Reference Values for Placental Weight and Placental:Fetal Weight Ratio in a Swedish Population.

INTRODUCTION: There is important clinical information from placental weight and its ratio to the fetal weight. The aim with this study was to establish reference values for the placental weight and the placental:fetal weight ratio for gestational weeks 13-43 in a Swedish population. MATERIALS AND METHODS: Cases were retrospectively collected from the database used at the Pathology Department at Karolinska University Hospital and information about the placental weight, fetal weight, and gestational age was retrieved. Conditions, which could affect the placental- or fetal weight were excluded. Thereafter percentile curves were calculated for the placental weight and the placental:fetal weight ratio for gestational weeks. RESULTS: A total of 730 cases were included and percentile curves for the placental weight for gestational week 13-43 and placental:fetal weight ratio for gestational week 18-43 are presented. CONCLUSIONS: Reference values for post fixation placental weight and its ratio to fetal weight for a Swedish population are presented. The reference values are lower than the current reference values used in our institution, and this will be of importance when interpreting findings after placental examination.

Is obesity in pregnancy associated with signs of chronic fetal hypoxia?

INTRODUCTION: The prevalence of obesity in pregnancy is increasing worldwide. Maternal obesity increases risks of severe fetal and neonatal complications. The underlying pathophysiological mechanisms are unclear. One possible contributing factor could be chronic fetal hypoxia. The aim of this study was to compare placentas from women with and without obesity with respect to placental lesions, which could reflect compensatory mechanisms in response to chronic fetal hypoxia as well as lesions possibly leading to chronic fetal hypoxia. In addition, levels of erythropoietin in cord blood were compared between offspring of lean and obese women. MATERIAL AND METHODS: This cohort study included 180 women with uneventful, full-term, singleton pregnancies, out of which 91 lean women had a body mass index (BMI) of 18.5-24.9 kg/m2 and 89 women had obesity (BMI ≥30 kg/m2 ). Women were recruited at Södersjukhuset between 16 October 2018 and 2 December 2019. Placentas were investigated by two senior perinatal pathologists, who were blinded for maternal BMI. Cord blood was analyzed for levels of erythropoietin. RESULTS: Levels of erythropoietin in cord blood increased with maternal BMI (P = .01, ß = 0.97, 95% CI 0.27-1.68). There was no difference between placentas of obese and lean women in number of placental lesions reflecting chronic fetal hypoxia or in lesions that could possibly lead to chronic fetal hypoxia. CONCLUSIONS: This study of term and uneventful pregnancies demonstrated a positive association between maternal obesity and concentrations of erythropoietin in cord blood at birth. This finding supports the hypothesis of chronic fetal hypoxia as a risk factor for complications in the pregnancies of obese women. There were no differences in lesions associated with hypoxia between placentas of obese and lean women.

Genetic Analysis of Copy Number Variation in Large Chorangiomas.

INTRODUCTION: Chorangioma (CA) is the most common nontrophoblastic, vascular tumor-like lesion of the placenta with a reported incidence of 0.5% to 1% in all examined placentas. The underlying molecular mechanisms of CAs are still poorly elucidated, and a systematic investigation of the genetic background of CAs has not previously been done. MATERIALS AND METHODS: Tissue biopsies from 8 large (>40 mm) histologically confirmed CAs and 8 unaffected matched placenta controls, along with standard control DNA samples were analyzed for large genomic deletions and duplications using array comparative genomic hybridization (array-CGH) method. RESULTS: Array-CGH analysis revealed no rare or novel copy number variants in the CA samples compared with either standard control DNA or unaffected placenta DNA from the same individual. DISCUSSION: In this study, a systematic genetic investigation of 8 large CAs failed to demonstrate any large-scale pathogenic genetic changes. This lack of association might support a nongenetic, nontumorous origin of these lesions; however, additional genetic studies focusing on smaller genomic alterations are required to fully assess any possible genetic contribution.

Placental pathology in a large (Swedish) cohort of SARS-CoV-2 infected mothers.

INTRODUCTION: SARS-CoV-2 placentitis is associated with placental destruction and insufficiency and can affect perinatal outcome. The aim of the current study was to contribute with increased knowledge regarding placental histology in maternal SARS-CoV-2 infection during the pregnancy, as well as the correlation to the severity of maternal SARS-CoV-2 infection. MATERIAL AND METHODS: This retrospective observational study included 116 women who had a verified SARS-CoV-2 infection during pregnancy and gave birth between April 2020 and February 2022 in the Stockholm region, Sweden. Placental tissue was evaluated regarding several histopathological parameters, amongst them detection of the triad of characteristics of placental SARS-CoV-2 infection: chronic histiocytic intervillositis, fibrin deposition and villous trophoblast necrosis, and immunohistochemistry for ORF-3 protein expression was used for confirmation. Medical records were reviewed for maternal characteristics and neonatal outcome. RESULTS: SARS-CoV-2 placentitis was present in one-fifth of the examined placentas admitted to the institute due to maternal SARS-CoV-2 infection, out of which 86,4 % were delivered by acute caesarian section (ACS), all on fetal indication, and one pregnancy ended in stillbirth. Half of the cases without placentitis were delivered by ACS, out of which 50 % were on fetal indication. There was a clear tendency of a shorter time gap between confirmed maternal SARS-CoV-2 infection and delivery in the placentitis group. DISCUSSION: The presence of SARS-CoV-2 placentitis does not seem to correlate with maternal factors or the severity of infection. It does correlate with development of placental dysfunction of acute/subacute onset and is often manifested as reduced fetal movements.

Deficiency of the complex I of the mitochondrial respiratory chain but improved adenylate control over succinate-dependent respiration are human gastric cancer-specific phenomena.

The purpose of study was to comparatively characterize the oxidative phosphorylation (OXPHOS) and function of respiratory chain in mitochondria in human gastric corpus mucosa undergoing transition from normal to cancer states and in human gastric cancer cell lines, MKN28 and MKN45. The tissue samples taken by endobiopsy and the cells were permeabilized by saponin treatment to assess mitochondrial function in situ by high-resolution oxygraphy. Compared to the control group of endobiopsy samples, the maximal capacity of OXPHOS in the cancer group was almost twice lower. The respiratory chain complex I-dependent respiration, normalized to complex II-dependent respiration, was reduced that suggests deficiency of complex I, but the respiratory control by ADP in the presence of succinate was increased. Similar changes were observed also in mucosa adjacent to cancer tissue. The respiratory capacity of MKN45 cells was higher than that of MKN28 cells, but both types of cells exhibited a deficiency of complex I of the respiratory chain which appears to be an intrinsic property of the cancer cells. In conclusion, human gastric cancer is associated with decreased respiratory capacity, deficiency of the respiratory complex I of mitochondria, and improved coupling of succinate oxidation to phosphorylation in tumor tissue and adjacent atrophic mucosa. Detection of these changes in endobiopsy samples may be of diagnostic value.

Maternal obesity and stillbirth at term; placental pathology-A case control study.

OBJECTIVE: The aim was to explore the potential role of the placenta for the risk of stillbirth at term in pregnancies of obese women. METHODS: This was a case-control study comparing placental findings from term stillbirths with placental findings from live born infants. Cases were singleton term stillbirths to normal weight or obese women, identified in the Stockholm stillbirth database, n = 264 and n = 87, respectively. Controls were term singletons born alive to normal weight or obese women, delivered between 2002-2005 and between 2018-2019. Placentas were compared between women with stillborn and live-born infants, using logistic regression analyses. RESULTS: A long and hyper coiled cord, cord thrombosis and velamentous cord insertion were stronger risk factors for stillbirth in obese women compared to normal weight women. When these variables were adjusted for in the logistic regression analysis, also adjusted for potential confounders, the odds ratio for stillbirth in obese women decreased from 1.89 (CI 1.24-2.89) to 1.63 (CI 1.04-2.56). CONCLUSION: Approximately one fourth of the effect of obesity on the risk of stillbirth in term pregnancies is explained by umbilical cord associated pathology.

Atrophic gastritis: deficient complex I of the respiratory chain in the mitochondria of corpus mucosal cells.

BACKGROUND: Mitochondrial dysfunction is one of the most characteristic properties of the cancer cell. However, it is not known whether oxidative energy metabolism has already become altered in conditions of atrophic gastritis, a precancerous state of gastric disease. The purpose of our study was to comparatively characterize oxidative phosphorylation (OXPHOS) in the atrophic and nonatrophic gastric corpus mucosa. METHODS: Mucosal biopsies were taken from 12 patients with corpus dominant atrophic gastritis and from 12 patients with nonatrophic mucosa (controls). One part of the tissue samples was permeabilized with saponin for analysis of the function of the respiratory chain using high-resolution respirometry, and another part was used for histopathological examination. The serum level of pepsinogen I (S-PGI) was determined with a specific enzyme immunoassay (EIA). RESULTS: Compared to the control group, the maximal capacity of OXPHOS in the atrophy group was almost twofold lower, the respiratory chain complex I-dependent respiration, normalized to complex II-dependent respiration, was reduced, and respiratory control by ADP in the presence of succinate was increased in the atrophic corpus mucosa. In the whole cohort of the patients studied, serum S-PGI level correlated positively with complex I-dependent respiration or complex I-dependent to complex II-dependent respiration ratio. CONCLUSIONS: Corpus dominant atrophic gastritis is characterized by decreased respiratory capacity and relative deficiency of the respiratory complex I of mitochondria in the mucosa, the latter defect probably limiting mitochondrial ATP production and energetic support of the secretory function of the zymogenic mucosal cells.

Exploring the association between chorangioma and infantile haemangioma in singleton and multiple pregnancies: a case-control study in a Swedish tertiary centre.

OBJECTIVES: Placenta or placental chorangioma could be the origin site of infantile haemangioma since they share various histochemical and genetic characteristics with placental vascular tissue. The aim of the current study was to investigate the association between chorangiomas and infantile haemangiomas in singleton and multiple pregnancies. MATERIALS AND METHODS: An informative questionnaire enquiring about the presence or not of infantile haemangioma and including illustrative photos of haemangioma was sent to 469 (153 cases with chorangioma and 316 controls) mothers of 323 singleton (104 cases and 219 controls) and 146 multiple (49 cases and 97 controls) liveborn neonates registered in Sweden. Overall, 310 mothers (66.1%) from 216 singleton and 94 multiple pregnancies (96 cases and 214 controls) provided feedback and their consent to participate in the current case-control study. RESULTS: The incidence of infantile haemangioma showed no statistically significant differences between cases and controls (18.8% vs 18.2%) or between singleton and multiple pregnancies (18.9% vs 17.0%). The frequency of pre-eclampsia was significantly higher in cases with chorangioma compared with controls (41.7% vs 24.3%, OR=2.22, 95% CI 1.33 to 3.71, p=0.0022) and in singleton compared with multiple pregnancies (33.3% vs 21.3%, OR=1.85, 95% CI 1.04 to 3.26, p=0.034), whereas there were no significant differences in the incidence of infantile haemangioma in neonates of mothers with or without pre-eclampsia or in neonates of mothers with multiple compared with singleton pregnancies. CONCLUSION: There was no association between placental chorangiomas and infantile haemangiomas. Multiple pregnancies or pre-eclampsia were not significantly related to higher incidence of infantile haemangioma.

Association of chorangiomas to hypoxia-related placental changes in singleton and multiple pregnancy placentas.

INTRODUCTION: Chorangiomas (CAs) are the most frequent non-trophoblastic tumor-like-lesions of the placenta, and since they occur with an unusual frequency in pregnancies at high altitude, they are considered as a part of a spectrum of hypoxia-related vascular lesions of the placenta. The aim of our study is to describe the morphological features of the CAs and to show associations between CAs and other hypoxia related morphological changes in placentas of singleton and multiple pregnancies. MATERIALS AND METHODS: Placentas from singleton (121 vs 242) and multiple (49 vs 98) pregnancies, with and without CAs, respectively, were selected from a cohort of 15,742 placentas and enrolled into a case control study. RESULTS: Singleton placentas with CAs showed increased incidence of hypoxia-related placental changes including accelerated maturation of chorionic villi (OR = 2.40, p < 0.001), infarction (OR = 2.89, p < 0.001), decidual arteriopathy (OR = 3.24, p < 0.001), fetal thrombosis (OR = 4.05, p < 0.001) and hypercoiled umbilical cords (OR = 5.55, p < 0.001). The incidence of CAs in multiple placentas was higher in our studied cohort and a significant associated change was shown with fetal thrombosis (OR = 4.58, p = 0.017). There were no significant morphological changes between CAs in singleton compared to multiple pregnancies. DISCUSSION: In singleton placentas, CA is associated with several placental changes related to hypoxia, whereas in multiple pregnancies this relationship is not present. We speculate that CAs in multiple pregnancies might reflect an adaptive mechanism for relative hypoxia per se in these pregnancies. CONCLUSION: Our study provides evidence that CAs are associated with an increased rate of hypoxia related changes in singleton placentas.

Clinical Outcome in Singleton and Multiple Pregnancies with Placental Chorangioma.

INTRODUCTION: Chorangiomas (CAs) are the most common non-trophoblastic tumor-like-lesions of the placenta. Although the clinical significance of small CAs is unknown, the large lesions are often associated with maternal and fetal complications. The aim of our study was to assess the maternal clinical characteristics and neonatal outcome in singleton and multiple pregnancies with placental CA. MATERIALS AND METHODS: Among 15742 selected placentas 170 CAs were diagnosed. Pregnancy and neonatal outcomes were analyzed in singleton (n = 121) and multiple (n = 49) pregnancy groups including 121 and 100 neonates, respectively. RESULTS: The frequency of APGAR score <7 at 5 minutes (p = 0,012), abnormal pulsatility index (p = 0,034), and abnormal blood flow class (p = 0,011) were significantly higher in neonates from singleton compared to multiple pregnancies. Significantly smaller CAs in singleton pregnancies were related to small for gestational age neonates (p = 0,00040) and neonates admitted to the neonatal care unit (p = 0,028). In singleton pregnancies, significantly smaller CAs were associated to maternal preeclampsia (p = 0,039) and larger CAs to multiparity (p = 0,005) and smoking (p = 0,001) groups. The frequency of preeclampsia was high in both singleton and multiple pregnancy groups (41,32% vs 26,53%, respectively), however, the difference did not reach the level of statistical significance. DISCUSSION: A high incidence of preeclampsia in cohort of placental CA might lead to a possible recognition of CAs as potential morphologic indicator of placental hypoxia. CONCLUSION: A more favorable pregnancy outcome in multiple gestations compared to the singleton gestations with CAs might reflect an adaptive mechanism for increased demand of oxygen and associated placental tissue hypoxia in this group.

Fetal calcifications are associated with chromosomal abnormalities.

OBJECTIVE: The biological importance of calcifications occasionally noted in fetal tissues (mainly liver) at autopsy or ultrasound is largely unexplored. Previous reports hint at an association to infection, circulatory compromise, malformations or chromosomal abnormalities. To identify factors associated with calcifications, we have performed a case-control study on the largest cohort of fetuses with calcifications described thus far. METHODS: One-hundred and fifty-one fetuses with calcifications and 302 matched controls were selected from the archives of the Department of Pathology, Karolinska University Hospital. Chromosome analysis by karyotyping or quantitative fluorescence-polymerase chain reaction was performed. Autopsy and placenta reports were scrutinized for presence of malformations and signs of infection. RESULTS: Calcifications were mainly located in the liver, but also in heart, bowel, and other tissues. Fetuses with calcifications showed a significantly higher proportion of chromosomal abnormalities than controls; 50% vs. 20% (p<0.001). The most frequent aberrations among cases included trisomy 21 (33%), trisomy 18 (22%), and monosomy X (18%). A similar distribution was seen among controls. When comparing cases and controls with chromosomal abnormalities, the cases had a significantly higher prevalence of malformations (95% vs. 77%, p=0.004). Analyzed the other way around, cases with malformations had a significantly higher proportion of chromosomal abnormalities compared with controls, (66% vs. 31%, p<0.001). CONCLUSION: The presence of fetal calcifications is associated with high risk of chromosomal abnormality in combination with malformations. Identification of a calcification together with a malformation at autopsy more than doubles the probability of detecting a chromosomal abnormality, compared with identification of a malformation only. We propose that identification of a fetal tissue calcification at autopsy, and potentially also at ultrasound examination, should infer special attention towards co-existence of malformations, as this would be a strong indicator for a chromosomal abnormality.

Unusual concurrence of heterotopic glial nodule of the scalp and congenital herpes simplex virus type-2 infection.

Heterotopic glial nodules are rare congenital cutaneous lesions; only 13 cases of scalp localized lesions of this kind are reported in the English medical literature. Herpes simplex virus is a rare cause of neonatal morbidity and mortality and is a rare cause of intrauterine infection. We report the first case of concurrent presence of a heterotopic glial nodule of the scalp and neonatal, in utero-acquired, fatal herpes simplex virus type-2 infection.

Fetal mediastinal tumor of neuroepithelial origin in a case of missed abortion.

We report a rare case of a primitive embryonal tumor discovered in the upper anterior mediastinum during routine autopsy of a macerated fetus at the 18th week of gestation. Our diagnosis was based on autopsy findings and histologic examination, which showed neuroepithelial differentiation of the tumor with frequent ependymal-type rosette formation; no structures of other germ cell layer origin were revealed. Additional positive immunohistochemical staining for CD56, CD57, and neurofilament protein confirmed the neural origin of the tumor, whereas the genetic analysis showed no MYCN gene amplification and no 11q23 deletion or rearrangement of EWS locus (22q12). Our findings exclude the possibility of teratoma and support the diagnosis of undifferentiated primitive tumor of neuroepithelial origin uncommonly located in the anterior mediastinum at the early 2nd trimester of gestation in a case of missed abortion.

WITHDRAWN: TNF-Related Apoptosis-Inducing Ligand TRAIL as a Potential Biomarker for Early Pregnancy Complications.

This paper was withdrawn at the request of the editors due to uncertainties inherent in the statistical analysis.

Immunohistochemical expression of the PRO2268 protein in psoriasis vulgaris skin.

The PRO2268 gene encodes for the PRO2268 molecule and maps to a chromosomal region (12q14), which clusters genes with a key role in immune signaling. Although the PRO2268 protein is as yet of unknown function, we should not exclude the possibility that the PRO2268 gene, because of its location, might have a distinct role in autoimmunity and inflammation. The aim of the present study was to investigate the expression pattern of the PRO2268 protein in psoriasis skin. Formalin-fixed paraffin-embedded sections from normal and psoriasis skin tissue were studied immunohistochemically using custom-ordered antibodies (anti-PRO2268#1 and anti-PRO2268#2) against the PRO2268. The present study revealed an expression of the anti-PRO2268#2 in the inflammatory infiltrate, and suggesting a possible role for the PRO2268 molecule in pathophysiology of psoriasis, which needs further investigation.