More Tools for Evaluating Decidual Artery Disease.

Introduction: Hypertensive disorders of pregnancy continue to pose the most important risks for adverse maternal and neonatal outcome. Among histological findings, decidual artery disease is one of the most common, one that has both good reproducibility among observers and whose abnormal vascular remodeling is the sole aspect of preeclampsia pathophysiology on which experts agree. Nevertheless, some aspects of arterial remodeling alterations are still under investigation. Methods: We selected 720 routine and consecutive placenta case studies, concordant with the Amsterdam consensus. From these studies, we collected maternal and neonatal clinical data and specific placental findings on spiral artery abnormalities. We took into account all criteria for decidual arteriopathy. Two hundred and fifteen (215) cases out of this population presented hypertensive disorders of pregnancy. Additional to expected arterial findings, we noted frequent persistent parietal trophoblast lining. Results: A large proportion of our population developed hypertensive disorders of pregnancy (30%). Among the histologic findings reported for preeclampsia, we paid particular attention to spiral artery abnormalities, and this interpretive analysis revealed high frequency of arterial remodeling abnormalities. We examined two additional aspects in our routine analysis: first, the novel one of parietal trophoblast persistence, and second, the established problem of associated acute inflammation, as a possible pitfall. Conclusion: In order to better understood, spiral maternal artery remodeling merits further study. The abnormalities in this process provide an objective tool in the study and diagnosis of important pregnancy complications; furthermore, abnormal remodeling is an expression of early pregnancy alteration, and subsequently related to preeclampsia etiology.

Heterotopic Adipose Tissue in the Placental Parenchyma: Case Report.

Objective. Reports of heterotopic tissue in the placenta are few and mainly include liver and adrenal cells. We report on adipose tissue found in the placenta. Case report. We present the case of a microscopic finding in a 25-year-old's placenta who suffered from hypertensive disorder in pregnancy. During routine microscopic study, we observed a heterotopic, benign, circumscribed and intervillous nodule of adipose tissue. Conclusion. To our knowledge, there is no other reported case of adipocytes among chorionic villi. Why foreign tissues show up in the placenta remains unknown; however, several new theories offer explanations.

Assessment of Placental Extracellular Vesicles-Associated Fas Ligand and TNF-Related Apoptosis-Inducing Ligand in Pregnancies Complicated by Early and Late Onset Preeclampsia.

Preeclampsia (PE) is a hypertensive disorder that affects 2-8% of pregnancies and is one of the main causes of fetal, neonatal, and maternal mortality and morbidity worldwide. Although PE etiology and pathophysiology remain unknown, there is evidence that the hyperactivation of maternal immunity cells against placental cells triggers trophoblast cell apoptosis and death. It has also been reported that placenta-derived extracellular vesicles (EV) carry Fas ligand (FasL) and Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and trigger apoptosis in Jurkat T cells. This study aimed to quantify and compare FasL and TRAIL expression in EV derived from cultures of placenta explants from women with PE (early versus late) and women with uncomplicated pregnancies. Also, the study assessed EV capacity to induce apoptosis in Jurkat T cells. The authors isolated EV from placenta explant cultures, quantified FasL and TRAIL using ELISA, and analyzed EV apoptosis-inducing capability by flow cytometry. Results showed increased FasL and TRAIL in EV derived from placenta of women with PE, and increased EV apoptosis-inducing capability in Jurkat T cells. These results offer supporting evidence that EV FasL and TRAIL play a role in the pathophysiology of PE.

Expression of tissue factor and thrombomodulin in the placentas of pregnancies affected by early-onset and late-onset preeclampsia.

AIM: To analyze the differential genetic expression and protein localization of thrombomodulin (THBD) and tissue factor (F3) in the placentas of pregnancies affected by preeclampsia. METHODS: We assessed the expression of THBD and F3 by immunohistochemistry and real-time polymerase chain reaction (PCR) in placentas from 20 PE cases: 10 early-onset PE placentas, 10 late-onset PE placentas, and 10 control cases (normal pregnancies). RESULTS: In cases, we found higher THBD and F3 RNA levels in placental tissue. Protein expression in controls differed from that in late-onset PE placentas, which had lower THBD levels in syncytiotrophoblasts and amniotic cells. Likewise, late-onset PE placentas exhibited comparatively lower F3 expression in the perivillous fibrin. In contrast, early-onset PE had high F3 expression in the subdecidual fibrin. We found no significant differences in the F3/THBD ratio between the groups. CONCLUSION: Our study supports evidence that shows the involvement of F3 and THBD in placental disorders. Furthermore, this finding contributes to a better understanding of the physio-pathological role that these molecules may play in the development of this heterogeneous disease.

Spiral Arteries in Second Trimester of Pregnancy: When Is It Possible to Define Expected Physiological Remodeling as Abnormal?

After undergoing remodeling, uterine spiral arteries turn into wide, flexible tubes, with low resistance. If remodeling does not occur, spontaneous abortions, intrauterine growth restriction, and pregnancy-related hypertensive disorders can ensue. Arterial transformation begins at a very early gestational stage; however, second quarter pregnancy histopathological samples have yet to pinpoint the exact moment when abnormal remodeling transpires. We examined 100 samples, taken from consecutive abortions at 12-23 gestational weeks. Following Pijnenborg and Smith guidelines, blinded pathologists analyzed clinical data on remodeling stages. Lab results showed that arterial remodeling is not synchronic in all vessels; a single sample can include various remodeling stages; neither is remodeling homogenous in a single vessel: change may be occurring in one part of the vessel, but not in another. To our knowledge, no one has published this finding. In the examined age group, Smith stage IV predominates; around week 14, substantial muscle and endothelium loss takes place. After week 17, endovascular or fibrin trophoblast does not usually occur. Although scant consensus exists on what defines preeclampsia etiology, it is clear that it involves abnormal remodeling in decidua vessels. Improved understanding requires further knowledge on both the physiological and pathological aspects of the remodeling process. We observed that muscle and endothelial tissues disappear from weeks 14-17, after which time reendothelization predominates. We list the expected proportion of spiral artery changes for each gestational age which, to date, has not been available.

Protein and genetic expression of CDKN1C and IGF2 and clinical features related to human umbilical cord length.

BACKGROUND: Umbilical cord (UC) abnormalities are related to neurological outcome and death; specific molecular factors that might be involved are, as yet, unknown; however, protein-coding genes insulin-like growth factor 2 (IGF2) and cyclin-dependent kinase inhibitor 1C (CDKN1C) have been identified as potential candidates. METHODS: An analytical observational study was carried out. Newborn UCs were collected, along with their clinical and morphological features. Immunohistochemical analysis was made on paraffin-embedded sections and quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in fresh UC tissue for the assessment of gene expression. RESULTS: A total of 100 newborns were included. A significant association was found between long UC and prematurity [odds ratio (OR) 9] and long UC and respiratory distress (OR 4.04). Gestational diabetes (OR 8.55) and hypertensive disorders of pregnancy (HDP) (OR 4.71) were found to be related to short UCs. The frequency for abnormal UC length was higher than expected. UC length was positively correlated with maternal, newborn and placental weight. No statistical association was found between IGF2 and CDKN1C (p57) expression and UC length; however, there was a tendency for higher CDKN1C expression in short UCs, while, on the contrary, higher IGF2 expression for long UCs. CONCLUSION: UC length was observed to be associated with maternal and newborn complications. Protein expression, messenger RNA (mRNA) activity and the activity of said genes seem to be related to UC length.

Effect of umbilical cord length on early fetal biomechanics.

The umbilical cord suspends the fetus within the amniotic cavity, where fetal dynamics is one of its many functions. Hence, the umbilical cord is a viable index in determining fetal activity. Fetal movements result in mechanical loads that are fundamental for fetal growth. At present, mechanical environment during early human fetal development is still largely unknown. To determine early fetal movement dynamics at given physiological (0.060 m) and pathological umbilical cord lengths (0.030 m, 0.020 m, 0.017 m and 0.014 m) a 2D computational model was created to simulate dynamic movement conditions. Main findings of this computational model revealed the shortest umbilical cord length (0.014 m) with a 6(10-6)N, twitch force amplitude had a two-fold increase on linear velocity (0.12 m/s) in comparison with other lengths (0.05m/s). Moreover, umbilical cord length effect presented an increasing exponential tension on the fetus body wall from longest to shortest, from 0 N in the control length to 0.05 N for the shortest umbilical cord. Last, tension was always present over a period of time for the shortest cord (0.03 N to 0.08 N). Collectively, for all variables evaluated the shortest umbilical cord (0.014 m) presented remarkable differences with other lengths in particular with the second shortest umbilical cord (0.017 m), suggesting a 0.003 m difference represents a greater biomechanical effect. In conclusion, this computational model brings new insights required by clinicians, where the magnitude of these loads could be associated with different pathologies found in the clinic.

Risk factors and fetal outcomes for preeclampsia in a Colombian cohort.

In Latin America and the Caribbean, hypertensive pregnancy disorders are responsible for almost 26% of all maternal deaths [1] and, in Colombia, they account for 59% of all severe maternal morbidity (SMM) cases, and 59.7% of all SMM cases in adolescents [2]. One of the most important hypertensive pregnancy disorders is preeclampsia (PE). Lives can be saved, if PE is prevented, or detected early and properly managed. Prevention and detection depend on identifying the risk factors associated with PE, and, as these have been shown vary by population, they should be determined on a population-by-population basis. The following study utilized the nested case-control model to evaluate 45 potential PE risk factors of a cohort in Bogotá, Colombia, making it perhaps the most comprehensive study of its kind in Colombia. It found PE to have a statistically significant association with 7 of the 45 factors evaluated: 1) pre-gestational BMI >30 kg/m2, 2) pregnancy weight gain >12 kg, 3) previous history preeclampsia/eclampsia, 4) previous history of IUGR-SGA (Intrauterine Growth Restriction-Small for Gestational Age), 5) maternal age <20 or ≥35 years (20-34 was not associated), and 6) family history of diabetes. Finally, prenatal consumption of folic acid was found to lower the risk of PE. We recommend that, in Colombia, factors 1-6 be used to identify at risk mothers during pregnancy check-ups; that mothers be encouraged to take folic acid during pregnancy; and, that Colombia's health system and public policy address the problem of pregestational obesity.

Impact of umbilical cord length on fetal circulatory system by Doppler assessment.

INTRODUCTION: Numerous studies have revealed the impact of umbilical cord (UC) length on fetal perfusion; abundant data implicate abnormal UC length to neurological delay and subsequent poor prognoses for fetuses and newborns. Indeed, our group previously developed theoretical approximations that contributed to formulas capable of explaining the impact of UC length on cardiac output. METHODS: We performed an observational study that measured the pulsatility index and flow velocity in umbilical arteries. A special Doppler measured proximal and distal indexes in both arteries. After birth, medical staff measured complete UC length. We obtained maternal and neonatal outcomes from clinical records. RESULTS: Our study enrolled 20 pregnant mothers. We found that flow velocities in the two edges were different: fetal edges exhibited greater velocity in the majority of cases; but, when we compared pressure differentials (ΔP), the pulsatility index was significantly related to umbilical cord length. CONCLUSIONS: Fetal perfusion, welfare, and viability are related to UC function as the conveyor of all fetal volemia. Excessive UC length affects cardiac dynamics and increases peripheral vascular resistance. Further studies could validate routine use of the differential proximal and distal measurements proposed in this article, and their implications in in utero fetal heart function. We also hope that early diagnosis or UC alterations could alert neonatologists and obstetricians to clinical conditions of the fetus.

Presentation of histoplasmosis as mononucleosis syndrome in an immunocompetent patient.

Histoplasmosis is a fungal disease usually occurring in endemic areas that can affect immuno-impaired patients in whom pulmonary involvement is the rule. We present the case of an 18 year-old immunocompetent, male patient, resident of the State of Florida, who showed signs of mononucleosis syndrome that included odynophagia, cervical adenomegaly, sporadic fever and rash; however, no pulmonary involvement or visceromegaly were present. Faced with this atypical and unexpected clinical picture, histoplasmosis infection was eventually diagnosed following cervical lymph-node biopsy. Disseminated histoplasmosis may have unexpected manifestations, as is pointed out in the case described below.

The umbilical cord, preeclampsia and the VEGF family.

Introduction: The VEGF family has been identified as abnormal in preeclampsia (PE). Hypertensive disorders of pregnancy (HDP) are major contributors to maternal and neonatal morbidity and mortality worldwide; likewise, umbilical cord anatomical abnormalities (UCAA) are linked to poor neonatal outcomes. Based on the relationship described between PE and UCAA and the role of the VEGF family in PE, this study explored VEGF expression in placental and UC tissued from patients with PE and with UCAA. Methods: We performed an observational, analytical study on placentas, comparing protein and mRNA expression in four groups: patients with PE, patients with UC abnormalities, patients with both, and patients with none of them. Using immunohistochemistry, we studied VEGF A, VEGF R1 (FLT1), MMP1, and PLGF. With quantitative reverse transcription polymerase chain reaction we described mRNA expression of PLGF, VEGF and sFLT1, and sFLT1/PLGF ratio. Results: Forty newborns were included. Sixty-seven percent of mothers and 45% of newborns developed no complications. Immunohistochemistry was performed on UC and placental disc paraffin-embedded tissue; in the latter, the mRNA of the VEGF family was also measured. Statistically significant differences were observed among different expressions in both HDP and UCAA groups. Interestingly, the UCAA group exhibited lower levels of sFLT1 and VEGF-A in comparison with other groups, with significant P-value for sFLT1 (P=0000.1). Conclusion: The origin of UCAA abnormalities and their relation with HDP are still unknown. VEGF family alterations could be involved in both. This study provides the first approach related to molecules linked to UCAA.

Anatomical Pathology of the Umbilical Cord and Its Maternal and Fetal Clinical Associations in 434 Newborns.

Introduction Umbilical cord (UC) abnormalities and their clinical relations in 434 newborns were analyzed. We had previously reported on clinical associations of long and short UCs with any kind of malformation. This study focuses on other UC features (insertion, vessels, entanglements, coiling, and knots) and their associations with clinical characteristics and neonatal prognosis. Methods An observational analytic study was performed on placentas from consecutive deliveries. Ordered logistic regression with bivariate and multivariate analysis was performed to evaluate the relationship between variables of interest concerning UC abnormalities. Results A total of 434 placentas made up the study. UC abnormalities were abnormal insertion, 82 (18.86%); coiling (hypo and hypercoiled), 177 (40.78%); single umbilical artery (SUA), 4 (0.92%); entanglements, 8 (1.84%); true knots, 3 (0.69%); webs in UC base, 9 (2.07%); and right twist, 68 (15.67%). After analyzing maternal and fetal complications during pregnancy, multivariate analysis confirmed the recognized association between malformations and SUA and male gender; further confirmation was also made between hypertensive disorders of pregnancy and true knots. Discussion UC abnormalities associated with undesirable outcomes are varied and should be recognized and described. Clinical factors associated with anatomical UC abnormalities are not completely understood and justify forthcoming studies.

Immunohistochemical protein expression profiling of growth- and apoptotic-related factors in relation to umbilical cord length.

INTRODUCTION: Umbilical cord (UC) alterations are related to fetal and neonatal deaths and late neurological complications. Abnormal UC length has been recognized as the most significant abnormality linked to unfavorable outcomes. Despite its importance, causal factors resulting in abnormally long or short UCs have yet to be established. The factors that govern UC length are largely unknown. Furthermore, there is a paucity of studies that assess molecular processes involved in the establishment of UC length. We hypothesize that UC length abnormalities in UC length are associated with altered protein expression patterns of known cell growth and/or apoptosis regulators. In this study we analyze diverse protein expression patterns in different UC cell types found in UCs of normal and abnormal length. METHODS: An analytical observational study was carried out on fetal autopsies; diagnosed abnormal length UCs were compared to normal controls by gestational age. Immunohistochemical analysis of expression levels of growth and pro- and anti-apoptotic factors was performed. RESULTS: We performed immunohistochemistry antibody tests against FAS, BAX, Ki67, cMyc, FGF2, TGFBR3, VEGF, Bcl2, p57 and IGF2 and analyzed UC cell expression patterns. We found significant differences in specific long and/or short cord cell types in comparison to those in normal cords. DISCUSSION: Factors that determine UC length are still largely unknown; however, this study demonstrates significant specific cell type differences in protein expression patterns of several genes related to cell proliferation. This preliminary study provides strong supporting data to continue the search for molecular factors that determine UC length.