Virtual Post Mortem in fetuses and newborns for the Verification of Congenital Heart Malformations

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To address this, we explored the use of virtual post-mortem examination (VPM) via computed tomography angiography (CTA) as a potential alternative. Methods The study was conducted at Sheba Medical Center from January 2013 to June 2019. It focused on 20 cases involving severe congenital heart defects or lung malformations affecting the heart. VPM imaging was performed using CTA with contrast medium injected into the umbilical artery and vein. Results Prenatal sonographic diagnoses were fully concordant with VPM findings, confirmed by authorized invasive autopsies in 7 cases. The standardized injection protocol enabled accurate imaging of the systemic and pulmonary vessels, aiding in the identification of vascular anomalies and the cardiac structures. However, visualization of intra-cardiac anatomy was limited, possibly due to valve competence and post mortem intra-ventricular Thrombi. Conclusions Compared to MRI, CT scans this method offers higher spatial resolution at a lower cost, making it a feasible complement to standard medical practice. Despite limitations in visualizing cardiac chambers, VPM with umbilical vessel injection proved highly accurate, particularly in assessing the great vessels. Overall, the findings suggest that VPM may offer a less invasive and acceptable alternative for grieving parents, providing valuable insights into complex congenital cardiac anomalies while respecting the sensitivity of post-mortem examinations in such cases. Figures Figure 1 Figure 2 Figure 3 Figure 4 What’s Known on This Subject VPM using CT or MRI was proved useful for fetal malformations diagnosis. To date, however, only a few reports of VPM as a diagnostic tool have used contrast media for the diagnosis and confirmation of congenital cardiac malformations. What This Study Adds: This study has a large cohort of media injected VPM, which proved this method reliable and useful for congenital malformations diagnosis. Yishay Salem MD and Jeffrey Jacobson MD conceptualized and designed the study, performed the procedures, drafted the initial manuscript, and critically reviewed and revised the manuscript Eitan Keizman MD, Liat Gindes MD, and Liat Gindes MD designed the data collection instruments, collected data, carried out the initial analyses, and critically reviewed and revised the manuscript. Orly Goiten MD, Eli Konen MD, Reuven Ahiron MD, and Shai Tejman-Yardem MD MSc MBA conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content. Debora Kidron MD reviewed the pathological data and critically reviewed and revised the manuscript. Eldad Katorza MD, David Mishali MD, Alain E Serraf MD PhD critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Introduction In cases of termination of pregnancy (TOP) due to severe congenital anomalies detected during prenatal screening and evaluation, autopsies are usually performed to confirm the prenatal diagnosis, assess the process, and provide feedback to the treating physician. Congenital heart defects (CHD) are estimated to account for approximately 20% of all neonatal deaths. Due to the complexity of the structure of the heart and the fact that 51% of CHD are isolated anomalies, prenatal examinations of the fetal heart are considered challenging. 1 – 6 According to Struksnaes et al. review of 1029 autopsy cases of congenital anomalies including chromosomal aberrations, 320 fetuses were diagnosed with congenital heart defects, with hypoplastic left heart syndrome (HLHS) being the most common diagnosis. 7 In addition, in 67 autopsies of fetuses with isolated CHDs, a detailed prenatal assessment and postmortem examination revealed 228 sub-diagnoses of CHD, with 97.4% agreement between prenatal ultrasound and autopsy findings. 7 Post-mortem examinations or autopsies are established techniques for determining the cause and mechanism of a patient's illness and death. This procedure can also be used for legal reasons in situations where a person's death was unnaturally caused by an accident, misconduct, or crime. Despite the fact that modern autopsies adhere to strict religious, legal, and social norms, autopsies on deceased fetuses and newborns are particularly difficult for the grieving parents. As an alternative to autopsy, post-mortem imaging using computed tomography (CT) or magnetic resonance imaging (MRI) can be implemented if anatomic cardiovascular defects alone need to be confirmed. In lay terms, this procedure is known as a virtual autopsy or virtual post mortem examination (VPM). 8 Various studies have demonstrated that VPM is a viable alternative to conventional invasive autopsies in situations where these procedures are not feasible for personal or religious reasons. 8 – 15 In the case of an induced TOP, when an autopsy may be required to verify the medical prenatal diagnosis, a VPM may be an acceptable and less traumatic alternative to a conventional autopsy. 10 Diagnostic imaging of CHDs is performed by injecting contrast media into the peripheral vessels and umbilical vessels or directly into the heart (CTA - CT angiography). To date, however, only a few evaluations of VPM as a diagnostic tool have used contrast media injection, which is nevertheless essential in cases of complex cardiovascular malformations. 8 – 10 This study reports the first series of VPM CTAs designed exclusively to verify the anatomical diagnosis of CHD. Our objective was to determine whether CTA, when combined with contrast injection into the umbilical vein and arteries, can accurately determine the cardiovascular anatomy of complex cardiovascular heart disease and/or pulmonary malformations affecting the cardiovascular system. The accuracy of the CTA diagnosis was assessed against prenatal cardiovascular ultrasound and the invasive autopsy in some cases. Method This study was approved by the Sheba Medical Center IRB ethics committee. All cases underwent VPM in the Radiology Department at Sheba Medical Center, Ramat-Gan, Israel. The parents of the deceased fetuses or neonates gave their written informed consent before the procedure was performed. Prenatal cardiac diagnosis was established by fetal echocardiography performed by a team consisting of a pediatric cardiologist specializing in cardiac imaging (YS), a radiologist specialized in cardiac imaging (JJ) and a gynecologist experienced in cardiac prenatal imaging (RA, LA). All the mothers had undergone a GE HealthCare Ultrasound (Chicago, Illinois, USA) at the Sheba MC maternity outpatient clinic. The diagnosis of severe cardiac malformation corresponded to cases of malformations requiring future complex cardiac surgeries and/or malformations that would severely curtail life expectancy. Twenty cases were examined. Twelve cases were delivered fetuses after induced TOP due to a prenatal diagnosis of severe CHD or lung malformations affecting the heart. Eight cases were deceased neonates or cases of intra-uterine fetal demise (IUFD) with a prenatal diagnosis of CHD or hypoplastic lungs. The parents were offered both conventional and virtual autopsies. The VPM took place within two hours after delivery in cases of TOP or two hours after death in the cases of the deceased neonates. VPM was performed in all 20 cases, whereas conventional invasive autopsies were only performed in seven cases. The echocardiographic prenatal diagnosis and the age at which the fetus was delivered are listed in Table 1. Virtual post-mortem (VPM) imaging VPM was performed using a CTA with contrast medium injection into the umbilical vessels. The performing cardiologist introduced two 6G or 2 mm diameter catheters into the umbilical vessels to the artery and the vein, for contrast administration. Each examination was composed of three scans. The first scan was performed without any contrast, the second scan was performed after a contrast medium injection into the umbilical vein, and the third scan was performed with a contrast medium injection into the umbilical artery. The contrast medium (10ml) was a diluted mixture of 30% Omnipaque (GE Healthcare), 20% polyethylene glycol and 50% saline, which was fully introduced with a 50 ml flush. The scans were acquired by a Philips IDT 256 multidetector in 18 cases and by a Philips Brilliance 64 multidetector in 2 cases. The imaging parameters were 100 KV 300 mAs collimation 128 pitch, with a slice thickness of 0.6 mm. The evaluations of the CT scans were performed on a dedicated workstation (Extended Brilliance Workspace version 4.5, Philips Healthcare Cleveland, OH, USA). The entire procedure took between 15 and 30 minutes. The VPM CTA scans were independently interpreted by an experienced pediatric cardiologist specialized in cardiac imaging (YS) and a radiologist experienced in cardiac and congenital heart defects (JJ). The CTA interpreters were aware of the prenatal diagnosis. The invasive autopsies were conducted by a single pathologist with expertise in CHD (DK). The pathologist was blind to the prenatal diagnosis and the VPM results. The interpreting physicians jointly reviewed all the results, including the prenatal diagnosis, VPM interpretations and the pathologist’s reports. Results From January 2013 to June 2019, a total of 20 VPMs were performed, of which 16 cases were for intra-uterine fetal demise (IUFD) or induced termination of pregnancy (TOP) performed after multidisciplinary pre-natal counseling based on ultrasound diagnosis. Four cases were of neonates who died within 12 hours from the time of delivery (Table 1). The mean maternal age at the event was 31 ± 4.9 years and the mean gestational age was 30w + 5d ± 3.5w (range: 24w to 37w + 5d). The average weight of the deceased fetus or newborn was 1,527 ± 642 grams. Five women were primigravida, whereas the rest had already given birth to at least one healthy child (Table 1), and except one mother who had undergone IVF, all other 19 pregnancies were spontaneously conceived. In each of the 20 cases in the cohort there was full concordance between the prenatal sonographic diagnosis and the VPM results, which, when performed, were also fully confirmed by an invasive autopsy where the pathologist was blinded to the previous diagnosis. During the procedure, all the deceased fetuses and newborns received the same injection protocol, regardless of their body weight. The venous injection enabled the imaging of the systemic venous system and the right atrium. The subsequent arterial injection enabled imaging of the aorta and both the pulmonary arteries through the patent ductus arteriosus (PDA). Since disseminated intravascular coagulation (DIC) occurs after death in conjunction with ethylene glycol, there were few clots in the blood vessels. Thus, the contrast administration protocol had high accuracy for all the main vessels, including both vena cavae, the four pulmonary veins, and the arterial tree. Stenosis of blood vessels, abnormal relationships between the vessels and related cardiac structures were also clearly defined. By contrast to the well-defined imaging of the great vessels, the imaging of the atria and the ventricles was not ideal, since most of the valves were competent and closed. Despite the sub-optimal depiction of the intra cardiac anatomy, full diagnosis was possible with the VPM contrast injection. Table 1 lists the fetal pathologies. The pathologies were classified into conotruncal and arterial anomalies (group I, 6 cases; 30%), hypoplastic ventricle (left or right) syndrome (group II, 3 cases; 15%), systemic or pulmonary vein anomalies (Group III, 5 cases, 25%), lung anomalies (group IV, 3 cases; 15%) and other extra cardiac anomalies (Group V, 3 cases; 15%). The cases in group I comprised fetuses with conotruncal anomalies such as the Tetralogy of Fallot with pulmonic atresia or with an absent pulmonary valve, fetuses with a transposition of the great arteries, a case of a double outlet right ventricle and a case of aorto-pulmonary window. Figure 1 shows a case of the Tetralogy of Fallot and pulmonary atresia in which both pulmonary arteries are well-developed, and fed by the ductus arteriosus; and Fig. 2 shows a case of transposition of the great arteries. Group II comprised fetuses with hypoplastic left heart syndrome (HLHS), or with a severe anomaly of the tricuspid valve and a hypoplastic right ventricle. Figure 3 shoes a case of a hypoplastic left ventricle (LV) with tubular hypoplasia of the aortic arch. Group III comprised cases with venous anomalies such as porto-systemic shunts or other intrahepatic shunts causing hydrops-fetalis, and one case of partial anomalous pulmonary venous drainage (PAPVD). Group IV consisted of three cases of hypoplastic lungs, Fig. 4 shows a case of hypoplastic lungs with very small pulmonary arteries. Group V consisted of 3 cases of a normal heart and lung anatomy, which nonetheless had an extracardiac tumor compressing the heart, making it incompatible with life. The VPM was fully concordant with the prenatal diagnosis in all 20 cases (100%). In the seven cases where a conventional autopsy was also performed, the results were fully concordant with the VPM. Discussion Virtual autopsy (VPM) has become a popular alternative or addition to conventional autopsy over the past two decades. As a result, a series of studies on VPM have been conducted to evaluate its reliability as compared to conventional autopsy. Many previously published studies have used MRI to perform VPM. These studies have demonstrated the accuracy of the technique in evaluating soft tissue abnormalities and structural abnormalities, but also pointed to the shortcomings of MRI in evaluating fetal hearts, and structurally complex congenital heart malformations in particular . 10 , 16 , 17 , 18 In complex CHD, a condition in which the involvement of the great vessels is a basic component of the malformation, the CT scan may provide a significantly better picture due to its higher spatial resolution. 8 – 15 In addition, since MRI is much more costly and takes longer, the use of a CT-VPM may be much more practical in everyday practice. Preliminary studies showed that a VPM CT scan can successfully identify cardiovascular system. 19 There is a general consensus that optimal visualization requires a contrast medium injection. In the largest reported study of VPM CTA published by Votino et al. 8 , fetal heart imaging was carried out after injection of contrast media either into the umbilical cord vessels or in most cases, directly into the heart. Of the 33 hearts examined in that study, five cases were diagnosed as having a congenital heart defect. The authors concluded that direct intracardiac injection was more accurate for visualizing the entire cardiac structure. For better analysis of post mortem fetal hearts, Micro-CT has also been studied. A review by Sandrini et al. showed that this method is technically feasible for postmortem examination of the human fetal heart, and can provide accurate diagnoses from the early stages of pregnancy onward. 20 The micro-CT achieved high diagnostic accuracy, and was reported to perform better than autopsy for small samples or in the case of early termination of pregnancy. 11 The purpose of the current study was to examine the feasibility of using VPM conducted with a conventional hospital-based CTA for the diagnosis of cardiac malformations. Twenty cases of severe cardiovascular malformations and mediastinal anomalies were examined by both prenatal ultrasound and CTA VPM with contrast injections into the umbilical vessels. The results showed full concordance between the VPM and the prenatal diagnosis in all 20 cases, as well as 100% agreement between the VPM and the invasive autopsy conducted in seven of these 20 cases. VPM CTA using contrast injection enabled optimal imaging of the great vessels (aorta, pulmonary arteries, ductus arteriosus and systemic and pulmonary veins) as well as a full evaluation of their relationship with the heart cavities. Despite incomplete heart cavity visualization in some of the cases, VPM CTA concorded fully with the pre-delivery or prenatal diagnosis and with the autopsy findings in our series. This was partially due to the fact, that most of the cases presented a well-known complex cardiac or pulmonary anomaly that allowed for a precise diagnosis of the malformation once the heart's great vessels were accurately imaged. The intra-cardiac anatomy was less well visualized, which may have been due to post-mortem processes and changes occurring within cardiac chambers, such as thrombi formation, cardiac muscle contractions, and the fact that most of the valves were competent and did not allow the contrast media to flow backward. This is an important issue, particularly if death occurs after surgery when complex intra cardiac repair has been performed. In these cases, VPM CTA diagnosis may not be as accurate as a conventional PM examination, which may also provide a better understanding of the surgical technique and the cause of death. The other cases in our series without a complex cardiac malformation presented lesions (e.g. intra-cardiac masses) that could be diagnosed at CTA without requiring accurate cardiac anatomy imaging. Our experience indicates that VPM intra-cardiac contrast injection for imaging cardiac malformations is not always needed and depends on the type of malformation involved. In cases in which the prenatal diagnosis suggests complex vessel, involvement (as occurs in most of the cases in which the pregnancy is terminated) umbilical vessel injection may produce diagnostic CTA images. Study limitations As noted above, the visualization of the cardiac chambers by VPM CTA scans with contrast injection into the umbilical vessels was suboptimal due to incomplete filling of the heart cavities, which was partly due to intracavitary post-mortem thrombi formation. This may be further aggravated in cases where one arterial valve is missing and the ductus arteriosus is closed or absent, as was seen in one case in our cohort; namely, a case of TOF with an absent pulmonary valve. It could be claimed that the technique presented in this study may impair the diagnosis of structural heart defects that are restricted to the atria and ventricles, such as atrial and ventricular septal defects, or mitral and tricuspid valve anomalies. However, this did not influence the correct diagnosis in our series of cases in which visualization of the cardiac chambers was not an indispensable part of the diagnosis. Despite these limitations, parents may be more at ease accepting the idea of VPM with umbilical vessel rather than intracardiac injection because of its less invasive nature. Conclusion Post-mortem autopsy is an essential part of medical practice and is also important from a scientific point of view. In this study we showed that a virtual autopsy using a CTA scan constitutes a reliable, simple method to diagnose complex cardiac and pulmonary anomalies in fetuses and newborns especially when the cardiac great vessels are involved. The use of this technique should be considered when post-mortem examination is requested after induced TOP or spontaneous delivery and neonatal death. Abbreviations VPM Virtual Post Mortem TOP termination of pregnancy CHD Congenital heart defects CT computed tomography. Declarations Conflict of Interest Disclosures (includes financial disclosures): The authors have no conflicts of interest to disclose. Funding/Support: No funding was secured for this study. Clinical Trial Registration (if any) : The Sheba Medical Center IRB committee approved the study, and data sharing is possible upon request. Abbreviations: VPM - Virtual Post Mortem, TOP - termination of pregnancy, CHD - Congenital heart defects, CT - computed tomography. Article Summary Virtual post-mortem (VPM) examination using computed tomography angiography offers a less invasive and accurate alternative for the diagnosis of congenital anomalies in fetuses and newborns Author Contribution Yishay Salem MD 1,2, Eitan Keizman MD 2,5, Jeffrey Jacobson MD 1,2, Orly Goiten MD 2,3, Eldad Katorza MD 2,4, Eran Kassif MD 2,4, David Mishali MD 2,5, Debora Kidron MD 2,6, Alain E Serraf MD PhD 2,5, Eli Konen MD 2,3, Reuven Ahiron MD 2,4, Liat Gindes MD 2,7, Shai Tejman-Yardem MD MSc MBA 1,2,8Affiliations: 1. Department of Pediatric Cardiology, The Edmond J. Safra International Congenital Heart Center, Sheba Medical Center, Ramat Gan, Israel. 2. Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel. 3. The Department of Radiology, Sheba Medical Center. Ramat Gan, Israel. 4. The Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat Gan, Israel. 5. Department of Cardiovascular Surgery, Sheba Medical Center, Ramat Gan, Israel. 6. Department of Pathology, Sheba Medical Center, Ramat Gan, Israel. 7. Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel. 8. The Engineering in Medicine research lab, Sheba Medical Center. Ramat Gan, IsraelYishay Salem MD and Jeffrey Jacobson MD conceptualized and designed the study, performed the procedures, drafted the initial manuscript, and critically reviewed and revised the manuscriptEitan Keizman MD, Liat Gindes MD, and Liat Gindes MD designed the data collection instruments, collected data, carried out the initial analyses, and critically reviewed and revised the manuscript.Orly Goiten MD, Eli Konen MD, Reuven Ahiron MD, and Shai Tejman-Yardem MD MSc MBA conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content.Debora Kidron MD reviewed the pathological data and critically reviewed and revised the manuscript.Eldad Katorza MD, David Mishali MD, Alain E Serraf MD PhD critically reviewed and revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. 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AJR Am J Roentgenol 190:1380–1389 Sandrini C, Boito S, Lombardi CM, Lombardi S (2021) Postmortem micro-CT of human fetal heart—a systematic literature review. J Clin Med 10(20):4726 Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Published Journal Publication published 07 Mar, 2025 Read the published version in Pediatric Cardiology → Version 1 posted Editorial decision: Revision requested 30 Oct, 2024 Reviews received at journal 18 Oct, 2024 Reviewers agreed at journal 20 Aug, 2024 Reviewers invited by journal 18 Aug, 2024 Editor assigned by journal 12 Aug, 2024 Submission checks completed at journal 12 Aug, 2024 First submitted to journal 10 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4892542","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":349171353,"identity":"d2e68c57-82b0-4525-8692-0d2fd1cbd2b2","order_by":0,"name":"Yishay Salem","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yishay","middleName":"","lastName":"Salem","suffix":""},{"id":349171354,"identity":"f5b0d355-e4a7-4857-b5fc-137832689fbb","order_by":1,"name":"Eitan Keizman","email":"","orcid":"","institution":"Sheba Medical 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Tejman-Yarden","email":"data:image/png;base64,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","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Shai","middleName":"","lastName":"Tejman-Yarden","suffix":""}],"badges":[],"createdAt":"2024-08-10 16:38:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4892542/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4892542/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00246-025-03787-8","type":"published","date":"2025-03-07T15:57:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66123751,"identity":"5755b6f1-16f1-46b8-bc3b-d94e399255cc","added_by":"auto","created_at":"2024-10-08 02:31:22","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35930,"visible":true,"origin":"","legend":"\u003cp\u003ecase # 4, a case of the Tetralogy of Fallot and pulmonary atresia. Both pulmonary arteries are well-developed, and fed by the ductus arteriosus.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4892542/v1/e6e109378757e4a077a45262.jpg"},{"id":66123754,"identity":"7d73a0e9-d70e-4b23-809c-90fda429e389","added_by":"auto","created_at":"2024-10-08 02:31:22","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57999,"visible":true,"origin":"","legend":"\u003cp\u003ecase #5 – transposition of the great arteries. 5A - The view shows a sagittal view of the aorta anterior to the pulmonary artery, with a left aortic arch. 5B shows a 3D reconstruction showing this anatomy.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4892542/v1/354fd0f0e78e5b5e699bb53a.jpg"},{"id":66125468,"identity":"d8b9a242-da7b-4840-bb42-b674946f0ce8","added_by":"auto","created_at":"2024-10-08 02:39:22","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34772,"visible":true,"origin":"","legend":"\u003cp\u003eCase #7, a hypoplastic left ventricle (LV) with tubular hypoplasia of the aortic arch. The view shows the small aortic arch with small branches coming out of it. The ascending and descending aorta are normal in size. There is no retrograde flow through the aortic valve so that the LV could not be documented.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4892542/v1/3db09df2ae17605f73e3f4bd.jpg"},{"id":66123753,"identity":"76742707-8b64-4536-86f2-df8d02e56017","added_by":"auto","created_at":"2024-10-08 02:31:22","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":27449,"visible":true,"origin":"","legend":"\u003cp\u003ecase #16 – hypoplastic lungs with very small pulmonary arteries. Both small pulmonary arteries are marked as the right (RPA) and left (LPA) pulmonary artery.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4892542/v1/282f4b4fc706cd14105a60da.jpg"},{"id":78191349,"identity":"86882436-aa62-4ca6-8f3d-b689aa72bc87","added_by":"auto","created_at":"2025-03-10 19:56:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":687169,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4892542/v1/96df5ce4-4bcc-4858-9bea-9674f5c68913.pdf"},{"id":66123755,"identity":"59977b9c-d041-41fb-be04-2da90fa11ee8","added_by":"auto","created_at":"2024-10-08 02:31:22","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":14878,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4892542/v1/40c6a34710684607c8054cc3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Virtual Post Mortem in fetuses and newborns for the Verification of Congenital Heart Malformations","fulltext":[{"header":"What’s Known on This Subject","content":"\u003cp\u003eVPM using CT or MRI was proved useful for fetal malformations diagnosis. To date, however, only a few reports of VPM as a diagnostic tool have used contrast media for the diagnosis and confirmation of congenital cardiac malformations. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat This Study Adds:\u0026nbsp;\u003c/strong\u003eThis study has a large cohort of media injected VPM, which proved this method reliable and useful for congenital malformations diagnosis.\u003c/p\u003e\n\u003cp\u003eYishay Salem MD and Jeffrey Jacobson MD \u003cem\u003econceptualized and designed the study, performed the procedures, drafted the initial manuscript, and critically reviewed and revised the manuscript\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEitan Keizman MD, Liat Gindes MD, and Liat Gindes MD \u003cem\u003edesigned the data collection instruments, collected data, carried out the initial analyses, and critically reviewed and revised the manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOrly Goiten MD, Eli Konen MD, Reuven Ahiron MD, and Shai Tejman-Yardem MD MSc MBA \u003cem\u003econceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDebora Kidron MD reviewed the pathological data\u0026nbsp;\u003cem\u003eand critically reviewed and revised the manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEldad Katorza MD, David Mishali MD, Alain E Serraf MD PhD \u003cem\u003ecritically reviewed and revised the manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/em\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eIn cases of termination of pregnancy (TOP) due to severe congenital anomalies detected during prenatal screening and evaluation, autopsies are usually performed to confirm the prenatal diagnosis, assess the process, and provide feedback to the treating physician. Congenital heart defects (CHD) are estimated to account for approximately 20% of all neonatal deaths. Due to the complexity of the structure of the heart and the fact that 51% of CHD are isolated anomalies, prenatal examinations of the fetal heart are considered challenging. \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e According to Struksnaes et al. review of 1029 autopsy cases of congenital anomalies including chromosomal aberrations, 320 fetuses were diagnosed with congenital heart defects, with hypoplastic left heart syndrome (HLHS) being the most common diagnosis. \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e In addition, in 67 autopsies of fetuses with isolated CHDs, a detailed prenatal assessment and postmortem examination revealed 228 sub-diagnoses of CHD, with 97.4% agreement between prenatal ultrasound and autopsy findings. \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePost-mortem examinations or autopsies are established techniques for determining the cause and mechanism of a patient's illness and death. This procedure can also be used for legal reasons in situations where a person's death was unnaturally caused by an accident, misconduct, or crime. Despite the fact that modern autopsies adhere to strict religious, legal, and social norms, autopsies on deceased fetuses and newborns are particularly difficult for the grieving parents. As an alternative to autopsy, post-mortem imaging using computed tomography (CT) or magnetic resonance imaging (MRI) can be implemented if anatomic cardiovascular defects alone need to be confirmed. In lay terms, this procedure is known as a virtual autopsy or virtual post mortem examination (VPM). \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVarious studies have demonstrated that VPM is a viable alternative to conventional invasive autopsies in situations where these procedures are not feasible for personal or religious reasons. \u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In the case of an induced TOP, when an autopsy may be required to verify the medical prenatal diagnosis, a VPM may be an acceptable and less traumatic alternative to a conventional autopsy. \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Diagnostic imaging of CHDs is performed by injecting contrast media into the peripheral vessels and umbilical vessels or directly into the heart (CTA - CT angiography). To date, however, only a few evaluations of VPM as a diagnostic tool have used contrast media injection, which is nevertheless essential in cases of complex cardiovascular malformations. \u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study reports the first series of VPM CTAs designed exclusively to verify the anatomical diagnosis of CHD. Our objective was to determine whether CTA, when combined with contrast injection into the umbilical vein and arteries, can accurately determine the cardiovascular anatomy of complex cardiovascular heart disease and/or pulmonary malformations affecting the cardiovascular system. The accuracy of the CTA diagnosis was assessed against prenatal cardiovascular ultrasound and the invasive autopsy in some cases.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eThis study was approved by the Sheba Medical Center IRB ethics committee. All cases underwent VPM in the Radiology Department at Sheba Medical Center, Ramat-Gan, Israel. The parents of the deceased fetuses or neonates gave their written informed consent before the procedure was performed. Prenatal cardiac diagnosis was established by fetal echocardiography performed by a team consisting of a pediatric cardiologist specializing in cardiac imaging (YS), a radiologist specialized in cardiac imaging (JJ) and a gynecologist experienced in cardiac prenatal imaging (RA, LA). All the mothers had undergone a GE HealthCare Ultrasound (Chicago, Illinois, USA) at the Sheba MC maternity outpatient clinic. The diagnosis of severe cardiac malformation corresponded to cases of malformations requiring future complex cardiac surgeries and/or malformations that would severely curtail life expectancy.\u003c/p\u003e \u003cp\u003eTwenty cases were examined. Twelve cases were delivered fetuses after induced TOP due to a prenatal diagnosis of severe CHD or lung malformations affecting the heart. Eight cases were deceased neonates or cases of intra-uterine fetal demise (IUFD) with a prenatal diagnosis of CHD or hypoplastic lungs. The parents were offered both conventional and virtual autopsies. The VPM took place within two hours after delivery in cases of TOP or two hours after death in the cases of the deceased neonates. VPM was performed in all 20 cases, whereas conventional invasive autopsies were only performed in seven cases. The echocardiographic prenatal diagnosis and the age at which the fetus was delivered are listed in Table\u0026nbsp;1.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eVirtual post-mortem (VPM) imaging\u003c/h2\u003e \u003cp\u003eVPM was performed using a CTA with contrast medium injection into the umbilical vessels. The performing cardiologist introduced two 6G or 2 mm diameter catheters into the umbilical vessels to the artery and the vein, for contrast administration. Each examination was composed of three scans. The first scan was performed without any contrast, the second scan was performed after a contrast medium injection into the umbilical vein, and the third scan was performed with a contrast medium injection into the umbilical artery. The contrast medium (10ml) was a diluted mixture of 30% Omnipaque (GE Healthcare), 20% polyethylene glycol and 50% saline, which was fully introduced with a 50 ml flush. The scans were acquired by a Philips IDT 256 multidetector in 18 cases and by a Philips Brilliance 64 multidetector in 2 cases. The imaging parameters were 100 KV 300 mAs collimation 128 pitch, with a slice thickness of 0.6 mm. The evaluations of the CT scans were performed on a dedicated workstation (Extended Brilliance Workspace version 4.5, Philips Healthcare Cleveland, OH, USA). The entire procedure took between 15 and 30 minutes.\u003c/p\u003e \u003cp\u003eThe VPM CTA scans were independently interpreted by an experienced pediatric cardiologist specialized in cardiac imaging (YS) and a radiologist experienced in cardiac and congenital heart defects (JJ). The CTA interpreters were aware of the prenatal diagnosis. The invasive autopsies were conducted by a single pathologist with expertise in CHD (DK). The pathologist was blind to the prenatal diagnosis and the VPM results. The interpreting physicians jointly reviewed all the results, including the prenatal diagnosis, VPM interpretations and the pathologist\u0026rsquo;s reports.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom January 2013 to June 2019, a total of 20 VPMs were performed, of which 16 cases were for intra-uterine fetal demise (IUFD) or induced termination of pregnancy (TOP) performed after multidisciplinary pre-natal counseling based on ultrasound diagnosis. Four cases were of neonates who died within 12 hours from the time of delivery (Table\u0026nbsp;1). The mean maternal age at the event was 31\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9 years and the mean gestational age was 30w\u0026thinsp;+\u0026thinsp;5d\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5w (range: 24w to 37w\u0026thinsp;+\u0026thinsp;5d). The average weight of the deceased fetus or newborn was 1,527\u0026thinsp;\u0026plusmn;\u0026thinsp;642 grams. Five women were primigravida, whereas the rest had already given birth to at least one healthy child (Table\u0026nbsp;1), and except one mother who had undergone IVF, all other 19 pregnancies were spontaneously conceived. In each of the 20 cases in the cohort there was full concordance between the prenatal sonographic diagnosis and the VPM results, which, when performed, were also fully confirmed by an invasive autopsy where the pathologist was blinded to the previous diagnosis.\u003c/p\u003e \u003cp\u003eDuring the procedure, all the deceased fetuses and newborns received the same injection protocol, regardless of their body weight. The venous injection enabled the imaging of the systemic venous system and the right atrium. The subsequent arterial injection enabled imaging of the aorta and both the pulmonary arteries through the patent ductus arteriosus (PDA). Since disseminated intravascular coagulation (DIC) occurs after death in conjunction with ethylene glycol, there were few clots in the blood vessels. Thus, the contrast administration protocol had high accuracy for all the main vessels, including both vena cavae, the four pulmonary veins, and the arterial tree. Stenosis of blood vessels, abnormal relationships between the vessels and related cardiac structures were also clearly defined. By contrast to the well-defined imaging of the great vessels, the imaging of the atria and the ventricles was not ideal, since most of the valves were competent and closed. Despite the sub-optimal depiction of the intra cardiac anatomy, full diagnosis was possible with the VPM contrast injection.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;1 lists the fetal pathologies. The pathologies were classified into conotruncal and arterial anomalies (group I, 6 cases; 30%), hypoplastic ventricle (left or right) syndrome (group II, 3 cases; 15%), systemic or pulmonary vein anomalies (Group III, 5 cases, 25%), lung anomalies (group IV, 3 cases; 15%) and other extra cardiac anomalies (Group V, 3 cases; 15%).\u003c/p\u003e \u003cp\u003eThe cases in group I comprised fetuses with conotruncal anomalies such as the Tetralogy of Fallot with pulmonic atresia or with an absent pulmonary valve, fetuses with a transposition of the great arteries, a case of a double outlet right ventricle and a case of aorto-pulmonary window. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows a case of the Tetralogy of Fallot and pulmonary atresia in which both pulmonary arteries are well-developed, and fed by the ductus arteriosus; and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows a case of transposition of the great arteries. Group II comprised fetuses with hypoplastic left heart syndrome (HLHS), or with a severe anomaly of the tricuspid valve and a hypoplastic right ventricle. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shoes a case of a hypoplastic left ventricle (LV) with tubular hypoplasia of the aortic arch. Group III comprised cases with venous anomalies such as porto-systemic shunts or other intrahepatic shunts causing hydrops-fetalis, and one case of partial anomalous pulmonary venous drainage (PAPVD). Group IV consisted of three cases of hypoplastic lungs, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows a case of hypoplastic lungs with very small pulmonary arteries. Group V consisted of 3 cases of a normal heart and lung anatomy, which nonetheless had an extracardiac tumor compressing the heart, making it incompatible with life. The VPM was fully concordant with the prenatal diagnosis in all 20 cases (100%). In the seven cases where a conventional autopsy was also performed, the results were fully concordant with the VPM.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVirtual autopsy (VPM) has become a popular alternative or addition to conventional autopsy over the past two decades. As a result, a series of studies on VPM have been conducted to evaluate its reliability as compared to conventional autopsy. Many previously published studies have used MRI to perform VPM. These studies have demonstrated the accuracy of the technique in evaluating soft tissue abnormalities and structural abnormalities, but also pointed to the shortcomings of MRI in evaluating fetal hearts, and structurally complex congenital heart malformations in particular .\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e In complex CHD, a condition in which the involvement of the great vessels is a basic component of the malformation, the CT scan may provide a significantly better picture due to its higher spatial resolution.\u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In addition, since MRI is much more costly and takes longer, the use of a CT-VPM may be much more practical in everyday practice.\u003c/p\u003e \u003cp\u003ePreliminary studies showed that a VPM CT scan can successfully identify cardiovascular system. \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e There is a general consensus that optimal visualization requires a contrast medium injection. In the largest reported study of VPM CTA published by Votino et al. \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, fetal heart imaging was carried out after injection of contrast media either into the umbilical cord vessels or in most cases, directly into the heart. Of the 33 hearts examined in that study, five cases were diagnosed as having a congenital heart defect. The authors concluded that direct intracardiac injection was more accurate for visualizing the entire cardiac structure. For better analysis of post mortem fetal hearts, Micro-CT has also been studied. A review by Sandrini et al. showed that this method is technically feasible for postmortem examination of the human fetal heart, and can provide accurate diagnoses from the early stages of pregnancy onward. \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e The micro-CT achieved high diagnostic accuracy, and was reported to perform better than autopsy for small samples or in the case of early termination of pregnancy. \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe purpose of the current study was to examine the feasibility of using VPM conducted with a conventional hospital-based CTA for the diagnosis of cardiac malformations. Twenty cases of severe cardiovascular malformations and mediastinal anomalies were examined by both prenatal ultrasound and CTA VPM with contrast injections into the umbilical vessels. The results showed full concordance between the VPM and the prenatal diagnosis in all 20 cases, as well as 100% agreement between the VPM and the invasive autopsy conducted in seven of these 20 cases.\u003c/p\u003e \u003cp\u003eVPM CTA using contrast injection enabled optimal imaging of the great vessels (aorta, pulmonary arteries, ductus arteriosus and systemic and pulmonary veins) as well as a full evaluation of their relationship with the heart cavities. Despite incomplete heart cavity visualization in some of the cases, VPM CTA concorded fully with the pre-delivery or prenatal diagnosis and with the autopsy findings in our series. This was partially due to the fact, that most of the cases presented a well-known complex cardiac or pulmonary anomaly that allowed for a precise diagnosis of the malformation once the heart's great vessels were accurately imaged. The intra-cardiac anatomy was less well visualized, which may have been due to post-mortem processes and changes occurring within cardiac chambers, such as thrombi formation, cardiac muscle contractions, and the fact that most of the valves were competent and did not allow the contrast media to flow backward. This is an important issue, particularly if death occurs after surgery when complex intra cardiac repair has been performed. In these cases, VPM CTA diagnosis may not be as accurate as a conventional PM examination, which may also provide a better understanding of the surgical technique and the cause of death.\u003c/p\u003e \u003cp\u003eThe other cases in our series without a complex cardiac malformation presented lesions (e.g. intra-cardiac masses) that could be diagnosed at CTA without requiring accurate cardiac anatomy imaging. Our experience indicates that VPM intra-cardiac contrast injection for imaging cardiac malformations is not always needed and depends on the type of malformation involved. In cases in which the prenatal diagnosis suggests complex vessel, involvement (as occurs in most of the cases in which the pregnancy is terminated) umbilical vessel injection may produce diagnostic CTA images.\u003c/p\u003e\n\u003ch3\u003eStudy limitations\u003c/h3\u003e\n\u003cp\u003eAs noted above, the visualization of the cardiac chambers by VPM CTA scans with contrast injection into the umbilical vessels was suboptimal due to incomplete filling of the heart cavities, which was partly due to intracavitary post-mortem thrombi formation. This may be further aggravated in cases where one arterial valve is missing and the ductus arteriosus is closed or absent, as was seen in one case in our cohort; namely, a case of TOF with an absent pulmonary valve. It could be claimed that the technique presented in this study may impair the diagnosis of structural heart defects that are restricted to the atria and ventricles, such as atrial and ventricular septal defects, or mitral and tricuspid valve anomalies. However, this did not influence the correct diagnosis in our series of cases in which visualization of the cardiac chambers was not an indispensable part of the diagnosis. Despite these limitations, parents may be more at ease accepting the idea of VPM with umbilical vessel rather than intracardiac injection because of its less invasive nature.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePost-mortem autopsy is an essential part of medical practice and is also important from a scientific point of view. In this study we showed that a virtual autopsy using a CTA scan constitutes a reliable, simple method to diagnose complex cardiac and pulmonary anomalies in fetuses and newborns especially when the cardiac great vessels are involved. The use of this technique should be considered when post-mortem examination is requested after induced TOP or spontaneous delivery and neonatal death.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eVPM\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVirtual Post Mortem\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTOP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etermination of pregnancy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCHD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCongenital heart defects\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures (includes financial disclosures):\u003c/strong\u003e The authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u003c/strong\u003e No funding was secured for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration (if any)\u003c/strong\u003e: The Sheba Medical Center IRB committee approved the study, and data sharing is possible upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations: VPM -\u0026nbsp;\u003c/strong\u003eVirtual Post Mortem,\u0026nbsp;\u003cstrong\u003eTOP\u003c/strong\u003e -\u0026nbsp;termination of pregnancy,\u0026nbsp;\u003cstrong\u003eCHD\u003c/strong\u003e - Congenital heart defects,\u0026nbsp;\u003cstrong\u003eCT\u003c/strong\u003e - computed\u0026nbsp;tomography. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eArticle Summary\u003c/strong\u003e Virtual post-mortem (VPM) examination using computed tomography angiography offers a less invasive and accurate alternative for the diagnosis of congenital anomalies in fetuses and newborns\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYishay Salem MD 1,2, Eitan Keizman MD 2,5, Jeffrey Jacobson MD 1,2, Orly Goiten MD 2,3, Eldad Katorza MD 2,4, Eran Kassif MD 2,4, David Mishali MD 2,5, Debora Kidron MD 2,6, Alain E Serraf MD PhD 2,5, Eli Konen MD 2,3, Reuven Ahiron MD 2,4, Liat Gindes MD 2,7, Shai Tejman-Yardem MD MSc MBA 1,2,8Affiliations: 1. Department of Pediatric Cardiology, The Edmond J. Safra International Congenital Heart Center, Sheba Medical Center, Ramat Gan, Israel. 2. Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel. 3. The Department of Radiology, Sheba Medical Center. Ramat Gan, Israel. 4. The Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat Gan, Israel. 5. Department of Cardiovascular Surgery, Sheba Medical Center, Ramat Gan, Israel. 6. Department of Pathology, Sheba Medical Center, Ramat Gan, Israel. 7. Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel. 8. The Engineering in Medicine research lab, Sheba Medical Center. Ramat Gan, IsraelYishay Salem MD and Jeffrey Jacobson MD conceptualized and designed the study, performed the procedures, drafted the initial manuscript, and critically reviewed and revised the manuscriptEitan Keizman MD, Liat Gindes MD, and Liat Gindes MD designed the data collection instruments, collected data, carried out the initial analyses, and critically reviewed and revised the manuscript.Orly Goiten MD, Eli Konen MD, Reuven Ahiron MD, and Shai Tejman-Yardem MD MSc MBA conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content.Debora Kidron MD reviewed the pathological data and critically reviewed and revised the manuscript.Eldad Katorza MD, David Mishali MD, Alain E Serraf MD PhD critically reviewed and revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAchiron R, Glaser J, Gelernter I, Hegesh J, Yagel S (1992) Extended fetal echocardiographic examination for detecting cardiac malformations in low-risk pregnancies. BMJ 304:671\u0026ndash;674\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitchell SC, Korones SB, Berendes HW (1971) Congenital heart disease in 56,109 births. Incidence and natural history. Circulation 43:323\u0026ndash;332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39:1890\u0026ndash;1900\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDolk H, Loane M, Garne E (2010) The prevalence of congenital anomalies in Europe. Adv Exp Med Biol 686:349\u0026ndash;364\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan der Linde D, Konings EE, Slager MA, Witsenburg M, Hel- bing WA, Takkenberg JJ, Roos-Hesselink JW (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58:2241\u0026ndash;2247\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhiteman VE, Reece EA (1994) Prenatal diagnosis of major con- genital malformations. Curr Opin Obstet Gynecol 6:459\u0026ndash;467\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCamilla Struksn\u0026aelig;s, Harm-Gerd K, Blaas SH, Eik-Nes E, Tegnander, Vogt C (2021) Postmortem Assessment of Isolated Congenital Heart Defects Remains Essential Following Termination of Pregnancy. Pediatr Dev Pathol 24(5):422\u0026ndash;429\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVotino C, Cannie M, Segers V, Dobersco O, Dessy H, Gallo V, Cos T, Damry N (2012) Jani. Virtual autopsy by computed tomographic angiography of the fetal heart: a feasibility study. Ultrasound Obstet Gynecol 39:679\u0026ndash;684\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSudhin Thayyil NJ, Sebire LS, Chitty A, Wade WK, Chong O, Olsen, Roxana S, Gunny AC, Offiah CM, Owens DE, Saunders, Rosemary J, Scott R, Jones W, Norman S, Addison A, Bainbridge, Ernest B, Cady E, De Vita, Nicola J, Robertson, Andrew M, Taylor (2013) Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation study. Lancet 382:223\u0026ndash;233\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCannie M, Votino C, Moerman PH, Vanheste R, Segers V, Van Berkel K, Hanssens M, Kang X, Cos T, Kir M, Balepa L, Divano L, Foulon W, De Mey J (2012) Jani. Acceptance, reliability and confidence of diagnosis of fetal and neonatal virtuopsy compared with conventional autopsy: a prospective study. Ultrasound Obstet Gynecol 39:659\u0026ndash;665\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLombardi CM, Zambelli V, Botta G, Moltrasio F, Cattoretti G, Lucchini V, Fesslova V (2014) Cuttin. Postmortem microcomputed tomography (micro-CT) of small fetuses and hearts. Ultrasound Obstet Gynecol 44:600\u0026ndash;609\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIan SD, Roberts RE, Benamore EW, Benbow SH, Lee JN, Harris A, Jackson (2012) Susan Mallett, Tufail Patankar, Charles Peebles, Carl Roobottom, Zoe C Traill. Post-mortem imaging as an alternative to autopsy in the diagnosis of adult deaths: a validation study. Lancet 379:136\u0026ndash;142\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOwen J, Arthurs A, Guy S, Thayyil A, Wade R, Jones W, Norman R, Scott NJ, Robertson TS, Jacques WK \u0026lsquo;Kling\u0026rsquo; Chong, Roxanna Gunny, Saunders D, Olsen OE, Owens CM, Offiah AC, Chitty LS (2016) Andrew M. Taylor, Neil J. Sebire. Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus MRI. \u003cem\u003eEur Radiol\u003c/em\u003e 26:2327\u0026ndash;2336\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVotino C, Jani J, Verhoye M, Bessieres B, Fierens Y, Segers V, Vorsselmans A, Kang X, Cos T, Foulon W, De Mey J (2012) Cannie. Postmortem examination of human fetal hearts at or below 20 weeks\u0026rsquo; gestation: a comparison of high-field MRI at 9.4 T with lower-field MRI magnets and stereomicroscopic autopsy. Ultrasound Obstet Gynecol 40:437\u0026ndash;444\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsaksen CV, Eik-Nes SH, Blaas H-G, Tegnander E, Torp SH (1999) Comparison of prenatal ultrasound and postmortem findings in fetuses and infants with congenital heart defects. Ultrasound Obstet Gynecol 13:117\u0026ndash;126\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBreeze AC, Jessop FA, Set PA, Whitehead AL, Cross JJ, Lomas DJ, Hackett GA, Joubert I, Lees CC (2011) Minimally-invasive fetal autopsy using magnetic resonance imaging and percutaneous organ biopsies: clinical value and comparison to conventional autopsy. Ultrasound Obstet Gynecol 37:317\u0026ndash;323\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThayyil S, Chitty LS, Robertson NJ, Taylor AM, Sebire NJ (2010) Minimally invasive fetal postmortem examination using magnetic resonance imaging and computerised tomography: current evidence and practical issues. Prenat Diagn 30:713\u0026ndash;718\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrookes JA, Hall-Craggs MA, Sams VR, Lees WR (1996) Non- invasive perinatal necropsy by magnetic resonance imaging. Lancet 348:1139\u0026ndash;1141\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoss S, Spendlove D, Bolliger S, Christe A, Oesterhelweg L, Grabherr S, Thali MJ, Gygax E (2008) Postmortem whole-body CT angiography: evaluation of two contrast media solutions. AJR Am J Roentgenol 190:1380\u0026ndash;1389\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandrini C, Boito S, Lombardi CM, Lombardi S (2021) Postmortem micro-CT of human fetal heart\u0026mdash;a systematic literature review. J Clin Med 10(20):4726\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4892542/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4892542/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and Objectives:\u003c/h2\u003e \u003cp\u003ePost-mortem examinations of fetuses and newborns with congenital anomalies pose significant challenges, especially in cases of induced termination of pregnancy. To address this, we explored the use of virtual post-mortem examination (VPM) via computed tomography angiography (CTA) as a potential alternative.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study was conducted at Sheba Medical Center from January 2013 to June 2019. It focused on 20 cases involving severe congenital heart defects or lung malformations affecting the heart. VPM imaging was performed using CTA with contrast medium injected into the umbilical artery and vein.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePrenatal sonographic diagnoses were fully concordant with VPM findings, confirmed by authorized invasive autopsies in 7 cases. The standardized injection protocol enabled accurate imaging of the systemic and pulmonary vessels, aiding in the identification of vascular anomalies and the cardiac structures. However, visualization of intra-cardiac anatomy was limited, possibly due to valve competence and post mortem intra-ventricular Thrombi.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCompared to MRI, CT scans this method offers higher spatial resolution at a lower cost, making it a feasible complement to standard medical practice. Despite limitations in visualizing cardiac chambers, VPM with umbilical vessel injection proved highly accurate, particularly in assessing the great vessels. Overall, the findings suggest that VPM may offer a less invasive and acceptable alternative for grieving parents, providing valuable insights into complex congenital cardiac anomalies while respecting the sensitivity of post-mortem examinations in such cases.\u003c/p\u003e","manuscriptTitle":"Virtual Post Mortem in fetuses and newborns for the Verification of Congenital Heart Malformations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-08 02:31:17","doi":"10.21203/rs.3.rs-4892542/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-30T16:44:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-18T15:31:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79502934678271712288281908871444204870","date":"2024-08-20T22:47:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-18T17:29:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-12T06:05:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-12T06:04:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Cardiology","date":"2024-08-10T16:30:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"54a3d62b-a284-4644-be29-6d6a1d19852f","owner":[],"postedDate":"October 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-10T19:56:53+00:00","versionOfRecord":{"articleIdentity":"rs-4892542","link":"https://doi.org/10.1007/s00246-025-03787-8","journal":{"identity":"pediatric-cardiology","isVorOnly":false,"title":"Pediatric Cardiology"},"publishedOn":"2025-03-07 15:57:02","publishedOnDateReadable":"March 7th, 2025"},"versionCreatedAt":"2024-10-08 02:31:17","video":"","vorDoi":"10.1007/s00246-025-03787-8","vorDoiUrl":"https://doi.org/10.1007/s00246-025-03787-8","workflowStages":[]},"version":"v1","identity":"rs-4892542","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4892542","identity":"rs-4892542","version":["v1"]},"buildId":"wLkW0s4AflPzk-lpfg-fK","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}