Pathophysiology of the human locus coeruleus complex in fetal/neonatal sudden unexplained death

Objectives: We investigated the locus coeruleus complex in the brainstems of 78 subjects aged from 24 gestational weeks to 8 postnatal months, who died of unknown (sudden unexplained fetal and infant deaths) and known causes (controls). The goals of this study were: (1) to obtain basic information about the morphology of the locus coeruleus complex and the expression of different biological parameters (tyrosine hydroxylase, neuromelanin and apoptosis) during the first phases of human nervous system development; (2) to evaluate possible alterations of this structure in victims of sudden death; and (3) to verify any correlation with risk factors. Methods: All the victims were subjected to a complete autopsy, including an in-depth histological examination of the autonomic nervous system and in particular of the locus coeruleus complex, the target of this study. Adrenergic neurons were identified by tyrosine hydroxylase (TH) immunohistochemistry and neuromelanin-containing neurons were specifically visualized by the application of Lillie’s method. In addition, the activation of programmed cell death (apoptosis) was studied by investigating DNA fragmentation (TUNEL-positive cells). Results: Alterations of the noradrenaline system, decreased neuromelanin, hypoplasia, in addition to a high neuronal death rate, were observed almost exclusively in the locus coeruleus complex of fetal and infant sudden deaths, and were significantly correlated to maternal smoking. Discussion: The developmental defects found in the locus coeruleus complex in victims of sudden unexplained fetal and infant death imply alterations of the vital activities related to the widespread brain connections arising from this neuronal center, including coordination of the sleep–waking cycle and control of the cardio-respiratory system.