(5/12/2022)

Dear Friends,

A number of articles hit the news in May 2022 regarding Butyrylcholinesterase levels and Sudden Infant Death Syndrome. The news refers an Australian study that appears in the online eBioMedicine published May 06, 2022. More information follows. We have received many e-mail messages asking for more information. The public has been on an information roller coaster, the result of an explosion of medical reports, each heralding a "breakthrough in SIDS research." We need to help people separate myth from fact and risk factor from cause. We will post information as it becomes available to us.

Please keep the following in mind:

- When it comes to media coverage of SIDS, we often feel a sense of frustration in being confronted with misleading headlines, announcements of so-called breakthroughs and statements taken out of context.

- Please read the articles, "Mass Media's" Role in SIDS Education, at <http://sids-network.org/media.htm>, and Clarifying Confusing Research Information.

- The Australian study does not claim that Butyrylcholinesterase levels cause SIDS.

We are currently gathering more information about this specific research and will keep you updated.

Thanks!

Chuck Mihalko
Executive Manager
SIDS Network

5/12/2022

Letter from Tom Keens, MD, to the California SIDS community.

SIDS RESEARCH:  POSSIBLE BIOMARKER FOR SIDS.

Many of you have seen recent headlines (May 10, 2022) suggesting that the cure for SIDS has been found.  A recent scientific publication from Australia describes an enzyme in the autonomic nervous system, which is decreased when measured at 2-4 days of life, in babies who will later die from SIDS.  The reference is: Harrington, C.T., N.. Al Hafid, and K.A. Waters.  Butyrylcholinesterase is a potential biomarker of sudden infant death syndrome.  eBiomedicine; 80: 104041, 2022.  I have appended a copy of the original research article to this email for your interest.

The study is interesting.  Butyrylcholinesterase (BChE) is a substance in the autonomic nervous system which has been found to correlate with arousal responses.  Recall that a hypothesis of how SIDS babies die is that they fail to arouse in response to a dangerous environmental challenge during sleep.  A number of substances active in the autonomic nervous systems have been studied in brainstems of SIDS babies.  However, we can not take samples from the brains of living babies to try to identify any abnormalities prior to death.  A quest of SIDS research has been to find some measure of babies at highest risk for SIDS death prior to death.  The hope would be that one could understand the cause of SIDS, and intervene on these high risk babies to prevent, or at least reduce the chance of, death.

This study is an attempt to do exactly that.  BChE can be measured in blood.  In this study, BChE was measured in a standard newborn screen blood spot taken at 2-4 days of age from 26 babies who would subsequently die from SIDS. 41 babies who would subsequently die from SUDI (not SIDS due primarily to not meeting age criteria; they were <3-weeks of age or >52-weeks of age), and 655 control infants who did not die.  BChE was found to be lower in the blood of babies who would die from SIDS than in babies who died from SUDI or controls who did not die.  However, there was quite a bit of overlap.  That is, BChE levels were not specific enough to identify only babies who would die from SIDS.

The importance of this study is that it is an attempt to find some biomarker which would predict a high risk for SIDS that can be measured while babies are still alive.  The study verifies the proof of concept that some substances exist, which can be measured early in life, and which may relate to SIDS.  However, the numbers of infants are small in this study, and these results would need to be verified by larger studies. The investigators did not attempt to correlate blood BChE with brain BChE.  If there was a correlation, it would strengthen the argument the BChE might be relevant to autonomic dysfunction which might increase the risk of SIDS.  Further, based on these results, it does not appear that BChE is specific enough to identify a group of babies for whom some intervention might prevent death.  Of course, this study does not elucidate the mechanism of SIDS, so what to do about a baby identified as high risk is still unclear.

So, in summary, this study does attempt to identify a biomarker which can be detected prior to death in babies who might die from SIDS.  The biomarker is probably not specific enough at this point in time to launch interventional efforts.  And, of course, we do not know what to do with babies identified as high risk.  Unfortunately, the media is overplaying this study as a cure for SIDS, which it is not.  It may be a step in the right direction, but it is not the answer.

If you have any comments or questions, please do not hesitate to contact me.  Thank you so much for everything you do to improve SIDS services, education, and research in California.
--- Tom Keens, Chair of the California SUDS Advisory Council

Commentary On
Butyrylcholinesterase Is A Potential Biomarker For Sudden Infant Death Syndrome
CT Harrington, N Al Hafid, KA Waters
eBioMedicine 2022;80: 104041
Published online 6 May 2022 https://doi.org/10.1016/j. ebiom.2022.104041

In a case-control study, Australian investigators measured butyrylcholinesterase specific activity (BChEsa) in dried blood spots obtained in newborns 2-4 days of age and found that it was lower in babies who subsequently died of SIDS than in infants who had died of identifiable causes or who survived (controls). This enzyme serves an important function in the autonomic system including arousal responses that have been implicated in SIDS. Based on these observations, the authors concluded “that a previously unidentified cholinergic deficit, identifiable by abnormal BChEsa, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death.”

The holy grail of basic SIDS research has always centered on finding causes and mechanisms of death thereby allowing the possibility of early screening that identifies babies at risk followed by interventions to reduce the risk or hopefully prevention of this tragedy. Therefore, the findings of these investigators are another important effort in that direction. It is unlikely however that a single abnormality is the cause of SIDS. All evidence to date strongly indicates SIDS is a complex event requiring 1. the simultaneous interaction of rapidly changing developmental physiology and anatomy occurring during infancy, 2. underlying pathologic abnormalities such as those identified in the serotonergic system, and 3. exogenous factors such as prone sleep position or cigarette smoke exposure. The “Triple Risk Model” captures each of these elements in our current understanding of SIDS. This model has been repeatedly supported by epidemiologic, death scene investigative and pathologic research.

Despite these provocative findings, it is premature to conclude with certainly that a newborn marker, namely low BChEsa, can predict future SIDS. This is especially true given the important limitations including those the authors have identified:

1. Aside from five cases reclassified as SIDS according to the San Diego definition, the remaining diagnoses were those of the Coroner since the details of the autopsies had not been obtained. As a result, the standardization, consistency and which SIDS definition was used for those cases,
2. Comparing BChEsa in the study cases to known BChEsa reference intervals is difficult since reference intervals refer to serum and not dried blood spots. Also reference levels are measured as BChEsa activity per liter and not to activity per gram of protein,
3. The dried blood samples analyzed in the study cases were over 2 years old, thus not accurately reflecting BChEsa in fresh dried blood specimens,
4. Despite evaluating over 600 control samples, the frequency of abnormal BChEsa is unknown in the general population thereby questioning the specificity of this finding,
5. The status of BChEsa at time of death was unknown as opposed to the status of BChEsa measured in the newborn dried blood spots; did the abnormality persist as was it important at the time of death or merely a hypothetical possibility? In this regard, it is also noteworthy that the measured BChEsa values crossed over between SIDS and non-SIDS cases as opposed to abnormal values being restricted to SIDS cases,
6. And it is possible that many of the post-natal changes that occur in the first six months of infancy may well affect any or all of the cholinesterases and the autonomic nervous system.

Finally, this is an important study that provides direction for another line of future research. A prospective study designed to measure BChEsa as well as other cholinesterases in the newborn period as well at the time of SIDS and other infant deaths as well as survivors of comparable age would be ideal, but it would require a very large number of study cases given the declining SIDS rates over the last decades. In the meantime, adherence to safe sleeping guidelines is still recommended as the optimal way to reduce the risk of SIDs.

Henry Krous, MD
San Diego, CA