Monday, May 16, 2022

Butyrylcholinesterase is a potential biomarker for sudden infant death syndrome

 Researchers at The Children’s Hospital at Westmead (CHW) have made a ground-breaking discovery, identifying the first biochemical marker that could help detect babies more at risk of Sudden Infant Death Syndrome (SIDS) while they are alive. 

In a study published on May 6, 2022, by The Lancet’s eBioMedicine, researchers found the activity of a specific enzyme, Butyrylcholinesterase (BChE), was significantly lower in babies who subsequently died of SIDS compared to living controls and other infant deaths. 

The study analyzed BChE activity in 722 Dried Blood Spots (DBS) taken at birth as part of the Newborn Screening Program, only utilizing samples parents approved for use in de-identified research. BCHE was measured in both SIDS and infants who died from other causes, and each was compared to 10 surviving infants with the same date of birth and gender. 

The researchers discovered infants with lower BChE levels had a much higher risk of dying from SIDS. BChE plays an important function in the brain’s arousal pathway and researchers believe its deficiency likely indicates an arousal deficit, which reduces an infant’s ability to wake or respond to the external environment, making them vulnerable to SIDS. 

Dr. Carmel Harrington, study lead and Honorary Research Fellow at CHW, said the findings are game-changing and not only offer hope for the future, but answers for the past. 

“An apparently healthy baby going to sleep and not waking up is every parent’s nightmare and until now there was absolutely no way of knowing which infant would succumb. But that’s not the case anymore. We have found the first marker to indicate vulnerability prior to death,” Dr. Harrington said.


“Babies have a very powerful mechanism to let us know when they are not happy. Usually, if a baby is confronted with a life-threatening situation, such as difficulty breathing during sleep because they are on their tummies, they will arouse and cry out. What this research shows is that some babies don’t have this same robust arousal response.” 

“This has long been thought to be the case, but up to now we didn’t know what was causing the lack of arousal. Now that we know that BChE is involved we can begin to change the outcome for these babies and make SIDS a thing of the past.” 

Dr. Harrington lost her own child to SIDS 29 years ago and has dedicated her career to researching the condition, supporting much of her research through her crowd-funding campaign, Damien’s Legacy. 

“This discovery has opened up the possibility for intervention and finally gives answers to parents who have lost their children so tragically. These families can now live with the knowledge that this was not their fault,” Dr. Harrington said. 

SIDS is the unexplained death of an apparently healthy infant less than one year of age, during a period of sleep. 

The incidence of SIDS has been more than halved in recent years due to public health campaigns addressing the known major risk factors of prone sleeping, maternal smoking and overheating. However, the rate of SIDS remains high, contributing to almost 50 percent of all post-neonatal deaths in Western countries. 

“There is this perception that SIDS isn’t a problem anymore or that the problem can be solved if all babies had the correct sleep conditions, but two children still die from SIDS in Australia every week. This finding gives our research a clear direction so that in future we will be able to do something to prevent it,” Professor Karen Waters, Head of the SIDS and Sleep Apnoea Research Group at CHW, said. 

Currently, the “triple risk model” is used to explain the occurrence of SIDS deaths, hypothesizing that three factors need to occur simultaneously; vulnerable infant, a critical developmental period and an exogenous stressor, however until now there has never been a way to identify those vulnerable infants. 

The identification of the BChE biochemical marker gives researchers a clear direction for the future, enabling them to focus attentions on introducing this marker into newborn screening and developing specific interventions to address the enzyme deficiency. 

It is expected the next stages of research will take around five years to complete. 

“This discovery changes the narrative around SIDS and is the start of a very exciting journey ahead. We are going to be able to work with babies while they are living and make sure they keep living,” Dr. Harrington said. 

Carmel Therese Harrington, Naz Al Hafid and Karen Ann Waters. Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome. 6 May 2022, eBioMedicineDOI: 10.1016/j.ebiom.2022.104041



Autonomic dysfunction has been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Butyrylcholinesterase (BChE) is an enzyme of the cholinergic system, a major branch of the autonomic system, and may provide a measure of autonomic (dys)function. This study was undertaken to evaluate BChE activity in infants and young children who had died from Sudden Infant Death or Sudden Unexpected Death.


In this case-control study we measured BChE activity and total protein in the eluate of 5μL spots punched from the dried blood spots taken at birth as part of the newborn screening program. Results for each of 67 sudden unexpected deaths classified by the coroner (aged 1 week-104 weeks) = Cases, were compared to 10 date of birth - and gender-matched surviving controls (Controls), with five cases reclassified to meet criteria for SIDS, including the criterion of age 3 weeks to 1 year.


Conditional logistic regression showed that in groups where cases were reported as “SIDS death” there was strong evidence that lower BChE specific activity (BChEsa) was associated with death (OR=0·73 per U/mg, 95% CI 0·60-0·89, P=0·0014), whereas in groups with a “Non-SIDS death” as the case there was no evidence of a linear association between BChEsa and death (OR=1·001 per U/mg, 95% CI 0·89-1·13, P=0·99).


BChEsa, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. We conclude 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.


  1. Hall PL, Matern D. Identification of Decreased Butyrylcholinesterase in Sudden Infant Death Syndrome Is, at Best, a First Step Toward Preventive Screening. Clin Chem. 2023 Feb 1;69(2):116-117. doi: 10.1093/clinchem/hvac134. PMID: 36327422. No abstract

  2. Harrington CT, Hafid NA, Waters KA. Letter Re: Butyrylcholinesterase is a potential biomarker for sudden infant death syndrome. EBioMedicine. 2022 Aug;82:104171. doi: 10.1016/j.ebiom.2022.104171. Epub 2022 Jul 15. PMID: 35841874; PMCID: PMC9297105.

    Dear Editor, Prof Durner,
    In 1968 WHO outlined the guiding principles of any newborn screening programme. In summary: the condition should be a significant problem with known natural history, an agreed policy on whom to treat and the availability of diagnostic and treatment facilities; there should be a suitable, acceptable test; and the cost of case-finding should be economically balanced in relation to medical costs as a whole.
    These principles guided the recent inclusion of spinal muscular atrophy into our newborn screening programme in NSW. Notwithstanding the fact that pre-symptomatic intervention with approved treatments resulted in better outcomes for affected individuals this benefit had to be balanced against numerous ethical considerations including introducing harms from unnecessary detection and treatment, particularly where some individuals may only have benign or mild disease associated with the abnormality.
    As we highlighted, outstanding questions pertaining to our findings include our inability to relate this to specific levels of BChE in the newborn period, associated phenotypic characteristics, availability of appropriate diagnostic pathway(s) and the lack of knowledge regarding potential treatment interventions.
    We trust that these limitations do not blind people to our novel finding which offers a new possibility for the identification of infants at risk for SIDS prior to their death. We are pleased to hear that others have taken an interest in our work and also support more research in this area to fully understand the implications of our new findings.
    With best regards,
    Carmel Harrington