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Background Current clinical post-mortem imaging techniques do not provide sufficiently high-resolution imaging for smaller fetuses after pregnancy loss. Post-mortem micro-CT is a non-invasive technique that can deliver high diagnostic accuracy for these smaller fetuses. The purpose of the study is to identify the main predictors of image quality for human fetal post-mortem micro-CT imaging. Methods Human fetuses were imaged using micro-CT following potassium tri-iodide tissue preparation, and axial head and chest views were assessed for image quality on a Likert scale by two blinded radiologists. Simple and multivariable linear regression models were performed with demographic details, iodination, tissue maceration score and imaging parameters as predictor variables. Results 258 fetuses were assessed, with median weight 41.7 g (2.6–350 g) and mean gestational age 16 weeks (11–24 weeks). A high image quality score (> 6.5) was achieved in 95% of micro-CT studies, higher for the head (median = 9) than chest (median = 8.5) imaging. The strongest negative predictors of image quality were increasing maceration and body weight (p Conclusions High micro-CT image quality score is achievable following early pregnancy loss despite fetal maceration, particularly in smaller fetuses where conventional autopsy may be particularly challenging. These findings will help establish clinical micro-CT imaging services, addressing the need for less invasive fetal autopsy methods.

Objectives To determine the diagnostic accuracy of postmortem magnetic resonance imaging (PM‐MRI) and postmortem ultrasound (PM‐US) for perinatal autopsy in the same patient cohort, and to determine whether PM‐US can provide the same anatomical information as PM‐MRI. Methods In this prospective, 5‐year (July 2014–July 2019) single‐center study, we performed 1.5‐T PM‐MRI and PM‐US in an unselected cohort of perinatal deaths. The diagnostic accuracies of both modalities were calculated, using autopsy as the reference standard. As a secondary objective, the concordance rates between the two imaging modalities for the overall main diagnosis and for five anatomical regions (brain, spine, thorax, heart and abdomen) were calculated. Results During the study period, 136 cases underwent both PM‐US and PM‐MRI, of which 88 (64.7%) also underwent autopsy. There was no significant difference in the rates of concordance with autopsy between the two modalities for overall diagnosis (PM‐US, 86.4% (95% CI, 77.7–92.0%) vs PM‐MRI, 88.6% (95% CI, 80.3–93.7%)) or in the sensitivities and specificities for individual anatomical regions. There were more non‐diagnostic PM‐US than PM‐MRI examinations for the brain (22.8% vs 3.7%) and heart (14.7% vs 5.1%). If an ‘imaging‐only’ autopsy had been performed, PM‐US would have achieved the same diagnosis as 1.5‐T PM‐MRI in 86.8% (95% CI, 80.0–91.5%) of cases, with the highest rates of agreement being for spine (99.3% (95% CI, 95.9–99.9%)) and cardiac (97.3% (95% CI, 92.4–99.1%)) findings and the lowest being for brain diagnoses (85.2% (95% CI, 76.9–90.8%)). Conclusion Although there were fewer non‐diagnostic cases using PM‐MRI than for PM‐US, the high concordance rate for overall diagnosis suggests that PM‐US could be used for triaging cases when PM‐MRI access is limited or unavailable. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation—within a few cell divisions of the zygote—of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development. Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.

To evaluate the ultrasound diagnostic rates of complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM) in women presenting with a missed miscarriage, the clinical complications at diagnosis and the risk of gestational trophoblastic neoplasia (GTN) after surgical evacuation and to compare our findings with those of the published literature by completing a systematic review and meta-analysis STUDY DESIGN: Retrospective review of the data of 295 women diagnosed with a histologically confirmed hydatidiform moles (HM) over a 15-year period, including 128 CHM and 167 PHM. All women were referred to a regional specialist centre for follow-up and further management. An electronic search of PubMed, Google Scholar and MEDLINE was performed for studies published between September 1973 and September 2017 reporting on the early ultrasound diagnosis of hydatidiform mole. Only cohort studies which provided ultrasound data confirmed by histopathology were included.In the cohort study, ultrasound imaging diagnosed a significantly (p0.001) higher number of CHM (95/128 (74.2%) than PHM (68/167 (40.7%). Ovarian theca lutea cysts were observed in three CHM and one PHM. There were no cases of pre-eclampsia or thyrotoxicosis at the time of diagnosis. Maternal serum β-human chorionic gonadotrophin levels were abnormally low (0.5 MoM) in 5/51 (10%) CHM and 23/43 (53%) PHM and abnormally high (2.0 MoM) in 20/51 (39%) CHM and 2/43 (5%) PHM. Seventeen (12.3%) CHM and two (1.4%) PHM developed a GTN requiring treatment. In the literature the proportion of histologically diagnosed HM, suspected on ultrasound in early pregnancy, ranged between 34.2 and 90.2% for HM, 57.8 and 95% for CHM and 17.6 and 51.6% for PHM. The meta-analysis indicated substantial heterogeneity in the overall ultrasound diagnosis of HM and in the differential diagnosis between CHM and PHM.As around a third of CHM and two thirds of PHM are not diagnosed on ultrasound in cases of missed miscarriage, histopathological examination of all products of conception in case of early pregnancy failure is essential to detect molar changes. This is particularly important for the management of women with CHM who have a higher risk of developing a GTN.

Objectives To determine the feasibility and tissue yield of a perinatal incisionless ultrasound‐guided biopsy procedure, the INcisionless Targeted Core Tissue (INTACT) technique, in the context of minimally invasive autopsy. Methods Cases of perinatal death in which the parents consented for minimally invasive autopsy underwent postmortem magnetic resonance imaging and an INTACT biopsy procedure, defined as needle biopsy of organs via the umbilical cord, performed under ultrasound guidance. In each case, three cores of tissue were obtained from seven target organs (both lungs, both kidneys, heart, spleen and liver). Biopsy success was predefined as an adequate volume of the intended target organ for pathological analysis, as judged by a pathologist blinded to the case and biopsy procedure. Results Thirty fetuses underwent organ sampling. Mean gestational age was 30 weeks (range, 18–40 weeks) and mean delivery‐to‐biopsy interval was 12 days (range, 6–22 days). The overall biopsy success rate was 153/201 (76.1%) samples, with the success rates in individual organs being highest for the heart and lungs (93% and 91%, respectively) and lowest for the spleen (11%). Excluding splenic samples, the biopsy success rate was 150/173 (86.7%). Histological abnormalities were found in 4/201 (2%) samples, all of which occurred in the lungs and kidneys of a fetus with pulmonary hypoplasia and multicystic kidney disease. Conclusions Incisionless ultrasound‐guided organ biopsy using the INTACT procedure is feasible, with an overall biopsy success rate of over 75%. This novel technique offers the ideal combination of an imaging‐led autopsy with organ sampling for parents who decline the conventional invasive approach. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: Pregnant women have been identified as a potentially at-risk group concerning COVID-19 infection, but little is known regarding the susceptibility of the fetus to infection. Co-expression of ACE2 and TMPRSS2 has been identified as a prerequisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. METHODS: We performed a retrospective analysis of a single cell data repository. The data were then validated at both gene and protein level by performing RT-qPCR and two-colour immunohistochemistry on a library of second-trimester human fetal tissues. FINDINGS: TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels only in the fetal intestine and kidney, and is not expressed in the fetal lung. The placenta also does not co-express the two proteins across the second trimester or at term. INTERPRETATION: This dataset indicates that the lungs are unlikely to be a viable route of SARS-CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the gastrointestinal tract is likely to be susceptible to infection due to its high co-expression of both proteins, as well as its exposure to potentially infected amniotic fluid. TWEETABLE ABSTRACT: This work provides detailed mechanistic insight into the relative protection & vulnerabilities of the fetus & placenta to SARS-CoV-2 infection by scRNAseq & protein expression analysis for ACE2 & TMPRSS2. The findings help to explain the low rate of vertical transmission. ispartof: BJOG vol:129 issue:2 pages:256-266 ispartof: location:England status: published

Ultrasound is an essential tool for guidance of many minimally-invasive surgical and interventional procedures, where accurate placement of the interventional device is critical to avoid adverse events. Needle insertion procedures for anaesthesia, fetal medicine and tumour biopsy are commonly ultrasound-guided, and misplacement of the needle may lead to complications such as nerve damage, organ injury or pregnancy loss. Clear visibility of the needle tip is therefore critical, but visibility is often precluded by tissue heterogeneities or specular reflections from the needle shaft. This paper presents the in vitro and ex vivo accuracy of a new, real-time, ultrasound needle tip tracking system for guidance of fetal interventions. A fibre-optic, Fabry-Pérot interferometer hydrophone is integrated into an intraoperative needle and used to localise the needle tip within a handheld ultrasound field. While previous, related work has been based on research ultrasound systems with bespoke transmission sequences, the new system-developed under the ISO 13485 Medical Devices quality standard-operates as an adjunct to a commercial ultrasound imaging system and therefore provides the image quality expected in the clinic, superimposing a cross-hair onto the ultrasound image at the needle tip position. Tracking accuracy was determined by translating the needle tip to 356 known positions in the ultrasound field of view in a tank of water, and by comparison to manual labelling of the the position of the needle in B-mode US images during an insertion into an ex vivo phantom. In water, the mean distance between tracked and true positions was 0.7 ± 0.4 mm with a mean repeatability of 0.3 ± 0.2 mm. In the tissue phantom, the mean distance between tracked and labelled positions was 1.1 ± 0.7 mm. Tracking performance was found to be independent of needle angle. The study demonstrates the performance and clinical compatibility of ultrasound needle tracking, an essential step towards a first-in-human study. ispartof: SENSORS vol:22 issue:23 ispartof: location:Switzerland status: published

Objective To determine the optimal duration of human chorionic gonadotrophin (hCG) surveillance following treatment for low and high risk gestational trophoblastic neoplasia (GTN) and establish whether the current surveillance protocol that recommends life-long hCG monitoring requires revision. Methods A population-based cohort study was undertaken using a national registry, comprising patients from both tertiary trophoblastic disease treatment units in the UK (London and Sheffield). All patients who received chemotherapy for low or high risk GTN in the UK between 1958 and 2014 in London and 1973 and 2015 in Sheffield (n = 4201) were included in the study. Patients with placental site trophoblastic tumours and epithelioid trophoblastic tumours were excluded due to their distinct clinical behavior, treatment and follow-up requirements. The risk of recurrence with time following completion of chemotherapy for low or high risk GTN was measured. Results The overall risk of relapse in this national cohort of 4201 patients was 4.7% (198/4201) with a median time to recurrence of 117.5 days (range 9 days to 6.54 years). The greatest risk of recurrence occurred in the first year after completing treatment for either low or high risk GTN measuring 72.7% (n = 112) or 86.4% (n = 38), respectively. The subsequent recurrence risk reduced over time with none observed beyond 7 years. Conclusions The absence of any recurrences beyond seven years following completion of chemotherapy for GTN indicates that the UK policy of life-long hCG surveillance is unnecessary. Our revised conservative protocol recommends stopping after 10 years.

Background Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors. Methods The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976–2006) were compared to our new modern cohort (2007–2014), when intensified treatments were introduced. Results Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8–87.6%) and 75% (95% CI 66.3–84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61–23.81, p = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17–50.96, p

OBJECTIVE: To assess the diagnostic accuracy of postmortem ultrasound performed by operators blinded to prenatal findings and to invasive autopsy results in fetuses at different gestational ages and to investigate the effect of various parameters on its diagnostic success. METHODS: We performed postmortem two-dimensional ultrasound examination, blinded to clinical details, on 163 fetuses at 13-42 weeks' gestation. Logistic regression analysis was used to investigate the effect of: (i) gestational age at postmortem ultrasound, (ii) presence of maceration and (iii) mode of death, on whether the exam succeeded or failed to reach a diagnosis. In 123 cases in which invasive autopsy was available, the diagnostic accuracy of ultrasound in detecting major organ abnormalities was evaluated, using invasive autopsy as the gold standard. RESULTS: For the fetal brain, postmortem ultrasound exam was non-diagnostic in significantly more fetuses with maceration (39.5%; 17/43) vs those without maceration (20.0%; 24/120) (P = 0.013). For the fetal thorax, the exam was non-diagnostic in 34.1% (15/44) of fetuses

Cancer during pregnancy has been associated with (pathologically) small for gestational age offspring, especially after exposure to chemotherapy in utero. These infants are most likely growth restricted, but sonographic results are often lacking. In view of the paucity of data on underlying pathophysiological mechanisms, the objective was to summarize all studies investigating placental pathology related to cancer(treatment). A systematic search in PubMed/Medline, Embase (OVID) and SCOPUS was conducted to retrieve all studies about placental pathology in cancer during pregnancy or after cancer treatment, published until August 2020. The literature search yielded 5784 unique publications, of which 111 were eligible for inclusion. Among them, three groups of placental pathology were distinguished. First, various histopathologic changes including maternal vascular malperfusion have been reported in pregnancies complicated by cancer and after cancer treatment exposure, which were not specific to type of cancer(treatment). Second, cancer(treatment) has been associated with placental cellular pathology including increased oxidative damage and apoptosis, impaired angiogenesis and genotoxicity. Finally, involvement of the placenta by cancer cells has been described, involving both the intervillous space and rarely villous invasion, with such fetuses are at risk of having metastases. In conclusion, growth restriction is often observed in pregnancies complicated by cancer and its cause can be multifactorial. Placental histopathologic changes, cellular pathology and genotoxicity caused by the cancer(treatment) may each play a role. ispartof: PLACENTA vol:111 pages:33-46 ispartof: location:Netherlands status: published

Background Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. Methods In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF ( Results Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p p p p p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35–3.86, p = 0.002). Conclusions Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. Impact Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort.

A well-functioning placenta is critical for healthy fetal development, as the placenta brings fetal blood in close contact with nutrient rich maternal blood, enabling exchange of nutrients and waste between mother and fetus. The feto-placental circulation forms a complex branching structure, providing blood to fetal capillaries, which must receive sufficient blood flow to ensure effective exchange, but at a low enough pressure to prevent damage to placental circulatory structures. The branching structure of the feto-placental circulation is known to be altered in complications such as fetal growth restriction, and the presence of regions of vascular dysfunction (such as hypovascularity or thrombosis) are proposed to elevate risk of placental pathology. Here we present a methodology to combine micro-computed tomography and computational model-based analysis of the branching structure of the feto-placental circulation in ex vivo placentae from normal term pregnancies. We analyse how vascular structure relates to function in this key organ of pregnancy; demonstrating that there is a 'resilience' to placental vascular structure-function relationships. We find that placentae with variable chorionic vascular structures, both with and without a Hyrtl's anastomosis between the umbilical arteries, and those with multiple regions of poorly vascularised tissue are able to function with a normal vascular resistance. Our models also predict that by progressively introducing local heterogeneity in placental vascular structure, large increases in feto-placental vascular resistances are induced. This suggests that localised heterogeneities in placental structure could potentially provide an indicator of increased risk of placental dysfunction.

Background: While pregnant women have been identified as a potentially at-risk group concerning COVID-19 infection, little is known regarding the susceptibility of the fetus to infection. Co-expression of ACE2 and TMPRSS2 has been identified as a pre-requisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. Methods: We performed a retrospective analysis of single cell data repositories. This data was then validated at both gene and protein level by performing qRT-PCR and two-colour immunohistochemistry on a library of second-trimester human fetal tissues. Findings: TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels, only in the fetal intestine and kidney and is not expressed in the fetal lung. The placenta is also negative for the two proteins both during development and at term. Interpretation: This dataset indicates that the lungs are unlikely to be a viable route of SARS-CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the GI tract is likely to be susceptible to infection due to its high co-expression of both proteins, as well as its exposure to potentially infected amniotic fluid. Funding Information: This work was made possible by an MRC / UKRI COVID-19 Rapid response initiative grant (MR/V028480/1). Declaration of Interests: The authors declare no conflicts of interest related to this work or its developments. DC is founder, shareholder, and consultant of Next Generation Diagnostic SRL. Ethics Approval Statement: Human fetal tissues were obtained with consent through the Human Developmental Biology Resource (HDBR; REC 18/LO/0822 – IRAS 244325; Project ID 2000478). Placental samples were obtained at delivery of an uncomplicated, full-term pregnancy (median 39 weeks PCW [Range 38+1 -39+4] for 6 patients recruited through the EVERREST Prospective Study as normal controls (National Research Ethics reference 13/LO/1254), NCT02097667 registered 31st October 2013[10].

Hydatidiform mole (HM) affects around 1/1000 pregnancies, and in such cases the recurrence risk is around 1%, being greater for those with complete HM (CHM). Whilst most cases appear sporadic with unknown mechanisms, there is a distinct subgroup of patients who suffer recurrent pregnancy loss, including multiple recurrent CHM (familial recurrent biparental HM syndrome). The majority of these cases are related to maternal genetic mutations in genes related to the control of imprinting, specifically NALP7 and KHDC3L. Oocyte donation is an effective treatment allowing these patients to have successful pregnancies. Approximately 1 in 50,000 pregnancies are complicated by twin pregnancy comprising normal foetus and HM, the majority of reported cases being CHM. Such pregnancies are at significantly increased risk of complications, including pregnancy loss, early-onset preeclampsia and severe preterm delivery, but when managed conservatively the delivery of a liveborn healthy infant occurs in around one-third of cases. Regardless of management, the risk of persistent GTD in such cases appears similar to that following singleton CHM. Rarely, other conditions mimic prenatal ultrasound appearances of twin pregnancy with HM, CHM mosaicism and placental mesenchymal dysplasia, both of which have distinctive histological and genetic features.

Context.— Fetal growth restriction is a risk factor for intrauterine fetal death. Currently, definitions of fetal growth restriction in stillborns are heterogeneous. Objectives.— To develop a consensus definition for fetal growth restriction retrospectively diagnosed at fetal autopsy in intrauterine fetal death. Design.— A modified online Delphi survey in an international panel of experts in perinatal pathology, with feedback at group level and exclusion of nonresponders. The survey scoped all possible variables with an open question. Variables suggested by 2 or more experts were scored on a 5-point Likert scale. In subsequent rounds, inclusion of variables and thresholds were determined with a 70% level of agreement. In the final rounds, participants selected the consensus algorithm. Results.— Fifty-two experts participated in the first round; 88% (46 of 52) completed all rounds. The consensus definition included antenatal clinical diagnosis of fetal growth restriction OR a birth weight lower than third percentile OR at least 5 of 10 contributory variables (risk factors in the clinical antenatal history: birth weight lower than 10th percentile, body weight at time of autopsy lower than 10th percentile, brain weight lower than 10th percentile, foot length lower than 10th percentile, liver weight lower than 10th percentile, placental weight lower than 10th percentile, brain weight to liver weight ratio higher than 4, placental weight to birth weight ratio higher than 90th percentile, histologic or gross features of placental insufficiency/malperfusion). There was no consensus on some aspects, including how to correct for interval between fetal death and delivery. Conclusions.— A consensus-based definition of fetal growth restriction in fetal death was determined with utility to improve management and outcomes of subsequent pregnancies.

Minimally invasive fetal interventions require accurate imaging from inside the uterine cavity. Twin‐to‐twin transfusion syndrome (TTTS), a condition considered in this study, occurs from abnormal vascular anastomoses in the placenta that allow blood to flow unevenly between the fetuses. Currently, TTTS is treated fetoscopically by identifying the anastomosing vessels, and then performing laser photocoagulation. However, white light fetoscopy provides limited visibility of placental vasculature, which can lead to missed anastomoses or incomplete photocoagulation. Photoacoustic (PA) imaging is an alternative imaging method that provides contrast for hemoglobin, and in this study, two PA systems were used to visualize chorionic (fetal) superficial and subsurface vasculature in human placentas. The first system comprised an optical parametric oscillator for PA excitation and a 2D Fabry‐Pérot cavity ultrasound sensor; the second, light emitting diode arrays and a 1D clinical linear‐array ultrasound imaging probe. Volumetric photoacoustic images were acquired from ex vivo normal term and TTTS‐treated placentas. It was shown that superficial and subsurface branching blood vessels could be visualized to depths of approximately 7 mm, and that ablated tissue yielded negative image contrast. This study demonstrated the strong potential of PA imaging to guide minimally invasive fetal therapies., Successful therapy of twin‐to‐twin transfusion (TTTS) syndrome requires accurate imaging to guide laser photocoagulation of the anastomosing placental vessels. Here, two volumetric photoacoustic imaging systems with optical (Fabry‐Pérot) and piezoelectric ultrasound receivers were used to image human ex vivo normal and TTTS‐treated placentas. With imaging depths of approximately 7 mm, vasculature and ablated regions were visualized. The strong potential of photoacoustic imaging to guide minimally invasive fetal therapies was demonstrated.

Three- and four-dimensional US techniques in antenatal screening are commonplace, but they are not routinely used for perinatal postmortem US. In this technical innovation, we performed both two-dimensional (2-D) and three-dimensional (3-D) postmortem US on 11 foetuses (mean gestation: 23 weeks; range: 15-32 weeks) to determine whether there was any benefit in 3-D over conventional 2-D methods. In one case of osteogenesis imperfecta, both 2-D and 3-D US images were non-diagnostic because of small foetal size. Of the remaining 10 foetuses, 7 were normal at imaging and autopsy, and 3 had abnormalities detected on both 2-D and 3-D US. There were no false-positive diagnoses by 2-D or 3-D US. Whilst 3-D postmortem US was a feasible technique, it did not provide additional information over 2-D US. Routine 3-D postmortem US cannot therefore be routinely recommended based on our findings.

Placental pathological abnormalities are more frequently observed in complicated pregnancies than in healthy pregnancies. Infiltration of CD8Fetal growth restriction (FGR) and pre-eclampsia are severe, adverse pregnancy outcomes. Alterations in placental histology are frequently reported in these pregnancy complications and are often based upon scoring by pathologists. However, many alterations are also observed in placenta from uncomplicated pregnancies. Moreover, knowledge of disease state may bias assessment. We sought to perform an objective comparison of placental microscopic appearance in normal and complicated pregnancies. Placental villous tissue (n = 823) and edge biopsies (n = 488) from 871 individual, singleton pregnancies were collected after delivery. Cases of small-for-gestational age (SGA) or pre-eclampsia were matched with healthy controls. A subset of the SGA cases displayed signs of FGR. Cases of preterm delivery were also included. Tissue sections were stained with haematoxylin and eosin or antibodies for CD8, CD14, CD31, CD79α and elastase. Images were scored by two experienced pathologists for pathological features or analysed by image analysis and stereology. Analyses were performed blind to case-control status and gestational age. Volume fraction of T-cells increased in placentas from pregnancies complicated by pre-eclampsia (adjusted odds ratio (aOR) 1.46, 95% CI: 1.12-1.90) and FGR (aOR 1.64, 95% CI: 1.11-2.43), whereas B-cells only increased in FGR (aOR 1.65, 95% CI: 1.05-2.60). Pathological abnormalities in villous tissue were reported in 21.4% (88/411) of complicated pregnancies and 14.3% (52/363) of controls (OR 1.62, 95% CI: 1.12-2.37). There were no differences in the fractions of endothelial cells, fibrin deposition, macrophages and neutrophils when comparing normal and complicated pregnancies. In conclusion, FGR and pre-eclampsia are associated with T-cell infiltration of the placenta and placental pathological abnormalities.

KEY POINTS: Placental pathological abnormalities are more frequently observed in complicated pregnancies than in healthy pregnancies Infiltration of CD8+ T-cells into the placental villous tissue occurred in both fetal growth restriction and pre-eclampsia, whereas CD79α+ B-cell infiltration was only apparent with reduced fetal growth. Vascularisation, fibrin depositions, macrophage and neutrophil infiltration in the placenta did not differ between healthy and complicated pregnancies. ABSTRACT: Fetal growth restriction (FGR) and pre-eclampsia are severe, adverse pregnancy outcomes. Alterations in placental histology are frequently reported in these pregnancy complications and are often based upon scoring by pathologists. However, many alterations are also observed in placenta from uncomplicated pregnancies. Moreover, knowledge of disease state may bias assessment. We sought to perform an objective comparison of placental microscopic appearance in normal and complicated pregnancies. Placental villous tissue (n = 823) and edge biopsies (n = 488) from 871 individual, singleton pregnancies were collected after delivery. Cases of small-for-gestational-age (SGA) or pre-eclampsia were matched with healthy controls. A subset of the SGA cases displayed signs of FGR. Cases of pre-term delivery were also included. Tissue sections were stained with H&E or antibodies for CD8, CD14, CD31, CD79α, elastase. Images were scored by two experienced pathologists for pathological features or analysed by image analysis and stereology. Analyses were performed blind to case-control status and gestational age. Volume fraction of T-cells increased in placentas from pregnancies complicated by pre-eclampsia (adjusted odds ratio (aOR) 1.46, 95% CI 1.12-1.90) and FGR (aOR 1.64, 95% CI 1.11-2.43), whereas B-cells only increased in FGR (aOR 1.65, 95% CI 1.05-2.60). Pathological abnormalities in villous tissue were reported in 21.4% (88/411) of complicated pregnancies and 14.3% (52/363) of controls (OR 1.62, 95% CI 1.12-2.37). There were no differences in the fractions of endothelial cells, fibrin deposition, macrophages, and neutrophils when comparing normal and complicated pregnancies. In conclusion, FGR and pre-eclampsia are associated with T-cell infiltration of the placenta and placental pathological abnormalities. This article is protected by copyright. All rights reserved.

Uterine artery application of adenoviral vascular endothelial growth factor A165 (Ad.VEGF-A165) gene therapy increases uterine blood flow and fetal growth in experimental animals with fetal growth restriction (FGR). Whether Ad.VEGF-A165 reduces lifelong cardiovascular disease risk imposed by FGR remains unknown. Here, pregnant guinea pigs fed 70% normal food intake to induce FGR received Ad.VEGF-A165 (1×1010 viral particles, n = 15) or vehicle ( n = 10), delivered to the external surface of the uterine arteries, in midpregnancy. Ad libitum-fed controls received vehicle only ( n = 14). Litter size, gestation length, and perinatal mortality were similar in control, untreated FGR, and FGR+Ad.VEGF-A165 animals. When compared with controls, birth weight was lower in male but higher in female pups following maternal nutrient restriction, whereas both male and female FGR+Ad.VEGF-A165 pups were heavier than untreated FGR pups ( P < 0.05, ANOVA). Postnatal weight gain was 10–20% greater in female FGR+Ad.VEGF-A165 than in untreated FGR pups, depending on age, although neither group differed from controls. Maternal nutrient restriction reduced heart weight in adult female offspring irrespective of Ad.VEGF-A165 treatment but did not alter ventricular wall thickness. In males, postnatal weight gain and heart morphology were not affected by maternal treatment. Neither systolic, diastolic, mean arterial pressure, adrenal weight, nor basal or challenged plasma cortisol were affected by maternal undernutrition or Ad.VEGF-A165 in either sex. Therefore, increased fetal growth conferred by maternal uterine artery Ad.VEGF-A165 is sustained postnatally in FGR female guinea pigs. In this study, we did not find evidence for an effect of maternal nutrient restriction or Ad.VEGF-A165 therapy on adult offspring blood pressure.

Objectives Diffusion-weighted MRI provides information regarding body water movement following death, which may be an imaging marker of post-mortem interval (time since death; PMI) or maceration (degree of tissue degradation during intra-uterine retention) in perinatal deaths. Our aim was to evaluate the relationship between maceration, PMI and body organ apparent diffusion coefficient (ADC) values in a cohort of subjects across a wide gestational range. Materials Whole body post-mortem MRI with diffusion-weighted imaging (DWI) sequences were performed at 1.5 T, with b values of 0, 500 and 1000 mm2/s. Mean ADC values were calculated from regions of interest (ROIs) placed in the lungs, myocardium, spleen, renal cortex, liver and psoas muscle by two independent readers. Multivariable regression analysis was performed against PMI, gestational age, post-mortem weight, maceration score and gender. Results Eighty perinatal deaths were imaged with mean gestational age of 32 weeks (18–41 weeks), of which 49 (61.3%) were male. The mean PMI was 8 days (1–18 days). Maceration scores were statistically significant predictive factors for ADC values in all included body organs except the lungs, but PMI was not a predictor for ADC values in any body organ. In the absence of maceration (n = 14), PMI was not statistically associated with ADC values in any of the body areas. The ratio of agreement in the majority of body areas was close to 1 (range between 0.95 and 1.10). Conclusion Maceration, not PMI, is significantly associated with ADC values in perinatal deaths. Further research is needed to understand organ-specific changes in the post-mortem period.

Perinatal death (PD) is a devastating obstetric complication. Determination of cause of death helps in understanding why and how it occurs, and it is an indispensable aid to parents wanting to understand why their baby died and to determine the recurrence risk and management in subsequent pregnancy. Consequently, a perinatal death requires adequate diagnostic investigation. An important first step in the analysis of PD is to identify the case circumstances, including relevant details regarding maternal history, obstetric history and current pregnancy (complications are evaluated and recorded). In the next step, placental examination is suggested in all cases, together with molecular cytogenetic evaluation and fetal autopsy. Investigation for fetal maternal hemorrhage by Kleihauer is also recommended as standard. In cases where parents do not consent to autopsy, alternative approaches such as minimally invasive postmortem examination, postmortem magnetic resonance imaging, and fetal photographs are good alternatives. After all investigations have been performed it is important to combine findings from the clinical review and investigations together, to identify the most probable cause of death and counsel the parents regarding their loss. (C) 2017 Elsevier Ltd. All rights reserved.

Pathological examination of the placenta is a well-established investigation following delivery in order to investigate the underlying mechanisms of a range of pregnancy related complications. Several recommendations and guidelines are available regarding the indications for such placental testing. The immediate clinical rationale for this process is to identify underlying disease processes which may have an impact on the management of either the infant or the mother in future pregnancies. Additional benefits include improved understanding of the pathophysiological processes of disease and potential medicolegal implications in cases with adverse outcome, including regarding possible timing of lesions. However, interpretation of findings in specific cases remains difficult for several methodological reasons. Future progress requires the use of high quality, well phenotyped tissue collections, with blinded assessment using consensus criteria. In addition, it is likely that novel discovery-based approaches will significantly change the concept of how placental disease is investigated, making tissue sampling even more important across a wide range of pregnancy-related diseases. This will be associated with more stringent conditions for placental evaluation and sampling, including strict definitions of sample site and interval post-delivery, the effects of which will vary depending on the precise assays and methodologies used.

Contains fulltext : 177307.pdf (Publisher’s version ) (Closed access) Background: Worldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible. Patients and methods: Between January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified. Results: Of the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5-10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7-44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0-16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3-3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9-12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4-30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system. Conclusion: Our simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.

Perinatal autopsy practice is undergoing a state of change with the introduction of evidence-based cross-sectional imaging, driven primarily by parental choice. In particular, the introduction of post mortem magnetic resonance imaging (PMMR) has helped to advance less-invasive perinatal autopsy in the United Kingdom (UK) and Europe. However, there are limitations to PMMR and other imaging techniques which need to be overcome, particularly with regard to imaging very small fetuses. Imaging is also now increasingly used to investigate particular deaths in childhood, such as suspected non-accidental injury (NAI) and sudden unexpected death in infancy (SUDI). Here we focus on current topical developments the field, with particular emphasis on the application of imaging to perinatal autopsy, and pediatric forensic deaths. Different imaging modalities and their relative advantages and disadvantages are discussed, together with other benefits of more advanced cross-sectional imaging which currently lie in the research domain. Whilst variations in local imaging service provision and need may determine different practice patterns, and access to machines and professionals with appropriate expertise and experience to correctly interpret the findings may limit current practices, we propose that gold standard perinatal and pediatric autopsy services would include complete PMMR imaging prior to autopsy, with PMCT in suspicious childhood deaths. This approach would provide maximal diagnostic yield to the pathologist, forensic investigator and most importantly, the parents.

In a model of growth-restricted sheep pregnancy, it was previously demonstrated that transient uterine artery VEGF overexpression can improve fetal growth. This approach was tested in guinea-pig pregnancies, where placental physiology is more similar to humans. Fetal growth restriction (FGR) was attained through peri-conceptual nutrient restriction in virgin guinea pigs. Ad.VEGF-A165 or Ad.LacZ (1 × 1010vp) was applied at mid-gestation via laparotomy, delivered externally to the uterine circulation with thermosensitive gel. At short-term (3-8 days post surgery) or at term gestation, pups were weighed, and tissues were sampled for vector spread analysis, VEGF expression, and its downstream effects. Fetal weight at term was increased (88.01 ± 13.36 g; n = 26) in Ad.VEGF-A165-treated animals compared with Ad.LacZ-treated animals (85.52 ± 13.00 g; n = 19; p = 0.028). The brain, liver, and lung weight and crown rump length were significantly larger in short-term analyses, as well as VEGF expression in transduced tissues. At term, molecular analyses confirmed the presence of VEGF transgene in target tissues but not in fetal samples. Tissue histology analysis and blood biochemistry/hematological examination were comparable with controls. Uterine artery relaxation in Ad.VEGF-A165-treated dams was higher compared with Ad.LacZ-treated dams. Maternal uterine artery Ad.VEGF-A165 increases fetal growth velocity and term fetal weight in growth-restricted guinea-pig pregnancy.

Introduction/Background Uncertainty remains regarding management of twin pregnancies comprising complete hydatidiform mole (CHM) and healthy co-twin. In 1998, we reported that continuing such pregnancies results in a 38% chance of a healthy baby, no maternal deaths or increased risk of malignancy requiring chemotherapy. However, other studies suggest a higher risk of malignancy and maternal mortality if such pregnancies are not terminated. Here, we re-examine this controversial issue in a new, larger national cohort. Methodology The UK hydatidiform mole databases were screened to identify all twin pregnancies with central pathology review confirming CHM and normal co-twin between 1998 and 2018. Data on rates of termination, spontaneous miscarriage, pregnancy complications, successful deliveries and need for chemotherapy were collected. Results 153 new patients had a confirmed CHM and healthy co-twin. Fifty electively terminated their pregnancy before 14 weeks. 103 continued beyond 14 weeks but 28 subsequently electively terminated, leaving 75 patients who continued their pregnancy. Their outcomes included: 11 terminations Conclusion Although malignancy risk is slightly greater following CHM and healthy co-twin than in singleton molar pregnancies, the risk does not increase with progression of pregnancy beyond the first trimester. Early termination is not necessary, and the likelihood of a healthy baby appears to be greater than previously reported. Disclosure MJS wishes to acknowledge support from the Imperial National Institute for Health Biomedical Research Centre and Cancer Research UK Imperial Experimental Cancer Medicine Centre. NJS is partly supported by an NIHR Senior Investigator award. JCR has nothing to disclose. IN has nothing to disclose. RAF has nothing to disclose. DS has nothing to disclose. JE has nothing to disclose. MW has nothing to disclose. PMS has nothing to disclose. NS has nothing to disclose. BWH has nothing to disclose. JT has nothing to disclose.

Introduction There are considerable variations in villous morphology within a normal placenta. However, whether there is a reproducible spatial pattern of variation in villous vascular density is not known. Micro-CT provides three-dimensional volume imaging with spatial resolution down to the micrometre scale. In this study, we applied Micro-CT and histological analysis to investigate the degree of heterogeneity of vascularisation within the placenta. Method Ten term placentas were collected at elective caesarean section, perfused with contrast agent and imaged whole with Micro-CT. Eight full depth tissue blocks were then taken from each placenta and imaged. Sections were taken for histological analysis. Data was analysed to investigate vascular fill, and vascular density in relation to location from cord insertion to placental edge at each scale. Results Whole placental imaging revealed no spatially consistent difference in villous vessel density within the main placental tissue, although there was a great degree of heterogeneity. Both block imaging and histological analysis found a large degree of heterogeneity of vascular density within placentas, but no strong correlation between villous vascular density and block location (rs = 0.066, p = 0.7 block imaging, rs = 0.06, p = 0.6 histological analysis). Discussion This work presents a novel method for imaging the human placenta vascular tree using multiscale Micro-CT imaging. It demonstrates that there is a large degree of variation in vascular density throughout normal term human placentas. The three-dimensional data created by this technique could be used, with more advanced computer analysis, to further investigate the structure of the vascular tree., Highlights • Micro-CT and histological investigation of vascular density in the placenta. • There is a large degree of variation in vascular density throughout placentas. • This imaging has potential for future spatial investigation of the 3D vascular tree.

OBJECTIVE: To achieve consensus on the minimum reporting set of study variables for fetal growth restriction (FGR) research studies. Determination of a list of variables considered essential to be reported independent of a specific hypothesis is likely to improve the study quality by inclusion of essential end-points, enhancing the consistency among studies and minimizing potential confounding. This in turn can accelerate generation of generalizable knowledge either by standardization of individual study designs or by enhancing the possibility of individual patient data meta-analysis merging a number of uniformly structured datasets.STUDY DESIGN: An expert panel, identified based on their publication record as lead or senior authors in studies of FGR, was requested to select a set of essential study parameters from a literature-based list utilizing the Delphi consensus methodology. We collected responses in four consecutive rounds by online questionnaires presented to panelists through a unique token-secured link for each round. Variables were selected in three rounds based on the concurrence on Likert scale scoring. In the final round, retained parameters were categorized as essential (to be reported in all FGR studies) or recommended (important but not mandatory).RESULTS: 87/100 experts agreed to participate and 62 (71%) completed all four rounds. Agreement was reached for 16 essential and 30 recommended parameters including maternal characteristics, prenatal investigations, management and pregnancy/neonatal outcomes. Essential parameters included hypertensive complications in the current pregnancy, smoking, parity, maternal age, abdominal circumference, estimated fetal weight, umbilical artery Doppler (pulsatility index and end-diastolic flow), middle cerebral artery Doppler, indications for intervention, pregnancy outcome (live birth, stillbirth or neonatal death), gestational age at delivery, birthweight, birthweight centile, mode of delivery and Apgar score at 5 minutes.CONCLUSIONS: We present a list of essential and recommended parameters that characterize FGR independent of study hypotheses. Uniform reporting of these variables in prospective clinical research is expected to improve data quality, study consistency and ultimately our understanding of FGR. This article is protected by copyright. All rights reserved.

Objective To investigate whether less invasive methods of autopsy would be acceptable to bereaved parents and likely to increase uptake. Design Mixed methods study. Setting Bereaved parents recruited prospectively across seven hospitals in England and retrospectively through four parent support organisations. Sample Eight hundred and fifty‐nine surveys and 20 interviews with bereaved parents. Methods Cross‐sectional survey and qualitative semi‐structured telephone interviews. Main outcome measures Likely uptake, preferences, factors impacting decision‐making, views on different autopsy methods. Results Overall, 90.5% of participants indicated that they would consent to some form of less invasive autopsy [either minimally invasive autopsy (MIA), non‐invasive autopsy (NIA) or both]; 53.8% would consent to standard autopsy, 74.3% to MIA and 77.3% to NIA. Regarding parental preferences, 45.5% preferred MIA, 30.8% preferred NIA and 14.3% preferred standard autopsy. Participants who indicated they would decline standard autopsy but would consent to a less invasive option were significantly more likely to have a lower educational level (odds ratio 0.49; 95% CI 0.35–0.70; P = 0.000062). Qualitative findings suggest that parents value NIA because of the lack of any incision and MIA is considered a good compromise as it enables tissue sampling while easing the parental burden associated with consenting to standard autopsy. Conclusion Less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience. Further health economic, validation and implementation studies are now required to assess the viability of offering these in routine widespread clinical care. Tweetable abstract Mixed methods UK study finds less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience., Tweetable abstract Mixed methods UK study finds less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience.

Background Noninvasive imaging autopsy alternatives for fetuses weighing

Objectives Of 780 000 births annually in the UK, around 3300 are stillborn, a rate of approximately 4 per 1000 births. Traditional epidemiological associations are based on historic data. The aim of this study was to document contemporary demographic findings in a large series of > 1000 deaths in utero in London and compare these with national datasets. Methods From a dedicated database, including > 400 data fields per case, of fetal, infant and pediatric autopsies performed at Great Ormond Street Hospital and St George's Hospital, London, we extracted information on all intrauterine deaths, excluding terminations of pregnancy, from 2005 to 2013, inclusive. Demographic data were analyzed according to the gestational age at which fetal death occurred (second-trimester intrauterine fetal death (IUFD), subdivided into early (< 20 weeks) and late (20–23 weeks) IUFD, and third-trimester stillbirth (≥ 24 weeks)) and compared with national datasets when available, using Mann–Whitney U-test and comparison of proportions testing as appropriate. Results Data were available from 1064 individual postmortem reports examining intrauterine deaths delivered between 12 and 43 weeks' gestation, including 425 IUFDs (246 early and 179 late) and 639 stillbirths. Compared with the overall UK pregnant population, women in whom an intrauterine death occurred were significantly older and more obese. White mothers had a higher proportion of stillbirths (as opposed to IUFDs) than did non-white mothers, whereas black mothers had a higher proportion of IUFDs relative to stillbirths. Increased body mass index was associated with increased risk across all groups. Women who had uterine fibroids, those who had a history of vaginal bleeding in early pregnancy and those who had undergone assisted conception had a relatively higher proportion of IUFDs than stillbirths. Conclusions Based on a large series of >1000 autopsies in cases of intrauterine death, these data highlight the increased risk for fetal loss associated with maternal demographic factors in contemporary clinical practice, particularly associations with increased maternal age and body mass index. Among women in whom an intrauterine death occurs, maternal ethnicity, mode of conception and gynecological history are associated with differing timing of fetal loss. Further research is required to understand the mechanisms involved in such maternal factors in order to develop preventative strategies. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies.The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks.The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin.PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles.

Cardiac rhabdomyoma is the most common tumour of the heart in infancy and childhood, representing approximately 60% of all primary cardiac tumours in these age groups. Though they have a tendency to regress with advancing age and are histologically benign, rhabdomyomas may cause mechanical obstruction to blood flow, arrhythmia, congestive cardiac failure and death and may be associated with underlying genetic syndromes such as tuberous sclerosis. We present the case of a primigravida in her early 20s with no significant medical history who was referred to the Fetal Medicine Unit at 34 weeks' gestation following the detection of an irregular fetal heartbeat. An anomaly scan at 20 weeks had been reported as normal.

Context.-The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories.Objective.-To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community.Data Sources.-Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible.Conclusions.-The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.

Objective To evaluate the diagnostic yield of postmortem magnetic resonance imaging (PM-MRI) compared with conventional autopsy in fetuses of early gestational age and low body weight. Methods Fetuses of Results Full datasets were examined of 204 fetuses, with mean gestational age of 20.95 ± 3.82 weeks (range, 12.0-30.7 weeks) and body-weight range of 15.9-1872 g. Body weight was the most significant predictor of diagnostic yield of PM-MRI. There was 95% confidence that 90% of fetuses will show diagnostic images by PM-MRI for all five organ systems when fetal body weight is ≥ 535 g, but Conclusion PM-MRI is highly likely to provide adequate diagnostic images for fetuses with a body weight > 500 g. Below this weight, the diagnostic yield of standard 1.5-T PM-MRI decreases significantly. These data should help inform parents and clinicians on the suitability of performing PM-MRI in fetuses with low body weight. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Administration of vaginal progesterone or intramuscular 17[alpha]-hydroxyprogesterone caproate has been found to prevent preterm birth in women with a short cervix and to reduce neonatal mortality as reported by the Cochrane Library meta-analysis. However, data on medium and long-term outcomes after the neonatal period are lacking. To this end, a double-blind randomized trial, OPPTIMUM (dOes Progesterone Prophylaxis To prevent preterm labour IMprove oUtcoMe?) was performed to determine the effect of vaginal progesterone prophylaxis on neonatal and childhood outcomes. A screening phase at 18 to 24 weeks' gestation, and a treatment phase commencing at between 22 and 24 weeks of gestation were conducted. The eligibility criteria for women included in the study were that they were 16 years or older, had a singleton pregnancy, displayed clinical risk factors for preterm birth and were fibronectin-positive at 22 to 24 weeks of gestation, or were fibronectin negative at 34 or less weeks of gestation, or had a cervical length of 25 mm or less at any time between 18 and 24 weeks' and 0 day gestation. The participants were randomly assigned through a Web portal to treatment, which comprised administration of either progesterone, 200 mg soft capsules or a placebo, beginning from approximately 22 to 24 weeks of gestation until 34 weeks or delivery of the baby, whichever was earlier. Data collection was done during screening, randomization, 34 weeks of gestation, labor and delivery, neonatal stay, and at 1 and 2 years after delivery to assess clinical outcomes. The assessment included the parent-completed structured clinical history, a parent-completed behavioral measure (the Strengths and Difficulties Questionnaire) and the cognitive scale of the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). Three primary outcomes (obstetric, neonatal, and childhood), secondary outcomes and safety outcomes were determined. Statistical analyses were undertaken by C-MM and AM as per the intention-to-treat principle. Of a total of 1228 women, 618 were randomly assigned to progesterone treatment and 610 to placebo between the years 2009 and 2013. Data on the obstetric, neonatal, and childhood primary outcomes were available for 597, 587, and 439 participants in the placebo group, and for 600, 589, and 430 participants in the progesterone group, respectively. Based on the odds ratio (OR), it was found that progesterone administration did not significantly change primary outcomes (OR, 0.86 [95% confidence interval [CI], 0.61–1.22] for the obstetric outcome; OR, 0.62 [95% CI, 0.38–1.03] for the neonatal outcome; and mean [SD] cognitive score, 97.7 [17.5] for placebo and 97.3 [17.9] for progesterone; difference in mean values, -0.48; adjusted 95% CI, -2.77 to 1.81). There was no statistical significance in differences between the progesterone and placebo groups recorded for secondary and safety outcomes. OPPTIMUM showed that progesterone did not have an effect on either preterm birth rates or neonatal composite outcomes, and neurodevelopmental outcomes for 2 years, thereby implying that progesterone treatment was safe at least until the child completed 2 years of age.

Objectives Congenital cardiac malformations are commonly identified at perinatal autopsy, which can be challenging in fetuses of early gestation and in macerated fetuses. Our objective was to examine fetal complex congenital heart disease by microcomputed tomography (micro-CT), using standard autopsy as the gold standard. Methods In this ethically approved study, ex-vivo isolated fetal heart and fetal heart-lung blocks underwent iodine preparation prior to micro-CT, and were fixed in formalin after the micro-CT examination. Images were acquired using a microfocus-CT scanner with individual specimen image optimization. Twenty-one indices assessed normally at autopsy were evaluated for each dataset. Cardiac dissection was performed using a dissecting microscope within 24 h of the micro-CT examination. Results We examined six fetal hearts, comprising five with complex congenital cardiac malformations at a gestational age of 17–23 weeks and an anatomically normal heart of 23 weeks' gestation for reference. All specimens demonstrated excellent internal contrast at micro-CT examination, and the correct overall diagnosis was made in all cases. There was agreement for 114/126 indices assessed on micro-CT and at autopsy dissection (overall concordance of 95.8% (95% CI, 90.5–98.2%)). Micro-CT was particularly useful in the assessment of ventricular morphology in macerated fetuses. Conclusions Micro-CT of small ex-vivo fetal specimens can provide highly accurate three-dimensional rendering of complex congenital fetal heart disease. This approach represents a significant advance in postmortem imaging and confirms the potential of this technology for non-invasive examination of small fetuses and organs. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE To compare the diagnostic rate and accuracy of 3-Tesla (T) postmortem magnetic resonance imaging (PM-MRI) and postmortem ultrasound (PM-US) in an unselected fetal population. METHODS We performed prospectively, in a blinded manner, 3-T PM-MRI and PM-US on 160 unselected fetuses at 13-41 weeks of gestation. All imaging was reported according to a prespecified template, for five anatomical regions: brain, thorax, heart, abdomen and spine. The rates of non-diagnostic results for PM-US and PM-MRI were compared and, for results that were diagnostic, we calculated sensitivity, specificity and concordance rates for each anatomical region, using conventional autopsy as the reference standard. RESULTS 3-T PM-MRI performed significantly better than did PM-US overall and in particular for fetuses ≥ 20 weeks' gestation. Specifically, the non-diagnostic rates for PM-MRI vs PM-US were 4.4% vs 26.9% (7/160 vs 43/160; P

Background: Perinatal autopsy provides useful clinical information in up to 40% of cases. However, there is a substantial unmet clinical need with regards to postmortem investigation of early gestation fetal loss for parents for whom standard autopsy is either not available or not acceptable. Parents dislike the invasive nature of autopsy, but current clinical imaging techniques do not provide high-enough imaging resolution in small fetuses. We hypothesized that microfocus computed tomography, which is a rapid high-resolution imaging technique, could give accurate diagnostic imaging after early gestation fetal loss. Objective: The objective of the study was to evaluate the diagnostic accuracy of microfocus computed tomography for noninvasive human fetal autopsy for early gestation fetuses, with the use of conventional autopsy as the reference standard. Study Design: We compared iodinated whole body microfocus computed tomography in 20 prospectively recruited fetuses (11–21 weeks gestation from 2 centers) withconventional autopsy in a double-blinded manner for a main diagnosis and findings in specific body organs. Fetuses were prepared with 10% formalin/potassium tri-iodide. Images were acquired with a microfocus computed tomography scanner with size-appropriate parameters. Images were evaluated independently by 2 pediatric radiologists, who were blinded to formal perinatal autopsy results, across 40 individual indices to reach consensus. The primary outcome was agreement between microfocus computed tomography and conventional autopsy for overall diagnosis. Results: Postmortem whole body fetal microfocus computed tomography gave noninvasive autopsy in minutes, at a mean resolution of 27μm, with high diagnostic accuracy in fetuses at 14 weeks gestation (agreement, 97.2% and 97.9%, respectively). Within first-trimester fetal loss cases (

Severe fetal growth restriction (FGR) affects 1 in 500 pregnancies, is untreatable, and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) is one cause. Transduction of uterine arteries in normal and FGR animal models using an adenovirus (Ad) encoding VEGF isoforms increases UBF and improves fetal growth in utero. Understanding potential adverse consequences of this therapy before first-in-woman clinical application is essential. The aims of this study were to determine whether Ad.VEGF-D

To compare the diagnostic yield of whole-body post-mortem computed tomography (PMCT) imaging to post-mortem magnetic resonance (PMMR) imaging in a prospective study of fetuses and children. We compared PMCT and PMMR to conventional autopsy as the gold standard for the detection of (a) major pathological abnormalities related to the cause of death and (b) all diagnostic findings in five different body organ systems. Eighty two cases (53 fetuses and 29 children) underwent PMCT and PMMR prior to autopsy, at which 55 major abnormalities were identified. Significantly more PMCT than PMMR examinations were non-diagnostic (18/82 vs. 4/82; 21.9 % vs. 4.9 %, diff 17.1 % (95 % CI 6.7, 27.6; p

Study question What is the risk of further molar pregnancies for women with one or more hydatidiform moles (HM) in relation to molar subtype. Summary answer Women with a complete hydatidiform mole (CM) have a 1 in 100 and 1 in 4 risk of further CM after one or two consecutive CM, respectively, while women with a partial hydatidiform mole (PM) have only a small increase in risk for further molar pregnancies. What is known already Women with a molar pregnancy have an increased risk of further HM. A small subgroup of women with recurrent HM has an autosomal recessive condition, familial recurrent hydatidiform moles (FRHM), that predisposes them to molar pregnancies. Study design, size, duration A retrospective study of subsequent pregnancies in 16 000 women registered at a centralized referral centre, with a CM or PM, between 1990 and 2009. Participants/materials, setting, methods One hundred and sixty-six women with two or more molar pregnancies were identified from electronic records and patient notes. Histopathological features of all molar tissue were reviewed in these cases and genotyping performed where diagnosis was not possible on the basis of histopathological features alone. In addition, genotyping of molar tissue was performed in all cases of women with three or more CM to establish whether the tissue was diploid and biparental or androgenetic. Main results and the role of chance This study confirms an increased recurrence risk of ∼1% for a second molar pregnancy and in addition that this risk is associated with CM rather than PM. The data further indicate that the risk of a third HM is associated almost exclusively with CM and enabled an estimate that 1 in 640 women registered with a CM has the rare condition FRHM. The study also found that there was no significant difference between the risk of developing gestational trophoblastic neoplasia (GTN) for typical sporadic CM and the diploid biparental CM associated with FRHM (GTN; proportion difference 0.05, Z = 0.87, P = 0.29). Limitations, reasons for caution While pathology was reviewed for all women with two or more molar pregnancies, not all cases registered underwent central review particularly those women registered in the early 1990s. It is therefore possible that the total number of CM and PM may differ slightly from that stated. While women were followed for a minimum of 5 years, it is possible that some women may subsequently have further molar pregnancies that will not have been included in the present study. Wider implications of the findings This is the largest study to date on recurrence for molar pregnancies, and as such provides the most detailed information so far regarding the risk of further molar pregnancies for women with a PM or CM. Furthermore, the data provide new insights into the incidence of the rare autosomal recessive condition, FRHM, important information for counselling women with molar pregnancies. Study funding/competing interests No competing interests declared. No funding was obtained for this study.

Introduction Human term placenta has attracted increasing attention as an alternative source of stem cells for regenerative medicine since it is accessible without ethical objections. The amniotic membrane (AM) contains at least two stem cell types from different embryological origins: ectodermal amniotic epithelial stem cells, and mesodermal mesenchymal stromal cells. Among the second group we studied the characteristics of amniotic mesenchymal cells (AMC) versus the ones enriched for the commonly used surface marker c-Kit (amniotic progenitor/stem cells-ASC), a stem cell factor receptor with crucial functions in a variety of biological systems and presents in early progenitors of different origin, as been already demonstrated in the enriched chorionic stem cells. Methods After isolation, cells from the amniotic membranes (amniotic cells-AC) were selected for c-Kit (ASC) and compared these cells with c-Kit unselected (AMC), evaluating the expression of other stem cell markers (Oct-4, Tra-1-81, SSEA-4), CD271 and Slug. Results Immunofluorescence analysis showed that ASC cells exhibited greater stem cell marker expression and included more CD271 and Slug positive cells. This was consistent with the interpretation that c-Kit enriched AC show greater stemness capacity compared to c-Kit unselected AMC. Discussion AMC and ASC can both differentiate into various cell types including adipogenic, osteogenic, chondrogenic, neurogenic and hepatic lineages, but the enrichment in c-Kit improved stemness and differentiation potential of ASC.

Background Although stillbirth is a significant health problem worldwide, the definitive cause of death remains elusive in many cases, despite detailed autopsy. In this study of partly explained and unexplained stillbirths, we used next-generation sequencing to examine an extended panel of 35 candidate genes known to be associated with ion channel disorders and sudden cardiac death. Methods and Results We examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy. We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies. We examined the functional significance of a selected variant by patch-clamp electrophysiological recording. No predicted damaging variants were identified in KCNQ1 (LQT1) or KCNH2 (LQT2). A rare putative pathogenic variant was found in KCNJ2 (LQT7) in 1 case, and several novel variants of uncertain significance were observed. The KCNJ2 variant (p. R40Q), when assessed by whole-cell patch clamp, affected the function of the channel. There was no significant evidence of enrichment of rare predicted damaging variants within any of the candidate genes. Conclusions Although a causative link is unclear, 1 putative pathogenic and variants of uncertain significance variant resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth, and these variants may have a role in fetal demise. Clinical Trial Registration URL: https://www.clinical trials.gov . Unique identifier: NCT01120886.

Objective To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines. Methods The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009. Results We identified 20,144 cases of HM, comprising 8400 CHM, 9586 PHM, and 2158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3195. Women with CHM where hCG normalisation occurred beyond 56days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN. Conclusions Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56days have a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged.

Proteomic characterisation of the placenta has largely been focused on effect of disease, anatomical features or specific cell types. We describe an unbiased proteomic mapping analysis to investigate how the placental proteome changes throughout the organ. A transverse slice of a human placenta was sectioned into 1 × 1cm samples. Sections were analysed using label free proteomics. Analysis revealed two distinct sub-proteomes that did not have anatomical significance. One had a muscular proteome and the other had distinct immunomodulation functions. Chorionic plate enriched proteins highlighted the fetal tissues high energy requirements whilst mechanisms of the decidua observed included modulation of cortisone levels.