Sudden Infant Death Syndrome: Risk Factors and Newer Risk Reduction Strategies

Sudden infant death syndrome (SIDS) continues to be one of the top causes of infant death in the U.S. Despite significant public health initiatives focused on high-risk populations to enhance sleep environments and techniques. The SIDS rate has remained stable in recent years. Risk factors and newer risk reduction strategies for SIDS are the focus of this review article. We conducted a comprehensive literature search on Medline, Cochrane, Embase, and Google Scholar until July 2022. The following search strings and Medical Subject Heading (MeSH) terms were used: "SIDS," "Sudden Infant Death" and "SUID". We explored the literature on SIDS for its epidemiology, pathophysiology, the role of various etiologies and their influence, associated complications leading to SIDS, and preventive and treatment modalities. Despite a more than 50% drop-in rates since the start of the "Back to Sleep" campaign in 1994, sudden infant death syndrome (SIDS) continues to be the top cause of post-neonatal mortality in the United States, despite continued educational initiatives that support safe sleep and other risk reduction strategies. The new American Academy of Pediatrics guidelines for lowering the risk of SIDS include a lot of emphasis on sleeping habits, bedding, and environment but also include elements that are frequently ignored (i.e., prenatal care, smoking, alcohol and drug use, and childhood vaccinations). This study highlights these less-frequently discussed aspects and identifies treatments that have produced beneficial behavioral shifts that benefit newborns as well as their mothers' health and wellbeing.


Introduction And Background
Sudden Infant Death Syndrome (SIDS) accounts for about 38.4 deaths per 100,000 live births (approximately 1,389 deaths) as per records of the year 2020 [1]. In the majority of the countries, there was a rapid surge in the cases of SIDS in the early 1980s followed by a decline in the 1990s. The main reason for this dramatic deterioration in the cases was the "Back to Sleep" campaign which was set in motion by the American Academy of Paediatrics in 1994, which raised awareness regarding a healthy sleeping environment [2]. Despite this, the past few years have seen a dramatic plateau in the rate of SIDS and it is still a notable cause of death for infants under the age of one year [3]. All these statistics suggest a multifactorial association in the causation of SIDS. SIDS can be defined as "The sudden death of an infant under one year of age which remains unexplained after a thorough case investigation, including the performance of a complete autopsy, examination of the death scene, and review of the clinical history" [4]. A large number of cases of SIDS are seen during the second, third, and fourth months of life (~90%) and are more prevalent amongst males as compared to females (3:2) [5]. SIDS clinically presents as an unanticipated death of an infant which occurs during sleep, particularly if the child is sleeping in a decumbent position. SIDS falls under a much larger category known as Sudden Unexpected Infant Death (SUID) which is defined as 'a sudden and unexpected death, whether explained or unexplained, occurring during infancy' [6].
When the cause of death remains unidentified and cannot be pointed toward any of the known causes of death (strangulation, suffocation, medical condition, or asphyxia) it is considered a case of SIDS [6]. Apart from sleeping practices like sleeping in a recumbent position, bed sharing with adults, and avoidance of room sharing, which has proven to be a major game-changer in the incidence of SIDS, several other risk factors have also been identified to be associated with SIDS. These include extrinsic factors like exposure to cigarette smoke, alcohol and drug consumption, bottle feeding, and intrinsic factors like demography, gender, premature birth, and intrauterine pathology [7][8][9].
It is important to understand how crucial each of these risk factors is in causing SIDS, and therefore the main objective of this review is to identify the majority of risk elements associated with SIDS and outline various modes of prevention and intervention in the reduction of infant mortality rate due to the same.

Review
Pathophysiology SIDS is considered a condition with unknown reasons even after autopsy because the pathogenesis of SIDS is combined by many conditions, including genes, environment, and socio-culture. Figure 1 describes the pathophysiology of SIDS. Three factors, including a fragile infant, a developing stage of homeostatic regulation and an external stressor(s) are suggested to play a role in SIDS [10].

SIDS: Sudden infant death syndrome
This hypothesis concluded that an infant must first have an underlying condition and then be influenced by an external source, such as an inappropriate sleeping position. Finally, to cause SIDS, all three need to happen together, meaning the stress must occur in a fragile infant in the first year of life, especially in the second to a fourth-month-old. The last components in the model have been well researched and used to educate the parents widely, but the vulnerable condition remains to be identified.
A vulnerable infant could be one with hidden biological vulnerability, such as the abnormal brainstem, cardiac conduction problems, gene, ion channel abnormalities, immunological response, and the nicotine effect on the immature brain [11]. We have discussed the genetic pattern in a separate part. Understanding brainstem abnormality would explain why SIDS occurs when a baby is sleeping. The age when SIDS happens the most is the infant age when most of their sleep is in the rapid eye movement (REM) stage. Different mechanosensory airway and chemosensory autonomic responses, which are essential for survival, are dysregulated during this stage of sleep [12,13].
Since the afferent inputs to mechanosensory pathways drive the genioglossus (an extrinsic muscle in the tongue) to physically activate to keep the upper airways open during inspiration, the dysregulation of these pathways would be harmful to babies [14][15][16][17]. The role of airway disturbance and collapse during sleep is considered one of the mechanisms contributing to SIDS [18,19]. Moreover, during REM sleep, a decrease in the activity of neurons secreting serotonin (5-HT) or norepinephrine [20] makes disturbances in serotonergic and noradrenergic mechanisms occur, and it is blamed as an important factor that makes a child vulnerable to SIDS [21][22][23][24][25]. These are the reasons why SIDS would not happen when a child is awake or in an older child when his motor behaviours are well developed.
An immune reaction is a crucial additional cause of SIDS [26]. Different studies are showing how SIDS could make the mucosal immune system stimulated [27,28]. There are some SIDS babies with increased density of immunoglobulin (Ig)G and IgA immune cells in the tonsils [28]. Additionally, salivary glands have been found to exhibit increased expression of HLA class I and II as well as higher expression of CD45+ stromal leukocytes and variable expression of human leukocyte antigen-antigen D (HLA-DR) [29].
SIDS has been linked to additional factors, including bacteriological findings of Staphylococcus aureus infections and staphylococcal endotoxins, and smoking [30]. Nicotine has been identified recently as a factor that could metabolise genes and become a SIDS cause [10]. This finding emphasises the significance of smoking cessation counselling in SIDS prevention efforts.
The interaction of internal (as mentioned above) and external elements (sleeping placements, pillows, blankets) could lead to a life-threatening situation during sleeping time. There are protective mechanisms during these episodes as if they fail to do their jobs, it would cause unexpected death. On the other hand, if one of these characteristics is not present, SIDS is less likely to happen [31,32].

Demographic Factors
Sudden infant death syndrome is uncommon until 2 to 4 months when it is the highest, following which it declines. Around 90% of deaths happen within six months of age. At a 60:40 ratio, males are more inclined to die than females [33]. In the last 20 years, SIDS incidence has dropped by more than 50%, partly due to the "Back to Sleep" campaign [34]. Relative to the 3500 newborns that die every year in the U.S. from sleeprelated reasons, including sudden infant death syndrome, a black baby dies in Indiana every 13 hours (SIDS) [6]. In 2013, the infant mortality rate for all infants was 7.2 deaths per 1000 live births, whereas it was 15.3 for Black infants [35]. Male population groups, including non-Hispanic black infants, American Indian or Alaska Native infants, and preterm are also intrinsic risk factors [36,37]. Although the most common sleeping position is supine among Native American, Alaska Native, Aboriginal Australian, and New Zealand Maori infants, these infants being exposed to increased levels of smoke put them at greater risk of SIDS [37]. Epidemiological research has shown that Native Americans, Maoris from New Zealand, and Aboriginal Australians have much higher rates of SIDS than non-Indigenous groups within the same nations [38].

Maternal Smoking and Smoke Exposure
According to a recent study, the quantity of cigarettes smoked daily during pregnancy has a linear relationship with the probability of a SIDS occurrence. Also, avoiding smoking during the first three months of pregnancy is closely linked to a significant reduction in SIDS risk. Reducing the number of cigarettes smoked per day also adds to a slight reduction in risk [39,40]. Beyond the first trimester of pregnancy, combined exposure to alcohol and smoking poses a more significant risk of the incidence of SIDS [41]. Tobacco smoke exposure during pregnancy is another major risk factor for SIDS. There is also a risk of postnatal exposure, which increases with other smokers in the family or the amount of time the infant is exposed to smoke-filled surrounding [42]. Bed-sharing adds substantially to the risk associated with maternal smoking [40]. Only a few researchers have looked into the link between substance abuse and SIDS. Substance misuse being frequently involved with multiple substances, make it hard to distinguish each effect [36].

Sleeping Positions
In several Western regions, it is recommended to lie down supine and in a bed other than put nearer to adults to avoid Sudden Infant Death Syndrome (SIDS) [43]. Mother-infant bed-sharing has been known to increase the risk of infant deaths from sleep-related causes, which affect African Americans at a vastly disproportionate higher rate [44]. Rebreathing of exhaled air, with increased carbon dioxide and reduced oxygen concentration levels, has long been involved in inexplicable SIDS, which takes place when infants are positioned to nap in a prone (facedown) position. This position has also been linked with lower hypertension and impeded lower blood pressure [45,46]. Both prone and side sleeping raise the risk of SIDS. Premature babies that are put prone are just as in danger for SIDS as babies born at gestation [47]. The risk is further increased in low birth weight babies, premature babies, and infants between the ages of 13 and 24 weeks, implying that SIDS may be induced by no obvious cause. The prone position generally tends to raise stimulation and wakening thresholds, encourages sleep, as well as minimises neurogenic action via reduced parasympathetic activity, reduced sympathetic activity, or perhaps a lack of balance between two systems [47,48]. Infant baroreflex function is influenced by the infant's sleeping position, sleep stage, and post-natal age, according to various cross-spectral analyses employing flex sensitivity (BRS). Decreased BRS in early infancy who are sleeping in a prone position may make them more susceptible to hypotensive episodes when they sleep and be crucial in the circumstances like SIDS whereby circulation insufficiency may be involved [45].
Even though there is little vulnerability to environmental and genetic factors, such as cigarette smoke, soft bed sheets, prone sleep position, and co-sleeping, newborns in childcare settings, i.e., those who appear to care for by a caretaker who is not a parent, which includes caretakers and child care providers-make up about 20% of SIDS deaths. However, it is unclear why there is such a large percentage of risk infants [49][50][51]. Crosssectional studies have indicated that despite the majority of healthcare professionals recognised the supine position as the position that minimises the risk of sudden infant death syndrome the most, only 30% acknowledged most frequently putting infants in that position to sleep, with the majority of staff (91%) claiming fear of aspiration as the reason for supine position avoidance [52]. Additionally, a significant number of these fatalities occur within a week of childcare [50]. Sudden infant death syndrome (SIDS) has been linked to a higher risk in infants who are overheated [53]. Thermal stress can cause mortality directly through hyperthermia (or hypothermia). It can also affect the body's central nervous system by affecting the respiratory rate, the larynx closing reflex, or the arousal processes [54,55].

Medical Conditions Affecting SIDS
Rate of SIDS incidences in various seasons: When SIDS occurrences rise in the cold season, they coincide with respiratory viral outbreaks and frequently show symptoms of respiratory system irritation and a history of mild sickness symptoms. There are physiological methods by which newborns can develop frequent or severe, potentially fatal hypoxemia. Respiratory infections are a major cause of newborns presenting with sudden events involving apnea and hypoxemia [56].
Parental room sharing: Sharing a room but not a bed is advised. It is advised to eliminate soft bedding such as pillows, blankets, and other items from the child's bedrooms [9]. Although it should be prevented in newborns in the first four weeks who are breastfeeding, pacifier use seems to reduce the incidence of sudden infant death syndrome [57].
Maternal smoking: Babies who are exposed to environmental tobacco smoke (ETS) are more likely to develop chronic obstructive pulmonary disease (COPD), bronchial asthma, and pneumonia, especially in the first two years of age [58]. Two to three times as many premature and low birth weight babies die abruptly and suddenly compared to normal newborns [59]. Cigarette smoke has an effect on prenatal and post-natal growth, raises the risk of infections, and increases the likelihood that perhaps the child may experience paediatric cardiac disease [60].

Genetics
Comprehension of the genetic markers predisposing to SIDS is a significant challenge. Before a genetic cause is successfully identified, a biological disease must first be detected and thoroughly characterised in most medical disciplines. In SIDS genetic research, however, the situation has been reversed: genetic testing and study have aided in elucidating potential mechanisms of death in SIDS. This is a multi-factorial syndrome, leaving us with a rudimentary understanding of the factors which contribute to the causes leading to infant death [61]. The Triple Risk Model of SIDS suggests that genetic components play a role in SIDS, with "vulnerable infants" affected by the genetic variables [62].
Metabolic diseases: Acyl-CoA Dehydrogenase Medium Chain (ACADM) is the gene that has been studied the most concerning metabolic problems in SIDS. It catalyses the initial step in the beta-oxidation of mediumchain fatty acids [63]. Autosomal recessive mutations in this gene result in MCAD (medium-chain acyl-CoA deficiency). In another study on the genetic investigation of 161 SIDS cases in 2017, two children with gene mutations that resulted in DOLK-congenital disorder of glycosylation and systemic primary carnitine insufficiency were found, accounting for 1% of the overall cohort [64].
Cardiac genes: SIDS cases with monogenic genetic cardiovascular problems comprise a significant but tiny percentage of total SIDS cases [61]. A study found possibly disease-causing variations in 20% of the 155 SIDS cases by considering a list of 192 genes linked to cardiovascular and metabolic illnesses. Gene variants linked to channelopathies (9%) and cardiomyopathies (7%) were found in a majority of these patients [62].  [65]. Further studies have also described SIDS patients with a history of Brugada syndrome in the family, genetic variants linked to Brugada syndrome, and operational data supporting this [66].
Epilepsy: Sudden unexpected death in epilepsy (SUDEP) is the sudden, unexpected, non-traumatic death of people who have epilepsy, with or without signs of a seizure, and for whom autopsy investigation reveals no structural or toxicological cause of death [23]. SCN1A (Sodium voltage-gated channel alpha subunit 1), SCN1B (Sodium channel subunit beta-1 ), and DEPDC5 (DEP domain-containing 5) are some of the genes for SUDEP that have been linked to SIDS [71][72][73][74][75]. Evidence suggests that sudden cardiac death, SIDS, and SUDEP have chromosomal complexity and a degree of commonality. In most situations, genetic risk factors and a susceptible infant are at fault [76].
Inflammation: Some cytokine gene polymorphisms may have a role in SIDS pathogenesis. However, polymorphisms are just one among the many factors resulting in SIDS risk, in addition to other intrinsic or extrinsic factors leading to SIDS [61].
Copy Number Variants (CNVs): One study investigating CNVs associated with SIDS discovered De novo CNVs in three of 27 SIDS patients. The significance of this discovery is unknown [77]. Figure 2 depicts an illustration of various factors affecting SIDS.  Exome or genome-wide investigations will become critical in identifying novel genotype-phenotype associations with SIDS, thereby promoting the finding of previously unknown genetic abnormalities involved in SIDS pathogenesis [61].

Diagnosis of SIDS
SIDS is defined as a diagnosis of exclusion after evaluating the medical history, complete postmortem examination, and scene investigation [78,79]. The accuracy of SIDS diagnoses is likely to be impacted by non-autopsy SIDS diagnoses. Table 1 summarizes the neurotransmitter abnormalities in the brainstem in SIDS.

ChAT b
Lowering in ChAT immunostaining in DMX c and HG d [82].

Muscarinic receptor
A decrease in binding to the arcuate nucleus with a limited number of immunopositive neurons for muscarinic receptors in the arcuate nucleus is observed, but this has little impact on the arcuate nucleus's muscarinic receptor immunostaining [82][83][84].

Histopathology
In a substantial percentage of patients, histopathological examinations have revealed subtle alterations in lung inflammation (indicating recent viral infection) [96,97]. Nevertheless, the brain occasionally exhibits minor alterations. There could be Inflammation or other changes in the intestines. Cardiomyocyte and diaphragm changes have been seen, although they do not seem to be confirmed [98,99]. Some SIDS instances have signs of a systemic inflammatory reaction.

Microbiology
In around one-fifth of instances, examination of the carcass in typically sterile places (heart blood, spleen, cerebrospinal fluid) reveals the presence of a bacterial infection (e.g., S aureus, Escherichia coli, and various coliforms) [100,101]. In SIDS cases, as opposed to non-SIDS deaths, Coliforms and S aureus were isolated from the lungs and airways more frequently [100,101].

Histology of Thymus
It has been discovered that SIDS has a very high rate of petechial thymus haemorrhages. It was possible to demonstrate bleeding everywhere, and it was histologically restricted in a distinctive fashion almost exclusively to the cortical zones of the lobes, usually missing or just a little in non-SIDS cases [102].

Genetic Variations in SIDS
Maximum newborns have a variety of genetic consequences associated with channelopathies (9%), accompanied by way of cardiomyopathies (7%) and metabolic problems (1%) [61]. However, fatal arrhythmia represents a workable cause and possible cause of death. Various cardiac genes within the SIDS were observed [62].

Sleeping Position
The supine position reduces the risk of SIDS. Therefore infants should be placed in the supine position while sleeping. However, there are some contraindications to placing an infant in a supine position while sleeping [103]. The prone position is recommended only when the baby is awake [104].
Sleeping in the prone position is also recommended when a baby has gastroesophageal disease, upper airway malformations, and active respiratory illness [105]. An infant placed in the prone position while sleeping has been shown to increase the risk of SIDS by 14-fold and causes additional stress on the cardiovascular and respiratory systems [106].

Bed Sharing
Co-sleeping with parents, albeit still under scrutiny, has been shown in recent studies to reduce the risk of SIDS. However, co-sleeping with parents is not advisable in certain conditions that include places like sofas, and armchairs, where one/both of the parents are either smokers/alcoholics or are under medication like anxiolytic and antidepressants [35].

Sleep Areas
The safest place for an infant to sleep is on a separate surface designed for infants close to their parent's bed. Sleeping in the parent's room on a separate surface can reduce the risk of SIDS by 50%. It prevents suffocation, strangulation, and entrapment that may occur when the infant is sleeping in an adult bed.
Infants should be placed near the parent's bed but on a separate, detached surface for at least six months as the rate of SIDS and other sleep-related deaths are higher in the first six months of life. Infants should never be left to sleep on couches or armchairs. Bedside sleepers that are attached to parents' beds are used by some parents so that monitoring infants and breastfeeding becomes easier [107][108][109][110].

Head Coverings
As the head is the most common site of heat production, covering an infant's head causes heat entrapment between the head surface and clothing and increases the risk of SIDS. Therefore infants' heads should be made free of coverings to reduce the risk of SIDS [111].

Bedding
Soft bedding plays the most common role in increasing the risk of SIDS. The surface under the infant gets depressed when the infant is placed over soft surfaces that constitute soft mattresses, sheepskin, soft pillows, and blankets and may result in suffocation, asphyxia, and overheating of the infant [112]. The risk of infant death increases if the infant is left to sleep on a couch or a sofa. A firm flat surface covered only by a thin fitted sheet should be used. Delicate items such as toys, crib bumpers, positioners, and pillows should be avoided [113].

Pacifier Use
The risk of SIDS had reduced with the usage of pacifiers. The use of pacifiers in infants older than one month is currently advised by numerous researchers to prevent sudden infant death syndrome and is related to various benefits for premature newborns, but it is also connected with a higher risk of otitis media. According to surveys, neonates have slept with pacifiers exhibited lower auditory arousal thresholds than infants who did not use pacifiers [114].
The pacifier should be used when placing the infants to sleep. Pacifier usage in breastfed infants isn't advisable until breastfeeding has been firmly established [115,116]. Due to the risk of strangulation, pacifiers shouldn't be placed around infants' necks. Pacifiers attached to toys or other items may lead to suffocation/choking [117].

Breastfeeding
The mechanism of the beneficial effect of breastfeeding with SIDS remains unclear. In some research, breastfeeding decreases the risk of SIDS by nearly 50% (odds ratio {OR} 0.52, 95% CI: 0.46 to 0.60) after ruling out possible confounding factors [117][118]. This protection may be a consequent effect because breastfeeding has an evitable protective effect on infections, such as gastroenteritis, otitis media, and lower respiratory tract infections, which is also a risk of SIDS. Moreover, breast milk is abundant in vitamins and antibodies, which could play a role in protecting babies from vulnerable factors [117,118]. In terms of the cardiovascular system, breastfed infants have obviously lower heart rates and are more easily aroused, compared with formula-fed ones, which could also protect the babies [119,120]. Another study showed that healthy breastfed babies were more likely to awaken from active sleep than formula-fed babies in response to nasal air-jet stimulation [121].
In addition, the brains of breastfed infants have docosahexaenoic acid, a long-chain polyunsaturated fatty acid (LCPFA), which is also found in breast milk and fish oil, which may hasten changes in the neurochemical makeup of the brain. The benefits of breastfeeding are undisputed. However, the evidence of its beneficial effect in reducing the risk of SIDS is not clear. Even with the effect on the brain by LCPFA, we have already put some in formulas nowadays. However, breastfeeding is proven to be a protective factor for many reasons; it should be encouraged to keep as long as possible. Moreover, in proportion to how long the mother breastfeeds, she also benefits from its prevention of breast and ovarian malignancies, as well as type 2 diabetes [122].

Smoking and Alcohol Avoidance
Children born to mothers who both drank and smoked have a 12-fold increased risk for SIDS. Avoiding the use of smoke and alcohol during pre and post-natal periods decreases the risk of SIDS [35]. Table 2 depicts all of the risk reduction interventions described above, and their effects on the occurrence of SIDS.

Risk factors Recommendations
Bed sharing Infants may be brought into the bed for feeding or comforting but should be returned to a separate sleep area when the parent is ready to return to sleep. It is prudent to provide separate sleep areas and avoid co-bedding for twins and other infants of multiple gestations. Room sharing without bed-sharing is recommended. Devices promoted to make bed-sharing safe are not recommended. There are specific circumstances in which bed-sharing is particularly hazardous, and it should be stressed to parents that they avoid bed-sharing during the following situations at all times: If either parent smokes If the infant is younger than three months If the infant is placed on excessively soft surfaces (e.g., waterbeds, sofas, armchairs) If soft bedding accessories (e.g., pillows, blankets) are used If there are multiple bed sharers If the parent has consumed alcohol If the infant is bed-sharing with someone who is not a parent Bedding Pillows, quilts, comforters, sheepskins, and other soft surfaces are hazardous when placed under the infant or when loose in the sleep environment. Wedges, positioning devices, bumper pads, and similar products are not recommended.

Breastfeeding
Breastfeeding is recommended. If a breastfeeding mother brings the infant into her bed for nursing, the infant should be returned to a separate sleep area when the mother is ready to return to sleep. Sleep areas Car seats and other sitting devices are not recommended for routine sleep at home or in the hospital, particularly for young infants. Infants should sleep in a safety-approved crib, portable crib, play yard, or bassinet.

Sleep position
Sleeping in the supine position is recommended for infants to reduce the risk of SIDS; prone or side sleeping is not safe and is not advised. Once an infant can roll from the supine to the prone position and back again, he or she can remain in either position during sleep. Supervised, awake tummy time on a daily basis can promote motor development and minimize the risk of positional plagiocephaly. SIDS = sudden infant death syndrome. Information from reference 5.

TABLE 2: Recommendations to reduce the risk of SIDS
Adapted with permission from [118].

Conclusions
SIDS is a complicated, multifaceted condition, and additional study is required to fully comprehend how intrinsic susceptibility, a crucial developmental stage, and the existence of environmental risk factors interact. We can only hope that with increased knowledge and the adoption of safe sleep practices from hospitals to homes, we may reduce the incidence of SIDS, which may never be totally eradicated. Despite the fact that the origin and causation of SIDS remain unclear, parents and caregivers need to be aware that changing particular habits, practices, and interventions may affect how an event turns out in the end. It is crucial for doctors, nurses, and other healthcare providers to convey a consistent message according to updated guidelines from the American Academy of Pediatrics and address the worries and misconceptions of parents and caregivers regarding safe sleep guidelines.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.