Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus MRI.

OBJECTIVES: To compare the diagnostic yield of whole-body post-mortem computed tomography (PMCT) imaging to post-mortem magnetic resonance (PMMR) imaging in a prospective study of fetuses and children. METHODS: We compared PMCT and PMMR to conventional autopsy as the gold standard for the detection of (a) major pathological abnormalities related to the cause of death and (b) all diagnostic findings in five different body organ systems. RESULTS: Eighty two cases (53 fetuses and 29 children) underwent PMCT and PMMR prior to autopsy, at which 55 major abnormalities were identified. Significantly more PMCT than PMMR examinations were non-diagnostic (18/82 vs. 4/82; 21.9 % vs. 4.9 %, diff 17.1 % (95 % CI 6.7, 27.6; p < 0.05)). PMMR gave an accurate diagnosis in 24/55 (43.64 %; 95 % CI 31.37, 56.73 %) compared to 18/55 PMCT (32.73 %; 95 % CI 21.81, 45.90). PMCT was particularly poor in fetuses <24 weeks, with 28.6 % (8.1, 46.4 %) more non-diagnostic scans. Where both PMCT and PMMR were diagnostic, PMMR gave slightly higher diagnostic accuracy than PMCT (62.8 % vs. 59.4 %). CONCLUSION: Unenhanced PMCT has limited value in detection of major pathology primarily because of poor-quality, non-diagnostic fetal images. On this basis, PMMR should be the modality of choice for non-invasive PM imaging in fetuses and children. KEY POINTS: • Overall 17.1 % more PMCT examinations than PMMR were non-diagnostic • 28.6 % more PMCT were non-diagnostic than PMMR in fetuses <24 weeks • PMMR detected almost a third more pathological abnormalities than PMCT • PMMR gave slightly higher diagnostic accuracy when both were diagnostic.

Diagnostic accuracy of post mortem MRI for abdominal abnormalities in foetuses and children.

BACKGROUND: To compare the diagnostic accuracy of post-mortem magnetic resonance imaging (PMMR) specifically for abdominal pathology in foetuses and children, compared to conventional autopsy. METHODS: Institutional ethics approval and parental consent was obtained. 400 unselected foetuses and children underwent PMMR using a 1.5T Siemens Avanto MR scanner before conventional autopsy. PMMR images and autopsy findings were reported blinded to the other data respectively. RESULTS: Abdominal abnormalities were found in 70/400 (12%) autopsies. Overall sensitivity and specificity (95% confidence interval) of PMMR for abdominal pathology was 72.5% (61.0, 81.6) and 90.8% (87.0, 93.6), with positive (PPV) and negative predictive values (NPV) of 64.1% (53.0, 73.9) and 93.6% (90.2, 95.8) respectively. PMMR was good at detecting renal abnormalities (sensitivity 80%), particularly in foetuses, and relatively poor at detecting intestinal abnormalities (sensitivity 50%). Overall accuracy was 87.4% (83.6, 90.4). CONCLUSIONS: PMMR has high overall accuracy for abdominal pathology in foetuses, newborns and children. PMMR is particularly good at detecting renal abnormalities, and relatively poor at detecting intestinal abnormalities. In clinical practice, PMMR may be a useful alternative or adjunct to conventional autopsy in foetuses and children for detecting abdominal abnormalities.

Diagnostic accuracy of post-mortem MRI for thoracic abnormalities in fetuses and children.

OBJECTIVES: To compare the diagnostic accuracy of post-mortem magnetic resonance imaging (PMMR) specifically for non-cardiac thoracic pathology in fetuses and children, compared with conventional autopsy. METHODS: Institutional ethics approval and parental consent was obtained. A total of 400 unselected fetuses and children underwent PMMR before conventional autopsy, reported blinded to the other dataset. RESULTS: Of 400 non-cardiac thoracic abnormalities, 113 (28 %) were found at autopsy. Overall sensitivity and specificity (95 % confidence interval) of PMMR for any thoracic pathology was poor at 39.6 % (31.0, 48.9) and 85.5 % (80.7, 89.2) respectively, with positive predictive value (PPV) 53.7 % (42.9, 64.0) and negative predictive value (NPV) 77.0 % (71.8, 81.4). Overall agreement was 71.8 % (67.1, 76.2). PMMR was most sensitive at detecting anatomical abnormalities, including pleural effusions and lung or thoracic hypoplasia, but particularly poor at detecting infection. CONCLUSIONS: PMMR currently has relatively poor diagnostic detection rates for the commonest intra-thoracic pathologies identified at autopsy in fetuses and children, including respiratory tract infection and diffuse alveolar haemorrhage. The reasonable NPV suggests that normal thoracic appearances at PMMR exclude the majority of important thoracic lesions at autopsy, and so could be useful in the context of minimally invasive autopsy for detecting non-cardiac thoracic abnormalities. KEY POINTS: • PMMR has relatively poor diagnostic detection rates for common intrathoracic pathology • The moderate NPV suggests that normal PMMR appearances exclude most important abnormalities • Lung sampling at autopsy remains the "gold standard" for pulmonary pathology.

Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children.

OBJECTIVES: The aim of this study was to compare the diagnostic accuracy of postmortem magnetic resonance (PMMR) imaging specifically for musculoskeletal pathology in fetuses and children, compared with conventional autopsy, with radiographic and histopathology assessment. METHODS: Institutional ethics approval and parental consent was obtained. A total of 400 cases underwent PMMR using a 1.5 T Siemens Avanto MR scanner before conventional autopsy. PMMR images and autopsy findings were reported blinded to the other data, respectively. RESULTS: A total of 400 cases were reported, with 277 (69%) fetuses (185 ≤24 weeks' gestation and 92 >24 weeks' gestation) and 123 children (42 newborns aged <1 month, 53 infants ≤12 months and 28 children ≤16 years). Musculoskeletal (MSK) abnormalities were found at autopsy in 47/400 (11.7%). Overall sensitivity and specificity (with 95% confidence interval) of PMMR for MSK pathology were 51.1% (37.0, 65.0) and 98.2% (96.2, 99.2), with positive and negative predictive values of 79.3% (61.6, 90.2) and 93.8% (90.8, 95.9), respectively. Overall accuracy between PMMR and autopsy for MSK abnormalities was 92.7% (89.7, 94.9). In some cases, PMMR detected MSK abnormalities not routinely examined for or detected at traditional autopsy. CONCLUSION: Minimally invasive autopsy has good diagnostic accuracy for the exclusion of MSK abnormalities, but sensitivity is relatively poor. When PMMR is used with clinical examination and skeletal radiographs, all skeletal and soft tissue abnormalities of clinical significance are likely to be detected, even if not directly relevant to the cause of death.

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.

Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes.

Postmortem cardiovascular magnetic resonance imaging in fetuses and children: a masked comparison study with conventional autopsy.

BACKGROUND: Perinatal and pediatric autopsies have declined worldwide in the past decade. We compared the diagnostic accuracy of postmortem, cardiovascular magnetic resonance (CMR) imaging with conventional autopsy and histopathology assessment in fetuses and children. METHODS AND RESULTS: We performed postmortem magnetic resonance imaging in 400 fetuses and children, using a 1.5-T Siemens Avanto magnetic resonance scanner before conventional autopsy. A pediatric CMR imager reported the CMR images, masked to autopsy information. The pathologists were masked to the information from CMR images. The institutional research ethics committee approved the study, and parental consent was obtained. Assuming a diagnostic accuracy of 50%, 400 cases were required for a 5% precision of estimate. Three cases were excluded from analysis, 2 with no conventional autopsy performed and 1 with insufficient CMR sequences performed. Thirty-eight CMR data sets were nondiagnostic (37 in fetuses ≤24 weeks; 1 in a fetus >24 weeks). In the remaining 359 cases, 44 cardiac abnormalities were noted at autopsy. Overall sensitivity and specificity (95% confidence interval) of CMR was 72.7% (58.2-83.7%) and 96.2% (93.5-97.8%) for detecting any cardiac pathology, with positive and negative predictive values of 72.7% (58.2-83.7%) and 96.2% (93.5-97.8%), respectively. Higher sensitivity of 92.6% (76.6-97.9%), specificity of 99.1% (97.4-99.7%), positive predictive value of 89.3% (72.8-96.3%), and negative predictive value of 99.4% (97.8-99.8%) were seen for major structural heart disease. CONCLUSIONS: Postmortem CMR imaging may be a useful alternative to conventional cardiac autopsy in fetuses and children for detecting cardiac abnormalities. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01417962.

Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation study.

BACKGROUND: Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children. METHODS: In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011. With conventional autopsy as the diagnostic gold standard, we assessed MRI findings alone, or in conjunction with other minimally invasive post-mortem investigations (minimally invasive autopsy), for accuracy in detection of cause of death or major pathological abnormalities. A radiologist and pathologist who were masked to the autopsy findings indicated whether the minimally invasive autopsy would have been adequate. The primary outcome was concordance rate between minimally invasive and conventional autopsy. FINDINGS: We analysed 400 cases, of which 277 (69%) were fetuses and 123 (31%) were children. Cause of death or major pathological lesion detected by minimally invasive autopsy was concordant with conventional autopsy in 357 (89·3%, 95% CI 85·8-91·9) cases: 175 (94·6%, 90·3-97·0) of 185 fetuses at 24 weeks' gestation or less, 88 (95·7%, 89·3-98·3) of 92 fetuses at more than 24 weeks' gestation, 34 (81·0%, 66·7-90·0) [corrected] of 42 newborns aged 1 month or younger, 45 (84·9%, 72·9-92·1) of 53 infants aged older than 1 month to 1 year or younger, and 15 (53·6%, 35·8-70·5) of 28 children aged older than 1 year to 16 years or younger. The dedicated radiologist or pathologist review of the minimally invasive autopsy showed that in 165 (41%) cases a full autopsy might not have been needed; in these cases, concordance between autopsy and minimally invasive autopsy was 99·4% (96·6-99·9). INTERPRETATION: Minimally invasive autopsy has accuracy similar to that of conventional autopsy for detection of cause of death or major pathological abnormality after death in fetuses, newborns, and infants, but was less accurate in older children. If undertaken jointly by pathologists and radiologists, minimally invasive autopsy could be an acceptable alternative to conventional autopsy in selected cases. FUNDING: Policy research Programme, Department of Health, UK.

Fowler syndrome-a clinical, radiological, and pathological study of 14 cases.

We report on 14 fetuses from 10 families with the autosomal recessive syndrome of proliferative vasculopathy and hydranencephaly-hydrocephaly (Fowler syndrome). In four families sibs were affected and in six the parents were consanguineous. Antenatal ultrasonography showed hydrocephaly in all except two fetuses, but hydranencephaly was diagnosed in only one case. Postural abnormalities were seen in 10 fetuses and structural brain abnormalities were suspected in 3. At autopsy the cerebral cortex appeared as a translucent membranous structure (hydranencephaly) in most fetuses. However, in one case, the ventricles were dilated but the cortical mantle was relatively well preserved. Histology of the brain showed the characteristic glomeruloid vascular proliferation of Fowler syndrome in all cases, but with variable extent of involvement of the central nervous system. Dystrophic calcification and necrosis were always present. Extra-cranial anomalies included micrognathia (10 fetuses), cleft palate (1 fetus), cystic hygroma (2 fetuses), joint contractures (12 fetuses), and pterygia (11 fetuses). The typical proliferative vasculopathy was never observed outside the central nervous system and karyotypes were normal in the 10 fetuses studied. Fowler syndrome should be considered in the differential diagnosis of lethal multiple pterygium syndrome, fetal akinesia, and hydrocephalus in addition to classical hydranencephaly. Autopsy and study of the brain are essential to differentiate autosomal recessive Fowler syndrome from other causes of hydrocephaly and hydranencephaly, which may have a lower recurrence risk.

Dichorionic triamniotic triplet pregnancy complicated by acardius acormus.

This report describes an acardiac fetus of the acormus phenotype in a triplet pregnancy. The diagnosis was confirmed at 15 weeks. In the absence of signs of heart failure in the co-fetus the pregnancy was managed conservatively. The pregnancy was complicated by preterm labour and the fetuses were delivered at 26+5 weeks. The prenatal diagnosis of the acormus phenotype with a well-developed cephalic pole is extremely rare and has never been described antenatally in a higher order multiple pregnancy. We suggest that this rare acardiac fetus phenotype may have a different pathophysiology than those of other phenotypes. The report also summarizes the perinatal outcomes of triplet pregnancies complicated by an acardiac fetus, where the median gestational age at delivery is 26-27 weeks, and discusses the possible therapeutic interventions.

Post-mortem examination of human fetuses: a comparison of whole-body high-field MRI at 9.4 T with conventional MRI and invasive autopsy.

BACKGROUND: Conventional whole-body MRI at 1.5 T does not provide adequate image quality of small fetuses, thus reducing its potential for use as an alternative to invasive autopsy. High-field whole-body MRI at 9.4 T provides good images of small animals. We therefore compared the diagnostic usefulness of high-field MRI with conventional MRI for post-mortem examination of human fetuses. METHODS: We did whole-body MRI at 9.4 T and 1.5 T on 18 fetuses of less than 22 weeks' gestation, using three-dimensional T(2)-weighted fast-spin echo sequences, before doing invasive autopsy. Images obtained with MRI for each system were compared with the findings of invasive autopsy in a blinded manner. Tissue contrast of 14 different regions was compared on 1.5 T and 9.4 T images that were provided by paediatric radiologists separately and in a random order, and image quality was scored on a four-point scale. The primary endpoint was diagnostic accuracy. FINDINGS: Spatial resolution, tissue contrast, and image quality of all organ systems were much better with high-field MRI than with conventional MRI. All structural abnormalities that were detected with invasive autopsy and internal examination of visceral organs were also detected with high-field MRI, whereas conventional MRI was not diagnostically useful in 14 (78%) cases. INTERPRETATION: Whole-body high-field MRI is a feasible option for post-mortem examination of human fetuses, and can provide good tissue characterisation even in small fetuses (5 g). The use of MRI at 9.4 T might be helpful in the development of a minimally invasive perinatal autopsy system. FUNDING: Department of Health Policy Research Programme, British Heart Foundation, National Institute of Health Research, Higher Education Funding Council for England, Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Great Ormond Street Hospital, University College London (UCL) Institute of Child Health, UCL Hospital, and UCL.

Abnormal folate metabolism in foetuses affected by neural tube defects.

Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs.

The effect of systemic administration of lipopolysaccharide on cerebral haemodynamics and oxygenation in the 0.65 gestation ovine fetus in utero.

OBJECTIVE: To investigate the effect of intravenous lipopolysaccharide on systemic and cerebral haemodynamics and oxygenation in the preterm ovine fetus. DESIGN: Prospective observational study. SETTING: Research centre for perinatal brain injury. SAMPLE: Nine fetal sheep at circa 93 days of gestation (0.65). METHODS: Fetal sheep were chronically instrumented with arterial and venous catheters and a flow probe in the carotid artery. Near-infrared spectroscopy was used to measure changes in cerebral oxygenation and total haemoglobin concentration. Three days after surgery, each fetus was given 100 ng/kg Escherichia coli lipopolysaccharide. Observations were continued for 48 hours post-injection and compared with baseline control values. MAIN OUTCOME MEASURES: Fetal heart rate, mean arterial pressure, carotid blood flow. RESULTS: Three fetuses died after administration of the lipopolysaccharide. In the survivors fetal heart rate rose from 193 (SEM 7) to a mean maximal level of 226 (SEM 31 bpm) (P = 0.01) after 6.5 (SEM 1.0) hours. The mean arterial pressure decreased from 40.5 (SEM 4.2) to 29.4 (SEM 1.6) mmHg (P < 0.05) after 7.0 (SEM 2.0) hours, and carotid blood flow increased from 29.6 (SEM 1.6) to 45.8 (SEM 5.7) mL/min (P = 0.0002) at 12 (SEM 3) hours. All values returned to control levels by 48 hours. Histological assessment showed evidence of periventricular leucomalacia in three out of six brains studied. CONCLUSION: These data do not suggest that cerebral ischaemia is the main aetiological factor in endotoxin-related fetal brain injury. Fetal tachycardia and cerebral vasodilation may indicate endotoxaemia in fetuses exposed to prenatal infection.