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Introduction: Recent reports suggest SARS-CoV-2, the virus causing COVID-19, may be transmittable from pregnant mother to placenta and fetus, albeit rarely. The efficacy of vertical transmission of SARS-CoV-2 critically depends on the availability of its receptor, ACE2, in the placenta. In the present study, we tested the hypothesis that placental ACE2 expression is oxygenation-dependent by studying the expression of ACE2 and associated cell entry regulators in the monochorionic twin anemia-polycythemia (TAPS) placenta, a model of discordant placental oxygenation., Methods: We performed a retrospective comparative immunohistochemical, immunofluorescence and Western blot analysis of ACE2, TMPRSS2 and Cathepsin B expression in anemic and polycythemic territories of TAPS placentas (N = 14)., Results: ACE2 protein levels were significantly higher in the anemic twin territories than in the corresponding polycythemic territories, associated with upregulation of the key ACE2-related cell entry regulators, TMPRSS2 and Cathepsin B, immunolocalized to villous trophoblastic and stromal cells. Cellular colocalization of ACE2 and TMPRSS2, suggestive of functionality of this cell entry axis, was demonstrated by double immunofluorescence studies., Discussion: Placental hypoxia is associated with upregulation of ACE2 expression, concomitant with increased expression of its key cell entry proteases. ACE2-regulated placental functions, both infection- and non-infection related, may be highly oxygenation-dependent., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ascending amniotic fluid bacterial infection is a cause of perinatal morbidity and mortality. A diagnosis of amniotic cavity infection can be inferred by documenting maternal (acute chorioamnionitis) and/or fetal (chorionic plate vasculitis; umbilical vasculitis/funisitis) inflammatory response. A definitive diagnosis of intrauterine/neonatal sepsis as a cause of stillbirth requires positive blood cultures obtained at postmortem examination. However, if postmortem examination is not performed, acute chorioamnionitis with/without fetal inflammatory response cannot be classified as a cause of demise. We present a case of intrauterine demise associated with acute chorioamnionitis, villitis, and intervillositis of the placenta. Although postmortem examination was denied, a conclusive diagnosis of intrauterine sepsis could be rendered by demonstration of gram-positive cocci within fetal vessels of umbilical cord, chorionic plate, and stem villi. This report highlights the importance of identification of placental intravascular organisms as unequivocal evidence of fetal sepsis, especially in cases where cultures cannot be obtained.

Objective: To determine the rate of histologic fetoplacental inflammation in fetuses and newborns with fatal perinatal Group B-Streptococcus (GBS) infection., Study Design: Autopsy files (1990 to 2002) were searched for fetuses and newborns with GBS-positive post-mortem blood and/or lung cultures. The rate of histological fetoplacental inflammation in preterm (< 36 weeks gestational age) and term (> or =36 weeks) fetuses/infants was compared using chi(2) test., Results: GBS infection was diagnosed in 4.9% (61/1236) of perinatal autopsies and was considered the exclusive cause of death in 58 cases (16 to 41 weeks gestation, median: 26 weeks). A total of 43 fetuses/infants (74%) were preterm, 24 (41%) were male and 33 (57%) stillborn. The histologic fetoplacental inflammatory response was age-dependent for the following variables: acute chorioamnionitis (seen in 67% of preterm vs 33% of term fetuses/infants, p < 0.05), multiple-vessel umbilical vasculitis (37 vs 7%, p < 0.05), funisitis (37 vs 13%, p < 0.05), and the presence of neutrophils in the gastrointestinal tract (35% vs none, p < 0.05). Neutrophils in the pulmonary airspaces (47 vs 33%) and pneumonia (16 vs 27%) were found with similar frequency in both groups., Conclusion: Histologic fetoplacental inflammation is a poor indicator of perinatal GBS infection; the sensitivity is 67% in preterm and 33% in term fetuses/newborns (overall sensitivity 59%). The higher rate of histologic inflammation in preterm fetuses/newborns suggests age-specific interactions between microorganism, host and placenta.

Objective: To determine the validity of existing imaging-derived formulas for predicting the fetal lung volume (FLV)., Methods: In a consecutive series of postmortem lungs without pulmonary anomalies, the observed FLV (FLV(obs)) after inflation was correlated with individual fetal variables used in imaging-derived formulas. In addition, FLV(obs) was correlated with the predicted FLV calculated according to these same formulas., Results: Postmortem FLV(obs) showed a strong correlation with estimated fetal body weight, biparietal diameter, and head circumference (r > 0.9). The correlation of FLV(obs) with gestational age, femur length, and liver weight was less strong (0.8 < r < 0.9). The correlation was strongest for midgestation fetuses (between 22 and 32 weeks' gestation). The predicted FLV calculated using formulas based on fetal body weight, biparietal diameter, and head circumference showed the strongest correlation with the actual FLV(obs) (r > 0.9)., Conclusions: Postmortem FLV(obs) strongly correlates with fetal body weight, biparietal diameter, and head circumference, especially in midgestation fetuses. Regression formulas based on these fetal variables provide the most accurate prediction of FLV., (Copyright 2003 S. Karger AG, Basel)

Background: The lungs of infants born with diaphragmatic hernia are hypoplastic, immature, and surfactant-deficient. Tracheal occlusion in utero, which is being proposed as antenatal treatment of diaphragmatic hernia by promoting compensatory lung growth, decreases surfactant production as well, through loss of type II pneumocytes. The authors studied whether temporary tracheal occlusion might cause 'catch-up' lung growth and maturation, without negative effects of prolonged tracheal occlusion on the surfactant system., Methods: Diaphragmatic hernia was created in time-dated fetal lambs (65 to 75 days). At 108 days, the trachea was occluded with an embolectomy catheter (DH + TO, n = 6). After day 14, the balloon was deflated. Six congenital diaphragmatic hernia (CDH) fetuses were left unobstructed (DH). For comparison, a group of fetuses without diaphragmatic hernia were subjected to prolonged tracheal ligation (TL; 4-week tracheal ligation, n = 3). Unoperated littermates (n = 8) were used as controls (CTR). All were killed near term. Lung tissue was processed for light and electron microscopy (computerized stereologic morphometry). Type II pneumocytes were identified with antisurfactant protein B antibody., Results: Four animals in DH + TO and four in DH survived to term. Lung fluid volume (LFV) at 108 days was 5.2 +/- 4.4 mL in DH and 24.6 +/- 6.8 mL in controls (P < .05, Student t test). In DH + TO, LFV increased ninefold (to 48.3 +/- 13.3 mL) by 1 week postocclusion, suggesting accelerated lung growth. At term, lung weight to body weight ratio (LW/BW) was higher in TL (9.85% +/- 1.81%) than in CTR (3.55% +/- 0.56%; P < .05, analysis of variance); LW/BW and parenchymal volume tended to be greater in DH + TO than in DH, and air-exchanging parenchymal volume in DH + TO was similar to CTR (v a 50% reduction in DH), indicating some degree of hyperplasia after temporary occlusion. Pneumocyte II numerical density was decreased more than 10-fold in TL (60 +/- 22 v 826 +/- 324 in CTR, P < .001; it was slightly lower in DH + TO than in CTR, but individual type II pneumocyte cell volume was greater in the latter, and they appeared more mature than in DH (increased granulation by light microscopy, fewer glycogen granules, and abundant lamellar bodies by electron microscopy). Surfactant was also seen in the air spaces in DH + TO and CTR; it was absent in unobstructed CDH and in TL., Conclusions: Temporary tracheal occlusion in utero does not cause the dramatic decrease in type II pneumocytes seen after prolonged occlusion. Although only minimal increase in lung volume is seen in CDH, catch-up parenchymal growth and maturation occur, most notably in the surfactant-producing system.

Tracheal occlusion in utero has been shown to cause accelerated fetal lung growth and is now being considered as a therapeutic modality for pulmonary hypoplasia. We report the effects of tracheal ligation on the surfactant-producing type II pneumocyte population. Three groups of fetal lambs underwent tracheal ligation of 2 weeks', 4 weeks' and 6 weeks' duration, respectively, and all were sacrificed at 136 days' gestation (9 days pre-term). Nonoperated twins served as controls. The type II pneumocyte population was studied morphometrically using a combination of anti-surfactant protein B immunohistochemistry and computer-assisted stereologic morphometry at light and electron microscopic levels. Single-factor ANOVA was used for statistical analysis. Two weeks of tracheal ligation resulted in doubling of the total lung volume as a result of airspace distension and, to lesser extent, growth of the tissue compartment. With increasing duration of tracheal ligation, there was no additional lung growth. However, more prolonged tracheal occlusion was found to result in significant reduction of the surfactant system, as reflected in the marked decrease of total pneumocyte type II volume (3.14 cm3, 0.95 cm3, and 0.46 cm3, after 2, 4, and 6 weeks of ligation, compared with 5.96 cm3 for controls) and total pneumocyte type II number (13.9 x 10(9), 3.8 x 10(9), and 2.4 x 10(9), compared with 53.2 x 10(9) for controls). Ultrastructural analysis of the type II cells in obstructed lungs showed vacuolar degenerative changes that, after 6 weeks of ligation, were apparently irreversible. In utero tracheal ligation causes fetal lung hyperplasia, but results in reduction of and injury to the surfactant-producing cell population. Before tracheal occlusion can find wide-spread clinical application, its pathophysiology needs to be further elucidated.

Tracheal occlusion in utero is a potent stimulus of fetal lung growth. We describe the early growth mechanics of fetal lungs and type II pneumocytes after tracheal ligation (TL). Fetal rabbits underwent TL at 24 days gestational age (DGA; late pseudoglandular stage; term = 31 to 33 days) and were sacrificed at time intervals ranging from 1 to 5 days after TL. Lung growth was measured by stereological volumetry and bromodeoxyuridine (BrdU) pulse labeling. Pneumocyte II population kinetics were analyzed using a combination of anti-surfactant protein A and BrdU immunohistochemistry and computer-assisted morphometry. Nonoperated littermates served as controls. TL resulted in dramatically enhanced lung growth (lung weight/body weight was 5.00 +/- 0.81% in TL versus 2.52 +/- 0.13% in controls at 29 DGA; P < 0.001, unpaired Student's t-test). Post-TL lung growth was characterized by a 3-day lag-phase typified by relative stagnation of growth, followed by distension of airspaces, increased cell proliferation, and accelerated architectural and cellular maturation by postligation days 4 and 5. During the proliferation phase, the replicative activity of type II cells was markedly increased (type II cell BrdU labeling index was 10.0 +/- 4.1% in TL versus 1.1 +/- 0.3% for controls at 29 DGA; P < 0.02), but their numerical density decreased (3.0 +/- 0.5 x 10(-3)/microm2 in TL versus 4.5 +/- 0.3 x 10(-3)/microm2 in controls at 29 DGA; P < 0.02), suggesting accelerated terminal differentiation to type I cells. In conclusion, post-TL lung development is characterized by a well defined temporal pattern of lung growth and maturation. The rabbit model lends itself well to study the regulatory mechanisms underlying accelerated fetal lung growth after TL.