Clinical Significance of the Large Fetal Vessel Lesions in Placental Fetal Vascular Malperfusion.

Fetal vascular malperfusion (FVM) is an important pattern of placental injury. Although the significance of distal villous FVM (clusters of sclerotic and/or mineralized chorionic villi) is well documented, the clinical significance of proximal (large vessel) lesions of FVM is less clear, which is the aim of this retrospective analysis. To evaluate the clinical significance and placental associations of single and coexisting categories of lesions of large vessel FVM, 24 clinical and 44 placental phenotypes of 804 consecutive placentas with at least 1 lesion of proximal vessel FVM from the second half of pregnancy, divided according to the type or category of the individual FVM lesion (fetal vascular ectasia, fetal vascular thrombi, intramural fibrin deposition, and stem vessel obliteration): 689, 341, 286, and 267 placentas, respectively (first analysis) and single or coexisting large fetal vessel lesions (1, 2, 3, and 4 coexisting categories of lesions: 276, 321, 162, and 45 placentas, respectively) were statistically compared (analysis of variance, χ2, univariate analysis). Because of multiple comparisons, Bonferroni-corrected P < .001 was used as a threshold of statistical significance. In this population of high-risk pregnancies dominated by fetal congenital anomalies, single individual or 1 to 2 coexisting categories of lesions of the large vessel FVM, including fetal vascular thrombi, did not consistently correlate with clinical or placental variables and were not prognostically useful, but the coexistence of 3 or 4 lesions was associated with the most advanced gestational age, fetal congenital anomalies, distal villous FVM, particularly high-grade, chorangioma or chorangiomatosis, hypercoiled umbilical cord, perivascular stem edema, and marginate or vallate placenta. Therefore, the finding of multiple lesions of the large vessel FVM not only merits a diligent search for the distal villous lesions including the CD34 immunostaining, but also justifies putting the large vessel (global) FVM on the final placental diagnosis line, which in the case of up to only 2 lesions may not be justified.

Chronic villitis as a distinctive feature of placental injury in maternal SARS-CoV-2 infection.

BACKGROUND: SARS-CoV-2 infection during pregnancy is associated with an increased risk for stillbirth, preeclampsia, and preterm birth. However, this does not seem to be caused by intrauterine fetal infection because vertical transmission is rarely reported. There is a paucity of data regarding the associated placental SARS-CoV-2 histopathology and their relationship with the timing and severity of infection. OBJECTIVE: This study aimed to determine if maternal SARS-CoV-2 infection was associated with specific patterns of placental injury and if these findings differed by gestational age at time of infection or disease severity. STUDY DESIGN: A retrospective cohort study was performed at the University of California San Diego between March 2020 and February 2021. Placentas from pregnancies with a positive SARS-CoV-2 test were matched with 2 sets of controls; 1 set was time-matched by delivery date and sent to pathology for routine clinical indications, and the other was chosen from a cohort of placentas previously collected for research purposes without clinical indications for pathologic examination before the SARS-CoV-2 outbreak. Placental pathologic lesions were defined based on standard criteria and included maternal and fetal vascular malperfusion and acute and chronic inflammatory lesions. A bivariate analysis was performed using the independent Student t test and Pearson chi-square test. A logistic regression was used to control for relevant covariates. Regions of SARS-CoV-2-associated villitis were further investigated using protein-based digital spatial profiling assays on the GeoMx platform, validated by immunohistochemistry, and compared with cases of infectious villitis and villitis of unknown etiology. Differential expression analysis was performed to identify protein expression differences between these groups of villitis. RESULTS: We included 272 SARS-CoV-2 positive cases, 272 time-matched controls, and 272 historic controls. The mean age of SARS-CoV-2 affected subjects was 30.1±5.5 years and the majority were Hispanic (53.7%) and parous (65.7%). SARS-CoV-2 placentas demonstrated a higher frequency of the 4 major patterns of placental injury (all P<.001) than the historic controls. SARS-CoV-2 placentas also showed a higher frequency of chronic villitis and severe chronic villitis (P=.03 for both) than the time-matched controls, which remained significant after controlling for gestational age at delivery (adjusted odds ratio, 1.52; 95% confidence interval, 1.01-2.28; adjusted odds ratio, 2.12; 95% confidence interval, 1.16-3.88, respectively). Digital spatial profiling revealed that programmed death-ligand 1 was increased in villitis-positive regions of the SARS-CoV-2 (logFC, 0.47; adjusted P value =.002) and villitis of unknown etiology (logFC, 0.58; adjusted P value =.003) cases, but it was conversely decreased in villitis-positive regions of the infectious villitis group (log FC, -1.40; adjusted P value <.001). CONCLUSION: Chronic villitis seems to be the most specific histopathologic finding associated with SARS-CoV-2 maternal infection. Chronic villitis involves damage to the vasculosyncytial membrane of the chorionic villi, which are involved in gas and nutrient exchange, suggesting potential mechanisms of placental (and perhaps neonatal) injury, even in the absence of vertical transmission. Surprisingly, changes in protein expression in SARS-CoV-2-associated villitis seem to be more similar to villitis of unknown etiology than to infectious villitis.

Single Umbilical Artery Umbilical Cord Is Associated With High-Grade Distal Fetal Vascular Malperfusion.

PURPOSE AND CONTEXT: Umbilical cord abnormalities with clinical signs of cord compromise are frequently associated with fetal vascular malperfusion (FVM). Single umbilical artery (SUA) has been reported to be associated with high-grade FVM in fetal growth restriction but not in an unselected population; our study aimed to address this issue. METHODS: Clinical and placental phenotypes of 55 consecutive placentas with SUA (Group 1) were compared with those of 655 placentas with 3-vessel umbilical cord (Group 2) from patients who were in the second half of their pregnancy. The placentas were histologically examined using hematoxylin and eosin (H&E) staining and CD 34 immunostaining. KEY RESULTS: Several umbilical cord phenotypes and high-grade distal FVM, based on H&E staining and endothelial fragmentation by CD34 were significantly more common in Group 1, whereas decidual clusters of multinucleate trophoblasts were more common in Group 2. Notably, H&E staining or CD34 immunostaining evaluated separately showed that high-grade distal FVM was more common in Group 1 than in Group 2, but the difference was not statistically significant. CONCLUSIONS: SUA predisposes to remote, advanced, and recent high-grade distal villous FVM, with a pathogenesis partly different from that of stasis-induced FVM, likely related to fetal anomalies associated with SUA.

Gross and Histologic Placental Abnormalities Associated With Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes. STUDY DESIGN: Multi-institutional retrospective case-control study of newborns with HIE (2002-2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls. RESULTS: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P = .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P = .004), and fetal vascular malperfusion (30.6% vs 9.0%, P = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P = .01). CONCLUSION: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes.

Placental inflammation in a fetal demise of a SARS-CoV-2-asymptomatic, COVID-19-unvaccinated pregnant woman: a case-report.

BACKGROUND: Intrauterine fetal demise is a recognized complication of coronavirus disease 2019 in pregnant women and is associated with histopathological placental lesions. The pathological mechanism and virus-induced immune response in the placenta are not fully understood. A detailed description of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced inflammation in the placenta during fetal demise is crucial for improved clinical management. CASE PRESENTATION: We report the case of a 27-week gestation SARS-CoV-2-asymptomatic unvaccinated pregnant woman without comorbidities or other risk factors for negative pregnancy outcomes with a diagnosis of intrauterine fetal demise. Histopathological findings corresponded to patterns of subacute inflammation throughout the anatomic compartments of the placenta, showing severe chorioamnionitis, chronic villitis and deciduitis, accompanied by maternal and fetal vascular malperfusion. Our immunohistochemistry results revealed infiltration of CD68+ macrophages, CD56+ Natural Killer cells and scarce CD8+ T cytotoxic lymphocytes at the site of placental inflammation, with the SARS-CoV-2 nucleocapsid located in stromal cells of the chorion and chorionic villi, and in decidual cells. CONCLUSION: This case describes novel histopathological lesions of inflammation with infiltration of plasma cells, neutrophils, macrophages, and natural killer cells associated with malperfusion in the placenta of a SARS-CoV-2-infected asymptomatic woman with intrauterine fetal demise. A better understanding of the inflammatory effects exerted by SARS-CoV-2 in the placenta will enable strategies for better clinical management of pregnant women unvaccinated for SARS-CoV-2 to avoid fatal fetal outcomes during future transmission waves.

Histological and immunohistochemical features of the placenta associated with COVID-19: a systematic review and meta-analysis.

OBJECTIVE: Aim: To make a systematic review and meta-analysis of published data on the study of histological and immunohistochemical features of the placenta in women who had acute coronavirus infection associated with SARS-CoV-2 ("Covid" placentas) during pregnancy. PATIENTS AND METHODS: Materials and Methods: The search for literature data is based on the PRISMA methodology); the MEDLINE database (PubMed®) was searched using Medical Subject Headings terms from January 2020 to July 2023. The project was registered in the Open Sience Frame (Project Identifier: DOI 10.17605/OSF.IO/GDR3S, Registration DOI: https://doi.org/10.17605/OSF.IO/H2KPU). Preference was given to studies in which the description of placentas met the requirements of the Amsterdam Placental Workshop Group Consensus Statement. RESULTS: Results: A total of 31 studies were included; the number of participants whose morphological and histological description of the placentas could be subjected to meta-analysis was 2401, respectively, in the group with a "Covid" history and 1910 - conditionally healthy pregnant women. Pathological changes in the placental complex were not detected in 42±19.62% of pregnant women with a history of Covid. Immunohistochemical examination of placentas preferably focuses on the detection of SARS-CoV-2 spike protein or ACE2. According to currently available studies, in the placentas of women who have had COVID-19 during pregnancy, there are no pathognomic histological patterns specific to this infection and direct damage to the placenta is rarely observed. Histological patterns in "covid" placentas are isolated, most often a combination of lesions in both the maternal and fetal malperfusion. CONCLUSION: Conclusions: According to currently available studies, in the placentas of women who have had COVID-19 during pregnancy, there are no pathognomic histological patterns specific to this infection and direct damage to the placenta is rarely observed. The probability of infection of the intrauterine fetus by the transplacental hematogenous route is the lowest compared to other routes, which, in our opinion, is a possible explanation for the high frequency of MVM without subsequent infection of the fetus.

Histopathologic and Transcriptomic Profiling Identifies Novel Trophoblast Defects in Patients With Preeclampsia and Maternal Vascular Malperfusion.

Preeclampsia (PE) is a heterogeneous disease for which the current clinical classification system is based on the presence or absence of specific clinical features. PE-associated placentas also show heterogeneous findings on pathologic examination, suggesting that further subclassification is possible. We combined clinical, pathologic, immunohistochemical, and transcriptomic profiling of placentas to develop integrated signatures for multiple subclasses of PE. In total, 303 PE and 1388 nonhypertensive control placentas were included. We found that maternal vascular malperfusion (MVM) in the placenta was associated with preterm PE with severe features and with small-for-gestational-age neonates. Interestingly, PE placentas with either MVM or no histologic pattern of injury showed a linear decrease in proliferative (p63+) cytotrophoblast per villous area with increasing gestational age, similar to placentas obtained from the nonhypertensive patient cohort; however, PE placentas with fetal vascular malperfusion or villitis of unknown etiology lost this phenotype. This is mainly because of cases of fetal vascular malperfusion in placentas of patients with preterm PE and villitis of unknown etiology in placentas of patients with term PE, which are associated with a decrease or increase, respectively, in the cytotrophoblast per villous area. Finally, a transcriptomic analysis identified pathways associated with hypoxia, inflammation, and reduced cell proliferation in PE-MVM placentas and further subclassified this group into extravillous trophoblast-high and extravillous trophoblast-low PE, confirmed using an immunohistochemical analysis of trophoblast lineage-specific markers. Our findings suggest that within specific histopathologic patterns of placental injury, PE can be subclassified based on specific cellular and molecular defects, allowing the identification of pathways that may be targeted for diagnostic and therapeutic purposes.

Placental fetal vascular malperfusion, neonatal neurologic morbidity, and infant neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the association of placental fetal vascular malperfusion lesions with neonatal brain injury and adverse infant neurodevelopmental outcomes. DATA SOURCES: PubMed and Medline, Scopus, and Cochrane databases were searched from inception to July 2022. STUDY ELIGIBILITY CRITERIA: We included cohort and case-control studies reporting the associations of fetal vascular malperfusion lesions with neonatal encephalopathy, perinatal stroke, intracranial hemorrhage, periventricular leukomalacia, and infant neurodevelopmental and cognitive outcomes. METHODS: Data were analyzed by including fetal vascular malperfusion lesions as an exposure variable and brain injuries or neurodevelopmental impairment as outcomes using random-effects models. The effect of moderators, such as gestational age or study type, was assessed by subgroup analysis. Study quality and risk of bias were assessed by applying the Observational Study Quality Evaluation method. RESULTS: Out of the 1115 identified articles, 26 were selected for quantitative analysis. The rates of neonatal central nervous system injury (neonatal encephalopathy or perinatal stroke) in term or near-term infants were more common among fetal vascular malperfusion cases (n=145) than among controls (n=1623) (odds ratio, 4.00; 95% confidence interval, 2.72-5.90). In premature deliveries, fetal vascular malperfusion lesions did not influence the risk of intracranial hemorrhage or periventricular leukomalacia (odds ratio, 1.40; 95% confidence interval, 0.90-2.18). Fetal vascular malperfusion-associated risk of abnormal infant neurodevelopmental outcome (314 fetal vascular malperfusion cases and 1329 controls) was modulated by gestational age being higher in term infants (odds ratio, 5.02; 95% confidence interval, 1.59-15.91) than in preterm infants (odds ratio, 1.70; 95% confidence interval, 1.13-2.56). Abnormal infant cognitive development and mental development were more common among fetal vascular malperfusion cases (n=241) than among controls (n=2477) (odds ratio, 2.14; 95% confidence interval, 1.40-3.27). The type of study (cohort vs case-control) did not influence the association between fetal vascular malperfusion and subsequent infant brain injury or abnormal neurodevelopmental outcome. CONCLUSION: The findings of cohort and case-control studies indicate a considerable association between fetal vascular malperfusion placental lesions and increased risk of brain injury in term neonates, and neurodevelopmental impairment in both term and preterm infants. A diagnosis of placental fetal vascular malperfusion should be taken into consideration by both pediatricians and neurologists during the follow-up of infants at risk of adverse neurodevelopmental outcomes.

Placental delayed villous maturation is associated with fetal congenital heart disease.

BACKGROUND: The placenta is crucial for the overall development and lifelong health of the fetus. Abnormal placental development and function occur in pregnancies with fetal congenital heart disease. However, studies that use standardized diagnostic criteria and incorporate control populations are lacking. This limits the generalizability of current research and the ability to determine the specific placental abnormalities associated with congenital heart disease. OBJECTIVE: This study applied consensus statement guidelines (known as the Amsterdam criteria) for placental pathology interpretation to compare the frequency and pattern of abnormalities in pregnancies with fetal congenital heart disease to demographically matched control pregnancies and evaluate for differences in placental abnormalities by cardiac physiology. STUDY DESIGN: A single-center retrospective cohort study was conducted from January 2013 to June 2019. Infants with a prenatal diagnosis of moderate-severe congenital heart disease who were born at ≥37 weeks of gestation were included. A control group born at ≥37 weeks of gestation but without fetal congenital heart disease or other major pregnancy complications was matched to the congenital heart disease group on maternal race and ethnicity and infant sex. Using the Amsterdam criteria, placental pathology findings were categorized as delayed villous maturation, maternal vascular malperfusion, fetal vascular malperfusion, and inflammatory lesions. The frequency of placental abnormalities was compared between groups, and logistic regression was performed to evaluate the association of clinical and sociodemographic factors with delayed villous maturation, maternal vascular malperfusion, and fetal vascular malperfusion. RESULTS: There were 194 pregnancies with fetal congenital heart disease and 105 controls included, of whom 83% in the congenital heart disease group and 82% in the control group were of non-Hispanic White race and ethnicity. Compared with controls, pregnancies with fetal congenital heart disease had higher rates of delayed villous maturation (6% vs 19%; P<.001) and maternal vascular malperfusion (19% vs 34%; P=.007) but not fetal vascular malperfusion (6% vs 10%; P=.23). Infants with congenital heart disease with 2-ventricle anatomy displayed the highest odds of delayed villous maturation compared with controls (odds ratio, 5.5; 95% confidence interval, 2.2-15.7; P<.01). Maternal vascular malperfusion was 2.2 times higher (P=.02) for infants with 2-ventricle anatomy and 2.9 times higher (P=.02) for infants with single-ventricle physiology with pulmonic obstruction. Within the congenital heart disease group, delayed villous maturation was associated with higher maternal body mass index, polyhydramnios, larger infant birth head circumference, and infant respiratory support in the delivery room, whereas maternal vascular malperfusion was associated with oligohydramnios. In multivariable models adjusting for cardiac diagnosis, associations of delayed villous maturation persisted for infant birth head circumference (odds ratio, 1.2; 95% confidence interval, 1.0-1.5; P=.02) and infant respiratory support in the delivery room (odds ratio, 3.0; 95% confidence interval, 1.3-6.5; P=.007). CONCLUSION: Pregnancies with fetal congenital heart disease displayed higher rates of delayed villous maturation and maternal vascular malperfusion than controls, suggesting that placental maldevelopment may relate to maternal factors. Future investigations are needed to determine the association of these abnormalities with postnatal infant outcomes.

Placental pathology is necessary to understand common pregnancy complications and achieve an improved taxonomy of obstetrical disease.

The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants.

Anatomy of the Ductus Arteriosus in Fetal Autopsies: Correlations With Placental Pathology and Cause of Death.

BACKGROUND: Differences in the shape of the ductus arteriosus (DA), an important vascular shunt between the pulmonary artery and aorta, may reflect fetoplacental blood flow. Our aim was to examine tapering of the DA in a fetal autopsy population and correlate it with placental pathology and cause of death (COD). METHODS: This autopsy case control study of stillborn fetuses selected cases (tapered DA) and consecutive age-matched controls (no DA tapering) between January 2017 and January 2022. We abstracted demographic and clinical data from pathology reports. Autopsy data included COD and histologic evidence of fetal hypoxia. Placental pathology included umbilical cord abnormalities, acute and chronic inflammation, fetal vascular malperfusion (FVM), and maternal vascular malperfusion (MVM). RESULTS: We identified 50 cases and 50 controls. Gestational age ranged from 18 to 38 weeks. Maternal and fetal demographic characteristics did not differ significantly between cases and controls. COD related to an umbilical cord accident/FVM was significantly more prevalent in cases vs controls (46% vs 26%, P = .037), and FVM in the placenta, regardless of COD, trended higher in cases than controls. CONCLUSION: Tapering of the DA is present in stillborn fetuses and associated with COD related to fetal vascular blood flow obstruction.

Histopathologic Findings in Large for Gestational Age Placentas and Correlation With CD15 Immunohistochemistry.

BACKGROUND: The histopathology and CD15 expression in large for gestational age (LGA) placentas is not well-documented. METHODS: To analyze this, we utilized 2 separate cohorts of placentas from singleton term deliveries. LGA and appropriate for gestational age (AGA) placentas were compared for major histopathologies including acute and chronic inflammation, maternal and fetal vascular malperfusion, delayed villous maturation (DVM), and villous hypervascularity/chorangiosis. We also examined CD15 immunohistochemistry in LGA and AGA placentas. Stained slides were reviewed blinded to the placental weight. Five random 20× fields were scored semi-quantitatively for CD15 staining of villous capillaries on a scale of 0 to 5 (0 = 0%, 1 = 1%-5%, 2 = 5%-25%, 3 = 25%-50%, 4 = 50%-75%, and 5 = >75%). RESULTS: In 1 cohort, 1238 LGA and 7908 AGA placentas were identified. Patients with LGA placentas were significantly more likely to have higher birthweight babies, obesity, hypertensive disorders, pre-gestational, and gestational diabetes. Also, LGA placentas had a higher prevalence of fetal vascular malperfusion, DVM, and villous chorangiosis. In other cohort of 75 LGA placentas and 73 AGA controls, the average score of CD15 staining in villous capillaries was significantly higher amongst LGA placentas. CONCLUSION: We conclude that LGA placentas have increased expression of CD15 in villous capillary endothelium and higher prevalence of FVM, DVM, and villous chorangiosis than AGA placentas.

Patterns of placental injury in various types of fetal congenital heart disease.

OBJECTIVES: Fetal blood circulation may be modified in congenital heart disease (CHD). This retrospective analysis was performed to study whether the type of CHD is associated with specific placental pathology. METHODS: Three types of CHD based on presumed proportion of placental and systemic blood distribution in fetal circulation were analyzed: Group 1: 89 cases with low placental blood content (hypoplastic left heart syndrome, transposition of great arteries, coarctation of aorta), Group 2: 71 placentas with intermediate placental and systemic blood content due to increased intracardiac blood mixing (tetralogy of Fallot, truncus arteriosus, double inlet/outlet ventricle), and Group 3: 24 placentas with high placental blood content (tricuspid or pulmonary atresia, Ebstein anomaly). Frequencies of 27 independent clinical and 47 placental phenotypes of 184 placentas in those three groups were statistically compared. RESULTS: The most advanced gestational age at delivery, and large vessel (global) fetal vascular malperfusion (FVM) were most common in Group 1, while macerated stillbirths, neonatal mortality, abnormal amniotic fluid volume (oligohydramnios or polyhydramnios), other congenital anomalies, distal villous lesions of FVM, placental edema and amnion nodosum were most common in Groups 2 and 3, although the frequencies of placental lesions were statistically not significant. CONCLUSIONS: Left heart obstructive lesions potentially associated with brain maldevelopment show increase in lesions of global FVM (in aggregate and individually fetal vascular ectasia, stem vessel obliteration and intramural fibrin deposition) as may be seen in umbilical cord compromise. CHD with increased intracardiac blood mixing or with right heart defects is associated with average preterm gestational age at delivery and placental lesions of distal villous FVM, villous edema and amnion nodosum.

The Placenta and Neonatal Encephalopathy with a Focus on Hypoxic-Ischemic Encephalopathy.

Background: Placental examination is important for its diagnostic immediacy to correlate with maternal and/or fetal complications and parturitional difficulties. In a broader context, clinicopathologic studies of the placenta have addressed a range of pathogenetic questions that have led to conclusive and inconclusive results and interpretations. Methods: Recent standardized morphologic criteria and terminology of placental lesions have facilitated the ability to compare findings from studies that have focused on complications and outcomes of pregnancy. This review is an evaluation of recent studies on placental lesions associated with hypoxic-ischemic encephalopathy (HIE). Conclusion: No apparent consensus exists on whether it is fetal inflammation with the release of cytokines or chronic maternal and/or fetal vascular malperfusion is responsible for HIE with a lowering of the threshold for hypoxic ischemia. The counter argument is that HIE occurs solely as an intrapartum event. Additional investigation is necessary.

Recurrent Second Trimester Fetal Demise Caused by Hypercoiled Umbilical Cords.

BACKGROUND: Umbilical cord flow impairment accounts for a majority of fetal vascular malperfusion (FVM). Hypercoiled umbilical cords are one cause of impaired fetal blood flow that may, in severe cases, result in intrauterine fetal demise (IUFD). Although the factors involved in umbilical cord patterning are incompletely understood, a limited number of reports have described recurrent intra-familial hypercoiling leading to death in the second trimester, suggesting a subset may have a genetic etiology. CASE REPORTS: Herein, we report two additional cases of recurrent second trimester IUFD secondary to FVM due to umbilical cord hypercoiling and briefly discuss all published cases. CONCLUSION: Our cases add to a small, but growing, body of literature that suggests a genetic etiology to a subset of hypercoiled umbilical cords.

The effect of endometriosis on placental histopathology and perinatal outcome in singleton live births resulting from IVF.

RESEARCH QUESTION: Does endometriosis have an effect on the placental histopathology pattern and perinatal outcome in singleton live births resulting from IVF treatment? DESIGN: Retrospective cohort study evaluating the data on all live births following IVF treatment between 2009 and 2017 at one university-affiliated tertiary hospital. All patients had placentas sent for full gross and histopathology assessment, irrespective of complication status or delivery mode. The primary outcomes of the study included anatomical, inflammation, vascular malperfusion and villous maturation placental disorders. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate logistic model was used to adjust the results for confounding factors potentially associated with significant placental characteristics. RESULTS: A total of 1057 live births were included in the final analysis and were allocated to the group of women with endometriosis (n = 75) and those without (n = 982). After adjustment for confounding factors, endometriosis was found to be significantly associated with acute chorioamnionitis with moderate to severe maternal (odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.1-4.6) and fetal (OR 4.9, 95% CI 1.8-13.1) inflammatory response, placenta previa (OR 3.1, 95% CI 1.2-7.8), subchorionic fibrin deposition (OR 3.4, 95% CI 1.2-9.1), intervillous thrombosis (OR 3.4, 95% CI 1.5-8.1), and fetal vascular malperfusion (OR 5.1, 95% CI 1.4-18.1), as well as with preterm birth (OR 2.5, 95% CI 1.4-4.7). CONCLUSIONS: Endometriosis has a significant impact on the placental histopathology and is associated with a higher incidence of preterm birth.

Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction.

BACKGROUND: Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined. OBJECTIVE: To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes. STUDY DESIGN: A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded. RESULTS: A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death. CONCLUSION: Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

A comprehensive analysis of the association between placental pathology and recurrent preterm birth.

BACKGROUND: Histologic examination of the placenta is often performed after preterm birth. Although placental examination cannot change the index pregnancy outcome, it may inform the risk of adverse outcomes in a subsequent pregnancy. Previous research has examined the association between individual histologic lesions and pregnancy outcomes without consistent results. OBJECTIVE: This study aimed to determine the independent contributions of the major placental pathology histologic types to recurrent preterm birth. STUDY DESIGN: This was a retrospective cohort study of deliveries at a tertiary care center from January 2009 to March 2018. Individuals with ≥2 births, an index birth of <37 weeks of gestation, and a placental pathology report from the index pregnancy were included. The presence of maternal vascular malperfusion, fetal vascular malperfusion, acute inflammation, and chronic inflammation was extracted from the pathology reports for each index placenta and classified as none, low grade, or high grade. A log-binomial model incorporating all 4 placental pathology histologic types, index gestational age, race, and maternal age was used to estimate the associations between each placental histologic type and risk of recurrent preterm birth. Moreover, 2-way interaction terms were studied among placental histologic types. In addition, 2 stratified analyses were completed on the basis of characteristics of the index preterm birth: (1) by late preterm (gestational age of 34-36 weeks) vs early-to-moderate preterm birth (<34 weeks) and (2) a subgroup analysis of those with spontaneous preterm birth. RESULTS: A total of 924 pregnancy pairs met the inclusion criteria. Only high-grade chronic inflammation was independently associated with an increased risk of recurrent preterm birth (adjusted risk ratio, 1.37; 95% confidence interval, 1.03-1.81). Stratified analysis by gestational age group demonstrated maternal vascular malperfusion was associated with recurrent preterm birth only among those with early preterm birth (adjusted risk ratio, 1.40; 95% confidence interval, 1.01-1.93). Among participants with spontaneous preterm labor, no association was found between pathology histologic types and risk of preterm birth. CONCLUSION: Among index preterm pregnancies, high-grade chronic placental inflammation was associated with recurrent preterm birth. Low-grade maternal vascular malperfusion was associated with recurrent preterm birth only among those with an early or moderate index preterm birth (<34 weeks of gestation). These findings may be useful in determining the risk profile for individual patients and may generate hypotheses as to the pathogenesis of recurrent preterm birth.

High-Grade Fetal Vascular Malperfusion Is Associated With Diffuse Chorionic Hemosiderosis.

INTRODUCTION: Diffuse chorionic hemosiderosis (DCH) is an abnormality of the placental membranes characterized by the deposition of iron pigment. It is usually secondary to recurrent venous bleeding in early pregnancy. In many papers, it is associated with pre-term delivery. Fetal vascular malperfusion (FVM) is an abnormality of the feto-placental circulation that may be seen at any stage of gestation, but most often in the third trimester. It may be graded as low grade (LGFVM) or high grade (HGFVM). No link has been identified in the placental literature between DCH and FVM, but we have noted the 2 co-existing in placentas submitted for analysis. This study explored a possible association of these 2 entities. METHODS: Laboratory records were searched for singleton cases coded as DCH based on diagnosis on H&E stain over a 6-year period. Of 4478 placentas reported, 66 cases were coded as DCH (1.5%). These were classified as showing HGFVM, LGFVM, or no FVM. Controls (n = 132) were gestational age-matched cases without DCH. Cord length, coiling, insertion, or other abnormalities were noted. Membranes were classified as normal or circumvallate. Results were analyzed using Graphpad. RESULTS: Gestation ranged between 16 and 41 weeks gestation. 14/66 (21%) cases of DCH showed HGFVM and 2/66 (3%) showed LGFVM. 16/132 (12%) controls showed HGFVM and 21/132 (15.9%) had LGFVM. Where FVM is present, high-grade FVM is significantly associated with DCH versus controls (P < .0031 Fischer's Test). DISCUSSION: HGFVM occurs significantly more often in placentas with DCH than in controls. Both FVM and DCH are associated with adverse perinatal outcomes, and a possible relationship between the 2 remains to be clarified.

Fetal Vascular Ectasia Can be an Artifact of Placental Fixation.

BACKGROUND: Placentas from outlying hospitals are formalin-fixed en route to our laboratory. We identified that chorionic, stem villus, and umbilical vessels in these fixed placentas are ectatic with greater frequency than in our in-house fresh placentas. METHODS: We searched our LIS for third trimester placentas using keywords "ectasia" or "ectatic" over a 12-month period. We fixed incoming in-house placentas over a 2-week period for 24-72 hours and tabulated the presence or absence of vascular ectasia as defined by Parast et al, 2008. RESULTS: The LIS search identified 61% of placental cases from outlying hospitals that had ectatic vessels vs 3% of in-house placentas (P < .001). Of 38 placentas fixed in a 2-week period, 45% had ectatic chorionic or stem villus vessels and 21% had umbilical vessel ectasia. In comparison, in the 2 subsequent weeks, 3.8% (P < .001) of fresh placentas had vascular ectasia. CONCLUSION: These data suggest that large fetal vessels in the placenta become engorged with blood at delivery and, if fixed soon after delivery, remain ectatic and congested when processed for pathology. The identification of artifactual ectasia is important because fetal vessel ectasia can suggest the presence of fetal vascular malperfusion (FVM) if diagnostic signs of FVM are present.