Quantification of Maceration Changes using Post Mortem MRI in Fetuses

BACKGROUND: Post mortem imaging is playing an increasingly important role in perinatal autopsy, and correct interpretation of imaging changes is paramount. This is particularly important following intra-uterine fetal death, where there may be fetal maceration. The aim of this study was to investigate whether any changes seen on a whole body fetal post mortem magnetic resonance imaging (PMMR) correspond to maceration at conventional autopsy. METHODS: We performed pre-autopsy PMMR in 75 fetuses using a 1.5 Tesla Siemens Avanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to the clinical history and autopsy data using a numerical severity scale (0 = no maceration changes to 2 = severe maceration changes) for 6 different visceral organs (total 12). The degree of maceration at autopsy was categorized according to severity on a numerical scale (1 = no maceration to 4 = severe maceration). We also generated quantitative maps to measure the liver and lung T2. RESULTS: The mean PMMR maceration score correlated well with the autopsy maceration score (R(2) = 0.93). A PMMR score of ≥4.5 had a sensitivity of 91%, specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver and lung T2 were increased in fetuses with maceration scores of 3-4 in comparison to those with 1-2 (liver p = 0.03, lung p = 0.02). CONCLUSIONS: There was a good correlation between PMMR maceration score and the extent of maceration seen at conventional autopsy. This score may be useful in interpretation of fetal PMMR

Social and behavioural factors in Non-suspicious unexpected death in infancy; experience from metropolitan police project indigo investigation

BACKGROUND: Risk factors for Sudden Unexpected Death in Infancy (SUDI) are well described, and such cases are now investigated according to standard protocols. In London, Project Indigo of the Metropolitan Police provides a unique, detailed framework for such data collection. We investigate such data to provide a contemporary account of SUDI in a large city and further link data to publically available datasets to investigate interactions with social factors. METHODS: Retrospective analysis of data routinely collected by the Metropolitan Police Service in all cases of non-suspicious SUDI deaths in London during a six year period. RESULTS: SUDI deaths are associated with markers of social deprivation in London. A significant proportion of such deaths are associated with potentially modifiable risk factors such as cigarette smoking and co-sleeping, such behaviour also being associated with social factors, including accommodation issues. CONCLUSIONS: Routinely collected data provide valuable insight into patterns and associations of mortality, with SUDI remaining a significant issue in London. Risk factors include social disadvantage, which may manifest in part by affecting behavioural patterns such as co-sleeping and public health interventions to reduce rates require significant social modification

Plasma-cell-rich infiltrates in paediatric renal transplant biopsies are associated with increased risk of renal allograft failure

BACKGROUND: Increased plasma cell infiltration in renal allograft biopsies is a rare finding associated with poor outcome in adult renal transplant recipients. The clinical impact of increased plasma cell infiltrates in paediatric renal transplant recipients (pRTR) remains unknown. METHODS: We conducted a retrospective case-control study from April 1996 to March 2014 comparing the outcome of pRTR with increased (>10 % of infiltrate) plasma cells in renal transplant biopsies to a control cohort of pRTR without increased plasma cell infiltration but similar grade of rejection according to Banff classification. RESULTS: Increased plasma cell infiltrates were present in 14 of 162 (9 %) reviewed pRTR aged 3.2-17.5 (median 13.4) years at time of transplantation. Compared with 14 pRTR renal transplant biopsies without significantly increased plasma cells, there were no significant differences in mismatch and baseline estimated glomerular filtration rate (eGFR). Plasma cells were present in case biopsies at a maximal density of 14-116 (median 33) plasma cells/HPF. Increased plasma cells were associated with decreased eGFR at biopsy (22 vs. 49 ml/min/1.73 m(2); p < 0.001) and 4 weeks post-biopsy (26 vs. 56 ml/min/1.73 m(2); p < 0.001) despite comparable eGFR 4 weeks prior to biopsy. Increased plasma cells were further associated with significantly increased frequency of renal allograft loss (71 % vs. 7 %; p < 0.001) at 0-27 (median 2) months after biopsy. CONCLUSION: Increased plasma cell infiltrates in pRTR are uncommon but associated with significantly reduced renal allograft survival as well as significantly reduced allograft function in surviving grafts

Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance

OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of patient and tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p <0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles

National registry for sudden unexpected deaths of infants and children in England: why do we need one and do families want one?

The sudden and unexpected death of an infant or child is devastating. An inability to explain why an infant or child died is difficult to accept for both families and professionals. No reliable national dataset exists to estimate precisely how many infants and children die unexpectedly each year in England. This lack of accurate epidemiological data belies the scale of this public health problem. Detailed controlled observational studies of infant deaths identifying risk factors and providing evidence-based advice for parents has seen a dramatic reduction in incidence over the last 30 years by almost 80% but greater knowledge is needed if future deaths of infants and older children are to be prevented and families optimally supported. We propose that a national registry of sudden unexpected deaths in infancy and childhood would accurately determine incidence, identify unknown risk factors and highlight good care practices, ensuring these can be standardised nationally. For such a project to be successful, however, parents must be at the heart of it. We held a consultation day between families, professionals and supporting charities (The Lullaby Trust, Child Bereavement UK, SUDC UK and CRY) to seek opinion on the desire for a registry and how best to ensure families are engaged. Here, we summarise our rationale for a registry and the feedback we received from attendees regarding their views of the proposal and the practical aspects of administering it

Stillbirth and intrauterine fetal death: factors affecting determination of cause of death at autopsy

Objectives There have been several attempts to classify cause of death (CoD) in stillbirth; however, all such systems are subjective, allowing for observer bias and making comparisons between systems challenging. This study aimed to examine factors relating to determination of CoD using a large dataset from two specialist centers in which observer bias had been reduced by classifying findings objectively and assigning CoD based on predetermined criteria. Methods Detailed autopsy reports from intrauterine deaths in the second and third trimesters during 2005–2013 were reviewed and findings entered into a specially designed database, in which CoD was assigned using predefined objective criteria. Data regarding CoD categories and factors affecting determination of CoD were examined. Results There were 1064 intrauterine deaths, including 246 early intrauterine fetal deaths (IUFD) (< 20 weeks), 179 late IUFDs (20–23 weeks) and 639 stillbirths (≥ 24 weeks' gestation). Overall, around 40% (n = 412) had a clear CoD identified, whilst around 60% (n = 652) were classified as ‘unexplained’, including around half with identified risk factors or lesions of uncertain significance, with the remaining half (n = 292 (45%)) being entirely unexplained. A stepwise increase in the proportion of unexplained deaths was observed with increasing maceration. Black and Asian women had significantly greater proportions of deaths due to ascending infection, whilst women aged over 40 years had significantly increased placenta-related CoDs. There was no significant difference in CoD distribution according to maternal body mass index or with increasing postmortem interval. Around half of those with an identifiable CoD could be identified from clinical review and external fetal examination or imaging, with most of the remainder being determined following placental examination. Conclusions Based on objective criteria, many intrauterine deaths throughout gestation remain unexplained despite autopsy examination. The rate of unexplained death varies from around 30% to 60% depending on interpretation of the significance of features. CoD determination is dependent on both the classification system used and subjective interpretation, such that variation in the proportion of ‘unexplained’ cases is based largely on speculation regarding mechanisms of death. Novel methods to determine objectively the mechanism of death at postmortem examination are required

Stillbirth and intrauterine fetal death: role of routine histological organ sampling to determine cause of death.

OBJECTIVES: Guidelines for the investigation of intrauterine death and sudden unexpected death in infancy (SUDI) recommend, based on expert opinion, autopsy procedures and tissue sampling strategies for histological analysis. Although stillbirth is much more common than SUDI, there have been no large-scale studies published which evaluate the usefulness of histological evaluation of specific organs in stillbirth for determining cause of death. Our aim was to evaluate the use of macroscopic and microscopic assessment of internal organs to determine cause of intrauterine death. METHODS: As part of a larger study evaluating several aspects of autopsy findings in intrauterine death, a dedicated database was used to collate antenatal and postmortem examination details for cases of intrauterine death examined between 2005 and 2013 at two tertiary specialist centers in London, UK. Histological findings for all organs were examined in relation to the final cause of death, as determined by objective criteria. RESULTS: Among 1064 intrauterine deaths, the majority (> 80%) of cases had internal organs that were normal on both macroscopic and microscopic examination. There was no case in which histological cardiac examination provided the cause of death when the macroscopic appearance of the heart was normal. Microscopic examination of lung tissue revealed 13 (1%) cases with histological abnormalities that provided the cause of death when the macroscopic appearance was normal, but there was only one (0.1%) case in which the diagnosis would not have been apparent on placental examination: a case of congenital cytomegalovirus infection. There was no case in which microscopic examination of macroscopically normal liver, kidneys, adrenals, spleen, thymus, intestines, pancreas, brain or thyroid provided the cause of death. CONCLUSION: In this large series of autopsies in cases of intrauterine death, only around 1% of cases demonstrated histological abnormalities which provided the cause of death when the internal organs appeared normal macroscopically. There was no case in which routine histological examination of most tissues provided diagnostically useful information that was not apparent from other examinations, such as placental pathology. There is little benefit, purely in terms of determining cause of death, in obtaining tissue from most macroscopically normal organs for routine histological examination

Placental Pathology in Relation to Uterine Artery Doppler Findings in Pregnancies with Severe Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler Changes

OBJECTIVES: Current guidelines for diagnosis and management of early-onset intrauterine growth restriction (IUGR) rely on umbilical artery Doppler (UAD), without including uterine artery Doppler (UtAD). We hypothesized that IUGR cases with abnormal UAD but normal UtAD has a different spectrum of placental pathology compared with those with abnormal UtAD. STUDY DESIGN: Retrospective review of pregnancies with sonographic evidence of IUGR and abnormal UAD prior to delivery. Cases with ≥ 1 UtAD record(s) after 18(+0) weeks' gestation and placental pathology were included. Cases were stratified according to initial UtAD pulsatility index (PI) values (n = 196): normal (n = 19; PI < 95th centile for gestational age/no notching), intermediate (n = 69; PI ≥ 95th centile/no/unilateral notching) and abnormal (n = 108; PI ≥ 95th centile/bilateral notching). Pregnancy outcomes and placental pathology were compared between groups. RESULTS: Women in the normal group delivered later than those in the abnormal group (30.1 ± 3.5 vs. 28.0 ± 3.5 weeks; mean ± standard deviation; p = 0.03). Their placentas exhibited higher rates of chronic intervillositis (15.8 vs. 0.9%; p = 0.01), chorangiosis (15.8 vs. 0.9%; p < 0.0001), and massive perivillous fibrin deposition (21.1 vs. 7.4%; p = 0.05), but had lower rates of uteroplacental vascular insufficiency (26.3 vs. 79.6%; p < 0.0001). CONCLUSION: Approximately 10% of pregnancies with early-onset IUGR and abnormal UAD exhibited normal UtAD waveforms. They delivered later, and their placentas exhibited unusual placental pathologies

Imaging the human placental microcirculation with micro-focus computed tomography: Optimisation of tissue preparation and image acquisition

Micro-CT provides 3D volume imaging with spatial resolution at the micrometre scale. We investigated the optimal human placenta tissue preparation (contrast agent, perfusion pressure, perfusion location and perfusion vessel) and imaging (energy, target material, exposure time and frames) parameters. Microfil (Flow Tech, Carver, MA) produced better fill than Barium sulphate (84.1%(±11.5%)vs70.4%(±18.02%) p = 0.01). Perfusion via umbilical artery produced better fill than via chorionic vessels (83.8%(±17.7%)vs78.0%(±21.9%), p < 0.05), or via umbilical vein (83.8%(±16.4%)vs69.8%(±20.3%), p < 0.01). Imaging at 50 keV with a molybdenum target produced the best contrast to noise ratio. We propose this method to enable quantification and comparison of the human fetoplacental vascular tree

Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts

This is the peer reviewed version of the following article: Badshah, I. I., et al. "Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts." British Journal of Dermatology 0(ja)., which has been published in final form at https://doi.org/10.1111/bjd.17352. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsFunding: RO, IB and SB are funded by the Great Ormond Street Children's Charity. This research was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centr