Prenatal Diagnosis Research Articles

Update on Placenta Accreta Spectrum Diagnosis and Management Challenges

Abstract: Placenta accreta spectrum (PAS) disorders, also known as morbidly adherent placenta (MAP) include anomalous adherence of the placenta to implantation location. : PAS could be classified into 3 categories based on the penetration distance of trophoblasts via the myometrium and serosa of the uterus into placenta accreta, increta, and percreta. : A recent study in 2020 showed that using the introduced model based on 3 parameters; uterovesical vascularity, unusual lacunae (grades 2 and 3), and bladder wall interruption, has 100% accuracy in the diagnosis of PAS. : Accurate diagnosis of morbidly adherent placenta (MAP), helps in multidisciplinary team management at delivery, with better maternal and neonatal outcomes. : PAS could be suspected early in pregnancy by recognizing women with doubted Cesarean scar pregnancy (CSP) because CSP in the first trimester and PAS in the second and third trimesters might denote various stages of a similar pathology. : Gray scale US with or without adding color Doppler and made by transabdominal or trans vaginal route are commonly utilized for prenatal screening and diagnosis of PAS. : In a recent study made by Alalfy et al. in 2021 they revealed the systematic combined approach with the use of Alalfy Simple Criteria for assessment of placenta previa and PAS using 3D TUI (Tomographic Ultrasound Imaging and 3D power Doppler has a high diagnostic value in the diagnosis of PAS from the non-adherent placenta, the estimation of the myometrial thickness and the depth of placental invasion with the determination of different PAS subgroup plus defining diffuse from focal invasion (Figs. 1 and 2).

Exploring the clinical utility of exome sequencing/Mono, Duo, Trio in prenatal testing: a retrospective study in a tertiary care centre in South India.

With the availability of Next Generation Sequencing (NGS) diagnosis of genetic disorders has improved significantly. Its use is also applicable to ascertain diagnosis and management in a perinatal setting. The study aims to detect the genetic aetiology of various congenital structural and functional defects using NGS technology in the reproductive cohort at a tertiary centre. The secondary objective is to address challenges in the interpretation of variants. This was a retrospective study of couples who underwent exome sequencing (Mono-testing proband only or Duo-testing parents only or Trio-testing proband and parents) for suspected single gene disorders between years 2020-2022 at a tertiary care perinatal center in the South India. American College of Medical Genetics (ACMG) guidelines were followed to classify the pathogenicity of the variants identified by exome sequencing. The overall diagnostic yield as defined by pathogenic/likely pathogenic variants obtained was (23/43) 53.4 %. The individual subsets have the following diagnostic yield viz., Mono 5/6 (83 %); Carrier 16/32 (50 %); Trio 2/5 (40 %). Diagnostic yield was significantly higher in consanguineous couples. However, miscarriage history, and organ system involvement did not have a significant effect on the diagnostic yield. Prenatal diagnosis was offered for seven patients based on the exome result. One fetus was confirmed with a compound heterozygous pathogenic variant. Diagnostic yield of exome sequencing in our cohort was 53 %. The detection of pathogenic variants was maximum in those cases undergoing Mono exome sequencing. In places where there is a high prevalence of consanguinity and endogamy, NGS may be offered as first line test in the context of prenatal diagnosis.

Analysis of PAH gene variants and prenatal diagnosis for 43 Chinese pedigrees affected with Phenylketonuria

To explore the characteristics of phenylalanine hydroxylase (PAH) gene variants and prenatal diagnosis for 43 Chinese pedigrees affected with Phenylketonuria (PKU). Forty three PKU pedigrees diagnosed at the First Affiliated Hospital of Zhengzhou University between 2019 and 2021 were selected as the study subjects. Variants of the PAH gene of the probands were screened by high-throughput sequencing, and candidate variants were verified by Sanger sequencing. Negative cases were further analyzed by multiplex ligation-dependent probe amplification (MLPA) to detect large fragment deletions and duplications of the PAH gene. For 43 women undergoing subsequent pregnancy, Sanger sequencing, MLPA, combined with short tandem repeats (STR) sequence-based linkage analysis, were carried out for prenatal diagnosis. Among the 86 alleles carried by the 43 probands, 78 nucleotide variants (90.70%) and 3 large deletions (3.49%) were found based on high-throughput sequencing and MLPA. The 81 mutant alleles had included 21 missense variants, 5 splice site variants, 4 nonsense variants, 2 microdeletions, 1 insertional variant and 2 large fragment deletions. Relatively common variants have included p.Arg243Gln (23.26%), p.Arg111Ter (8.14%), EX6-96A>G (6.98%), p.Val399Val (5.81%) and p.Arg413Pro (4.65%). Most of the variants were located in exons 7, 11, 3, 6 and 12. For the 43 families undergoing prenatal diagnosis, 9 fetuses (20.45%) were diagnosed with PKU, 20 (45.45%) were heterozygous carriers, and 15 (34.09%) did not carry the same pathogenic allele as the proband. All neonates were followed up till 6 months old, and the accuracy of prenatal diagnosis was 100%. The combination of high-throughput sequencing, Sanger sequencing, MLPA and linkage analysis can increase the diagnostic rate of PKU and attain accurate prenatal diagnosis.

Expert consensus on the prenatal diagnosis and genetic counseling for uniparental disomy-related imprinting disorders

Uniparental disomy (UPD)-related imprinting disorders are a group of congenital disorders which can lead to severe birth defects. Their molecular etiology is the occurrence of UPD in the genomic imprinting regions, which may cause disturbed expression of parent-of-origin imprinted genes. With the widespread applications of genetic testing techniques, the prenatal diagnosis of UPD-related imprinted diseases has gradually become clinical routines. However, due to the complicated pathogenesis of such disorders, currently there is still a lack of standards and norms for the understanding, diagnosis, management and genetic counseling. By referring to the relevant guidelines and consensus, the latest progress of research, and opinions from experts in the relevant fields, the writing group has formulated a consensus over the prenatal diagnosis and genetic counseling for UPD-related imprinting disorders, with an aim to provide a more accurate and rational evaluation in prenatal clinics.

Specification for genetic diagnosis of congenital heart disease

Congenital heart disease (CHD) is one of the most common congenital malformations and a major cause of mortality among neonates and children. Conventional methods for the diagnosis of CHD have relied on clinical features and imaging findings. With the rapid development of genetic techniques, to identify the cause of CHD through genetic diagnosis has gained great significance for the early diagnosis, treatment, and prevention of CHD. However, currently there is still a lack of norms and standards for the genetic diagnosis of CHD. In view of this, experts from the relevant fields have formulated the present norm by integrating the latest research advances on CHD-related genes with the current clinical practice on the diagnosis and treatment of CHD and status quo of genetic diagnosis in China. The norm has been recommended by the Cardiology Section of the Chinese Medical Education Association, the Medical Genetics Branch and the Heart Group of Pediatric Surgery Branch of the Chinese Medical Association, which has formulated the procedures and norms of genetic testing, prenatal diagnosis, and genetic counseling for CHD, with an aim to provide reference for clinicians as the standards for the integrated diagnosis, early treatment, and prevention of CHD.

Expert consensus on the test development and preliminary implementation of whole genome sequencing for fetal structural abnormalities

Fetal structural anomalies and birth defects are primarily caused by genetic variants such as chromosomal number abnormalities, copy number variations (CNV), single nucleotide variants (SNV), and small insertions and deletions (indel). Whole-genome sequencing (WGS) based on next-generation sequencing (NGS) as an emerging technology for genetic disease diagnosis can detect the aforementioned types of variants. In recent years, high-depth WGS (> 30×) for prenatal diagnosis has also become available, and proved to be practical for unraveling the genetic etiology of fetal developmental abnormalities. To facilitate clinical practice, test development and preliminary implementation of WGS for diagnosing fetal structural anomalies, we have formulated a consensus over the application of WGS in prenatal diagnosis by compiling previously published consensuses, guidelines, and research findings to provide a guidance on data analysis, reporting recommendations, and consultation of prenatal WGS results.

Genetic analysis of two families with abnormal findings upon prenatal diagnosis

To carry out genetic analysis on two families with carriers of small terminal translocations using karyotyping analysis and genomic copy number variation sequencing (CNV-seq). Two couples undergoing prenatal diagnosis at the Tianjin Central Hospital of Obstetrics and Gynecology respectively on April 12, 2020 and December 17, 2021 were selected as the study subjects. With informed consent, amniotic fluid and peripheral blood samples were collected and subjected to conventional karyotyping and CNV-seq analysis for the detection of chromosomal microdeletion/duplications. Both couples had given births to children with chromosomal aberrations previously, and both fetuses were found to have abnormal karyotypes. CNV-seq showed that they had harbored microdeletion/duplications, and their mothers had both carried balanced translocations involving terminal fragments of chromosomes. For fetuses with small chromosomal segmental abnormalities, their parental origin should be traced, and the diagnosis should be confirmed with combined genetic techniques.

Prenatal Diagnosis, Conventional/4-Dimensional Imaging, Pregnancy, and Postnatal Outcome of Unicuspid Unicommissural Aortic Valve.

Prenatal Diagnosis, Conventional/4-Dimensional Imaging, Pregnancy, and Postnatal Outcome of Unicuspid Unicommissural Aortic Valve.

Phenotypic and genotypic analysis of 11 fetal cases with Bardet-Biedl syndrome.

To present the prenatal sonographic features and genomic spectrum of pregnancies with fetal Bardet-Biedl syndrome (BBS). This was a retrospective study of 11 cases with BBS diagnosed by prenatal ultrasound and confirmed by genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, molecular testing sequencing results, and pregnancy outcomes. All cases had unremarkable first-trimester ultrasound scans without reporting limb malformations. All had second-trimester abnormal ultrasounds: postaxial polydactyly in nine cases (9/11), renal abnormalities in seven (7/11), reduced amniotic fluid volume in two (2/11), central nervous system anomalies in two (2/11), and ascites in three (3/11). Ten fetuses presented with at least two-system anomalies, and one (Case 11) presented with only postaxial polydactyly. Variants were detected in five genes, including BBS2, ARL6/BBS3, BBS7, CEP290/BBS14 and IFT74/BBS22. Ten pregnancies were terminated in the second trimester, while one continued to term. Enlarged hyperechogenic kidneys and postaxial polydactyly are the two most common sonographic features of fetal BBS. Prenatal diagnosis of BBS can be done with ultrasound and genetic testing although the diagnosis may be made in the second trimester.

Associations and outcomes of prenatally detected rhombencephalosynapsis.

To describe the association between prenatal imaging and neurodevelopmental outcomes of fetuses with rhombencephalosynapsis (RES). Thirty-four pregnancies complicated by RES were identified from our institutional databases based on US and/or MRI findings. Genetic testing results were gathered. In cases of termination of pregnancy, we studied the association between prenatal imaging and neuropathologic findings. For those who opted for expectant management, comprehensive developmental assessments and postnatal MRI imaging were evaluated. Over one third of fetuses in our cohort had complete RES. Common intracranial anomalies identified were mesencephalosynapsis, aqueduct stenosis and diencephalosynapsis. The degree of RES was not associated with the frequency of additional central nervous system anomalies. MRI had a good correlation with neuropathologic findings with regard to the degree of RES, aqueduct stenosis and mesencephalosynapsis. Postmortem autopsy showed that one third of our cases had VACTERL-H and almost all of those had complete RES. All liveborn neonates(n=6) had aqueduct stenosis requiring ventriculoperitoneal shunting within days of delivery (median 5days). While a large proportion of prenatally suspected complete RES were found to have partial RES on postnatal imaging, prenatal diagnosis of aqueduct stenosis remained unchanged. All children that were at least 2years old (n=3) had global developmental delay. Prenatal assessment of the RES severity is challenging and may be unreliable. Nevertheless, postnatal prognosis is poor for both complete and partial RES. Associated aqueductal stenosis, can be reliably assessed prenatally and this may contribute to worse postnatal prognosis than the degree of RES.

Routine antenatal molecular testing for α-thalassemia at a tertiary referral hospital in China: ten years of experience.

This study aimed to evaluate the efficacy of α-thalassemia gene testing as a part of an antenatal intervention program over a 10-year period. All patients underwent α-thalassemia gene testing, which included the analysis of three types of deletions and mutations. Rare α-thalassemia gene testing was performed using Sanger sequencing, multiplex ligation-dependent probe amplification, and sequencing techniques. Prenatal diagnosis was performed in high-risk couples using chorionic villus sampling or amniocentesis. From 2010 to 2019, among the 91,852 patients examined, α-thalassemia mutations were identified in 41.78% of patients. The most frequent α0 gene mutation was--SEA, followed by--THAI. Two rare α0-thalassemia gene mutations at --32.8 and --230, were also observed. A total of 2,235 high-risk couples were identified, of which 562 were affected, including three with the--SEA/--THAI genotype and one with the--SEA/--230 genotype. Additionally, prenatal diagnosis revealed four cases of fetal anemia and/or mild edema, along with two cases of severe fetal edema. Chromosome and gene chip results were normal. Thalassemia gene testing showed an αCSα/αCSα genotype in four patients with anemia and/or mild edema, while two patients with severe fetal edema had one--SEA/αCSα genotype and one--SEA/--GX genotype. Using the cut-off points of 74.6fL and 24.4pg as criteria for identifying α0-thalassemia carriers and HbH disease, the detection rate of missed diagnoses in high-risk couples is consistent with national guidelines for standards, potentially saving 10,217,700 ¥. Routine molecular testing for α-thalassemia in high-risk prenatal populations effectively prevented severe α-thalassemia births. Despite the high cost, the cutoff points proposed by this study suggest that implementing screening using a new parameter has the potential to reduce current expenses.

Ultrasound examination in antenatal diagnosis of placenta accreta spectrum

The rise in caesarean section rates worldwide has led to a great increase in placenta accreta spectrum cases. Accurate diagnostics of placenta accreta before delivery is still difficult, as one-half to two-thirds of placenta accreta cases remain undiagnosed until delivery. Domestic and foreign sources use the diagnostic accuracy of ultrasonography (US) as the most commonly used method for placenta accreta image because of its inexpensiveness, non invasiveness, and rapidness. In this review, we highlighted the possibilities of prenatal ultrasound diagnosis of placenta accreta. Diagnostic accuracy may be reduced due to posterior wall placenta location and a higher body mass index (BMI). US and MRI are highly specific and useful in diagnosing or ruling out placenta accreta. Unlike MRI, the accuracy of ultrasound depends on the qualification, and therefore single-center studies often overestimate the accuracy of ultrasound. It is necessary to continue studying diagnostic methods for placenta accreta in order to select logical obstetric tactics for managing pregnant women with this pathology.

Anesthetic considerations of EXIT procedure: A case report

The ex-utero intrapartum treatment (EXIT) is a rare surgical procedure performed in cases of expected postpartum fetal airway obstruction. This procedure technique lies in a safe establishment of a patent airway during labor in anticipation of a critical respiratory event, without the interruption of maternal-fetal circulation. Anesthetic management in the EXIT procedure is substantially different from that of the standard cesarean delivery and its main goals include uterine relaxation, fetal anesthesia, and placental blood flow preservation. We report the first case of an EXIT procedure performed on a fetus with a prenatal diagnosis of multiple oral masses at King Khalid University Hospital, Riyadh, Saudi Arabia.

Fetal heart segmentation in a virtual reality environment.

This study presents the initial results of a pilot project using the Elucis Virtual Reality (VR) platform for fetal heart segmentation. Twelve fetal heart cases, ranging in gestational age from 24 to 30 weeks, including various cardiac conditions, were reconstructed using 3D models facilitated by the Elucis platform's integration of automated algorithms and manual adjustments. The models, which were evaluated by four experts in virtual and 3D printed formats, were of high quality and offered improved visuospatial visualization and detailed anatomical insights. This research highlights the potential of VR technology to improve prenatal diagnosis and planning for complex cardiac conditions, suggesting significant implications for continuing medical education and clinical practice in fetal cardiology.

A rare case of polysplenia syndrome associated with atrioventricular canal defect and type four ileal atresia in a preterm neonate: A case report and literature review

Antenatal diagnosis of heterotaxy syndrome is only the tip of the iceberg. These neonates can have a myriad of multi-system anomalies, each of which requires anticipation and an individualized management plan. The spectrum of heterotaxy syndrome ranges from incidentally detected innocuous anomalies to major life-threatening congenital malformations such as atrioventricular canal defects and bowel atresia. Neonatal sepsis tends to be more fulminant and catastrophic in these neonates with complex anomalies and poor outcomes that necessitates better-informed antenatal counseling regarding the termination of such pregnancies.

Case Report of Recurrent Popliteal Pterygium Syndrome

AbstractA 23 week pregnant woman with a history of a child with facial and limb malformations underwent a fetal ultrasound revealing similar abnormalities in the current fetus. Genetic testing confirmed a new IRF6 gene mutation consistent with popliteal pterygium syndrome type 1. This case highlights the potential for recurrence and the role of genetic testing in prenatal diagnosis.

Role of artificial-intelligence-assisted automated cardiac biometrics in prenatal screening for coarctation of aorta.

Although remarkable strides have been made in fetal medicine and the prenatal diagnosis of congenital heart disease, around 60% of newborns with isolated coarctation of the aorta (CoA) are not identified prior to birth. The prenatal detection of CoA has been shown to have a notable impact on survival rates of affected infants. To this end, implementation of artificial intelligence (AI) in fetal ultrasound may represent a groundbreaking advance. We aimed to investigate whether the use of automated cardiac biometric measurements with AI during the 18-22-week anomaly scan would enhance the identification of fetuses that are at risk of developing CoA. We developed an AI model capable of identifying standard cardiac planes and conducting automated cardiac biometric measurements. Our data consisted of pregnancy ultrasound image and outcome data spanning from 2008 to 2018 and collected from four distinct regions in Denmark. Cases with a postnatal diagnosis of CoA were paired with healthy controls in a ratio of 1:100 and matched for gestational age within 2 days. Cardiac biometrics obtained from the four-chamber and three-vessel views were included in a logistic regression-based prediction model. To assess its predictive capabilities, we assessed sensitivity and specificity on receiver-operating-characteristics (ROC) curves. At the 18-22-week scan, the right ventricle (RV) area and length, left ventricle (LV) diameter and the ratios of RV/LV areas and main pulmonary artery/ascending aorta diameters showed significant differences, with Z-scores above 0.7, when comparing subjects with a postnatal diagnosis of CoA (n = 73) and healthy controls (n = 7300). Using logistic regression and backward feature selection, our prediction model had an area under the ROC curve of 0.96 and a specificity of 88.9% at a sensitivity of 90.4%. The integration of AI technology with automated cardiac biometric measurements obtained during the 18-22-week anomaly scan has the potential to enhance substantially the performance of screening for fetal CoA and subsequently the detection rate of CoA. Future research should clarify how AI technology can be used to aid in the screening and detection of congenital heart anomalies to improve neonatal outcomes. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Detecting Mosaicism of Monosomy X Using FISH in Prenatal Samples: Post High Risk NIPT

AbstractNoninvasive prenatal testing (NIPT) is a highly specific and sensitive aneuploidy screening method with low false positive results. Sex chromosome aneuploidy (SCA) is not picked up in prenatal ultrasounds, as they may not have antenatally identifiable features, except for hydrops in monosomy X cases. Women with high risk NIPT results for SCAs are recommended to go for invasive prenatal diagnosis for confirmation by diagnostic tests like chromosome microarray, karyotyping, and/or fluorescence in situ hybridization (FISH). We present two cases that showed a high risk for monosomy X on NIPT. Chromosomal microarray was negative for SCA. Further, FISH was done to confirm the results and confirm the presence of low level mosaicism for monosomy X. FISH proves to be the test of choice to detect low level mosaicism in high risk NIPT cases with high positive predictive values.

Prevalence of congenital anomalies and prenatal diagnosis by birth institution (public vs. non-public): indicators of inequality in access to elective termination of pregnancy for fetal anomalies.

Congenital anomalies (CA) encompass all morphological or functional alterations originating prenatally and present at birth. The prenatal diagnosis of these anomalies can significantly impact the overall health of the pregnant individual and may influence her decision regarding the continuation of the pregnancy. In contexts where safe pregnancy termination is not guaranteed by the state, it can lead to unsafe procedures with severe consequences. In our research, we analyzed epidemiological information on CA to develop potential indicators of inequity in access to safe abortion prior to the legalization of legal termination of pregnancy in Argentina. We included cases from 13 public hospitals and 9 non-public subsector hospitals, from the period 2013-2020. Two groups of specific CA were selected: 1) CA capable of being prenatally diagnosed, and 2) CA related to vascular disruptive events. 10/18 of the selected CA capable of being prenatally diagnosed had a significantly higher prevalence in public hospitals (anencephaly, encephalocele, spina bifida, microcephaly, hydrocephalus, holoprosencephaly, hydranencephaly, diaphragmatic hernia, gastroschisis, bilateral renal agenesis). Non public hospitals had higher prenatal detection. Birth prevalence of CA related with vascular disruptive events (limb reduction, Moebius syndrome, amniotic band sequence) were significantly higher in public hospitals. These results suggest disparities in access to prenatal diagnosis and safe abortion based on socioeconomic status. There was a significant gap in access to prenatal diagnosis for CA and possibly to safe elective abortion depending on the type of institution (public vs. non-public).

Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4.

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes. For the efficient prenatal diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents. A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; Chr2[GRCh38]: g.130142742_130202459del) were detected by whole-exome sequencing (WES). We have reported for the first time the biallelic loss-of-function mutations in SMPD4 in patients born to unrelated parents in China. WES could replace chromosomal microarray analysis and copy number variation sequencing as a more cost-effective genetic test for detecting CNVs and diagnosing highly heterogeneous conditions.