Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Association of late second trimester miscarriages with placental histology and autopsy findings.

OBJECTIVES: To describe the placental histology and autopsy findings in pregnancies where fetal demise occurred before a gestational age of 22 weeks. STUDY DESIGN: This study was a subset of a larger study where the effect of alcohol exposure during pregnancy on stillbirths was studied. In a prospective cohort, 7,010 singleton pregnancies were followed from the first antenatal visit until infant one year of age visit. Gestational age was assessed by ultrasound, preferably at the first antenatal visit. All pregnancy losses were identified and when the fetuses delivered at or after a gestation of 20 weeks, the mother or parents were approached for consent for autopsy. This study describes the placental pathology and findings at autopsy in losses before 22 weeks gestation (late second trimester miscarriages). RESULTS: Fourteen cases were identified in which 13 had an autopsy and 12 had a histological examination of the placenta. The most prevalent histological abnormality was placental abruption which was seen in 6 miscarriages, occasionally on its own, or in combination with maternal vascular malperfusion or acute chorioamnionitis. The second most frequent finding was maternal vascular malperfusion, as found in five placentas, alone or in combination with other pathology. The third most frequent pathology was acute chorioamnionitis, found in four placentas, in combination or alone. Other causes were diffuse chronic villitis due to cytomegalovirus infection and early amnion rupture with anhydramnios and cord obstruction. CONCLUSIONS: Causes of fetal demise at the end of the second trimester differ little from causes of stillbirth. There is value in using placental histology in late second trimester miscarriages to try to identify the cause of demise.

Fetal foot length at delivery as a tool for determining gestation length in non-macerated stillbirths.

OBJECTIVE: To assess whether fetal foot length at autopsy could reliably indicate gestation duration at stillbirth and the effects of maceration on this method. METHODS: The present cross-sectional secondary analysis was part of the Safe Passage Study; all Safe Passage Study participants who experienced a stillbirth at Tygerberg Academic Hospital, Cape Town, South Africa, between August 1, 2007, and January 31, 2015, were eligible to participate. After providing written informed consent for autopsy, the duration of gestation calculated using early ultrasonography and fetal foot length were compared. RESULTS: There were 69 fetal autopsies included in the present study; placental histology was available for 65. Generally, the gestation length calculated from the first ultrasonography scan correlated well with that calculated from the fetal foot length (Spearman correlation=0.85). However, significant differences were found in the gestation lengths calculated when the fetus was macerated (P<0.001), or when umbilical cord pathology (P<0.001) or maternal vascular malperfusion (P<0.001) was the cause of fetal death. CONCLUSION: Foot length at stillbirth was a good indicator of gestation length; however, it was a weaker indicator if fetal maceration had occurred.

Serotonin Receptors in the Medulla Oblongata of the Human Fetus and Infant: The Analytic Approach of the International Safe Passage Study.

The Safe Passage Study is an international, prospective study of approximately 12 000 pregnancies to determine the effects of prenatal alcohol exposure (PAE) upon stillbirth and the sudden infant death syndrome (SIDS). A key objective of the study is to elucidate adverse effects of PAE upon binding to serotonin (5-HT) 1A receptors in brainstem homeostatic networks postulated to be abnormal in unexplained stillbirth and/or SIDS. We undertook a feasibility assessment of 5-HT1A receptor binding using autoradiography in the medulla oblongata (6 nuclei in 27 cases). 5-HT1A binding was compared to a reference dataset from the San Diego medical examiner's system. There was no adverse effect of postmortem interval ≤100 h. The distribution and quantitated values of 5-HT1A binding in Safe Passage Study cases were essentially identical to those in the reference dataset, and virtually identical between stillbirths and live born fetal cases in grossly non-macerated tissues. The pattern of binding was present at mid-gestation with dramatic changes in binding levels in the medullary 5-HT nuclei over the second half of gestation; there was a plateau at lower levels in the neonatal period and into infancy. This study demonstrates feasibility of 5-HT1A binding analysis in the medulla in the Safe Passage Study.