February 4, 2010 — A new study confirms that infants who die of sudden infant death syndrome (SIDS) have a serotonin (5-hydroxytryptamine [5-HT]) abnormality in the brainstem that affects responses to breathing and carbon dioxide, as well as to temperature, blood pressure, and heart rate.
"These functions may be compromised during sleep if a baby is lying face down and rebreathing carbon dioxide," said lead study author Hannah C. Kinney, MD, from Harvard Medical School and Children's Hospital Boston in Massachusetts.
The findings appear to confirm the hypothesis that SIDS — the unexplained death of an infant within a year of birth — results from lower levels, rather than an excess, of medullary 5-HT.
This fits into the triple-risk model of SIDS, suggesting it occurs when 3 elements come together: an infant with an underlying vulnerability, in this case, a low serotonin level; a critical period of development during the first year of life; and an external stressor, sleeping face down.
"We call this a perfect storm," said Dr. Kinney: "You have a baby with the underlying vulnerability but that becomes unmasked when the baby is asleep and when the baby undergoes stress."
The study is published in the February 3 issue of the Journal of the American Medical Association.
For the study, researchers used fresh tissue samples from the medulla, the brain region that regulates basic functions, including breathing, collected at autopsy between 2004 and 2008. They compared samples from infants who died of SIDS with control infants who died acutely but not of SIDS and with infants who had been hospitalized with chronic oxygenation disorders, including lung malformations.
The study included a hospital control group because, said Dr. Kinney, if the problem in SIDS was due to hypoxia, then SIDS infants would have the same defect as the hospitalized infants.
The researchers found that age-adjusted mean levels of 5-HT in the 35 SIDS cases were 26% lower than in 5 controls in both the paragigantocellularis lateralis (PGCL) and the raphé obscurus.
Table. Age-Adjusted Mean Levels of 5-HT in SIDS Cases and Controls By Region
|Region||SIDS Subjects (n = 35)||Control Subjects (n = 5)||P Value|
|PGCL, pmol/mg protein||31.4||40.0||.04|
|Raphé obscurus, pmol/mg protein||55.4||75.5||.05|
5-HT = 5-hydroxytryptamine; PGCL = paragigantocellularis lateralis; SIDS = sudden infant death syndrome
Levels of tryptophan hydroxylase (TPH2), the enzyme that makes serotonin, were 22% lower in 34 SIDS cases compared with 5 control cases (151.2% of standard vs 193.9%, P = .03).
The hospitalized infants displayed different abnormalities, including higher 5-HT and PGCL levels and lower TPH2 levels, compared with the SIDS group.
"The way we interpret that is that the problem in SIDS isn't just a reflection of chronic hypoxia, that is, having nights where they drop their O2 during sleep, but rather it's probably something more fundamental," said Dr. Kinney.
These results represent "a step, we believe a major step" in learning what factors may contribute to SIDS, said Dr. Kinney. However, she stressed there's still "a lot to be done" to discover how serotonin deficiency may be treated and how it can be identified in the living infant.
It's not a single factor but a culmination of abnormalities that result in the death, stressed Dr. Kinney. She noted that in 88% of the SIDS cases the researchers examined, 2 or more risk factors, including an illness or exposure to cigarette smoke, as well as infant sleep position, were present.
The goal of this research is to eventually find ways to determine if an infant is deficient in serotonin, said David S. Paterson, PhD, another study author also at Harvard Medical School and Children's Hospital Boston.
We'd like to have some way of identifying babies who are at risk, and then ultimately we would like to be able to have some intervention strategy, maybe a drug, that would help them get over this period of risk for SIDS," he said. "At the moment, we're not anywhere near having a diagnostic test for SIDS in a newborn infant, but that's really what we'd like."
Putting an infant on its back is a first step in reducing that perfect storm, Dr. Kinney added. An infant's risk of dying on his stomach is probably at least 3 times that on his back.
Link to Autism?
The rate of SIDS decreased by 50% in some populations after a widespread public awareness campaign was initiated in 1994 but has plateaued during the last decade, said Dr. Kinney. According to the National Center for Health Statistics, SIDS is the third leading cause of infant death, claiming more than 2300 lives in 2006.
If infants with a serotonin deficiency survive infancy, what then happens to them? According to Dr. Paterson, there is some speculation that the decrease in SIDS deaths may somehow be related to the increased incidence of autism, a disorder that is also linked to a serotonin abnormality.
"It's speculative at the moment, but people are thinking that an increase in something like autism might be a manifestation of babies who survive that critical period for SIDS."
Reached for a comment, Michael Goldstein, MD, a child neurologist at Western Neurological Associates, Salt Lake City, Utah, thought the study authors did "an excellent job" of describing the serotonin deficit in SIDS.
"I think their sophisticated approach was carefully thought out and carefully reasoned, and their conclusions are significant," he said. However, he added, "there's a long way between the understanding that this paper generates and trying to help prevent SIDS."
The researchers recognize that SIDS is not just a matter of having too much or too little serotonin but a dysfunction in at least 1 serotonin system, said Dr. Goldstein. He said the study authors make "a very good case" that the dysfunctional system is in the medulla.
The study results reinforce the notion that the brain is not a "big soup pot" where serotonin, dopamine, and other brain chemicals are poured in, said Dr. Goldstein. "That's an oversimplification. It isn't just whether you have more or less; it's which systems are being activated and which systems are depleted or which systems are not sufficient."
Several risk factors are likely required to cause SIDS, and the more factors present, the higher the likelihood for this condition, said Dr. Goldstein.
The study authors have disclosed no relevant financial relationships.
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