SARS-COV2 placentitis and pregnancy outcome: A multicentre experience during the Alpha and early Delta waves of coronavirus pandemic in England.

Background: Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis. Methods: The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected. Findings: 59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79.7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25.5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described. Interpretation: SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike 'classical' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation. Funding: There was not funding associated with this study.

Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1-Mutant Diffuse Intrinsic Pontine Glioma.

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (K d = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood-brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. SIGNIFICANCE: Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275.

Early prenatal presentation of the cartilage-hair hypoplasia / anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia.

Three sibling fetuses identified with limb shortening and thoracic narrowing at twelve weeks' gestation on first trimester ultrasound examination are presented. The parents were non-consanguineous, Caucasian, healthy, of normal stature and had a healthy normal daughter. The radiographic abnormalities were highly suggestive of thanatophoric dysplasia, but molecular analysis failed to identify a pathogenic variant in FGFR3. The three fetuses were found to have identical compound heterozygous mutations in RMRP in trans, one inherited from the mother and one from the father. This represents the early prenatal presentation and fetal findings of metaphyseal dysplasia type McKusick (Cartilage-hair hypoplasia; CHH)/anauxetic dysplasia spectrum of disorders.

Proteomic profiling reveals sub proteomes of the human placenta.

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

Use of the complement inhibitor Coversin to treat HSCT-associated TMA.

Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor.Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab.

A rapid high throughput proteomic method based on profiling of proteolytic free peptides to assess post-delivery degradation of placental tissue.

A rapid method to determine quality for placental proteomic studies is required due to varying lengths of time between delivery and sampling in routine protocols. We developed a rapid 10 min LC-MS based scanning method to profile free peptides liberated from natural proteolytic degradation. The assay was applied to placenta samples obtained following refrigeration for varying time periods post-delivery (12 h, +24 h, +48 h and +72 h). Analysis reveals time dependant overlapping profiles for groups <24 to +48 h with greatest variation in the +72 h group, indicating that significant proteolysis affects tissue integrity between 48 and 72 h.

Brain weight in sudden unexpected death in infancy: experience from a large single-centre cohort.

AIMS: Published reports of brain weight in sudden infant death syndrome (SIDS) are contradictory, although several have concluded that brain weight is increased in SIDS compared with controls or reference data. This is important as, if brain weight is significantly different, it may be of diagnostic use or provide insights into the aetiology of SIDS. The aim of this study was to use a large series of well-characterized sudden unexpected infant deaths from a single centre to provide definitive data regarding this issue. METHODS: A retrospective review identified 1100 infants who had died suddenly and undergone a comprehensive autopsy at Great Ormond Street Hospital between 1996 and 2011. They were split into two groups: those in whom death could be explained and those whose deaths remained unexplained despite full investigation (SIDS/unexplained sudden unexpected death in infancy). RESULTS: There were 1100 cases of whom 573 (52%) were unexplained and 527 (48%) explained. Multiple regression analysis, which adjusted for sex, age and post-mortem interval, showed no difference in the ratio of brain weight : body weight between those infants dying of explained causes and those in whom no cause could be found. This finding remained true when restricting analysis to those with macroscopically normal brains. CONCLUSIONS: In this large series of infants dying of both explained and unexplained causes, brain weight, once corrected for body weight, did not vary consistently with the cause of death. Brain weight cannot be used as a diagnostic indicator of the cause of death or to inform hypothetical models of the pathogenesis of SIDS.

Potentially preventable infant and child deaths identified at autopsy; findings and implications.

PURPOSE: The purpose of the study was to determine the proportion of pediatric deaths investigated by HM Coronial autopsy which were potentially preventable deaths due to treatable natural disease, and what implications such findings may have for health policies to reduce their occurrence. METHODS: A retrospective study of 1779 autopsies of individuals between 7 days and 14 years of age requested by HM Coroner, taking place in one specialist pediatric autopsy center, was undertaken. Cases were included if they involved a definite natural disease process in which appropriate recognition and treatment was likely to have affected their outcome. Strict criteria were used and cases were excluded where the individual had any longstanding condition which might have predisposed them to, or altered the recognition of, acute illness, or its response to therapy. RESULTS: Almost 8% (134/1779) of the study group were potentially preventable deaths as a result of natural disease, the majority occurring in children younger than 2 years of age. Most individuals reported between 1 and 7 days of symptoms before their death, and the majority had sought medical advice during this period, including from general practitioners within working hours, and hospital emergency departments. Of those who had sought medical attention, around one-third had done so more than once (28%, 15/53). Sepsis and pneumonia accounted for the majority of deaths (46 and 34% respectively), with all infections (sepsis, pneumonia and meningitis) accounting for 110/134 (82%). CONCLUSION: Around 10% of pediatric deaths referred to HM Coroner are potentially preventable, being the result of treatable natural acute illnesses. In many cases medical advice had been sought during the final illness. The results highlight how a review of autopsy data can identify significant findings with the potential to reduce mortality, and the importance of centralized investigation and reporting of pediatric deaths.

Immersion-related deaths in infants and children: autopsy experience from a specialist center.

PURPOSE: To investigate the demographics, circumstances and autopsy findings in infants and children dying following immersion. METHODS: A retrospective review of a pediatric autopsy database at a specialist center over a 16-year period (1995-2010) was undertaken to identify deaths between 7 days and 16 years of age in whom death occurred following immersion. RESULTS: 28 infants and children died following immersion during the study period. 82 % were aged <4 years, with peak age of death between 1 and 2 years. Immersion occurred at home in a bath or private pool in 70 % of cases. There was a lack of direct supervision in all but two cases where the information was recorded (91 %); one of these cases occurred in a public swimming lesson, and in the other the carer was incapacitated. Autopsy findings were non-specific. Facial or subconjunctival petechial hemorrhages were a feature of 18 % of cases. There was increased lung weight, or histological pulmonary edema/intra-alveolar hemorrhage in all but one case. CONCLUSIONS: The data suggest that the majority of pediatric immersion-related deaths were potentially preventable with appropriate supervision. The findings strongly support the role of education regarding adequate carer supervision of infants and children while bathing, particularly in children with underlying conditions such as epilepsy. As private pools and "hot tubs" become more common in the UK and other jurisdictions, specific recommendations such as fencing pools will need to be included in advice to carers. So-called 'dry drowning" appears to be an uncommon mechanism of death in this age group.

Reference ranges for organ weights of infants at autopsy: results of >1,000 consecutive cases from a single centre.

BACKGROUND: Infancy is the most common period for childhood death, including both neonatal deaths from obstetric or medical complications and sudden unexpected infant deaths. The weighing of organs at autopsy is an established process and is recommended in current protocols. However, minimal contemporary data is available regarding reference ranges for organ weights of infants. METHODS: Organ weight data for consecutive infant autopsies over a 14 year period performed at a single tertiary centre, including >1,000 cases, were examined in order to provide up to date reference ranges across this age range, using linear regression modelling and the standard LMS method. RESULTS: 1,525 infant autopsies were analysed, of which 1,190 were subsequently used in the creation of linear regression models prior to performance of the LMS method. Organ weight charts were produced for the 5th, 25th, 50th, 75th and 95th centiles for the heart, lungs, liver, spleen, kidneys, pancreas, thymus gland and adrenal glands. CONCLUSION: This study provides the largest single centre contemporary dataset of infant autopsies allowing provision of up-to-date 'normal' ranges for all major organ weights across this age range.

Sudden unexpected infant deaths associated with car seats.

The purpose of this study was to investigate the frequency, circumstances, demographics, and causes of death of infants dying while seated in car safety seats. A retrospective review of a pediatric autopsy database at a specialist center over a 16-year period was undertaken to identify any infant deaths (aged <1 year), in whom death occurred while seated in a car safety seat. Fourteen car seat-associated deaths were identified from a total of 1,465 coronial infant autopsies (0.96 %). Four involved infants were being appropriately transported in the car seat, all of whom had a medical underlying cause of death (one infection and three congenital heart disease). The majority (10 cases; 70 %) occurred while car seats were being inappropriately used, outside of the car, including as an alternative to a cot or high-chair. Five of these infants died of explained causes, but four deaths remained unexplained after autopsy, and in one no cause of death was available. There were no cases of previously healthy infants dying unexpectedly in a car seat when it was being used appropriately, and in this series there were no cases of traumatic death associated with car seats, either during road traffic accidents, or from falling or being suspended from a car seat. Infant deaths in car seats are rare. These data support the recommendation that car seats be used only for transport and not as alternatives for cots or high-chairs. More research is required to investigate the effect of travel in car seats on infants with underlying conditions. There appears to be no increased risk of unexpected deaths of healthy infants transported appropriately in car seats.

Fatal aspiration of foreign bodies in infants and children.

PURPOSE: To investigate the frequency, circumstances, demographics and autopsy findings of infants and children dying as a result of foreign body aspiration. METHODS: Retrospective review of autopsy cases in children aged between seven days and 18 years, at one specialist centre over a 16-year period, in which death was the result of aspiration of a foreign body. RESULTS: Ten cases were identified out of a total autopsy population of 2165. Only one individual had an underlying diagnosis potentially contributing to aspiration. All but one case involved aspiration of food, with grapes being a feature of four cases. In cases with a prolonged survival interval, autopsy demonstrated bronchopneumonia and hypoxic-ischaemic encephalopathy. In the remaining cases autopsy findings were non-specific. CONCLUSIONS: Fatal aspiration of a foreign body is rare in this population. The cases involve normal children who aspirate food, particularly grapes. There are typically minimal, non-specific findings at autopsy.

Myocardial necrosis and infarction in newborns and infants.

PURPOSE: This study aimed to investigate the incidence, and underlying associations, of myocardial necrosis occurring in infants undergoing autopsy. METHODS: An autopsy database containing anonymized details of all infant autopsies conducted at Great Ormond Street Hospital between January 1996 and December 2010 was searched to identify all infants with myocardial necrosis. The characteristics of the necrosis and any underlying associations were reviewed. RESULTS: Myocardial necrosis was recorded in 187 autopsies out of a total of 1,637 (11.4%), and was localized to the papillary muscles, subendocardial region, or trabeculae in 50.8% of cases. The most common associations were congenital heart disease, perinatal asphyxia, coronary artery abnormalities, or sepsis. Three cases of apparently idiopathic myocardial infarction were identified and are described in detail. CONCLUSIONS: Myocardial necrosis is relatively common in infants who die and undergo autopsy, and is most commonly associated with congenital heart disease and perinatal asphyxia. Myocardial infarction can occur in infancy in the absence of any apparent underlying cause: the etiology of these cases is unclear.

Clinicopathological features of fatal cardiomyopathy in childhood: an autopsy series.

AIM: Cardiomyopathy, a group of primary myocardial disorders, is an uncommon, but important, cause of death in childhood. This study examines the demographic, clinical and pathological features of fatal cardiomyopathy in childhood with particular reference to its classification and autopsy findings. METHOD: The method of this study was a retrospective structured review of all paediatric autopsies performed at a single specialist centre from 1995 to 2009 inclusive, in order to determine the demographic, clinical and pathological features of fatal cardiomyopathy. RESULTS: From a total of 2229 autopsies performed at the centre during the study period on live-born infants and children, 34 confirmed cases of cardiomyopathy were identified (1.5%). More than half (59%) of these cases occurred in infants (less than 1 year of age). Heart weight of cardiomyopathy cases was significantly greater than those with normal hearts (P < 0.001), and 77% had heart weights above the 95th percentile of the normal expected range for age, including all of those over 1 year age. Of cardiomyopathy cases, 50% were primary dilated cardiomyopathy and 27% were primary hypertrophic cardiomyopathy. Twelve of 34 cases (35%) presented as sudden unexpected death, the diagnosis of cardiomyopathy being only made at autopsy. CONCLUSION: Cardiomyopathy is an uncommon cause of death in infancy and childhood. It can present as sudden unexpected death and encompasses a range of aetiologies. Heart weight above the 95th percentile at autopsy is present in most cases but heart weight may be within the normal range in infants.

Postmortem tandem mass spectrometry profiling for detection of infection in unexpected infant death.

Numerous hypotheses have been suggested to explain the cause of sudden unexpected infant death, including infection. As part of the autopsy, routine ancillary investigations are performed, including blood/bile tandem mass spectrometry (TMS) primarily for detection of metabolic disease. The aim of this study was to evaluate and assess TMS derived acylcarnitine profiles to determine whether infectious deaths were associated with characteristic profiles. As part of a retrospective study including >2,500 pediatric autopsies at a single specialist centre over a 14 year period, acylcarnitine profiles were reviewed. Using multiple linear regression, standardised residuals were prepared and findings compared between different cause of death groups, including unexplained, focal infection, microbiological infection and accidental injuries. 415 blood samples from SUDI autopsies were identified. Statistically significant differences in TMS profiles were identified between those dying of infection and the unexplained SUDI group, including changes in free carnitine, short chain acylcarnitines and octanoylcarnitine. Cases with microbiological infection diagnosed only from postmortem cultures did not show any significant difference from the unexplained group. Postmortem TMS profiling identifies SUDI deaths which are associated with histological evidence of infection, and an acylcarnitine profile suggesting perturbation of oxidative metabolism. Such findings raise the possibility that more comprehensive TMS profiling may offer additional diagnostic clues beyond screening for metabolic disorders, and may contribute to determination of mode of death.

Difficulties in interpretation of post-mortem microbiology results in unexpected infant death: evidence from a multidisciplinary survey.

BACKGROUND: Post-mortem (PM) microbiological investigations are recommended in cases of sudden unexpected death in infancy (SUDI), and infection is a recognised cause of such deaths, but no current evidence-based guidelines exist for the appropriate interpretation of results. AIM: To assess interpretive difficulties using a targeted cross-specialty questionnaire. METHODS: 109 consultant specialists involved in infant death management were given a questionnaire providing information on five hypothetical standardised SUDI cases, which differed only in their PM microbiology findings. Participants classified each case into categories: definite bacterial infection, probable bacterial infection, bacterial growth of uncertain significance and PM contamination. RESULTS: 63 (57%) specialists responded. There was no clinical scenario in which complete concordance in interpretation of PM microbiology results was established among participants. In cases with pure growth of Group 2 pathogens such as Group B ß-haemolytic Streptococcus, 96% of respondents agreed upon probable or definite bacterial infection. With mixed growth of Group 2 pathogens, 83% reported probable or definite bacterial infection. Growth of organisms such as Staphylococcus aureus caused the most difficulty, with almost equal numbers of participants interpreting the finding as significant or non-significant. There were no consistent differences in interpretation between different specialist groups. CONCLUSIONS: While there is general agreement in interpretation of PM microbiology findings in some SUDI scenarios, no consensus was achieved for any clinical setting, and variation in the presumed significance between specialists was apparent. In the absence of appropriate evidence-based guidelines, this has practical implications for the management of such deaths in a multidisciplinary setting.

Microbiological findings in sudden unexpected death in infancy: comparison of immediate postmortem sampling in casualty departments and at autopsy.

AIM: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of post-neonatal infant death in the UK. This audit reviews current practice in the investigation of SUDI deaths, with particular regard to the practice of microbiological sampling in emergency departments (ED) compared with samples obtained at the time of autopsy for establishing the cause of death, as suggested by current guidelines. METHODS: Coronial autopsies performed for the indication of SUDI over a 4-year period at a single specialist centre were reviewed with particular regard to the findings of microbiological investigations performed in ED compared with those performed at the time of autopsy. RESULTS: Of 229 SUDI postmortems performed during the period, there were 136 cases in which both bacteriological samples taken in ED and at autopsy were available, including 109 with blood cultures taken at both time points. 66 cases had sterile blood cultures in ED of which 37 (56%) showed positive microbiological growth from autopsy samples including nine (14%) cases with group II pathogens. Group II pathogens were identified from ED samples in six (6%) of the total cases; all but two cases of Staphylococcus aureus were not detected at autopsy. CONCLUSION: Blood cultures obtained at autopsy are associated with a significantly higher rate of positive microbial cultures compared with blood samples taken in life. Most represent easily identified postmortem translocation or overgrowth rather than infection as the cause of death. No cases with a final infective cause of death would have been missed if ED sampling had not been performed.

Sudden unexpected death in infancy associated with an epithelial-type hepatoblastoma in a 6-month-old infant.

Sudden unexpected death in infancy and childhood attributable to undiagnosed neoplasia is rare. Malignant neoplasms are very uncommon in infancy, with an age-standardized incidence rate of 118.3 per million. Primary malignant liver tumors are rare, with hepatoblastoma accounting for up to two thirds of cases. Although hepatoblastoma is the most common malignant neoplasm of the liver in childhood, it only accounts for 3.1% of childhood cancers for infants less than 12 months of age. We describe the first case of sudden death in an apparently healthy 6-month-old infant whose autopsy revealed an epithelial type hepatoblastoma with mixed fetal and embryonal patterns.