Overview

Typically the infant is found dead after having been put to bed, and exhibits no signs of having suffered.

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

1. an autopsy;
2. investigation of the scene and circumstances of the death;
3. exploration of the medical history of the infant and family.

SIDS was responsible for 0.543 deaths per 1,000 live births in the U.S. in 2005. 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 infants after one month of age.

SIDS deaths in the U.S. decreased from 4,895 in 1992 to 2,247 in 2004. But, during a similar time period, 1989 to 2004, SIDS being listed as the cause of death for sudden infant death (SID) decreased from 80% to 55%. According to Dr. John Kattwinkel, chairman of the Center for Disease Control (CDC) Special Task Force on SIDS "A lot of us are concerned that the rate (of SIDS) isn't decreasing significantly, but that a lot of it is just code shifting”.

Nomenclature

Australia and New Zealand are shifting to the term Sudden Unexplained Death in Infancy (SUDI) for professional, scientific and coronial clarity.

The term SUDI is now often used instead of Sudden Infant Death Syndrome (SIDS) because some coroners prefer to use the term ‘undetermined’ for a death previously considered to be SIDS. This change is causing diagnostic shift in the mortality data.

SIDS Back To Sleep campaign: history and theory

In 1985 Davies reported that in Hong Kong, where the common Chinese habit was for supine infant sleep position (face up), SIDS was a rare problem. In 1987 the Netherlands started a campaign advising parents to place their newborn infants to sleep on their backs (supine position) instead of their stomachs (prone position). This was followed by infant supine sleep position campaigns in the United Kingdom, New Zealand, and Australia in 1991, the U.S. and Sweden in 1992, and Canada in 1993.

This advice was based on the epidemiology of SIDS and physiological evidence which shows that infants who sleep on their back have lower arousal thresholds and less slow-wave sleep (SWS) compared to infants who sleep on their stomachs. In human infants sleep develops rapidly during early development. This development includes an increase in non-rapid eye movement sleep (NREM sleep) which is also called quiet sleep (QS) during the first 12 months of life in association with a decrease in rapid eye movement sleep (REM sleep) which is also known as active sleep (AS). In addition, slow wave sleep (SWS) which consists of stage 3 and stage 4 NREM sleep appears at 2 months of age and it is theorized that some infants have a brain-stem defect which increases their risk of being unable to arouse from SWS (also called deep sleep) and therefore have an increased risk of SIDS due to their decreased ability to arouse from SWS.

Studies have shown that preterm infants, full-term infants, and older infants have greater time periods of quiet sleep and also decreased time awake when they are positioned to sleep on their stomachs. In both human infants and rats, arousal thresholds have been shown to be at higher levels in the electroencephalography (EEG) during slow-wave sleep.

In 1992, a SIDS risk reduction strategy based upon lowering arousal thresholds during SWS was implemented by the American Academy of Pediatrics (AAP) which began recommending that healthy infants be positioned to sleep on their back (supine position) or side (lateral position), instead of their stomach (prone position), when being placed down for sleep. In 1994, a number of organizations in the United States combined to further communicate these non-prone sleep position recommendations and this became formally known as the “Back To Sleep” campaign. In 1996, the AAP further refined its sleep position recommendation by stating that infants should only be placed to sleep in the supine position and not in the prone or lateral positions.

In 1992, the first National Infant Sleep Position (NISP) Household Survey was conducted to determine the usual position in which U.S. mothers placed their babies to sleep: lateral (side), prone (stomach), supine (back), other, or no usual position. According to the 1992 NISP survey, 13.0% of U.S. infants were positioned in the supine position for sleep. According to the 2006 NISP survey 75.7% of infants were positioned in the supine position to sleep.

Since 1998 there have been several studies published which report that infants placed to sleep in the supine position lag in motor skills, social skills, and cognitive ability development when compared to infants who sleep in the prone position. In a 1998 article entitled “Effects of Sleep Position on Infant Motor Development.” by Davis, Moon, Sachs, and Ottolini, the authors state “We found that sleep position significantly impacts early motor development.” The prone (stomach) sleeping infants in this study slept an average of 225.2 hours (8.3%) more in their first 6 months of life than the supine (back) sleeping infants.

In the 1998 article entitled “Does the Supine Sleeping Position Have Any Adverse Effects on the Child? II. Development in the First 18 Months” by Dewey, Fleming, Golding, and the ALSPAC Study Team the objective of the study was “To assess whether the recommendations that infants sleep supine could have adverse consequences on their motor and mental development.” They used the Denver Developmental Screening Test (DDST) and studied infants at 6 and 18 months. According to the study, at 6 months of age, the infants who were placed to sleep in the prone position had statistically significant higher social skills scores, gross motor scores, and total development scores than those infants who were put to sleep in the supine position. In the 2005 article entitled “Influence of supine sleep positioning on early motor milestone acquisition” by Majnemer and Barr they used the Alberta Infant Motor Scale Scores (AIMS Scores) to analyze the impact of infant sleep position. They reported that “Typically developing infants who were sleep-positioned in supine had delayed motor development by age 6 months, and this was significantly associated with limited exposure to awake prone positioning.” But, the authors also note that awake prone (stomach) positioning is associated with prone (stomach) sleeping. No studies have been conducted which compare supine sleeping infants who have regular awake prone positioning (tummy time) to prone sleeping infants who have regular awake prone positioning (tummy time).

Placing infants on their stomachs while they are awake (tummy time) has been recommended to offset the motor skills delays associated with the back sleep position but positioning the infant on their stomach while awake will not impact the amount of slow wave sleep since tummy time only occurs when an infant is awake.

Undiagnosed conditions

Some conditions that may be undiagnosed and thus could be alternative diagnoses to SIDS include:

• medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency)
• infant botulism
• long QT syndrome (accounting for less than 2% of cases)
• infections with the bacterium Helicobacter pylori
• shaken baby syndrome and other forms of child abuse
• overlying

For example an infant with MCAD deficiency could have died by 'classical SIDS' if found swaddled and prone with head covered in an overheated room where parents were smoking. Genes of susceptibility to MCAD and Long QT syndrome do not protect an infant from dying of classical SIDS. Therefore presence of a susceptibility gene, such as for MCAD, means the infant may have died either from SIDS or from MCAD deficiency. It is impossible for the pathologist to distinguish between them.

Risk factors

The cause of SIDS is unknown. Any proposed causation factor must be either necessary and sufficient to cause SIDS by itself (as the rabies virus causes rabies) or necessary and insufficient to cause SIDS by itself (as the typhus bacillus may or may not cause typhoid, see Typhoid Mary). 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 potential causes. The frequency of SIDS appears to be a strong function of the infant's sex, age and ethnicity, and the education and socio-economic-status of the infant's parents.

According to a study published on November 1, 2006 in the Journal of the American Medical Association, babies who die of SIDS have abnormalities in the brain stem (the medulla oblongata), which helps control functions like breathing, blood pressure and arousal, and abnormalities in serotonin signaling. According to the National Institutes of Health, which funded the study, this finding is the strongest evidence to date that structural differences in a specific part of the brain may contribute to the risk of SIDS.

In a British study released May 29, 2008 researchers discovered that the common bacterial infections Staphylococcus aureus (staph) and Escherichia coli (E. coli) appear to be a risk factor in some cases of Sudden Infant Death Syndrome. Both bacteria were present at greater than usual concentrations in infants who died from SIDS. SIDS cases peak between eight and ten weeks after birth, which is also the time frame in which the antibodies that were passed along from mother to child are starting to disappear and babies have not yet made their own antibodies.

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

Prenatal risks

• maternal nicotine use (tobacco or nicotine patch)
• inadequate prenatal care
• inadequate prenatal nutrition
• use of heroin, cocaine and other drugs
• subsequent births less than one year apart
• alcohol use
• infant being overweight
• mother being overweight
• Teen pregnancy (if the baby has a teen mother, it has a greater risk)
• infant's sex (60% of SIDS cases occur in males)

Post-natal risks

• mold (can cause bleeding lungs plus a variety of other uncommon conditions leading to a misdiagnoses and death). It is often misdiagnosed as a virus, flu, and/or asthma-like conditions.
• low birth weight (in the U.S. from 1995-1998 the rate for 1000-1499 g was 2.89/1000 and for 3500-3999 g it was 0.51/1000)
• exposure to tobacco smoke
• prone sleep position (lying on the stomach, see sleep positioning below)
• not breastfeeding
• elevated or reduced room temperature
• excess bedding, clothing, soft sleep surface and stuffed animals
• Co-sleeping with parents or other siblings may increase risk for SIDS, but the mechanism remains unclear
• infant's age (incidence rises from zero at birth, is highest from two to four months, and declines towards zero at one year)
• premature birth (increases risk of SIDS death by about 4 times. In 1995-1998 the U.S. SIDS rate for 37–39 weeks of gestation was 0.73/1000; The SIDS rate for 28–31 weeks of gestation was 2.39/1000)
• anemia

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.

Environment

• Sleep positioning

Sleeping on the back has been recommended by (among others) the American Academy of Pediatrics (starting in 1992) to avoid SIDS, with the catchphrases "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. However, the absolute incidence of SIDS prior to the Back to Sleep Campaign was already dropping in the US, from 1.511 per 1000 in 1979 to 1.301 per 1000 in 1991.

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[63] 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.

Arguments against infant back-sleeping include concerns that an infant could choke on fluids it brings up. Hospital neonatal-intensive-care-unit (NICU) staff commonly place preterm newborns on their stomach, although they advise parents to place their infants on their backs after going home from the hospital.

Other concerns raised about the Back to Sleep Campaign have included the possible increased risk of positional facial and head deformities (see positional plagiocephaly), possible interference with development of good sleep habits (which in turn may have other bad effects), and possible interference with motor skills 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 compared with 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." However, a more recent study shows that breast feeding reduces the risk of SIDS by approximately 50% at all infant ages.

• Co-sleeping

In nearly all incidences, the higher the rate of co-sleeping, the lower the rate of SIDS and vice versa. The data has suggested that almost all SIDS deaths in adult beds would be occurring when other prevention methods, such as placing infants on their backs, are not used. Co-sleeping studied in the West has been present mostly in poorer families where other risk factors are present. While co-sleeping in other cultures such as in China is more prevalent and is done in combination with practices such as sleeping children on their back, correlating with a significantly lower rate of SIDS than the West. Further studies have suggested that factors associated with safe co-sleeping such as enhanced infant arousals are responsible for a positive contribution to SIDS prevention.

A 2005 policy statement by the American Academy of Pediatrics on sleep environment and the risk of SIDS deemed co-sleeping and bed sharing unsafe. One article reports that co-sleeping infants have a greater risk of airway covering than when the same infant sleeps alone in a cot.

• Secondhand smoke reduction

According to the U.S. Surgeon General’s Report, 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 body fluids than those who die from other causes. 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.

The maternal pregnancy smoking rate decreased by 38% between 1990 and 2002.

Sleeping area

• Bedding

Product safety experts advise against using pillows, sleep positioners, bumper pads, stuffed animals, or fluffy bedding in the crib and recommend instead dressing the child warmly and keeping the crib "naked."

Blankets should not be placed over an infant's head. It has been recommended that infants should be covered only up to their chest with their arms exposed. This reduces the chance of the infant shifting the blanket over his or her head.

• Sleep sacks

In colder environments where bedding is required to maintain a baby's body temperature, the use of a "baby sleep bag" or "sleep sack" is becoming more popular. This is a soft bag with holes for the baby's arms and head. A zipper allows the bag to be closed around the baby. 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 its 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." The American Academy of Pediatrics also recommends them as a type of bedding that warms the baby without covering its head. The use of swaddling clothes, a traditional form of infant restraint which leaves only the head uncovered, is controversial.

• Pacifiers

According to a 2005 meta-analysis, most studies favor pacifier use. According to the American Academy of Pediatrics, pacifier use seems to reduce the risk of SIDS, although the mechanism by which this happens is unclear. SIDS experts and policy makers haven't recommended the use of pacifiers to reduce the risk of SIDS because of several problems associated with pacifier use, like increased risk of otitis, gastrointestinal infections and oral colonization with Candida species. A 2005 study indicated that use of a pacifier is associated with up to a 90% reduction in the risk of SIDS depending on the ambient factors, and it reduced the effect of other risk factors. 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. If a postmortem investigation does not occur or is insufficient, a suffocated baby may be misdiagnosed with SIDS.

• 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, stating:

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.

Other hypotheses

• Mattress bugs

A 2004 study hypothesized that bugs feeding on baby vomit and dust could be fatal for small children, creating 'supertoxins' which spur the baby's body into overreacting, leading to anaphylactic shock.

• Brain disorder

A recently published research article showed evidence that cells in the brainstem fail to develop receptors for serotonin in the womb. This abnormality can continue postpartum until the end of the 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. Males have fewer serotonin receptors than females, perhaps contributing to the increased incidence of SIDS in the demographic.

In addition, a study done in 2006 showed that a possible cause of SIDS is because parents leave their infants in a position known as Trendelenburg position. This position can cause the brain stem to fall, and in a result, the brain becomes "crushed". The proper position for an infant is either Fowler's position or Sims'.

• Air circulation with fan use

According to a study of nearly 500 babies published the October 2008 Archives of Pediatrics & Adolescent Medicine, using a fan to circulate air correlates with a lower risk of sudden infant death syndrome. Researchers took into account other risk factors and found that fan use was associated with a 72% lower risk of SIDS. Only 3% of the babies who died had a fan on in the room during their last sleep, the mothers reported. That compared to 12% of the babies who lived. Using a fan reduced risk most for babies in poor sleeping environments. Author De-Kun li said that "the baby's sleeping environment really matters" and that "this seems to suggest that by improving room ventilation we can further reduce risk."

However, Dr John Olssen at East Carolina University has pointed out that this study had a number of methodological flaws, such selection and recall bias, low enrollment numbers, and dissimilar study groups. Olssen argues that although fan use is probably not harmful, it should not be recommended as a means to reduce the risk of SIDS

• Vitamin C

In the 1970s, high doses of vitamin C were touted as a preventive measure for SIDS, although the claim was controversial even then. Subsequent study failed to support a preventive role for vitamin C in SIDS. To the contrary, a 2009 study found that high levels of vitamin C were strongly associated with SIDS, possibly through a pro-oxidant interaction with iron.

• Toxic gases

In 1989, a controversial piece of research by UK Scientist Barry Richardson claimed that all cot deaths were 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.

Support for this hypothesis was based on the observation that the risk of cot death rises from one sibling to the next. Richardson claimed 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; thus, a 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.

Dr. Jim Sprott recommends new parents either buy bedding free of the toxic compounds or to wrap the mattresses in a barrier film to prevent the escape of the gases. 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." 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."

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.

• Cervical spinal injury from birth trauma

During birth, if the infant's head is traumatically turned side to side, upper cervical spinal injury can result. Difficulty breathing is a classic sign of upper spinal cord and brain-stem injury. When infants with undiagnosed upper cervical spinal cord injury are continually placed on their stomach for sleep, they are forced to turn their head to the side to breathe. This is hypothesised to aggravate and prolong the spinal cord injury sustained during birth, preventing proper healing and ultimately leading to fatal breathing difficulty.

• Genetics

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. This value of 61% in the U.S. is an average of 57% black male SIDS, 62.2% white male SIDS and 59.4% for all other races combined. Note that when multiracial parentage is involved, infant "race" is arbitrarily assigned to one category or the other; most often it is chosen by the mother. The X-linkage hypothesis for SIDS and the male excess in infant mortality have shown that the 50% male excess could be related to 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 for an X-linkage is found by examination of other causes of infant respiratory death, such as suffocation by inhalation of food and other foreign objects. Although food is prepared identically for male and female infants, there is a similar 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.

The JAMA 2006 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,". but the authors could not reproduce it in their 2010 paper. However, such neurological prematurity decreases with age, but the male fraction of approximately 0.61 persists each month throughout the first year of life. Furthermore, this cannot explain the identical male fraction of 0.61 in other respiratory mortality causes such as respiratory distress syndrome or suffocation from inhalation of food or foreign objects cited above, that also exists for all ages 1 to 14 years in the U.S. from 1979 to 2005.

• Child abuse

Several instances of infanticide have been uncovered where the diagnosis was originally SIDS. This has led some researchers to estimate that 5% to 20% of SIDS deaths are infanticides. In 1997 The New York Times, covering a book called The Death of Innocents: A True Story of Murder, Medicine and High-Stakes Science, wrote:

The misdiagnosis of infanticide as SIDS "happens all over," Ms. Talan, a medical reporter at Newsday, said. "A lot of doctors and police don't know how to handle it. They don't take it as seriously as they should." As a result of the book's revelations, people are starting to scrutinize possible cases of this "perfect crime," which involves no physical evidence and no witnesses.

A former pediatrician Roy Meadow from United Kingdom 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 Meadow's theories into disrepute. 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

According to the US Centers for Disease Control and Prevention, several studies have failed to provide sufficient evidence of a causal link between vaccinations and SIDS. They state:

From 2 to 4 months old, babies begin their primary course of vaccinations. This is also the peak age for sudden infant death syndrome (SIDS). The timing of these two events has led some people to believe they might be related. However, studies have concluded that vaccines are not a risk factor for SIDS.

• Inner ear damage

Records of hearing tests (oto-acoustic emissions, OAEs) administered to certain infants show that those who later died of SIDS had differences in the pattern of these tests compared with normal babies. To be specific the OAE signal to noise ratio was reduced in the right ear in the SIDS babies. (Rubens DD et al. Early Human Development 84, 225-9 (2008)). It should be noted this was a small study (n=31 cases and 31 controls), had serious limitations (several significant factors were not controlled), and has been criticised from various perspectives. The authors' suggestion for the cause of SIDS is that the deaths are caused by disturbances in respiratory control (from other than suffocation). 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 relevant, it may be possible to take corrective measures. Researchers are beginning animal studies to explore the connection.

Side effects of SIDS risk reduction recommendations

Dr. Rafael Pelayo from Stanford University and a number of other pediatric sleep researchers in the U.S. have stated that they believe that the American Academy of Pediatrics' recommendations regarding cosleeping and pacifier use may have unintended consequences. They have stated that the SIDS prevention strategy of the American Academy of Pediatrics which keeps infants at a low arousal threshold and reduces the time in quiet sleep may be unhealthy for children. They state that slow wave sleep is the most restorative form of sleep and limiting this sleep in the first 12 months of life may have unintended consequences to both the sleep and the infant.

According to a 1998 study by British researchers that compared back sleeping infants to stomach sleeping infants there were developmental differences at 6 months of age between the two groups. At 6 months of age the stomach sleeping infants had higher gross motor scores, social skills scores, and total development skills scores than the back sleeping infants. The differences were apparent at the 5% statistical significant level. But, at 18 months the differences were no longer apparent. The researchers deemed the lower development scores of back sleeping infants at 6 months of age to be transient and stated that they do not believe the back sleeping recommendations should be changed. Other scientists have stated that the conclusion that the negative effects of back sleep at 18 months of age is transient is based upon very little evidence and that no long-term randomized trials have been completed.

Other side effects of the back sleeping position include increased rates of shoulder retraction, positional plagiocephaly, and positional torticollis. Some scientists dispute that plagiocephaly is a negative side effect. Dr. Peter Fleming, who is co-author of the study that deemed delays at 6 months of age to be transient, has stated that he does not think plagiocephaly is a negative side effect of back sleep. In an interview with the Guardian Dr. Fleming stated "I do not think it is a medical problem—it is more of a cosmetic one. Mothers may feel it is a syndrome and a problem when it really is nonsense." A research study on children with plagiocephaly found that 26% had mild to severe psychomotor delay. This study also showed that 10% of infants with plagiocephaly had mild to severe mental development delay.

Because of the delays caused by back sleep some medical professionals have suggested that the "normal" ages at which children had previously attained developmental milestones should be pushed back. This would enable medical professionals to consider "normal" children who previously were considered developmentally delayed.

Additional studies have reported that the following negative conditions are associated with the back sleep position: increase in sleep apnea, decrease in sleep duration, strabismus, social skills delays, deformational plagiocephaly, and temporomandibular jaw difficulties. In addition, the following are symptoms that are associated with sleep apnea: growth abnormalities, failure to thrive syndrome in infants, neurocognitive abnormalities, daytime sleepiness, emotional problems, decrease in memory, decrease in learning, and a delay in nonverbal skills. The conditions associated with deformational plagiocephaly include visual impairments, cerebral dysfunction, delays in psychomotor development and decreases in mental functioning. The conditions associated with gross motor milestone delays include speech and language disorders. In addition, it has been hypothesized that delays in motor skills can have a negative impact on the development of social skills. In addition, other studies have reported that the prone position prevents subluxation of the hips, increases psychomotor development, prevents scoliosis, lessens the risk of gastroesophageal reflux, decreases infant screaming periods, causes less fatigue in infants, and increases the relief of infant colic. In addition, prior to the “Back to Sleep” campaign many babies self-treated their own torticollis by turning their heads from one side to the other while sleeping in the prone position. Supine sleeping infants cannot self-treat their own torticollis.
 

The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti-inflammatory and anti-apoptotic activities. It also plays a role in the development of thrombosis and ischemic stroke.

Role in disease

Protein C deficiency is a rare genetic disorder that predisposes to venous thrombosis and habitual abortion. If homozygous, this presents with a form of disseminated intravascular coagulation in newborns termed purpura fulminans; it is treated by replacing the defective protein C.

Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations.

Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K inhibitor anticoagulant warfarin. In initial stages of action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to paradoxical activation of coagulation and necrosis of skin areas.

HDL and the effects of activated protein C (APC) on cells is very important.

Pharmacology

Drotrecogin alpha(activated) is recombinant activated protein C from Eli Lilly Co, USA. It is used in the treatment of severe sepsis, septic shock and disseminated intravascular coagulation. Its use has been very controversial since the results of clinical studies have been markedly varied. A new clinical trial of activated protein C for severe sepsis is currently underway.
 

Genetic predisposition

There is evidence that genetic factors may play a role in the development of fibromyalgia. For example, there is a high aggregation of fibromyalgia in families. The mode of inheritance is currently unknown, but it is most probably polygenic. Research has demonstrated that fibromyalgia is associated with polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems. However, these polymorphisms are not specific for fibromyalgia and are associated with a variety of allied disorders (e.g. chronic fatigue syndrome, irritable bowel syndrome) and with depression.

Stress

Stress may be an important precipitating factor in the development of fibromyalgia. Fibromyalgia is frequently comorbid with stress-related disorders such as chronic fatigue, posttraumatic stress disorder, irritable bowel syndrome and depression. Two studies that employed single-voxel magnetic resonance spectroscopy (1H-MRS) reported metabolic abnormalities within the hippocampal complex in patients with fibromyalgia, with significant correlations between hippocampal metabolic abnormalities and severity of clinical symptoms.

Other authors have proposed that, because exposure to stressful conditions can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, the development of fibromyalgia may stem from stress-induced disruption of the HPA axis. This proposition is supported in part by a prospective epidemiology study which found that variations in HPA function characterized by high levels of circulating cortisol following dexamethasone suppression testing, low levels of morning salivary cortisol and high levels of evening salivary cortisol are all associated with the development of chronic widespread pain.

Central dopamine dysfunction (hypodopaminergia)

The 'dopamine hypothesis of fibromyalgia’ proposes that the central abnormality responsible for symptoms associated with fibromyalgia is a disruption of normal dopamine-related neurotransmission. Dopamine is a catecholamine neurotransmitter with roles in pain perception and natural analgesia. There is also strong evidence for a role of dopamine in restless leg syndrome, which is a condition found frequently in patients with fibromyalgia. Some fibromyalgia patients responded in controlled trials to pramipexole, a dopamine agonist that selectively stimulates dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless leg syndrome.

Abnormal serotonin metabolism

In 1975, researchers hypothesized that serotonin, a neurotransmitter that regulates sleep patterns, mood, concentration and pain, could be involved in the pathophysiology of fibromyalgia-associated symptoms. In 1992, decreased serotonin metabolites in patient blood samples and cerebrospinal fluid were reported. However, selective serotonin reuptake inhibitors (SSRIs) have met with limited success in alleviating the symptoms of the disorder, while drugs with activity as mixed serotonin-norepinephrine reuptake inhibitors (SNRIs) have been more successful. Duloxetine (Cymbalta), a SNRI originally used to treat depression and painful diabetic neuropathy, has been demonstrated by controlled trials to relieve symptoms of some patients. However, the relevance of dysregulated serotonin metabolism to pathophysiology is a matter of debate. Complicating the analysis, one of the more effective types of medication for the treatment of the disorder (i.e. serotonin 5-HT3 antagonists) actually blocks some of the effects of serotonin.

Deficient growth hormone (GH) secretion

Levels of hormones under the direct or indirect control of growth hormone (GH), including IGF-1, cortisol, leptin and neuropeptide Y may be abnormal in people with fibromyalgia, but supplementing growth hormone in patients does not have large effects, and a 2007 literature review reported a need for "further study before any solid recommendations can be made." There is disagreement about the role of HGH in fibromyalgia.

Psychological factors

There is strong evidence that major depression is associated with fibromyalgia[54], although the nature of the association is controversial. A comprehensive review into the relationship between fibromyalgia and major depressive disorder (MDD) found substantial similarities in neuroendocrine abnormalities, psychological characteristics, physical symptoms and treatments between fibromyalgia and MDD, but currently available findings do not support the assumption that MDD and fibromyalgia refer to the same underlying construct or can be seen as subsidiaries of one disease concept. Indeed, the sensation of pain has at least two dimensions: a sensory dimension which processes the magnitude of the pain, and an affective-motivational dimension which processes the unpleasantness. Accordingly, a study that employed functional magnetic resonance imaging to evaluate brain responses to experimental pain among fibromyalgia patients found that depressive symptoms were associated with the magnitude of clinically-induced pain response specifically in areas of the brain that participate in affective pain processing, but not in areas involved in sensory processing which indicate that the amplification of the sensory dimension of pain in fibromyalgia occurs independently of mood or emotional processes.

An alternative hypothesis regarding the development of fibromyalgia in relationship to psychological conflict proposes that the disorder may be a psychosomatic illness as described by John E. Sarno's writing related to "tension myositis syndrome," in which chronic pain is proposed to be a psychic diathesis of the mind's subconscious strategy of distracting painful or dangerous emotions. Education, attitude change, and in some cases, psychotherapy are proposed as treatments.

Other hypotheses

Other hypotheses have been proposed. One of these is an aberrant immune response to intestinal bacteria.

Because there is currently no completely objective clinical test for fibromyalgia, and "because everyone has had the experience of pain and therefore knows how it should appear to others,"[59] fibromyalgia is thought to be relatively easy to simulate. A significant percentage of reported cases may be due to malingering, a type of fraud wherein a patient feigns having an illness or exaggerates symptoms for non-medical personal gain (often financial), including obtaining access to prescription drugs for recreational use or for illegal resale. A 2007 review states that 25-30% of diagnosed fibromyalgia cases may be due to malingering, and a review of personal injury claims finds that 35-39% of fibromyalgia and chronic fatigue syndrome claims appear to be feigned, based on clinicians' impressions of "multiple sources of evidence, including reported severity, illness patterns, cognitive impairment inconsistent with the purported condition, and discrepancies among records, self-report, and observed behavior."
 

Fatigue is considered a symptom, as opposed to a medical sign, because it is reported by the patient instead of being observed by others. Fatigue and ‘feelings of fatigue’ are often confused.

Types

Physical fatigue

Physical fatigue or muscle weakness (or "lack of strength") is a direct term for the inability to exert force with one's muscles to the degree that would be expected given the individual's general physical fitness.

A test of strength is often used during a diagnosis of a muscular disorder before the etiology can be identified. Such etiology depends on the type of muscle weakness, which can be true or perceived as well as central or peripheral. True weakness is substantial, while perceived rather is a sensation of having to put more effort to do the same task. On the other hand, central muscle weakness is an overall exhaustion of the whole body, while peripheral weakness is an exhaustion of individual muscles.

Mental fatigue

In addition to physical, fatigue also includes mental fatigue, not necessarily including any muscle fatigue. Such a mental fatigue, in turn, can manifest itself both as somnolence (decreased wakefulness) or just as a general decrease of attention, not necessarily including sleepiness. It may also be described as more or less decreased level of consciousness. In any case, this can be dangerous when performing tasks that require constant concentration, such as driving a vehicle. For instance, a person who is sufficiently somnolent may experience microsleeps. However, objective cognitive testing should be done to differentiate the neurocognitive deficits of brain disease from those attributable to tiredness.

Differential diagnosis

The majority of people who have fatigue do not have an underlying cause discovered after a year with the condition. In those who do have a possible diagnosis musculoskeletal (19.4%) and psychological problems (16.5%) are the most common. Definitive physical conditions were only found in 8.2%.

Fatigue is typically the result of working, mental stress, overstimulation and understimulation, jet lag or active recreation, depression, and also boredom, disease and lack of sleep. It may also have chemical causes, such as poisoning or mineral or vitamin deficiencies. Massive blood loss frequently results in fatigue.

The sense of fatigue is believed to originate in the reticular activating system of the lower brain. Musculoskeletal structures may have co-evolved with appropriate brain structures so that the complete unit functions together in a constructive and adaptive fashion. The entire systems of muscles, joints, and proprioceptive and kinesthetic functions plus parts of the brain evolve and function together in a unitary way.

Temporary fatigue is likely to be a minor illness like the common cold as one part of the sickness behavior response that happens when the immune system fights an infection. Chronic fatigue, on the other hand, meaning of six months or more duration, is a symptom of a large number of different diseases or conditions. Some major categories of diseases that feature fatigue include:

Diseases

• Autoimmune diseases such as celiac disease, multiple sclerosis, and spondyloarthropathy
• Blood disorders such as anemia and hemochromatosis
• Cancer
• Chronic fatigue syndrome (CFS)
• Depression and other mental disorders that feature depressed mood
• Eating disorders, which can produce fatigue due to inadequate nutrition
• Endocrine disease like diabetes mellitus and hypothyroidism
• Fibromyalgia
• Heart disease
• Infectious diseases such as infectious mononucleosis and influenza
• Leukemia or lymphoma
• Neurological disorders such as Parkinson's disease and post-concussion syndrome
• Physical trauma and other pain-causing conditions, such as arthritis
• Pregnancy
• Sleep deprivation or sleep disorders
• uremia
• hepatic failure

Medications

• Certain medications, e.g. lithium salts, ciprofloxacin
• Beta blocker medication causes fatigue, especially after exertion, inducing exercise intolerance.
• Many cancer treatments cause fatigue, particularly chemotherapy and radiotherapy