Identification of Decreased Butyrylcholinesterase in Sudden Infant Death Syndrome Is, at Best, a First Step Toward Preventive Screening

The identification of a biomarker associated with increased risk of sudden infant death syndrome (SIDS), as described by Harrington et al. (1) is an exciting yet cautionary tale combining the incremental progress of scientific research and the hazards of media hype. The authors propose an association of decreased butyrylcholinesterase (BChE) activity levels in newborn screening (NBS) dried blood spots collected from infants who died of SIDS compared to surviving controls. This association was not seen in a cohort of non-SIDS deaths when compared to surviving controls. The authors theorize that decreased BChE activity is a marker for autonomic dysfunction, a vulnerability previously suspected to be implicated in the triple risk model for SIDS (2). While considerable decreases in SIDS deaths have been accomplished through NBS programs and safe sleep education, a significant number of infants still die of SIDS, and other promising diagnostic approaches (e.g., genomic analyses) are so far only pursued in the research environment (3). Harringtons study had a robust design with well-defined cases and controls. Utilizing NBS dried blood samples recognizes the need for future screening to work within existing systems for sample collection and availability, and takes advantage of preserved samples for the potential benefit of babies and families in the future. This study was made possible in part by the recognition that stored NBS blood samples can provide valuable information for future expansion of NBS panels. The rarity of most conditions targeted for NBS precludes prospective case identification. Regions that destroy samples after short retention periods are limiting opportunities for improvement and expansion of screening programs, as well as for families to obtain critical information from these samples. Harrington et al. recognize the potential for inclusion of SIDS in NBS and recommend urgent work on this potential biomarker; however, they do not provide an assessment of SIDS in terms of its readiness for screening. Specific inclusion criteria for NBS panels can vary by jurisdiction, but at a minimum they require a defined condition, an appropriate test, and an effective intervention. As an initial evaluation, SIDS is the outcome of an important medical condition that can lead to mortality without intervention, and there are no obvious clinical signs present at birth, therefore meeting one criterion for population screening. Harrington et al. propose BChE as a screening biomarker because its activity can be measured in blood spots and in their study the median concentration of BChE in the affected vs the control population reached a statistically significant difference. However, their data also show that as an individual marker, BChE concentrations significantly overlap with the control population where the lowest value measured in the controls is even lower than the lowest value identified in the affected cases. With no separation between affected and unaffected BChE activities, this marker becomes useless. The problem of a poor biomarker for SIDS is confounded by the lack of both a diagnostic approach to confirming a presumptive positive screening result and a strategy to prevent SIDS in these cases. A crude estimate of screening performance can be made by comparing the SIDS cases to their respective controls, as shown in Table 1 and Figure 2 in the Harrington paper. If a single analyte cutoff were proposed at the highest BChE activity observed in a case (10.8 U/mg), this would be above the 75th percentile of the control population as shown on the right side of Figure 2. In 2020, the CDC reported 38.4 deaths attributed to SIDS per 100 000 live births, an approximate incidence of 1:2600 live births (4). Given the estimated performance of BChE as a screening marker, the identification of one infant at risk of SIDS would result in approximately 1950 (2600 0.75) infants and families receiving a false positive result. While false positive results for NBS conditions have been shown to have wide ranging effects on parents, the receipt of a false positive result for SIDS would be uniquely terrifying, particularly in the absence of an appropriate intervention. The identification of BChE activity as a marker for SIDS in NBS is an exciting possibility, however, it is the first step in a long process rather than a finished product. NBS programs around the world exist to prevent newborns and their families from suffering potentially devastating outcomes that there were no warning signs of. SIDS is certainly a devastating outcome that has no known warning signs, but the data so far indicate that screening for it with BChE as a marker is not warranted. Whether more promising results would have been obtained if NBS samples had been analyzed within days of collection is unlikely given existing stability data for BChE but has not been shown conclusively. The relevance of BChE deficiency as a predictor of possible SIDS can also be questioned. There is little published data on the robustness of the assay in blood spots, and the use as a predictive tool for SIDS has not been previously described, nor likely included in any validation protocols. BChE deficiency is a recognized disorder, however, the currently described phenotype (pharmacogenomics and postanesthetic apnea) does not include sudden death. Recent genomic studies of SIDS deaths did not identify BCHE variants as a potential cause of SIDS, however, this is likely due to BCHE not being previously associated with sudden death. An exploratory study of BCHE sequencing in these cases could be informative. It may also provide an explanation for decreased BChE levels in unaffected infants. The analysis of BChE presented in this paper may be most useful as pathway elucidation and exploration rather than a proposed screening strategy using this specific biomarker. Such research is a foundation for many clinical tests and represents progress in a field where there have been few recent advancements (5). In addition, it may represent a new frontier for the molecular genetic investigations of SIDS. Sequence analysis of BCHE in the dried blood spots from infants included in this study (cases and controls) could be informative for driving future work in this area. On publication, this article was met with headlines that seemed outlandish relative to the scope of the paper. A preliminary biomarker identification was touted by some headlines as a cure for SIDS, a wildly irresponsible interpretation of the research. While the discussion section of the article was more measured, it is incumbent on scientists and researchers to ensure their work is placed in the proper context. Incremental progress is progress, and a step toward reduction or elimination of SIDS should be celebrated, even if outside expectations need to be tempered at the same time. SIDS, sudden infant death syndrome; BChE, butyrylcholinesterase; NBS, newborn screening. BCHE, butyrylcholinesterase gene. All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. No authors declared any potential conflicts of interest.