Stratification Of Women Research Articles

Endometrial compaction to predict pregnancy outcomes in patients undergoing assisted reproductive technologies: a systematic review and meta-analysis.

Does endometrial compaction (EC) help predict pregnancy outcomes in those undergoing ART? EC is associated with a significantly higher clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR), but this does not translate to live birth rate (LBR). EC describes the progesterone-induced decrease in endometrial thickness, which may be observed following the end of the proliferative phase, prior to embryo transfer. EC is proposed as a non-invasive tool to help predict pregnancy outcome in those undergoing ART, however, published data is conflicting. A literature search was carried out by two independent authors using PubMed, Cochrane Library, MEDLINE, Embase, Science Direct, Scopus, and Web of Science from inception of databases to May 2023. All peer-reviewed studies reporting EC and pregnancy outcomes in patients undergoing IVF/ICSI treatment were included. The primary outcome is LBR. Secondary outcomes included other pregnancy metrics (positive pregnancy test (PPT), CPR, OPR, miscarriage rate (MR)) and rate of EC. Comparative meta-analyses comparing EC and no EC were conducted for each outcome using a random-effects model if I 2 > 50%. The Mantel-Haenszel method was applied for pooling dichotomous data. Results are presented as odds ratios (OR) with 95% CI. Out of 4030 screened articles, 21 cohort studies were included in the final analysis (n = 27 857). No significant difference was found between LBR in the EC versus the no EC group (OR 0.95; 95% CI 0.87-1.04). OPR was significantly higher within the EC group (OR 1.61; 95% CI 1.09-2.38), particularly when EC ≥ 15% compared to no EC (OR 3.52; 95% CI 2.36-5.23). CPR was inconsistently defined across the studies, affecting the findings. When defined as a viable intrauterine pregnancy <12 weeks, the EC group had significantly higher CPR than no EC (OR 1.83; 95% CI 1.15-2.92). No significant differences were found between EC and no EC for PPT (OR 1.54; 95% CI 0.97-2.45) or MR (OR 1.06; 95% CI 0.92-1.56). The pooled weighted incidence of EC across all studies was 32% (95% CI 26-38%). Heterogeneity due to differences between reported pregnancy outcomes, definition of EC, method of ultrasound, and cycle protocol may account for the lack of translation between CPR/OPR and LBR findings; thus, all pooled data should be viewed with an element of caution. In this dataset, the significantly higher CPR/OPR with EC does not translate to LBR. Although stratification of women according to EC cannot currently be recommended in clinical practice, a large and well-designed clinical trial to rigorously assess EC as a non-invasive predictor of a successful pregnancy is warranted. We urge for consistent outcome reporting to be mandated for ART trials so that data can be pooled, compared, and concluded on. H.A. was supported by the Hewitt Fertility Centre. S.G.P. and J.W. were supported by the Liverpool University Hospital NHS Foundation Trust. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). N.T. was supported by the National Institute for Health and Care Research. D.K.H. had received honoraria for consultancy for Theramex and has received payment for presentations from Theramex and Gideon Richter. The remaining authors have no conflicts of interest to report. PROSPERO CRD42022378464.

Abstract 16941: Breast Artery Calcification for Primary Prevention of Major Adverse Cardiovascular Outcomes: A New Risk Stratification Tool for Women

Introduction: Reductions in cardiovascular mortality among women lag behind men. There is a critical need for improved primary prevention of major adverse cardiovascular events (MACE) in women. We examined if breast artery calcification (BAC), detected on screening mammograms, prognosticates long-term MACE. Methods: In this retrospective study of consecutive women age 40-75 years without coronary disease from 2011-12, followed for 10 years at Dartmouth-Hitchcock Medical Center, we recorded baseline mammograms, clinical parameters and 10-year MACE risk was estimated via the pooled cohort equation (PCE). The association of BAC and MACE was examined by a multivariable, interactive logistic regression model with MACE as dependent variable, adjusting for confounders and an interaction of BAC with 3 strata of PCE predicted risk: low (&lt;5%), moderate (5-7.5%) and high (&gt;7.5%). The primary endpoint was MACE over 10 years. Results: Among 1216 women, 19% had BAC. Women with BAC were older, had more hypertension and diabetes, and a higher baseline PCE score. Over 10 years of follow-up, 21% of women with BAC developed MACE compared to 11% women without BAC (p&lt;0.001). This association was independent of risk factors and statin use. Among women with low (&lt; 5%) risk of MACE, those with BAC had an 18% incidence of MACE, compared to 7% in women without BAC (OR 2.8, 95% CI 1.5 - 5.0) (Fig 1A). The incremental increase in MACE in patients with BAC decreased with higher PCE-predicted risk. Peak interaction occurred at a PCE-predicted risk of 10% (Fig 1B). Among women with a PCE-predicted risk &lt;10%, BAC was a strong predictor of MACE with an attributable fraction of 20% (Fig 1B). Conclusions: BAC is a strong, independent predictor of MACE, particularly in women at low risk by PCE. Although PCE is used widely to risk stratify women for MACE, our study suggests it severely underestimates risk in women with a low PCE score. Further prospective trials are needed to validate these findings.

A Systematic Review of Risk Factors for Development, Recurrence, and Progression of Vulvar Intraepithelial Neoplasia.

Vulvar intraepithelial neoplasia (VIN) is a premalignant condition with high recurrence rates despite treatment. Vulvar intraepithelial neoplasia develops through separate etiologic pathways relative to the presence or absence of human papillomavirus (HPV) and TP53 mutations. This systematic review was conducted (1) to identify historical risk factors for the development, recurrence, and progression of VIN and (2) to critique these risk factors in the context of advances made in the stratification of VIN based on HPV or TP53 status. A systematic search was performed on MEDLINE, Embase, Cochrane Database, PsychInfo, and CINAHL from inception to July 5, 2021. Three gynecologic oncologists independently evaluated the eligibility of studies based on predetermined inclusion and exclusion criteria, abstracted data, and then analyzed the relevant data. A total of 1,969 studies (involving 6,983 patients) were identified. Twenty-nine studies met inclusion criteria. The quality of evidence was low; primarily level 2b (Oxford Centre for Evidence-Based Medicine). Risk factors associated with the development of VIN include: smoking and coexisting vulvar dermatoses. Risk factors associated with recurrence include: smoking, multifocal disease, and positive surgical margins. Recent studies identified the presence of differentiated VIN/TP53 mutation as the most significant risk factor for both VIN recurrence and malignant progression. The current body of evidence consists primarily of small retrospective observational studies. Well-designed retrospective case-control series and/or prospective observational studies are urgently needed. Ideally, future studies will collect standardized data regarding associated risk factors and stratify women with VIN based on HPV and TP53 status.

Abstract P2-10-06: Validation of abridged breast cancer risk assessment model for the general population

Abstract The ability to efficiently and accurately risk stratify women can lead to improved risk-reduction measures. Actionable risk thresholds for both screening and risk-reduction guidance exist; however, despite several clinical risk models currently in existence, the utilization of such models is underwhelming. We have developed and validated an abridged clinical risk model, COSMO (Clinical pOlygenic denSity faMily mOdel), incorporating three of the most relevant epidemiological risk factors associated with sporadic and familial breast cancer in a format that is designed for “ease of use”. Polygenic risk is recognized as a promising epidemiological risk factor however, its value is greater when integrated with other phenotypic risk factors including 1st and 2nd family history, breast density menopausal status, BMI and age. We used 200,009 active UK Biobank (UKB) members who were female, genetically Caucasian, had SNP data for 313 breast cancer associated variants and aged 40 to 69 years at baseline assessment date. We used age and date of baseline assessment to calculate censoring age for those who had died before completing 5 years of follow-up and to determine the date at which 5 years of follow-up was completed for the others. We used both self-reported and linked cancer registry data (ICD9 code 174 or ICD10 code C50) to determine the earliest diagnosis of invasive breast cancer for each affected woman. In terms of discrimination, COSMO (AUC=0.651; 95% CI 0.642, 0.661) performed better than the Gail model (AUC=0.567; 95% CI=0.557, 0.567); P value for difference &amp;lt;0.0001. Overall calibration showed the number of breast cancers expected using COSMO was slightly higher than the number observed (SIR=0.94; 95% CI=0.91, 0.97), while for the Gail model, the number of breast cancers was lower than the number observed (SIR=1.07; 95% CI=1.04, 1.11). The modest over estimation may be explained by the “healthy volunteer” selection bias of the UKB. Importantly, COSMO significantly improved predicted risk classification of women compared to the Gail when stratified according to actionable thresholds. (Table) Limitations to the validation include the lack of mammographic breast density data in the UKB—a critical factor in COSMO. To this end, we have an ongoing validation in a Nurses’ Health Study population (1,269 cases and 1,812 controls) that includes breast density data. Ongoing model comparison studies will confirm the equivalence of COSMO to standard clinical models. If performance is equivalent, COSMO has an advantage in clinical implementation because the abridged model can be less time consuming to implement in a general practice or screening clinic setting due to the truncated pedigree. Furthermore, as multiethnic cohort data access continues to improve, the epidemiological components can be recalibrated for application across any ethnicity. COSMO integrates the most impactful epidemiological risk factors, is well calibrated for the general population and provides improved discrimination over a standard risk model. General population risk assessment like COSMO can lead to the identification of more women who would benefit from clinical intervention based on current risk-reduction guidelines. Beyond that, incidental by products of a general population risk assessment include promoting breast cancer awareness, empowering women to understand their own risk, and encouraging all women to consider their lifestyle habits. Citation Format: Erika Spaeth, Gillian Dite, Richard Allman. Validation of abridged breast cancer risk assessment model for the general population [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-06.

Risk stratification of women with peripartum cardiomyopathy at initial presentation: A dobutamine stress echocardiography study

Risk stratification of women with peripartum cardiomyopathy at initial presentation: A dobutamine stress echocardiography study

Gene Expression and Mutation Analysis of Early-Stage Recurrent Endometrial Cancer

Purpose/Objective(s)As currently under investigation in PORTEC-4a, an integrated molecular model of endometrial cancer is postulated to risk stratify women to better identify those more likely to benefit from adjuvant radiation therapy following hysterectomy for early-stage disease. Stratification of tumor biology is based on several features, including: p53 mutation, POLE mutation, CTNNB1 mutation, microsatellite instability (MSI), LICAM expression and the presence of LVSI. TCGA data evaluating a large cohort of early and advanced stage endometrial tumors suggests that gene expression profiles may also distinguish between favorable and unfavorable biology of endometrial tumors. We aimed to determine whether recurrent early-stage endometrial tumors have distinct gene-expression patterns from early-stage tumors that did not recur.Materials/MethodsUsing the TCGA-UCEC dataset available via the Genomic Data Commons, 394 Stage I-II tumors’ gene expression data were evaluated and analyzed using R (R Core Team, 2020). Of these cases, 17 were confirmed as relapsed endometrial cancer (10 endometrioid and 7 serious/mixed) and 370 were tumors without documentation of a recurrence. Gene expression analysis was performed with limma, gene set variation analysis with GSVA, and gene enrichment with Metascape. The frequency of several common mutations was evaluated in the recurrent tumor subset.ResultsThere were 860 differentially expressed genes in recurrent versus not recurrent early-stage tumors identified from the TCGA-UCEC dataset. The most significant of which include DDIT3, THAP12, EMSY, CLNS1A, and AAMDC (log[Fold Change] > 1000, adjusted P-value < 0.001). Differentially expressed genes show pathway enrichment in GO Biologic Processes and Reactome Gene Sets, specifically, mitochondrion organization, proteolysis, organelle disassembly, translation, response to endoplasmic reticulum stress, proteinases, cellular component disassembly, covalent chromatin modification, and intrinsic apoptotic signaling pathway. Non-overlapping mutations within the recurrent tumors include, 9 of 17 recurrent tumors with p53 mutation, 3 of 17 with CTNNB1 mutation, 4 of 17 with PIK3R1, PIK3CR and PIK3CB mutation, and 1 of 17 a mutation in POLE.ConclusionOf recurrent early-stage tumors within the TCGA-UCEC dataset, of which as least a majority classify as intermediate or unfavorable according to PORTEC-4a criteria, differential gene expression in recurrent tumors compared to not recurrent tumors demonstrate relative increased expression of genes involved in catabolic and cell cycle processes. PORTEC-4a does not employ gene expression signatures to distinguish amongst favorable, intermediate, and unfavorable subtypes of early-stage endometrial tumors. However, further investigation may prove gene expression incorporation into stratification beneficial. As currently under investigation in PORTEC-4a, an integrated molecular model of endometrial cancer is postulated to risk stratify women to better identify those more likely to benefit from adjuvant radiation therapy following hysterectomy for early-stage disease. Stratification of tumor biology is based on several features, including: p53 mutation, POLE mutation, CTNNB1 mutation, microsatellite instability (MSI), LICAM expression and the presence of LVSI. TCGA data evaluating a large cohort of early and advanced stage endometrial tumors suggests that gene expression profiles may also distinguish between favorable and unfavorable biology of endometrial tumors. We aimed to determine whether recurrent early-stage endometrial tumors have distinct gene-expression patterns from early-stage tumors that did not recur. Using the TCGA-UCEC dataset available via the Genomic Data Commons, 394 Stage I-II tumors’ gene expression data were evaluated and analyzed using R (R Core Team, 2020). Of these cases, 17 were confirmed as relapsed endometrial cancer (10 endometrioid and 7 serious/mixed) and 370 were tumors without documentation of a recurrence. Gene expression analysis was performed with limma, gene set variation analysis with GSVA, and gene enrichment with Metascape. The frequency of several common mutations was evaluated in the recurrent tumor subset. There were 860 differentially expressed genes in recurrent versus not recurrent early-stage tumors identified from the TCGA-UCEC dataset. The most significant of which include DDIT3, THAP12, EMSY, CLNS1A, and AAMDC (log[Fold Change] > 1000, adjusted P-value < 0.001). Differentially expressed genes show pathway enrichment in GO Biologic Processes and Reactome Gene Sets, specifically, mitochondrion organization, proteolysis, organelle disassembly, translation, response to endoplasmic reticulum stress, proteinases, cellular component disassembly, covalent chromatin modification, and intrinsic apoptotic signaling pathway. Non-overlapping mutations within the recurrent tumors include, 9 of 17 recurrent tumors with p53 mutation, 3 of 17 with CTNNB1 mutation, 4 of 17 with PIK3R1, PIK3CR and PIK3CB mutation, and 1 of 17 a mutation in POLE. Of recurrent early-stage tumors within the TCGA-UCEC dataset, of which as least a majority classify as intermediate or unfavorable according to PORTEC-4a criteria, differential gene expression in recurrent tumors compared to not recurrent tumors demonstrate relative increased expression of genes involved in catabolic and cell cycle processes. PORTEC-4a does not employ gene expression signatures to distinguish amongst favorable, intermediate, and unfavorable subtypes of early-stage endometrial tumors. However, further investigation may prove gene expression incorporation into stratification beneficial.

Should Age-Dependent Absolute Risk Thresholds Be Used for Risk Stratification in Risk-Stratified Breast Cancer Screening?

In risk-stratified cancer screening, multiple risk factors are incorporated into the risk assessment. An individual’s estimated absolute cancer risk is linked to risk categories with tailored screening recommendations for each risk category. Absolute risk, expressed as either remaining lifetime risk or shorter-term (five- or ten-year) risk, is estimated from the age at assessment. These risk estimates vary by age; however, some clinical guidelines (e.g., enhanced breast cancer surveillance guidelines) and ongoing personalised breast screening trials, stratify women based on absolute risk thresholds that do not vary by age. We examine an alternative approach in which the risk thresholds used for risk stratification vary by age and consider the implications of using age-independent risk thresholds on risk stratification. We demonstrate that using an age-independent remaining lifetime risk threshold approach could identify high-risk younger women but would miss high-risk older women, whereas an age-independent 5-year or 10-year absolute risk threshold could miss high-risk younger women and classify lower-risk older women as high risk. With risk misclassification, women with an equivalent risk level would be offered a different screening plan. To mitigate these problems, age-dependent absolute risk thresholds should be used to inform risk stratification.

First trimester angiogenic and inflammatory factors in women with chronic hypertension and impact of blood pressure control: a case-control study.

To assess first trimester serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFLT-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), endothelin and vascular cell adhesion molecule (VCAM) in women with chronic hypertension (CH) stratified according to blood pressure (BP) control. Case-control. Tertiary referral centre. 650 women with CH, 142 normotensive controls. In the first trimester, patients with CH were subdivided into four groups. Group 1 included women without pre-pregnancy CH presenting with BP ≥140/90 mmHg. Groups 2-4 had pre-pregnancy CH; in group 2 the BP was <140/90 mmHg without antihypertensive medication, in group 3 the BP was <140/90 mmHg with antihypertensive medication, and in group 4 the BP was ≥140/90 mmHg despite antihypertensive medication. PLGF, sFLT-1, IL-6, TNF-α, endothelin and VCAM were measured at 11+0 -13+6 weeks' gestation and converted into multiples of the expected median (MoM) using multivariate regression analysis in the controls. Comparisons of MoM values of PLGF, sFLT-1, endothelin, IL-6, TNF-α and VCAM between the entire cohort of women with CH and the control group were made using Student's t-test or Mann-Whitney U-test. Comparisons between the four CH groups were made using analysis of variance or Kruskal-Wallis tests. Compared with the control group, women with CH had significantly lower MoM of PLGF, sFLT-1 and IL-6 and a significantly higher MoM of endothelin. Between the four groups of women with CH, there were no significant differences in the MoM of sFLT-1, PLGF, sFLT-1/PLGF ratio, endothelin, IL-6 or VCAM, or in the levels of TNF- α. In women with CH, differences exist in first trimester angiogenic and inflammatory profiles when compared with normotensive pregnancies. However, these differences do not assist in the stratification of women with CH to identify those with more severe underlying disease and worse pregnancy outcomes. First trimester blood pressure control impacts on serum PLGF, sFLT-1, endothelin and IL-6 in women with chronic hypertension.

Potential clinical impact of reporting breast arterial calcifications on screening mammograms in women without known coronary artery disease.

Cardiovascular disease remains a leading cause of death in women. 10-year likelihood for a cardiovascular event is determined by the American College of Cardiology Atherosclerotic Cardiovascular disease risk score calculator (ASVCD); however, this does not encompass risk factors unique to women. Breast arterial calcifications (BAC) detected on screening mammography may serve as a proxy for coronary atherosclerosis (CAC) in women. Our purpose was to investigate the correlation between BAC and CAC on imaging in women without a diagnosis of atherosclerosis to determine the potential clinical impact. Retrospective review was performed on a cohort of females evaluated by internists at our institution in 2019. Study patients had a screening mammogram within 1year of a noncardiac chest CT. Clinical data were collected to determine ASCVD risk score. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of BAC in detecting CAC were determined. 222 women met inclusion criteria, ranging from 41 to 77years of age, among which 25% (56/222) had BAC. 84% (47/56) of women with BAC had CAC on CT, yielding a sensitivity, specificity, PPV, and NPV of 51%, 93%, 84%, and 72%, respectively. Of the 47 patients who had both BAC and CAC, 66% had an unknown or low-to-borderline ASCVD score. Women with BACs have a high specificity for CAC. The reporting of BACs should prompt clinicians to risk stratify women for atherosclerotic disease. These women may otherwise be undetected by conventional risk calculators.

Abstract 15793: Joint Prediction of Hard Ascvd by Pooled Cohorts Equations Risk and Presence of Breast Arterial Calcification: The Minerva Study

Introduction: Prior studies have documented independent associations of breast arterial calcification (BAC) detected on mammographic screening with coronary artery disease or prospective cardiovascular disease outcomes. This study aims to ascertain the additional predictive ability for hard atherosclerotic cardiovascular disease (ASCVD) imparted by presence of BAC on top of the 10-year AHA/ACC Pooled Cohort Equations (PCE) Risk estimator. Hypothesis: BAC presence on mammograms will help further risk stratify women for risk of ASCVD. Methods: We used data from MINERVA, a multiethnic cohort of women aged 60 to 79 years at baseline (2012-15), free of symptomatic CVD, and recruited after mammography screening at Kaiser Permanente of Northern California. The sample available for analyses with complete data on BAC and PCE was 5,046. A BAC continuous mass score (mg) was obtained from digital mammograms using a validated densitometry method. BAC presence was BAC score &gt; 0 mg. Follow-up for hospitalization and death was through 5/31/20 (mean, 6.2 years). We defined hard ASCVD as acute myocardial infarction or stroke or CVD death (n=122 events). Results: The mean (SD) age at baseline was 66 (4) years; 47 percent were non-white. Overall, 26.4 percent had a BAC score &gt; 0 mg, 33 percent had low (&lt; 5%), 36 percent intermediate (between 5 and 10%) and 31 percent high (&gt; 10%) PCE risk. Using Cox models, there was a graded association by level of PCE risk and, within each level of PCE risk, women with BAC presence were at higher risk for ASCVD than women without BAC. In models adjusting for age, race/ethnicity, education level, BMI, statin use, menopausal hormone therapy, breast feeding and parity, being in the intermediate PCE risk group (relative to being at low PCE risk and having no BAC) was associated with 3.1 (95% CI, 1.5 - 6.5) increased hazard of ASCVD when no BAC was present and with 3.8 (95% CI, 1.7 - 8.7) increased hazard of ASCVD when BAC was present. Corresponding hazard ratios for women in the high PCE risks were 4.3 (95% CI, 1.9-9.6) and 7.5 (95% CI, 3.1-17.8), respectively. Conclusions: Our findings support additional predictive utility of BAC for ASCVD. In women at intermediate or high risk for ASCVD, BAC presence may help guide primary prevention.

Placental growth factor measurements in the assessment of women with suspected Preeclampsia: A stratified analysis of the PARROT trial.

Placental growth factor testing decreases time to recognition of preeclampsia and may reduce severe maternal adverse outcomes. This analysis aims to describe the clinical phenotype of women by PlGF concentration, and to determine the mechanism(s) underpinning the reduction in severe maternal adverse outcomes in the PARROT trial, in order to inform how PlGF testing may be optimally used within clinical management algorithms. This was a planned secondary analysis from the PARROT trial that compared revealed PlGF testing and management guidance with usual care in the assessment of women with suspected preterm preeclampsia. Maternal and perinatal outcomes following stratification of women by trial group, and measured PlGF concentration. 1006 women were included. PlGF<100pg/ml identified women with more marked hypertension, increased adverse maternal outcomes and preterm delivery rates, and higher rates of small for gestational age infants. There was a reduction in adverse maternal outcomes in women whose results were revealed when PlGF levels were 12-100pg/ml compared to usual care (3.8% vs 6.9%; aOR 0.15(95% CI 0.03-0.92). There was no significant difference in gestation at delivery between concealed or revealed groups in any PlGF categories. Low PlGF concentrations are associated with severe preeclampsia. The reduction in severe adverse maternal outcomes may be mediated through quicker diagnosis and intensive surveillance, as recommended by the management algorithm for those at increased risk. PlGF is particularly beneficial in those who test 12-100pg/ml, as these may be women with silent multi-organ disease who otherwise may go undetected.

Cytokine profiling: variation in immune modulation with preterm birth vs. uncomplicated term birth identifies pivotal signals in pathogenesis of preterm birth.

To assess deviations in longitudinally measured cytokines with preterm birth (PTB). Prospective longitudinal study targeting 80 subjects. Phlebotomy specimens for broad panel of cytokine analysis were obtained at three time (T)intervals: first trimester (T1: 8-14weeks' gestation), second trimester (T2: 18-22weeks' gestation), and third trimester (T3: 28-32weeks' gestation). Important demographics and outcomes were tracked. Data were stratified and the target groups were analyzed as follows: "Uncomplicated" (delivered≥37weeks) or "Preterm Birth" (<37weeks). Generalized Linear Modeling determined rate of change T1-T3 by outcome. Complete data replete with phlebotomy at all three visits were obtained on 80 women. Birth outcomes were as follows: 11 Uncomplicated Term Birth (UTB), 28 PTB, 4 low birth weight (LBW), 16 OB complications (OBC), 11 current infections (IFN), and 10 mixed complications (MC=2 or more of the above). 28 PTB were compared to 11 uncomplicated term deliveries. In both groups, T helper type 1 (TH1) cytokine (IL-1β), pleiotrophic pro-inflammatory cytokine (IL-6), and counter-regulatory cytokine (IL-10) responses decreased over gestation, but rates of change in IL-1β, IL-6, and IL-10 were significantly different. Stratification of women by smoking status additionally demonstrated significant variance in immune status over the course of pregnancy. Women delivering PTB demonstrated significant differences in cytokine trajectory over pregnancy; these data further validate key role played by immune regulation in directing pregnancy outcome. Likewise, smoking impacts longitudinal trajectory of cytokines over pregnancy.

Abstract 2322: A polygenic risk score-based genetic stratification for endometrial cancer

Abstract Endometrial cancer (EC) is the most common of gynecological cancers in the UK. There is evidence for genetic predisposition to EC, however, single nucleotide polymorphisms have not been considered in risk prediction models so far. We hypothesized that a polygenic risk score (PRS) based on a panel of robust SNPs may be useful to predict women at high risk of developing EC. We conducted a systematic review to identify the most robust SNPs which may be associated with EC risk. The resulting panel of SNPs was validated in an independent cohort comprising EC cases, and control women with intact uterus. In the present study, we used 560 cases and 1202 controls of broad-European origin to construct a PRS. Our systematic review suggested twenty four SNPs, nineteen of which were reported to reach genome-wide significance in large GWAS. Preliminary results using 560 cases and 1202 controls produced effect sizes, directions and dosages similar to published data. The mean PRS for EC cases was 0.64 (SD=0.43, 95%CI 0.60-0.68) while mean PRS for controls was 0.48 (SD=0.42, 95% CI 0.46-0.51). The AUC of the PRS achieved was 0.61. Women in the highest tertile of the PRS score had a 2.4 times increased risk of developing EC compared to women in the lowest tertile (OR=2.40, 95%CI 1.85-3.09, p = 1.47E-11). Women in the mid tertile also had a modestly increased risk of EC compared to the lowest tertile (OR=1.40, 95%CI 1.06-1.84, p = 0.017). There was a clear trend of increasing risk with category (p = 6.25E-12). There is mounting evidence for polygenic input from common variants in EC susceptibility. Our results, for the first time, validate the potential use of a PRS for risk stratification of women at high risk of EC. When considered alongside epidemiological risk factors, the PRS could provide a good discrimination for early detection and prevention of EC in a clinical setting. Citation Format: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Miriam J. Smith, Joe Dennis, Gareth D. Evans, Emma J. Crosbie. A polygenic risk score-based genetic stratification for endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2322.

Reflex cytology for triage of high-risk human papillomavirus positive self-sampled material in cervical cancer screening: a prospective cohort study.

ObjectiveHigh‐risk human papillomavirus (HrHPV)‐positive women detected by self‐sampling require an extra visit at the general practitioner for additional cytology testing, but the loss to follow up within this triage is substantial. The aim of this study was to evaluate the clinical utility of reflex cytology on hrHPV‐positive self‐samples for immediate stratification of women who need referral for colposcopy.DesignA prospective cohort study.SettingTwo Dutch cervical cancer‐screening laboratories.Population1014 screenees who tested hrHPV‐positive on self‐samples between 1 December 2018 and 1 August 2019.MethodsSelf‐samples were directly used for cytological analysis. Cytological and histological outcomes during follow up were obtained from the Dutch Pathology Registry (PALGA).Main outcome measuresTest performance of reflex cytology on self‐samples was determined for different thresholds and compared with physician‐taken cytology and histological outcomes.ResultsReflex cytology on self‐samples for detecting abnormal cytology showed a sensitivity of 26.4% (95% CI 21.8–31.3) and specificity of 90.5% (95% CI 87.7–92.8). Of all ≥CIN2 cases, 29.4% (95% CI 22.5–37.1) were detected with reflex cytology on self‐samples. The positive predictive value for detection of ≥CIN2 was higher with cytology on self‐collected samples than on physician‐collected samples. Of women who were lost to follow up, 12.9% were found to have abnormal cytology on their self‐sampled material.ConclusionCytology testing is achievable on hrHPV‐positive self‐samples, could decrease the loss to follow up in screening and is easily implementable in the current clinical practice. Of all hrHPV‐positive women with abnormal cytology on additional physician‐collected samples, 26.4% could have been directly referred for colposcopy if triage with reflex cytology on self‐sampled material had been performed.Tweetable abstractReflex cytology for triage of hrHPV+ self‐samples is of added value for direct referral of women for colposcopy.

Maternal Cardiac Assessment at 35 to 37 Weeks Improves Prediction of Development of Preeclampsia.

Preeclampsia at term accounts for half of maternal deaths from hypertensive disorders. We aimed to assess differences in maternal cardiac indices at 35+0 to 36+6 weeks' gestation between women who subsequently developed preeclampsia at term compared with those with uncomplicated pregnancy and to evaluate whether cardiac indices offer incremental prognostic value to the available screening algorithm for preeclampsia. We recruited 1602 women with singleton pregnancies who attended for a routine hospital visit at 35+0 to 36+6 weeks' gestation between April and November 2018. We recorded maternal characteristics and preeclampsia-risk-score derived from a competing risks model and measured cardiac indices. Preeclampsia developed in 3.12% (50/1602) of participants. Women with preeclampsia, compared with those without, had increased mean arterial pressure (97.6, SD, 5.53 versus 87.9, SD, 6.82 mm Hg), systemic vascular resistance (1500, interquartile range, 1393-1831 versus 1400, interquartile range, 1202-1630 PRU) and preeclampsia-risk-score (23.4, interquartile range, 9.13-40 versus 0.9, interquartile range, 0.32-3.25). Multivariable analysis demonstrated independent association between the incidence of preeclampsia and E/e' (hazard ratio, 1.19/unit [95% CI, 1.03-1.37]; P=0.018) as well as left ventricular mass indexed for body surface area (hazard ratio, 1.03/[g·m2] [95% CI, 1.003-1.051]; P=0.029). Women with E/e' ≥7.3 and left ventricular mass indexed for body surface area ≥63.2 g/m2 had an increased risk for developing preeclampsia, despite low preeclampsia-risk-score <5% (hazard ratio, 20.1 [95% CI, 10.5-38.7], P<0.001). Increased left ventricular mass and E/e' offer incremental information to available scoring systems and better stratify women at risk of developing preeclampsia at term.

Suspected Placenta Accreta: Using Imaging to Stratify Risk of Morbidity.

This study was aimed to compare clinical outcomes and use of interventions in women with suspected accreta based on the degree of antenatal suspicion. This was a retrospective cohort study of women with suspected accreta from 2007 to 2019. Included patients had one or more imaging studies suggestive of accreta. Cases were classified as "lower risk" if imaging showed possible signs of accreta including mild or superficial myometrial infiltration, an abnormal uterine contour, an abnormal uteroplacental interface, or loss of the retroplacental hypoechoic zone and "higher risk" if there was clear evidence of more than superficial myometrial infiltration, placental tissue extruding beyond the uterine serosa, bridging vessel(s), or placental lacunae with high velocity and/or turbulent flow. The primary study outcome was a composite maternal morbidity including cesarean hysterectomy, transfusion of blood or blood products, unintentional cystotomy, or intensive care unit (ICU) admission. Chi-square, Fisher's exact test, and Mann-Whitney U-test were used for analysis. A total of 78 women had a suspected accreta on imaging, 36 with "lower risk" features and 42 with "higher risk" features. There were no differences in baseline maternal demographics. Women in the "higher risk" group were more likely to have a placenta previa (p < 0.01) and preoperative consultation with gynecologic oncology (p = 0.04). There was a significant difference in composite maternal morbidity between patients with "lower risk" and "higher risk" features of accreta on imaging (50 vs. 92.9%, p < 0.01). Median gestational age at planned and actual delivery were earlier in the "higher risk" group (36.6 vs. 34.9 weeks, p < 0.01; 36.0 vs. 34.7 weeks, p < 0.01). Stratification of women with suspected accreta based on imaging corresponded to rates of maternal morbidity and operative complications, and appears to have been used clinically in selecting timing of delivery and interventions. · Increased morbidity with high risk accreta imaging.. · Interventions correlate with accreta imaging risk.. · Imaging can be used to stratify accreta cases..

Diagnostic accuracy of repeat placental growth factor measurements in women with suspected preeclampsia: A case series study.

IntroductionPreeclampsia affects about 3% of singleton pregnancies and is characterized by placental dysfunction. It is associated with significant maternal and perinatal morbidity and mortality. The diagnosis of preeclampsia remains a challenge, and the clinical course can develop for weeks before a diagnosis is confirmed. National guidelines have approved placental growth factor (PlGF) testing to rule out suspected preeclampsia, but the utility of repeated PlGF measurement is unknown. The aim of this case series analysis was to evaluate the test performance of repeated PlGF sampling in women presenting with suspected preeclampsia, and to describe relevant clinical outcomes.Material and methodsWomen who presented to maternity services with suspected preeclampsia between 20+0 and 36+6 weeks’ gestation who underwent repeat PlGF sampling with a minimum test interval of 7 days were assessed. The outcomes were delivery for preeclampsia within 14 days of sampling, the proportion changing PlGF categories, and time to delivery.ResultsIn total, 289 women with suspected preeclampsia undergoing repeat PlGF sampling were included. PlGF <100 pg/mL had a high sensitivity (87.5%, 95% confidence interval [CI] 67.6%‐97.3%) and a negative predictive value (97.7%, 95% CI 93.5%‐99.5%) at the initial test (receiver operating characteristic [ROC] area 0.79, 95% CI 0.68‐0.89). Similar test performance was seen for PlGF <100 pg/mL when undertaken as a repeat test (sensitivity 90.7%, 95% CI 85.2%‐95.9%, negative predictive value 92.2%, 95% CI 85.3‐96.6%). Overall, 25.6% of women changed PlGF category between the first and second PlGF tests. For each PlGF category, determination of time to delivery was similar for first and second tests.ConclusionsRepeat PlGF measurement demonstrates high negative predictive value for determining preeclampsia requiring delivery in 14 days. Repeat testing may be clinically useful to risk stratify women with ongoing symptoms of disease. Confirmation of the impact of these findings is required in further studies.

Sex Differences in Coronary Artery Calcium and Long-term CV Mortality.

To summarize differences in plaque depositions, coronary artery calcium (CAC) scoring, and the role of CAC in predicting atherosclerotic cardiovascular disease (ASCVD) mortality in men and women. Women have coronary plaque that is more lipid-rich, dense, and less calcified than their male counterparts. CAC scoring has emerged as a useful tool to quantify ASCVD burden. However, recent evidence favors the use of sex-adjusted CAC cutoffs for women to account for the relatively lower overall CAC burden and therefore risk stratify women appropriately. Several studies have identified CAC distribution patterns in women associated with increased CV mortality, particularly the number of lesions involved, CAC volume, and size. Multiple studies have shown that the pathophysiology and associated risks of ASCVD are different in women when compared with men. CAC scoring is a tool that is widely being used for ASCVD risk stratification. Recent studies have shown that although men have higher CAC burdens, women are more likely to develop plaque erosions with non-calcified plaque that carries a greater risk for cardiovascular events. Providers should be aware of sex-specific CAC patterns carrying increased mortality risk for women, particularly increasing lesion size and number. Given the differences in plaque composition and distribution, revised sex-adjusted CAC scoring is suggested to better risk stratify patients, especially those deemed intermediate risk, and decrease CV mortality.

Comparison of the lower uterine segment in pregnant women with and without previous cesarean section in 3\u2009T MRI

BackgroundPrenatal risk stratification of women with previous cesarean section (CS) by ultrasound thickness measurement of the lower uterine segment (LUS) is challenging. There is a wide range of proposed cutoff values and a valuable algorithm for selection before birth is not available. Using 3 T magnetic resonance imaging (MRI), we aimed to identify possible shortcomings of the current protocols used for birth selection after CS. Therefore, we evaluated anatomic and morphologic differences of the LUS and its thickness in patients with CS and those without. Possible impact factors on LUS thickness were studied.MethodsWe retrospectively analyzed 3 T MRI scans of 164 pregnant women in their second or third trimester, with (patient group, n = 60) and without previous CS (control group, n = 104). Sagittal T2-weighted images were studied. Normal findings of the LUS in MRI, reliability of MRI measurements, as well as factors influencing LUS thickness were assessed. MRI findings were compared to intraoperative findings.ResultsMRI provided good intra- (ICC 0.872) and fair inter-rater reliability (ICC 0.643). The relationship of the LUS and the cesarean scar to the surrounding anatomical structures and also its morphology varied strongly in patients and controls. Scar identification was possible in only 9/60 (15.0%) patients. The LUS was thinner in patients (1.9 ± 0.7 mm) than in controls (2.7 ± 1.3 mm). An LUS thinning up to 1 mm was observed in 23% of women without a previous CS and in 34% of women with normal intraoperative findings. Suspicion of a uterine dehiscence (LUS thickness < 1 mm) was only found in the patient group (5/59 (8.5%)) and was intraoperatively confirmed. In controls, LUS thickness was influenced by fetal weight, gestational age and amniotic fluid amounts.ConclusionVariability in anatomy, thickness and morphology seem to limit common prenatal LUS imaging diagnostics. Therefore, we consider that diagnostic protocols must be re-evaluated and imaging should be adjusted to the individual patient conditions. Due to its independency of ultrasound limitations, an additional MRI might be useful for altered anatomy and impaired ultrasound conditions. An LUS thinning up to 1 mm might be a normal finding and should be further investigated as reference value.

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.