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• Published: 12 May 2023

Current SIDS research: time to resolve conflicting research hypotheses and collaborate

• Paul N. Goldwater   ORCID: orcid.org/0000-0003-4822-8488 1  

Pediatric Research volume  94 ,  pages 1273–1277 ( 2023 ) Cite this article

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From the earliest publications on cot death or sudden infant death syndrome (SIDS) through to this day, clinical pathology and epidemiology have strongly featured infection as a constant association. Despite mounting evidence of the role of viruses and common toxigenic bacteria in the pathogenesis of SIDS, a growing school of thought featuring a paradigm based on the triple risk hypothesis that encompasses vulnerability through deranged homoeostatic control of arousal and/or cardiorespiratory function has become the mainstream view and now dominates SIDS research. The mainstream hypothesis rarely acknowledges the role of infection despite its notional potential role as a cofactor in the triple hit idea. Decades of mainstream research that has focussed on central nervous system homoeostatic mechanisms of arousal, cardiorespiratory control and abnormal neurotransmission has not been able to provide consistent answers to the SIDS enigma. This paper examines the disparity between these two schools of thought and calls for a collaborative approach.

The popular research hypothesis explaining sudden infant death syndrome features the triple risk hypothesis with central nervous system homoeostatic mechanisms controlling arousal and cardiorespiratory function. Intense investigation has not yielded convincing results. There is a necessity to consider other plausible hypotheses (e.g., common bacterial toxin hypothesis).

The review scrutinises the triple risk hypothesis and CNS control of cardiorespiratory function and arousal and reveals its flaws.

Infection-based hypotheses with their strong SIDS risk factor associations are reviewed in a new context.

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Introduction.

There are two leading research hypotheses used to explain sudden infant death syndrome (SIDS). The mainstream popular research hypothesis features the triple risk hypothesis 1 with central nervous system (CNS) homoeostatic mechanisms controlling arousal and cardiorespiratory function and invokes prone sleep position as playing a causal role. 2 The other is the common bacterial toxin hypothesis, 3 , 4 , 5 which utilises experimental and epidemiological evidence indicating viral infection combined with bacterial toxaemia and prone positioning may produce a fatal outcome through super antigenic shock. The review scrutinises these hypotheses and suggests a different way forward.

The common bacterial infection hypothesis

From the earliest epidemiological studies on cot death or as it was later defined 6 , 7 , 8 as SIDS, there were clear indications that infection, especially respiratory viral, was associated with these deaths. 9 , 10 , 11 , 12 , 13 The common bacterial toxin hypothesis was developed on the basis that a viral infection (along with prone positioning) induced upper respiratory tract changes conducive to toxin production by toxigenic bacteria (including Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli ), all of which were commonly found to colonise the nasopharynx. 14 , 15 , 16 In >50% of cases, Staphylococcal toxins were demonstrated in SIDS babies’ tissues. 17 , 18 , 19 , 20 These were identified in tissues of 33/62 (53%) SIDS infants from three different countries: Scotland (10/19, 56%); France (7/13, 55%); Australia (16/30, 53%). In the Australian series, toxins were identified in only 3/19 (16%) non-SIDS deaths ( χ 2  = 5.42, P  < 0.02). 17 Harrison et al. 18 demonstrated that sleeping prone caused pooling of secretions and increased numbers of toxigenic bacteria in the nasopharynx and Malony et al. 19 showed prone sleeping increased the local temperature into ranges known to induce bacterial toxin production. 19

The hypothesis suggested viral infection acted as a trigger for events leading to super antigenic toxic shock through T-cell activation by staphylococcal enterotoxins or toxic shock syndrome toxin-1. Staphylococcal enterotoxin- like proteins also act as superantigens. 20 and could also be involved in SIDS. A mouse model developed by Nobel Laureate Peter Doherty and colleagues showed that mice infected with the respiratory zoonotic pathogen lymphocytic choriomeningitis virus (LCMV) were unharmed, but in virally infected mice given an intraperitoneal injection of Staphylococcal enterotoxin B, this was rapidly lethal. Staphylococcal toxin injection alone was non-lethal. 21

The respiratory tract in SIDS frequently shows evidence of inflammatory involvement of the airways and lungs. 11 , 22 , 23 The inflammatory process may involve platelet aggregation and obstruction of the lung capillaries by blood platelet aggregates and leucocytes. 24 This could provide clues to the pathogenesis of intrathoracic petechial haemorrhages observed in 80–90% of SIDS cases. Intrathoracic petechial haemorrhages have been explained by mainstream researchers as resulting from agonal changes in intrathoracic pressure. 25 Animal experimentation has failed to affirm this idea. 26

My interest in SIDS research was aroused through my colleague, the late Dr Karl A. Bettelheim who had demonstrated in a paper given at a meeting in Auckland in the early 1980s that sera obtained from cases of SIDS was lethal to infant mice upon intraperitoneal injection. Whether the mice were also congenitally infected with an enzootic virus was not at the time a consideration. Karl had published widely on E. coli and human infant disease. Knowledge of the various toxins of E. coli and the common finding of the bacterium in the respiratory tract of SIDS babies led us to investigate the possible role of E. coli in SIDS. Interesting but inconclusive correlations were found. 27 , 28

As mentioned, S. aureus is also commonly found in the upper and lower respiratory tract of SIDS cases. 18 , 29 Significantly greater proportions of SIDS compared with control/comparison babies were positive for S. aureus (68.4% vs. 40.5%) and for staphylococcal enterotoxin genes (43.8% vs. 21.5%), suggesting a possible role in SIDS. 30

The further analysis enabled us to demonstrate a significant relationship between colonisation with S. aureus and the risk factor of prone sleep position in SIDS. 31 The work showed numerous combinations of the nine enterotoxins in the cases of SIDS. However, the DNA extracts used in the Highet et al. study 31 were re-examined using an lllumina MiSeq platform by Leong et al. 32 In this study, the frequency of detection of S. aureus did not differ significantly from the comparison babies. 32 We explain the disparity between the studies on methodological differences.

Derived from the staphylococcal enterotoxin study, 30 we proposed that contamination of the baby’s sleeping surface with S. aureus might explain the relationship with prone sleeping, given that potentially contaminated sleeping surfaces such as the parental bed, 33 sofa, 33 , 34 and used cot mattresses 35 were established risk factors for SIDS.

The idea that prone positioning in relation to SIDS could affect the vagus nerve 36 and its multitudinous functions, including influence on the gut microbiota, on gut hormones and the cholinergic anti-inflammatory pathway, were based on the vagus nerve inflammatory reflex, known to prevent cytokine-induced tissue damage and death. Vagal stimulation in animal models prevents cytokine release and damage during sepsis, shock, endotoxemia, etc. Prone positioning may affect vagal neurophysiology adversely. This subject remains unexplored in the context of SIDS.

Reappraisal of the popular mainstream SIDS research hypothesis

The triple risk hypothesis 1 formed the basis for hypotheses centred on the CNS/brainstem control of arousal, respiration, and cardiac function as well as a focus on the prone sleep position and the sleeping environment. 2 The paradigm explains prone sleep position as playing a causal role; 37 this seems disingenuous given that babies die in supine and side positions which should necessarily dictate different mechanisms of demise. Rather, it would be logical to consider a prone sleep position increasing the risk of SIDS through an unknown mechanism. Airway obstruction in prone sleepers would make it implausible to attribute non-prone SIDS deaths to a similar mechanism. An explanation may reside in an increased risk in prone over other positions. As alluded to previously, such increased risk could relate to prone sleep position increasing the likelihood of colonisation by toxigenic bacteria from the sleeping surface and the increased likelihood of induction of bacterial lethal toxins. This is discussed further below.

In a different context, the attribution of sleep position with causality has led to an argument for a causal relationship between supine sleep position and autism spectrum disorder; based on the increase in autism rates following the introduction of the Back-to-Sleep (BTS)/Reducing-the-Risk (RTR) campaign in five different countries. 38 Association does not equal causation.

Neuropathology and SIDS

In 1990, Oehmichen 39 described the state of SIDS neuropathological research as ‘Due to differences in the findings as well as methodologic and interpretative problems, no definitive pathogenetic concept based on the available neuropathologic findings can be formulated at present, even though many observations tend to indicate that the brainstem, as the central organ controlling respiration, is probably of prime importance in SIDS. Even the classification of the described phenomena as primary and secondary changes can be and is disputed. No diagnostic criteria for classification of SIDS and control cases could be established, since all obtained criteria are nonspecific, and the described criteria are not present in all SIDS cases’. Two decades on and the same message applies with the possible role of the CNS in SIDS remaining confused. Findings involving neurotransmitters (e.g., 5HT, its receptors and gene polymorphisms) 40 have not led to conclusive results. While hypoxic-ischaemic neuronal injury (and neuronal apoptosis) is generally thought to be common in SIDS cases, 41 , 42 , 43 none of the authors have considered a role for sepsis in these processes. Sepsis is an established leading cause of hypoxia/ischaemia and neuronal apoptosis. 44 , 45

The researchers consider that the described neuropathology is a primary phenomenon and have rarely considered that these changes could be the result of a secondary effect, say, from cytokine responses to viral infection or effects of bacterial toxaemia/super antigenic shock. Many of the CNS findings seen in SIDS cases are also observed in control babies. 46 In rare attempts to correlate CNS findings with epidemiological risk factors have not resulted in substantial success. Examples of such correlation include male sex and age for a restrictive pattern of neuropathological findings. 47 On the other hand, Duncan et al. 43 found no male gender relationship with various neuropathological/neurotransmitter findings in SIDS brains. 43 Suffice to say, the role of infection in SIDS has been largely ignored by mainstream researchers.

Explaining the prone position risk factor

Blackwell et al. 48 and Goldwater 49 , 50 listed the genetic, developmental and environmental SIDS risk factors, all indicating susceptibility to infection. This list, with some modifications, is shown in Table  1 . This information might help convince researchers of the importance of infection in SIDS.

A convincing explanation of the risk factor of prone sleep position has not been achieved by the mainstream. There is, however, a compelling explanation provided in two well-designed and independent, geographically disparate epidemiological studies (Tasmanian 51 and Scandinavian 52 ) that link infection (with prone sleep position) to SIDS. In the Tasmanian study, infection and prone sleep position featured strongly: the study revealed a 10-fold increased risk of SIDS if prone-sleeping babies were ill with features of an infection, but it was associated with only a slight increase in risk among infants considered well. The Scandinavian study revealed a 29-fold increase in risk if prone-sleeping babies had an infection. Both studies showed that exposure to cigarette smoke increased the risk of SIDS. Smoke and infection combine with lethal consequences: in general, bacterial and viral infections can be synergistic 53 , 54 and both are exacerbated by exposure to smoke. 55

There are laboratory findings on SIDS which point to the underlying infection. These are set out in Table  2 .

Prone sleep position and the Back-to-Sleep/Reducing-the-Risks campaigns

The BTS and RTR campaigns have drawn some of their success from an anomaly of how SIDS deaths were recorded in the 1970s, 1980s and 1990s. There is compelling evidence of diagnostic shifting during those decades resulting in a possible exaggerated rise in SIDS numbers in the 1980s and a complimentary fall in the 1990s. 56 , 57 , 58 , 59 , 60 , 61 , 62 The introduction of new infant vaccines in 1990 could possibly have contributed. The apparent relationship between the BTS/RTR campaigns and the reduction in SIDS deaths has not been subjected to rigorous scientific scrutiny. Assumptions have been accepted without question. This is not to say that putting babies on their backs to sleep has not had beneficial effects. However, the effect of supine sleeping in the USA and several other countries has plateaued and SIDS numbers remain unacceptably high. 63 Moreover, SIDS deaths significantly increased between 2019 and 2020. 64 It is yet to be determined whether SARS-Cov-2 virus played a role.

SIDS is largely a disease of poverty, poor hygiene, overcrowding, prematurity, exposure to smoke in pregnancy and postnatally. These are features common to many transmissible infectious diseases. Sleeping prone on second-hand mattresses, 33 the parental bed, 31 or sofa 32 (contaminated surfaces) increases the risk of SIDS, as do male sex 65 and high birth order with older siblings bringing viral infection home. 65 SIDS is more frequent in rural areas 66 and tends to occur more frequently in winter. 67 , 68 These facts should alert us to the possibility of an epizootic agent playing a role, in addition to seasonal respiratory viruses. LCMV would fit well here. 69 As mentioned, a convincing SIDS animal model has been demonstrated with this virus. 19

All research should be founded on logical and scientifically plausible constructs. Without these, a successful conclusion would be impossible. The apparent lack of progress in determining a cause or causes of SIDS (despite the help of twenty-first-century science and technology) should call for a reappraisal of the fundamental mainstream hypotheses.

SIDS research is encumbered with unusual limitations; 70 these include ethical issues regarding consent for obtaining and retaining tissue, and the problem of difficulty in obtaining suitable control material for meaningful research. Notwithstanding these, infection, a key pointer in the SIDS story, has been largely ignored by mainstream research or given minimal attention. Few, if any, of the key infection-related papers on SIDS mentioned above are ever cited in mainstream papers. Is this citation amnesia 71 or the ‘disregard syndrome?’ 72 Both are well described in many areas of scientific research and are counterproductive and unethical. The basis of this failure to acknowledge established evidence of the role of infection in SIDS is difficult to understand, but its origins are likely to involve the politics of research grant funding and restrictive thinking. Continuation of such a narrowed approach will delay the explanation of the tragic enigma of SIDS. It is surely time to reconsider and collaborate. The items listed in Tables  1 and 2 provide fertile ground upon which to develop productive research outcomes. The overwhelming number of infection-related factors, including risk factors (age, sex, immunity, smoke exposure, seasonality, rural preponderance, etc.), would surely invite serious investigation. Using contemporary application of Koch’s postulates 73 interpretation of key infection-related findings such as staphylococcal toxins in SIDS tissues 9 , 10 , 11 , 12 , 13 , 14 , 15 (especially when these are found in cases from three different geographical regions 15 ) would, on the evidence, be regarded by infectious diseases experts as ‘the main cause of death’ in babies meeting the SIDS definition. Paradoxically, if a multidisciplinary death review panel agreed that a staphylococcal toxin was the cause of death, then, based on the Bajanowski et al. recommendations, 20 the case would then be classified as an explained infant death. It is reasonable to ask why the staphylococcal toxin findings 9 , 10 , 11 , 12 , 13 , 14 , 15 in more than 50% of cases have been ignored for so long and that routine testing for these toxins had not been widely applied by those responsible for investigating sudden unexpected infant deaths? Given the findings of this review, a way forward could benefit from a broader collaborative approach to this singularly challenging task.

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Goldwater, P.N. Current SIDS research: time to resolve conflicting research hypotheses and collaborate. Pediatr Res 94 , 1273–1277 (2023). https://doi.org/10.1038/s41390-023-02611-4

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Defined preventive interventions for children under five years of age: evidence summaries for primary health care in the WHO European region

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Sudden infant death syndrome prevention

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We looked at existing recommendations and supporting evidence for successful strategies to prevent the sudden infant death syndrome (SIDS).

We conducted a literature search up to the 14th of December 2020 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.

Current evidence supports statistical associations between risk factors and SIDS, but there is globally limited evidence by controlled studies assessing the effect of the social promotion strategies to prevent SIDS through knowledge, attitude and practices, due to obvious ethical reasons. A dramatic decline in SIDS incidence has been observed in many countries after the introduction of “Back to Sleep” campaigns for prevention of SIDS. All infants should be placed to sleep in a safe environment including supine position, a firm surface, no soft objects and loose bedding, no head covering, no overheating, and room-sharing without bed-sharing. Breastfeeding on demand and the use of pacifier during sleep time protect against SIDS and should be recommended. Parents should be advised against the use of tobacco, alcohol and illicit drugs during gestation and after birth.

Introduction

The World Health Organization (WHO) European Region is developing a new pocket book for primary health care for children and adolescents in Europe. This article is part of a series of reviews, which aim to summarize the existing recommendations and the most recent evidence on preventive interventions applied to children under 5 years of age to inform the WHO editorial group to make recommendations for health promotion in primary health care. In this article, we looked at existing recommendations and supporting evidence for successful strategies to prevent the sudden infant death syndrome (SIDS).

What is the sudden infant death syndrome?

SIDS is ‘the sudden death on an infant under one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history’ [ 1 ]. The sudden unexpected infant death (SUID) or sudden unexpected death in infancy is a broader term referring to ‘a sudden and unexpected death, whether explained or unexplained, occurring during infancy’ and includes the SIDS and other sleep-related infant death such as ill-defined death and accidental suffocation and strangulation in bed [ 2 ]. Therefore, for any SUID, when the cause of death after case investigation is not attributed to any explained cause such as suffocation, asphyxia, infection or metabolic diseases, the case is classified as SIDS, which is an ultimate diagnosis reached by exclusion.

Although defined by an unexplained origin, several risk factors have been associated with the incidence of SIDS. Despite the success of several preventive campaigns started in the 1990’s targeting modifiable risk factors related with the SIDS, it remains a leading cause of infant mortality in high-income countries. The rate of SIDS was estimated at 19.8 per 100,000 live births among 14 European countries between 2005 and 2015, ranging from 1.4 to 29.2 between countries [ 3 ]. It is therefore imperative to identify and assess the effective strategies to prevent SIDS.

Key questions

Which are the most important risk factors associated with the SIDS?

Which are the successful strategies to prevent SIDS?

Search methods and selected manuscripts

We described the search methods, data collection and data synthesis in the second paper of this supplement (Jullien S, Huss G, Weige R. Supporting recommendations for childhood preventive interventions for primary health care: elaboration of evidence synthesis and lessons learnt. BMC Pediatr. 2021. https://doi.org/10.1186/s12887-021-02638-8 ).

We conducted the search up to the 14th of December 2020, by manual search and by using the search terms “sudden death”, “unexpected death”, “sudden infant death syndrome”, and “SIDS”. We found a bulletin from the WHO with a short comment on the topic. No document was identified from the US Preventive Services Task Force (USPSTF) website, but we found their position published through the American Academy of Pediatrics (AAP), in a manuscript that was first published in 2011, with updated recommendations in 2016 [ 2 ]. The recommendations from the PrevInfad workgroup (Spanish Association of Primary Care Pediatrics) were also published in 2016, together with their supportive document [ 4 ]. The Centers of Disease Control and Prevention (CDC) supports the AAP recommendations and summarize them in their website [ 5 , 6 ]. We found 72, 36, 18, and 10 documents by using the search terms cited above, respectively, in the National Institute for Health and Care Excellence (NICE) official website. Out of them, we retrieved two NICE guidelines that addressed SIDS, but recommendations were from a single guideline [ 7 ]. The search in the Cochrane library returned 17 reviews and no protocols. By screening the titles and abstracts, we included one systematic review [ 8 ].

All the included manuscripts for revision in this article are displayed in Table  1 .

Existing recommendations

Both the WHO and CDC promote the AAP recommendations. In the NICE guideline ‘Postnatal care up to 8 weeks after birth’ the recommendations provided are as follows [ 7 ]:

“Recognise that co-sleeping can be intentional or unintentional. Discuss this with parents and carers and inform them that there is an association between co- sleeping (parents or carers sleeping on a bed or sofa or chair with an infant) and SIDS.”

“Inform parents and carers that the association between co-sleeping (sleeping on a bed or sofa or chair with an infant) and SIDS is likely to be greater when they, or their partner, smoke.”

“Inform parents and carers that the association between co-sleeping (sleeping on a bed or sofa or chair with an infant) and SIDS may be greater with parental or carer recent alcohol consumption, or parental or carer drug use, or low birthweight or premature infants.”

The AAP and the PrevInfad documents, published the same year, provide a list of very similar recommendations that we summarized together with the strength of each recommendation (as per their authors) in Table  2 . Many of the modifiable and non-modifiable risk factors identified for SIDS are very similar to those for other sleep-related infant deaths such as suffocation or asphyxia. In their document, the AAP provides recommendations for a safe sleep environment with the aim of reducing all sleep-related infant deaths [ 2 ]. Recommendations related to sleeping environment apply to infants up to 12 months of age.

Existing evidence

With the aim to analyse preventive measures to reduce SIDS, factors that increase or decrease the risk of SIDS have been identified. However, the identification of statistical associations between risk factors and SIDS does not prove a causal link or mechanistic explanation. The different institutions developed their recommendations based on these statistical associations together with the assessment of other factors such as the balance between potential benefit from reducing the risk and any harm derived from the preventive strategy. Although the evidence exposed below show the association between identified risk factors and SIDS, there is limited evidence assessing the effect of the recommendations through knowledge, attitude, and practices, with the exception of the sleep position [ 4 , 11 ].

We mainly retrieved the evidence from the two supportive documents developed for the PrevInfad and AAP recommendations [ 2 , 4 , 10 ]. Therefore, the references cited below were used in these documents and do not correspond with an additional literature review conducted by the authors of this summary document. As already indicated by the AAP, there are no randomized controlled trials (RCTs) with regard to SIDS and other sleep-related deaths. Evidence mainly derives from case-control studies and national pre and post intervention data. Currently, it is very unlikely that any clinical trial will be initiated to assess effectiveness of known risk factors due to obvious ethical reasons. The only Cochrane review identified aimed to assess the use of infant pacifiers for reduction of SIDS but no RCT addressing the topic was found. We summarize below the evidence supporting the recommendations addressing the most relevant or controversial risk factors.

Modifying behaviours and care related to the sleeping environment and nutrition

Supine position for sleeping, recommendations.

“Avoid prone sleeping position in infants less than 6 months old. Sleeping in supine decubitus position is the safest and clearly preferable to lateral decubitus. Only in a specific medical indication (severe gastroesophageal reflux, active respiratory illness in preterm infants and certain upper way malformations) can prone decubitus be recommended.” ( Grade A recommendation ) [ 4 ].

“To reduce the risk of SIDS, infants should be placed for sleep in the supine position (wholly on the back) for every sleep period by every caregiver until 1 year of age. Side sleeping is not safe and is not advised.” ( Grade A recommendation ) [ 2 ].

This is the main modifiable risk factor identified for SIDS. Consistent findings across the world and decreasing trend on the incidence of SIDS in countries that have implemented the ‘Back to Sleep’ recommendations support the hypothesis that the supine position for sleep protects against SIDS [ 4 ]. Indeed, case-control studies, conducted in Europe and the United States indicate that the prone position during sleep increases the risk of SIDS as compared to supine position with adjusted odds ratio (AOR) ranging from 2.3 and 13.1 [ 12 , 13 , 14 , 15 , 16 ]. Similarly, the lateral side has been associated with increased risk of SIDS when compared to supine position, with AOR ranging from 1.31 to 2 [ 13 , 14 , 15 ]. These five case-control studies were conducted in the US [ 12 , 13 , 16 ], the UK [ 14 ] and in 20 regions of Europe [ 15 ] from 1992 and 2000, including 1432 SIDS cases and 3905 matched controls. In addition, countries with preventive campaigns for avoiding prone position in infants during sleep that have been successful for reducing the prevalence of infants sleeping in such position have estimated a 30 to 50% decrease in the mortality associated to SIDS [ 4 ].

Supine position does not increase the risk of choking and aspiration [ 2 , 4 ]. Only infants with certain upper airway disorders such as type 3 or 4 laryngeal clefts in which the risk of death from gastroesophageal reflux disease may outweigh the risk of SIDS can be considered to be placed in prone position during sleep [ 2 ].

Supervised awake tummy time

“When awake, infants can be placed in prone position with supervision.” (Recommended but not graded) [ 4 ].

“Supervised, awake tummy time is recommended to facilitate development and to minimize development of positional plagiocephaly.” ( Grade B recommendation ) [ 2 ].

Sustained supine position combined with restricted motor abilities lead to postural plagiocephaly [ 4 ]. In addition, prone position facilitates the development of the upper shoulder girdle strength [ 2 ]. Therefore, although there is no data to support this recommendation and to establish the frequency and duration of it, experts recommend “a certain amount of prone positioning, or ‘tummy time,’ while the infant is awake and being observed” [ 17 ].

Firm surface for sleeping

“Firm surfaces should always be used: the mattresses must be firm and maintain their shape even when covered with the sheets, so that there are no gaps left between the mattress and the crib railing. Adjustable sheets and specific bedding should be used.” [ 4 ].

“Infants should be placed on a firm sleep surface (eg, mattress in a safety-approved crib) covered by a fitted sheet with no other bedding or soft objects to reduce the risk of SIDS and suffocation.” ( Grade A recommendation ) [ 2 ].

Soft sleep surface has consistently been reported as a risk factor for SIDS. A case-control study conducted in the US among 260 SIDS cases and 260 matched living controls, showed an association between soft sleep surface and a higher risk of SIDS (AOR 5.1 [95% CI: 2.9 to 9.2]) [ 12 ]. The risk was significantly higher when prone position and soft sleep surface were combined (AOR 21.0 [95% CI: 7.8 to 56.2]) [ 12 ]. Soft mattresses could create a pocket around the infant within which the CO2 dispersal is limited, increasing the risk of rebreathing or suffocation in infants placed in prone position [ 2 , 18 ].

Soft objects and loose bedding away from the sleep area

“Other loose accessories such as blankets, quilts and pillows, cushions, soft objects and neck pendants” should be kept away from the infant’s sleep area [ 4 ].

“Keep soft objects and loose bedding away from the infant’s sleep area to reduce the risk of SIDS, suffocation, entrapment, and strangulation.” [ 2 ].

Several publications pointed out that soft objects (pillows, pillow-like toys, quilts, comforters, sheepskins) and loose bedding (blankets, nonfitted sheets) can cause the obstruction of an infant’s external airways, leading to an increased risk of suffocation, rebreathing, and SIDS [ 2 , 10 ]. In an already mentioned study, the use of pillow and covering the head or face with bedding were associated to an increased risk of SIDS (AOR 3.1 [95% CI 1.6 to 5.8] and AOR 2.5 [95% CI 1.2 to 5.2]) [ 12 ]. A higher risk was found when the use of pillow was combined with prone position (AOR 11.8 [95% CI 4.0 to 34.4]) [ 12 ]. In another study conducted in the US among 206 SIDS cases showed that the use of comforters (AOR 2.46) and pillows (AOR 3.31) increased the risk of death (95% CI not provided, but p  ≤ 0.05 for both comparisons) [ 19 ]. Other studies reported that infants victim of SIDS were found in supine position with their head covered by loose bedding.

Avoid overheating and head covering

“Avoid overheating and avoid the head to be covered while sleeping” “The recommendation to prevent the head from covering is to put the infant at the foot of the bed and the blanket up to the chest.” ( Grade I recommendation ) [ 4 ].

“Avoid overheating and head covering in infants.” “In general, infants should be dressed appropriately for the environment, with no greater than 1 layer more than an adult would wear to be comfortable in that environment.” ( Grade A recommendation ) [ 2 ].

Overheating has been identified as a risk factor for SIDS, especially when the head is covered. Both the AAP and PrevInfad have stated that several studies had shown that overheating (including external temperature and the child’s clothes) was associated with an increased risk of SIDS, but that it was difficult to provide any specific room temperature recommendation as the definition of overheating varies across studies [ 2 , 4 ]. When looking at the ‘several studies’ mentioned above, we found no references from PrevInfad, and four references cited in the AAP document. Three manuscripts are case-control studies published between 1990 and 2002 that showed an increased risk of SIDS when infants were heavily wrapped, when the heating was on all night, or when the infants slept with two or more layers of clothing, showing a small effect or a broad confidence interval [ 20 , 21 , 22 ]. The fourth study analysed data from one of the three cited case control by the same first author, and a prospective cohort, to emphasize the increased risk of SIDS when the prone position is associated with other risk factors including overheating [ 23 ]. To avoid overheat, several strategies have been put in place. PrevInfad recommends a temperature of 20 to 22 °C and to avoid excessive clothing, especially if the infant has fever. AAP recommends that ‘in general, infants should be dressed appropriately for the environment, with no greater than one layer more than an adult would wear to be comfortable in that environment’ and that ‘parents and caregivers should evaluate the infant for signs of overheating, such as sweating or the infant’s chest feeling hot to the touch’. Both identities agree that ‘there is currently insufficient evidence to recommend the use of a fan as a SIDS risk-reduction strategy’.

A systematic review including 10 case-control studies conducted between 1958 and 2003 found that the prevalence of head covering was higher in SIDS cases (24.6% [95% CI 22.3 to 27.1%]) than in controls (3.2% [95% CI 2.7 to 3.8%]) [ 24 ]. The AOR was 16.9 (95% CI 12.6 to 22.7) and the risk associated to SIDS was consistently significant across studies. The review did not establish a causal mechanism between head covering and SIDS, but the authors concluded that head covering is a major modifiable risk factor associated with SIDS. With a potential high attributable risk of 27.1% and the ease of adopting this measure with low cost and no adverse effect, avoiding head covering was adopted as a recommendation to decrease deaths related to SIDS [ 25 ]. As a strategy to avoid head covering, a ‘Feet to foot’ campaign was initiated, which recommends placing the baby at the foot of the cot. However, this strategy was established following common sense, but there is no evidence showing that this measure does reduce head covering and has any impact on SIDS.

Overall, it seems that there is low quality evidence regarding overheating and head covering and that current strategies are based on common sense that have not been proved to reduce SIDS.

Room-sharing with the infant on a separate sleep surface

“The crib in the parents’ bedroom is the safest place.” ( Grade B recommendation ) [ 4 ].

“Recommend against co-sleeping if father or mother are tobacco smokers, have drunk alcohol, anxiolytic, antidepressant or hypnotic drugs have been used and in case of extreme exhaustion. Co-sleeping is advised against also in sofas, armchairs or any other place but the bed.” ( Grade B recommendation ) [ 4 ].

“Inform parents that there is not enough evidence to recommend against bed-sharing when infants are breastfed and there are no other risk factors” ( Grade I recommendation ) [ 4 ].

“It is recommended that infants sleep in the parents’ room, close to the parents’ bed, but on a separate surface designed for infants, ideally for the first year of life, but at least for the first 6 months.” ( Grade A recommendation ) [ 2 ].

“Infants should never be placed on a couch or armchair for sleep.” [ 2 ].

Co-sleeping and bed-sharing do not mean the same. The term co-sleeping refers to parents and infant sleeping in close proximity, which can be bed-sharing (sleeping on the same surface) or sleeping in the same room in close proximity on separate surfaces [ 10 ]. Room-sharing has been shown to reduce the risk of SIDS by as much as 50% [ 2 , 4 ]. However, bed-sharing between parents and infant remains highly controversial. While bed-sharing has been associated with an increased risk of SIDS, bed-sharing has also been assessed to improve attachment and breastfeeding, considered as a protecting factor to SIDS (see below).

A meta-analysis published in 2012 and including 11 studies conducted between 1987 and 2006 looked at the association between bed-sharing and SIDS. Authors found an increased risk of SIDS among those bed-sharing with an odds ratio (OR) of 2.89 (95% CI: 1.99 to 4.18) and an increased risk among smoking mothers (OR 6.27 [95% CI 3.94 to 9.99]; 4 studies) [ 26 ]. Carpenter et al. pooled data from five case-control studies including Scotland, Germany, Ireland, other European countries, and New Zealand to look at the same association of bed-sharing and the risk of SIDS, among breastfed infants with non-smoking parents and with no maternal use of alcohol or drugs, with no other associated risk factors [ 27 ]. They found an increased risk of SIDS among infants with bed-sharing versus room sharing with an AOR of 2.7 (95% CI 1.4 to 5.3) and a higher risk in infants less than 3 months (AOR 5.1 [95% CI 2.3 to 11.4]).

Blair et al. had opposite findings when assessing the same association of bed sharing with SIDS among infants without other risk factors from two different case-control studies conducted between 1993 and 2006 in the UK [ 28 ]. They found no association between bed sharing and SIDS globally (OR 1.1 [IC 95% 0.6 to 2]) and among infants under 3 months of age (OR 1.6 [95% CI 0.96 to 2.7]). Among infants above 3 months of age, authors found bed sharing to be protector for SIDS, with an OR of 0.1 (95% CI 0.01 to 0.5). These findings were independent of whether the infant was breastfed or not. When looking at this association in presence of parents who consumed tobacco or alcohol, they found similar findings to Carpenter.

Facing these contradicting findings and recommendations between Carpenter et al. and Blair et al., the US task force requested an independent review of both manuscripts, reported by the AAP. They concluded that both studies have strengths and weaknesses, and that both studies lacked power to examine the association in subgroups of children (under or above 3 months of age). “Clearly, these data do not support a definitive conclusion that bed-sharing in the youngest age group is safe, even under less hazardous circumstances.” [ 10 ].

In summary, there is a lack of evidence to determine the balance between harm and benefits of bed-sharing among infants without other risk factors associated (parental use of tobacco or alcohol), taking breastfeeding into consideration. Accordingly, in case of breastfed infants with no other risk factors, PrevInfad recommends to inform parents that there is not enough evidence to recommend against bed-sharing ( Grade I recommendation ) [ 4 ]. However, there are specific circumstances that have been shown to substantially increase the risk of SIDS, independently to the form of feeding and that should be avoided. Those are summarized by the AAP as follows, and are in agreement with the PrevInfad and NICE recommendations [ 4 , 7 , 10 ]: “when one or both parents are smokers, even if they are not smoking in bed (OR 2.3 to 21.6); when the mother smoked during pregnancy; when the infant is younger than four months of age, regardless of parental smoking status (OR 4.7 to 10.4); when the infant is born preterm and/or with low birth weight; when the infant is bed-sharing on excessively soft or small surfaces, such as waterbeds, sofas and armchairs (OR 5.1 to 66.9); when soft bedding accessories such as pillows or blankets are used (OR 2.8 to 4.1); when there are multiple bed sharers (OR 5.4); when the parent has consumed alcohol (OR 1.66 to 89.7) and/or illicit or sedating drugs; and when the infant is bed-sharing with someone who is not a parent (OR.5.4).”

Consider offering a pacifier at naptime and bedtime

“Not rejecting the use of a pacifier during sleeping time in the first year of life seems to be a cautious measure.” ( Grade B recommendation ) [ 4 ].

“Consider offering a pacifier at naptime and bedtime” ( Grade A recommendation ) [ 2 ].

“Offer a pacifier to the infant when put to sleep in supine position, and do not reinsert it once the infant is asleep. If the infant refuses the pacifier, do not force him or her to use it.” [ 2 , 4 ].

“For breastfed infants, pacifier introduction should be delayed until breastfeeding is firmly established” [ 2 ] or until the infant is 1 month of age [ 4 ].

Although the mechanism is unclear, the use of pacifier during the sleep has a protective effect on SIDS [ 2 , 4 ]. A Cochrane review was published in 2017, after the development of both the PrevInfad and the AAP recommendations [ 8 ]. The aim of this review was to evaluate the use of infant pacifiers versus no pacifiers during sleep in reducing the risk of SIDS. However, the review authors found no randomized controlled trials addressing this topic.

Recommendations are mainly based on findings from another systematic review that was conducted by Hauck et al. and included case control studies published between 1993 and 2004 [ 29 ]. A protector effect of pacifier was shown for usual pacifier use (AOR 0.71 [95% CI 0.59 to 0.85]; 4 studies) and for use of pacifier in the last sleep (AOR 0.39 [95% CI 0.31 to 0.50]; 7 studies). Authors also estimated the number needed to treat as 2733 (95% CI 2416 to 3334), meaning that one SIDS death could be prevented for every 2733 infants using a pacifier during the sleep.

Pacifier can be introduced as soon as desired after birth in not breastfed infants, but it is recommended to delay its introduction in breastfed infants until breastfeeding is well established [ 2 , 4 ]. There is however a lack of evidence to confirm the belief that the use of pacifier interferes with breastfeeding [ 4 ].

Breastfeeding on demand

“Recommend breast-feeding on demand.” ( Grade A recommendation ) [ 4 ].

“Unless contraindicated, mothers should breastfeed exclusively or feed with expressed milk (i.e., not offer any formula or other nonhuman milk- based supplements) for 6 months, in alignment with recommendations of the AAP” ( Grade A recommendation ) [ 2 ].

Breastfeeding is a clear protective factor for SIDS. Exclusive breastfeeding is recommended for the first 6 months of life, in line with global recommendations [ 30 ]. A systematic review included 18 case control studies (published between 1976 and 2009) for meta-analysis [ 31 ]. The univariate analysis showed a protector effect of any breastfeeding (any amount for any duration) versus no breastfeeding (OR 0.40 [95% CI 0.35 to 0.44]; 18 studies), which was maintained with multivariate analysis from seven of the included studies (AOR 0.55 [95% CI 0.44 to 0.69]; 7 studies). The protective effect was higher in infants who were exclusively breastfed for any duration in univariate analysis (OR 0.27 [95% CI 0.24 to 0.31]; 8 studies), with no data provided in the included studies allowing multivariate analysis [ 31 ].

Counselling to modify beneficial behaviours and care related to maternal factors

Regular prenatal care.

“Recommend appropriated control of pregnancy and perinatal period.” ( Grade B recommendation ) [ 4 ].

“Pregnant women should obtain regular prenatal care” ( Grade A recommendation ) [ 2 ].

This recommendation is mainly based on the findings of a case control study nested in a large cohort of all live births in the US between 1995 and 1998, which aimed to identify maternal and obstetric risk factors for SIDS [ 32 ]. From 12,404 cases (SIDS) and 49,616 controls, authors found an increased risk for SIDS when there was no prenatal care (OR 1.70 [95% CI 1.44 to 2.0]).

Avoid smoke exposure during pregnancy and after birth

“Recommend against tobacco smoking to parents, especially to the mother during pregnancy, although also after delivery. Don’t allow anybody smoking in the infants’ presence.” ( Grade A recommendation ) [ 4 ].

“Smoking during pregnancy, in the pregnant woman’s environment, and in the infant’s environment should be avoided.” ( Grade A recommendation ) [ 2 ].

Maternal smoking is an independent risk factor for SIDS. This association has been found independently for both maternal smoking during pregnancy and after birth, from several studies [ 2 , 4 ]. The large case-control nested study mentioned above for prenatal care, also associated maternal smoking during pregnancy with an increased risk of SIDS (OR 3.19 [95% CI 3.03 to 3.37]) [ 32 ]. Several studies have confirmed the association between foetal nicotine exposure and neuropathological and neurochemical anomalies. These anomalies are translated into dysregulation of the autonomic nervous system, prompting disruption of ventilation and cardiac rhythm control, leading to sudden and unexpected death [ 33 ]. In addition, it is also well known that smoke exposure is associated with an increased risk of preterm birth and low birth weight, which are both identified risks for SIDS [ 2 ].

Regarding exposure to smoke in any circumstances such as in the same house or car, 13 studies found that the maternal or paternal habit of smoking after birth increased the risk of SIDS 2.31 times (95% CI 2.02 to 2.59%) [ 4 ]. The association between smoke exposure and SIDS is dose dependent. The risk increases substantially when there is bed sharing between the infant and the smoker, even if the adult does not smoke in bed [ 10 ].

Avoid alcohol and illicit drug use during pregnancy and after birth

“Avoid the prenatal and postnatal use of alcohol and illegal drugs.” ( Grade B recommendation ) [ 4 ].

“Avoid alcohol and illicit drug use during pregnancy and after the infant’s birth.” ( Grade A recommendation ) [ 2 ].

The use of alcohol or illicit drugs during prenatal (periconceptional and gestational) and postnatal periods has been associated with increased risk of SIDS [ 2 , 4 ]. Similarly to smokers, the risk increases when alcohol or drug user share the bed with the infant [ 2 , 4 ].

Summary of findings

Current evidence supports statistical associations between risk factors and SIDS, but there is globally limited evidence by controlled studies assessing the effect of the social promotion strategies to prevent SIDS through knowledge, attitude and practices, due to obvious ethical reasons.

A dramatic decline in SIDS incidence has been observed in many countries after the introduction of “Back to Sleep” campaigns for prevention of SIDS.

All infants should be placed to sleep in a safe environment including supine position, a firm surface, no soft objects and loose bedding, no head covering, no overheating, and room-sharing without bed-sharing.

Breastfeeding on demand and the use of pacifier during sleep time protect against SIDS and should be recommended.

Parents should be advised against the use of tobacco, alcohol and illicit drugs during gestation and after birth.

The American Academy of Pediatrics recommendations updated in 2016 are the most comprehensive resume about SIDS prevention.

Availability of data and materials

Not applicable.

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I am very grateful to María Jesús Esparza, Laura Reali, and Gottfried Huss for carefully reviewing and providing valuable feedback for each article. I am also grateful to Ralf Weigel and Gottfried Huss for proofreading the final version of this document.

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Jullien, S. Sudden infant death syndrome prevention. BMC Pediatr 21 (Suppl 1), 320 (2021). https://doi.org/10.1186/s12887-021-02536-z

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Does citing early SIDS research skew contemporary conclusions?

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Research on infants who have allegedly succumbed to sudden infant death syndrome (SIDS) has been of variable quality over the years. Even now peer-reviewed papers are being published on cases termed ‘SIDS’ without autopsies having been performed, despite this being a requirement of the three major definitions for over five decades. Clearly cases used in earlier research studies could not have complied with the requirements of as-yet unpublished definitions/guidelines. For this reason care must be taken in citing initial papers as their results may have been skewed by the presence of non-SIDS cases. This may have particular relevance for meta analyses. Reviewing the literature on substance P and its relationship to SIDS provides an excellent example of how diametrically opposed conclusions were reached at different time points. Early studies on SIDS, and studies that use cases that were classified before the standard NICHD and San Diego definitions, should, therefore, be approached with a degree of scepticism and not cited in contemporary papers or at meetings as they have the potential to confuse rather than clarify.

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Byard, R.W., Vink, R. Does citing early SIDS research skew contemporary conclusions?. Forensic Sci Med Pathol (2024). https://doi.org/10.1007/s12024-024-00848-x

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PERSPECTIVE article

The science (or nonscience) of research into sudden infant death syndrome (sids).

• Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia

This Viewpoint paper presents a timely and constructive critique of mainstream SIDS research. It is concerning that twenty-first century medical science has not provided an answer to the tragic enigma of SIDS. The paper helps explain why this is so and illustrates possible shortcomings in the investigation of Sudden Infant Death Syndrome/Sudden Unexplained Infant Death (SIDS/SUID) by mainstream researchers. Mainstream findings are often based on questionable and dogmatic assumptions that return to founding notions such as the Triple Risk Hypothesis and the contention that the mechanisms underlying SIDS/SUID are heterogeneous in nature. The paper illustrates how the pathological findings in SIDS have been under-investigated (or ignored) and that key epidemiological risk factors have slipped from memory. This apparent amnesia has resulted in failure to use these established SIDS facts to substantiate the significance of various neuropathological, neurochemical, or other research findings. These unsupported findings and their derivative hypotheses are therefore ill-founded and lack scientific rigor.

Conclusion: The deficits of SIDS “science” revealed in this paper explain why the SIDS enigma has not yet been solved. To make progress in understanding SIDS, it is important that researchers, as scientists, uphold standards of research. Encouragement for new directions of research is offered.

Introduction

Over the past 30 years, as a Sudden Infant Death Syndrome (SIDS)/Sudden Unexplained Infant Death (SUID) researcher, the author has followed mainstream's progress and has realized that mainstream approaches to the problem are flawed at a fundamental level. To address this, leading peer-reviewed publications were reviewed using PubMed and Google Scholar (search terms: “Sudden Infant Death Syndrome,” “SIDS”) to provide evidence as to why the SIDS enigma remains unexplained. Where possible, papers cited were selected on the basis of the senior author having published a minimum of 10 papers on the subject and that the papers concerned the prevailing hypotheses on SIDS. While this paper is a critique of mainstream research, its aim, through the arguments herein put, is to encourage SIDS researchers to reconsider their hypotheses in the hope of yielding improved research outcomes.

There are not many issues in medical science that lack explanation. It could be argued that current mainstream SIDS research remains at a stage not dissimilar to that of peptic ulceration in the pre- Helicobacter era. To achieve an understanding of a condition, respect must be paid to the essential elements of the condition: these elements include the epidemiology (e.g., risk factors), the pathology (including the laboratory findings), and the physiological findings. Based on these, a case definition is developed. The definition of SIDS has undergone several iterations ( 1 – 3 ). The often-used San Diego definition ( 3 ) states “the sudden and unexpected death of an infant under 1 year of age, with the onset of the lethal episode, apparently occurring during sleep, that remains unexplained after a thorough investigation including a performance of a complete autopsy, and review of the circumstances of death and the clinical history.” The definition is unhelpful in that its usefulness is limited to being exclusive. However, this definition, in extended form, is more helpful than previous ones, as it provides categories based on some pathological findings. All definitions could be misleading in relation to the reference to sleep . This allusion has led many researchers to explore physiological events during infant sleep, and such work has extended to investigate arousal mechanisms ( 4 , 5 ). With very few exceptions, the results of these investigations do not refer to epidemiological risk factors or the gross pathological findings of SIDS. Therefore, these findings are unsupported in obvious ways. Death during sleep is not a prerequisite for diagnosing SIDS/SUID: cases occur in awake infants ( 6 ), although the San Diego definition ( 3 ) with its “ during sleep” restriction would exclude these cases. Such restriction is only academic, as proof of being asleep cannot be ascertained. Additionally, it is known that SIDS occurs at all times of the day, suggesting that an infant could have been awake. Most SIDS cases occur between midnight and 0600 h ( 7 ).

A more recent development regarding the SIDS definition deemed as a new classification of SUID has surfaced, which is heavily weighted toward asphyxia as the underlying event ( 8 ). The study re-examined cases originally designated SIDS; a panel of reviewers ascertained that asphyxia potentially contributed to death in 40–59% of the cases based on a potentially risky sleeping environment. The authors “ suggest that SIDS not be used if a potential (but not necessarily proven) other cause of death exists .” This should raise many questions: no mention in this article of extrathoracic petechial hemorrhages was made. Such a pathological finding would raise suspicion and strongly indicate an asphyxial mode of death. Other risk factors, such as prone sleeping and features of infection, were not examined, nor were the ages of cases reported; asphyxia appears to be uncommon in older cases than the peak age (2–4 months) of SIDS. In a similar study, Garstang et al. ( 9 ) found that only 14% of SUID could be reclassified as caused by asphyxia, which puts the findings of Randall et al. under further question.

The Importance of Autopsy Findings

In understanding the fundamental facts about SIDS, the shortcomings of mainstream SIDS/SUID research will become obvious. The current dogma purports that the gross pathology of SIDS is unremarkable ( 10 ). This is fundamentally erroneous. As with the investigation of adult deaths the autopsy remains the mainstay for proper diagnosis ( 11 ). The same applies to the investigation of SIDS. Standardized autopsy protocols go some way in improving the investigation of sudden deaths but these, unfortunately, are not universally applied. In regard to SIDS, where autopsies have been conducted by pediatric pathologists, it is remarkable that the pathological findings ( 12 , 13 ) are very consistent and can be applied to approximately 90% of cases. The gross findings include

• Intrathoracic petechial hemorrhages in and on the thymus, epicardium, and visceral pleura/lungs.

• Heavy fluid-laden lungs with early subtle acute inflammatory changes.

• Heavier than normal thymus ( 13 , 14 ), brain ( 13 – 21 ) and liver ( 13 , 22 , 23 ).

• Liquid blood in the chambers of the heart ( 12 ).

• Empty bladder ( 12 ).

• Raised core temperature ( 24 ).

The autopsy extends to histopathological findings and laboratory findings. These are discussed below.

Laboratory Data

As part of the autopsy investigation, laboratory findings can also provide clues to underlying pathogenetic mechanisms in SIDS/SUID. These include increased tissue proinflammatory cytokines IFN-alpha, TNF and IL-6 ( 25 – 30 ), including increased IL-6 in cerebrospinal fluid and vitreous in the eye ( 26 , 31 ). Raised serum fibrin degradation products (FDPs, D-dimer) ( 32 ) provide another clue, as does lower than normal serum melatonin ( 33 ). Infection and sepsis stimulate the release of serotonin, increasing serum levels of this related hormone ( 34 ). Histopathological findings also support the infection model. These include low-grade lung inflammation ( 35 ) and/or myocardial inflammation ( 35 ) and changes typical of haematogenous shock ( 36 ) and shock-like diaphragmatic muscular degeneration ( 37 , 38 ). Neuropathological features that could reflect shock include neuronal apoptosis ( 39 ) and microglial activation ( 40 ). Microbiological investigation reveals detection of bacterial toxins in SIDS tissues ( 41 , 42 ), isolation of bacterial pathogens (e.g., Staphylococcus aureus and Escherichia coli ) from normally sterile sites ( 43 , 44 ), and despite these clues, infection and sepsis have not been widely examined in relation to most aspects of SIDS research and despite the findings of those proposing the Infection Model of SIDS ( 25 – 32 , 35 , 41 – 49 ).

While serotonin has been a major focus of SIDS research, the work has lacked meaningful results because there has been no or minimal supporting epidemiological or clinicopathological correlation ( 50 ). Without this, interpretation of results is impossible. In regard to serotonin levels, these are confusing; for example, some studies show raised blood levels ( 50 ), while brainstem levels of tryptophan hydroxylase and serotonin receptor binding were found to be lowered ( 51 ). This seems counterintuitive. Moreover, important correlations with SIDS risk factors could not be found in these publications.

Physiological Clues

Also important are clinicophysiological findings ( 52 ): computer memory monitored babies have been recorded as apparent SIDS/SUID deaths. These recordings demonstrated bradycardia followed by asystole. Gasping respirations and cessation of breathing followed the cardiological events and suggest that the cause lies within the heart rather than respiratory control. Prone sleeping has been assumed to be related to asphyxia, but its likely real reason for increased SIDS risk has been overlooked (vide infra) .

Triple Risk Hypothesis

In fashioning a research direction, a number of models incorporating known risk factors have been proposed and refined ( 53 – 55 ). These eventuated in the SIDS “triple risk” model ( 56 , 57 ). It supposes that the risk of SIDS is increased when a vulnerable infant is exposed to environmental stressors. The three components of the model are (1) a critical developmental period in homeostatic control (from 1 to 6 months, especially 2–4 months, the “SIDS peak”); (2) exposure to stressors (overheating, infection), and (3) underlying susceptibilities (age, sex, race, etc.) ( 57 ). The model has since been modified, but its essence remains much the same ( 57 ). Guntheroth and Spiers ( 57 ) concluded after analyzing in detail the series of hypotheses… “ The advantage of any of the triple risk hypotheses in understanding SIDS has not been demonstrated.” This warning has not been heeded, and researchers still use the triple risk hypothesis as a platform upon which they base their research. More recently, Spinelli et al. ( 58 ) errantly continue the notion of its usefulness: the authors state that it… “ assists in helping to conceptualize SIDS” and “ continues to provide an extremely useful framework to guide current and future research.” Of additional concern is the emphasis of the triple risk hypothesis on homeostatic control . This has been misleading and requires new thinking.

In seeking a homeostatic control answer, researchers tried to link apparent abnormalities in the brainstems of SIDS cases ( 59 , 60 ). They found that 40–50% of SIDS babies' brainstems appeared abnormal. Some controls had similar abnormalities.

This led a quest for a common underlying pathogenetic mechanism and advanced the theory of failure in homeostatic control (breathing and/or cardiac arrhythmia) to be central to SIDS. This approach has yet to provide a definitive answer despite concerted efforts. This focus on homeostatic control has generally ignored [with a few exceptions ( 39 )] the key clinicopathological and epidemiological findings herein set out. The physiological monitoring information clearly relates to cardiac control ( 52 ). Investigation into the heart (and potential underlying mechanisms, e.g., sepsis) is therefore appropriate. Continuation of respiratory control research without physiological evidence of an abnormality in respiratory control would deem this line of research fruitless. Evidence of chronic hypoxia in some SIDS cases ( 11 , 61 ) may have led researchers to explore a respiratory-based paradigm; however, data pertaining to “chronic hypoxia” are contradictory ( 62 ) and place this paradigm on shaky ground. Consideration of and active research into other possible causes of hypoxia (sepsis being one) ( 62 , 63 ) has not occurred.

Infection and Epidemiology

Several authors have hypothesized that SIDS could be caused by a dual infection with a respiratory virus and toxigenic bacteria ( 22 , 41 – 49 ).

The epidemiology and gross pathology of SIDS clearly demonstrate evidence for respiratory viral infection, which could possibly act as a SIDS trigger ( 48 ). In many studies, more than 75% of SIDS babies featured recent or active respiratory tract infections ( 64 , 65 ).

In matched case-control studies, living babies showed rates of infection similar to those of SIDS and reflected the epidemiology extant at the time. Numerous studies [reviewed by Prandota et al. ( 66 )] have attempted to demonstrate a link between respiratory infection and SIDS. These studies naturally were unable to show a difference in viral infection [and lung pathology ( 67 )] between SIDS and controls. However, the results of the study by Bajanowski et al. ( 68 ) favored the hypothesis that respiratory viral infection could act as a trigger in SIDS. Despite the positive findings of Bajanowski et al. ( 68 ) researchers tended to discount the possible role of infection in SIDS. Regrettably, this attitude has largely continued to this day, despite all the established infection-related epidemiological features listed below:

• seasonality (the winter peak) ( 47 , 69 )

• a pronounced association with epidemic viral diseases, including influenza A ( 70 , 71 )

• Acute illness (e.g., URTI/otitis media) with symptoms present at the time of death but are not significant as a cause of death ( 72 ). Susceptibility to infection could be influenced by genetic make-up (vide infra)

• male sex ( 73 )

• Low socioeconomic status ( 74 ), as measured by deprivation indices, overcrowding, maternal age and maternal education, etc.

• sleeping on contaminated surfaces (the parental or other shared bed ( 75 ), used mattress ( 76 ), or sofa ( 77 )

• high birth order wherein older siblings bring viral infection home ( 78 )

• prematurity/preterm birth ( 79 )

• smoke exposure ( 80 )

• lack of breastfeeding ( 81 )

• waning maternal transplacental IgG ( 82 )

• Overcrowding, low socioeconomic status ( 74 , 83 )

• Prone sleep position (the effect of this appears only to operate when there is a coincident infection) ( 84 – 86 ) (vide infra) .

Prone Sleep Position and Infection

The above features uphold the infection model for SIDS. Interaction between viral respiratory tract infection, prone sleeping and secondary nasopharyngeal bacterial flora changes leading to fatal sepsis provides a simple and plausible mechanism ( 48 , 49 ).

The role of infection in SIDS has been previously addressed ( 45 , 46 ) and remains salient. As suggested above, the mechanism underlying SIDS/SUDI could involve an abnormal response to viral respiratory infection at a time a bacterially colonized infant becomes challenged by a bacterial toxin. An experimental model for SIDS was suggested by Nobel Laureate Peter Doherty and his colleagues: mice exposed to a virus and challenged with a staphylococcal enterotoxin died of hematogenous shock when dually exposed. Mice did not die when exposed to the single agents ( 87 ).

Except for several research groups ( 41 , 42 , 45 , 48 , 49 , 82 , 88 – 94 ), support for a role of infection has been largely unexplored by mainstream SIDS researchers. The Tasmanian SIDS Study of Ponsonby et al. ( 84 ) unaccountably failed to reawaken interest in infection. The study was able to reveal the plausibly true nature and effect of prone sleep position and showed that the risk of SIDS was increased 10-fold if a baby slept prone when it had features of a concurrent upper respiratory tract or other viral-like illness . In addition, the risk of prone sleeping was hardly affected if infants were apparently infection-free. The Nordic Epidemiological Study ( 85 , 86 ) confirmed the Tasmanian findings and showed an even higher risk (29-fold) of prone-plus-infection . Mainstream SIDS researchers have failed to acknowledge or appreciate this important finding: a nearly two-decade blind spot that may have kept a solution to the SIDS problem in the dark.

Studies featuring epidemiological, sociological and pregnancy risk factors for the prone sleeping position in SIDS often showed a relationship to winter seasonality ( 95 , 96 ). It is surprising that these studies overlooked the obvious connection with infection. However, other studies had no trouble making the connection ( 96 ). It is of value to quote from the latter study by Froggatt et al. ( 97 ) “Any orthodox interpretation of our results must ascribe some role to infection, mainly respiratory infection. The greatest incidence is in Belfast among the lowest socioeconomic groups and the most crowded houses, in the coldest months, with serial correlation between SUD frequency and documented major virus epidemics, and with “season”/“city” contingency. Cases in Belfast in the winter being disproportionately prevalent;” ( 97 ).

The sleeping position of babies is featured in numerous recent and current SIDS research papers. Researchers have posited (without providing supportive evidence) that prone sleep position has a causal relationship with mortality ( 98 ). Such uncorroborated statements are not scientifically acceptable and have until now remained unaddressed. SIDS occurs in supine and side sleeping infants.

Heterogeneous Pathogenesis vs. Single Mode of Death

Another aspect of SIDS research is the dogma promoting the notion of a heterogeneous pathogenetic process. As indicated above, the Triple Risk Hypothesis ( 56 – 58 ) has led the approach to the SIDS problem. The hypothesis' ( 56 – 58 ) focuses on homeostatic control , and the generally accepted abiding notion that SIDS has a heterogeneous pathogenesis deserves further consideration. This question has been put forth in previous publications: ( 23 , 45 , 46 ) why do ~90% of SIDS cases have very similar gross pathological findings? The consistent finding of intrathoracic petechiae involving the thymus, pleura and heart, the unclotted/liquid heart chamber blood, the congested lungs (usually with low-grade inflammatory changes), the empty bladder, the raised core temperature, and the characteristic organ weight findings (a large thymus, brain and liver) ( 46 ) make this collective pathology an important phenomenon that could not plausibly be a coincidence. On balance of probability, heterogeneous pathogenesis would imply a panoply of various pathological findings and therefore several implied modes of death. Similar pathological findings in any collection of SIDS/SUID babies logically point to a single mortal process. Other or absent pathological findings (not conforming to the classical gross pathology of SIDS), which could include cases resulting from genetic mutations resulting in cardiac arrhythmia, etc. would be candidates for the remaining ~10% of cases that do not conform to the classical gross pathology of SIDS/SUID. The pathological picture in SIDS should be a guide for future research efforts.

Other Unanswered Questions

These have been discussed in detail previously ( 99 ) and deserve brief revisiting. The almost universal finding of intrathoracic petechiae in SIDS stands out as a poorly investigated phenomenon. To date, there have been no transmission electron microscopy or other relevant studies to help ascertain the nature of the vasculopathy. Studies using asphyxiated animals did not provide convincing answers ( 99 ). Another almost universal finding is liquid/unclotted blood in SIDS cases. Nevertheless, only one study has investigated this ( 32 ) and revealed increased D-dimer (FDPs), strongly suggesting coagulopathy; infection is a possible primary underlying mechanism. The review by Blackwell et al. ( 89 ) provides a comprehensive overview of key findings and risk factors and how they act through inflammatory responses and their genetic control. A number of genetic polymorphisms have been shown to be related to infection and inflammatory responses, which could help explain the increased susceptibility in SIDS babies. As indicated above, ethnicity (e.g., Australian Aboriginals and Indigenous North Americans) and male sex provide evidence of increased susceptibility and, obviously, both infer a genetic link; however, these effects can be complicated by socioeconomic and other factors (e.g., smoking) ( 89 ). The finding of cardiac ion channel mutations in a small proportion of SIDS cases remains unresolved as to whether death is with or due to the genetic mutation ( 100 ).

The consistently observed organ weight changes (heavy thymus, brain and liver) in SIDS deserve fulsome investigation. Thymic enlargement suggests some perturbation of innate or adaptive immune responses wherein infection deserves special attention ( 22 , 23 ).

New tools for investigation of SIDS such as the liquid biopsy, utilizing the science of proteomics to seek new molecular biomarkers may provide interesting results.

SIDS research appears to have lost its way because researchers appear to have forgotten or overlooked the epidemiological risk factors and clinical pathology because these are essential pointers to the underlying cause of SIDS/SUID. It is hoped that this article is seen as a constructive critique that highlights these neglected areas and provides encouragement for fresh thinking and therefore influence future SIDS research toward a more productive course and outcome. A recently published and easily tested novel hypothesis may provide new insights into the SIDS problem for it upholds all the epidemiological features of SIDS and is consistent with the clinicopathology of the syndrome ( 101 ).

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The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

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PG as the sole author, is responsible for all aspects of this paper (including conception, literature review, writing all drafts, and final version) and approved the article for publication and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Abbreviations

SIDS, sudden infant death syndrome; SUID, sudden unexplained infant death; SUDI, sudden unexplained death in infancy; IFN, interferon; IL-6, interleukin-6; FDP, fibrin degradation products.

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Keywords: Sudden Infant Death Syndrome, SIDS, Sudden Unexplained Infant Death, SUID, pathology, epidemiology, physiology

Citation: Goldwater PN (2022) The Science (or Nonscience) of Research Into Sudden Infant Death Syndrome (SIDS). Front. Pediatr. 10:865051. doi: 10.3389/fped.2022.865051

Received: 29 January 2022; Accepted: 03 March 2022; Published: 15 April 2022.

Reviewed by:

Copyright © 2022 Goldwater. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Paul Nathan Goldwater, pgoldwater@gmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Sudden Infant Death Syndrome (SIDS) Research: Dogma disguised as science

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Sudden infant death syndrome: What questions should we ask?

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Jane L. Pearce, Richard K.J. Luke, Karl A. Bettelheim, Sudden infant death syndrome: What questions should we ask?, FEMS Immunology & Medical Microbiology , Volume 25, Issue 1-2, August 1999, Pages 7–10, https://doi.org/10.1111/j.1574-695X.1999.tb01321.x

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A limited historical perspective can affect the questions we pose about the sudden infant death syndrome (SIDS) issue. Evidence is presented from the literature that the SIDS rate in Western countries was low prior to World War II and peaked in the 1980s. An analogy is drawn with the trends in the prevalence of some infectious diseases, and questions are posed from the perspective of a bacterial toxin hypothesis of SIDS causation.

Inevitably, the questions we ask about a problem influence the answers we obtain. This certainly applies to sudden infant death syndrome (SIDS), which was only defined as such in 1969 [1] . The tracing of statistics relating to sudden death of infants prior to this date is not a straightforward task and it is easy to lose historical perspective.

It is widely recognised that there has been a significant and widespread fall in SIDS rates in Western countries since 1990. These rates are now similar to those in Asian regions such as Hong Kong and Japan where, as far as can be determined, there has been less than one SIDS case per 1000 live births for at least 18 years [2] . The falling death rate in Western countries is indeed gratifying, but underlying mechanisms are still sought. While SIDS organisations have worked hard to decrease the prevalence of risk behaviours, it is simplistic to assume that the reduced SIDS rates can be attributed wholly to changes in infant-care practices such as supine sleeping and reduced heat while sleeping.

It seems that few pathologists or medical scientists have journeyed to the basement, blown off the dust, and analysed the records of the sudden deaths of infants prior to the adoption of the SIDS definition. Where this has been done, there have been some interesting results. In the USA, McLaughlin et al. [3] reviewed all the original reports of infant death cases in Olmstead county, Minnesota, from 1945 to 1992. For this period, 82 cases of SIDS were identified. The incidence increased from 0.18 per 1000 live births in 1945–49 to a peak of 2.11 in 1982–85 and subsequently decreased to 1.28 in 1990–92.

A 1986 analysis of post-neonatal deaths [4] during the period 1924–1983 was carried out in an attempt to determine whether or not the probable SIDS rate in the Dunedin region of New Zealand had changed during that period. Records of police investigations and coroners' enquiries are available that include place of death, length of final illness and official cause of death. This study concluded that the probable SIDS rate for that region had risen from 0.33 to 4.73 per 1000 live births between the decades 1924–33 and 1974–83, reaching a rate of 8.14 per 1000 live births in the 3-year period 1981–83.

The health district of Christchurch in New Zealand is directly to the north of Dunedin and its 1968–1983 post-neonatal mortality rate records have also been analysed [5] . During this period, the post-neonatal mortality rate increased from four to eight per 1000 live births. It was concluded that the rise reflected a greater number of SIDS cases.

A more recent example of an increase in SIDS is that of Scandinavia during the period 1978–88. In 1972–75 the SIDS rate in Denmark was 0.4 per 1000 live births but this increased to 1.9 in 1987. Norway also had a clear increase in the reported SIDS rate during this period [6] . Although there appears to be no evidence of any movement toward prone sleeping, at the present there is a significant increase in SIDS cases in Japan and Hong Kong [2] .

What is the message behind these geographically diverse, retrospective studies? During the earlier part of this century, was there a genuine increase in deaths from SIDS in Western nations, peaking in the late 1980s? Have areas such as Olmstead county, and perhaps Norway [3 , 6] , experienced this increase as fluctuations within a wave? The answers to these questions are unknown. If SIDS does indeed come in waves, it is possible that the recently observed decline in incidence may represent a temporary phenomenon rather than defeat of this scourge.

If the 1990s have seen a decline to the SIDS rate which was typical prior to the 1950s, i.e., to what may be its ‘normal’ low level, perhaps our pertinent questions should be:

Why was the SIDS rate so high in the 1960s through to the 1980s in the developed countries?

Why did that very high SIDS rate appear to be a phenomenon in these more wealthy countries with temperate climates?

Will the SIDS rate increase in those Asian countries that are now experiencing lifestyle changes associated with increased standards of living or an increase in the prevalence of smoking among women?

If the causal factor(s) of SIDS remain unidentified, might we see, as part of a cycle, a return to the very high SIDS rates of the 1960s to 1980s in developed countries as well?

There are parallels to such wave-like patterns of incidence in infectious diseases worth considering. For example, Mycoplasma pneumoniae infections tend to recur as a 5-yearly epidemic cycle [7] . Other infectious diseases have been prevalent for a number of decades and then the rate has decreased for no known reason. One example of this is seen in the rise and fall of enteropathogenic Escherichia coli infections of infants. These caused many problems with infantile gastro-enteritis in the 1940s and 1950s [8] , especially in the developed countries from which they have now virtually disappeared; however, they remain a problem in the developing countries. An example of an infectious disease which has had more serious consequences in developed countries is polio. The incidence of polio paralysis has been low amongst the people of developing countries but waves of polio epidemics have swept through the Western nations this century. The disease is actually so prevalent in Third World countries that most people become immune to the polio virus before they reach the age when a polio infection is likely to cause paralysis [9] . Thus, as standards of living rose, so did the incidence of paralysis and mortality and the awareness of polio.

Some might assume that if the fall in the SIDS rate is due to the changed practice of placing infants in the supine rather than the prone sleeping position, the increase must have been due to the practice of prone sleeping becoming prevalent. While it is true that prone sleeping became common in the 1970s in many Western countries [10] , one must still account for the fact that an infant does not die because it is placed prone. The prone sleeping position is a risk factor, not a cause.

There has been increasing interest in recent years in the proposition that bacterial toxins are responsible for or at least contribute to SIDS. While no particular toxin has, as yet, been shown definitively to cause SIDS, a number of toxins have been implicated in this syndrome [11] . Most of the organisms commonly associated with SIDS in the literature are found primarily in the gut, particularly the large intestine, which is relatively impermeable to larger molecules. Arnon et al. [12] have estimated that for a large toxin molecule such as botulinum toxin (~150 kDa), only one molecule in about 10 3 –10 6 would be absorbed into the circulation. Various factors influence such absorption [13 , 14] . Clearly, therefore, any factor that causes bacterial overgrowth or that increases the probability of toxin molecules being absorbed into the systemic circulation could influence the outcome for the host. Arnon et al. suggest that exposure of infants to Clostridium botulinum in the USA is probably a fairly common event which only infrequently results in infant botulism. They recognise that other factors must contribute to the pathogenesis of this disease, a disease which shows a pattern similar to that of SIDS with respect to the age of its victims and its tendency to be less common amongst first-born infants. Perhaps this is one of the suggestions we should consider when we attempt to assess the reasons for the changing SIDS rates during this century.

Lifestyle-related factors such as diet influence the concentration and composition of the bacterial flora of adults. The dietary intake of infants affects their Gram-negative flora. Bottle-fed infants are more likely to have a higher faecal coliform count between 1 and 3 months of age [15] .

Our ability to grapple effectively with the SIDS problem is directly related to the assumptions we make about this syndrome. There is real disagreement over whether to regard SIDS as a single entity or as a ‘catch-all’ label with which to describe the final results of a wide variety of processes. If the latter view is correct, then probably all we can do is to continue with reducing the risk factors. If we adopt the former stance and treat the bacterial toxin theory with the seriousness it deserves, we might regard the current, lower, SIDS rate as ‘normal’. We might then postulate: (1) that one or more causative agents of SIDS are less prevalent in the environment than they were between the 1960s and the 1980s, and/or (2) that some important risk factor (or factors) was significantly more prevalent during these years, thus magnifying the effect of the causal agent(s). Factors claimed to affect the SIDS rate such as prone sleeping position and other lifestyle-related factors might act by increasing the carriage of a toxigenic organism, increasing the amount of toxin produced by the bacterial flora, or increasing the probability that a toxin will penetrate into the systemic circulation. It is possible that the ‘agent of SIDS’ could be fairly prevalent but relatively ineffective unless another element, even another toxin, is present to help it gain access to the systemic circulation. We suggest that a clearer geographical and historical perspective on the changes in the SIDS rate may lead us to pose new questions and/or to re-interpret existing data from a fresh, more rewarding, perspective.

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JSmol Viewer

New step in understanding the pathogenetic mechanism of sudden infant death syndrome: involvement of the pontine reticular gigantocellular nucleus.

1. Introduction

2.1. morphological examination of the pgcn, 2.2. th—immunohistochemical examination of the pgcn, 2.3. correlation of the results with risk factors, 2.3.1. correlations with cigarette smoke, 2.3.2. correlations with alcohol/drug misuse and environmental pollutants, 3. discussion, 3.1. genetics of the th enzyme, 3.2. limitations of the study, 3.3. conclusions, 4. materials and methods, 4.1. study subjects.

• The SIDS group was composed of 28 cases (12 females and 16 males, aged from 1 to 7 postnatal months). SIDS was diagnosed because the routine post-mortem examination was unable to establish any cause of death. Therefore, an in-depth analysis of the nervous system was carried out with particular investigation of the brainstem, where main nervous centers of vital importance are located, in accordance with the directives of Italian law n.31/2006 “Regulations for Diagnostic Post Mortem Investigation in Victims of Sudden Infant Death Syndrome (SIDS) and Unexpected Fetal Death” [ 54 ]. These 28 cases were selected from a large number of SIDS victims in which no developmental abnormalities in the main vital nervous centers were detected at the thorough neuropathological examination.
• The control group was composed of 20 suddenly deceased subjects (8 females and 12 males, aged from 2 to 7 postnatal months) for whom a complete autopsy and clinical history analysis established a precise cause of death. Specific diagnoses included the following: congenital heart disease ( n = 6); respiratory infection ( n = 6); disorders related to prematurity ( n = 2); traumatic incident ( n = 2); congenital malformations ( n = 2); medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficit ( n = 1); sepsis ( n = 1).

4.2. Risk Factor Information

4.3. neuropathological examination, th (tyrosine-hydroxylase) immunohistochemistry, 4.4. statistical methods, 4.5. ethics approval and consent, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Lavezzi, A.M.; Mehboob, R.; Piscioli, F.; Pusiol, T. New Step in Understanding the Pathogenetic Mechanism of Sudden Infant Death Syndrome: Involvement of the Pontine Reticular Gigantocellular Nucleus. Int. J. Mol. Sci. 2024 , 25 , 6920. https://doi.org/10.3390/ijms25136920

Lavezzi AM, Mehboob R, Piscioli F, Pusiol T. New Step in Understanding the Pathogenetic Mechanism of Sudden Infant Death Syndrome: Involvement of the Pontine Reticular Gigantocellular Nucleus. International Journal of Molecular Sciences . 2024; 25(13):6920. https://doi.org/10.3390/ijms25136920

Lavezzi, Anna Maria, Riffat Mehboob, Francesco Piscioli, and Teresa Pusiol. 2024. "New Step in Understanding the Pathogenetic Mechanism of Sudden Infant Death Syndrome: Involvement of the Pontine Reticular Gigantocellular Nucleus" International Journal of Molecular Sciences 25, no. 13: 6920. https://doi.org/10.3390/ijms25136920

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A systematic review of the burden and risk factors of sudden infant death syndrome (SIDS) in Africa

Godwin k osei-poku.

1 Boston University School of Public Health, Department of Global Health, Boston, Massachusetts, USA

Sanya Thomas

Lawrence mwananyanda.

2 Right to Care – Zambia, Lusaka, Zambia

Rotem Lapidot

3 Boston University School of Medicine, Department of Pediatrics, Boston, Massachusetts, USA

4 Boston Medical Center, Division of Pediatric Infectious Diseases, Department of Pediatrics, Boston, Massachusetts, USA

Patricia A Elliott

5 Boston University School of Public Health, Department of Community Health, Boston, Massachusetts, USA

William B Macleod

Somwe wa somwe.

6 University of Zambia, School of Medicine, Department of Pediatrics, Lusaka, Zambia

Christopher J Gill

Associated data.

While sudden infant death syndrome (SIDS) has long been recognized as a leading preventable cause of infant mortality in high-income countries, little is known about the burden of SIDS in Africa. To address this knowledge gap, we conducted the first systematic review of SIDS-related publications in Africa. Our objective was to assess the prevalence of SIDS and its risk factors in Africa.

We systematically searched PubMed, Embase, Web of Science, Cochrane, and Google Scholar to identify studies published until December 26, 2020. Review authors screened titles and abstracts, and selected articles independently for full-text review. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) or a modification. Data on the proportion of infants who died of SIDS and reported prevalence of any risk factors were extracted using customized data extraction forms in Covidence.

Our analysis rested on 32 peer-reviewed articles. Nine studies presented prevalence estimates on bedsharing and prone sleeping, suggesting near-universal bedsharing of infants with parents (range, 60 to 91.8%) and frequent use of the prone sleeping position (range, 26.7 to 63.8%). Eleven studies reported on the prevalence of SIDS, suggesting high rates of SIDS in Africa. The prevalence of SIDS ranged from 3.7 per 1000 live births in South Africa, 2.5 per 1000 live births in Niger, and 0.2 per 1000 live births in Zimbabwe. SIDS and other sudden infant deaths accounted for between 2.5 to 21% of infant deaths in South Africa and 11.3% in Zambia.

Conclusions

Africa may have the highest global rate of SIDS with a high burden of associated risk factors. However, majority of the studies were from South Africa which limits generalizability of our findings to the entire continent. There is an urgent need for higher quality studies outside of South Africa to fill this knowledge gap.

Protocol registration

Prospero Registration Number: CRD42021257261

In wealthier countries, sudden infant death syndrome (SIDS), a subset of sudden unexpected infant death (SUID), is recognized as a leading preventable cause of infant mortality. According to the US Centers for Disease Control and Prevention (CDC), SIDS was the leading cause of post-neonatal mortality and the fourth leading cause of infant mortality in the United States in 2017 [ 1 ]. SIDS is “the sudden and unexpected death of an infant under 12 months of age that remains unexplained after a review of the clinical history, complete autopsy and death scene investigation, with the onset of the fatal episode occurring during sleep” [ 2 , 3 ]. Nearly 90 percent of SIDS cases occur between birth and six months of age with a peak incidence around two to four months [ 4 , 5 ]. And while the pathobiology of SIDS may involve genetic or developmental factors, a key event in many SIDS cases is some form of respiratory stress, culminating in accidental suffocation. This is a critical point to note since the interventions that have successfully reduced SIDS deaths in the US and similar settings have largely focused on changes in infant sleeping conditions, most notably having infants sleep on their backs.

Sleeping in the prone or side position and bedsharing are recognized as major risk factors of SIDS [ 6 ]. The risk of re-breathing expired gases is increased in the prone or side sleeping position leading to hypoxia or hypercapnia [ 7 ]. Bedsharing is also important in suffocation deaths due to being accidentally rolled on by a sleeping adult. Infections and genetic polymorphisms have also been suggested in the etiology of SIDS [ 8 , 9 ]. Since symptoms of infectious diseases can be subtle in infants and hence not recognized ante-mortem, much attention has focused on the post-mortem identification of infectious pathogens. Multiple SIDS deaths in one family may also suggest a genetic link in the etiology of SIDS [ 10 ]. Other risk factors include little or no prenatal care, maternal age less than 20 years, prematurity or low birth weight, and maternal use of alcohol or smoking during pregnancy [ 11 - 14 ].

In sub-Saharan Africa, the contribution of SIDS to infant mortality has not been well understood. Very few studies have tried to estimate the incidence or prevalence of SIDS in Africa [ 15 ], and even fewer have studied the risk factors of SIDS [ 16 ]. Given the paucity of published studies on SIDS/SUID in Africa, this cause of child mortality has not been viewed as a high priority and has largely been ignored. And yet there is no reason to believe that SIDS is not a problem in African populations as it has been wherever else SIDS has been studied. Prior systematic reviews have used data from studies performed in high-income countries [ 17 ]. To the best of our knowledge, no systematic review has focused on SIDS/SUID in Africa.

To fill this knowledge gap, we conducted a systematic review of SIDS/SUID studies conducted in Africa. Our review focused on two main questions:

• What is the prevalence of known and hypothesized risk factors of SIDS/SUID in Africa?
• What is the burden of SIDS and/or SUID deaths in Africa?

Database and hand searching

PubMed, Embase, Web of Science, Cochrane, and Google Scholar were searched with search terms developed in collaboration with a librarian. The PubMed search was developed first using the following search terms: ((“Sudden Infant Death”[Mesh] OR “Sudden Infant Death Syndrome” OR “SIDS” OR “Sudden Infant Death” OR “Sudden Unexpected Infant Death” OR “Cot Death” OR “Cot Deaths” OR “Crib Death” OR “Crib Deaths” OR “Accidental Suffocation” OR “Unintentional Suffocation” OR “Strangulation in Bed” OR “ASSB”)) and an African search filter previously developed by Pienaar et al [ 18 ] (Appendix S1 in the Online Supplementary Document ).

All articles up to December 26, 2020 (the date on which the search was executed) were included. There was no prior date restriction on the search. All returned articles were then imported into Covidence (Covidence.org, Melbourne, Australia, https://www.covidence.org ), a systematic review software, for screening and data extraction. Duplicate articles were removed using the de-duplication feature in Covidence. Duplicate articles that were missed in this initial phase were removed during full-text review manually by the review authors.

Selection process

Two review authors (GKO-P and ST) independently screened titles and abstracts to identify any relevant articles. Articles that passed this initial review were included in a full-text review. The full texts of included studies were then screened. Articles that met the inclusion criteria were included in the review. Disagreements were resolved through discussion between reviewers until consensus was reached.

Inclusion/exclusion criteria

Articles were included for review if they met the following inclusion criteria:

• Original research articles, case reports, and case series were included. Editorials, letters to the editor, opinions, and review articles were excluded.
• Articles were restricted geographically to Africa (including North Africa and sub-Saharan Africa).
• Non-English language articles were included if an English translation was available or if it could be translated into English using Google Translate.
• Articles that specifically mentioned or reported data on Sudden Unexpected Infant Death (SUID) or Sudden Infant Death Syndrome (SIDS) (known or hypothesized risk factors or burden of disease) were included. Articles that reported on a population that included infants but were not necessarily limited to infants were included if they reported on the prevalence of SIDS/SUID in the cohort of infants.

Data collection and analysis

We independently extracted the following data using customized data extraction forms in Covidence: author and institutional affiliation, source of funding and conflict of interest, year of publication, study design, study aim, country of the population studied, sample size including total number of infants studied, number and proportion of infants who died of SIDS and/or SUID, and reported prevalence of any risk factors.

We independently assessed risk of bias for each included study using the Newcastle Ottawa Scale for observational studies [ 19 ] or a modification [ 20 - 23 ]. Case-control and cohort studies were assessed on three main domains of selection, comparability, and ascertainment of exposure and outcome. For case reports/case series studies, we excluded items on comparability and adjustment since these studies were non-comparable [ 20 - 22 ]. We assessed cross-sectional/prevalence studies on representativeness of the sample and size, comparability between respondents in different outcome groups, and appropriateness and completeness of the statistical test/analysis [ 23 ].

We did not receive nor require ethical approval for this study, as it does not involve human and animal subjects.

Prospero Registration Number: CRD42021257261 (Protocol available here: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=257261 )

Study characteristics

Our search yielded 880 articles. 221 were identified as duplicates and were removed by the de-duplication feature in Covidence. The titles and abstracts of 659 articles were then reviewed and 576 were judged to be irrelevant. For example, 67 studies were identified with the acronym SIDS which also refers to Small Island Developing States – these were deemed irrelevant.

The full texts of 83 articles were reviewed and 51 were excluded. These were: commentaries, editorials, and reviews (n = 18); studies that reported on the wrong population, exposure, or outcomes (n = 15); conference abstracts/papers (n = 3); wrong study setting or non-African studies (n = 6); and duplicate articles (n = 9) which were missed using the de-duplication feature in Covidence. Thirty-two full-text articles were included in the final qualitative review/synthesis (25 original studies and 7 case reports/case series). This process is summarized in the PRISMA flow diagram ( Figure 1 ).

PRISMA flow diagram of search strategy. The PRISMA diagram details our search and selection process during the review. Source: [ 24 ]. For more information, visit: http://www.prisma-statement.org/ .

Year of publication:

The included studies were published from 1983 to 2021 (we received the pre-print version of the 2021 article from the study authors in December 2020) with most conducted in the last decade. Sixty-nine percent were published between 2010 and 2021, with the majority in 2018 (n = 5, 16%) ( Figure 2 ).

Distribution of included studies by year of publication. The figure shows the distribution of included studies by year of publication. Until recently, SIDS has been a low priority for researchers in Africa. More than half (52%) of the included studies were published between 2013 and 2021.

Geographic distribution of included studies

Geographically, the articles were skewed to southern Africa (n = 25, 78%) with few from west Africa (n = 4, 13%), north Africa (6%), and east Africa (3%). The majority and nearly all of those from southern Africa were published in South Africa (n = 23, 72%) with three from Nigeria (9%) and one each from Egypt, Niger, Tunisia, Uganda, Zambia, and Zimbabwe ( Figure 3 ) .

Distribution of included studies across the African continent. The figure shows the distribution of included studies across the African continent. Overall, the studies were skewed to southern Africa with the majority (72%) from South Africa. Slightly more than a quarter (28%) of the studies were conducted outside of South Africa.

Quality scores

The 25 original articles were assessed for bias on a 9-point scale and classified as high (8-9), medium (5-7), or low quality (0-4). By study design, four case-control studies and three prospective cohort studies were included in this review. We rated all the case-control studies as medium quality, rated one cohort study as high quality and the remaining two as medium quality ( Table 1 ). Eighteen studies were described as cross-sectional or retrospective/prospective audits. We rated the majority (67%, n = 12) of these studies as medium quality ( Table 2 ).

Methodological quality scores for case-control and prospective cohort studies*

*A maximum of 2 points was assigned to comparability, all others were assigned a score of 1 if the criterion was satisfied; 0-4 was considered low quality; 5-7 was considered medium quality; and 8-9 was considered high quality.

Methodological quality scores for cross-sectional/retrospective audits*

*A maximum of 2 points was allocated to comparability and assessment of outcome, all others were assigned 1 point if the criterion was met; 0-4 points was considered low quality; 5-7 was considered medium quality; and 8-9 was considered high quality.

The 7 case reports/case series were assessed for bias on a 5-point scale and rated similarly as high (5), medium (4), or low quality (0-3). Most of the case reports/case series were also rated as medium quality (57%, n = 4) as shown in Table 3 . Overall, 4 high-quality studies were included in this review.

Methodological quality scores for case reports/case series studies*

*Each criterion was assigned a score of 1; 0-3 was considered low quality; 4 was considered medium quality and 5 was considered high quality

SIDS awareness

Awareness of SIDS was low in the general population. Three studies provided data on SIDS awareness, reporting a SIDS awareness rate of between 12.2% to 44.3% [ 39 , 45 , 46 ]. Two of these studies were of low quality and one of medium quality. The medium-quality study reported that 49 (12.2%) of respondents claimed to have heard of SIDS but only 5 (1.2%) had good knowledge of SIDS in a survey of 401 mothers of infants in Enugu, Nigeria [ 46 ] ( Table 4 ).

Characteristics and findings of studies focused on infant sleep practices and other maternal risk factors

y – years, mo – months

*This was a pre/post study. Prevalence estimates are baseline results

†Thesis/Dissertation study.

Risk factors for SIDS

Risk factors intrinsic to the infant.

The peak age of SIDS/SUID varied across studies. Two medium quality South African studies found the peak age of SIDS/SUID deaths to be 1-2 months [ 40 , 48 ] while another reported a peak age of 2-4 months [ 37 ]. Slightly more male than female infants died of SIDS/SUID [ 37 , 40 , 48 ]. Three medium-quality studies, two from South Africa and the other from Uganda, explored prematurity as a risk factor of SIDS. The South African studies reported that 27% to 40.6% of SUID cases were preterm [ 41 , 48 ]. The Ugandan study found that suspected SIDS was the second leading cause of death in a cohort of preterm infants, accounting for nearly 25% of all deaths in that cohort [ 30 ].

Risk factors intrinsic to the mother

Six studies provided prevalence estimates on maternal/parental smoking and alcohol use. One medium-quality study reported a 10.2% prevalence of exposure to tobacco smoke in Nigeria among mothers at a well-baby clinic [ 46 ]. Among SUID cases, exposure to tobacco smoke was reported at a rate of 29% to 53.1% in South Africa [ 40 , 41 , 43 , 44 , 48 ]. Maternal use of alcohol was reported at a rate of 18% to 37.1% among SUID cases in South Africa [ 40 , 41 , 43 , 44 , 48 ]. One high-quality study in South Africa specifically focused on estimating the risk of SIDS in a cohort of infants due to prenatal exposure to alcohol and tobacco smoke. The study found that the adjusted relative risk for SIDS was 2.6 times higher for those who were exposed to alcohol compared to those who were not, and 3.8 times higher for those who were exposed to smoking compared to those who were not [ 31 ]. The study cohort included mothers and infants from South Africa and the US [ 31 ] It is not clear what the actual risk is in the African cohort.

Infant sleep practices

Nine of the included studies reported on infant sleep practices in Nigeria, Egypt and South Africa, either as the main outcome of the study or as secondary outcomes [ 33 , 36 , 39 , 41 , 43 - 46 , 48 ]. Four articles reported on infant sleeping practices among mothers of infants at well-baby clinics while the remainder of these articles reported on infant sleep practices among SUID cases admitted to medico-legal laboratories in South Africa. The prone sleeping position was preferred by 26.7% to 63.8% of mothers of infants at well-baby clinics [ 33 , 36 , 39 , 46 ]. The lateral sleep position was preferred by 20.6% to 51.8% of mothers [ 33 , 36 , 39 , 46 ]. Pactice of the recommended supine position for infants is less common. A minority (2.7% to 21.5%) of mothers placed their babies in the supine position during sleep [ 33 , 36 , 39 , 46 ].

Among SUID cases, a majority of infants were reported to have been placed in the side position prior to death. The proportion of SUID cases placed to sleep in the side position was reported as 53% to 64% compared to 10% to 12% in the supine or back position [ 43 , 44 ]. 23.6% to 37% of SUID cases were placed in the prone position [ 41 , 43 , 44 ]. Bedsharing was also very common. Bedsharing was reported at a rate of 60% to 91.8% among mothers of infants at well-baby clinics [ 33 , 36 , 39 , 46 ]. Among SUID cases, the rate was nearly 95% [ 48 ]. One included study using post-mortem biomarkers of hypoxia did not find any significant differences between hypoxanthine and urate concentrations in vitreous humor samples of SIDS victims and infants who died of other causes [ 26 ]. Table 4 summarizes the main findings of studies focused on infant and maternal risk factors.

Infectious risk factors

Six studies explored the role of infectious agents in the pathogenesis of presumed SIDS in Africa. One medium-quality study highlighted the likely role of tuberculosis in SIDS-like deaths and found evidence of primary pulmonary tuberculosis on autopsy in a 4.5-month-old male infant whose history and death scene investigation fit the profile of a SIDS death [ 53 ]. The remaining five studies explored the role of viruses in SIDS deaths. These medium-quality studies used PCR testing to detect viral pathogens in a cohort of SIDS/SUID infants. The commonest viruses detected were HRV, RSV, HCoV, and CMV [ 40 , 41 , 43 , 44 ]. Viruses were detected in nearly half of the SIDS cases using PCR in South Africa [ 40 ]. Another medium-quality study detected Coxsackie B virus in nearly 23% of presumed SIDS cases in Tunisia [ 27 ] ( Table 5 ).

Characteristics and findings of studies that assessed the role of infections and genetic factors in SIDS/SUID

HCoV – human coronavirus, HRV - human rhinovirus, EV – enterovirus, CMV – cytomegalovirus, RSV – respiratory syncytial virus, B19 – parvovirus B19, HMPV – human metapneumovirus, PIV3 – parainfluenza virus type 3, IHC – Immunohistochemistry, PCR – polymerase chain reaction, FFPE – formalin fixed, paraffin-embedded (FFPE), SCN5A – sodium voltage-gated channel alpha subunit 5, SCN10A – sodium voltage-gated channel alpha subunit 10, LQTS – long QT syndrome, GALT – galactose-1-phosphate uridylyl transferase, TB – tuberculosis

*Infant was of African ancestry.

Genetic risk factors

Five studies, all from South Africa, explored the role of genetic risk factors in SIDS/SUID cases. The earliest study is a case report from 1983 which found genetic factors to be the likely cause of death in one case of three sudden infant deaths in the same family [ 50 ]. Recently, one medium-quality study found that 12.8% of mothers of SUID cases had a previous history of SUID [ 48 ] ( Table 2 ). Pathogenic/probably pathogenic genetic variants were detected in two of these studies. One medium-quality study detected pathogenic/probably pathogenic genetic variants in 20.8% of the SUID cases studied [ 28 ]. The SCN5A variant which is associated with the long QT syndrome was detected in 6.25% of cases [ 28 ]. Another case report detected a pathogenic variant in the SCN10A gene, a gene associated with Brugada syndrome, in a three-month-old male infant who had died of SUID [ 55 ]. Other genes and anatomic abnormalities identified in these African studies included GALT:c.404c>G, a gene associated with galactosemia [ 56 ], and left ventricular hyper-trabeculation (an anatomic defect that can lead to fatal arrhythmias) [ 52 ] ( Table 5 ).

Burden of SIDS/SUID

Eleven studies explored the burden of SIDS/SUID in Africa. These studies provided very wide-ranging rates of SIDS in Africa, from an implausibly low rate of 0.2 per 1000 live births as reported from a study in Zimbabwe [ 34 ] to a high of 3.89 per 1000 live births in South Africa [ 25 ]. The Zimbabwean study estimated a SIDS prevalence rate of 0.2 per 1000 live births in the general population. However, we rated their statistical analyses to have a high risk of bias since the denominator for the population at risk was not the same from which the infants with apparent SIDS were sampled. In addition, one study from Niger reported a SIDS prevalence rate of 2.5 per 1000 live births in healthy infants and 40 per 1000 live births in infants with sickle cell disease [ 32 ]. We also rated this study as low quality since there was a high risk of bias in the statistical analysis.

The South African studies provided relatively stronger estimates of the SIDS prevalence rate in the general population. The earliest estimate of SIDS prevalence in South Africa was in 1989 when one medium-quality study reported a SIDS prevalence rate of 3.01 per 1000 live births [ 25 ]. Recently, one high-quality prospective cohort study reported an unadjusted risk of SIDS in a cohort of infants in Cape Town as 3.7 per 1000 live births [ 31 ]. Among deceased infants, SIDS accounted for between 2.5% to 21% of infant deaths in South Africa [ 37 , 38 , 42 , 54 ]. However, very few studies outside of South Africa provided estimates on the proportion of infant deaths due to SIDS. One medium-quality study from Zambia estimated that 11.3% of infant deaths were due to suspected SIDS [ 49 ] ( Table 6 ) .

Characteristics and findings of studies on the burden of SIDS/SUID and diagnostic challenges in Africa

Diagnostic challenges

Two studies reported on the challenge of making a diagnosis of SIDS. One medium-quality study from South Africa reported on the inadequacy of death scene investigation in SUID cases in South Africa. They noted that only 59.2% of SUID cases had a complete death scene investigation [ 47 ]. To account for the uncertainty posed by an asphyxia risk in making an accurate diagnosis of SIDS, study authors in another medium-quality study incorporated asphyxia in a new classification schema for SUID cases. They found that this classification schema performed well in assigning the cause of death compared to the standard classification schema [ 51 ] ( Table 6 ).

Our main conclusions are that, with the singular exception of studies from South Africa, there is a paucity of information about the risk factors for or burden of SIDS in Africa. Overall, this supports our initial concerns that SIDS in Africa has historically been a very low priority for the global health community, except for a recent set of publications. And yet there is no reason to believe that SIDS would not be a major cause of infant mortality in Africa as it has proven to be wherever else SIDS has been studied. In support of this argument, our review found a high burden of SIDS/SUID and high rates of known risk factors of SIDS in Africa. The rates of the prone and side sleeping positions in this review are much higher than the rates reported from other countries such as the US and the UK. In the UK, the prone sleeping position has remained relatively stable at a rate of 23% to 24% in recent years [ 57 ]. In the US, 7.8% of mothers reported placing their infants to sleep in the prone position in a study of 3297 mothers [ 58 ]. Additionally, the CDC reported that 21.9% of mothers placed their infants to sleep in a non-supine position in 2015 [ 59 ]. In Brazil, findings from the 2015 Pelotas Birth Cohort study estimated that less than 2% of mothers placed their infants in the prone sleeping position [ 60 ]. The American Academy of Pediatrics (AAP) recommends that infants be placed in the supine position to sleep. The AAP further recommends that infants do not share the same sleep surface with their caregivers [ 5 ]. It is worrying that very few infants are placed in the recommended supine/back position to sleep in this review. The reported rates of 2.7% to 21.5% are much lower than the rates reported elsewhere (77% in the US) [ 58 ]. The side or prone sleeping position poses a risk of rebreathing expired gases which can lead to hypoxia or hypercapnia [ 7 ]. The results of one included study did not support the view that pre-mortem hypoxia is a common feature in SIDS when compared with other causes of death [ 26 ]. However, the validity of this forensic tool in the evaluation of SIDS has recently been called into question [ 61 ].

The rates of bedsharing of 60% to 91.8% in this review are also much higher than the rates reported from the US and Australia. In the US, it is estimated that 20.7% to 24.4% of mothers reported bedsharing with their infants [ 59 , 62 ]. In Australia, a study by Cunningham et al. revealed a 44.7% bedsharing rate among 2745 mothers in Victoria [ 63 ]. Since bedsharing and prone or side sleeping appear to be highly prevalent in the African studies in our review, there appears to be a significant unexplored opportunity to reduce infant mortality in these settings.

Previous studies have established prematurity as a risk factor of SIDS [ 64 - 66 ]. Findings from this review suggest a high risk of SIDS for preterm infants in Africa. Almost half of the SUID cases in South Africa were preterm. Moreover, SIDS was the leading cause of death among a cohort of preterm infants in Uganda. These findings are consistent with results from developed countries. Malloy in 2013 showed that despite the decline in SIDS rates among term infants, the risk of SIDS among the preterm remained high [ 66 ]. We also found high rates of maternal smoking and alcohol use among mothers of infants with SUID in South Africa. For instance, almost half of the SUID cases in South Africa were exposed to tobacco smoke either through the mother or another person in the household, and more than a quarter of these mothers reported using alcohol [ 48 ]. The reported rates of tobacco smoke exposure to infants in this review are also higher than the rates reported elsewhere. Using linked birth and infant death data from 2007 to 2011, one large study in the US reported that 8.9% of mothers smoked during pregnancy [ 67 ] compared to the 10.2% found in this review [ 46 ].

Infectious agents and genetic factors have been suggested as likely causes in the pathogenesis of SIDS [ 8 , 9 ]. There is evidence to suggest that viral agents play a role in the pathogenesis of SIDS either directly or indirectly through interactions with bacteria [ 68 ]. Previous studies have suggested that 80% of SIDS cases report a mild upper respiratory tract infection in the days prior to death [ 8 , 68 ]. Respiratory viruses were detected in nearly half of the SIDS/SUID cases in this review, lending credence to the possible role of respiratory viruses in the pathogenesis of SIDS. In addition, genetic testing detected pathogenic/probably pathogenic genetic variants in nearly 21% of SUID cases in one included study and a pathogenic variant of the SCN5A gene in 6.25% of SIDS cases in another included study in this review. Our findings are consistent with prior research by Weese-Mayer et al. who estimated that between 5% to 10% of SIDS cases had novel mutations in the SCN5A gene leading to the long QT syndrome [ 69 ]. These studies confirm the need for more detailed investigations to fully identify the cause of death in SIDS/SUID cases. Given the low rates of genetic testing in Africa, these causes of infant mortality are likely going undetected. Whether this represents another opportunity to reduce infant mortality in Africa is very unclear, however. Prospective screening has failed to be effective in high-income settings, making it hard to argue for operationalizing this ineffective strategy in a low-resource setting. They however highlight that these lesser-known risk factors of SIDS are likely present in Africa.

Findings from this review also indicate that Africa likely has some of the highest rates of SIDS in the world. Relying on methodological quality, the most recent estimate from South Africa indicates a SIDS rate of 3.7 per 1000 live births [ 31 ]. This rate is significantly higher than current estimates from the UK (0.3 per 1000 live births)[ 57 ], US (0.3 per 1000)[ 70 ], Australia (SUID rate 0.5 per 1000), Germany (0.53 SUID rate per 1000) and Japan (0.6 SUID rate per 1000) [ 6 ]. Collectively these studies suggest that SIDS probably accounts for a larger share of infant deaths in Africa than has generally been appreciated. Given the high rates of prone/lateral sleeping position and bedsharing in this review, more studies conducted outside of South Africa may find the SIDS burden across Africa is actually even higher.

Ultimately, SIDS is a diagnosis of exclusion and can only be diagnosed when other causes of death have been ruled out following death scene and detailed post-mortem investigations. Most countries in Africa lack the resources to conduct a proper SIDS investigation. Even South Africa, which is sort of a pioneer in SIDS investigations, lags other well-developed economies. Moreover, distinguishing between SIDS and suffocation deaths due to an unsafe sleep environment can be challenging. This challenge is emphasized when one considers that infants who may have a genetic predisposition to SIDS may only experience SIDS in the setting of an additional proximal factor, such as sleep position, bedding composition, or swaddling practices.

Strengths and limitations

The main strength of this review is that this is the first systematic review on SIDS in Africa. To our knowledge, no other review has been conducted on SIDS/SUID using studies from Africa. Our study is not without limitations. The majority of the included studies were conducted in South Africa which may affect the generalizability of our findings to the entire continent. However, most of the South African studies were conducted on predominantly Black or bi-racial populations and thus results can be extrapolated to other similar populations on the continent.

CONCLUSIONS

National campaigns to promote a safe sleep environment are lacking in Africa. The “back to sleep” campaign in the UK for instance led to a 40% decline in the SIDS rate in the first year alone [ 57 ]. Similar declines were noted in the US following the implementation of safe sleep campaigns [ 71 ]. These campaigns target some of the major risk factors of SIDS, such as prone sleeping and bedsharing [ 57 ], and would be worthwhile in Africa to tackle the high infant mortality rates. However, the paucity of high-quality studies outside of South Africa limits our ability to make recommendations for such campaigns. Future research should focus on prospectively estimating the prevalence of SIDS in countries other than South Africa.

Additional material

Acknowledgements.

We wish to acknowledge the contribution of Elizabeth Jenkins, MS, Education, and Information Librarian at the Boston University Alumni Library for her assistance with developing the search strategy, without whom our search would have yielded very few articles.

Funding support: No funding was secured for this study.

Authorship contributions: CJG conceptualized and designed the study, coordinated, and supervised the review, reviewed, and revised the manuscript. GKO-P conceptualized and designed the study, conducted the initial and full-text review, drafted the initial manuscript, reviewed, and revised the manuscript. ST conducted the initial and full-text review, reviewed, and revised the manuscript. LM and RL critically reviewed the manuscript for important intellectual content. PAE, WBM, and SWS advised on the study design and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Competing interest: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest.

Helping Your Baby Reach Greater Wonders

SIDS Breakthrough: New Research Indicates Possible Cause for Sudden Infant Death Syndrome

Researchers at the SIDS and Sleep Apnoea Research Group at The Children’s Hospital at Westmead Australia released findings in the June 2022 edition of The Lancet’s eBioMedicine from a long-range study looking at possible markers for SIDS in newborn babies.

My research started 29 years ago with the death of my precious son, Damien. Long and challenging work, but now we know that SIDS babies have low levels of the enzyme BChE. First time ever we can work with babies while still alive and prevent SIDS. https://t.co/70miO5lfLA — Carmel Harrington (@CarmelHarring18) May 9, 2022

Current research has shown that SIDS is most likely not caused by one thing, but rather presents as a “triple risk model” with three factors contributing to a baby’s risk level:

• A vulnerable infant
• A critical development period (ie first 6 months of life)
• An external stressor

While this model has been accepted by most medical experts, the biggest unanswered question has been what makes a baby vulnerable? Now we may know the answer.

The breakthrough discovered by the Australian team shows that babies who succumb to SIDS are much more likely to have low levels of Butyrylcholinesterase (BChE). 

“The study found BChE levels were significantly lower in babies who subsequently died of SIDS compared to living controls and other infant deaths,” according to Sydney Children’s Hospital Network . “BChE plays a major role in the brain’s arousal pathway and researchers believe its deficiency likely indicates an arousal deficit, which reduces an infant’s ability to wake or respond to the external environment, causing vulnerability to SIDS.”

In other words, most 0-6-month-old infants faced with an external stressor (such as overheating or difficulty breathing) while sleeping would wake and cry for help and attention, but babies with low BChE may not be able to rouse themselves.

Dr. Carmel Harrington, the lead researcher in the study, points out just how important this new information really is. She says that we have always suspected that babies at high risk for SIDS must have difficulty responding to external dangers, “but up to now we didn’t know what was causing the lack of arousal. Now that we know that BChE is involved we can begin to change the outcome for these babies and make SIDS a thing of the past.”

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