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Endometrial injury or ‘scratch’ preceding an assisted reproductive therapy (ART) cycle has recently been shown not to improve livebirth rates among women undergoing ART. The objective of this study was to compare pregnancy outcomes in nulliparous women who underwent an accurately timed mid-luteal scratch biopsy prior to ART with those who did not. This was a prospective cohort study. Women were recruited between October 2016 and February 2018 inclusive. Women who met the inclusion criteria and who did not undergo an endometrial scratch in the study period were used as a comparison group. Patients underwent a cycle of ART in the menstrual cycle following endometrial scratch. Ninety-eight women were eligible for participation in the study. There were no differences in rates of implantation (35.7% (n = 20/56) vs. 35.4% (n = 17/48); p = 1.00), clinical pregnancy (40.0% (n = 20/50) vs. 39.5% (n = 17/43); p = 1.00) or live birth (34.0% (n = 17/50) vs. 25.6% (n = 11/43); p = 0.50) per embryo transfer between those who underwent a scratch and those who did not. Endometrial scratch is a simple, inexpensive and low-risk procedure. However, in this relatively small cohort study, no differences in rates of implantation, clinical pregnancy or live birth in women with primary infertility were determined between those who underwent a scratch and those who did not.

STUDY QUESTION Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1β, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S) Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER NA.

Context.— A severe third wave of COVID-19 disease affected Ireland in the first 3 months of 2021. In this wave, 1 second-trimester miscarriage and 6 stillbirths were observed in the Irish population because of placental insufficiency as a result of SARS-CoV-2 placentitis. This observation was at odds with the country's previous experience with COVID-19 disease in pregnant mothers. Objective.— To describe the clinical and pathologic features of these pregnancy losses. Design.— Retrospective review of clinical and pathologic data of cases of second-trimester miscarriage, stillbirth, or neonatal death identified by perinatal pathologists as being due to SARS-CoV-2 placentitis during the third wave of COVID-19 in Ireland. Results.— Clinical and pathologic data were available for review in 6 pregnancies. Sequencing or genotyping of the virus identified SARS-CoV-2 alpha (B.1.1.7) in all cases. Three of the 6 cases had maternal thrombocytopenia, and fetal growth restriction was not prominent, suggesting a rapidly progressive placental disease. Conclusions.— The identification of SARS-CoV-2 alpha in all these cases suggests that the emergence of the variant was associated with an increased risk of fetal death due to SARS-CoV-2 placentitis when compared with the original virus. Maternal thrombocytopenia may have potential as a clinical marker of placentitis, but other inflammatory markers need investigation. Three of the 6 women had been assessed for reduced fetal movements in hospital some days before the fetal deaths actually occurred; this could suggest that there may be a window for intervention in some cases.

Background Obesity drives endometrial cancer (EC). Metabolic surgery (MS) induces sustained weight loss, reduces EC risk and has been shown to reverse histological changes of endometrial hyperplasia. One mechanism is increased GLP-1 post surgery. Few interventional studies have been conducted in the BDII/Han rat; an animal model of spontaneous EC. This study aimed to examine whether high fat diet (HFD) and weight gain, as well as subsequent intentional weight loss using Liraglutide (a GLP-1 receptor agonist) alters EC tumour biology and burden in the BDII/Han rat. A rat imaging protocol was validated to assess development and longitudinally track tumours. Methods An imaging protocol was developed and validated. 7 BDII/Han rats were fed normal chow (NC) and 8 weight-matched rats fed HFD from 3 months of age. Longitudinal PET-CT was conducted at 7, 9, 12 and 15 months. Abdominal visceral fat was analysed from L1-L5 on CT. Subsequently, an intervention study compared the 8 HFD-Control rats to 8 weight-matched HFD-fed rats treated with Liraglutide from 12-15 months. PET-CT was used to assess disease progression. Analysis of histological, immunohistochemical and transcriptomic parameters were used to compare cohorts. All rats were euthanased aged 15-months. Imaging was correlated with necropsy findings and histopathology. Results HFD rats had more abdominal fat on CT imaging (8.6cm3±0.7vs4.0cm3±0.6;p Conclusions This study has established a safe, sensitive and specific imaging protocol for longitudinal assessment of EC progression in BDII/Han rats. The HFD intervention used did not accelerate EC burden. However, it did create an obese phenotype and gave new information on the pathological variations of EC in the BDII/Han rat. Intentional weight loss from Liraglutide halved EC burden compared to controls in this study. An absence of GLP-1R expression may suggest weight loss dependent mechanisms. This novel pilot study is a foundation for future studies assessing the effect of intentional weight loss using metabolic surgery in obesity-related cancer.

Study question Do women undergoing surgery for endometrioma due to pain, a cyst and/or subfertility understand the impact of the disease and its treatment on ovarian reserve and fertility. Summary answer The majority of women treated in a fertility setting are well informed compared to those in a general medical setting. What is known already: Infertility affects 30% to 50% of women with endometriosis. Ovarian endometriomas are reported in 17–44% of infertile women with endometriosis and are typically associated with more severe disease. Endometriomas are associated with diminished ovarian reserve, due to the endometrioma per se or due to surgical interventions required to treat and excise the disease. ESHRE guidelines recommend that women should be informed pre-operatively of the potential reduction in ovarian reserve associated with surgery and that ovarian reserve tests should be performed when future fertility is a concern. Study design, size, duration In conjunction with our histopathology colleagues we identified a cohort of women with a histological diagnosis of one or more ovarian endometriomas who underwent surgery in our unit between 2010 and 2019. We developed a scoping questionnaire, targeted at women currently over the age of 40, who had previously undergone surgery for endometrioma under the age of 35. Patients were contacted by telephone and consent obtained to send an email with a survey link. Participants/materials, setting, methods We identified 47 women who had a histological diagnosis of endometrioma. Of these, 30 were contactable by telephone, of whom 29 consented to being sent information regarding the study and a link to the questionnaire. 21 women completed the survey. Respondents were divided into 2 groups for analysis. Group 1 cited ‘fertility’ or ‘both pain and fertility’ as an indication for their surgery while group 2 had ‘pain’ or ‘ovarian cysts’ but no fertility concerns. Main results and the role of chance: The majority (62%) of patients were diagnosed with endometriosis while aged 25–34. The indication for surgery was evenly divided between pain (32%), fertility (37%) and ovarian cysts (37%). 60% of women reported having endometriomas diagnosed preoperatively. Striking differences were noted between groups 1 and 2. Of the women who cited ‘fertility’ or ‘both pain and fertility’ (n = 9) as an indication for their surgery, 78% (n = 7) reported being aware of any possible negative impact of endometriosis on their fertility, with 78% also being aware of the possible negative impact of surgery for endometriosis on their fertility. This compared to only 36% (n = 4) and 27% (n = 3) respectively in Group 2. In group 1, 56% (n = 5) remembered having an AMH level checked pre operatively while 78% (n = 7) also had an ultrasound pre-operatively. In contrast, only 33% (n = 3) of Group 2 remember having an AMH level checked pre operatively though 64% (n = 7) had an ultrasound pre-operatively. Of those whose surgery was performed by a fertility specialist, 75% (n = 6) reported being aware of the impact of endometriosis and also the impact of surgery on ovarian reserve, compared to 44% (n = 4) of those who surgery was performed by a non-fertility specialist. Limitations, reasons for caution This is a retrospective study and the numbers are small. We were only able to identify women with an endometrioma via pathology records, so those with no excision of disease (eg those who had ablation of an endometrioma) were excluded from this analysis. Wider implications of the findings: This suggests the majority of patients treated in a fertility setting are counselled regarding the benefit of surgery but also the risk to ovarian reserve. This is not the case in other settings. It is time to disseminate guidelines such as those produced by ESHRE to our general gynaecology colleagues. Trial registration number Not applicable

Histological chorioamnionitis (HCA) is associated with preterm birth and adverse neonatal outcomes. We evaluated the rise in C-reactive protein (CRP) in preterm infants as a predictor of HCA severity and outcomes.Consecutive preterm infants, born January 2009 to January 2014 in the National Maternity Hospital, Dublin, under 32 weeks' gestation or1.5 kg birthweight, were included. Histological chorioamnionitis was staged as maternal inflammatory response, foetal inflammatory response and non-HCA.Preterm infants (n = 518) were included with a mean gestational age 28.5 ± 2.8 weeks, birthweight 1.1 ± 0.3 kg, and 53.5% were male. Histological chorioamnionitis was found in 25.4%. Histological chorioamnionitis was present in 93.7% when CRP 5 mg/L, 65.2% when CRP 1-5 mg/L and in 19.4% when CRP 1 mg/L. When both the immature to total neutrophil (IT) ratio was0.2 and the CRP 1 mg/L the positive predictive value and negative predictive value for HCA were 92.5% and 84.9%, respectively. Histological chorioamnionitis was associated with more resuscitation and respiratory distress syndrome (both P .001). A CRP 10 mg/L was associated with a foetal inflammatory response and increased early-onset sepsis.Higher early CRP was a surrogate predictor of HCA and correlated with the severity of HCA. Higher CRP and HCA were associated with adverse early outcomes.

OBJECTIVE Placenta accreta spectrum (PAS) is associated with significant maternal morbidity mainly related to blood loss. Pre-operative planning is aided by antenatal ultrasound and magnetic resonance imaging. We sought to assess whether three-dimensional (3D) models from MR images were accurate when compared with surgical and pathological findings. METHODS Digital Imaging and Communications in Medicine files containing MR images with varying severity of PAS (n = 4) were modeled using 3D Slicer. Placenta, bladder, and myometrial defects were modeled. Myometrial defects at three different uterine locations were included-anterior, lateral and inferior. 3D models were used to identify the relationship between the myometrial defect and the internal cervical os. Findings were validated in a larger series of PAS cases (n = 14) where patterns of invasion were compared with estimated blood loss and distance from defect to the internal os. RESULTS The defect illustrated in the four 3D models correlates to both surgical and pathological findings in terms of depth and pattern of invasion, location of defect, bladder involvement. Blood loss and topography of the defect from 3D modeling were examined in 14 further cases. Inferior defects were associated with increased blood loss compared with anterior defects. Increased distance from cervix was associated with reduced blood loss (R2 = 0.352, P = 0.01). CONCLUSION Three-dimensional models of PAS provide an accurate preoperative description of placental invasion and should be investigated as a tool for selecting patients for uterine-conserving surgery. Accurate 3D models of placenta accreta spectrum are achievable and may provide additional information, such as distance of the defect from the internal os.

Traditionally, the assessment of endometrial receptivity at transvaginal ultrasound scan has been based on the thickness and the morphological appearance of the endometrium. The objective of this study was to prospectively evaluate endometrial thickness (ET), endometrial morphology and uterine artery Doppler parameters prior to assisted reproduction treatment (ART) in the prediction of pregnancy outcome. This was a prospective cohort study. ET, morphology and uterine artery Doppler (UtAD) pulsatility index (PI) and resistance index (RI) were measured in the mid-luteal stage of the menstrual cycle ultrasonographically, timed with urinary luteinizing hormone testing. A total of 50 women were included in the analysis. The clinical pregnancy rate (CPR) per embryo transfer was 42.0% (

We sought to validate the BDII/Han rat model as a model for diet-induced obesity in endometrial cancer (EC) and determine if transcriptomic changes induced by a high fat diet (HFD) in an EC rat model can be used to identify novel biomarkers in human EC. Nineteen BDII/Han rats were included. Group A (n = 7) were given ad lib access to a normal calorie, normal chow diet (NCD) while Group B (n = 12) were given ad lib access to a calorie rich HFD for 15 months. RNAseq was performed on endometrial tumours from both groups. The top-ranking differentially expressed genes (DEGs) were examined in the human EC using The Cancer Genome Atlas (TCGA) to assess if the BDII/Han rat model is an appropriate model for human obesity-induced carcinogenesis. Weight gain in HFD rats was double the weight gain of NCD rats (50 g vs. 25 g). The incidence of cancer was similar in both groups (4/7&mdash, 57% vs. 4/12&mdash, 33%, p = 0.37). All tumours were equivalent to a Stage 1A, Grade 2 human endometrioid carcinoma. A total of 368 DEGs were identified between the tumours in the HFD group compared to the NCD group. We identified two upstream regulators of the DEGs, mir-33 and Brd4, and a pathway analysis identified downstream enrichment of the colorectal cancer metastasis and ovarian cancer metastasis pathways. Top-ranking DEGs included Tex14, A2M, Hmgcs2, Adamts5, Pdk4, Crabp2, Capn12, Npw, Idi1 and Gpt. A2M expression was decreased in HFD tumours. Consistent with these findings, we found a significant negative correlation between A2M mRNA expression levels and BMI in the TCGA cohort (Spearman&rsquo, s Rho = &minus, 0.263, p &lt, 0.001). A2M expression was associated with improved overall survival (HR = 0.45, 95% CI 0.23&ndash, 0.9, p = 0.024). Crabp2 expression was increased in HFD tumours. In human EC, CRABP2 expression was associated with reduced overall survival (HR = 3.554, 95% CI 1.875&ndash, 6.753, p &lt, 0.001). Diet-induced obesity can alter EC transcriptomic profiles. The BDII/Han rat model is a suitable model of diet-induced obesity in endometrial cancer and can be used to identify clinically relevant biomarkers in human EC.

The purpose of this study is to compare maternal outcomes in patients with placenta accreta spectrum (PAS) when managed as part of a multi-disciplinary team (MDT) compared to standard care.Patients in the standard care group were retrospectively identified from pathology records, with patients in the MDT group prospectively collected on an electronic database. Data on maternal demographics, delivery, estimated blood loss (EBL), transfusion requirements, and morbidity were recorded.Sixty patients were diagnosed with PAS between 2006 and 2019, of whom 32 were part of the standard care group and 28 in the MDT group. Compared to standard care, MDT care was associated with an increase in antenatal diagnosis from 56.3 to 92.9% (p0.0001), a significant reduction in EBL (4150 mL (800-19500) vs 1975 (495-8500), p0.0001), and transfusion requirements (median 7 (0-30) units of RCC vs 1 (0-13), p0.0001).PAS is associated with significant maternal morbidity and warrants management in an MDT setting with specialist input, which is associated with improved outcomes.

An amendment to the 1962 Coroner’s Act in the Republic of Ireland mandated that all stillbirths and neonatal deaths were to be reported to the local coroner’s office. In response to this, the bereavement team and department of anatomic pathology modified the pathway for placental examination following stillbirth and reporting deaths to the coroner. This paper is a review of the effect of this practice. This study is a review of all cases of stillbirths for 9 months following the amendment of the Coroner’s Act. A descriptive, exploratory design was used involving a retrospective chart review. Twenty-nine cases of stillbirth occurred during the study period. In cases where a placental examination was performed (n = 22), a cause of death was identified in the placenta or cord for seventeen (68%) of these cases. Seven cases had a consented autopsy with six cases confirming the initial diagnosis made at the time of gross placental examination. In one case, the cause of the stillbirth remained unexplained following placental examination and a full autopsy. No new information was gained from the autopsy in these seven cases. A further two cases had an autopsy directed by the coroner; the cause of death in these cases will be decided by the coroner. The introduction of the pathway has improved the care provided to bereaved parents by providing parents with timely information about the potential cause of stillbirth and thereby reduces the need for an autopsy examination.

BackgroundMany health and social needs can be assessed and met in community settings, where lower-cost, person-centered, preventative and proactive services predominate. This study reports on the development and implementation of a person-centered care model integrating dental, social, and health services for low-income older adults at a community dental clinic co-located within a senior wellness center.MethodsA digital comprehensive geriatric assessment (CGA) and referral system linking medical, dental, and psychosocial needs by real-time CGA-derived metrics for 996 older adults (age ≥ 60) was implemented in 2016–2018 as part of a continuous quality improvement project. This study aims to describe: 1) the development and content of a new CGA; 2) CGA implementation, workflows, triage, referrals; 3) correlations between CGA domains, and adjusted regression models, assessing associations with self-reported recent hospitalizations, emergency department (ED) visits, and clinically-assessed dental urgency.ResultsThe multidisciplinary team from the senior wellness and dental centers planned and implemented a CGA that included standard medical history along with validated instruments for functional status, mental health and social determinants, and added oral health. Care navigators employed the CGA with 996 older adults, and made 1139 referrals (dental = 797, care coordination = 163, social work = 90, mental health = 32). CGA dimensions correlated between oral health, medical status, depressive symptoms, isolation, and reduced quality of life (QoL). Pain, medical symptoms, isolation and depressive symptoms were associated with poorer self-reported health, while general health was most strongly correlated with lower depressive symptoms, and higher functional status and QoL. Isolation was the strongest correlate of lower QoL.Adjusted odds ratios identified social and medical factors associated with recent hospitalization and ED visits. General and oral health were associated with dental urgency. Dental urgency was most strongly associated with general health (AOR = 1.78,95%CI [1.31, 2.43]), dental symptoms (AOR = 2.39,95%CI [1.78, 3.20]), dental pain (AOR = 2.06,95%CI [1.55–2.74]), and difficulty chewing (AOR = 2.80, 95%CI [2.09–3.76]). Dental symptoms were associated with recent ED visits (AOR = 1.61, 95%CI [1.12–2.30]) or hospitalizations (AOR = 1.47, 95%CI [1.04–2.10]).ConclusionCommunity-based inter-professional care is feasible with CGAs that include medical, dental, and social factors. A person-centered care model requires coordination supported by new workflows. Real-time metrics-based triage process provided efficient means for client review and a robust process to surface needs in complex cases.

INTRODUCTION: Stillbirth remains an often unpredictable and devastating pregnancy outcome, and despite thorough investigation, the number of stillbirths attributable to unexplained causes remains high. Placental examination has become increasingly important where access to perinatal autopsy is limited. We aimed to examine the causes of stillbirth in normally formed infants over 30 years and whether a declining autopsy rate has affected our ability to determine a cause for stillbirths. MATERIAL AND METHODS: All cases of normally formed singleton infants weighing ≥500 g that died prior to the onset of labor from 1989 to 2018 were examined. Trends for specific causes and uptake of perinatal autopsy were analyzed individually. RESULTS: In all, 229 641 infants were delivered, with 840 stillbirths giving a rate of 3.66/1000. The rate of stillbirth declined from 4.84/1000 in 1989 to 2.51 in 2018 (P

Endometrial injury or 'scratch' preceding an assisted reproductive therapy (ART) cycle has recently been shown not to improve livebirth rates among women undergoing ART. The objective of this study was to compare pregnancy outcomes in nulliparous women who underwent an accurately timed mid-luteal scratch biopsy prior to ART with those who did not.This was a prospective cohort study. Women were recruited between October 2016 and February 2018 inclusive. Women who met the inclusion criteria and who did not undergo an endometrial scratch in the study period were used as a comparison group. Patients underwent a cycle of ART in the menstrual cycle following endometrial scratch.Ninety-eight women were eligible for participation in the study. There were no differences in rates of implantation (35.7% (n = 20/56) vs. 35.4% (n = 17/48); p = 1.00), clinical pregnancy (40.0% (n = 20/50) vs. 39.5% (n = 17/43); p = 1.00) or live birth (34.0% (n = 17/50) vs. 25.6% (n = 11/43); p = 0.50) per embryo transfer between those who underwent a scratch and those who did not.Endometrial scratch is a simple, inexpensive and low-risk procedure. However, in this relatively small cohort study, no differences in rates of implantation, clinical pregnancy or live birth in women with primary infertility were determined between those who underwent a scratch and those who did not.

Background. Placenta accreta spectrum (PAS) is a condition of abnormal placental invasion encompassing placenta accreta, increta, and percreta and is a major cause of severe maternal morbidity and mortality. The diagnosis of a PAS is made on the basis of histopathologic examination and characterised by an absence of decidua and chorionic villi are seen to directly adjacent to myometrial fibres. The underlying molecular biology of PAS is a complex process that requires further research; for ease, we have divided these processes into angiogenesis, proliferation, and inflammation/invasion. A number of diagnostic serum biomarkers have been investigated in PAS, including human chorionic gonadotropin (HCG), pregnancy-associated plasma protein-A (PAPP-A), and alpha-fetoprotein (AFP). They have shown variable reliability and variability of measurement depending on gestational age at sampling. At present, a sensitive serum biomarker for invasive placentation remains elusive. In summary, there are a limited number of studies that have contributed to our understanding of the molecular biology of PAS, and additional biomarkers are needed to aid diagnosis and disease stratification.

AIM Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models. We aimed to profile the systemic pro-and anti-inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy. METHOD In a tertiary referral university neonatal intensive care unit, serial blood samples were analysed from 41 term infants (requiring resuscitation at birth) in this prospective observational pilot study. Serum levels of 10 pro-and anti-inflammatory cytokines were evaluated including interleukin(IL)-1α, IL-1β, IL-6, IL-8, IL-10, tumour necrosis factor(TNF)-α, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), granulocyte/colony-stimulating factor (G-CSF) and granulocyte macrophage/colony-stimulating factor (GM-CSF). RESULTS Infants with neonatal encephalopathy and abnormal neuroimaging (n = 15) had significantly elevated granulocyte macrophage/colony-stimulating factor at 0-24 h and interleukin-8, interleukin-6 and interleukin-10 at 24-48 hour. Tumour necrosis factor-α and vascular endothelial growth factor levels were lower at 72-96 hour (p < 0.05). Significantly elevated levels of interleukin-10 were associated with mortality. CONCLUSION Serum cytokine changes and innate immune dysregulation in the first week of life may be indicators of outcome in neonatal encephalopathy but require validation in larger studies.

Perinatal autopsy is one the most valuable investigations to ascertain the cause of death (Nijkamp et al., Seminars in Fetal & Neonatal Medicine. 22:167-175, 2017; Korteweg et al., AJOG 53, e1-12, 2012; Late Interuterine Death and Stillbirth’ RCOG Green-top Guideline No.55, 2015). Discussions about perinatal autopsy can be difficult for parents and healthcare professionals. Perinatal staff need a good level of knowledge and understanding regarding perinatal autopsy in order to discuss the procedure with parents. This study aims to investigate healthcare professionals’ knowledge regarding perinatal autopsy. An audit conducted in a large teaching hospital using a questionnaire was developed and distributed to healthcare professionals in the hospital. Seventy healthcare professionals participated in the audit. Of those surveyed, 64% (n = 45) have discussed perinatal autopsy with a mother and the majority of healthcare professionals (67%) found this difficult. Self-reported levels of understanding were found to be low with just 10% reporting ‘excellent understanding’. The results of this audit highlight the need for further education among all healthcare professionals working with bereaved families.

Objective To assess the effect of aspirin use in low-risk pregnancy on: (1) pregnancy-associated plasma protein-A (PAPP-A) and placental-like growth factor (PLGF); (2) urinary albumin-to-creatinine ratio (ACR) and blood pressure; (3) fetal growth parameters; and (4) placental histopathology. Study Design This secondary analysis from the T rial of low-dose aspirin with an E arly S creening T est for preeclampsia and growth restriction randomized controlled trial was based on low-risk nulliparous women randomized at 11 weeks to (1) aspirin 75 mg; (2) no aspirin; and (3) aspirin based on the preeclampsia Fetal Medicine Foundation screening test. At baseline, women underwent assessment of blood pressure, PAPP-A, PLGF, and ACR, repeated 9 to 10 weeks postaspirin, in addition to fetal growth assessment. Gross and histopathological placental analyses were performed in line with Amsterdam criteria. Results A total of 445 subjects were included (aspirin n = 163 [36.6%]; no aspirin n = 282 [63.4%]). Although the fetal-to-placental weight ratio was significantly greater in the aspirin group (7.5 [±1.3] vs. 7.3 [±1.4], p = 0.045), as was change in ultrasound assessed estimated fetal weight from second to third trimesters (1,624.5 g [±235.1] vs. 1,606.2 [±189.4], p = 0.042), this was invalidated by the lack of a difference in birth weight. Aspirin did not significantly impact on change in serum or urine preeclampsia biomarkers, maternal blood pressure, or placental histopathology. Conclusion Aspirin use in low-risk pregnancy does not appear to impact on preeclampsia biomarkers, fetal growth, or placental pathology.

Purpose To assess if three dimensional power Doppler (3DPD) placental ultrasound, evaluating volume, vascularisation, and blood flow in post-term pregnancies differs from normal pre-term third trimester pregnancies and to examine whether computer analysis identifies the continual increase in calcification in post-term pregnancies. Materials and methods A prospective cohort study of 50 women with post-term pregnancies (40 + 0 to 41 + 6 weeks) and 58 controls (36–40 weeks). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Calcification percentage was calculated, by computer analysis. Results were compared with previously determined normal values and correlated with uterine, middle cerebral and umbilical artery Doppler values and placental histology. Results Placental volume, VI, FI and VFI are not influenced by GA beyond 40 weeks gestation and are similar between post-term and normal pregnancies (36–40 weeks). Placental volume decreased as the mean uterine artery pulsatility index (UtA PI) increased; p = 0.047. FI was reduced where chorangiosis was found at histology ( p = 0.033). Computer analysis of placental calcification identified the increased calcification expected after 40 weeks, and showed that calcification continues to increase between 40 and 42 weeks ( p = 0.029). Conclusion Although the sample size limits the generalisability of the findings, we found that calcification of the placenta continues to increase between 40 and 42 weeks gestation, that there is an association between an increasing UtA PI and a decreasing placental volume and that FI measurement may be useful in the identification of chorangiosis in post-term pregnancies.

ObjectiveEvaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction.DesignMulticentre open-label feasibility randomised controlled trial.SettingTwo tertiary maternity hospitals in Dublin, Ireland.Participants546 low-risk nulliparous women completed the study.InterventionsWomen underwent computerised randomisation to: Group 1—routine aspirin 75 mg from 11 until 36 weeks; Group 2—no aspirin and; Group 3—aspirin based on the Fetal Medicine Foundation screening test.Primary and secondary outcome measures(1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses.Results546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0–26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8).ConclusionLow-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach.Trial registration numberISRCTN (15191778); Post-results.

Introduction Fatal antepartum fetomaternal hemorrhage is a relatively uncommon clinical presentation, though one that appears quickly and without warning. The pathophysiology of this disease is unclear, and the incidence does not appear to be decreasing in line with overall antepartum mortality. This study was undertaken to analyse trends in antepartum fetal death from fetomaternal hemorrhage over a 25-year period in a single maternity hospital in Dublin, Ireland. Material and methods A cross-sectional study of 192 132 nonanomalous infants weighing 500 g or more, delivered in a single tertiary-referral university institution between 1987 and 2011. Data was compared using Fisher's exact test, univariate analysis, and Cuzick's test for trend. Results There was no decrease in the rate of fatal fetomaternal hemorrhage over the past 25 years (p = 0.29), despite a decline in overall antepartum deaths (p = 0.0049). Fetomaternal hemorrhage accounted for 4.1% (34/828) of antepartum stillbirths. A higher proportion of these stillbirths occurred at term gestations (74%; 25/34) compared with other causes (40%; 321/794; p = 0.0003). Female infants were statistically more likely to be involved than males [odds ratio (OR) 2.33, 95% confidence interval (CI) 1.08–5.47, p = 0.02). Multiple gestations were up to six times as likely to be affected as singleton pregnancies (OR 6.52, 95% CI 1.67–18.50, p = 0.005). Conclusions Over the past 25 years there has been no reduction in rates of fatal fetomaternal hemorrhage. Female infants and multiple gestations remain at higher risk of antepartum death from fatal fetomaternal hemorrhage.

Activated leukocytes and infection are implicated in neonatal brain injury. Leukocyte surface receptors are increased in stroke models and may be targets for future adjunctive therapies. Serial blood samples were analyzed from preterm infants (n = 51

Objectives: Management of women with pre-gestational diabetes continues to be challenging for clinicians. This study aims to determine if 3D power Doppler (3DPD) analysis of placental volume and flow, and calculation of placental calcification using a novel software method, differ between pregnancies with type 1 or type 2 diabetes and normal controls, and if there is a relationship between these ultrasound placental parameters and clinical measures in diabetics. Methods: This was a prospective cohort study of 50 women with diabetes and 250 controls (12–40 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental calcification was calculated by computer analysis. Results in diabetics were compared with control values, and correlated with early pregnancy HbA1c, Doppler results and placental histology. Results: Placental calcification and volume increased with advancing gestation in pre-gestational diabetic placentae. Volume was also found to be significantly higher than in normal placentae. VI and VFI were significantly lower in diabetic pregnancies between 35 and 40 weeks gestation. A strong relationship was seen between a larger placental volume and both increasing umbilical artery pulsatility index and decreasing middle cerebral artery pulsatility index. FI was significantly lower in cases which had a booking HbA1c level ≥6.5%. Ultrasound assessed placental calcification was reduced with a histology finding of delayed villous maturation. No other correlation with placental histology was found. Conclusions: This study shows a potential role for 3D placental evaluation, and computer analysis of calcification, in monitoring pre-gestational diabetic pregnancies. Author approved cutting out material that is not written by her - MEL 14/01/2016

Umbilical artery thrombosis is a rare occurrence and is associated with poor neonatal outcomes. We present a series of 7 cases occurring over a 13-year period. The National Maternity Hospital is a tertiary referral center with approximately 10 000 births per annum. Cases were identified by a keyword search on the laboratory computer system. Seven cases were retrieved over a 13-year period (from an estimated 116 000 births): 5 cases from 7306 placentas and 2 cases from 1174 autopsies performed. Only cases with isolated umbilical artery thrombosis were included in the study. Placental histology from all cases was examined, placental gross findings were recorded, and clinical information and Doppler findings were obtained. Two infants were stillborn, and an additional 3 of the 7 cases were small for dates. All liveborn infants had a complicated neonatal course: 1 infant had a caudate infarction, 1 was born with partial acrania and schizencephaly, and 1 had a prolonged intensive care unit admission for low birth weight and jaundice. One case had absent end diastolic flow on Doppler ultrasound. Three cases had a cord diameter narrower than that expected for gestational age. All cases showed evidence of placental hypoperfusion. Umbilical artery thrombosis is a rare occurrence and carries a poor prognosis.

Purpose. To investigate cardiomyopathy in offspring in a mouse model of pregestational type 1 diabetic pregnancy.Methods. Pregestational diabetes was induced with STZ administration in female C57BL6/J mice that were subsequently mated with healthy C57BL6/J males. Offspring were sacrificed at embryonic day 18.5 and 6-week adolescent and 12-week adult stages. The size and number of cardiomyocyte nuclei and also the extent of collagen deposition within the hearts of diabetic and control offspring were assessed following cardiac tissue staining with either haematoxylin and eosin or Picrosirius red and subsequently quantified using automated digital image analysis.Results. Offspring from diabetic mice at embryonic day 18.5 had a significantly higher number of cardiomyocyte nuclei present compared to controls. These nuclei were also significantly smaller than controls. Collagen deposition was shown to be significantly increased in the hearts of diabetic offspring at the same age. No significant differences were found between the groups at 6 and 12 weeks.Conclusions. Our results from offspring of type 1 diabetic mice show increased myocardial collagen deposition in late gestation and have increased myocardial nuclear counts (hyperplasia) as opposed to increased myocardial nuclear size (hypertrophy) in late gestation. These changes normalize postpartum after removal from the maternal intrauterine environment.

Objectives: To determine the infectious aetiology of peripartum maternal pyrexia and to assess the diagnostic accuracy of obstetric systemic inflammatory response syndrome criteria and cardiotocography as predictors of peripartum infection, in order to guide appropriate antibiotic management of mother and neonate. Study Design: This study was carried out in a tertiary referral maternity hospital in Dublin, Ireland. A prospective cohort analysis was performed of 175 mother-newborn pairs with maternal pyrexia (≥38 °C) that developed after labour onset or within four hours postnatal. Infection was confirmed microbiologically in the case of sterile site infection, urinary tract infection (UTI) or growth of a significant perinatal pathogen from a placental swab. Infection was confirmed histologically by gross and microscopic examination of placentas in cases where there was growth of potentially pathogenic micro-organisms at a non-sterile site. Systemic inflammatory response syndrome criteria and cardiotocography in patients with confirmed infection versus those without evidence of infection were compared using independent samples t-test for continuous data and pearson chi-square test for nominal data. Diagnostic accuracy of obstetric systemic inflammatory response syndrome criteria (elevated maternal heart rate, elevated respiratory rate, decreased systolic blood pressure and elevated white cell count) for the identification of infection among women with peripartum pyrexia was determined using receiver operating characteristic curves. Results: The infection rate was 17.1% (30/175). The rate was 22% (22/100) for pyrexia that occurred during labour and 10.7% (8/75) if it occurred within four hours after delivery. Obstetric systemic inflammatory response syndrome criteria and cardiotocography were not predictive of infection in women with peripartum pyrexia. No significant differences were observed in mean temperature, heart rate, respiratory rate, systolic blood pressure or white cell count between those with infections and those with no evidence of infection. Conclusions: Peripartum pyrexia is predominantly of non-infectious origin. Improved diagnostic criteria are needed to identify infection for this indication. Early discontinuation of antibiotic treatment is appropriate in the majority of patients who develop term peripartum pyrexia after onset of labour. Keywords: Pyrexia, Labour, Infection, Diagnostic Criteria

Introduction The objectives of this study were firstly to determine the proportion of placental pathology in fetuses affected by trisomy 21 (T21) using current pathological descriptive terminology and secondly to examine if a correlation existed between the finding of an abnormal umbilical artery Doppler (UAD) waveform, the presence of T21 and defined placental pathological categories. Methods This case-control study assessed singleton fetuses with karyotypically confirmed trisomy 21 where placental histopathology had been conducted from 2003 to 2015 inclusive, within a university tertiary obstetric centre. This was compared with unselected normal singleton control pregnancies matched within a week of gestation at delivery. Data included birthweight centiles and placental histopathology. Comparisons of Doppler findings across placental pathological categories were performed using statistical analysis. Results 104 cases were analysed; 52 cases of trisomy 21 and 52 controls. Fetal vascular malperfusion (48.1% vs. 5.8%, p = 0.001) and maturation defects (39.2% vs. 15.7%, p = 0.023) were more common in trisomy 21 placentas. Compared with controls, trisomy 21 fetuses were more likely to have shorter umbilical cords (p = 0.001) and had more UAD abnormalities. Amongst T21 pregnancies, umbilical artery Doppler abnormalities are associated with the presence of maternal vascular malperfusion. Discussion Fetal vascular malperfusion and maturation defects are more common in trisomy 21 placentas. Abnormal umbilical artery Doppler waveforms are more common in T21 and are associated with maternal vascular malperfusion. Placental disease may explain the increased rate of intrauterine death in T21.

Objective Pre-eclampsia remains a worldwide cause of maternal and perinatal morbidity and mortality. Low dose aspirin (LDA) can reduce the occurrence of pre-eclampsia in women with identifiable risk factors. Emerging screening tests can determine the maternal risk of developing placental disease, such as pre-eclampsia from the first trimester of pregnancy. The aim of this study is to determine if it is more beneficial in terms of efficacy and acceptability to routinely prescribe LDA to nulliparous low-risk women compared to test indicated LDA on the basis of a positive screening test for placental disease. Methods We propose a three armed multi-center open-labeled randomized control trial of; (i) routine LDA, (ii) no aspirin, and (iii) LDA on the basis of a positive first trimester pre-eclampsia screening test. LDA (75 mg once daily) shall be given from the first trimester until 36-week gestation. The primary outcome measures include; (i) the proportion of eligible women that agree to participate (acceptability), (ii) compliance with study protocol (acceptability and feasibility), (iii) the proportion of women in whom it is possible to obtain first trimester trans-abdominal uterine artery Doppler examination (feasibility) and (iv) the proportion of women with a completed screening test that are issued the screening result within one week of having the test performed (feasibility). Conclusion This will be the first clinical trial to determine the efficacy and acceptability in low-risk women of taking routine LDA versus no aspirin versus LDA based on a positive first trimester screening test for the prevention of placental disease.

Novel targeted treatment of non-small cell lung cancer (NSCLC) requires accurate classification of NSCLC as squamous cell carcinoma (SCC) and adenocarcinoma (AC). This study details the CK5/6 and TTF-1 immunoprofile of surgical resections of 45 NSCLCs (24 ACs and 21 SCCs) in tissue microarrays. All SCCs were CK5/6 positive, TTF-1 negative. 20 of 24 adenocarcinomas had the reverse pattern. In conclusion, all SCCs in this study were CK5/6 positive and TTF-1 negative, and therefore tumours that do not display this phenotype are unlikely to be SCCs. CK5/6 and TTF-1 is therefore a practical panel for the distinction between pulmonary SCC from AC in routine histopathology practice.

BACKGROUND UK Biobank is a prospective study that is collecting biological samples and health and lifestyle data from 500 000 volunteer participants over a 4-year period. These data will be used to facilitate biological and medical research. METHODS Modern manufacturing principles were used to direct the development of the sample processing facility and automated systems. RESULTS A fit for purpose facility comprising technology, systems, dedicated process, infrastructure and an appropriate staff structure has been implemented that will deliver and maintain a resource that will support the long-term goals of the UK Biobank study. CONCLUSIONS Modern manufacturing principles are appropriate for use in the development of a high throughput biological sample processing facility.

Objective Pre-eclampsia (PET) and intrauterine growth restriction (IUGR), often associated with impaired placental function, are among the most common conditions contributing to increased perinatal mortality and morbidity. This study investigates if three dimensional power Doppler (3DPD) of the placenta and computerised analysis of placental calcification is different between PET/IUGR and normal pregnancies. Study design This was a prospective cohort study involving 50 women with pre-eclampsia and/or IUGR, or with IUGR only from 24 to 40 weeks' gestation. 3DPD ultrasound was used to calculate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Following each scan the percentage of placental calcification was also calculated, by computer analysis. Results were compared with normal (control) values, and findings correlated with maternal and fetal Doppler parameters and placental histology. Results Volume, VI, and VFI are not influenced by gestational age in PET/IUGR pregnancies. FI was found to increase with gestational age ( p =0.009) and was lower than normal in the total study group from 24 to 30 weeks ( p =0.006). In the pregnancies affected by PET, whether or not IUGR was present, all three indices were lower than normal values between 24 and 30 weeks (VI: p =0.038, FI: p =0.004, VFI: p =0.015). Vascularisation and flow indices were less than the normal 50th centile in the majority of cases of utero-placental insufficiency ( p =0.047), and vascularisation and vascularisation flow indices were lower in cases of accelerated placental maturation ( p =0.016 and 0.041 respectively). Placental volume greater than the 50th centile between 24 and 30 weeks was associated with the presence of infarction on histology ( p =0.021). Flow index ( p =0.002) and vascularisation flow index ( p =0.036) were lower in the presence of bilateral uterine artery notches. Calcification, similar to the control group, was related to an increasing UAPI ( p =0.041) and MCA PI p =0.010). Conclusions The study findings suggest that there may be a role for 3DPD placental assessment of volume, vascularisation and blood flow and computer analysis of placental calcification in the identification and management of PET/IUGR pregnancy.

The challenge of understanding the determinants of common life-threatening and disabling conditions is substantial. These conditions are typically caused by a combination of lifestyle, environmental, and genomic factors, with individually modest effects and complex interactions, the detection and quantification of which require studies with large numbers of disease cases. While retrospective case-control studies of particular diseases [1] or existing prospective studies of particular risk factors can help to address this challenge [2,3], a complementary approach is to establish large prospective cohorts designed to study a much wider range of known and novel risk factors for a wide range of diseases [4]. Prospective studies can assess exposures before the onset and treatment of disease, diseases that are not readily investigated by retrospective studies, and both the adverse and beneficial effects of a specific exposure on the lifetime risks of different diseases.\ud \ud UK (United Kingdom) Biobank is a very large, population-based prospective study, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases of middle and old age [5,6]. It aims to combine extensive and precise assessment of exposures with comprehensive follow-up and characterisation of many different health-related outcomes, as well as to promote innovative science by maximising access to the resource. Recruitment of 500,000 participants and the collection of an unprecedented wealth of baseline data and samples were completed in 2010. Activity is now focused on further phenotyping of participants and their health outcomes and on providing access to researchers from around the world.

OBJECTIVE To report and compare the data obtained from the BAUS UK national laparoscopic nephrectomy audit over the past 3 years. METHODS Each year, consultants performing laparoscopic nephrectomy are invited to submit prospectively collected data on all patients so treated at their centres. The data from each centre is entered into a nationally established database using a standard data-collection sheet. The indications for surgery, and data during and after surgery are collected. Since 2001, data were reported on 1294 laparoscopic nephrectomies. RESULTS Over the 3 years, the number of centres returning data has increased from 25 to 48. In 2002, data on 263 nephrectomies were returned; by 2004, this had increased to 598. In all three audits, most cases were for nonfunctioning kidneys and renal cell carcinoma, with transitional cell carcinoma and stones forming a smaller proportion. Over the 3 years, the mean (range) operative duration has reduced from 173 (89–335) to 166 (42–395) min. The median postoperative stay remained at 4–5 days, with a wide range reflecting other than clinical reasons for delayed discharge. The mortality rate remained low, at 0.7% and 0.2%, respectively, for 2002 and 2004. The mean conversion rate remained at 6–8% and the mean complication rate at 17–21%, but the proportion of major complications reduced from 10% to 4%. The transfusion rate also reduced from 10% to 7%. The operative duration, transfusion and conversion rates were higher in those centres performing fewer than 12 cases/year than in those performing at least one case per month. CONCLUSION The BAUS laparoscopic nephrectomy audit is an effective method for ensuring both the safe and widespread implementation of this relatively new technique to the UK, and compliance with internationally accepted standards. This audit has shown differences in clinical outcomes in favour of high-volume centres, which may help to inform decisions about the centralization of urological laparoscopy services.

The Section of Endourology of the BAUS present an audit of their experience with laparoscopic nephrectomy covering a 1-year period. In this detailed analysis of results from 25 centres in the UK they found that results were similar to those reported in other parts of the world. They also showed that there was no difference in results between larger and smaller centres performing fewer than five cases per year, but suggest that this is a result of careful case selection and the use of mentors. OBJECTIVE To report the first UK national audit of laparoscopic nephroureterectomy, radical and simple nephrectomy. METHODS All members of the British Association of Urological Surgeons (BAUS) undertaking laparoscopic nephrectomy were invited to submit prospectively collected data from their centres to a nationally established database, using a standard proforma. The period covered by the audit was 1 July 2001 to 30 June 2002. The indications for surgery, peri- and postoperative data, and some demographic details were collected. RESULTS Data were received from 25 centres; 13 had undertaken five or fewer cases per year; 263 procedures were reported, including 20 of hand-assisted nephrectomy. Most cases were for nonfunctioning kidneys, or renal cell carcinoma, with transitional cell cancer and stones forming a smaller proportion. The mean (range) operative duration was 173 (89–335) min. The median postoperative stay was 4 days, with a wide range reflecting clinical and other reasons for delayed discharge. Two deaths were reported, giving a mortality of 0.7%. The mean conversion rate was 5.7% and the mean complication rate 16.8%; these rates were no higher in centres undertaking fewer than five cases per year than in the centres with a greater volume. CONCLUSION Encouragingly, this first UK audit of laparoscopic nephrectomy shows similar results to those published worldwide. The lack of any difference in outcome between smaller and larger centres may be explained by case selection and the use of mentors, as recommended by the BAUS Section of Endourology.

AIMS To measure inflammatory markers in offspring of pregestational type 1 diabetic mothers. METHODS Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Offspring from control C57BL6/J and type 1 diabetic mothers were followed up to adulthood and blood was collected at 6 and 12 weeks of age, representing adolescent and adult stages respectively. Five well-established inflammatory markers; Matrix metalloproteinase 9, soluble E-selectin, sICAM-1, sVCAM-1, and total plasminogen activator inhibitor-1 (PAI-1) were measured on an inflammatory multiplex assay in plasma. RESULTS Blood plasma from adolescent offspring from diabetic mothers displayed an increase in all five inflammatory markers when compared to controls, and there was a highly significant increase in sVCAM-1 (64.56 ± 20.1 vs. 33.8 ± 20.75; p < 0.01) and tPAI-1 (0.05 ± 0.02 vs. 0.02 ± 0.01; p < 0.01) expression. CONCLUSION Our findings show that inflammatory markers are increased in offspring of pregestational diabetic mothers. This may represent a mechanism for increased risk of cardiovascular disease evident in these offspring.