Acute Thymic Involution in Unexplained Third Trimester Stillbirth: Frequency, Grade, and Correlation with Neuropathologic Injury

Abstract

Many 3rd-trimester stillbirths are unexplained, including the time course of the illness. Histologic acute thymic involution (ATI), when graded, correlates with duration of acute illness (grade 0, <12 hours; grade 4, >72 hours). Histologic brain injury is also common in stillbirth. We investigated ATI in unexplained stillbirth and correlated it with neuropathologic injury by identifying 58 autopsies of unexplained, 3rd-trimester stillborns (preterm, n = 24; term, n = 34) that included brain examination and graded ATI from 0 (resting state) to 4 (pronounced lymphodepletion). Gray matter injury (GMI) and white matter injury (WMI) were classified as older, recent, or absent, and ATI was correlated with GMI, WMI, thymic weight, and clinical data. Nine cases (16%) had ATI grade 0-1; 19 (33%), grade 2; 24 (41%), grade 3; and 6 (10%), grade 4. Older GMI and WMI were present in 39 (67%) and 10 (17%) stillborns, respectively. Higher ATI grade correlated significantly with older GMI (P < 0.001) and WMI (P = 0.014). The ATI grade was higher in the small-for-gestational stillborns compared with the appropriate- or large-for-gestational stillborns (P = 0.017) but did not correlate significantly with gestational age or other clinical or demographic factors evaluated. The ATI grades 2-4 were found in 84% of the stillborns, consistent with onset of acute illness between 24 and >72 hours before demise. Higher ATI grade correlated significantly with older brain injury, suggesting similar time of onset and shared underlying pathophysiologic events, the specific nature of which remains unclear.

Acute Thymic Involution and Mechanisms for Recovery

“…ATI as a bystander effect associated with brain injury has been reported in several cases of stillbirths of unknown causes during the third trimester of human pregnancies (Jacques et al 2014(Jacques et al , 2015. Moreover, the existence of thymic petechiae together with ATI contributed to the clinical diagnosis of placental abruption (Jacques and Qureshi 2016).…”

“…After this point, it involutes slowly during further aging (Aspinall and Andrew 2000). In contrast, ATI is usually seen during gestational (Ekin et al 2016;Jacques et al 2014Jacques et al , 2015 and neonatal life (Eriksen et al 2014;Nickels et al 2015;Toti et al 2000) in humans. However, ATI in experimental animal models has been reported to occur not only during gestational periods (Kunzmann et al 2010;between ATI in adult experimental subjects and ageassociated thymic atrophy during the mid-phase of life in human beings is that the former occurs due to an increase in the death of thymocytes and has the ability to recover after the removal of the insult (Duan et al 2015;Lee et al 2011;Park et al 2007), whereas the latter is characterized by the substitution of lymphoid tissue with fat (adipose tissue) in a progressive time-dependent manner (Bodey et al 1997;Henry and Anderson 1987;Quaglino et al 2014).…”

“…ATI is a common and well-known feature in various fungal Mendes-Giannini et al 2008;Souto et al 2003), viral (Duan et al 2015;Falkenberg et al 2014;Gao et al 2015) and bacterial infectious diseases (LeyvaRangel et al 2015;Ross et al 2012;Savino 2006). ATI can also be caused by immune suppression (Billard et al 2011;Zhou et al 2016), hunger (Gavia-García et al 2015;Savino et al 2007), chemotherapy, radiography (DeBo et al 2015;Lynch et al 2009), pregnancy (Ekin et al 2016;Jacques et al 2014Jacques et al , 2015, transplant rejection (Gracia-Ahufinger et al 2015;Krenzien et al 2015) and other severe disease conditions (Wang et al 2016). ATI in certain physiological conditions (e.g., during malnutrition and pregnancy) is usually mediated by the neuroendocrine system, and the transient thymic regression is characterized by increased thymocyte death, with the capability to recuperate after the removal of the insult (Gruver and Sempowski 2008;Shanley et al 2009).…”

Do Increased Intra-alveolar Squamous Cells at Autopsy Correlate With Acute Fetal Asphyxia?

“…Because the abruption group was selected to represent acute asphyxia death, and because it is recognized that less than complete placental separation can cause death by gradual asphyxia, 7 inclusion in the abruption group also required autopsy findings supporting an acute asphyxial death, including the presence of thymic petechiae and/or the absence of severe ATI (grades 3-4). 3,7,8 All autopsies were performed by 2 experienced perinatal pathologists (SMJ and FQ), and included removal and weighing of all major organs, and also sectioning for microscopic examination, including both lungs. The lungs were not inflated.…”

“…2 Intrauterine asphyxia is the most common mechanism of fetal demise, and the fetal autopsy is a useful tool in helping determine whether this occurred over an acute, subacute, or chronic time course. 1 Several autopsy findings have been shown to be useful in separating fetal demise due to acute asphyxia from subacute or chronic modes of demise, and these findings include acute thymic involution (ATI), 3,4 adrenal changes (hemorrhage, cytoplasmic eosinophilia, and cystic change), 5 gray and white matter brain injury, 6 and petechial hemorrhages on the surfaces of thoracic viscera. 7,8 It is a generally held concept that increased numbers of aspirated amniotic fluid squames support a diagnosis of acute fetal asphyxia.…”