Pediatric Annals

Special Issue Article 

The Evolving Understanding of Sudden Unexpected Infant Death

Christine G. McIntosh, BSc, MBChB, Dip Paed, Dip Obs&Gyn, FRNZCGP; Edwin A. Mitchell, FRSNZ, BSc, MB BS, FRACP, FRCPCH, DSc

Abstract

Sudden unexpected infant death (SUID) is the leading cause for post-neonatal mortality in industrialized nations. Case-control studies have identified risk factors for SUID that have shaped research into studies of causation. Most current hypotheses for the mechanisms for SUID contribute to the “SUID sequence”—hypoxia and/or hypercarbia in sleep to which a vulnerable infant fails to respond adequately and that results in death. Reducing vulnerability in infants and promoting safe sleep for infants is important for prevention and requires knowledge of the prevalence of risk factors within the target population and a culturally sensitive approach. [Pediatr Ann. 2017;46(8):e278–e283.]

Abstract

Sudden unexpected infant death (SUID) is the leading cause for post-neonatal mortality in industrialized nations. Case-control studies have identified risk factors for SUID that have shaped research into studies of causation. Most current hypotheses for the mechanisms for SUID contribute to the “SUID sequence”—hypoxia and/or hypercarbia in sleep to which a vulnerable infant fails to respond adequately and that results in death. Reducing vulnerability in infants and promoting safe sleep for infants is important for prevention and requires knowledge of the prevalence of risk factors within the target population and a culturally sensitive approach. [Pediatr Ann. 2017;46(8):e278–e283.]

Sudden unexpected infant death (SUID) is the term used to describe the sudden and unexpected death of an infant younger than age 1 year who was thought to be healthy or have only minor symptoms in the 24 hours prior to death, which generally occurs during sleep. Despite a dramatic reduction in infant deaths after the “Back to Sleep” campaign in the early 1990s, SUID remains the leading cause of postneonatal deaths in industrialized nations (England and Wales 0.45/1,000 live births, United States 0.95/1,000, and New Zealand 1.01/1,000).1

This article discusses the development of the classification, the epidemiology and evidence for current hypotheses for the mechanism of SUID, and how knowledge is shaping interventions for prevention.

Classification

SUID is an umbrella term that includes deaths due to accidental suffocation or strangulation in bed (International Statistical Classification of Diseases and Related Health Problems, version 10 [ICD-10]2 Code W75), deaths for which a medical explanation is found postmortem (such as congenital heart disease or pneumonia), and unexplained deaths. Unexplained death, or sudden infant death syndrome (SIDS), is a diagnosis of exclusion in which a thorough clinical history, death scene examination, and autopsy do not establish an adequate cause of death. As described in Figure 1, there is an overlap in the causes of SUID. For example, asphyxia is indistinguishable at autopsy from SIDS and relies on the interpretation of what is found on the death scene examination. In New Zealand, and to a lesser extent the US, there has been an increasing attribution of SUID deaths to accidental suffocation, with a corresponding reduction in the SIDS classification.1 In contrast, in England and Wales, deaths are rarely classified as accidental asphyxia in bed but are more likely to be classified as unascertained.1 Pathological findings are commonly found in cases of SUID; however, whether the abnormality is sufficient to cause death is often a matter of opinion. There is considerable similarity in risk factors for explained SUID compared with SIDS (except prone sleeping, which is only associated with SIDS). This supports the possibility that there is considerable overlap of causation within these classifications (Figure 1).3

The overlap of International Statistical Classification of Diseases and Related Health Problems,2 version 10 codes for SIDS, SUID, and medical causes of death. SIDS, sudden infant death syndrome; SUID, sudden unexpected infant death.

Figure 1.

The overlap of International Statistical Classification of Diseases and Related Health Problems,2 version 10 codes for SIDS, SUID, and medical causes of death. SIDS, sudden infant death syndrome; SUID, sudden unexpected infant death.

A major challenge in SUID research has been the variability in coding of SUID internationally. Thoroughness of postmortem investigation and death scene examination differs considerably and therefore affects the uniformity of classification of deaths.1 Recently Taylor et al.1 have proposed a limited set of ICD-10 codes for SUID. These codes cover specific R codes and W codes (Figure 1). International implementation of the coding would help with comparison of SUID mortality data between countries and over time.

Association to Causation

Observational studies from the 1940s through to the 1970s provided the first clues on factors associated with SUID.4 There was early recognition that deaths peaked at age 2 to 3 months and that most cases occurred before age 6 months. This age distribution has remained remarkably steady over time.5 Sudden infant death was also associated with socioeconomic deprivation, younger mothers, less antenatal care, small babies at birth, prematurity, winter season, and having an illness in the weeks prior to death.6 Subsequent large case-control studies have provided a sound epidemiological base for a comprehensive list of factors associated with SUID (Table 1).

Factors Contributing to Risk for Sudden Unexpected Infant Death

Table 1.

Factors Contributing to Risk for Sudden Unexpected Infant Death

Prone Sleeping

Non-supine (prone and side) sleep position was recognized as a major risk factor for SIDS in the New Zealand Cot Death Study, a 3-year case-control study from 1987–1990.7 Publication of the first data in 1991 provided the strongest evidence at that time, which, when combined with other studies, led to the recommendation for supine sleeping. The Back to Sleep campaign has been the most effective intervention for prevention of SUID to date and resulted in a rapid and sustained reduction in SUID.8

Smoking

Subsequent to the decline in the prevalence of infants sleeping in the prone and side position, maternal smoking has become the leading risk factor for SUID.9 To support this epidemiological finding there is now compelling evidence that maternal smoking and second-hand smoke exposure during pregnancy causes dose-dependent fetal damage.10 Smoking-induced chronic hypoxic stress in the fetus and nicotine exposure are both known teratogens in neurodevelopment in animal models and result in decreased respiratory drive and reduced arousal from sleep.10,11

Bed Sharing

Sleeping infants that share a bed with another sleeping person are at increased risk of SUID.12 Now that fewer infants sleep prone, bed sharing has become relatively more important, such that more than 50% of deaths occur in a bed sharing context.13,14 The New Zealand study was the first case-control study examining the risk associated with bed sharing that adjusted for potential confounders and the first to identify the interaction with maternal smoking.15

Interaction of Risk Factors

Although most risk factors are independent of each other, several important interactions have been identified in which the combined risk is much greater than the individual components, especially maternal smoking and bed sharing. Bed sharing also interacts with age, so that bed sharing is especially dangerous in infants younger than age 3 months. This results in an astounding 65-fold increased risk of sudden infant death where both parents smoke and the baby is bed sharing at age 2 weeks.16

Triple-Risk Model

Filiano and Kinney's triple-risk model describes SIDS as a result of a vulnerable infant in a critical developmental period experiencing the impact of an exogenous stressor.17 It provides a useful framework from which to understand the interaction of epidemiologically determined risk factors. For example, prone sleeping position is clearly causally associated with SIDS, as the change in sleep position alone was associated with a marked reduction in mortality.8 Avoiding prone sleeping (the stressor) has been enough to uncouple the triple-risk model and prevent SIDS for many infants.

The Suid Sequence

In the face of not knowing the exact mechanisms of SIDS, epidemiology has played an important role in guiding research into the mechanisms in SIDS/SUID and in formulating interventions. What follows here is a synthesis of hypotheses into what is considered to be the mechanism of the majority of SUID deaths (Figure 2).

The major hypothesis for the sequence of events causing death in sudden unexpected infant death (SUID).

Figure 2.

The major hypothesis for the sequence of events causing death in sudden unexpected infant death (SUID).

Poets18 reported on cardiorespiratory recordings of nine infants who died of SIDS who had memory monitors in use at the time of death. The study made the following important observations: prolonged apnea and bradycardia were observed (but neither was thought to be the primary mechanism), there was a notable absence of arousal, and auto-resuscitation was ineffective. They speculated that severe hypoxemia had preceded the event, resulting in hypoxic cardiac depression and bradycardia, even though the infant was making breathing movements. When the heart rate slowed to 40 to 50 beats per minute, respiration was affected and gasping should have occurred. In many instances, there was either an absence of gasping or inadequate gasping, resulting in a failure of auto-resuscitation and death.19 Although the report was only on a small number of infants, further case reports of monitored SIDS deaths showed similar cardiorespiratory patterns.20,21

Mechanisms for Hypoxia/Hypercarbia in Sleep

Positional asphyxia has been described as a mechanism for respiratory compromise leading to SUID. It has been shown by Tonkin et. al.19 that young infants are particularly vulnerable to upper airway obstruction because their tongue is susceptible to posterior displacement, resulting in narrowing of the oropharyngeal airway.19 Mandibular pressure can occur in prone positioning, flexion of the neck in infants who become wedged, in car seats, on pillows, and in a caregiver's arms. It has been postulated that the distribution of petechiae found in up to 90% of cases of SUID, and uncommonly found in other causes of death, suggests a pattern of high negative intra-thoracic pressures, such as would be generated by an infant attempting to breathe or gasp against upper airway obstruction.22

Both rebreathing and thermal stress have also been proposed as mechanisms for SIDS caused by prone sleeping. Kemp23 has demonstrated in animal models that lethal hypercarbia occurs on softer bedding types but does not occur on firmer mattresses, despite face-down positioning. The finding of an interaction of prone sleep with thermal factors suggests the mechanism by which prone sleep causes death is related either directly or indirectly with thermal stress.24 Prolonged apnea due to thermal stress in infants occurs with the same environmental stressors for rebreathing (eg, with the baby covered in blankets or face enveloped by soft bedding).25 However, Guntheroth and Spiers25 point out that there are several risk factors for SIDS associated with thermal stress that are independent of rebreathing and should, therefore, be considered as separately causative without the requirement for rebreathing.

The concept that infection could be implicated in SUID is longstanding; however, there is not a single viral or bacterial cause that has been consistently implicated. Current thinking is that the inflammatory response of the infant, mediated by age, genetic factors, and environmental factors, such as second-hand tobacco smoke, creates the susceptibility to sudden death.26

Failure of Arousal and the Brainstem Hypothesis

Mild and self-limited hypoxia and hypercarbia are probably common for infants, so other factors must result in an infant not arousing and responding to this situation. The association with sleep and the observed lack of arousal suggests a failure of the brainstem to initiate an adequate response to hypoxemia. Kinney et al.27 proposed the “brainstem hypothesis,” in which “abnormal brainstem mechanisms in the control of respiration, chemosensitivity, autonomic regulation, and/or arousal which impairs the infant's response to life-threatening, but often occurring, stressors during sleep… and leads to sudden death in a vulnerable developmental period.” Supporting this hypothesis are abnormalities found in serotoninergic neurons, and reduction in cholinergic receptor density and binding dysfunction in the hypoglossal nucleus and dorsal motor nucleus of the vagus in babies who died from SIDS, leading to a deficient autonomic and respiratory response to hypoxia and or hypercarbia.28 Whether damage to the brainstem occurs prenatally, postnatally, or both is unknown. In addition to this anatomic deficiency, physiological studies have shown that prone positioning, maternal smoking, head covering, and prematurity all have substantial effects on cardiovascular homeostasis and arousal responses.29

Genetic Factors

SUID deaths may be related to genetic anomalies affecting metabolism, immune function, autonomic regulation, and cardiac ion channel function.30 These factors may alter the normal physiological responses. Wilders31 concludes from population-based cohort studies that one-fifth of SIDS victims carry a mutation in cardiac ion channel-related genes, although this has been challenged by Glengarry et al.,32 who found that only 4% of unselected SUID cases had rare genetic variance of doubtful pathogenicity. Better case selection and enhancements in postmortem testing will enable a better understanding of the relative contribution of these conditions to SUID.

Prevention and Intervention

The success of the Back to Sleep campaign was due to the fact that prone sleeping was a major risk factor for SIDS, and this one simple message (ie, place your baby on their back to sleep) was easy to implement for most families. For some ethnic groups with a higher prevalence of risk factors other than prone sleeping (eg, Maori people in New Zealand), the reduction in SUID was less marked and widened the disparity in infant mortality between Maori and non-Maori in New Zealand.33 SUID prevention strategies have grappled with a relatively large set of risk factors, some of which interact and are prevalent at different rates within different populations. Cultural and socioeconomic determinants of SUID risk add a further complexity, and the important challenge is to implement SUID interventions that reduce deaths and at the same time address the inequity of SUID prevalence in different ethnic groups.

Most SUID risk factors are potentially modifiable at a population level as well as at an individual level. Cigarette smoking is a major risk factor for SUID and should be addressed at all levels. Salm Ward and Balfour34 concluded from reviewing the effectiveness of safe sleep interventions that it was important to have “multi-pronged, consistent (safe sleep) messaging across multiple levels,” but that it was also important that safe sleep interventions should be crafted specifically for higher risk groups. An example of this approach is in New Zealand, where there has been targeted intervention with on-bed baby beds (eg, the wahakura [a traditional baby crib used by Maori people] and a modern plastic version known as the Pepi-pod) in recognition of the cultural preference by Maori families for bed sharing. Since the widespread introduction of the baby-beds within a structured face-to-face education program, there has been a significant reduction in SUID mortality for Maori infants, with greater than 40% reduction in district health board areas that used this program.35

Conclusions and Future Directions

SUID research will be greatly aided by improved consistency internationally in SUID ICD-10 coding and mandated thorough autopsy, clinical history, and death scene investigation of all SUID deaths. Ongoing epidemiological research is required to understand the changing prevalence of SUID within populations to enable targeted interventions and to understand the effects of new interventions. Interventions should aim to reduce inequity by being population and culturally appropriate and aimed at both reducing infant vulnerability and enabling safe-sleep infant-care practices by caregivers.

References

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Factors Contributing to Risk for Sudden Unexpected Infant Death

Risk and Protective Factors Multivariate Odds Ratio 95% Confidence Interval

Maternal and paternal smoking
  Mother 1.5 1.2–2.1
  Father 1.1 0.8–1.4
  Both 2.9 2.3–3.6

Bed sharinga at younger than age 3 months 2.7 1.4–5.3

Not breast-feeding 1.5 1.2–1.8

Sleep position
  Side 1.5 1.2–2.1
  Prone 10.5 7.5–14.6

Maternal drug and or alcohol use
  Alcohol (>2 units in past 24 hours) 4.8 2.6–8.9
  Illegal drugs since baby was born 11.5 2.2–59.5

Male gender
  Matched studies 0.8 0.6–1.1
  Unmatched studies 1.6 1.3–1.9

Non-white ethnicity 1.5 1.1–1.9

Low birth weight
  2,500–3,499 g 1.7 1.4–2
  2,000–2,499 g 4.2 2.9–6
  <2,000 g 9.6 6.2–14.7

Younger maternal age
  26–30 years 1.9 1.5–2.3
  21–25 years 3 2.4–3.8
  19–20 years 7.7 5.2–11.4
  18 and younger 9.1 5.9–14.1

Higher birth order
  2 2.3 1.9–2.9
  5 or more 7.7 5.3–11.3

Pacifier use 0.4b 0.3–0.5

Mothers marital status (single) 1.9 1.5–2.4

Not sleeping in same room as parent 2.4 2–2.9
Authors

Christine G. McIntosh, BSc, MBChB, Dip Paed, Dip Obs&Gyn, FRNZCGP, is a Senior Lecturer, Department of Paediatrics: Child and Youth Health, The University of Auckland. Edwin A. Mitchell, FRSNZ, BSc, MB BS, FRACP, FRCPCH, DSc, is a Professorial Research Fellow, Department of Paediatrics: Child and Youth Health, The University of Auckland.

Address correspondence to Edwin A. Mitchell, FRSNZ, BSc, MB BS, FRACP, FRCPCH, DSc, Department of Paediatrics: Child and Youth Health, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; email: e.mitchell@auckland.ac.nz.

Grant: The authors were partially supported by grant #4003 from Cure Kids (an organization that funds child health research in Auckland, New Zealand).

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20170719-01

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