A Biomarker for vulnerability to SIDS? Interesting but not ready for primetime!

Eileen Tyrala, MD, FAAP

A Biomarker for vulnerability to SIDS? Interesting but not ready for primetime!

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Our understanding of SIDS and sleep-related infant deaths has focused on the concept that these deaths are multifactorial in origin. The “triple risk model”, the most widely accepted model for SIDS causation, states that a SIDS death will occur when 3 factors are present simultaneously: a critical infant developmental stage for homeostatic control, the presence of exogenous environmental stressors, and an inherent infant vulnerability.

As the vast majority of SIDS and other sleep-related infant deaths occur in the first 4 months of life, this is generally considered to be the critical time for the development and maturation in the brain of homeostatic control of the basic biologic functions of heart rate, blood pressure, respirations, and thermoregulation. Exogenous or outside stressors are the factors in the physical environment that we as caregivers provide to infants in both their general living environment (i.e. cigarette smoke exposure)  and sleep environment (bed-sharing, prone sleep position, etc). Over the last 25 years, we have spent most of our time and attention on educating families about safe sleep environments, the only modifiable element of the Triple Risk model. Unfortunately, despite all of our efforts, we have experienced less success in reducing the number of sleep-related infant deaths than we would have hoped for and expected. The area that has remained most elusive, however, is our ability to proactively identify the inherently vulnerable infant. We know statistically that infants exposed in utero to cigarette smoke have a significantly higher risk of succumbing to a SIDS death and appropriately view them as inherently more vulnerable, although the reason for this increased vulnerability is not yet fully understood.  Work by Dr. Hannah Kenney in the 1990s suggested that biochemical deficiencies related to the neurotransmitter serotonin in the brain stem of infants who died of SIDS had led to a state of delayed arousal in response to either decreasing levels of oxygen or increasing levels of carbon dioxide that occured when the infant was placed in a “stressful” physical environment.  There is no way of identifying in a living infant if this neurochemical deficiency exists and is thus at an increased risk to succumb to SIDS.

A study from Australia by Harrington et al published in Lancet (online (https://doi.org/10.1016/j.ebiom.2022.104041) and in print, June 2022) claims to have identified a biochemical marker that can be detected in an infant’s blood at 2 days of life and is predictive of their vulnerability to SIDS. The researchers took blood from the filter paper that is routinely collected on all newborns for detection of specific inborn errors of metabolism and retrospectively analyzed it for an enzyme called Butyrlcholinesterase. This enzyme, along with acetylcholinesterase, is responsible for breaking down the major neurotransmitter of the autonomic nervous system, acetylcholine. Deficiencies in either one of these enzymes could theoretically result in autonomic dysfunction and blunt the ability of an infant to autoresuscitate or arouse under conditions of stress. In this study, 26 infants who were later identified to have died of SIDS were found to have lower blood levels of Butyrlcholinesterase as compared to 41 infants who died of non SIDS deaths and as compared to 545 birthdate and gender-matched control infants. The authors concluded that decreased cholinergic activity is an important risk factor for SIDS. Despite its small size and the considerable overlap in results between SIDS and non-SIDS cases,  this study received widespread publicity in both the medical and lay press. It is not a test that would be recommended to screen infants for SIDS risk at this time. Although intriguing, it needs to be repeated on a larger scale to verify its validity.  Its main contribution right now may be an increased and renewed focus of attention on the importance of the identification of the biologic factors that contribute to the inherent vulnerability of an infant who succumbs to SIDS. Whether the answer lies in blood biochemistry, genetic analysis, biologic markers for asphyxia, epigenetics, or something completely different is still to be determined. Stay tuned! More will be coming.