Prenatal detection of placenta accreta spectrum using a sonographic checklist.

INTRODUCTION: The European Working Group for Abnormally Invasive Placenta proposed a checklist of ultrasound features for the antenatal detection of placenta accreta spectrum (PAS). This study aims to assess the performance of the checklist in identifying histopathologically confirmed PAS cases in a cohort with a high pre-test probability of PAS, and identify if particular features are associated with PAS. MATERIAL AND METHODS: This is a prospective multi-site cohort study conducted between 2018 and 2023. Consecutive patients who underwent ultrasound assessment for suspicion of PAS were included, and the sonographic checklist was completed at the time of ultrasound. Cases were defined as PAS where they had intraoperative findings as described by the International Federation of Gynecology and Obstetrics (FIGO) grading, and histopathological findings for hysterectomy and myometrial resection cases. All non-PAS cases in this study had placenta previa and at least one prior cesarean delivery. RESULTS: Seventy-eight participants met inclusion criteria, of whom 63 (80.7%) were diagnosed with PAS. Cesarean hysterectomy was performed in 49 cases (62.8%). Overall, third-trimester ultrasound performed at a median gestational age of 32 weeks (IQR 30-34 weeks) had a sensitivity of 0.84 (95% CI 0.73 to 0.92) and specificity of 0.73 (95% CI 0.45 to 0.92) for detecting PAS, with a positive and negative likelihood ratio of 3.15 (95% CI 1.35 to 7.35) and 0.22 (95% CI 0.11 to 0.41), respectively. Features most associated with PAS were abnormal placental lacunae (Odds Ratio [OR] 5.40 [95% CI 1.61 to 18.03] and myometrial thinning OR 6.87 [95% CI 1.93 to 24.4]). While many of the ultrasound features seen in PAS were also present in cases of placenta previa with prior Cesarean section, the median (IQR) number of features present in PAS cases was significantly higher than in the non-PAS placenta previa group (six features [3-8] vs. two features [0-3] p = 0.001). No case of non-PAS placenta previa had more than five features present. CONCLUSIONS: The use of a standardized sonographic checklist had a high sensitivity and good specificity for the detection of PAS in this prospective cohort of well-classified PAS cases.

Spatial proteomics and transcriptomics of the maternal-fetal interface in placenta accreta spectrum.

In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+ and CD8+ T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITGß1, including with fibronectin and ADAMS, emerging as central in increta. These ITGß1 ligand interactions are involved in activation of epithelial-mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring.

Radiomic study of antenatal prediction of severe placenta accreta spectrum from MR imaging.

OBJECTIVE: We previously demonstrated the potential of radiomics for prediction of severe histological Placenta Accreta Spectrum (PAS) subtypes using T2-weighted MRI. We aim is to validate our model using an additional dataset. Secondly, we explore whether performance is improved using a new approach to develop a new multivariate radiomics model. METHODS: Multi-centre retrospective analysis conducted between 2018-2023. Inclusion criteria: MRI performed for suspicion of PAS from ultrasound, clinical findings of PAS at laparotomy and/or histopathological confirmation. Radiomic features were extracted from T2-weighted MRI. The previous multivariate model was validated. Secondly, a 5-radiomic feature random forest classifier was selected from a randomised feature selection scheme to predict invasive placenta increta PAS cases. Prediction performance was assessed based on several metrics including Area Under the Curve (AUC) of the receiver operating characteristic curve (ROC), sensitivity and specificity. RESULTS: We present 100 women (mean age 34.6 (±3.9) with PAS, 64 of whom had placenta increta. Firstly, we validated the previous multivariate model and found a Support Vector Machine classifier had a sensitivity of 0.620 (95% CI: 0.068; 1.0), specificity of 0.619 (95% CI: 0.059; 1.0), an AUC of 0.671 (95% CI: 0.440; 0.922) and accuracy of 0.602 (95% CI: 0.353; 0.817) for predicting placenta increta. From the new multivariate model, the best 5-feature subset selected via the random subset feature selection scheme comprised of 4 radiomic features and 1 clinical variable (number of previous caesareans). This clinical-radiomic model achieved an AUC of 0.713 (95% CI: 0.551; 0.854), accuracy of 0.695 (95% CI 0.563; 0.793), sensitivity of 0.843 (95% CI 0.682; 0.990) and specificity of 0.447 (95% CI 0.167; 0.667). CONCLUSION: We validated our previous model and present a new multivariate radiomic model for prediction of severe placenta increta from a well-defined, cohort of PAS cases. ADVANCES IN KNOWLEDGE: Radiomic features demonstrate good predictive potential for identifying placenta increta. This suggests radiomics may be a useful adjunct to clinicians caring for women with this high-risk pregnancy condition.

Looking back to look forward: Has the time arrived for active management of obstetricians in placenta accreta spectrum?

Placenta accreta spectrum (PAS) is a relatively new obstetric condition which, until recently, was poorly understood. The true incidence is unknown because of the poor quality and heterogeneous diagnostic criteria. Classification systems have attempted to provide clarity on how to grade and diagnose PAS, but these are no longer reflective of our current understanding of PAS. This is particularly true for placenta percreta, which referred to extrauterine disease, as recent studies have demonstrated that placental villi associated with PAS have minimal potential to invade beyond the uterine serosa. It is accepted that PAS is a direct consequence of previous iatrogenic uterine injury, most commonly a previous cesarean section. Here, we "look back to look forwards"-starting with the primary predisposing factor for PAS, an iatrogenic uterine injury and subsequent wound healing. We then consider the evolution of definitions and diagnostic criteria of PAS from its first description over a century ago to current classifications. Finally, we discuss why modifications to the current classifications are needed to allow accurate diagnosis of this rare but life-threatening complication, while avoiding overdiagnosis and potential patient harm.

Appraisal of hydatidiform mole incidence and registration rates in Ireland following the establishment of a National Gestational Trophoblastic Disease Registry.

AIMS: This study aimed to re-evaluate the incidence of hydatidiform mole (HM) and determine gestational trophoblastic disease (GTD) registration rates in Ireland following the establishment of the National GTD Registry in 2017. METHODS: We performed a 3-year retrospective audit of HM cases (January 2017 to December 2019) reported in our centre. In 2019, we surveyed Irish pathology laboratories to determine the number of HMs diagnosed nationally and compared this data to that recorded in the National GTD Registry. Additionally, we compared both local and national HM incidence rates to those reported internationally. RESULTS: In the 3-year local audit, we identified 87 HMs among 1856 products of conception (POCs) providing a local HM incidence rate of 3.92 per 1000 births. The 1-year pathology survey recorded 170 HMs in 6008 POCs, yielding a national incidence rate of 2.86 per 1000 births. Importantly, the local HM incidence rate exceeded the national incidence rate by 37% and the local partial HM incidence (1 in 296 births) was 64% higher than the nationally incidence rate (1 in 484 births). Notably, 42% of the HM and atypical POCs diagnosed nationally were not reported to the National GTD Registry. CONCLUSIONS: Our study reveals increased HM incidence rates both locally and nationally compared with previous Irish studies. The higher local PHM incidence may reflect more limited access to ploidy analysis in other pathology laboratories nationally. Significantly, almost half of the women with diagnosed or suspected HM were not registered with the National GTD Centre.

Practical guidelines of the EOTTD for pathological and genetic diagnosis of hydatidiform moles.

Hydatidiform moles are rare and thus most pathologists and geneticists have little experience with their diagnosis. It is important to promptly and correctly identify hydatidiform moles given that they are premalignant disorders associated with a risk of persistent gestational trophoblastic disease and gestational trophoblastic neoplasia. Improvement in diagnosis can be achieved with uniformization of diagnostic criteria and establishment of algorithms. To this aim, the Pathology and Genetics Working Party of the European Organisation for Treatment of Trophoblastic Diseases has developed guidelines that describe the pathological criteria and ancillary techniques that can be used in the differential diagnosis of hydatidiform moles. These guidelines are based on the best available evidence in the literature, professional experience and consensus of the experts' group involved in its development.

Radiomics-based prediction of FIGO grade for placenta accreta spectrum.

BACKGROUND: Placenta accreta spectrum (PAS) is a rare, life-threatening complication of pregnancy. Predicting PAS severity is critical to individualise care planning for the birth. We aim to explore whether radiomic analysis of T2-weighted magnetic resonance imaging (MRI) can predict severe cases by distinguishing between histopathological subtypes antenatally. METHODS: This was a bi-centre retrospective analysis of a prospective cohort study conducted between 2018 and 2022. Women who underwent MRI during pregnancy and had histological confirmation of PAS were included. Radiomic features were extracted from T2-weighted images. Univariate regression and multivariate analyses were performed to build predictive models to differentiate between non-invasive (International Federation of Gynecology and Obstetrics [FIGO] grade 1 or 2) and invasive (FIGO grade 3) PAS using R software. Prediction performance was assessed based on several metrics including sensitivity, specificity, accuracy and area under the curve (AUC) at receiver operating characteristic analysis. RESULTS: Forty-one women met the inclusion criteria. At univariate analysis, 0.64 sensitivity (95% confidence interval [CI] 0.0-1.00), specificity 0.93 (0.38-1.0), 0.58 accuracy (0.37-0.78) and 0.77 AUC (0.56-.097) was achieved for predicting severe FIGO grade 3 PAS. Using a multivariate approach, a support vector machine model yielded 0.30 sensitivity (95% CI 0.18-1.0]), 0.74 specificity (0.38-1.00), 0.58 accuracy (0.40-0.82), and 0.53 AUC (0.40-0.85). CONCLUSION: Our results demonstrate a predictive potential of this machine learning pipeline for classifying severe PAS cases. RELEVANCE STATEMENT: This study demonstrates the potential use of radiomics from MR images to identify severe cases of placenta accreta spectrum antenatally. KEY POINTS: • Identifying severe cases of placenta accreta spectrum from imaging is challenging. • We present a methodological approach for radiomics-based prediction of placenta accreta. • We report certain radiomic features are able to predict severe PAS subtypes. • Identifying severe PAS subtypes ensures safe and individualised care planning for birth.

Selective modulation of monocyte and neutrophil responses with activated protein C in preterm infants.

BACKGROUND: Inflammation is associated with many disorders of preterm infants including periventricular leukomalacia, chronic lung disease, and necrotizing enterocolitis. Activated protein c (APC) has shown positive immunomodulatory effects. OBJECTIVES: We aimed to study neutrophil and monocyte function in response to lipopolysaccharide (LPS) and APC stimulation ex vivo in preterm infants <32 weeks gestation over the first week of life compared to neonatal and adult controls. METHODS: Peripheral blood was taken on day 1, 3, and 7 and stimulated with LPS in the absence or presence of APC. Expression of toll-like receptor 4 (TLR4) and CD11b and reactive oxygen intermediate (ROI) release from neutrophils and monocytes was examined by flow cytometry. RESULTS: LPS induced neutrophil ROI in adults and preterm infants and was significantly reduced by APC. Baseline and LPS-induced monocyte ROI production in preterm neonates was increased compared to adult and term controls. Neutrophil TLR4 baseline expression was higher in term controls compared to preterm infants. CONCLUSION: Increased systemic ROI release in preterm infants may mediate tissue damage, ROI was reduced by APC. However, due to the high risk of hemorrhage further examination of APC mutant forms with anti-inflammatory but decreased anticoagulant properties is merited.