Secondhand Smoking and Sudden Infant Death Syndrome: How can in Silico Pharmacokinetics and Circulation Models Contribute?

Sudden Infant Death Syndrome (SIDS) is the leading cause of death in infants in developed countries (Moon et al., 2007) (Rogers, 2009).The cardio-respiratory distress due to infant sleep position was considered as the leading risk factor that causes arousal and/or auto-resuscitation deficiency under hypoxia conditions (Moon et al., 2007).The "Back to sleep" campaign of the early 1990s recommended placing sleep babies in a supine position.The campaign led to a substantial decrease in SIDS cases (Rogers, 2009).However, nearly 3 decades later, SIDS remains one of the leading causes of infant death.Among many risk factors, exposure to passive or secondhand smoking (SHS) pre-and postpartum has attracted many research studies (Mitchell et al., 1997) (McMartin et al., 2002) (Albuquerque et al., 2004) (Raghuveer et al., 2016) (Tang et al., 2020).Indeed, SHS exposure and maternal smoking are considered the most modifiable risk factor associated with SIDS (Cnattingius, 2004).It is estimated that if all fetuses had not been exposed to maternal smoking in utero, about one-third of all SIDS deaths might have been prevented (Mitchell et al., 1997).Blood flow measurements in fetuses and neonates seem to support the viewpoint.The systolic to diastolic (S/D) ratio in the fetal umbilical and middle cerebral arteries is greater in those exposed to maternal smoking than those without exposure (Albuquerque et al., 2004).High S/D ratios are associated with a lower or absent end-diastolic flow, which is typical in fetuses with intrauterine growth restriction (IUGR) (Albuquerque et al., 2004).More direct pieces of evidence are the measurements of nicotine and cotinine (the major metabolite of nicotine) in biopsy tissues of SIDS and non-SIDS victims (McMartin et al., 2002) (Milerad et al., 1994).From the 73 lung samples, McMartin and his co-workers found that there was a significantly higher nicotine concentration in the SIDS cases (19.64 ± 2.61 ng/g) than in non-SIDS cases (7.86 ± 1.63 ng/g).In contrast, there was no significant difference in cotinine concentrations between SIDS (10.87 ± 2.32 ng/g) and non-SIDS cases (8.71 ± 1.47 ng/g).In another study (Milerad et al., 1994), it was found that in the pericardial fluid of SIDS victims, about 70% of the 24 consecutively autopsied cases were moderately (10-20 ng) or heavily (20-50 ng) exposed to SHS.Early intervention is critical for the prevention of SIDS.However, clinical investigations are hampered by the inaccessibility of fetal, neonatal, and infant tissues and in vivo measurements.Alternatively, animal models, e.g.mice models are used to investigate the effects of SHS (Hu et al., 2012) (Calton et al., 2016).It was found that SHS exposure induced a reduction in the ability of the pre-Bötzinger Complex, a region of inspiratory rhythm generation (Ramirez et al., 2012), to maintain a respiratory rhythm during exposure to severe hypoxia (Hu et al., 2012).However, it is still difficult to verify the underlying mechanisms in animal experiments that involve interweaving factors, as only a limited set of parameters could be tested.