A potential biological cause for sudden infant death syndrome (SIDS)
Defective serotonin pathways in the brainstem may increase infants' vulnerability
October 31, 2006
New autopsy data provide the strongest evidence yet that sudden infant death syndrome (SIDS) is not a "mystery" disease but has a concrete biological basis. In the November 1 issue of JAMA, researchers at Children's Hospital Boston document abnormalities in the brainstem -- a part of the brain that regulates breathing, blood pressure, body heat, and arousal -- in babies who died from SIDS.
SIDS is the leading cause of death in American infants after the newborn period, affecting 0.67 in 1,000 live-born babies. Although epidemiologic studies have identified risk factors for SIDS, such as putting babies to sleep on their stomachs, and protective factors like pacifier use, there has been little understanding of SIDS's biologic basis.
Researchers led by neuropathologist Hannah Kinney, MD, and neuroscientist David Paterson, PhD, at Children's Hospital Boston and Harvard Medical School examined brain autopsy specimens from 31 infants who had died from SIDS and 10 who had died acutely from other causes, provided by the San Diego Chief Medical Examiner's office. Examining the lowest part of the brainstem, known as the medulla oblongata, they found abnormalities in nerve cells that make and use serotonin, one of over 100 chemicals in the brain that transmit messages from one nerve cell to another.
Based on their findings, Kinney, Paterson and colleagues hope to develop a diagnostic test to identify infants at risk for SIDS. They also envision a drug or other type of treatment to protect infants who have abnormalities in their brainstem serotonin system.
The brainstem serotonin system is thought to help coordinate breathing, blood pressure, sensitivity to carbon dioxide, and temperature during waking and sleep. When babies sleep face down or have their faces covered by bedding, they are thought to re-breathe exhaled carbon dioxide, therefore breathing in less oxygen. Normally, the rise in carbon dioxide activates nerve cells in the brainstem, which in turn stimulate respiratory and arousal centers in the brain so that the baby doesn't asphyxiate.
"A normal baby will wake up, turn his or her head, and start breathing faster when carbon dioxide levels rise," explains Kinney.
But in babies who die from SIDS, defects in the serotonin system may impair these reflexes, the researchers believe.
Kinney previously documented serotonin receptor abnormalities in two other populations of SIDS infants, including American Indian infants in the Northern Plains, whose SIDS rate is among the highest in the world. The current study confirms those findings in a third population and, for the first time, pinpoints multiple defects in the serotonin system other than those in serotonin receptors: deficiencies in a particular type of serotonin receptor (called 5HT1A), an abnormally high number of serotonergic neurons (neurons that make and release serotonin), a preponderance of immature serotonergic neurons, and evidence for insufficient amounts of the serotonin transporter protein, which "recycles" serotonin so that nerve cells can reuse it.
"We provide strong evidence that SIDS is a biological problem, and that the brainstem serotonin system is a good place to focus continued research efforts," says Paterson.
He and Kinney believe that the abnormalities they observed begin during early fetal development, and that prenatal insults like maternal smoking and alcohol use may adversely affect development of the brainstem serotonin system during this time. More research is needed to explain what causes the abnormalities and how they can be prevented.
The findings also provide a biological explanation for why SIDS occurs twice as often in males than females -- male SIDS infants had significantly fewer 5-HT1A receptors than female SIDS infants.
In addition, serotonin abnormalities help explain why infants under 6 months are most vulnerable to SIDS. At birth, babies must adjust from being totally dependent on their mother to breathing on their own and maintaining their own blood pressure. If the brainstem serotonin system is defective or still immature, this transition to total independence in the control of vital functions may be impaired during the crucial first six months of life.
"We think that the control systems for vital or homeostatic functions reach full maturity only towards the end of the first year of life," Kinney says.
The researchers note that despite the national Back to Sleep campaign, which urges caregivers to put babies to bed on their backs, 65 percent of the SIDS infants in this study were found sleeping on their stomach or side.
The study was funded by the National Institute of Child Health and Human Development. Additional funding came from private SIDS foundations such as the CJ Foundation for SIDS, the First Candle/SIDS Alliance, the CJ Murphy Foundation, the Barrett Fellowship for SIDS Research and the Scottish Cot Death Foundation.
Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: www.childrenshospital.org/newsroom.