SIDS and SIUDS

Sudden infant death syndrome (SIDS) and sudden intrauterine unexplained death syndrome (SIUDS)

Sudden intrauterine unexpected fetal death syndrome (SIUDS) and sudden infant death syndrome (SIDS) represent facets of a multifactorial problem that has not yet found a univocal approach on the clinical plane. The fundamental component is pathological anatomy.

SIDS is defined as the sudden death of an infant under one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and a review of the clinical history. The SIDS strikes one infant every 750-1,000 live births, being the most frequent cause of demise within the first year of life. As reported by WHO, in the Western Countries the SIUDS is about ten-fold more frequent than SIDS.

The inherent emotional consequences among families are devastating and the cost of adaptation therapies is particularly heavy, in addition to the damage due to the loss of many potentially productive individuals. The need to submit the young victims to necropsy procedures is unanimously recognized and the chance of preventing SIUDS and SIDS relies mainly on a better knowledge of the underlying alterations of the autonomic nervous system and etiopathogenetic mechanisms. Similarly, for diagnostic purposes, an accurate and careful examination of the circumstantial and environmental situation is extremely important.

Our studies have revealed frequent morphological alterations of the autonomic nervous system centers checking the vital functions and/or of the cardiac conduction system in victims of SIUDS and SIDS. These alterations are mainly of congenital nature and therefore represent a common morphological substrate in both fetal and infant sudden death.

Alterations of the autonomic nervous system

Brainstem and cerebellum developmental alterations are frequently observed in both SIUDS and SIDS. These defects are more widespread and more intensive as earlier is the death.

Frequent is the hypoplasia of the arcuate nucleus, a component of the ventral surface of the medulla oblongata which partecipates in chemoreception (1-4). This hypoplasia is associated in sudden intra-partum deaths to hypodevelopment of the Kölliker-Fuse nucleus, that has an important function during intrauterine life inhibiting the response of central and peripheral chemoreceptors, and therefore any respiratory reflex. After birth, the Kölliker-Fuse becomes active as a respiratory center (5,6). The agenesis/hypoplasia of the parafacial nucleus, a "pre-inspiratory" center, is frequently observed in unexpected fetal deaths, in association with the hypoplasia of the arcuate nucleus (7).

Delayed maturation of the cortex layers and of the deep nuclei of the cerbellum (8,9), and the immaturity with decreased number of pyramidal cells in the cerebral cortex (prevalently in the prefrontal area) are signigicant findings. (10).

Among the functional alterations, defective expression of neurotransmitters are frequently observed in the brainstem, particularly of catecholamines in the locus coeruleus (11), and of the somatostatin in the hypoglossus nucleus (12), besides altered apoptotic programs in the cerebellum (8,9).

Alterations of the cardiac conduction system

The finding of accessory AV communications, particularly nodo-fascicular ventricular bundles (Mahaim fibers) is frequent in perinatal unexplained loss and SIDS. Accessory AV communications of Kent and James type are uncommon (13,14). These lesions have been attributed to the variable outcome of a “resorptive degeneration” process that normally reshapes the functional pathways in fetal and early neonatal period. The accessory pathways represent the main cause of perinatal reentrant arrhythmias and also of the sudden death of the young, especially of the sportsman and of the athlete, often coincident with physical and/or psychic stress in competitive activities.

Risk factors

Among the causes which trigger unexplained death, exogenous risk factors that alter the intrauterine environment are relevant, such as tobacco smoking, drug abuse, maternal alcoholism and air pollution (15,16). Such toxic agents are responsible of deep changes in blood-brain barrier which enhance their penetration into the brain parenchyma (17,18). Besides they are able to alter the structure of genes involved in the development of the nervous system, causing mutations, or to affect their expression leading to morphological and functional alterations of the vital nervous centers (19).

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The scientific-financial advantages deriving from a better understanding of SIDS and late unexpected fetal death are certainly significant. Indeed, the identification of the pathogenetic mechanisms of these deaths can be the premise for understanding many diseases of adulthood and even the elderly. Numerous postnatal disorders of fetal origin are already been identified, such as defective maturation of the lung (20), substratum of frequent inflammatory and allergic respiratory diseases in infants, and developmental abnormalities of the cerebral cortex, plausible pathogenesis of behavioral troubles, attention and memory disorders in infants. Interesting is the identification of the fetal origin of the atherosclerosis , frequently due to cigarette smoke absorption (21 -23).

References

1. Matturri L, Ottaviani G, Alfonsi G, Crippa M, Rossi L, Lavezzi AM. Study of the brainstem, particularly the arcuate nucleus, in sudden infant death syndrome (SIDS) and sudden intrauterine unexplained death (SIUD). Am J Forensic Med Pathol 2004; 25: 44-48.

2. Matturri L, Minoli I, Lavezzi AM, Cappellini A, Ramos S, Rossi L. Hypoplasia of medullary arcuate nucleus in unexpected late fetal death (stillborn infants): a pathologic study. Pediatrics 2002; 109: E43.

3. Lavezzi AM, Ottaviani G, Mauri M, Terni L, Matturri L. Involvement of the En-2 gene in normal and abnormal development of the human arcuate nucleus. Int J Exp Pathol 2005; 86: 25-31.

4. Lavezzi AM, Ottaviani G, Mauri M, Matturri L. Hypoplasia of the arcuate nucleus and maternal smoking during pregnancy in sudden unexplained perinatal and infant death. Neuropathology 2004; 24: 284-289.

5. Lavezzi AM, Ottaviani G, Ballabio G, Rossi L, Matturri L. Preliminary Study on the cytoarchitecture of the human parabrachial/Kölliker-Fuse complex, with reference to sudden infant death syndrome and sudden intrauterine unexplained death. Pediatr Dev Pathol 2004; 7: 171-179.

6. Lavezzi AM, Ottaviani G, Rossi L, Matturri L. Cytoarchitectural organization of the parabrachial/Kölliker-Fuse complex in man.mBrain Dev 2004; 26: 316-320.

7. Lavezzi AM, Matturri L. Hypoplasia of the parafacial/facial complex: a very frequent finding in sudden unexplained fetal death. Open Neurosci J 2008; 2: 1-5.

8. Lavezzi AM, Ottaviani G, Matturri L. Ontogenesis of human cerebellar cortex and biopathological characterization in sudden unexplained fetal and infant death. Virchows Arch 2007; 450: 31-40.

9. Lavezzi AM, Ottaviani G, Terni L, Matturri L. Histological and biological developmental characterization of the human cerebellar cortex. Int J Dev Neurosci 2006; 24: 365-371.

10. Lavezzi AM, Mauri M, Mecchia D, Matturri L. Developmental alterations of the prefrontal cerebral cortex in sudden unexplained perinatal and infant deaths. J Perinat Med 2009; 37: 297-303.

11. Lavezzi AM, Ottaviani G, Mingrone R, Matturri L. Analysis of the human locus coeruleus in perinatal and infant sudden unexplained death. Possible role of the cigarette smoking in the development of this nucleus. Dev Brain Res 2005; 154: 71-80.

12. Lavezzi AM, Ottaviani G, Matturri L. Role of somatostatin and apoptosis in breathing control in sudden perinatal and infant unexplained death. Clin Neuropathol 2004; 23: 304-310.

13. Ottaviani G, Matturri L. Histopathology of the cardiac conduction system in sudden intrauterine unexplained death. Cardiovasc Pathol 2008; 17: 146-155.

14. Matturri L, Ottaviani G, Lavezzi AM, Turconi P, Cazzullo A, Rossi L. Expression of apoptosis and proliferating cell nuclear antigen (PCNA) in the cardiac conduction system in crib death (SIDS). Adv Clin Pathol 2001; 5: 79-86.

15. Matturri L, Ottaviani G, Lavezzi AM. Maternal smoking and sudden infant death syndrome: epidemiological study related to pathology. Virchows Arch 2006; 449: 697-706.

16. Lavezzi AM, Ottaviani G, Matturri L. Adverse effect of prenatal tobacco smoke exposure on biological parameters of the developing brainstem. Neurobiol Dis 2005; 20: 601-607

17. Lavezzi AM, Corna MF, Matturri L. Ependymal alterations in sudden intrauterine unexplained death and sudden infant death syndrome: possible primary consequence of prenatal exposure to cigarette smoking. Neural Dev 2010; 5: 17-25.

18. Lavezzi AM, Mecchia D, Matturri L. Neuropathology of the area postrema in sudden intrauterine and infant death syndromes related to tobacco smoke exposure. Auton Neurosci 2012; 166: 29-34.

19. Lavezzi AM, Casale V, Oneda R, Weese-Mayer DW, Matturri L. Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphe nuclei and serotonin transporter gene promoter polymorphism. Ped Res 2009; 66: 22-27.

20. Matturri L, Lavezzi AM, Cappellini A, Ottaviani G, Minoli I, Rubino B, Rossi L. Association between pulmonary hypoplasia and hypoplasia of arcuate nucleus in stillbirth. J Perinatol 2003; 23: 328-332.

21. Matturri L, Lavezzi AM, Ottaviani G, Rossi L. Intimal pre-atherosclerotic thickening of the coronary arteries in human fetuses of smoker mothers. J Thromb Haemost 2003; 1: 2234-2238.

22. Matturri L, Mecchia D, Lavezzi AM. Birth and progression of systemic atherosclerosis in human fetus and infant of smoker parents: a pathological study. JCCM 2009; 4: 544-557.

23. Matturri L, Lavezzi AM. Fetal arterial changes in response to maternal cigarette smoking: revisiting the natural history of the earliest stage of atherosclerosis. Curr Cardiol Rev 2006; 2: 255-259.

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