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.

Comparison of Placental Pathology Reports From Spontaneous Preterm Births Finalized by General Surgical Pathologists Versus Perinatal Pathologist: A Call to Action.

Placental examination, frequently performed by general surgical pathologists, plays an important role in understanding patient outcomes and explaining the underlying mechanisms leading to preterm birth (PTB). This secondary analysis of a larger study recurrent PTB aimed to compare diagnoses between general surgical pathologists (GSP) and a perinatal pathologist (PP) in preterm placentas examined between 2009 and 2018 at a single institution. Pathology diagnoses were coded into 4 categories (acute inflammation [AI], chronic inflammation, fetal vascular malperfusion, maternal vascular malperfusion) based on original reports for the GSP and second review by the single PP. A total of 331 placentas were included, representing placentas finalized by 17 GSPs. The prevalence of all 4 placental diagnostic categories was higher for the PP, and nearly half (49.2%) of placentas finalized by GSP had no diagnostic findings. Agreement was highest for AI at κ=0.50 (weak agreement). However, there was no agreement for maternal vascular malperfusion (κ=0.063), chronic inflammation (κ=0.0026), and fetal vascular malperfusion (κ = -0.018). Chronic basal deciduitis with plasma cells had the highest false-negative rate (missed in 107 cases by GSP). Villous infarction had the highest false-positive rate (overcalled in 28/41 [68%] cases) with the majority of the "infarcts" representing intervillous thrombi. In conclusion, there is no agreement between GSP and PP when assessing placental pathology other than AI, and weak agreement even for AI. These findings are a call to action to implement educational efforts and structural/organizational changes to improve consistency of placental pathology reporting.

Patterns of placental pathology associated with preeclampsia.

INTRODUCTION: Maternal vascular malperfusion (MVM) is commonly observed in early onset preeclampsia, but less prevalent in late onset preeclampsia. The purpose of our analysis was to investigate patterns of placental pathology in preeclampsia. METHODS: Electronic health records for all singleton livebirths from 2009 to 2018 at a single institution with a diagnosis of preeclampsia were obtained. Text searching was used to obtain placental data from pathology reports, including lesions of MVM, fetal vascular malperfusion (FVM), chronic inflammation (CI), and acute inflammation (AI). Placental pathology was compared based on timing of delivery and latent class analysis (LCA) was used to investigate subtypes of preeclampsia based on 22 placental variables. RESULTS: 728 patients were included in the analysis. Prevalence of MVM decreased with advancing gestation (95.4% at <34 weeks, 69.8% at 34-36 weeks, and 50%, ≥37 weeks; p < 0.01). LCA identified five classes based on placental pathology: (1) high grade MVM, (2) CI and FVM, (3) low grade MVM, (4) AI, (5) other. Preterm birth varied across the classes (p < 0.01), with the highest prevalence observed among the classes characterized by MVM (high grade: 87.6%; low grade: 63.0%) and the lowest prevalence among the class characterized by AI (23.5%). DISCUSSION: Placental pathology in preeclampsia differs based on gestational age at delivery with MVM seen in nearly all early onset preeclampsia cases. Latent classes largely grouped by previously defined patterns of placental injury (MVM, CI, FVM, AI), and again revealed the highest likelihood of preterm birth in classes characterized by MVM. Results suggest there may be multiple mechanisms leading to the clinical manifestations of preeclampsia.

Measures of Fetal Growth and Cardiac Structure in Stillbirths With Placental Maternal Vascular Malperfusion: Evidence for Heart Weight Sparing and Structural Cardiac Alterations in Humans.

BACKGROUND: Placental maternal vascular malperfusion (MVM) is associated with fetal growth restriction (FGR). While FGR increases the risk of cardiovascular disease, the impact of MVM on fetal cardiac structure is understudied. METHODS: We utilized a cohort of autopsied stillbirths; 29 with MVM as the cause of death and 21 with a cause of death unrelated to MVM. Fetal and organ weights and heart measurements were standardized by gestational age and compared between MVM and non-MVM stillbirths. Differences in standardized fetal organ and cardiac measures as compared to standardized fetal body weight were calculated to account for body size. RESULTS: MVM stillbirths had smaller organ and heart weights than non-MVM stillbirths; however, after accounting for gestational age, heart weight was the least affected among all organs. In an analysis of organ weights relative to body size, heart weights were 0.31 standard deviations (SD) larger than expected relative to body weight (95% CI: 0.04, 0.57). Right and left ventricle thicknesses and mitral valve circumference were also larger than expected relative to body weight. CONCLUSION: Stillbirth due to MVM was associated with relative sparing of heart weight and other heart measurements. The significance of these findings in liveborn infants needs further study.

Epidemiology beyond its limits.

In 1995, journalist Gary Taubes published an article in Science titled "Epidemiology faces its limits," which questioned the utility of nonrandomized epidemiologic research and has since been cited more than 1000 times. He highlighted numerous examples of research topics he viewed as having questionable merit. Studies have since accumulated for these associations. We systematically evaluated current evidence of 53 example associations discussed in the article. Approximately one-quarter of those presented as doubtful are now widely viewed as causal based on current evaluations of the public health consensus. They include associations between alcohol consumption and breast cancer, residential radon exposure and lung cancer, and the use of tanning devices and melanoma. This history should inform current debates about the reproducibility of epidemiologic research results.

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.

Complaints about excessive use of police force in women's neighborhoods and subsequent perinatal and cardiovascular health.

There are substantial, unexplained racial disparities in women's health. Some of the most pronounced involve elevated rates of preterm delivery (PTD) and cardiovascular disease (CVD) among Black women. We hypothesized that stress associated with excessive use of force by police may contribute to these disparities. In two prospective cohorts derived from electronic health records (pregnancy cohort, N = 67,976; CVD cohort, N = 6773), we linked formal complaints of excessive police force in patients' neighborhoods with health outcomes. Exposed Black women were 1.19 times as likely to experience PTD [95% confidence interval (CI): 1.04 to 1.35] and 1.42 times as likely to develop CVD (95% CI: 1.12 to 1.79), even after adjustment for neighborhood disadvantage and homicide. The excess risks of PTD were also observed in maternal fixed-effects analyses comparing births to the same woman. These findings suggest police violence may be an unrecognized contributor to health inequity for Black women.

Living in a block group with a higher eviction rate is associated with increased odds of preterm delivery.

BACKGROUND: Housing instability is associated with adverse pregnancy outcomes. Recent studies indicate that eviction, which may affect a larger segment of the population than other forms of housing instability, is also associated with adverse pregnancy outcomes. However, these studies evaluate eviction across large areas, such as counties, so it remains unclear whether these patterns extend to individual-level pregnancy outcomes. METHODS: We used data on a cohort of all singleton live births at a single Chicago hospital between March 2008 and March 2018 to investigate the associations between block-group eviction rates and individual adverse pregnancy outcomes. Eviction data were obtained from the Eviction Lab at Princeton University. Generalised estimating equations were used to estimate associations and account for correlations among individuals living in the same block groups. RESULTS: Individuals living in block groups in the highest quartile for eviction filing rate were 1.17 times as likely to deliver preterm (95% CI: 1.08 to 1.27) and 1.13 times as likely to deliver a small for gestational age infant (95% CI: 1.03 to 1.25) as compared with individuals living in block groups in the lowest quartile. Further, tests for linear trend indicated that for each quartile increase in eviction filing rate, there was a corresponding increase in odds of adverse outcomes (p<0.05). Results were strongest in magnitude for those with low neighbourhood and individual socioeconomic status, who are most likely to be renters and affected by local eviction policies. CONCLUSION: Our results suggest that individuals living in block groups with higher eviction rates are more likely to deliver preterm. Future research should explore associations of individual experience with eviction on adverse pregnancy outcomes and examine whether policies to improve tenant protections also impact pregnancy outcomes.

Chronic villitis: Refining the risk ratio of recurrence using a large placental pathology sample.

INTRODUCTION: Chronic villitis is an inflammatory lesion that affects 5-15% of placentas and is associated with adverse pregnancy outcomes. Chronic villitis may also recur; however, studies estimating recurrence are based on small samples and estimates of recurrence range from 10 to 56%. METHODS: We utilized data from placentas submitted to pathology at a Chicago hospital between January 2009 and March 2018. During the study period, 883 patients had two placentas submitted to pathology. We estimated the risk of recurrent chronic villitis, adjusted for maternal and pregnancy characteristics. We also evaluated whether prevalence of small for gestational age infant differed for those with recurrent chronic villitis and we investigated whether placental pathology worsened in the second study pregnancy among those with recurrent chronic villitis. RESULTS: The overall prevalence of recurrent chronic villitis in the study sample was 11.5%. Among those with chronic villitis in the first pregnancy, 54% developed chronic villitis in the second pregnancy, corresponding to an adjusted risk ratio of 2.36 (95% confidence interval: 1.92, 2.91). Recurrent chronic villitis was not associated with increased prevalence of small for gestational infant as compared with non-recurrent villitis. Among those with recurrent chronic villitis, high-grade chronic inflammation and fetal vascular malperfusion were more common in the second pregnancy as compared with the first. DISCUSSION: Our results suggest that those with chronic villitis in the first pregnancy are over twice as likely to develop chronic villitis in the second pregnancy and that chronic inflammation and fetal vascular malperfusion may worsen among those with recurrent chronic villitis.

Time-dependent changes in placental mRNA expression after delivery due to delayed specimen collection.

PROBLEM: Current scientific guidelines recommend collecting placental specimens within two hours of delivery for gene expression analysis. However, collecting samples in a narrow time window is a challenge in the dynamic and unpredictable clinical setting, so delays in placental specimen collection are possible. The purpose of our analysis was to investigate temporal changes in placental gene expression by longitudinally sampling placentas over a 24 h period. METHOD OF STUDY: Eight placentas from individuals with uncomplicated, term pregnancies delivered by scheduled cesarean section were collected and sampled following the placental delivery and again at 1, 2, 4, 6, and 24 h post-delivery. At each time point, biopsies of chorionic villous tissue were taken from 3 cotyledons to account for intra-placental heterogeneity. The 3 biopsies from each time point were pooled prior to RNA extraction. Expression of 382 mRNA transcripts was quantified using the NanoString nCounter System. Fold change values were calculated for each time point relative to delivery, and a fold change threshold of 1.25 was used to determine a meaningful change from delivery. RESULTS: Based on a fold change threshold of 1.25, 84.3% of transcripts were stable for at least 1 h, 80.2% were stable for at least two hours, and 20.6% of transcripts were stable through the collection at 24 h. CONCLUSION: Our results suggest that for some mRNA transcripts, expression changes as time to sample collection increases. We have developed a Web application to allow investigators to explore transcripts relevant to their research interests and to set appropriate thresholds to aid in determining whether placentas with delayed sample collection can be included in analyses (https://placentaexpression.foundationsofhealth.org/).

Adverse Pregnancy Outcomes Following the Assassination of John F. Kennedy in 1963.

INTRODUCTION: Women exposed to stressful events during pregnancy are thought to be at increased risk of adverse birth outcomes. However, studies investigating stressful events are often unable to control for important confounders, such as behavioral and genetic characteristics, or to isolate the impact of the stressor from other secondary effects. We used a discordant-sibling design, which provides stronger inferences about causality, to examine whether a widespread stressor with limited impact on day-to-day life (John F. Kennedy assassination) resulted in an increased risk of adverse birth outcomes. METHODS: Data were obtained from the Collaborative Perinatal Project, a prospective, multi-site cohort study conducted in the US from 1959 to 1965. Our analysis was restricted to singleton live births ≥24 weeks born before the assassination (n = 24,406) or in utero at the time (n = 5833). We also evaluated associations within siblings discordant for exposure (n = 1144). We used survival analysis to evaluate associations between exposure and preterm birth and marginal models to evaluate associations with birthweight and placental pathology. RESULTS: First trimester exposure was associated with preterm birth (hazard ratio (HR): 1.17; 95% CI: 1.05, 1.31). In the discordant-sibling model, the point estimate was similar (HR: 1.22; 95% CI: 0.36, 4.06). Third trimester exposure was associated with increased odds of fetal acute inflammation in the placenta (odds ratio (OR): 1.34, 95% CI: 1.05, 1.71). CONCLUSIONS FOR PRACTICE: First trimester exposure to an acute stressor was associated with preterm birth. We did not observe increased odds of placental pathology with first trimester exposure; however, stress may increase preterm birth risk through chronic placental inflammation, which was not evaluated in this sample.

Formulating a Meaningful and Comprehensive Placental Phenotypic Classification.

INTRODUCTION: While many placental lesions have been identified and defined, the significance of multiple overlapping lesions has not been addressed. The purpose of our analysis was to evaluate overlapping patterns of placental pathology and determine meaningful phenotypes associated with adverse birth outcomes. METHODS: Placental pathology reports were obtained from a single hospital between 2009 and 2018. Placental lesions were grouped into four major categories: acute inflammation (AI), chronic inflammation (CI), maternal vascular malperfusion (MVM), and fetal vascular malperfusion (FVM). Within each category, lesions were classified as not present, low grade or high grade. Combinations of pathologies were evaluated in relation to preterm birth (<37 weeks) and small for gestational age (SGA) infant (birthweight <10th percentile). RESULTS: During the study period, 19,027 placentas were reviewed by pathologists. Results from interaction models indicate that MVM and MVM in combination with CI and/or FVM are associated with the greatest odds of SGA infant and PTB. When incorporating grade, we identified 21 phenotype groups, each with characteristic associations with the SGA infant and patterns of PTB. DISCUSSION: We have developed a comprehensive and meaningful placental phenotype that incorporates severity and multiplicity of placental lesions. We have also developed a web application to facilitate phenotype determination (https://placentaexpression.shinyapps.io/phenotype).

Seasonal Variation of Chronic Villitis of Unknown Etiology.

INTRODUCTION: Chronic villitis of unknown etiology (VUE) is a chronic inflammatory lesion of the placenta. VUE is hypothesized to result from an alloimmune response or as response to an unidentified infection. Lack of a seasonal trend is thought to support VUE as an alloimmune response, though data on seasonal VUE trends are limited. METHODS: Data were obtained from a hospital in Chicago, Illinois, from 2011-2016. Placentas sent to pathology were reviewed using a standardized protocol, and VUE cases were identified based on an automated text search of pathology records. We used monthly VUE prevalence estimates to investigate the annual trend, and we used Poisson regression to evaluate seasonal variation in the number of VUE cases. RESULTS: There were 79 825 deliveries within the study period. Pathologists evaluated 12 074 placentas and identified 2873 cases of VUE. Regression results indicate that the risk of VUE is 16% to 17% higher in the fall and winter as compared to the summer (fall relative risk [RR]: 1.17, 95% confidence interval [CI]: 1.06-1.29; winter RR: 1.16, 95% CI: 1.05-1.29). DISCUSSION: Our results suggest that there may be seasonal variation in VUE prevalence, particularly for low-grade VUE. Future studies should evaluate seasonal variation in a representative sample rather than relying on pathology reports to estimate prevalence.

The association of stillbirth with placental abnormalities in growth-restricted and normally grown fetuses.

BACKGROUND: Stillbirth, defined as foetal death ≥20 weeks' gestation, is associated with poor foetal growth and is often attributed to placental abnormalities, which are also associated with poor foetal growth. Evaluating inter-relationships between placental abnormalities, poor foetal growth, and stillbirth may improve our understanding of the underlying mechanisms for some causes of stillbirth. OBJECTIVE: Our primary objective was to determine whether poor foetal growth, operationalised as small for gestational age (SGA), mediates the relationship between placental abnormalities and stillbirth. METHODS: We used data from the Stillbirth Collaborative Research Network study, a population-based case-control study conducted from 2006-2008. Our analysis included 266 stillbirths and 1135 livebirths. We evaluated associations of stillbirth with five types of placental characteristics (developmental disorders, maternal and foetal inflammatory responses, and maternal and foetal circulatory disorders) and examined mediation of these relationships by SGA. We also assessed exposure-mediator interaction. Models were adjusted for maternal age, race/ethnicity, education, body mass index, parity, and smoking status. RESULTS: All five placental abnormalities were more prevalent in cases than controls. After adjustment for potential confounders, maternal inflammatory response (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.77, 3.75), maternal circulatory disorders OR 4.14, 95% CI 2.93, 5.84, and foetal circulatory disorders OR 4.58, 95% CI 3.11, 6.74 were strongly associated with stillbirth, and the relationships did not appear to be mediated by SGA status. Associations for developmental disorders and foetal inflammatory response diverged for SGA and non-SGA births, and strong associations were only observed when SGA was not present. CONCLUSIONS: Foetal growth did not mediate the relationships between placental abnormalities and stillbirth. The relationships of stillbirth with maternal and foetal circulatory disorders and maternal inflammatory response appear to be independent of poor foetal growth, while developmental disorders and foetal inflammatory response likely interact with foetal growth to affect stillbirth risk.

Interpregnancy interval and risk of stillbirth: a population-based case control study.

PURPOSE: We examined the association between interpregnancy intervals (IPIs) and stillbirth (defined as fetal death ≥20 weeks), as both short and long IPIs have been associated with adverse perinatal outcomes. Prior pregnancy loss is also a known risk factor for stillbirth, and women who suffer a prior loss often have shorter IPIs. For these reasons, we also sought to quantify the proportion of the association between prior pregnancy loss and subsequent stillbirth risk that may be attributed to a short IPI. METHODS: We used data from the Stillbirth Collaborative Research Network, a multisite case-control study conducted in 2006-2008, restricted to singleton pregnancies among multiparous or multigravid women (985 controls and 291 cases). We accounted for complex sample design and nonparticipation with weighted multivariable logistic regression. RESULTS: In the adjusted models, IPIs <6 months, as compared with a reference of 18-23 months, were associated with increased odds of stillbirth (aOR 1.6, 95% CI: 0.8, 3.4). Long IPIs (60-100 months) were also associated with an increased odds of stillbirth (aOR 2.4, 95% CI: 1.2, 4.5). After control for covariates, about one-fifth (21.2%) of the association of prior pregnancy loss (stillbirth, ectopic pregnancy, molar pregnancy, or spontaneous abortion) and stillbirth may be attributable to a short IPI. CONCLUSIONS: Our results suggest that women who experience a prior pregnancy loss may benefit from additional counseling on adequate birth spacing to reduce subsequent stillbirth risk.

Associations Between the Features of Gross Placental Morphology and Birthweight.

The placenta plays a critical role in regulating fetal growth. Recent studies suggest that there may be sex-specific differences in placental development. The purpose of our study was to evaluate the associations between birthweight and placental morphology in models adjusted for covariates and to assess sex-specific differences in these associations. We analyzed data from the Stillbirth Collaborative Research Network's population-based case-control study conducted between 2006 and 2008, which recruited cases of stillbirth and population-based controls in 5 states. Our analysis was restricted to singleton live births with a placental examination (n = 1229). Characteristics of placental morphology evaluated include thickness, surface area, difference in diameters, shape, and umbilical cord insertion site. We used linear regression to model birthweight as a function of placental morphology and covariates. Surface area had the greatest association with birthweight; a reduction in surface area of 83 cm2, which reflects the interquartile range, is associated with a 260.2-g reduction in birthweight (95% confidence interval, -299.9 to -220.6), after adjustment for other features of placental morphology and covariates. Reduced placental thickness was also associated with lower birthweight. These associations did not differ between males and females. Our results suggest that reduced placental thickness and surface area are independently associated with lower birthweight and that these relationships are not related to sex.

Associations Between Features of Placental Morphology and Birth Weight in Dichorionic Twins.

Low birth weight is associated with perinatal and long-term morbidity and mortality, and may be a result of abnormal placental development and function. In studies of singletons, associations have been reported between features of placental morphology and birth weight. Evaluating similar associations within twin pairs offers a unique opportunity to control for key confounders shared within a twin pair, including gestational age, parental characteristics, and intrauterine environment. Data from 3 studies in the United States that were completed from 2012 to 2013, 2006 to 2008, and 1959 to 1966 were used in our analysis of 208 sets of dichorionic twins with unfused placentas. We used linear regression to model difference in birth weight within a twin pair as a function of differences in placental characteristics (i.e., thickness, 2-dimensional surface area, intraplacental difference in diameter). After controlling for sex discordance, a 75.3- cm2 difference in placental surface area, which reflects the interquartile range, was associated with a difference in birth weight of 142.1 g (95% confidence interval (CI): 62.9, 221.3). The magnitude of the association also may be larger for same-sex male pairs than same-sex female pairs (males: 265.8 g, 95% CI: 60.8, 470.8; females: 133.0 g, 95% CI: 15.7, 250.3). Strong associations between surface area and birth weight are consistent with reported results for singleton pregnancies.

Comparison of diameter-based and image-based measures of surface area from gross placental pathology for use in epidemiologic studies.

Placental surface area is often estimated using diameter measurements. However, as many placentas are not elliptical, we were interested in the validity of these estimates. We compared placental surface area from images for 491 singletons from the Stillbirth Collaborative Research Network (SCRN) Study (416 live births, 75 stillbirths) to estimates obtained using diameter measurements. Placental images and diameters were obtained from pathologic assessments conducted for the SCRN Study and images were analyzed using ImageJ software. On average, diameter-based measures underestimated surface area by -5.58% (95% confidence interval: -30.23, 19.07); results were consistent for normal and abnormal shapes. The association between surface area and birthweight was similar for both measures. Thus, diameter-based surface area can be used to estimate placental surface area.

Factors Impacting the Performance Characteristics of Bile Duct Brushings: A Clinico-Cytopathologic Analysis of 253 Patients.

CONTEXT: - Literature on factors impacting bile duct brushings (BDBs) performance characteristics remain limited. OBJECTIVE: - To capture the current state of daily practice with BDB sign-out. DESIGN: - Two hundred fifty-three of 444 BDBs signed out by more than 7 cytopathologists, with histopathologic and/or clinical follow-up of at least 18 months, were examined. RESULTS: - One hundred thirty-five of 253 BDBs (53%) had histologically confirmed malignancies, 22 (9%) had cancer-related deaths, and 96 (38%) were benign. Cytologic diagnoses in the 444 BDBs were nondiagnostic (11 [2.5%]), negative (284 [64%]), atypical (62 [13.9%]), suspicious (34 [7.7%]), and malignant (53 [11.9%]). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of malignancy detection were 35%, 100%, 100%, 58%, and 66%, respectively. When atypical, suspicious, and malignant (ASM) categories were combined, sensitivity increased (58%), specificity and PPV dropped (97%), and accuracy increased (73%). Carcinoma type (bile-duct versus pancreatic-ductal) had no effect on accuracy ( P = .60) or diagnostic class ( P = .84), nor did time of performance (first 7.5 versus latter 7.5 years, P = .13). Interestingly, ThinPrep + cell block (n = 41) had higher sensitivity (61%) and lower specificity (80%) than ThinPrep only (versus 51% and 100%, respectively). Sensitivity and specificity were higher (47% and 100%) in nonstented than stented specimens (59% and 97%). Relative risk of malignancy for "suspicious" (2.30) and "atypical" (2.28) categories was lower but not very different from that of "malignant" category (2.41). CONCLUSIONS: - Bile duct brushings had fairly low sensitivity but high specificity and PPV with no false positives. Sensitivity almost doubled and specificity dipped minimally when ASM categories were combined, highlighting the need for better classification criteria for atypical/suspicious cases. Higher specificity, PPV, NPV, and accuracy but lower sensitivity in stented BDBs suggest that they be called malignant only when evidence is overwhelmingly convincing.

Cytologic predictors of malignancy in bile duct brushings: a multi-reviewer analysis of 60 cases.

Diagnosing malignancy in bile duct brushings is highly challenging. Seven reviewers of variable backgrounds and levels of participation in bile duct brushing sign out blindly reviewed 60 specimens (30 malignant with histologic confirmation and 30 benign (15 stented) with resection or ≥18 months of uneventful follow-up), testing the utility of 14 malignant characteristics. Eleven characteristics were statistically significantly associated with malignancy including 3-dimensional clusters (63% in malignant vs 3% in benign, odds ratio 50, P=0.0003), pleomorphism (62 vs 3, odds ratio 48, P=0.0004), 2-cell population (60% vs 3, odds ratio 44, P=0.0005), chromatin pattern (hypo/hyperchromasia) changes (70% vs 7%, odds ratio 33, P<0.0001), high nuclear-to-cytoplasmic ratio (48 vs 3%, odds ratio 27, P=0.0023), cytoplasmic vacuoles (43 vs 3%, odds ratio 22, P=0.0042), nuclear irregularity (70 vs 10%, odds ratio 21, P<0.0001), cellular discohesion (38 vs 3%, odds ratio 18, P=0.0082), hypercellularity (23% vs 0), nuclear molding (20% vs 0) and prominent nucleoli (21% vs 0). Necrosis and infiltrating inflammation were not helpful in identifying malignancy ('neutrophil cannibalism' was noted in 43% malignant); 21/30 (70%) malignant brushings had ≥3 malignant characteristics, while 23 (77%) benign brushings had none. Of 20 brushings with ≥4 characteristics, 1(5%) proved benign and showed detachment atypia, a close malignant mimicker in brushings. Identification of 3 characteristics maximized the combined sensitivity (70%), specificity (97%) and accuracy (83%), but sensitivity dropped as number of characteristics increased. Identification of 3/11 characteristics (3-dimensional clusters, pleomorphism, high nuclear-to-cytoplasmic ratio, nuclear irregularity, hypercellularity, discohesion, chromatin changes, vacuoles, prominent nucleoli, molding and 2-cell population) improves pathologists' overall performance greatly.