By Shayla Durfey, MD, ScM (’23)
Faculty Reviewer: Dr. Joe Bliss
BACKGROUND
Sudden Infant Death Syndrome, or SIDS, is the sudden death of an infant between 1 month and 1 year of age in which no cause of death can be identified. SIDS is the leading cause of infant death in developed countries. One theory on why these deaths occur is the ‘Triple Risk’ model, which states that there are three overlapping factors leading to a SIDS death: 1) An underlying biologic vulnerability, 2) A critical developmental period, and 3) An exogenous stressor. Efforts to reduce SIDS deaths have overwhelmingly focused on reducing exogenous stressors, such as suffocation, by focusing on safe sleep practices. These efforts have been successful in reducing deaths from SIDS by up to 80%.
However, given that these deaths are not entirely eliminated by preventive measures and declined only modestly in the past two decades, the question remains of whether an underlying biologic vulnerability contributes to SIDS deaths and what that vulnerability might be. Some hypothesized biological explanations include genetic differences in cardiac ion channels or abnormalities in neurotransmitters such as acetylcholinesterase or butyrylcholinesterase (a modulator of acetylcholinesterase). The cholinesterase system plays a role in arousal, and abnormalities in this system could lead to reduced ability to self-arouse during, for example, a suffocation event. The article “Butyrylcholinesterase is a potential biomarker for SIDS” aims to determine whether autonomic dysfunction plays a role in SIDS deaths by studying levels of butyrylcholinesterase in newborn blood samples of infants who died compared to matched controls.
THE STUDY
The authors identified infants that died of a sudden cause in Australia from forensic pathology records and separated them into two groups: those that died of an identifiable cause or SUID (sudden unexpected infant death) and those that died of an unidentifiable cause or SIDS. Each ‘case,’ or infant who died, was matched to 10 control patients by birth date, gender, and day of life at newborn screen sample collection. Butyrylcholinesterase levels, eluted from dried newborn screen samples taken at birth, were compared between the cases and controls. The study concluded that butyrylcholinesterase levels were significantly lower in babies who died of SIDS vs babies who died of SUID or who survived.
Figure 2, which is a box plot comparing the mean, median, and range of butyrylcholinesterase levels for each subgroup, is shown below. The red circle denotes the subgroup of patients who died of SIDS. Unfortunately, there is significant overlap between the subgroups, which represents a substantial limitation to the potential utility of butyrylcholinesterase as a biomarker. For example, imagine that butyrylcholinesterase levels were measured in every newborn screen sample as a screening test for SIDS risk. If a newborn screen sample were found to have a butyrylcholinesterase level of 5.5, which is near the mean (5.6) and median (5.2) of levels for patients who died of SIDS, that level of butyrylcholinesterase could also be seen in patients who did not die at all.
This study had several important additional limitations. First, butyrylcholinesterase levels from the newborn screen do not have any known standard values for the general population, limiting the interpretation of these findings or their use as a biomarker for SIDS. Butyrylcholinesterase levels at death were also not available in this study and could provide further information on whether a trend in these levels is associated with death from SIDS.
Second, the authors only had access to the names of the infants in the study, and had to match these names to maternal surnames on dried blood spot samples from birth. If the infant’s surname was not the same as the maternal surname at the time of death, then that infant was not able to be included in the study. The authors call the mismatch of surnames a “random issue.” However, this matching strategy, although shaped by the availability of demographic information, may have excluded groups of people including infants from married couples, those from higher or lower socioeconomic status, or those who identify with a culture that has specific naming practices.
Third, control subjects were matched by birth date, gender, and day of life at newborn screen sample collection. However, there are many other known risk factors for SIDS, such as gestational age, smoking in the home and co-sleeping or prone sleeping, which were not accounted for in this study.
INTERPRETING THE RESULTS
After publication, this article was quickly called a “breakthrough study” by media articles and in some cases the findings were extrapolated to mean that the cause of SIDS had been found. Twitter abounded with response, with some Twitter users calling the results “a miracle” and one stating “They found the cause of SIDS. Excuse me while I cry for all the parents… And cry happy tears for parents in the future who will have access to screening and prevention.”
Dr. Harrington, first author of this study, was quoted as saying that “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.”
This study certainly provides a clue into a potential underlying biologic vulnerability that could predispose infants to death from SIDS. However, due to the substantial overlap in between-group butyrylcholinesterase levels as well as the limitations described above, this piece of evidence requires far more study before it could be used as a screening tool for SIDS. Further, even if measurement of butyrylcholinesterase provided very distinct groups in terms of risk for SIDS, an intervention to prevent these deaths would need to be developed and tested. Moreover, the data on underlying vulnerabilities leading to SIDS deaths remains very limited, and this study does little to pinpoint a single unifying cause of SIDS.
Although the media’s misinterpretation of this study is problematic in terms of spreading scientific disinformation, this study and its widespread media coverage have helped to refocus attention on the potential for an underlying biologic vulnerability to SIDS death and away from a strictly prevention-based conversation. The Tweets and quotes above hint that our focus on prevention has led to parental guilt as well as to a public misunderstanding that SIDS is entirely preventable. Using this study’s popularity, pediatricians have an opportunity to re-frame the conversation around SIDS as one that encompasses all three components of the Triple Risk Model.
LEARNING POINTS
- Differences in butyrylcholinesterase levels may be one underlying biologic vulnerability for patients due to SIDS, but far more research is needed to investigate the utility of this enzyme as a biomarker of SIDS risk.
- Safe Sleep is still important, but we should also remain aware of all three components in the Triple Risk model to reduce parental blame and guilt over SIDS deaths and help guide further study into the biological risk factors of SIDS.
- Media misinterpretation of scientific studies can lead to disinformation and ultimately to patient harm. It is our responsibility as pediatricians to understand the data and guide families.
References:
- Goldstein RD, Kinney HC, & Guttmacher AE. Only halfway there with Sudden Infant Death Syndrome. N engl j med. 2022;386(20).
- Harrington CT, Hafid NA, Waters KA. Butyrylcholinesterase is a potential biomarker for SIDS. eBioMedicine. 2022;80:104041.
- Matthews, E. Refocusing SIDS research: Is butylcholinesterase a predictive biomarker? eBioMedicine. 2022;80:104041.
- Mazer B. How a SIDS study became a media train wreck. The Atlantic. May 17, 2022. Accessed Nov 21, 2022. https://theatlantic.com/