Hypoplasia of Medullary Arcuate Nucleus in Unexpected Late Fetal Death (Stillborn Infants): A Pathologic Study

Abstract

ABSTRACT. Objectives. To evaluate the frequency, morphology, and pathogenesis (primary or secondary) of the abnormally developed medullary arcuate nucleus (ARCn) in stillbirths.Methods. We examined 26 stillbirths (24 antepartum, 2 intrapartum) that had a gestational age between 25 and 40 weeks and a normal karyotype. All of the stillborns were described as well-developed, with body length and weight proportional to their gestational age. Each case was submitted to complete autopsy examination, which included a systematic gross and microscopic evaluation of the body, the placental disk, and the umbilical cord and membranes. The brainstem was the particular focus of the histologic examination. The study of the various nuclei (nucleus hypoglossus, dorsal vagus motor nucleus, tractus solitarii nucleus, nucleus ambiguus, trigeminal tractus and nucleus, arcuate nucleus, and ventrolateral reticular formation and its neurons and parabrachial/ Kö lliker-Fuse complex) was performed on transversal serial sections through the entire pons and medulla oblongata. The histologic analysis was supplemented by volumetric reconstruction and immunohistochemical detection of both apoptosis and proliferating cell nuclear antigen.Results. Histologic examination showed abnormalities of the medulla oblongata ARCn in 9 fetuses (35%). In 8, a marked hypoplasia was evident, characterized by a volume reduction of the nucleus accompanied by neuronal depletion, whereas in 1 fetus the nucleus was completely absent (agenesis). The absence of gliosis, the negativity of the proliferating cell nuclear antigen analysis, and the similarities in apoptotic indices between the hypoplastic and well-developed arcuate are in keeping with a primary developmental defect. This anomaly is frequently associated with hypoplasia of the reticular formation and chronic hypoxia. ABBREVIATIONS. SIDS, sudden infant death syndrome; ARCn, arcuate nucleus; VMS, ventral medullary surface; PCNA, proliferating cell nuclear antigen; PBS, phosphate-buffered saline; TdT, terminal deoxynucleotidyl transferase; dUTP, digoxigenin-conjugated deoxyuridine; GFAP, glial fibrillary acidic protein.S tillbirth is defined as late fetal death before the complete expulsion or retraction of the fetus from the mother. 1 Advances in maternal and fetal care have produced a significant reduction in perinatal mortality but have not changed the prevalence of stillbirth. With a prevalence of 5 to 12 per 1000 births, 2,3 stillbirths represent approximately half of the cases of perinatal mortality. The risk of unexplained, near-term, intrauterine death is present in any pregnancy, and the cause remains obscure in most instances. 4 Unexpected and unexplained fetal death is far more common than sudden infant death syndrome (SIDS), but the pathologic investigations that have been conducted in it unfortunately are sporadic and incomplete. [5][6][7][8] Investigations of the pathology of the autonomic nervous system in fetuses are sadly lacking, despite that abnormalities of these structures are often the...

Study of the Brainstem, Particularly the Arcuate Nucleus, in Sudden Infant Death Syndrome (SIDS) and Sudden Intrauterine Unexplained Death (SIUD)

“…15 Recent studies have stressed the frequent alterations, mainly congenital in nature, of both the autonomic nervous system, central and peripheral, and the cardiac conduction system. 11,12,16,17 Limiting the study of the autonomic nervous system to the brainstem, the congenital anomalies represented by dendritic spines, markers of neuronal immaturity, and most of all by hypoplasia of ARCn are of particular interest and frequency. 8 -12 Recent observations point out that such developmental alterations appear with a similar incidence in SIDS and SIUD victims.…”

“…8 -12 Recent observations point out that such developmental alterations appear with a similar incidence in SIDS and SIUD victims. 3,11,12 ARCn hypoplasia is a congenital anomaly, not referable to any acquired alterations, and, particularly in SIUD, is associated with hypoplasia of other brainstem structures, particularly of the reticular respiratory formation. 3 FIGURE 2.…”

“…[7][8][9][10][11][12] The ARCn is an important cardiorespiratory center of the ventral medullary surface, characterized by a great morphologic variability. 8,11 ARCn hypoplasia, detected in over 30% of SIDS and SIUD cases, 10 -12 is of great interest, particularly because of its frequency and its pathogenic implications. Sometimes it is associated with alterations in other brainstem structures, particularly the respiratory reticular formation, the tractus solitarius nucleus, the muscarinic cholinergic receptors, etc.…”

Crib death: further support for the concept of fatal cardiac electrical instability as the final common pathway

“…Particularly, much attention has been directed at the arcuate nucleus that is postulated to be involved in chemoreception, respiratory and blood pressure responses [63]. The arcuate nucleus hypoplasia seems to play an important role among the causative factors of crib death, as well as of unexpected late fetal death [31,52,64]. However, these centrally mediated ventilatory and cardiovascular reflex/control mechanisms most often have peripheral originating sites within the heart itself.…”

Study of the human hypoglossal nucleus: Normal development and morpho-functional alterations in sudden unexplained late fetal and infant death

“…These include, in particular in the brainstem, hypoplasia of the arcuate nucleus, pre-Bö tzinger nucleus, tractus solitarius nucleus, parafacial complex and parabrachial/ Kö lliker-Fuse complex [1][2][3][4][5][6][7]. The present study was performed with the purpose to deepen our knowledges by evaluating the development and the involvement in these pathologies even of the hypoglossal nucleus (HGN), a nucleus of the dorsal part of the medulla oblongata that, even if not generally included among the so defined vital centers, takes part in specific phases of breathing.…”