Fetal Diagnosis Research Articles

Perinatal Mental Health Disorders and Resilience in Patients with Fetal Anomalies.

Pregnant women face heightened vulnerability to mental health disorders (MHDs). There remains a lack of data during the antenatal period, particularly for high-risk subpopulations such as those with fetal anomalies. Understanding the psychological impact of women receiving a fetal anomaly diagnosis is crucial, as it can lead to MHDs. Additionally, maternal stress due to such diagnoses can have adverse effects on short- and long-term health outcomes for both the mother and the child. This study aimed to address the gap in knowledge regarding prenatal MHDs in women with fetal anomalies by characterizing maternal peripartum psychological health and identifying factors related to MHDs. Women diagnosed with fetal anomalies (N = 110) were recruited from a tertiary fetal care center and completed surveys assessing resilience, anxiety, depression, and posttraumatic stress symptoms (PTSs). Demographic characteristics were also collected and analyzed. Multiple regression analyses were conducted to explore associations between demographic variables and mental health outcomes. Participants endorsed elevated depressive symptoms (45%), anxiety (43%), and PTSs (39%). Private insurance and relationship status were positively associated, and resilience was negatively associated, with depression and anxiety levels. Maternal perception of diagnostic severity correlated with increased depressive symptoms and PTSs, whereas physician ratings of diagnostic severity did not. The findings underscore the prevalence of MHD among pregnant women with fetal anomalies and emphasize the importance of assessing maternal perception of severity in predicting mental health outcomes. Identifying risk factors like insurance status and relationship status suggests avenues for targeted screening and intervention. Multidisciplinary collaboration is essential for implementing effective strategies to address peripartum psychopathology related to fetal anomalies and improve overall maternal and fetal health. · Pregnant women with fetal anomalies face poor mental health.. · Resilience is negatively related to poor mental health.. · Perception of severity impacts mental health symptoms..

In utero progression of cephaloceles: prenatal to postnatal analysis.

The natural history of cephaloceles is not well understood. The goal of this study was to better understand the natural history of fetal cephaloceles from prenatal diagnosis to the postnatal period. Between January 2013 and April 2023, all patients evaluated with a cephalocele at the Center for Fetal Diagnosis and Treatment were identified. All patients underwent prenatal and postnatal MRI. Demographic and imaging covariates were obtained from the electronic medical record. Volumetric analyses were performed to determine the percentage of neural tissue within the cephalocele. Progressive herniation was defined as an increase in cephalocele absolute neural tissue volume ≥ 5% or new herniation of an additional intracranial structure into the cephalocele. A total of 25 patients met the inclusion criteria. Of these patients, 6 (24%) exhibited progressive cephalocele herniation from the prenatal to postnatal MRI. The median sac volume was 2.2 mL (mean 6.2 mL, range 0.3-40.5 mL). The median change in brain volume in the patients with cephalocele progression was a decrease of 1.5% (mean -7.3%, range -36.4% to 3.1%). Cephalocele sac volume at the time of fetal imaging was predictive of progressive herniation, which persisted on multivariate analysis when controlling for gestational age, sex, and percentage of herniated neural tissue. While 44% of the patients had ventriculomegaly, 56% ultimately required permanent CSF diversion. Progressive neural herniation from the fetal to postnatal period is not commonly seen in fetal cephaloceles. Sac volume is associated with an increased risk of progressive herniation into the cephalocele.

Contemporary uses of "lethal" or "life limiting" terminology in perinatal research.

A life-limiting fetal diagnosis (LLD) refers to a medical condition identified during pregnancy that is expected to lead to stillbirth, preclude ex utero survival, or significantly reduce neonatal life expectancy. The terms 'lethal' or 'life-limiting' are used to prognosticate early death for various anatomic or physiologic causes, although the expected timeframe is nonspecific. The purpose of this manuscript is to review how the terms 'lethal' or 'life limiting' are used in contemporary perinatal research. Depending on the study design, 'life-limiting' is defined either prior to data analysis (such as prospective cohort studies), or after outcomes are assessed (such as case series). When 'life-limiting' is defined prior to data analysis, study-specific specific definitions may include timeframes from birth to death, probability of neonatal mortality, or a list of diagnoses based off billing codes. Professional societies have guidelines to standardize the reporting of vital statistics, including early death. While these fall short of defining LLDs comprehensively, they present an opportunity for more specific prognostication following prenatal diagnosis, which may improve research standardization to facilitate a clearer understanding of LLDs in clinical practice.

Genetic Diagnosis and Clinical Features of Fetuses With Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a rare abnormality with highly heterogeneous genetic causes. This study investigated chromosomal and monogenic abnormalities in fetal CDH patients and evaluated the efficacy of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) for genetic diagnosis. The clinical features of the patients were also evaluated. We evaluated the genetic and clinical data of 51 prenatally diagnosed fetuses with CDH. CMA was performed for every patient. If CMA did not yield diagnostic results, the samples were subjected to WES. Compared with fetuses with isolated CDH (n=42), those with non-isolated CDH (n=9) presented a higher genetic diagnostic rate (22.2% vs. 2.4%). The overall diagnostic yield was 5.9%, comprising 3.9% from chromosomal microarray analysis (CMA) and an additional 2.0% from whole exome sequencing (WES). CMA identified (1) mosaic trisomy 18 in a patient with isolated CDH; and (2) 4q terminal deletion syndrome in a patient with non-isolated CDH. WES identified a novel missense mutation, PLS3 c.1763A>G, associated with X-linked CDH in a patient with non-isolated CDH and a family history of recurrent CDH. Genetic testing should be offered for all fetuses with CDH, regardless of whether the cases are isolated or non-isolated. WES should be considered if CMA fails to provide a diagnostic result, particularly in patients with non-isolated CDH and a family history of recurrent CDH.

Fetal death: Expert consensus of the French College of Obstetricians and Gynecologists.

Fetal death is defined as the spontaneous cessation of cardiac activity after 14 weeks gestational age (GA). Regarding prevention of fetal death in the general population, it is not recommended to counsel or prescribe rest, aspirin, vitamin A, vitamin D, or micronutrient supplementation; systematically look for nuchal cord during prenatal screening ultrasound; or perform systematic antepartum monitoring by cardiotocography for the sole purpose of reducing the risk of fetal death. It is recommended to offer vaccination against influenza in epidemic periods and against SARS-CoV-2. Regarding evaluation in the event of fetal death, it is recommended that a fetal autopsy and anatomopathologic examination of the placenta be performed; chromosomal analysis be performed by microarray testing, rather than by conventional karyotype (with postnatal sampling of the fetal placental surface preferred for genetic purposes); testing for antiphospholipid antibodies be performed, with systematic Kleihauer-Betke testing and for irregular agglutinins; and summary consultation to discuss these examination results be offered. Regarding announcement and support, it is recommended that fetal death be announced without ambiguity, using simple words adapted to each situation, after which the couple should be supported with empathy across the different stages of their care. Regarding patient management in cases of fetal death, it is recommended that: in the absence of risks for disseminated intravascular coagulation or maternal demise, the patient's wishes regarding the timing between the fetal death diagnosis and labor induction should be considered; return home is possible, according to the patient's wishes; in all situations except maternal life-threatening emergencies, the preferred mode of delivery is vaginal, regardless of previous cesarean section(s); mifepristone 200 mg be prescribed at least 24 h before induction; and perimedullary analgesia be initiated at the start of induction if requested by the patient, regardless of GA. Of note, there is insufficient evidence to recommend either the administration route (i.e., vaginal or oral) of misoprostol or prostaglandin type. Regarding the risk of recurrence after unexplained fetal death: the incidence does not appear to be increased in subsequent pregnancies; in cases with a history of fetal death due to vascular problems, low-dose aspirin is recommended to reduce perinatal morbidity (otherwise, evidence is insufficient to recommend the prescription of aspirin); no optimal delay in initiating another pregnancy should be recommended based solely on a history of fetal death; fetal heart rate monitoring is not indicated based solely on a history of fetal death; although systematic labor induction is not recommended, induction may be considered depending on the context and parental request, and considering fetal age, benefits, and risks, especially before 39 weeks GA. Note that if the cause of fetal death is identified, management should be adjusted on a case-by-case basis. Regarding fetal death in a twin pregnancy, it is recommended that the surviving twin be examined immediately upon fetal death diagnosis; in a dichorionic twin pregnancy, preterm delivery induction is not recommended; in a monochorionic twin pregnancy, the surviving twin should be immediately evaluated for signs of acute fetal anemia, with weekly ultrasound monitoring for the first month, though immediate labor induction is not recommended.

Analysis of the clinical outcomes of fetal 6p22.1-p21.32 duplications signaled by non-invasive prenatal screening

To summarize the results of prenatal diagnosis and outcome of pregnancy of fetuses with a high risk for 6p22.1.1-p21.32 duplication signaled by non-invasive prenatal screening (NIPS). Clinical information, results of prenatal diagnosis and pregnancy for fetuses with a high risk for 6p22.1-p21.32 duplication were collected and analyzed. This study has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Ethic No. 2018-YB-08). Forty three pregnant women with a high risk for 6p22.1-p21.32 duplication were identified by NIPS, among whom 30 had accepted invasive prenatal diagnosis, and 27 fetuses were verified to be false positive. Three fetuses were found to have other chromosomal abnormalities, among whom two were rated to be likely benign CNV and 1 was rated to be likely pathogenic. Follow up of the 43 pregnant women revealed that 35 fetuses were normal after birth, 1 pregnancy was terminated, and 7 were lost to follow up. For pregnant women with a high risk for 6p22.1-p21.32 duplication signaled by NIPS, genetic counselor need to inform them the high false positive rate and recommend invasive prenatal diagnosis and/or ultrasound examination in order to reduce the psychological and economic burdens.

MHealth for Women with Pregnancies with Fetal Anomalies: A Scoping Review.

The purpose of this review is to investigate the current landscape of evidence-based mHealth resources designed to support pregnant patients with fetal anomalies, with a focus on enhancing maternal wellbeing, disseminating relevant information, and facilitating communication with nurses, physicians, and other health care professionals. Using the JBI (formerly known as the Joanna Briggs Institute) scoping review protocol and the PRISMA-ScR framework, we conducted a comprehensive search across databases including CINAHL, Medline, Web of Science, and Google Scholar. A keyword search was conducted, resulting in 227 unique records. Articles discussing mobile apps for pregnancies with a fetal diagnosis or fetal risk for anomaly were included, including hospital-affiliated or telehealth apps that were adapted for use with this specific population. Ten articles were selected for inclusion. Our analysis identified several predominant themes. The surge of mHealth, influenced in part by the COVID-19 pandemic, has provided critical access to care for pregnant patients with fetal anomalies through mobile platforms. Comprehensive resource tools integrating informational components via mHealth are needed to offer flexibility to patients as well as nurses, physicians, and other health care professionals. Adopting a patient-driven approach in developing mHealth resources is important in meeting the needs of patients, their families, and their health care team. A framework for the development and implementation of high-fidelity mHealth resources tailored to this vulnerable population is needed. Emphasizing a patient-centered approach in the creation of mHealth resources is paramount to ensuring their effectiveness and usefulness for pregnant women experiencing fetal anomalies, their families, and the perinatal health care team.

Mapping genetic susceptibility to spontaneous preterm birth: Analysis of Utah pedigrees to find inherited genetic factors.

Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. Despite recent advancements in identifying genetic risk factors, the mechanisms of many SPTBs remain poorly understood due to the phenotypic heterogeneity and complexity. Large family-based studies decrease heterogeneity and improve power to identify genetic causes of SPTB. To identify inherited genetic factors in SPTB etiology using large families. Using the Utah Population Database, which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks' gestation) and any SPTB (<37 weeks' gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Enrolled women with SPTB underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segments analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB. We identified two genome-wide significant chromosomal regions. In single-pedigree SGS analysis, a 1.75 Mega base region in chromosome 8 (8q24.23) was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate=0.028). In duo-pedigree analysis, a 1.05 Mega base region in the same 8q24.23 locus was identified in a second pedigree (false-positive rate [duo]= 0.0019). The intersecting region at the 8q24.23 locus contains FAM135B (family with sequence similarity 135 member B) and KHDRBS3 (KH RNA binding domain containing, signal transduction associated 3) genes, which have previously been implicated in oncogenesis and ovarian cancer, respectively. Duo-pedigree SPTB analysis also identified a second genome-wide significant 67 kilo base locus in chromosome 12 (12q21.1-q21.2) that was shared by all women with SPTB in two independent pedigrees (false-positive rate [duo] =0.01). The intersecting region at the 12q21.1-q21.2 locus contains CAPS2 (calcyphosine 2) and KCNC2 (potassium voltage-gated channel subfamily C member 2) genes, both implicated in vascular-related complications of pregnancy and preterm labor. Using large SPTB families, we identified shared chromosomal regions (8q24.23 and 12q21.1-q21.2), providing evidence for inherited (segregating) risk loci in SPTB etiology. Further investigation into genes in SPTB etiology, including functional validation may provide avenues for novel therapeutic development and guide efforts for SPTB prevention to prolong pregnancy and improve outcomes.

Evaluating How Beliefs Among Pediatric Cardiology Providers May Affect Fetal Cardiac Counseling-A National Perspective.

Prenatal counseling following a fetal diagnosis of critical congenital heart disease (CCHD) is challenging and requires delivery of detailed and complete information to ensure appropriate decision making and pregnancy support. An anonymous 50-item survey was distributed to providers who performed fetal cardiac counseling. The primary purpose was to evaluate on a national scale physician beliefs and attitudes toward available choices after a fetal diagnosis of CCHD and their association with reported counseling practices. Participants were specifically asked to indicate how likely they were to recommend postnatal interventional and/or surgical treatment, postnatal palliative care, or termination of pregnancy. The primary outcome variables were provider responses to statements about pregnancies complicated by CCHD diagnosed in utero. There were 138 respondents, with most somewhat or strongly agreeing that providing counseling on surgical and catheter-based interventions anticipated in the short- and long-term (99%, 136/138), counseling on a "comfort care" alternative with limited intervention (97%, 134/138), and options for pregnancy termination at different stages (91%, 126/138) should be included. Physicians that disagreed with the statement "some life is better than no life at all" were statistically more likely (p<0.001) to report that prenatal counseling regarding "options for pregnancy termination services at different stages of pregnancy" was important. There was a statistically significant difference in the counseling provided to parents based on the physician's personal and professional views on palliative care and termination of pregnancy. Physicians' self-reported beliefs impact the counseling content provided to families in the setting of a prenatal diagnosis of CCHD.

Fetal Cardiovascular Magnetic Resonance: History, Current Status, and Future Directions.

Fetal cardiovascular magnetic resonance imaging (MRI) has emerged as a complementary modality for prenatal imaging in suspected congenital heart disease. Ongoing technical improvements extend the potential clinical value of fetal cardiovascular MRI. Ascertaining equivocal prenatal diagnostics obtained with ultrasonography allows for appropriate parental counseling and planning of postnatal surgery. This work summarizes current acquisition techniques and clinical applications of fetal cardiovascular MRI in the prenatal diagnosis and follow-up of fetuses with congenital heart disease. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Angle between vein of Galen and straight sinus: a novel marker on microvascular flow imaging for prenatal assessment of tentorium cerebelli position.

Posterior fossa anomalies (PFAs) are associated with a wide spectrum of neurodevelopmental disabilities, with presentation ranging from no obvious clinical symptoms to severe neurodevelopmental delay. The differential diagnosis of fetal PFAs using imaging is crucial for prenatal counseling and prognostic evaluation. Imaging of the tentorium cerebelli (TC) is critical for the differential diagnosis of fetal PFAs; however, achieving this using prenatal grayscale ultrasound is challenging. This study aimed to establish a reference range for a new measurement, the angle between the vein of Galen and the straight sinus (AVGS), measured using microvascular flow imaging, and to evaluate prospectively the effectiveness of AVGS for assessment of the position of the fetal TC. This was a single-center prospective validation study including singleton pregnancies examined between 16 and 38 gestational weeks at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, between January 2022 and July 2023. AVGS was measured in normal fetuses and used to establish a reference range. AVGS was then used to predict prospectively the position of the TC in 50 fetuses with one or more intracranial malformations, using cut-offs of ≤ 5th centile or ≥ 95th centile to define abnormal AVGS. All intracranial malformations and the position of the TC in these fetuses were confirmed using fetal brain magnetic resonance imaging. The sensitivity, specificity, positive and negative predictive values and likelihood ratios were calculated to assess the performance of AVGS in the prediction of abnormal position of the fetal TC. The study group comprised 602 singleton pregnancies, including 522 normal fetuses and 50 fetuses with an intracranial anomaly. A reference range for fetal AVGS was established. Fetal AVGS decreased with advancing gestational age. Ten of the 50 fetuses with an intracranial anomaly had an abnormally positioned TC. The sensitivity and specificity of AVGS for the prediction of abnormal position of the TC in fetuses with an intracranial malformation were 90.0% (95% CI, 71.4-100.0%) and 95.0% (95% CI, 88.2-100.0%), respectively. The positive and negative predictive values were 81.8% (95% CI, 47.8-96.8%) and 97.4% (95% CI, 84.9-99.9%), respectively, and the positive and negative likelihood ratios were 18.000 (95% CI, 4.590-70.592) and 0.105 (95% CI, 0.016-0.677), respectively. AVGS is a new and useful marker for the prenatal evaluation of fetal TC position. Increased AVGS (≥ 95th centile) suggests an abnormally elevated position of the TC, while decreased AVGS (≤ 5th centile) suggests an abnormally low TC. AVGS is helpful for differential diagnosis in fetuses with PFA and can inform appropriate prenatal counseling. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Surgical Outcomes of Patients With Heterotaxy Syndrome - The Japanese Congenital Cardiovascular Surgery Database.

Cardiac malformations are a major component of heterotaxy syndrome and result in significant mortality and morbidity. This multicenter nationwide Japanese study evaluated mortality and morbidity after initial surgical palliation for patients with heterotaxy syndrome and determined predictors for mortality and morbidity among patients enrolled in the study. The Japanese Congenital Cardiovascular Surgery Database (JCCVSD) collects clinical data from 119 domestic institutions specializing in congenital heart disease, covering almost all major congenital heart surgery programs in Japan. Clinical data on preoperative, operative, and postoperative characteristics and survival data within 30 and 90 days were available from the JCCVSD database. Of the 561 patients with heterotaxy syndrome who underwent any of 8 specific initial cardiovascular surgeries, 45 (8.2%) and 75 (13.4%) had died at 30 and 90 days, respectively. Preoperative emergency transport, type of heterotaxy syndrome, low hospital volume, the repair of total anomalous pulmonary vein connection, and the repair of a common atrioventricular valve were identified as significant predictive factors for operative mortality. Improvements in some medical circumstances, such as fetal diagnosis and the patient transport system, will be needed to improve outcomes for severely ill patients with heterotaxy syndrome. This study describes early outcomes for the largest number of main cardiovascular surgeries to date in infants with heterotaxy syndrome.

Artificial Intelligence in Fetal Echocardiography

Background: Congenital heart diseases (CHD) are one of the most common birth defects, occurring in 5-9 per 1000 newborns. CHD are the second leading cause of infant mortality and account for 47% of all causes of death from birth defects.The main method for assessing the anatomy and function of the heart is 2-dimensional ultrasonography. Artificial intelligence (AI) technologies are great at recognizing images, thus facilitating quick scanning and analysis of visual information in order to speed up and simplify the diagnostic ultrasonography.All AI software for obstetrics use static images. In our study conducted at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov (Moscow, Russian Federation) in 2022-2023, we used video files including 1-5 standard heart views for each fetus.Objective: To create a data set for development of an AI tool that improves the quality of fetal CHD diagnosis and to develop an algorithm for examining the fetal heart using AI. Resulting medical reports could be either “normal” (correct structure of the heart; no sign of CHD) or “abnormal” (incorrect structure of the heart; CHD cannot be excluded; extended fetal echocardiography is recommended as soon as possible).Materials and methods: The examination was conducted at 18-21 weeks’ gestation. Each examination contained video files of 5 standard views of the heart per patient. Each view is at least 25 frames. Verification was performed by confirming/changing the diagnosis by a physician and confirming the diagnosis after birth.Conclusions: As a result, the task of determining zones of the fetal chest and heart was solved with an approximate accuracy of 98%; the task of classifying the heart view on the frame was solved with an approximate accuracy of 82%, and the task of determining the disease on the heart views was solved with an approximate accuracy of 77%.

Multimodal Approach (MRI and Ultrasonography) to the Diagnosis of Fetal Congenital Heart Diseases

Introduction: As the rate of congenital heart diseases (CHD) remains high, medical imaging specialists face a task of early diagnosis of CHD with minimal cost and burden to pregnant women and fetuses and need to verify the prenatal diagnosis in order to develop a strategy for managing pregnant women carrying a fetus with CHD.Objective: To optimize diagnostic measures in fetuses with CHD by comparing fetal echocardiography and cardiac magnetic resonance imaging (MRI).Materials and methods: We retrospectively evaluated findings from 35 fetal standard ultrasonography reports, 29 echocardiography reports, and 35 fetal autopsy reports (termination for medical reasons). We assessed 18 cases of CHD diagnosed by ultrasonography findings on the second screening; in 34% of the cases patients also underwent MRI at that time and a repeated procedure 30 weeks later.Results: When standard ultrasonography and an extended protocol with echocardiography were used together, diagnostic errors were 14.3%. In 85.7% of the fetuses, the findings of different imaging techniques fully coincided with the autopsy findings.Conclusions: In this cohort of pregnant women, the second screening should include more examinations to verify the diagnosis of CHD. Based on the first screening findings (increased nuchal translucency thickness and ductus venosus pulsatility index) patients should be referred to an expert for the second screening. If necessary, to verify the diagnosis of CHD ultrasonography and MRI can be combined during the third screening (34-36 weeks) in order to plan postnatal management of the newborn. The proposed algorithm for fetal CHD diagnosis enables to minimize the likelihood of error and maintain continuity of care between obstetricians-gynecologists, ultrasonographers, radiologists, neonatologists, and cardiologists.

Incidence of new, non-physiologic maternal findings on fetal magnetic resonance imaging.

Fetal magnetic resonance imaging (MRI) is increasingly used for evaluation of fetal anomalies, and rates of incidental maternal findings are not well characterized. Our objective was to evaluate the rate of incidental maternal findings at the time of antenatal MRI performed for fetal indications. This was a retrospective cohort study that included all fetal MRIs performed between 2018-2023 at a single tertiary care institution with a multidisciplinary fetal diagnosis and treatment center. The electronic medical record was reviewed to identify all documented maternal findings and any new, non-physiologic maternal findings. The latter was defined as previously unknown abnormalities of maternal structures unrelated to normal physiology. Our study included 834 imaging events, performed at an average gestational age of 23 weeks. The most common indication for imaging was fetal anomaly (81.1%). The most common imaging type was fetal brain MRI (81.4%). Overall, 16.2% reported a maternal finding and 7% reported a new, non-physiologic finding. The most common new, non-physiologic findings were renal cysts (n=11), liver cysts (n=6), and gallstones or gallbladder sludge (n=5). Compared to imaging events that included a fetal brain MRI, imaging events that included a fetal body MRI had a significantly higher rate of any maternal findings (53.0% vs 10.4%, p< 0.001) and new, non-physiologic maternal findings (26.9% vs 3.7%, p< 0.001). Our results suggest that the risk of identifying new, non-physiologic maternal findings on fetal MRI is low. The rate of any maternal and new, non-physiologic maternal findings may differ by fetal MRI type due to differences in imaging depth and extent of radiology subspecialist review. These data should be incorporated into pre-test counseling for patients planning to have fetal MRI.

Prenatal diagnosis analysis of three cases of Turner syndrome fetuses with complex mosaic small supernumerary marker chromosomes

To explore the value of applying multiple genetic testing techniques for the prenatal diagnosis of Turner syndrome fetuses with complex mosaic small supernumerary marker chromosomes (sSMC). Chromosomal karyotypes of amniotic fluid samples from 5 030 pregnant women who had undergone amniocentesis at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January to December 2022 were retrospectively reviewed. Three fetuses with complex mosaicism fetuses (carrying 2 types of sSMC) were selected as the study subjects. Genetic tests including G-banded chromosomal karyotyping analysis, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) were used to clarify the origin and mosaic status of the sSMC. This study has been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (No. 2023-159-01). G-banded chromosomal analysis of fetus 1 showed a karyotype of 45,X[64]/46,X,+mar1[13]/46,X,+mar2[3]. FISH results showed that 52% of of its cells had contained one X chromosome signal, whilst 48% contained two X chromosome signals. CMA results revealed the fetus had harbored a 32.32 Mb and a 50.93 Mb deletion in Xp22.33p21.1 and Xq22.2q28 regions, respectively, in addition with mosaic deletions of approximately 1.43 copies, 1.78 copies and 1.43 copies in the Xp21.1p11.1, Xq11.1q21.1 and Xq21.2q22.2 regions, respectively. The fetus 2 had a karyotype of 45,X[27]/46,X,+mar1[14]/46,X,+mar2[12]. FISH results indicated that 88% of its cells contained one X chromosomes signal and two Y chromosome signals, and 12% contained signals for one X chromosomes signal and one Y chromosome signal. CNV-seq results revealed a deletion of 7.74 Mb in the Yq11.222q11.23 region and a mosaic duplication of approximately 1.738 copies in the Yp11.31q11.221 region. The fetus 3 had a karyotype of 45,X[60]/46,X,+mar1[11]/46,X,+mar2[6]. FISH results showed that 28% of its cells contained one X chromosome signal, and 72% contained tow X chromosome signals. CNV-seq results revealed deletions of 55.60 Mb and 53.50 Mb in the Xp22.33p11.1 and Xq22.1q28 regions, respectively, along with a mosaic deletion of approximately 1.85 copies in the Xp11.1q13.2 region and a mosaic repeats of approximately 2.66 copies in the Xq13.2q22.1 region. The sSMCs in the 3 fetuses had all originated from sex chromosomes and were of complex mosaic type. After genetic counseling, the three couples had all opted to terminate the pregnancy. The combined use of multiple genetic testing techniques has determined the origin and structure of complex mosaic sSMCs and provided a basis for prenantal diagnosis and genetic counseling.

Genetic correlation between fetal nuchal translucency thickening and cystic hygroma and exploration of pregnancy outcome

Chromosome microarray analysis (CMA) and whole exome sequencing (WES) are increasingly utilized in prenatal diagnosis of abnormal ultrasound findings, but studies on correlation between pathogenic copy number variations (pCNVs) and single-gene mutations in fetuses with nuchal translucency (NT) thickening/cystic hygroma (CH), and pregnancy outcomes, are rare. This study aimed to investigate clinical value of CMA and WES for NT thickening/CH in fetuses, explore genetic correlation between fetal NT thickening and CH, and analyze pregnancy outcomes. We retrospectively selected 215 pregnant women diagnosed with fetal NT thickening (NT > 95th)/CH who underwent invasive prenatal diagnosis at our hospital from January 2020 to June 2022. With negative chromosomal karyotype analysis (KA) and CMA results, patients voluntarily underwent WES. Patients were grouped by NT thickening/CH, and application value of KA, CMA, and WES examined. Ultrasound findings, pregnancy outcomes, and fetal growth post-birth were followed during mid/late pregnancy and post-delivery. Abnormalities in chromosomal number were detected in 28 of 215 samples, with a detection rate of 13.0%, and pCNVs were detected in 12 cases, with a detection rate of 5.6%. The most common abnormality in fetuses from both groups suggested by CMA was 22q11.21 microdeletion-microduplication syndrome. 35 patients with negative KA and CMA results underwent WES, and single gene variants were detected in 12 fetuses, with an abnormality rate of 34.3%. The incidence of adverse pregnancy outcomes was 28.2% in the NT thickening group and 82.9% in the CH group (P < 0.05). Overall, fetal NT thickening/CH was associated with genetic abnormalities, WES further improved the diagnosis of abnormal fetuses after negative KA and CMA results in both groups, and the incidence of adverse pregnancy outcomes was lower in the NT thickening group than in the CH group. The management of pregnancy outcomes could guide clinical genetic counselling.

Implementation of a national rapid prenatal exome sequencing service in England: evaluation of service outcomes and factors associated with regional variation.

Prenatal exome sequencing (pES) can enhance genetic diagnosis of fetuses with structural anomalies and has recently been introduced as a national service in England. We aimed to examine service outcomes such as diagnostic yield (definite final diagnosis), referral rate, and sources of referral, and explore variation in outcomes of pES by individual or service level factors between 01 October 2021 and 30 June 2022. pES testing results from the National Health Service laboratories performing testing were linked to National Congenital Anomaly and Rare Disease Registration Service data and the Maternity Services Data Set and descriptive statistics computed. There were 475,089 women who gave birth in England during the study period. The referral rate for pES was 8.6 (95% CI 7.8, 9.4) per 10,000 maternities. About 59% of those referred proceeded with pES testing and 35% of women who proceeded received a definite final diagnosis with a median turnaround time of 15days. Of those who had pES testing, 64.6% had a live birth, 25.3% underwent termination of pregnancy (median gestational age at termination: 26weeks), and 9.3% had a stillbirth. Among the 85 women who had a definite final diagnosis, 40% had a termination of pregnancy, 18% had a stillbirth, and 42% had a live birth. The corresponding figures among women without a definite final diagnosis were 18%, 5%, and 78%, respectively. Among women who had a termination of pregnancy, the median gestational age at final report was 24.9weeks and 26.2weeks at termination. Variation observed in some of the characteristics and outcomes between regional services were limited by small sample size. This study showed that of those referred, pES testing provided a diagnosis for one in three pregnancies with a fetal anomaly across England during the study period when other tests had been non-informative. Women who opted for a termination of pregnancy underwent the procedure at relatively late gestations. Earlier referral for pES, streamlining pathways, and faster turnaround times may help results to be available at an earlier gestation to allow families more time to make decisions around continuing or terminating their pregnancy. The variation in service outcomes between regional services needs to be investigated further to understand the reasons for these differences.

Lingering impact: Maternal SARS-CoV-2 infection during early pregnancy results in fetal situs inversus

In this issue of Med, Guo etal.1 describe their observed association of maternal SARS-CoV-2 infection in early (4-6weeks) pregnancy with a confirmed fetal diagnosis of situs inversus congenital heart disease. Using sophisticated genomic tools and population-based statistical modeling, the study's authors present a very convincing argument causally linking maternal SARS-CoV-2 infection and resultant fetal situs inversus.

Identification of mutations using whole exome sequencing in eight fetuses presenting with short femur

BackgroundFemur length is one of the important indicators for evaluating fetal growth and development. Short femur is a common prenatal ultrasound finding. This study aimed to investigate the genetic etiology of fetal short femur using trio-based whole exome sequencing (WES), so as to provide evidence for prenatal diagnosis and evaluate the application of trio-WES in prenatal diagnosis of fetal short femur. MethodsWe retrospectively analyzed the clinical phenotype and WES results of eight fetuses with short femur diagnosed by prenatal ultrasound. The results of WES were validated by Sanger sequencing. The pathogenicity of the mutations was evaluated. Minigene assay was performed to investigate the effects of intronic mutation on mRNA splicing. The pregnancy outcome was followed up. ResultsA total of seven mutations were detected in eight short femur fetuses. Among them, COL2A1 (p.Gly1107Glu), GNAS (p.Lys739Glu) and FGFR3 (c.1075 + 95C > G) were novel mutations that had not been reported. Minigene assay showed that c.1075 + 95C > G in FGFR3 partially retained a 90 bp sequence in intron 8. ConclusionsThe results of this study enriched the mutant spectrums of COL2A1, GNAS and FGFR3 genes, and demonstrated the value of trio-WES in prenatal diagnosis of fetuses with short femur.