Perinatal Autopsy Research Articles

Maternal Cytomegalovirus (CMV) Serology: The Diagnostic Limitations of CMV IgM and IgG Avidity in Detecting Congenital CMV Infection.

Congenital cytomegalovirus (cCMV) is a common congenital viral infection. Testing for cCMV usually begins with assessing maternal CMV serology, specifically IgM and IgG antibodies. A negative maternal CMV IgM suggests a low risk of recent maternal CMV infection, thereby suggesting a low risk of cCMV in the fetus. Consequently, cCMV is often ruled out when maternal CMV IgM is negative. In our perinatal autopsy and placental pathology database, we identified 5 cases of cCMV despite negative maternal CMV IgM results in the second trimester. In all 5 cases, fetal abnormalities were first detected by ultrasound in the second trimester, prompting maternal CMV testing. Since second trimester maternal CMV IgM was negative in all cases, cCMV was considered unlikely, thus precluding further prenatal CMV testing in 4 of these cases. The diagnosis of cCMV was subsequently made through placental and/or autopsy examinations. Following this diagnosis, retrospective CMV serology and IgG avidity testing was performed on stored frozen first-trimester maternal blood samples in 3 cases. Among these, the first-trimester samples in 2 cases were IgG+, IgM+, and exhibited low IgG avidity, suggesting a primary maternal CMV infection around the time of conception. In the third case, both first and second-trimester maternal blood samples were IgG+, IgM-, and showed high IgG avidity, suggesting a non-primary maternal CMV infection (i.e., reactivation or reinfection of CMV). A negative maternal CMV IgM in the second trimester cannot exclude cCMV infection. While CMV IgG avidity testing and analysis of stored frozen first-trimester maternal blood samples provide valuable insights, they have limitations. CMV PCR performed on amniotic fluid is a useful prenatal diagnostic tool. For cases of unexplained fetal abnormalities or death, autopsy and placental examination are recommended.

Practical Approach to Congenital Anomalies of the Kidneys: Focus on Anomalies With Insufficient or Abnormal Nephron Development: Renal Dysplasia, Renal Hypoplasia, and Renal Tubular Dysgenesis.

Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for up to 30% of antenatal congenital anomalies and is the main cause of kidney failure in children worldwide. This review focuses on practical approaches to CAKUT, particularly those with insufficient or abnormal nephron development, such as renal dysplasia, renal hypoplasia, and renal tubular dysgenesis. The review provides insights into the histological features, pathogenesis, mechanisms, etiologies, antenatal and postnatal presentation, management, and prognosis of these anomalies. Differential diagnoses are discussed as several syndromes may include CAKUT as a phenotypic component and renal dysplasia may occur in some ciliopathies, tumor predisposition syndromes, and inborn errors of metabolism. Diagnosis and genetic counseling for CAKUT are challenging, due to the extensive variability in presentation, genetic and phenotypic heterogeneity, and difficulties to assess postnatal lung and renal function on prenatal imaging. The review highlights the importance of perinatal autopsy and pathological findings in surgical specimens to establish the diagnosis and prognosis of CAKUT. The indications and the type of genetic testing are discussed. The aim is to provide essential insights into the practical approaches, diagnostic processes, and genetic considerations offering valuable guidance for pediatric and perinatal pathologists.

Single umbilical artery and associated birth defects in perinatal autopsies: prenatal diagnosis and management.

The umbilical cord forms the connection between the fetus and the placenta at the feto-maternal interface and normally comprises two umbilical arteries and one umbilical vein. In some cases, only a single umbilical artery (SUA) is present. This study was conducted to evaluate associations between SUA and other congenital malformations discovered in perinatal autopsies and to ascertain the existence of preferential associations between SUA and certain anomalies. We evaluated records of all fetuses sent for autopsy to the Department of Pathology during the 10-year period from 2013 through 2022 (n = 1,277). The data were obtained from the hospital's pathology laboratory records. The congenital anomalies were grouped by organ or system for analysis and included cardiovascular, urinary tract, nervous system, gastrointestinal tract, musculoskeletal, and lung anomalies. A SUA was present in 8.61% of the autopsies. The gestational age of the affected fetuses ranged between 13 to 40 weeks. An SUA presented as an isolated single anomaly in 44 cases (3.4%). Of the 110 SUA cases, 60% had other congenital anomalies. There was a significant association between birth defects and SUAs (p < .001). Strong associations between SUA and urinary tract, lung, and musculoskeletal anomalies were observed. A SUA is usually seen in association with other congenital malformations rather than as an isolated defect. Therefore, examination for associated anomalies when an SUA is detected either antenatally or postnatally is imperative. The findings of this study should be helpful in counseling expectant mothers and their families in cases of SUA.

A role for immunohistochemical stains in perinatal brain autopsies.

Identification of central nervous system injury is a critical part of perinatal autopsies; however, injury is not always easily identifiable due to autolysis and immaturity of the developing brain. Here, the role of immunohistochemical stains in the identification of perinatal brain injury was investigated. Blinded semiquantitative scoring of injury was performed on sections of frontal lobe from 76 cases (51 liveborn and 25 stillborn) using H&E, GFAP, Iba-1, and β-APP stains. Digital image analysis was used to quantify GFAP and Iba-1 staining. Commonly observed pathologies included diffuse white matter gliosis (DWMG) and white matter necrosis (WMN). DWMG scores were very similar on H&E and GFAP stains for liveborn subjects. For stillborn subjects, DWMG scores were significantly higher on GFAP stain than H&E. β-APP was needed for identification of WMN in 71.4% of stillborn subjects compared to 15.4% of liveborn subjects. Diffuse staining for Iba-1 within cortex and white matter was positively correlated with subject age. Staining quantification on digital image analysis was highly correlated to semiquantitative scoring. Overall, GFAP and β-APP stains were most helpful in identifying white matter injury not seen on H&E in stillborn subjects. Immunostains may therefore be warranted as an integral part of stillborn brain autopsies.

Development of A Micro-CT Scanner with Dual-Energy Option and Endovascular Contrast Agent Administration Protocol for Fetal and Neonatal Virtual Autopsy.

The rate of parental consent for fetal and perinatal autopsy is decreasing, whereas parents are more likely to agree to virtual autopsy by non-invasive imaging methods. Fetal and perinatal virtual autopsy needs high-resolution and good soft-tissue contrast for investigation of the cause of death and underlying trauma or pathology in fetuses and stillborn infants. This is offered by micro-computed tomography (CT), as opposed to the limited resolution provided by clinical CT scanners, and this is one of the most promising tools for non-invasive perinatal postmortem imaging. We developed and optimized a micro-CT scanner with a dual-energy imaging option. It is dedicated to post-mortem CT angiography and virtual autopsy of fetuses and stillborn infants in that the chamber can be cooled down to around 5 °C; this increases tissue rigidity and slows decomposition of the native specimen. This, together with the dedicated gantry-based architecture, attempts to reduce potential motion artifacts. The developed methodology is based on prior endovascular injection of a BaSO4-based contrast agent. We explain the design choices and considerations for this scanner prototype. We give details of the treatment of the optimization of the dual-energy and virtual mono-energetic imaging option that has been based on minimizing noise propagation and maximizing the contrast-to-noise ratio for vascular features. We demonstrate the scanner capabilities with proof-of-concept experiments on phantoms and stillborn piglets.

Fraser syndrome with limb reduction defect: a rare and unique anatomic variation.

Fraser syndrome, named after George Fraser, is an autosomal recessive disorder showing a highly variable interfamilial phenotypic variation, with malformations ranging from minor symptoms to lethal anomalies like renal agenesis, incompatible with survival. Limb reduction defects have not been reported to be associated with it. A 21-year-old primigravida presented to the antenatal outpatient department with a level two targeted anomaly scan report suggestive of severe oligohydramnios with suspected renal agenesis. The cranial vault bones were compressed, and orbital globes and lenses could not be visualized. Renal agenesis was confirmed due to sleeping adrenals sign, non-visualization of the urinary bladder, and Doppler of renal arteries. A detailed examination of the fetal head in the sagittal section showed the absence of an eye globe and lens, arousing suspicion of Fraser syndrome. After pregnancy termination, a complete fetal autopsy was done to look for any additional findings. Patients who have a syndromic mix of acrofacial and urogenital abnormalities with or without cryptophthalmos should be evaluated for Fraser syndrome, which can be diagnosed by clinical examination and perinatal autopsy.

Single Umbilical Artery and Associated Systemic Anomalies in Foetal and Perinatal Autopsy: An Observational Study

Introduction: Single Umbilical Artery (SUA) is a congenital anomaly that can occur either as an isolated finding or in association with other systemic anomalies. Several studies have reported that SUA is linked to dysplastic kidneys, ventricular septal defects, oesophageal atresia, spina bifida, diaphragmatic hernia and cystic hygromas. Therefore, investigating cases of SUA in autopsies is crucial. Aim: To estimate the frequency of SUA in foetal autopsies and determine the association between SUA and other systemic anomalies. Materials and Methods: The present ambispective observational study was conducted in the Department of Pathology, Shri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital, Dharwad, Karnataka, India, over a 13 year period from January 2009 to December 2021. A total of 63 cases of SUA detected during foetal autopsies were included. Factors such as age, parity and multiple births were collected where available. The hospital-based frequency of SUA was calculated as a percentage. The association between SUA and systemic anomalies was assessed using the Chi-square test. Results: A total of 1338 perinatal autopsies were performed during the study period, with SUA present in 63 (4.70%) cases. The most common associated anomaly was genitourinary defects identified in 16 (25.39%) cases. However, a statistically significant association was observed with musculoskeletal (11.11%), nervous (11.11%), and gastrointestinal system anomalies (19.04%) with a p-value of &lt;0.0001. Conclusion: In the present study, SUA accounted for 4.70% of the foetal autopsies conducted during the study period. The most common associated anomalies were bilateral cystic kidneys, and VATER (Vertebral, Anal, Tracheo-oesophageal, and Renal anomalies) was the most common syndromic associations with SUA.

Role of Autopsy and Genetic Testing in the Diagnosis of Perinatal Deaths due to Congenital Anomalies: A Cross-sectional Study

Introduction: Foetal autopsy is one of the primary modalities for establishing the underlying causative aetiology in congenitally anomalous foetuses. Genetic aetiology is the cause in at least half of the foetuses. A correlative approach including dysmorphological evaluation, histopathology, imaging studies, and genetic testing plays a significant role in establishing the final diagnosis and management of such cases. Aim: To investigate the cause of perinatal death through a correlative approach involving Ultrasonography (USG), cytogenetic analysis, and autopsy in congenitally malformed neonates. Materials and Methods: This cross-sectional study was conducted in the Department of Pathology and Obstetrics and Gynaecology at SCB Medical College, Cuttack, Odisha, India, from June 2018 to June 2020. The study included 19 congenitally malformed foetuses/aborted foetuses/neonates not compatible with life, born in the labour room. Written informed consent was obtained, and cord/cardiac blood/soft tissue samples from congenitally anomalous foetuses were collected in a heparinised vial/sterile container during delivery and sent for cytogenetic testing. The deceased foetuses were weighed, external abnormalities and anthropometry were recorded, and then they were preserved in 10% formalin. Autopsies were performed using Virchow’s method. All internal abnormalities were recorded, and sections were sent for Histopathological (HP) study. All the data was analysed using the Statistical Package for Social Sciences (SPSS) software version 20.0. Results: The study included a total of 19 cases, including 11 (57.8%) cases of Intrauterine Deaths (IUD). The majority were males 8 (42%), in the gestational age group of 20-25 weeks (36.7%). Maternal age ranged from 21 to 30 years, with the majority being nine cases (47.3%), and 13 cases (68.3%) without antenatal check-ups. The study comprised 6 cases (31.57%) of genetic syndromes, including Trisomy 21, 13, 18, and Monosomy X, 5 cases (26.3%) of musculoskeletal defects such as Meckel Gruber syndrome, Heterotaxy syndrome, and Thanatophoric dysplasia, and 5 cases (26.3%) of neural tube defects. Conclusion: Autopsy determined the cause of death in 90% of the cases and, when combined with genetic analysis, established the syndromic diagnosis. Autopsy findings can complement or modify the ultrasonographic findings. Therefore, perinatal autopsy should always be included in the management of deaths due to congenital anomalies.

Comprehensive phenotyping of fetuses with trisomy 18: a perinatal center experience.

Trisomy 18 is the second most common aneuploidy after trisomy 21. It presents with varying degrees of heterogeneous clinical phenotypes involving multiple organ systems, with a high mortality rate. Clinical assessment of fetal trisomy 18 is always challenging. In this study, we describe the phenotypes of the fetuses with trisomy 18 from a perinatal cohort. We reviewed fetuses with trisomy 18 in referrals for perinatal autopsy over the period of 15 years. A detailed phenotyping of the fetuses with trisomy 18 was executed by perinatal autopsy. Appropriate fetal tissues were obtained to perform genomic testing. We observed trisomy 18 in 16 fetuses (2%) in our cohort of 784 fetal/neonatal losses and a perinatal autopsy was performed on all of them. Abnormal facial profile was the most frequent anomaly (10/16, 62%) followed by anomalies of the extremities (9/16, 56%), and cardiac defects (6/16, 37%). We also observed esophageal atresia, diaphragmatic hernia, and neural tube defect. The study represents one of the largest cohorts of trisomy 18 from a perinatal center from a developing country and highlights the clinical heterogeneity attributed to trisomy 18. We also report a recurrence of trisomy 18 in a family.

Causes of stillbirth in ethnically diverse women in a Perth metropolitan hospital: A retrospective study.

Most published reports analysing the differences in causation of stillbirth between different ethnic groups focus on stillbirth risk factors, with a paucity of data comparing actual causes of stillbirth. To determine whether causes of stillbirth differ between Caucasian and non-Caucasian ethnic groups in an Australian context. Data from all stillbirths occurring at 20 or more completed weeks of gestation between 1 January 2010 and 31 December 2020 at a secondary level, outer metropolitan hospital, were analysed in this retrospective case series. Causes of stillbirth as determined by perinatal autopsy and placental histopathology were categorised using the Perinatal Society of Australia and New Zealand Perinatal Death Classification and compared between Caucasian and non-Caucasian groups. Ninety-two stillbirths (0.7% of all births) were identified during the study period. A greater proportion of non-Caucasian women had small for gestation age placentas compared to Caucasian women (n = 22/43 (51%) vs n = 12/49 (24%); P = 0.025). A greater proportion of stillbirths were caused by hypoxic peripartum death in non-Caucasian than in Caucasian women (n = 4/43 (9%) vs n = 0/49 (0%); P = 0.044), and a greater prevalence of placental dysfunction was seen in the non-Caucasian cohort compared to Caucasian women (n = 14/43 (33%) vs n = 8/49 (16%); P = 0.057). The differences observed in causes of stillbirth between Caucasian and non-Caucasian women are hypothesis generating and warrant further larger-scale, multi-centred studies using standardised definitions and classification systems to determine whether these differences persist in a more representative sample.

The importance of fetal autopsy: An institutional review and development of best practices for reporting size and estimating gestational age at demise.

Fetal and neonatal autopsy offers critical insight into disease processes and clinical decision-making in reproductive medicine. Elucidating the cause of death and gaining a deeper understanding of the entities leading to fetal demise aids in anticipatory guidance for physicians and patients. Accurate assessment of growth and dating of fetuses is an important aspect of classifying pathology in the fetal and neonatal population. This study aims to optimize the autopsy approach to sizing and dating discrepancies, in addition to exploring the current trends in causes of stillbirth, with respect to placental, fetal/neonatal, and maternal factors, and rates of cases that remain undetermined after autopsy. A single-institution retrospective review of autopsy reports from mid-2008 through 2021 revealed 243 complete perinatal autopsy examinations. Placental cause of demise was identified in 46% of cases. Cause of demise was undetermined in 22% of cases. Evaluation of a subset of cases exposed minimal to no reporting of size and/or dating discrepancies in almost half of cases with undetermined cause of death. "Best practice" suggestions for sizing and dating fetuses/neonates in the postmortem period have been developed to aid in delivering clear, consistent reports. Because fetal and neonatal autopsy is an invaluable tool for understanding the factors that contribute to stillbirth, it is important to use appropriate sizing and dating methods and consistent language to deliver proper patient education and clinical guidance.

An audit of autopsy-confirmed diagnostic errors in perinatal deaths: What are the most common major missed diagnoses

Perinatal autopsies are essential to establish the cause of stillbirth or neonatal death and improve clinical practice. Limited studies have provided detailed major missed diagnoses of perinatal deaths in current clinical practice. In this retrospective audit of 177 perinatal autopsies including 99 stillbirths and 78 neonatal deaths with complete pathologic evaluation, 66 cases (21 Class I and 45 Class II diagnostic errors) were revealed as major discrepancies (37.3%), with complete agreements in 80 cases (45.2%). The difference in major discrepancies between stillbirth and neonatal death groups was significant (P < 0.001), with neonatal deaths being more prone to Class I errors. Various respiratory diseases (25/66, 37.9%) and congenital malformations (16/66, 24.2%) accounted for the majority of missed diagnoses (41/66, 62.1%). More importantly, neonatal respiratory distress syndrome (NRDS) was the most common type I missed diagnosis (7/8, 87.5%), markedly higher than the average 11.9% of all Class I errors. Our findings suggest that there are high disparities between clinical diagnoses and autopsy findings in perinatal deaths, and that various respiratory diseases are mostly inclined to cause major diagnostic errors. We first demonstrated that NRDS is the most common type I missed diagnosis in perinatal deaths, which clinicians should pay special attention to in practice.

Perinatal hypoxic-ischemic brain injury: What's behind the "ribbon effect"?

Ribbon effect describes a perceived macroscopic color reversal of the gray and white matter, characterized by a pale cortex and diffusely dusky underlying white matter. This finding is thought to be unique to the perinatal period and indicative of hypoxic-ischemic injury. However, the clinical and microscopic correlates of this macroscopic finding have not been clearly defined. A 21-year retrospective study of autopsies was performed. Ribbon effect was seen in 190 subjects, ages 20 weeks gestation to 9.5 months adjusted age. Clinical associations and radiographic findings were similar in ribbon effect cases and controls. A variety of histologic findings were observed including acute neuronal injury, diffuse white matter gliosis, and white matter necrosis. Only white matter vascular congestion was significantly correlated to the macroscopic severity of ribbon effect; the severity of white matter injury and acute neuronal injury were not significantly correlated to ribbon effect. While hypoxic-ischemic changes were present in nearly all cases of ribbon effect, the location, severity, and chronicity of these changes varied considerably, and similar findings were observed in controls. The presence of ribbon effect therefore does not predict microscopic findings apart from vascular congestion, highlighting the importance of microscopic examination in perinatal brain autopsies.

Congenital hyperoxalosis: a rare metabolic disorder in a term neonate with perinatal autopsy findings

Introduction: Primary hyperoxaluria (PH) is a rare autosomal recessive metabolic disorder resulting from an inborn error of metabolism. It causes renal tubular oxalosis which often leads to renal failure and early foetal demise. Only a few cases of PH detected in the neonatal period have been published in the literature.Case report: This baby girl was the second child of a 30-year-old woman of a second-degree consanguineous marriage. Maternal gestational diabetes mellitus was diagnosed during the antenatal period. The baby was delivered at 37 weeks + 2 days of gestation following an emergency lower segment caesarean section due to the absence of liquor. A few hours after birth the baby developed respiratory distress and reduced urine output. Investigations revealed high serum creatinine levels. The ultrasound scan was suggestive of acute kidney injury and the baby died on day 2. There was no known family history of renal diseases. During the pathological autopsy examination, there were no definite dysmorphic features. The internal examination revealed bilateral lung hypoplasia and patent ductus arteriosus. The kidneys were of normal size and shape and the microscopy showed numerous, widespread, polarizable oxalate crystals within the renal tubules, in favour of primary hyperoxaluria.Discussion and conclusion: The extensive renal damage imparted by oxalate deposition may have contributed to the impaired renal function and resulted in obstruction to the urine output, leading to oligohydramnios and pulmonary hypoplasia. Confirmation of the diagnosis of PH requires examination of urine and serum for high oxalate levels and detection of specific genetic mutations. Family screening and genetic counselling are necessary.

Study of Central Nervous System Malformations of Perinatal Autopsies

Abstract Background: Congenital malformations remain a common cause of perinatal deaths accounting for 10-15% in developing countries like India. They are the most severe disorders of the central nervous system. Although antenatal screening for congenital anomalies has been improved over the years, fetal autopsy remains the gold standard for the identification and confirmation of congenital malformations. The present study emphasizes the importance of perinatal autopsy for understanding the cause of death and also conformation of the antenatal diagnosis of the spectrum of various congenital CNS malformations. Methods: We studied 644 perinatal autopsies conducted in our hospital. The duration of the study was 5 years, from 1st August 2015 to 31st July 2020 that included all perinatal autopsies with gestational age of 22 weeks to less than 7 days. Results: Out of 644 perinatal autopsies 125 cases (19.4%) had congenital anomalies, of which 62 cases (9.6%) showed CNS malformations. The most common CNS anomalies encountered were anencephaly 14 cases (22.6%) followed by 10 cases (16.1%) each of spina bifida and meningocele, and 8 cases (12.9%) of meningomyelocele. In the present study, 6 (9.7%) cases of CNS malformations were associated with known syndromes namely Edward syndrome, Potter’s syndrome, and KlippelFeil syndrome. Along with CNS in 21 (33.9%) cases we observed associated malformations of other systems with 7 cases involving the musculoskeletal system, 3 cases involving the genitourinary system, and 5 (8.1%) cases showing multisystem involvement. Conclusion: Antenatal screening for congenital anomalies has been improved over the years. Even then fetal autopsy remains the gold standard for the identification and confirmation of congenital malformations. Understanding this gives valuable information that can be further helpful in the genetic counseling of the parents.

Attitude of perinatal pathologists to seeking consent for autopsies from parents: a web-based survey

Background: Perinatal pathologists who know the value and process of autopsy rarely see parents, and there is argument among perinatal pathologists whether or not they should see parents regarding the autopsy. Consent rates for perinatal autopsies have dropped significantly. Poor communication between professionals and parents about autopsies and uncertainty about the value of autopsies from the professionals are two of many reasons for reduced perinatal autopsy rate.

Aetiology of hydrops fetalis: a 10-year retrospective audit of perinatal autopsies

Aim: A 10-year retrospective audit of perinatal autopsies reported in an Australian tertiary perinatal pathology centre to identify the diagnostic yield of autopsy in determining the underlying causes of hydrops fetalis.

Meticulous morphological assessment and correlation with genomics in diagnosing a rare genetic syndrome in the second trimester: a case report of Apert syndrome

Whilst modern imaging modalities have far advanced antenatal diagnoses, the perinatal autopsy remains the gold standard in confirming and assessing fetal dysmorphology. The presence of multiple abnormalities involving several organ systems raises clinical suspicion of an underlying genetic syndrome.

A Compendium on Perinatal Autopsy in Neonats.

Professionals who work in perinatal care must understand the advantages and disadvantages of perinatal autopsy since they are an essential tool for determining fetal and neonatal mortality. Perinatal is the period five months before one month after birth, while prenatal is before birth. The traditional prenatal autopsy is still the gold standard for establishing the cause of death and providing an accurate report, notwithstanding the development of new technology. The ideal locations for a prenatal autopsy are tertiary institutes that offer these procedures. It emphasizes the need for systematic histopathologic sampling, rigorous record-keeping, technological adaptation, and wise laboratory test use. When a laboratory does a microbiologic examination with a focus on the genital tract and neonatal problems, it is very beneficial. Karyotyping needs to be selective and works best when there are many aberrations if resources are to be saved. A perinatal autopsy is insufficient without examining the placenta, and severe lesions should be distinguished from deformities and abnormalities brought on by fetal death. In addition to providing epidemiology teams and auditing committees with high-quality data, the pathologist's role in perinatal medicine also includes participating in the multidisciplinary management of fetal abnormalities identified during pregnancy, monitoring the patterns of iatrogenic disease, and aiding the perinatal grief management process. Investigations into complicated multiple pregnancies, hydrops, bone dysplasias, and unexpected intrauterine fetal deaths provide unique obstacles and diagnostic difficulties. There hasn't been any research that contrasts postmortem computed tomography with postmortem x-rays in pregnant women, as far as we know. Histological analysis of many perinatal autopsies revealed healthy developing tissues. Only a tiny percentage of histological abnormalities can be expected in fetal anomaly terminations. On prenatal imaging, many organ abnormalities are commonly anticipated. A thorough database search was done in Pubmed, Medline, and Scopus using the phrases "fetal abnormalities," "karyotyping," "fetal abnormality," "postmortem," and "perinatal autopsy."

Whole Exome Sequencing in an Enriched Population of Fetuses with Structural Anomalies

Exome Sequencing (ES) has emerged as a newer diagnostic modality with a reported detection rate of up to 20% in the prenatal setting among fetuses with multiple congenital anomalies. The objective of this study was to review the clinically-relevant detection rate among fetuses with congenital anomalies, given the number of anomalies and whether perinatal autopsy was performed. A single-center retrospective chart review was conducted for all pregnancies that underwent ES over a 10 year period from May 2012 – June 2022. Imaging modalities included high-resolution ultrasound, fetal echocardiography and in some cases fetal MR. Medical record review included maternal demographics, fetal imaging, and genetic diagnoses. 231 anomalous fetuses that underwent ES were identified. Initiation of ES occurred prenatally in 32%, at termination of pregnancy in 60%, neonatally in 11%, or following fetal demise in 6%. Of the exomes performed prenatally, 32.8% ended in termination while awaiting the ES results, 65.7% continued the pregnancy to delivery, and 1% resulted in fetal demise. The overall positive rate was 37.2%. The rate was higher in cases with multiple malformations (40%) versus single anomaly (31%). The rate was higher amongst those who underwent perinatal autopsy (51.8%) compared to those who did not (33.3%), which was found to be statistically significant (p = 0.01). Of note, both groups had a similar distribution of fetuses with multiple malformations (72% in the autopsy vs 64% in the no-autopsy group) that was not statistically different. Families who had a previously affected child had a higher diagnostic rate (53%) compared to those with a single occurrence (36%). A genetic diagnosis was made in 37.2% of anomalous fetuses undergoing ES in an enriched population. The utility of ES in prenatal diagnosis will certainly continue to increase as more individuals undergo testing and the positive diagnostic rate increases. Additionally, families in this setting are often experiencing grief and may learn meaningful information from ES that may assist in their coping.