The SIDS–critical diaphragm failure hypothesis revisited

Dear Sir, Since the publication of the sudden infant death syndrome (SIDS)–critical diaphragm failure (CDF) hypothesis in 2011 (1), it has attracted the attention of several investigators active in the field (2,3). In addition to the published commentary, the author has corresponded with several colleagues regarding the potential role of critical diaphragm failure in SIDS. In several of these communications, I have been asked about three salient characteristics of SIDS that were not discussed in the original article. They relate to the inverse correlation between SIDS and breast-feeding, and the positive correlations between the male gender and cigarette smoke and SIDS. In this letter, I will briefly describe how the SIDS–CDF hypothesis would approach these questions and highlight implications for future SIDS research. The SIDS–CDF hypothesis postulates that the cause of death in SIDS is respiratory failure precipitated by the failure of the primary respiratory muscle, the diaphragm. Several factors can reduce the forcegenerating capacity of the diaphragm, and in certain circumstances the cumulative effect of these factors can lead to a self-reinforcing cycle that results in death that has no single identifiable cause. As discussed in our original article, SIDS is saliently associated with infections, the prone sleeping position, low birth weight and prematurity, sleep, non-monotonic death rate (low at age 0–1 month, peak at age 2–4 months, and rare after age 6 months), the male gender, cigarette smoke, and absence of breast-feeding (1). The SIDS–CDF hypothesis postulates that when several of these factors manifest simultaneously, infants can suffer critical diaphragm and respiratory failure that has no single cause. It is well established that even trivial infections can cause a rapid and significant reduction in the diaphragm force generation capacity. It is also well known that the prone sleeping position significantly increases the respiratory load of the diaphragm. It is similarly well established that during REM sleep, the secondary respiratory muscles (intercostals) that stabilize the highly compliant rib-cage of the infant and support the primary respiratory muscles, as well as the muscles of the upper airway, are partially or totally inactive. Likewise it has been shown that the respiratory force and endurance of a neonate diaphragm correlates with its birth weight and term maturity, and that the diaphragm reaches full force generation capacity and endurance by approximately 6 months of age. It is also established that during the first month of life when SIDS is rare, the infants enjoy the immunological benefit of passive maternal antibodies (that rapidly wane after the first month post partum) and that during the first 6 months of life the innate immune function is underdeveloped. Finally, we draw attention to the obvious physiological reality that compromised respiratory function can lead to diminished oxygen supply required for normal muscle function, including that of the diaphragm. The causal links between these features and SIDS are addressed in detail in our original article (1). However, the possible connection between male gender, absence of breast-feeding, and cigarette smoke and SIDS has not been previously examined in the context of CDF. I will address the 60/40 male preponderance among SIDS victims first. Here I would like to thank Professor Goldwater for highlighting this enigmatic aspect of SIDS in his recent article (2). Males and females display significant differences in their immune responses, and as Fish notes in her comprehensive review article titled ‘The X-files in immunity’,