higher risk for hypothermia because of several unique characteristics (Table 1). Preterm infants can only maintain core temperatures in a narrow range of environmental temperatures. They have a greater ratio of skin surface to body weight, almost 4 times that of adults, compared with term infants, who have a ratio 3 times that of adults. This larger skin surface area leads to more radiant heat loss and eventually, more insensible losses. Transepidermal water loss varies inversely with the gestational age; preterm infants can lose as much as 15 times more water per kilogram of body weight compared with term neonates. Because sweat glands are not functional in preterm infants, vasodilation is inefficient. (3)

Brown fat may not be well-developed until 26 to 30 weeks of gestation. Even the usual surge observed in the thyrotropin levels after birth is low, especially in infants born before 30 weeks of gestation. Hypoxemia is also known to impair brown fat metabolism, and because many preterm infants have a delay in transition, hypothermia risk is greater. (17)(18)(19)

There is a close association among temperature maintenance, oxygen consumption, and glucose utilization. (18)(19) Cold stress leads to increased oxygen consumption, which can result in tissue hypoxia and metabolic acidosis. Metabolic acidosis can, in turn, inhibit the formation of surfactant. The norepinephrine that is released from brown fat can cause systemic and pulmonary vasoconstriction. Pulmonary vasoconstriction can lead to increased pulmonary vascular resistance with decreased oxygen delivery to the cells and tissues. Hypothermia can lead to increased glucose consumption, and can result in exhaustion of glycogen stores. Increased insensible heat loss can lead to dehydration, fluid electrolyte imbalance, hypotension, irritability, and poor feeding. Untreated hypothermia eventually leads to altered physiology and may cause seizure activity or even death. To prevent these morbidities, it is imperative to recognize cold stress as soon as possible.

An infant can lose heat to the surroundings by 4 distinct routes (Table 2). (14) Evaporation is the most common route of heat loss occurring immediately after birth in both term and preterm infants and in the first few weeks after birth in preterm infants, especially those born before 28 weeks of gestation. Heat loss can occur soon after delivery or later during bathing or from wet linens or clothing. Evaporative losses can be enormous and may total up to 200 kcal/kg per minute. (18)(19) Radiant heat loss occurs when infants are near but not in direct contact with cold surfaces, such as cold sides of the incubator or cold walls in the surroundings. This is the predominant route of heat loss in preterm infants of more than 28 weeks’ gestation and term infants. Heat loss via conduction occurs when infants are in direct contact with cold surfaces, such as cold weighing scales or a cold mattress. Convective heat loss occurs when cold air flows through open doors or from air conditioners. Because infant mortality can be as high as 98% if an infant’s core temperature falls below 89.6°F (32°C), (2) strategies to prevent heat loss need to be applied (Table 2).

Maintaining preterm infants in a neutral thermal environment (NTE) is crucial for their well-being. The NTE denotes environmental conditions at which metabolic demands are minimal; it is not a fixed range of temperatures but instead, varies with the age of the newborn, as well as gestational age and birthweight. (3)(11)(20) When environmental temperatures fall below the NTE, metabolic demands increase. This then leads to increased oxygen consumption. If this cascade continues, compensatory mechanisms are exhausted and eventually, the infant’s temperature begins to decrease. Hypothermia can be classified based on core temperatures as follows:

• Cold stress (96.8°F–97.5°F [36°C–36.4°C])

• Moderate hypothermia (89.6°F–96.6°F [32°C–35.9°C])

• Severe hypothermia (<89.6°F [32°C]).

Clinical providers should attempt to obtain normal newborn temperatures by starting with the maintenance of normal maternal temperatures before delivery. In a recent study by de Almeida et al, 30% of pregnant women were found to have temperatures below 96.8°F (36°C), and up to 44% and 51% of newborns born preterm were found to be less than 96.8°F (36°C) at 5 minutes of age and at the time of NICU admission, respectively. (21) Hospitals should optimize the ambient temperature of delivery rooms. The International Liaison Committee on Resuscitation recommends room temperatures of 78.8°F (26°C) for anticipated preterm births and 75.2°F to 77°F (24°C–25°C) for term infants. (22) The Neonatal Resuscitation Program recommends that delivery room temperatures should be between 73.4°F and 77°F (between 23°C and 25°C). This range of delivery room temperatures has been perceived to be helpful in maintaining neonatal temperatures immediately after birth.

Delayed cord clamping has become increasingly common. Though concerns have been expressed over maintaining an infant’s temperature during delayed cord clamping, a 2008 systematic review found that infants had higher temperatures if cord clamping was delayed; however, findings were not statistically significant. (23)

The use of warm weighing scales and blankets in the delivery room helps prevent any conductive and convective heat losses. Approaches such as wrapping a newborn in warm blankets, covering an infant’s head with a hat, and drying can reduce heat losses immediately after birth.

Credit for the use of modern-day incubators is attributed to Budin and his associates, though the concept of an incubator to provide warmth to fragile newborns may have been conceived as early as the mid-19th century. (3)(11) The incubator has revolutionized the management of hypothermia, significantly reducing neonatal mortality and morbidity.

Budin designed incubators with an emphasis on monitoring the environmental temperature with a provision of unidirectional flow of air that gets heated. (3) Subsequently, in the 1950s, as described by Korones, Silverman and Blanc demonstrated that maintaining body temperature through control of the thermal environment significantly reduced mortality in low-birthweight infants. They reported that higher humidity was associated with higher temperatures, which improved survival. (3) When humidity was controlled, the resulting incubator temperatures were 2°C warmer. The impact was most pronounced in infants weighing less than 1,500 g. Subsequently, single-walled incubators were replaced by double-walled incubators. Double-walled incubators reduced the radiant heat loss further by adding another layer of acrylic glass. A 2007 Cochrane review reaffirmed the aforementioned advantages of reduced heat loss, radiant heat loss, and oxygen consumption with the use of incubators. (24)

Over time, the mode of temperature monitoring has shifted from air temperature to skin. Currently, skin servo control is preferable to air temperature control, especially in low-birthweight infants, with the target skin temperature set at 96.8°F (36°C). (3) A Cochrane review reported that skin servo control mode reduces neonatal death compared with air temperature control at 89.2°F (31.8°C). (25) To avoid recording falsely high temperatures, the temperature probe must not be placed on areas of brown fat such as the interscapular region, the axilla, or neck. Instead, the clinician should place the probe on the infant’s upper abdomen, usually midway between the xiphoid process and the umbilicus. Infants should never be placed on the probe, because this can lead to falsely high temperature readings and cause the warmer to provide less heat.

Incubators can function in dual modes; if kept open, they function as a radiant warmer and if closed, they are similar to an incubator. The closed mode allows care in a humidified environment while the open mode allows access to the infant for procedures, handling, or family interactions. Several studies have compared the effect of radiant warmers and incubators on heat and insensible water loss. (26) Radiant warmers were found to be associated with increased insensible water losses, though no associated increase in oxygen consumption has been noted. However, evidence suggesting that one mode is preferable to the other is insufficient.

Because extremely preterm infants have high evaporative heat losses, humidity has become an essential component in the care of this group of patients. However, there are no standards for percentage of humidity (typically ranging between 60% and 100%) or length of exposure (up to 28 days after birth). The use of humidity greater than 70% during the first week of age followed by 50% to 60% in the subsequent weeks can reduce insensible water loss and minimize weight loss. (27) This approach has also been found to be associated with a lower incidence of hypernatremia without any concomitant increase in the incidence of infection.

Incubators have undergone multiple modifications over the past decades to attempt to reduce the spread of bacteria. Filters and use of sterile water have been incorporated, and water is heated and evaporated as an additional measure to kill all pathogens.

The use of plastic wraps and plastic bags is the most inexpensive innovation to prevent hypothermia in preterm infants. Recent trials have confirmed that there is a significant decrease in the incidence of hypothermia with the use of plastic wraps and bags in preterm infants of less than 28 weeks’ gestation without an associated increase in hyperthermia. (28)(29) Reilly et al observed a significant reduction in both hypothermia and pulmonary hemorrhage in the study group that was kept warm with plastic wraps. (30) These wraps can be used extensively in resource-limited settings because of their affordability and accessibility.

A 2010 Cochrane review reported that plastic wraps and bags were effective in preterm infants of less than 28 weeks’ gestation but not among infants of 28 to 31 weeks’ gestation. (31) The American Heart Association recommends placing preterm infants born before 30 weeks of gestation in polyethylene bags or wraps immediately after birth. (32) These materials should cover infants up to their necks, without removing the amniotic fluid on their body because the retained vernix significantly improves hydration of the skin. Next, the clinical team should cover the infant’s head with a cap. (22) All subsequent resuscitation measures should be undertaken through the plastic bag. This approach not only reduces heat loss but also maintains adequate humidity. However, data on long-term neurodevelopmental outcome is still lacking.

Another innovative method for neonatal thermoregulation is the use of a thermostable gel mattress. These mattresses have long been used to maintain temperatures during the transport of newborns. So it was not surprising to see their use being extended to the delivery room. Several trials have evaluated the use of a gel mattress in the delivery room; most have shown that the mattress is equally effective at minimizing hypothermia and improving admission temperatures compared with plastic bags. (33)(34) These mattresses can be used effectively for 2 hours. Although concerns of increased rates of hyperthermia have been raised, especially when used with bags, more studies need to be conducted. (34)

Evidence establishing the effectiveness of heated humidified gases is insufficient. A few studies have shown that heated humidified gases are helpful in reducing the postnatal drop in temperatures, especially in very low-birthweight infants. (35)(36) Since 2013, European guidelines recommend the use of heated humidified gases in infants born at less than 28 weeks’ gestation. (37) Larger trials with power to assess the use of heated humidified gases are required to confirm the benefits, especially during resuscitation. (36)

Most studies analyzing skin-to-skin contact have shown that this approach prevents hypothermia in stable preterm newborns weighing more than 1,800 g. (38)(39) A 2016 Cochrane meta-analysis of 38 trials demonstrated a statistically significant reduction in the risk of mortality, sepsis, and hypothermia with the use of skin-to-skin contact. (40)

During transport, neonatal providers should continue all of the delivery room heat maintenance practices to further minimize the risk of hypothermia. (41) A radiant warmer or incubator should be used for transport. (42) Incubator doors need to be closed because admission temperatures are lower when the doors remain open. This is particularly true when infants are transferred to the NICU on continuous positive airway pressure. Humidity of more than 60% should be added to the incubator as soon as possible.

Neonatal providers should continue all of the aforementioned measures in the NICU, with the goal of stabilization during the first hour after birth. If any procedures are performed, clinicians should be as efficient as possible. If the top of the incubator is open during the procedure, infants can be covered with additional warm drapes and blankets. Clinicians should only expose the targeted procedural site and continue to monitor the infant’s temperature during procedures. If an infant is at high risk for hypothermia and becomes hypotensive, warm fluid boluses can be used.

Observational studies and 1 randomized controlled trial have found benefit in the use of thermal mattresses in addition to plastic wraps and radiant warmers without risk of hyperthermia. (38)(43) Benefits have also been found when the following interventions were combined: environmental temperature maintained between 73.4°F and 77°F (between 23°C and 25°C), use of plastic wraps without removing the amniotic fluid, placement of head caps, use of a thermal mattress, and placement on a radiant warmer. With the integration of all of these interventions, the incidence of hyperthermia in the population was not increased. (5)(22)(44)(45)(46) Thus, for newborns of less than 32 weeks’ gestation, this combination is recommended (Table 3).

For successful implementation of these interventions, coordination among health care professionals in the labor and delivery room as well as the NICU is essential, with a goal of maintaining axillary temperatures between 97.7°F and 99.5°F (between 36.5°C and 37.5°C). In resource-restricted settings, the combination of using plastic wraps, initiating skin-to-skin contact in stable infants, and applying warm blankets or clothes can help control an infant’s core temperature.

If a preterm infant develops hypothermia after a bath, providers should start by drying the infant well, especially the head and neck areas, which are rich in thermoreceptors. Next, the provider should cover the infant’s head with a cap and then dress the infant. Before changing a soiled dressing, warm fluids can be applied to the site in infants at high risk for hypothermia.

If a premature infant needs to be rewarmed, the vital signs should be closely monitored every 15 to 30 minutes. This should include the infant’s core temperature, skin temperature (which may be higher than the axillary temperature), blood pressure, heart rate and cardiac rhythm, respiratory rate and effort, oxygen saturations, acid-base balance, and blood glucose levels. This monitoring is critical to avoid the risk of vasodilation and hypotension that is associated with active rewarming, as well as the potential for bradycardia or arrhythmias when rewarming is too slow or too fast, respectively. To avoid hypotension, the clinical provider should rewarm the infant slowly by approximately 0.5°C per hour. Use of an incubator provides better control than a radiant warmer and temperatures should be set 1°C–1.5°C above the infant’s core temperature. If the infant’s core temperature reaches the set temperature and the infant is stable, the set temperature should be increased again. This process should continue until the infant’s temperature reaches the normal range.

There is very little evidence and lack of consensus on the optimal age for transferring a preterm infant to an open crib. (47) A 2011 Cochrane review found that if an infant continues to have stable temperatures at an incubator temperature of 84.2°F (29°C), weighs at least 1,600 g, and has consistent weight gain for at least 5 days, then the infant is ready to be weaned from the incubator. (43) In the absence of consensus guidelines, different strategies have been used. Some NICUs switch to the air-control mode before weaning, while others prefer to challenge the clothed infant in a crib. Less common techniques include switching to single-walled incubators or using a heating mattress or blanket during the transition.

Hyperthermia is defined as a core temperature that is higher than 99.5°F (37.5°C). Neonatal hyperthermia most often occurs because of environmental factors leading to overheating, rather than as a result of a disease process. Hyperthermia can lead to lethargy, irritability, apnea, dehydration, peripheral vasodilation and flushing, tachycardia, tachypnea, and poor feeding. Hyperthermia can be as dangerous as hypothermia and can lead to increased metabolism, resulting in increased water loss and possibly increased mortality. (48) The infant’s clinical providers should move affected infants away from the source of heat (if relevant) and remove the infant’s clothing until the infant’s temperature is lower. If the infant is in an incubator, providers should decrease the air temperature and provide additional fluids to prevent dehydration. If untreated, hyperthermia may lead to severe dehydration, fluid electrolyte imbalance, and even shock. Providers should maintain active temperature reduction methods to a minimum to prevent sudden heat loss. To avoid catastrophic events, the temperature of the infant and the incubator needs to be monitored every 15 to 30 minutes.

Despite these preventive approaches, neonatal hypothermia still occurs in preterm infants. Most centers adopt many preventive practices to optimize a preterm infant’s temperature because any one method has not been shown to be sufficiently effective. Quality improvement projects are being undertaken to find an effective way of incorporating and optimizing each method to achieve the maximal benefit. (21)(22)(46) Data on the impact of thermoregulation on long-term neurodevelopment are still lacking. Although hypothermia in preterm infants is preventable, it still occurs because of lack of awareness and rarely, because of limited equipment. (49) To achieve optimal temperatures, clinicians should attempt to prevent hypothermia before the birth of a preterm infant. Postnatally, providers should target temperatures between 97.7°F and 99.5°F (between 36.5°C and 37.5°C). Because preterm infants may be unable to overcome cold stress, NICUs should enforce a rigorous approach to hypothermia prevention in this population.

NTE

neutral thermal environment

T3

thyroxine

T4

triiodothyronine