Impact of villitis of unknown etiology and adverse acute neonatal outcomes in Eastern Ontario.

INTRODUCTION: Villitis of unknown etiology (VUE) is a histopathological lesion associated with adverse neonatal outcomes. We seek to define the obscure relationship between the severity and distribution of VUE and adverse neonatal outcomes. METHODS: A retrospective chart review was conducted of pathologic findings from singleton placentas diagnosed with VUE between 2013 and 2019. Control placentas were matched 1:1 for gestational age and presence/absence of fetal IUGR. Neonatal outcomes of interest included: newborn resuscitation, NICU admission, Apgar scores and cord blood acidosis. Odds ratio and 95 % confidence intervals were calculated with controls as the reference. RESULTS: 452 placentas were included. 35 % of pregnancies were complicated by IUGR. When analyzed by severity (low-grade: OR = 4.75 [2.86-8.14]; high-grade: OR = 4.76 [2.71-8.79]) and distribution (focal: OR = 5.24 [2.87-10.17]; multifocal: OR = 4.90 [2.90-8.59]), VUE was significantly associated with need for newborn resuscitation. No other neonatal outcomes of interest were significantly associated with VUE diagnosis. DISCUSSION: We determined a statistically significant association between VUE severity and distribution and the need for newborn resuscitation. VUE lesions were not associated with any additional neonatal outcomes of interest. Further studies with larger sample sizes are required to confirm these associations for obstetric and neonatal case management.

Placental Pathology and Pregnancy Complications.

Placental pathology assessment following delivery provides an opportunity to identify the presence and type of disease that can mediate major obstetrical complications, especially in cases where the fetus is growth-restricted, born premature, or stillborn, or if the mother suffers from severe hypertensive morbidities [...].

Synoptic Reporting in Clinical Placental Pathology: A Preliminary Investigation Into Report Findings and Interobserver Agreement.

INTRODUCTION: Placental pathology is key for investigating adverse pregnancy outcomes, however, lack of standardization in reporting has limited clinical utility. We evaluated a novel placental pathology synoptic report, comparing its robustness to narrative reports, and assessed interobserver agreement. METHODS: 100 singleton placentas were included. Histology slides were examined by 2 senior perinatal pathologists and 2 pathology residents using a synoptic report (32 lesions). Historical narrative reports were compared to synoptic reports. Kappa scores were calculated for interobserver agreement between senior, resident, and senior vs resident pathologists. RESULTS: Synoptic reporting detected 169 (51.4%) lesion instances initially not included in historical reports. Amongst senior pathologists, 64% of all lesions examined demonstrated fair-to-excellent agreement (Kappa ≥0.41), with only 26% of Kappas ≥0.41 amongst those examined by resident pathologists. Well-characterized lesions (e.g., chorioamnionitis) demonstrated higher agreement, with lower agreement for uncommon lesions and those previously shown to have poor consensus. DISCUSSION: Synoptic reporting is one proposed method to address issues in placenta pathology reporting. The synoptic report generally identifies more lesions compared to the narrative report, however clinical significance remains unclear. Interobserver agreement is likely related to differential in experience. Further efforts to improve overall standardization of placenta pathology reporting are needed.

Establishing normal ranges for fetal and neonatal small and large intestinal lengths: results from a prospective postmortem study.

Objective: To establish reference intervals (RIs) for fetal and neonatal small and large intestinal lengths. Methods: Linear measurements on small and large intestines were made upon postmortem examination of 131 preterm and term infants with gestational ages between 13 and 41 weeks. All cases were referred from the Eastern Ontario and Western Québec regions to a tertiary care hospital. Age and sex partitions were considered and RI limits were estimated. Results: Data consisted of 72 male (54.96%) and 59 female (45.04%) fetuses and neonates with mean gestational age of 25.6 weeks. Results showed that small and large intestinal lengths increased linearly with gestational age. RIs for small intestinal length (cm) of fetuses and neonates aged 13-20 weeks were (21.1, 122.4); of those aged 21-28 weeks were (57.7, 203.8); of those aged 29-36 weeks were (83.6, 337.1); and of those aged 37-41 weeks were (132.8, 406.4). RIs for large intestinal length (cm) of fetuses and neonates from the same four age groups were (5.1, 21.4), (12.7, 39.7), (32.4, 62.4), and (29.1, 82.2). Conclusions: Establishing accurate RIs for premature and term infants has clinical relevance for pathologists performing postmortem analysis and for surgeons planning postoperative management of patients. The results of this study reaffirm that fetal small and large intestinal lengths increase linearly with gestational age irrespective of sex. Future studies should aim to further investigate the role of possible confounders on growth of fetal intestinal length, including maternal factors such as age and substance use during pregnancy.

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Acute chorioamnionitis in pregnancies complicated by placental abruption and short-term neonatal outcomes: A retrospective cohort study.

We examined neonatal outcomes in pregnancies complicated by placental abruption (PA) and acute chorioamnionitis (CA). Exposure was acute CA; primary outcome - fetal death; secondary outcomes - adverse Apgar score, neonatal intensive care unit (NICU) admission, and cardiac depression. 267 placentas - 18.4% exhibited acute CA. PA pregnancies with CA - 29% experienced fetal death. Funisitis, acute CA and adverse neonatal outcomes are dependent. Without accounting for funisitis, aforementioned findings hold, though effect sizes are smaller. PA, acute CA with funisitis could affect fetal death and NICU admission. Acute CA and PA alone could impact fetal death and adverse Apgar scores.

Association of distinct features of villitis of unknown etiology histopathology and fetal growth restriction diagnosis in a retrospective cohort from Eastern Ontario.

INTRODUCTION: Villitis of unknown etiology (VUE) is associated with fetal growth restriction (FGR) and adverse short-term neonatal outcomes. No investigation to date has found which VUE features are driving the association with FGR diagnosis. METHODS: A retrospective cohort study of placenta pathology specimens (2013-2017) was conducted. Independent variables of interest were: VUE distribution (focal vs diffuse), location (basal vs non-basal), and grade (high vs low). The primary outcome was FGR, and secondary outcomes were neonatal intensive care unit (NICU) admission, NICU length of stay, Apgar scores <7 at 1, 5, and 10-min, and recurrence rate of villitis in subsequent pregnancies. Association between VUE characteristics and our primary outcome were investigated using logistic regression. Secondary outcomes were explored with regression analyses and recurrence rate of VUE for members of the cohort with a recorded subsequent pregnancy was calculated. RESULTS: One hundred and twenty seven placentas were included. Adjusted models showed no difference in the odds of FGR between high-grade versus low-grade VUE [aOR 1.25 95% CI (0.50, 3.26), p = 0.6], focal/multi-focal vs diffuse cases [aOR 1.03 95% CI (0.28, 4.34), p = >0.9], and basal vs non-basal VUE [aOR 0.06 95% CI (0.00, 1.10), p = 0.058]. After adjusting for prematurity <37 weeks, there were lower odds of NICU admission in basal vs non-basal cases [aOR 0.25, 95% CI (0.06, 0.90), p = 0.048). There was no difference in the odds of neonates presenting with Apgar <7 for the distinct VUE histopathology features. Three cases had recurrent VUE, resulting in a 6.8% [95% CI (3.02%, 10.61%)] recurrence rate. All recurrent cases were high-grade and identified with basal localization. DISCUSSION: There are no statistical associations between distinct VUE features and FGR diagnosis, however location of villitis may be associated with worse neonatal outcomes. Villitis of any type (severity, degree, location) could potentially drive insufficient placental function and poor fetal growth.

Peri-Operative Liver Fibrosis and Native Liver Survival in Pediatric Patients with Biliary Atresia: A Systematic Review and Meta-Analysis.

No systematic review to date has examined histopathological parameters in relation to native liver survival in children who undergo the Kasai operation for biliary atresia (BA). A systematic review and meta-analysis is presented, comparing the frequency of native liver survival in peri-operative severe vs. non-severe liver fibrosis cases, in addition to other reported histopathology parameters. Records were sourced from MEDLINE, Embase, and CENTRAL databases. Studies followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and compared native liver survival frequencies in pediatric patients with evidence of severe vs. non-severe liver fibrosis, bile duct proliferation, cholestasis, lobular inflammation, portal inflammation, and giant cell transformation on peri-operative biopsies. The primary outcome was the frequency of native liver survival. A random effects meta-analysis was used. Twenty-eight observational studies were included, 1,171 pediatric patients with BA of whom 631 survived with their native liver. Lower odds of native liver survival in the severe liver fibrosis vs. non-severe liver fibrosis groups were reported (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.08-0.33; I2 =46%). No difference in the odds of native liver survival in the severe bile duct destruction vs. non-severe bile duct destruction groups were reported (OR, 0.17; 95% CI, 0.00-63.63; I2 =96%). Lower odds of native liver survival were documented in the severe cholestasis vs. non-severe cholestasis (OR, 0.10; 95% CI, 0.01-0.73; I2 =80%) and severe lobular inflammation vs. non-severe lobular inflammation groups (OR, 0.02; 95% CI, 0.00-0.62; I2 =69%). There was no difference in the odds of native liver survival in the severe portal inflammation vs. non-severe portal inflammation groups (OR, 0.03; 95% CI, 0.00-3.22; I2 =86%) or between the severe giant cell transformation vs. non-severe giant cell transformation groups (OR, 0.15; 95% CI, 0.00-175.21; I2 =94%). The meta-analysis loosely suggests that the presence of severe liver fibrosis, cholestasis, and lobular inflammation are associated with lower odds of native liver survival in pediatric patients after Kasai.

Workload Measurement in Subspecialty Placental Pathology in Canada.

BACKGROUND: Workload measurement is important to help determine optimal staffing and workload distribution for pathology laboratories. The Level 4 Equivalent (L4E) System is the most widely used Anatomical Pathology (AP) workload measurement tool in Canada. However, it was initially not developed with subspecialties in mind. METHODS: In 2016, a Pan-Canadian Pediatric-Perinatal Pathology Workload Committee (PCPPPWC) was organized to adapt the L4E System to assess Pediatric-Perinatal Pathology workload. Four working groups were formed. The Placental Pathology Working Group was tasked to develop a scheme for fair valuation of placental specimens signed out by subspecialists in the context of the L4E System. Previous experience, informal time and motion studies, a survey of Canadian Pediatric-Perinatal Pathologists, and interviews of Pathologists' Assistants (PA) informed the development of such scheme. RESULTS: A workload measurement scheme with average L4E workload values for examination and reporting of singleton and multiple gestation placentas was proposed. The proposal was approved by the Canadian Association of Pathologist - Association canadienne des pathologistes Workload and Human Resources Committee for adoption into the L4E System. CONCLUSION: The development of a workload measurement model for placental specimens provides an average and fair valuation of these specimen types, enabling its use for resource planning and workload distribution.

An unusual case of pediatric embryonal rhabdomyosarcoma with subsequent diagnosis of neurofibromatosis type 1.

A 10-month-old girl presented with a 4-month history of a rapidly growing lesion on the lower lip. Initial assessment and Doppler ultrasound supported a diagnosis of pyogenic granuloma. However, emergent biopsy revealed an embryonal rhabdomyosarcoma, a highly malignant tumor commonly associated with cancer-susceptible syndromes including neurofibromatosis type 1 (NF1). Despite having no apparent clinical features of NF1 at initial presentation, she was later found to have multiple café-au-lait spots and a subsequent diagnosis of NF1 was made.

Evaluating the Prognostic Implication of the Collins Histology Scoring System in a Pediatric Eastern Ontario Population With Eosinophilic Esophagitis.

INTRODUCTION: Collins et al developed a histology scoring system (EoE HSS) to assess multiple pathologic features. The aim of this study is to identify if the EoE HSS can better detect endoscopic and symptom improvement vs the Peak Eosinophilic Count (PEC). METHODS: A retrospective chart review was performed for patients during 2014-2016. All patients ≤18 years old with a diagnosis of EoE and whose records included initial and follow-up upper gastrointestinal endoscopies were included. Severity and extent of endoscopic features were scored using 8 parameters, from normal to maximum change for each location of the esophageal biopsy. RESULTS: Forty patients with EoE were included in the study, of which 35 (87.5%) patients demonstrated symptom and 25 (62.5%) endoscopic improvement at the time of follow-up. In the proximal esophagus, the EoE HSS outperformed the change in eosinophil count of the Children's Hospital of Eastern Ontario (CHEO) practice in predicting endoscopic improvement by 16.8% when examining the change in grade and 17.1% when examining the change in stage scores. CONCLUSIONS: At our institution, adoption of the EoE HSS in assessing biopsies of EoE patients might be warranted, compared to the traditional practice. However, a bigger sample size may give a more robust difference in all locations.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Porokeratotic eccrine ostial and dermal duct nevus associated with an 11 megabase 3p deletion.

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare eccrine hamartoma; the etiology is incompletely understood. A patient presented with congenital, widespread PEODDN. Clinical assessment, histopathologic, cytogenetic, and molecular genetic investigations on affected cells were pursued. Histopathology confirmed PEODDN, and chromosomal microarray on affected tissues identified a mosaic 3p26.3p25.3 deletion in affected tissues. This 11Mb deletion encompasses 47 OMIM genes. We propose that this and other chromosomal deletions may be implicated in some cases of PEODDN, suggesting locus heterogeneity and underscoring the importance of incorporating cytogenetic and molecular investigations into the multidisciplinary care of individuals with suspected mosaic genetic skin disorders.

The Association of Placental Abruption and Pediatric Neurological Outcome: A Systematic Review and Meta-Analysis.

Placental histopathology provides insights, or "snapshots", into relevant antenatal factors that could elevate the risk of perinatal brain injury. We present a systematic review and meta-analysis comparing frequencies of adverse neurological outcomes in infants born to women with placental abruption versus without abruption. Records were sourced from MEDLINE, Embase, and the CENTRAL Trials Registry from 1946 to December 2019. Studies followed the PRISMA guidelines and compared frequencies of neurodevelopmental morbidities in infants born to pregnant women with placental abruption (exposure) versus women without placental abruption (comparator). The primary endpoint was cerebral palsy. Periventricular and intraventricular (both severe and any grades of IVH) and any histopathological neuronal damage were the secondary endpoints. Study methodologic quality was assessed by the Ottawa-Newcastle scale. Estimated odds ratios (OR) and hazards ratio (HR) were derived according to study design. Data were meta-analyzed using a random effects model expressed as pooled effect sizes and 95% confidence intervals. We included eight observational studies in the review, including 1245 infants born to women with placental abruption. Results of the random effects meta-analysis show that the odds of infants born to pregnant women with placental abruption who experience cerebral palsy is higher than in infants born to pregnant women without placental abruption (OR 5.71 95% CI (1.17, 27.91); I2 = 84.0%). There is no statistical difference in the odds of infants born to pregnant women with placental abruption who experience severe IVH (grade 3+) (OR 1.20 95% CI (0.46, 3.11); I2 = 35.8%) and any grade of IVH (OR 1.20 95% CI (0.62, 2.32); I2 = 32.3%) vs. women without placental abruption. There is no statistically significant difference in the odds of infants born to pregnant women with placental abruption who experience PVL vs. pregnant women without placental abruption (OR 6.51 95% CI (0.94, 45.16); I2 = 0.0%). Despite our meta-analysis suggesting increased odds of cerebral palsy in infants born to pregnant women with placental abruption versus without abruption, this finding should be interpreted cautiously, given high heterogeneity and overall poor quality of the included studies.

Impact of Co-Existing Placental Pathologies in Pregnancies Complicated by Placental Abruption and Acute Neonatal Outcomes.

Placental abruption (PA) is a concern for maternal and neonatal morbidity. Adverse neonatal outcomes in the setting of PA include higher risk of prematurity. Placental pathologies include maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), acute chorioamnionitis, and villitis of unknown etiology (VUE). We aimed to investigate how placental pathology contributes to acute neonatal outcome in PA. A retrospective cohort study of all placentas with PA were identified. Exposures were MVM, FVM, acute chorioamnionitis and VUE. The primary outcome was NICU admission and the secondary outcomes included adverse base deficit and Apgar scores, need for resuscitation, and small-for-gestational age. A total of 287 placentas were identified. There were 160 (59.9%) of placentas with PA alone vs 107 (40.1%) with PA and additional placental pathologies. Odds of NICU admission were more than two times higher in pregnancies with placental pathologies (OR = 2.37, 95% CI 1.28-4.52). These estimates were in large part mediated by prematurity and birthweight, indirect effect acting through prematurity was OR 1.79 (95% CI 1.12-2.75) and through birthweight OR 2.12 (95% CI 1.40-3.18). Odds of Apgar score ≤ 5 was more than four times higher among pregnancies with placental pathologies (OR = 4.56, 95% CI 1.28-21.26). Coexisting placental pathology may impact Apgar scores in pregnancies complicated by PA. This knowledge could be used by neonatal teams to mobilize resources in anticipation of the need for neonatal resuscitation.

Pandemic stress and SARS-CoV-2 infection are associated with pathological changes at the maternal-fetal interface.

INTRODUCTION: The reported effects of SARS-CoV-2 on pregnancy outcomes are conflicting; studies frequently overlook the placenta, which is critical for the health of the mother and infant(s). This study aimed to determine the effect of pandemic stress ± SARS CoV-2 infection on placental histopathology. METHODS: Women were recruited in Canada (n = 69); France (n = 21) or in the UK (n = 25), between March and October 2020. Historic controls (N = 20) were also included. Placenta and fetal membrane samples were collected rapidly after delivery and were fixed and stained for histopathological analysis. Maternal demographical data and obstetric outcomes were recorded. RESULTS: Over 80% of the placentas from SARS-CoV-2+ pregnancies had histopathological abnormalities: predominantly structural (71-86%) or inflammatory (9-22%), depending on geographical location. Excessive fibrin was seen in all sites, whereas deciduitis (Canada), calcifications (UK), agglutinations and chorangiosis (France) predominated in different locations. The frequency of abnormalities was significantly higher than in SARS-CoV-2 negative women (50%, p < 0.05). Demographic and obstetric data were similar in the SARS-CoV-2+ women across all sites - characterised by predominantly Black/Middle Eastern women, and women with elevated body mass index. DISCUSSION: Overall, the frequency of placental abnormalities is increased in SARS-CoV-2+ women, but the incidence of placental abnormalities is also higher in SARS-CoV-2- women that gave birth during the pandemic, which highlights the importance of appropriate control groups to ascertain the roles of pandemic stress and SARS-CoV-2 infection on the placenta and pregnancy outcomes.

Examining the Relationship Between Gastroschisis and Placental Fetal Vascular Malperfusion.

INTRODUCTION: Gastroschisis is a congenital malformation characterized by intestinal herniation through an abdominal wall defect. Despite its unknown pathogenesis, known risk factors include maternal smoking, alcohol use, and young maternal age. Previous work has shown that gastroschisis is associated with placental delayed villous maturation, and the goal of this study was to assess for additional associated placental pathologies that may help clarify the pathogenesis of gastroschisis. METHODS: We conducted a retrospective slide review of 29 placentas of neonates with gastroschisis. Additionally, we reviewed pathology reports from one control group of 30 placentas with other congenital malformations. Gross and histological data were collected based on a standardized rubric. RESULTS: Gastroschisis was associated with increased placental fetal vascular malperfusion (FVM) in 62% of cases (versus 0% of controls, p < 0.0001). It was also associated with increased placental villous maldevelopment in 76% of cases (versus 3% of controls, p < 0.0001). CONCLUSION: Our study demonstrates an association between gastroschisis and FVM. While FVM could be the consequence of vascular disruption due to the ventral location of gastroschisis, it could also reflect estrogen-induced thrombosis in early pregnancy. Further research is needed to separate these possibilities and determine the cause of the placental FVM observed in gastroschisis.

Placenta pathology in recipient versus donor oocyte derivation for in vitro fertilization in a setting of hypertensive disorders of pregnancy and IUGR.

INTRODUCTION: Assisted reproductive technology including in vitro fertilization (IVF) and oocyte donation (OD) may increase risk for placenta-mediated diseases. Comprehensive analysis of histopathological placental lesions according to source of oocytes used in the IVF procedure - recipient derived (RD-IVF) vs oocyte donation (OD-IVF), has not been conducted in a population with a hypertensive disorder of pregnancy (HDP) and/or intrauterine growth restriction (IUGR). METHODS: A retrospective cohort study of archived placenta specimens from RD-IVF and OD-IVF pregnancies affected by HDP and/or IUGR was conducted with blinded histopathological placental examination. Three categories of lesions were differentiated and defined as main outcomes: maternal vascular malperfusion (MVM), chronic inflammation, and fetal vascular malperfusion (FVM). To determine the relationship between conception method and placental lesions, multivariable regressions were performed with maternal age, gestational age, HDP, birth and placental weight percentiles as model covariates. RESULTS: 115 placentas were included 83 (72.2%) RD-IVF, 32 (27.8%) OD-IVF. Adjusted OR (aOR) for conception method was 5.05 (95%CI 0.58-43.90, p=0.142) for MVM, 1.87 (95%CI 0.68-5.15, p=0.228) for chronic inflammatory and 0.61 (95%CI 0.15-2.37, p=0.471) for FVM lesions. Multiple gestation demonstrated borderline association with MVM (aOR=0.24, 95%CI 0.04-1.51, p=0.129) and total pathology score (aRR=0.79, 95%CI 0.62-1.01, p=0.058). Subgroup analysis suggested greater odds of villitis of unknown etiology (VUE) for OD-IVF (aOR=2.98, 95%CI 1.12-7.93, p=0.029). DISCUSSION: Source of oocyte derivation demonstrated no evidence of association with main outcomes in cases of HDP and/or IUGR. Subgroup analysis demonstrated increased rates of inflammatory lesions for OD-IVF. Multiple gestation may be associated with decreased MVM and total lesions.