Sudden infant death syndrome

Overview
Sudden infant death syndrome (SIDS) is a syndrome marked by the symptoms of sudden and unexplained death of an apparently healthy infant aged one month to one year. The term cot death is often used in the United Kingdom, Australia and New Zealand, while crib death is used in North America.

Diagnosis
SIDS is a diagnosis of exclusion. It should only be applied to an infant whose death is sudden and unexpected, and remains unexplained after the performance of an adequate postmortem investigation including Typically the infant is found dead after having been put to sleep, and exhibits no signs of having suffered.
 * 1) an autopsy;
 * 2) investigation of the scene and circumstances of the death; and
 * 3) exploration of the medical history of the infant and family.

Conditions that may be undiagnosed and thus result in a diagnosis of SIDS

 * Medium chain acyl CoA dehydrogenase deficiency (MCAD deficiency)
 * Infant botulism
 * Long QT syndrome
 * Shaken baby syndrome

Risk factors and statistics
SIDS is responsible for roughly 0.05%, or 50 deaths per 100,000 births in the U.S. It is responsible for far fewer deaths than congenital disorders and disorders related to short gestation, though it is the leading cause of death in healthy babies after one month of age.

Very little is known for sure about the possible causes of SIDS, and there is no proven method for prevention. Although studies have identified risk factors for SIDS, such as putting infants to bed on their stomachs, there has been little understanding of the syndrome's biological cause or causes. The frequency of SIDS appears to be a strong function of infant sex and the age, ethnicity, education, and socio-economic status of the parents.

According to a study published in October 2006 in the Journal of the American Medical Association, babies who die of SIDS have abnormalities in the part of the brain that helps control functions like breathing, blood pressure and arousal. Researchers examined the brains of 31 babies who had died of SIDS and 10 who had died from other causes. They found that abnormalities in the brain stem appear to affect the ability to use and recycle serotonin, which is responsible for regulating mood as well as vital body functions. According to the National Institutes of Health, which funded the study, the new finding is the strongest evidence to date suggesting that innate differences in a specific part of the brain may place some at increased risk of dying from SIDS.

Listed below are several factors associated with increased probability of the syndrome based on information available prior to this recent study.

Prenatal risks

 * inadequate prenatal care
 * inadequate prenatal nutrition
 * tobacco smoking
 * use of heroin
 * subsequent births less than one year apart
 * alcohol abuse

Post-natal risks

 * low birth weight (especially less than 1.5 kg (~3.3 lb))
 * exposure to tobacco smoke
 * laying an infant to sleep on his or her stomach (see sleep positioning below)
 * failure to breastfeed
 * excess clothing and overheating
 * excess bedding, soft sleep surface and stuffed animals
 * gender (61% of SIDS cases occur in males)
 * age (incidence rises from zero at birth, is highest from two to four months, and declines towards zero at one year)
 * premature birth (increase risk of SIDS death by 50 times)

Risk reduction for SIDS
Though SIDS cannot be prevented, parents of infants are encouraged to take several precautions in order to reduce the likelihood of SIDS.

Sleep positioning
Sleeping on the back has been recommended by (among others) the American Academy of Pediatrics (starting in 1994) to avoid SIDS, with the catchphrase "Back To Bed" and "Back to Sleep." The incidence of SIDS has fallen sharply in a number of countries in which the back to bed recommendation has been widely adopted, such as the US and New Zealand. Mitchell EA, Hutchison L, Stewart AW, The continuing decline in SIDS mortality, ARCHIVES OF DISEASE IN CHILDHOOD 92 (7): 625-626 JUL 2007. However, the absolute incidence of SIDS prior to the Back to Sleep Campaign was already low in the US. Thus, while it is true that SIDS mortality has fallen roughly 50% since that campaign began, it is also true that the campaign has at best prevented only one infant death in 2,127 live births in the US. Pelligra R, Doman G, Leisman G, A reassessment of the SIDS Back to Sleep Campaign,THE SCIENTIFIC WORLD JOURNAL 5: 550-557 JUL 2005.

Among the theories supporting the Back to Sleep recommendation is the idea that small infants with little or no control of their heads may, while face down, inhale their exhaled breath (high in carbon dioxide) or smother themselves on their bedding -- the brain-stem anomaly research (above) suggests that babies with that particular genetic makeup do not react "normally" by moving away from the pooled CO2, and thus smother. Another theory is that babies sleep more soundly when placed on their stomachs, and are unable to rouse themselves when they have an incidence of sleep apnea, which is thought to be common in infants.

A concern that has been voiced about infants sleeping on the back is, that if they burp and bring up fluids while sleeping on their backs that they could choke. Newborns in the first few days after birth are commonly placed on their side by hospital staff, who nonetheless advise parents to place their infants on their backs after going home from the hospital.

Another concern raised about the Back to Sleep Campaign is that placing babies on their backs may increase the risk of positional facial and head deformities (see positional plagiocephaly), may interfere with good sleep habits (which in turn may have other bad effects), and development (as infants delay attempts to lift their heads, crawl, etc.).

Breastfeeding
A 2003 study published in Pediatrics, which investigated racial disparities in infant mortality in Chicago, found that previously or currently breastfeeding infants in the study had 1/5 the rate of SIDS as non-breastfed infants, but that "it became nonsignificant in the multivariate model that included the other environmental factors. These results are consistent with most published reports and suggest that other factors associated with breastfeeding, rather than breastfeeding itself, are protective."

Co-sleeping
A controversial approach to lowering SIDS rates is co-sleeping. Although a 2005 policy statement by the American Academy of Pediatrics on sleep environment and the risk of SIDS condemned all co-sleeping and bedsharing as unsafe, empirical data has suggested that almost all SIDS deaths in adult beds occur when other prevention methods, such as placing the infant on his back, are not used. Infant deaths in adult beds are also reduced when parents are non-smoking, not impaired by drugs or alcohol, not obese, and are not using fluffy comforters and pillows. A firm sleeping surface is also required, which rules out waterbeds or soft mattresses. With these factors accounted for, SIDS rates for co-sleeping infants are actually lower than for crib-sleeping infants. Parents also have newer room and bedsharing options including bedside and bedtop sleeping devices to make co-sleeping safer and more convenient.

A 2005 study states that "sleeping with an attentive, unimpaired mother is not only safe but biologically sound". The practice of solitary sleep for infants leads, among other things, to an absence of exogenous stimuli that influence breathing, cardiovascular function, and sleep architecture in the sleeping infant. Sleep and waking states and state transitions are apparently produced by suites of state regulatory mechanisms that function as a dynamical system. Modeling of dynamical systems has demonstrated that they are organized, or “tweaked” by episodic, irregular inputs. Some investigators (Mosko et al., 1993; McKenna, 1996) have argued that cosleeping provides infants with stimuli that organize their immature systems and thereby buffer them from risk for regulatory failures in sleep over a developmentally vulnerable postnatal period. 

Research on co-sleeping indicates an excess risk with an adjusted Odds-Ratio of 2.71. There is a good deal of debate and discussion in the medical literature about this (see below). For example, though findings are still preliminary and unpublished, the proximity of a parent's respiration is thought by some to stimulate proper respiratory development in the infant. It is interesting to note that the first epidemiologic investigation of sudden unexpected infant deaths by Templeman in Dundee in 1892 were shown to be probably from suffocation by overlaying.

Sleeping near the baby
Parents are also encouraged to sleep near their babies. 'Near' is generally understood to mean in the same room, but not in the same bed. Adult bedding often does not follow the 'no pillows, no fluffy blankets and firm mattresses only' instructions mentioned above. Keeping the baby in the same room as the parent is thought to allow the parent to be wakened by a baby in distress even if the child is unable to cry.

Secondhand smoke reduction
According to the U.S. Surgeon General’s Report (Chapter 5; pages 180–194), secondhand smoke is connected to SIDS. Infants who die from SIDS tend to have higher concentrations of nicotine and cotinine (a biological marker for secondhand smoke exposure) in their lungs than those who die from other causes. Infants exposed to secondhand smoke after birth are also at a greater risk of SIDS. Parents who smoke can significantly reduce their children's risk of SIDS by either quitting or smoking only outside and leaving their house completely smoke-free.

Bedding
Only use a firm mattress with tight-fitting sheets in a crib or bassinet. No pillows, stuffed animals, or fluffy bedding should be used or placed in a crib. In cold weather, dress the infant warmly in well fitted clothing. Wearable blankets are preferable over loose blankets. These directions also stem from the belief that small babies with little or no control of their bodies may inadvertently smother themselves in their sleep.

Sleep sacks
In colder environments where bedding is required to maintain a baby's body temperature, the use of a sleep sack is becoming more popular. A study published in the European Journal of Pediatrics in August 1998 has shown the protective effects of a sleep sack as reducing the incidence of turning from back to front during sleep, reinforcing putting a baby to sleep on their back for placement into the sleep sack and preventing bedding from coming up over the face which leads to increased temperature and carbon dioxide rebreathing. They conclude in their study "The use of a sleeping-sack should be particularly promoted for infants with a low birth weight."

Pacifiers
A 2005 study indicated that use of a pacifier is associated with a 90% reduction in the risk of SIDS (Li et al). It has been speculated that the raised surface of the pacifier holds the infant's face away from the mattress, reducing the risk of suffocation. Although suffocation is an actual cause, while SIDS refers to an unexplained infant death, in the absence of sufficient postmortem investigation, a SIDS diagnosis may result.

Bumper pads
Bumper pads may be a contributing factor in SIDS deaths and should be removed. Health Canada, the Canadian government's health department, issued an advisory recommending against the use of bumper pads, with the warning that they may decrease the amount of oxygen rich air available to the baby:

"The presence of bumper pads in a crib may also be a contributing factor for Sudden Infant Death Syndrome (SIDS). These products may reduce the flow of oxygen rich air to the infant in the crib. Furthermore, proposed theories indicate that the rebreathing of carbon dioxide plays a role in the occurrence of SIDS."

Baby monitors
The use of baby monitors, particularly those with motion sensors, can allow the parents to remotely keep track of their child and respond if the child is in distress. However, there is no evidence, despite various studies, that use of a baby monitor has any effect at all on reducing the number of SIDS deaths. This is because the first symptom of SIDS is death. There is no such thing as a "near-SIDS" experience.

Speculated associations
A number of theoretical causes have been proposed as a trigger for SIDS, but many of them are unproven or have not been thoroughly studied and peer-reviewed.

Brain disorder
A recently published research article by the Journal of the American Medical Association showed evidence that cells in the brainstem fail to develop receptors for Serotonin in the womb. This abnormality continues until after birth, supposedly until the end of their first year. This would account for there being few to no SIDS deaths after the first year of infancy and the reason the risk is more for premature infants. The SIDS Alliance/First Candle has posted a message about this along with a link to the abstract on their website (www.firstcandle.com), which can be accessed from the front page.

Vitamin C
According to a 1993 article in Journal of Orthomolecular Medicine, Australian medical doctor Archie Kalokerinos performed research showing that high doses of vitamin C eliminates SIDS. As SIDS was shown to be caused solely by vitamin deficiency, the article stated that it was no longer a syndrome, and that the proper disease name is now SID. As of January 2007, the Journal of Orthomolecular Medicine was not included among journals selected by the U.S. National Library of Medicine for inclusion in their Medline database.

Toxic gases
In 1989, a controversial piece of research by UK Scientist Barry Richardson claimed that all cot death was the result of toxic nerve gases being produced through the action of fungus in mattresses on compounds of phosphorus, arsenic and antimony. These chemicals are frequently used to make mattresses fire-retardant. A major plank in this explanation is the widely-observed phenomenon that the risk of cot death rises from one sibling to the next. No satisfactory biological explanation for this has ever been put forward. Richardson claims that the cause is that parents are more likely to buy new bedding for their first child, and to re-use that bedding for later children. The more frequently used the bedding is, the more chance there will be that fungus has become resident in the material and thus the higher chance of cot death. A paper by Peter Fleming and Peter Blair references evidence from other studies that both supports and refutes the increasing occurrence of SIDS with mattress sharing and suggests that this is still inconclusive. In 1994, the New Zealand government, under the advice of Dr. Jim Sprott, issued advice recommending new parents to either buy bedding free of the toxic compounds or to wrap the mattresses in a barrier film to prevent the escape of the gases. Dr. Sprott claims that no case of cot death has ever been traced back to a properly manufactured or wrapped mattress. However, a final report of The Expert Group to Investigate Cot Death Theories: Toxic Gas Hypothesis, published in May 1998 concluded that "there was no evidence to substantiate the toxic gas hypothesis that antimony- and phosphorus-containing compounds used as fire retardants in PVC and other cot mattress materials are a cause of SIDS. Neither was there any evidence to believe that these chemicals could pose any other health risk to infants." (See FSID Press release). The report also states that "in normal cot-like conditions it is not possible to generate toxic gas from antimony in mattresses" and "babies have also been found to die on wrapped mattresses." Dr. Sprott's website, however, claims  that the study does not actually refute his theory: "Contrary to media publicity, the 1998 UK Limerick Report did not disprove the toxic gas theory - as a highly qualified environmental scientist has stated in the New Zealand Medical Journal. In fact, the Limerick Committee's experiments proved the fungal generation of toxic gases (forms of stibine and arsine) from cot mattress materials." According to Dr. Sprott, as of 2006, the New Zealand government has not reported any SIDS deaths when babies have slept on mattresses wrapped according to his method. While the Limerick report claims that babies have been found to die on wrapped mattresses, Dr. Sprott argues that a chemical analysis of the bedding should be performed. He additionally claims that this part of the report was flawed : "In February 2000 Dr Peter Fleming (a co-author of the Limerick Report and principal author of the UK CESDI Report) conceded that the claim that three babies in the United Kingdom had died of cot death on polythene-covered mattresses could not be substantiated."

Central Respiratory Pattern Deficiency
There is ongoing research in the pediatric/neonatal community that has begun to associate apnea-like breathing cessations in animal models with unusual neural architecture or signal transduction in central pattern generator circuits including the pre-Bötzinger complex. It is possible that irregularities in neurotransmitter release (such as GABA, adenosine, and NMDA) or deficiencies in their associated receptors (including both GABAA, GABAB subtypes and NMDA-glutamate receptors) are linked to incomplete prenatal development as is evident in pre-term infants.

Genetic factors are also being studied with several rat and mouse knockouts.

Sex
There is a consistent 50% male excess in SIDS per 1000 live births of each sex. Given a 5% male excess birth rate (105 male to 100 female live births) there appear to be 3.15 male SIDS per 2 female SIDS for a male fraction of 0.61. See http://wonder.cdc.gov and http://www3.who.int/whosis/menu.cfm?path=whosis,inds,mort&language=english for data on SIDS by gender in the U.S. and throughout the world. Mage and Donner (The fifty percent male excess of infant respiratory mortality. Acta Paediatr. 2004 Sep;93(9):1210–5; The X-linkage hypotheses for SIDS and the male excess in infant mortality. Med Hypotheses. 2004;62(4):564–7.) have shown that the 50% male excess could be caused by a dominant X-linked allele that occurs with a frequency of ⅓ that is protective of transient cerebral anoxia. An unprotected XY male would occur with a frequency of ⅔ and an unprotected XX female would occur with a frequency of $4⁄9$. The ratio of ⅔ to $4⁄9$ is 1.5 to 1 which matches the observed male 50% excess rate of SIDS. Although many authors have found autosomal and mitochondrial genetic risk factors for SIDS they cannot explain the male excess because such gene loci have the same frequencies for males and females. Supporting evidence is found by examination of other causes of infant respiratory death, such as inhalation of food and other foreign objects. Although food is prepared identically for male and female infants, there is a 50% male excess of death from such causes indicating that males are more susceptible to the cerebral anoxia created by such incidents in exactly the same proportion as found in SIDS. See the data found at http://wonder.cdc.gov for 9ICD 911 and 912 death rates by sex. The study which indicated that there was a relationship between fewer serotonin binding sites and SIDS noted that the boys "had significantly fewer serotonin binding sites than girls".

SIDS and child abuse
British former pediatrician Roy Meadow believes that many cases diagnosed as SIDS are really the result of child abuse on the part of a parent displaying Munchausen Syndrome by Proxy (a condition which he was first to describe, in 1977). During the 1990s and early 2000s, a number of mothers of multiple apparent SIDS victims were convicted of murder, to varying degrees on the basis of Meadow's opinion. In 2003 a number of high-profile acquittals brought Sir Roy's theories into disrepute, and many now doubt their credibility. Several hundred murder convictions were reviewed, leading to several high-profile cases being re-opened and convictions overturned. The Royal Statistical Society issued a media release refuting the expert testimony in one UK case in which the conviction was subsequently overturned.

Nitrogen dioxide
A 2005 study by researchers at the University of California, San Diego found that "SIDS may be related to high levels of acute outdoor NO2 exposure during the last day of life." While nitrogen dioxide (NO2) exposure may be one of many possible risk factors, it is not considered causal, and the report cautioned that further studies were needed to replicate the result.

Vaccination
Some mention has been made of the link between vaccinations and SIDS, however no evidence has been presented to confirm this link. A study in the British Medical Journal determined that there was actually a decrease in SIDS risk for infants that had undergone immunizations. Other studies indicate that there is no significant difference in risk.

Inner Ear Damage
Records of hearing tests administered to certain infants show that those who later died of SIDS had a unique pattern of partial hearing loss, according to the journal Early Human Development. One suggestion for the cause of SIDS is that the deaths are caused by disturbances in respiratory control. The vestibular apparatus of the inner ear has been shown to play an important role in respiratory control during sleep. It is speculated that this inner ear damage could be linked to SIDS. It is speculated that the damage occurs during delivery, particularly when prolonged contractions create greater blood pressure in the placenta. The right ear, is directly in the "line of fire" for blood entering the fetus from the placenta, and thus could be most susceptible to damage. If the findings are correct, it may be possible to take corrective measures. Researchers are beginning animal studies to explore the connection.