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.

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.

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.

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.

Classification of causes and associated conditions for stillbirths and neonatal deaths.

Accurate and consistent classification of causes and associated conditions for perinatal deaths is essential to inform strategies to reduce the five million which occur globally each year. With the majority of deaths occurring in low- and middle-income countries (LMICs), their needs must be prioritised. The aim of this paper is to review the classification of perinatal death, the contemporary classification systems including the World Health Organization's International Classification of Diseases - Perinatal Mortality (ICD-PM), and next steps. During the period from 2009 to 2014, a total of 81 new or modified classification systems were identified with the majority developed in high-income countries (HICs). Structure, definitions and rules and therefore data on causes vary widely and implementation is suboptimal. Whereas system testing is limited, none appears ideal. Several systems result in a high proportion of unexplained stillbirths, prompting HICs to use more detailed systems that require data unavailable in low-income countries. Some systems appear to perform well across these different settings. ICD-PM addresses some shortcomings of ICD-10 for perinatal deaths, but important limitations remain, especially for stillbirths. A global approach to classification is needed and seems feasible. The new ICD-PM system is an important step forward and improvements will be enhanced by wide-scale use and evaluation. Implementation requires national-level support and dedicated resources. Future research should focus on implementation strategies and evaluation methods, defining placental pathologies, and ways to engage parents in the process.

Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement.

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.

Stillbirths: recall to action in high-income countries.

Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.

Folate, vitamin B12, vitamin B6 and homocysteine: impact on pregnancy outcome.

Good clinical practice recommends folic acid supplementation 1 month prior to pregnancy and during the first trimester to prevent congenital malformations. However, high rates of fetal growth and development in later pregnancy may increase the demand for folate. Folate and vitamins B12 and B6 are required for DNA synthesis and cell growth, and are involved in homocysteine metabolism. The primary aim of this study was to determine if maternal folate, vitamin B12, vitamin B6 and homocysteine concentrations at 18-20 weeks gestation are associated with subsequent adverse pregnancy outcomes, including pre-eclampsia and intrauterine growth restriction (IUGR). The secondary aim was to investigate maternal B vitamin concentrations with DNA damage markers in maternal lymphocytes. A prospective observational study was conducted at the Women's and Children's Hospital, Adelaide, South Australia. One hundred and thirty-seven subjects were identified prior to 20 weeks gestation as at high or low risk for subsequent adverse pregnancy outcome by senior obstetricians. Clinical status, dietary information, circulating micronutrients and genome damage biomarkers were assessed at 18-20 weeks gestation. Women who developed IUGR had reduced red blood cell (RBC) folate (P < 0.001) and increased plasma homocysteine concentrations (P < 0.001) compared with controls. Maternal DNA damage, represented by micronucleus frequency and nucleoplasmic bridges in lymphocytes, was positively correlated with homocysteine (r = 0.179, P = 0.038 and r = 0.171, P = 0.047, respectively). Multivariate regression analysis revealed RBC folate was a strong predictor of IUGR (P = 0.006). This study suggests that low maternal RBC folate and high homocysteine values in mid pregnancy are associated with subsequent reduced fetal growth.

Stillbirths: the way forward in high-income countries.

Stillbirth rates in high-income countries declined dramatically from about 1940, but this decline has slowed or stalled over recent times. The present variation in stillbirth rates across and within high-income countries indicates that further reduction in stillbirth is possible. Large disparities (linked to disadvantage such as poverty) in stillbirth rates need to be addressed by providing more educational opportunities and improving living conditions for women. Placental pathologies and infection associated with preterm birth are linked to a substantial proportion of stillbirths. The proportion of unexplained stillbirths associated with under investigation continues to impede efforts in stillbirth prevention. Overweight, obesity, and smoking are important modifiable risk factors for stillbirth, and advanced maternal age is also an increasingly prevalent risk factor. Intensified efforts are needed to ameliorate the effects of these factors on stillbirth rates. Culturally appropriate preconception care and quality antenatal care that is accessible to all women has the potential to reduce stillbirth rates in high-income countries. Implementation of national perinatal mortality audit programmes aimed at improving the quality of care could substantially reduce stillbirths. Better data on numbers and causes of stillbirth are needed, and international consensus on definition and classification related to stillbirth is a priority. All parents should be offered a thorough investigation including a high-quality autopsy and placental histopathology. Parent organisations are powerful change agents and could have an important role in raising awareness to prevent stillbirth. Future research must focus on screening and interventions to reduce antepartum stillbirth as a result of placental dysfunction. Identification of ways to reduce maternal overweight and obesity is a high priority for high-income countries.