The global burden of neonatal hypothermia: systematic review of a major challenge for newborn survival

The global burden of neonatal deaths and its relation to hypothermia

The global under-5 child mortality rate has decreased continuously during the last three decades, from 110 per 1,000 in 1980 to 60 per 1,000 in 2009, and the number of child deaths worldwide each year has decreased from 13.5 million in 1980 to an estimated 7.7 to 8.8 million in 2008 [1–4]. The number of neonatal deaths (newborns dying under the age of 28 days) has also decreased, from 4.6 million deaths in 1990 to approximately 3.1 to 3.6 million in 2009 [3, 5]. However, neonatal mortality has declined at a lower rate than child mortality, so the proportion of newborn deaths among all child deaths has been increasing.

Neonatal deaths are unequally distributed around the globe. Half of the world's newborns die at home, and more than 99% of all deaths occur in developing countries, where the average neonatal mortality rate is 33 per 1,000, compared with 4 per 1,000 in high-income countries. Since neonatal deaths account for more than 40% of under-5 mortalities [3], reaching Millennium Development Goal (MDG) 4 will require a substantial reduction in newborn mortality. Although addressing neonatal hypothermia might facilitate this goal, it has so far been a neglected challenge. Maintaining a normal body temperature is a critical function for newborn survival. Newborns achieve this through sophisticated mechanisms of body temperature regulation controlled by the hypothalamus and mediated by endocrine pathways through shivering and non-shivering thermogenesis [6]. However, particularly in premature and low birth weight infants, thermoregulatory mechanisms are easily overwhelmed, leading to metabolic deterioration and direct death from hypothermia or indirect mortality from associated mortalities such as severe infections [7].

The attribution of neonatal hypothermia to indirect or direct causes of newborn death is complex and difficult for several reasons. Most neonatal deaths occur in regions without vital registrations or other reliable data sources. In countries where neonatal deaths are estimated to be highest, mortality data are based on national sample death registration at best [3] and mostly rely on verbal autopsy data-based models with less-than-optimal sensitivity and specificity to correctly identify causes of deaths [8]. Only 2.5% of global neonatal deaths data are based on reliable vital registration systems [9], while 97% derive from systematic estimations or household surveys [10].

Moreover, causes of death are difficult to ascertain in newborns because, especially at the beginning of life, infants exhibit few specific symptomatic reactions to illnesses. Clinical manifestations of various diseases overlap considerably in neonates. Early deaths and those in very small babies are often misclassified due to varying definitions of stillbirth and neonatal deaths, or due to other misreporting of data, such as avoiding filling out death certificates [8].

Globally, severe infections account for an estimated 36% of all neonatal deaths, while problems associated with prematurity account for another 29%, and birth asphyxia makes up 23% (with congenital malformations and a variety of other causes responsible for 19% of neonatal deaths) [3]. While all these causes of death are associated with neonatal hypothermia, the direction of causality is unclear [7]. Although usually infections (mostly sepsis and pneumonia) are listed as cause of death rather than hypothermia, it is unclear whether hypothermia is the underlying cause or the consequence of severe infections. Like severe infections, prematurity is associated with mortality from hypothermia. While only half of the babies born are weighed at birth (and even fewer are of known gestational age), it is estimated that annually 18 million, or 14% of all babies, are born with low birth weight (LBW), half of them in South Asia. LBW infants account for 60% to 80% of neonatal deaths. Birth asphyxia is associated with hypothermia, and prevention or treatment of hypothermia is an important therapeutic principle during and after resuscitation in both developing and developed settings [11, 12].

Daily mortality rates for the neonatal period are 30-fold higher than later during infancy [10]. Immediately after birth, an infant is at highest risk of dying, with 25% to 45% of neonatal mortality occurring during the first 24 h [10] and 75% of neonatal mortality during the first week of life [13]. Assuming that early deaths are caused mainly by prematurity and asphyxia, interventions addressing hypothermia management and resuscitation might have a substantial impact on neonatal mortality prevention.

This review analyzes the global epidemiological situation of neonatal hypothermia for the purpose of guiding future policy and research efforts.

The prevalence of neonatal hypothermia globally

These, and an earlier community-based study from Nepal [19], found newborn hypothermia to be almost universal at birth. Overall in community-based studies (all conducted in Nepal or India), hypothermia prevalence ranged from 11% to 92%. Perhaps not surprisingly, lower ambient temperatures [20, 21] and cold season [22] were associated with a higher incidence of hypothermia in Indian studies.

However, not only in climatic regions perceived as high risk for hypothermia such as the hills and mountains of Nepal, Northern India, Bangladesh, Pakistan and Bhutan [22] do infants get too cold. Hypothermia is a problem even in tropical countries and warm climates, as was first reported more than fifty years ago [23]. A classic study from Dakar, Senegal found only 5 in 78 babies with a temperature over 36°C [24]. All identified studies from Africa to date are hospital based, report poor newborn practices and high prevalences of newborn hypothermia ranging from 44% to 69% in Zambia [25, 26] to 53% in Ethiopia [27], 62% to 68% in Nigeria [28], and 85% in Zimbabwe [29]. Large studies from other countries confirm the global tendency for newborn hypothermia in different climate conditions, from Asia (China) (cited in [30]), [31], the Middle East (Iran) [32, 33] and South America (Brazil) [34].

Risk factors for hypothermia

Various studies identified several risk factors for newborn hypothermia, which we categorize as follows.

Associations of hypothermia with newborn morbidity and mortality

Several studies investigated the association between neonatal hypothermia and associated mortality risks. In our review, case fatality rates (CFR) for newborn hypothermia globally range from 8.5% to 52% [21, 26, 34, 59, 60]. A study from India that included only hypothermic babies specifically investigated morbidities and mortalities and found CFRs that ranged from 39.3% for mild hypothermia to 80% for severe hypothermia. This study demonstrated a dramatic effect of comorbidities and confirmed that hypothermia has a much worse outcome when associated with other newborn problems. Fatality rates increased to 71.4% with hypoglycemia, 83.3% with hypoxia, and 90.9% with shock [61].

However, the above-cited studies do not sufficiently control for potential confounders of the effect of hypothermia on mortality and thus provide implausibly high CFRs in the context of high hypothermia prevalence particularly in community settings. Furthermore, these studies reflect the higher risk of hospital populations selected for these studies, and their CFRs are therefore not applicable to community settings. Yet, hypothermia has been shown to be associated with mortality in a community setting. A community-based study conducted in Sarlahi, Nepal found that mortality increased by approximately 80% for every degree Celsius decrease in first observed axillary temperature and that relative risk of death ranged from 2 to 30 times within the current WHO classification for moderate hypothermia, increasing with greater severity of hypothermia [18].

The evidence on the effect of thermal protection on morbidity and mortality is currently limited. Skin-to-skin care has been shown to substantially reduce neonatal mortality among preterm infants born in facilities [62], but its effectiveness for infants born at term and in communities is less clear. In Zambia, we recently showed that training traditional birth attendants in newborn care emphasizing simple thermal protection (wiping the newborn dry and wrapping the dried infant in a separate piece of cloth), along with resuscitation and early treatment of possible sepsis where indicated, reduced mortality rates at day 28 after birth by 45% [63].

Whether wrapping the newborn in plastic (polyethylene or vinyl) bags is sufficient for thermal protection in low birth weight and premature infants remains controversial. While one recent study failed to show an effect of wrapping on hypothermia rates [64], others found that this approach effectively raised body temperature [65, 66] and did so more quickly than radiant heaters [67, 68], however did not reduce mortality [69].

Rethinking and redefining neonatal hypothermia

Our and other reviews [36, 70] suggest that the burden of hypothermia is still highly prevalent including in tropical countries, practices contributing to heat loss in the newborn are still deeply rooted in many cultures and are difficult to change, technologies adapted to resource-poor environments are still at a developmental stage, simple thermoprotective interventions and behaviors are insufficiently practiced, providers and caretakers lack an understanding of the problem, and adverse health outcomes continue to take their toll in morbidity and mortality in newborns. There is thus a critical need for researchers and policy makers to take on the challenge of newborn hypothermia and address it within a larger framework of maternal and child health programs.

Qualitative studies from Africa and South Asia suggest that delivery and newborn care practices contributing to heat loss are still common globally. Various cultural and sometimes economic barriers often interfere with implementing simple steps to prevent hypothermia. Heating the birth place is costly for families in resource-poor countries [51], and drying and wrapping the baby is often not a priority when the mother needs attention after delivery [50]. In Ghana, for example, the practice of bathing newborns immediately after delivery is sometimes rooted in concerns about 'ritual pollution' [71] or the belief of helping the baby sleep and feel clean, and reducing body odor in later life; attitudes that informants felt would be difficult to change [72] and which need to be taken into account when programming for behavior change.

Major gaps in our understanding of neonatal hypothermia

Since in most parts of the world temperature is not measured and recorded in most newborns immediately after birth, the epidemiological picture of hypothermia and its clinical consequences is yet incomplete. Hypothermia is believed to be a common problem not only in developing countries, but also in formerly socialist countries [56]. There are few studies from current lower-middle-income countries.

To the best of our knowledge, no population risk attributable to hypothermia has been published yet. There is no consistent definition of normal newborn body temperature, and consequently data that would allow for pooled risk estimates for newborn hypothermia are still incomplete. Temperatures have been shown to vary widely in healthy newborns [73], and standard medical textbooks disagree on the lower normal limit, ranging from 35.5 to 36.5°C, as well as the normal upper level, citing values from 37.0 to 37.9°C [74].

Standard randomized controlled trials to define temperature thresholds associated with adverse health effects (morbidity as well as mortality) and to quantify the contribution of hypothermia to neonatal mortality as specific cause of death have not been conducted. In fact, those studies might be methodologically impossible to undertake, or at least ethically problematic, because the detection of hypothermia prompts therapeutic intervention and thus artificially reduces the associated mortality risk.

Given these limitations, standard measurements of body temperature could be included in newborn studies to complement available epidemiologic data. Newborn trials conducted for other reasons that include data on newborn body temperature could facilitate further investigation of the association of newborn hypothermia with morbidities and disease-specific mortalities. Axillary measurements with standard digital thermometers are inexpensive and can easily be incorporated into most newborn care clinical guidelines and study protocols.

Currently, the best available data come from trials with hypothermia-unrelated interventions providing temperature data, such as the Sarlahi trial in Nepal [18]. Further studies on the mortality and morbidity risks posed by newborn hypothermia are warranted, particularly in sub-Saharan Africa, to refine the current WHO classification scheme for hypothermia that, as has been suggested, might have to revised into narrower categories to more appropriately reflect the overall mortality-hypothermia risk relationship [18, 70].

Further research is needed to understand the magnitude and perception of the problem as well as the feasibility and effectiveness of thermoprotective interventions for newborn morbidity and mortality. Methodologically sound hospital-based and community-based studies are required to understand the problem in sub-Saharan Africa specifically. These studies will ideally include potential confounders and mediating factors that have largely not been adequately addressed so far, such as maternal temperature, environmental conditions, and sociocultural contexts and their association with newborn hypothermia.

Various international neonatal advocacy alliances have included thermoprotection strategies in their newborn health programming, including the Healthy Newborn Partnership (Save the Children), Partnership for Safe Motherhood and Newborn Health (WHO), and the Child Survival Partnership (UNICEF). Nevertheless, hypothermia remains a major challenge for newborn survival. Globally, progress has been particularly slow in improving survival in infants less than 7 days old [10]. This might be attributable to the delivery gap in developing countries for interventions addressing early causes of death such as preterm birth and asphyxia, both of which have worse outcomes in the presence of hypothermia.

More than a quarter of a century ago, a study from Senegal reported: 'Deaths [from hypothermia] seem easy to avoid. Purchasing blankets, putting the newborn babies with their mother and not in cots, prohibiting unnecessary washing of the babies, and supplying maternity hospitals with solar water heaters are all easy steps which could greatly reduce this problem. These improvements are gradually being introduced in the maternity hospital we surveyed though it is proving very difficult to persuade elderly auxiliary midwives not to remove the vernix caseosa by thorough washing, this being part of a strong tradition. Health workers in dispensaries should also be aware of the problem of neonatal hypothermia. We frequently see at our clinic mothers with young infants whose growth seems unsatisfactory. They usually complain about not having enough milk. If the infant is lightly clothed and his rectal temperature is well below normal, he may be expending too much energy on thermogenesis. Advising such mothers to use warmer clothing for their babies is usually enough to make them put on weight. Artificial feeding would be wholly inappropriate in such conditions and could even prove fatal' [24]. As our review suggests, most of these statements and easy remedies still hold true today in most of the world.