Distribution of cord inflammation in cases with clinical suspicion of chorioamnionitis.

INTRODUCTION: Identification of acute funisitis, a sign of foetal inflammatory response (FIR), is crucial as their presence is associated with ominous neonatal outcomes. Recommendation on which part of umbilical cord should be sampled to facilitate optimal identification of acute funisitis is limited. METHODS: This is a retrospective cross-sectional study over a seven-month duration recruiting all patients with clinical suspicion of chorioamnionitis and/or maternal intrapartum pyrexia. The distribution and the degree of cord inflammation were assessed. The cases were also evaluated for maternal inflammatory response (MIR) and chorionic vasculitis (CV). RESULTS: Of the 191 placentas, 88 (46.1%) had some degree of cord inflammation. Forty-nine (55.7%) had a differential in cord inflammation, with distal cord section (n = 38) demonstrating significant greater inflammation than that of proximal cord section (n = 11) (p<0.001). There were 20 cases with phlebitis only and 8 cases demonstrated arteritis only in either proximal or distal cord sections. Increasing magnitude of cord inflammation was significantly associated with increasing severity of MIR and the rate of CV (p<0.001). CV was observed in 25 (24.3%) cases showing absence of cord inflammation, while 12 (13.6%) cases with cord FIR demonstrated no CV. DISCUSSION: Inflammatory reaction can occur variably throughout the length of the umbilical cord and chorionic plate vessels, with greater inflammation seen in the distal cord section. We affirm the current Amsterdam recommendation of submitting at least two cross sections of the cord representing proximal and distal sites and two sections from placental parenchyma to facilitate the identification of FIR.

MicroRNA profiling in complete and partial hydatidiform moles.

INTRODUCTION: Hydatidiform mole is one of the gestational trophoblastic disease and comprises complete (CM) and partial moles (PM), which carries a risk of developing persistence disease, invasive mole or choriocarcinoma. MicroRNAs (miRNAs) have been discovered in various tissues, including neoplastic tissues. Its role in the pathogenesis of molar pregnancy or as biomarkers are still largely uncertain. The aim of this study is to identify the differentially expressed miRNAs in CM and PM. MATERIALS AND METHODS: Using next-generation sequencing, the miRNAs profiles of CM (n=3) and PM (n=3) moles, including placenta of non-molar abortus (n=3) as control were determined. The differentially expressed miRNAs between each group were analysed. Subsequently, bioinformatics analysis using miRDB and Targetscan was utilised to predict target genes. RESULTS: We found 10 differentially expressed miRNAs in CMs and PMs, compared to NMAs, namely miR- 518a-5p, miR-423-3p, miR-503-5p, miR-302a-3p, and miR-1323. The other 5 miRNAs were novel, not listed in the known database. The 3 differentially expressed miRNAs in CMs were predicted to commonly target ZTBT46 and FAM73B mRNAs. DISCUSSION: miR-518 was consistently observed to be downregulated in CM versus PM, and CM versus NMA. Further bioinformatic analysis to provide insight into the possible role of these miRNAs in the pathogenesis of HMs, progression of disease and as potential diagnostic biomarkers as well as therapeutic targets for HMs is needed.

Placental histopathology and correlated clinical outcomes in kidney transplant recipients.

Pregnancies after kidney transplantation are high-risk. Whilst previous studies have explored pregnancy outcomes, there are no existing data on the placental histopathology findings of kidney transplant recipients and how these correlate with clinical outcomes. From 1976 to 2020, 62 pregnancies to 37 transplant recipients were identified in a South Australian clinical unit. The medical records were evaluated to identify if placental tissue had been sent for histopathology. The histology was reviewed contemporaneously, blinded to outcomes, following the Amsterdam consensus. The findings were correlated with the clinical data. Placental tissue was referred for histopathological examination in 20 pregnancies to 15 women. A high rate of adverse perinatal outcomes was noted, with fetal growth restriction (FGR; n=6), pre-eclampsia (n=8), worsening renal function with >10% increase in serum creatinine from preconception (n=9), pre-term birth (n=15), and antenatal hypertension (n=12). Maternal vascular malperfusion was seen in 14/20 pregnancies, including in all cases with pre-eclampsia, and was commonly observed with FGR (5/6 cases), decline in kidney function (8/9), antenatal hypertension (7/12) and preterm birth (12/15). In this high-risk population, increased obstetric ultrasound scans with uterine and umbilical Doppler should be considered to monitor and manage maternal uteroplacental vascular perfusion. We recommend all placental tissue from transplant recipients be referred for histopathological examination.

Response adaptive salvage with KTd and ASCT for functional high-risk multiple myeloma-The Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial.

We evaluated re-induction incorporating carfilzomib-thalidomide-dexamethasone (KTd) and autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) refractory, or demonstrating a suboptimal response, to non-IMID bortezomib-based induction. KTd salvage consisted of thalidomide 100 mg daily and dexamethasone 20 mg orally combined with carfilzomib 56 mg/m2 days 1, 2, 8, 9, 15 and 16, of each 28-day cycle. Following four cycles, patients achieving a stringent complete response proceeded to ASCT whereas those who did not received a further two cycles then ASCT. Consolidation consisted of two cycles of KTd then Td to a total of 12 months post-ASCT therapy. Primary end-point was the overall response rate (ORR) with KTd prior to ASCT. Fifty patients were recruited. The ORR was 78% with EuroFlow MRD negativity of 34% in the intention-to-treat population and 65% in the evaluable population at 12 months post-ASCT. With follow-up >38 months median PFS and OS have not been reached with PFS and OS at 36 months of 64% and 80%, respectively. KTd was well tolerated with grade 3 and grade ≥4 adverse events rates of 32% and 10%, respectively. Response adaptive utilisation of KTd with ASCT is associated with both high-quality responses and durable disease control in functional high-risk NDMM.

Validation of a tool for determining the clinical utility of stillbirth investigations.

BACKGROUND: Up to 20% of all stillbirths and 45% of term stillbirths are currently classified as unexplained. Many of these stillbirths do not undergo currently recommended investigations. This may leave questions unanswered and not identify stillbirths with a recurrence risk in subsequent pregnancies. AIMS: To validate a new tool (Stillbirth Investigation Utility Tool) to identify the clinical utility of investigations in stillbirth and the inter-rater agreement on cause of stillbirth using the Perinatal Society of Australia and New Zealand-Perinatal Death Classification (PSANZ-PDC). MATERIALS AND METHODS: Thirty-four stillbirths were randomly selected for inclusion, each assessed independently by five blinded assessors. The investigations were grouped into three categories: clinical and laboratory; placental pathology; and autopsy examination. The cause of death was assigned at the end of each group. Outcome measures were clinical utility of investigations measured by assessor rated usefulness and inter-rater agreement on the assigned cause of death. RESULTS: Comprehensive maternal history, maternal full blood count, maternal blood group and screen and placenta histopathology were useful in all cases. Clinical photographs were not performed and should have been performed in 50% of cases. The inter-rater agreement on cause of death assigned after all investigation results was 0.93 (95% CI 0.87-1.0). CONCLUSIONS: The new Stillbirth Investigation Utility Tool showed very good agreement in assigning the cause of death using PSANZ-PDC. Four investigations were useful in all cases. Minor refinements will be made based on feedback to enhance usability for wider implementation in research studies to assess the yield of investigations in stillbirths.

Real-world experience of adding placental histopathology studies into perinatal clinical trials.

Addition of placental histopathology studies to obstetric trials is likely to be cost-effective and may reveal structural changes suggestive of functional dysfunction to explain the success or failure of a clinical intervention. We share our recent experience in adding placental pathological examination to two clinical trials, retrospectively in one and at the outset in the other, so that other clinical trial investigators may benefit from it. The practical issues can be summarised as being regulatory and ethical, operational and reporting. Prospective inclusion of placental pathological examination as part of a clinical trial protocol is easier than retrospective, and is facilitated by fully-costed funding.

SARS-CoV-2 Transplacental Transmission: A Rare Occurrence? An Overview of the Protective Role of the Placenta.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis, causing substantial concern especially to the pregnant population. Pregnant women infected with SARS-CoV-2 are at greater risk of devastating pregnancy complications such as premature delivery and stillbirth. Irrespective of the emerging reported cases of neonatal COVID-19, reassuringly, confirmatory evidence of vertical transmission is still lacking. The protective role of the placenta in limiting in utero spread of virus to the developing fetus is intriguing. The short- and long-term impact of maternal COVID-19 infection in the newborn remains an unresolved question. In this review, we explore the recent evidence of SARS-CoV-2 vertical transmission, cell-entry pathways, placental responses towards SARS-CoV-2 infection, and its potential effects on the offspring. We further discuss how the placenta serves as a defensive front against SARS-CoV-2 by exerting various cellular and molecular defense pathways. A better understanding of the placental barrier, immune defense, and modulation strategies involved in restricting transplacental transmission may provide valuable insights for future development of antiviral and immunomodulatory therapies to improve pregnancy outcomes.

Changing Laboratory Practice for Early Detection of a Fetal Inflammatory Response: A Contemporary Approach.

Neonates born with the fetal inflammatory response (FIR) are at risk of complications such as early-onset neonatal sepsis, meningitis, and pneumonia. Providing an early histopathological diagnosis of FIR is important to guide management but can be a challenge in busy laboratories. This is a retrospective cross-sectional study over a four-month duration recruiting all placental cases with histological chorioamnionitis in our institution. The diagnostic performance of the umbilical cord (UC) section in identifying FIR, relative to the corresponding subsequent placental sections, was assessed. Clinical predictors of umbilical cord FIR were also investigated. A total of 390 UC sections were analyzed, of which 206 (52.8%) were found positive for FIR: 111 cases (53.9%) stage 1, 87 (42.2%) stage 2, and 8 (3.9%) stage 3. Our data revealed a good diagnostic sensitivity, specificity, positive predictive value, and accuracy of 76.2% (95%CI: 68.6-82.7%), 82.4% (95%CI: 65.5-93.2%), 95.0% (95%CI: 90.2-97.6%), and 77.3% (95%CI: 70.6-83.1%) respectively, in cases when clinical chorioamnionitis, fever and/or prolonged rupture of membrane (PROM) were suspected, with the area under the curve of 0.793. A maternal inflammatory response (MIR) was correlated with FIR (p < 0.001). Multivariate logistic regression analysis indicated that the higher the gestational age, clinical suspicion of chorioamnionitis, fever, and/or PROM, and the higher the stage of MIR significantly increased the odds of FIR (p < 0.001). UC section diagnosis of FIR is reasonably accurate in cases with clinical chorioamnionitis, fever, and/or PROM. Changing current laboratory practice to rapid processing of UC ahead of the rest of the other placental sections can be recommended in busy pathology departments.

Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death.

Pregnancy loss and perinatal death are devastating events for families. We assessed 'genomic autopsy' as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.

Placental pathology of resuscitated apparent stillbirth.

Resuscitated apparent stillbirth (RAS) is defined as an infant with APGAR scores of 0 at 1 minute of life who receives successful resuscitation. Assessment of placental pathology is considered standard of care in such infants, but the clinical significance of these placental findings as they relate to clinical outcomes has yet to be described within the literature. We report the findings of a retrospective study of placental pathology as defined by the Amsterdam and Dublin criteria of RAS infants born in South Australia over an 8-year period. The aim of this study was to assess whether placental pathology was able to predict RAS clinical outcomes of death, survival with adverse neurological outcomes, and survival with normal neurological outcomes. The RAS cohort within our study is small, reflecting the low incidence of RAS. Of the 25 RAS subjects 16 survived, five with abnormal neurological outcomes and 11 with normal neurological outcomes. No statistically significant difference was seen between the clinical outcome groups in the incidence of specific macroscopic and microscopic placental findings. No sentinel lesion was seen in any one clinical outcome group. Relevant placental pathology was found in all but one subject validating the role of placental pathology in determination of the aetiology of RAS. The most common finding was maternal vascular malperfusion. Placental pathology in RAS infants remains relevant but is unable to contribute to the matrix of predictive information available to the clinician and family.

Cardiovascular determinants of impaired placental function in women with cardiac dysfunction.

Female heart disease has for a long time been an underrecognized problem in the field of cardiology. With an ever-growing number of these patients getting pregnant, cardiac dysfunction during pregnancy is an increasingly large medical problem. Previous work has shown that maternal heart disease may have an adverse effect on pregnancy outcome in both mother and child. The placenta forms the connection and it is postulated that cardiac dysfunction negatively affects the placenta, and consequently, neonatal outcome. Given the paucity of data in this field, more research on the influence of cardiac (mal)function on placental (mal)function is needed. The present review describes placental function in women with various types of cardiac dysfunction, thereby aiming to provide more insight into possible underlying mechanisms of placental malfunction. Organ dysfunction in patients with heart failure is for an important part based on reduced perfusion and venous congestion. This has been shown in other organs such as kidneys, liver and brain. In pregnant women with cardiac dysfunction, placental dysfunction may follow similar patterns. Moreover, other factors, such as pre-existing hypertension and chronic hypoxia may lead to further impairment of placental function, through abnormal vascular remodeling of the uterine spiral arteries. The pathophysiology of placental dysfunction in pregnant women with cardiac dysfunction may thus be multifactorial. It is therefore important to monitor closely cardiac and placental function in such high-risk pregnancies. Gaining a better understanding of the underlying pathophysiological mechanisms may have important clinical implications in terms of pregnancy counseling, monitoring and outcome.

Diagnostic utility of p57 immunohistochemistry and DNA ploidy analysis by fluorescence in situ hybridisation in hydatidiform moles.

INTRODUCTION: Hydatidiform moles (HMs) include complete and partial moles, are the result of abnormal fertilisation. The accurate classification of HMs and its distinction from non-molar specimens is utmost important for clinical management and risk assessment. It is diagnostically challenging if the distinction is based solely on histomorphology with poor interobserver reproducibility, especially in early gestations. This study aimed to investigate the diagnostic ability of combined p57 immunohistochemistry and DNA ploidy analysis to distinguish between complete moles, partial moles and non-molar abortus. MATERIALS AND METHODS: We included all HMs cases diagnosed in our centre over a six-year period. p57 immunohistochemistry stain was performed. Only nuclear immunoreactivity in >50% of cytotrophoblasts and villous stromal cells was regarded as positive for p57. DNA ploidy status was determined by fluorescence in situ hybridisation. A total of 250 cells from five chorionic villi were counted and were scored as diploid or triploid if more than 10% of nuclei demonstrated two or three signals, respectively. RESULTS: A total of 51 cases originally diagnosed by histomorphology as complete mole (n = 18), partial mole (n = 24) and non-molar abortus (n = 9) were recruited. The cases were reclassified based on the p57 immunostaining pattern and DNA ploidy status, into 27 complete moles (p57-/diploid), 9 partial moles (p57+/triploid) and 15 non-molar abortus (p57+/diploid). The diagnostic accuracy by histomorphological features alone in each category: complete moles, partial moles and non-molar abortus was 78.4%, 70.6% and 88.2% respectively. CONCLUSION: This study highlighted the importance of the utility of combined p57 immunostain and DNA ploidy analysis in arriving at an accurate diagnosis in HMs. An algorithmic approach utilising these ancillary techniques is advocated in routine diagnostic workup for a more refined diagnostic approach to HMs.

Healthcare costs of investigations for stillbirth from a population-based study in Australia.

Objective Stillbirth investigations incur healthcare costs, but these investigations are necessary to provide information that will help reduce the risk of a recurrent stillbirth, as well as advice regarding family planning and future pregnancies. The aims of this study were to determine the healthcare costs of investigations for stillbirths, identify drivers and assess cost differences between explained and unexplained stillbirths. Methods Data from 697 stillbirths were extracted from the Stillbirth Causes Study covering the period 2013-18. The dataset comprised all investigations related to stillbirth on the mother, baby and placenta. Unit costs applied were sourced from the Australian Medicare Benefits Schedule, local hospital estimates and published literature. Multivariable regression analyses were used to assess key factors in cost estimates. Results In all, 200 (28.7%) stillbirths were unexplained and 76.8% of these had between five and eight core investigations. Unexplained stillbirths were twice as likely to have eight core investigations as explained stillbirths (16.5% vs 7.7%). The estimated aggregated cost of stillbirth investigations for 697 stillbirths was A$2.13 million (mean A$3060, median A$4246). The main cost drivers were autopsies or cytogenetic screening. Mean costs were similar when stillbirths had known or unknown causes and by reason for stillbirth among cases with definable causes. Conclusion Investigations for stillbirth in Australia cost approximately A$4200 per stillbirth on average and are critical for managing future pregnancies and preventing more stillbirths. These findings improve our understanding of the costs that may be averted if stillbirths can be prevented through primary prevention initiatives. What is known about the topic? Approximately 2000 stillbirths occur each year in Australia, and this trend has not changed for several decades. Stillbirth investigations incur healthcare costs, but these investigations are necessary to provide information to help reduce the risk of a recurrent stillbirth and advice regarding family planning and future pregnancies. Recommendations for the core set of stillbirth investigations have recently been agreed upon by consensus. What does this paper add? The costs of stillbirth investigations are unknown in Australia. The assessment of these costs is challenging because not all investigations involved in stillbirths are recorded within formal administrative systems because a stillborn baby is not formally recognised as a patient. The present population-based analysis of 697 stillbirths in Australia estimated that, on average, A$4200 was spent on investigations for each stillbirth, with key drivers being autopsies and cytogenetic screening. These costs are typical, with most cases having between five and eight of the core eight recommended investigations. What are the implications for practitioners? There are cost implications for stillbirth investigations, and this analysis gives a true account of current practice in Australia. Together with the high downstream economic costs of stillbirths, the cost burden of stillbirth investigations is high but ultimately avoidable when practitioners adhere to the core investigations, build knowledge around preventable risk factors and use this information to reduce the number of stillbirths.

Placental pathology in cancer during pregnancy and after cancer treatment exposure.

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.

Estimating umbilical cord flow resistance from measurements of the whole cord.

Measuring umbilical blood pressure in utero is challenging and for this reason non-invasive methods are required. However, the total vessel blood pressure drop can be estimated using numerical and empirical results by studying the mechanics of fluids in coiled and straight tubes. Two key findings emerge from such an analysis. Firstly, the total pressure drop along a vessel at a given blood flow-rate depends on both the tightness of the coils and the total cord length. Relatively short and straight cords exhibit low pressure, while long, tightly coiled cords with large width exhibit high pressure. It follows that an estimate of the pressure requires three measurements: the full cord length, its average width and number of coils. Using this result we propose two prototype indices for clinical testing that estimate umbilical cord flow resistance. The umbilical pressure index (PX) and flow index (QX) quantify the deviation of a cord geometry from defined typical conditions by considering the steady pressure drop and flow-rate, respectively. These indices can be quickly calculated, and require only a single additional measurement to the conventional umbilical coiling index (UCI); namely the cord coiling width. Unlike the UCI, these indices are derived from blood-flow properties and provide a measure of the relative flow-resistance inherent to a cord geometry. Furthermore, the pressure index can be applied to irregularities, including loose true knots, which we show must be accounted for.

Classification and reporting guidelines for the pathology diagnosis of placenta accreta spectrum (PAS) disorders: recommendations from an expert panel.

The terminology and diagnostic criteria presently used by pathologists to report invasive placentation is inconsistent and does not reflect current knowledge of the pathogenesis of the disease or the needs of the clinical care team. A consensus panel was convened to recommend terminology and reporting elements unified across the spectrum of PAS specimens (i.e., delivered placenta, total or partial hysterectomy with or without extrauterine tissues, curetting for retained products of conception). The proposed nomenclature under the umbrella diagnosis of placenta accreta spectrum (PAS) replaces the traditional categorical terminology (placenta accreta, increta, percreta) with a descriptive grading system that parallels the guidelines endorsed by the International Federation of Gynaecology and Obstetrics (FIGO). In addition, the nomenclature for hysterectomy specimens is separated from that for delivered placentas. The goal for each element in the system of nomenclature was to provide diagnostic criteria and guidelines for expected use in clinical practice.

Placenta Accreta in an Oragnutan (Pongo abelii) and a Chimpanzee (Pan troglodytes).

Placenta accreta is defined as abnormal adherence of the placenta to the uterine wall. Placenta accreta is recognized as a common problem in human medicine, but has apparently not been reported previously in great apes, despite similarity in their reproductive biology. A 36-year-old multiparous female Sumatran orangutan (Pongo abelii) and a 20-year-old nulliparous female chimpanzee (Pan troglodytes), with gross uterine and histological uterine vascular changes that are characteristic of placenta accreta, are presented.