Prenatal Diagnosis Research Articles

Facilitating home birth in perinatal palliative care: A case report.

Perinatal palliative care can offer compassionate support to families following diagnosis of a life-limiting illness, to enable them to make valued choices and the most of the time that they have with their newborn. However, home birth is usually only offered in low-risk pregnancies. A couple who received an antenatal diagnosis of hypoplastic left heart syndrome and who had made a plan to provide palliative care to their baby after birth requested the option of a home birth. Recommend birth at hospital or explore the possibility of a home birth with perinatal palliative care support. Multidisciplinary discussion and collaboration enabled a plan for home birth to be made which anticipated potential complications. The baby was born at home and died on day 5 of life receiving outreach nursing, paediatric and palliative care support and buccal and oral opioids for symptom management. We include reflections from the family on the importance of this experience. We provide a list of potential criteria for considering home birth in the setting of perinatal palliative care. Facilitating a home birth in the setting of perinatal palliative care is an option that can be hugely valued by families, but this service may be practically difficult to deliver in many contexts. Further research is needed to understand the preferences of women and families receiving perinatal palliative care.

Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review.

Noonan syndro me is a rare autosomal dominant congenital abnormality associated with a gene defect located on the short arm of chromosome 12. It is characterized by dysmorphic facies, webbed neck, short stature, lymphatic obstruction, cardiac anomalies, and intellectual disability. Prenatal diagnosis of Noonan syndrome is rare because there are no pathognomonic sonographic signs. Studies on the prenatal sonographic features of Noonan syndrome have been reported in very limited numbers. This case series of severe fetal Noonan syndrome, together with a literature review, was conducted to establish prenatal sonographic features highly suggestive of Noonan syndrome to facilitate early detection by clinicians. This study reveals that Noonan syndrome has a relatively specific pattern, which facilitates prenatal molecular genetic diagnosis. Increased nuchal translucency (NT) in the late first trimester and fluid collection in the early second trimester could be warning signs for follow-up, prompting further investigation to detect late-onset features and leading to molecular genetic confirmation. Most structural abnormalities appear in the second trimester, with progressive changes noted throughout gestation. This review better characterizes the sonographic features of fetal Noonan syndrome based on a larger sample size, illustrating a wider spectrum of prenatal phenotypes, including lymphatic drainage disorders, cardiac abnormalities, polyhydramnios, and absent ductus venosus.

An inherited TBX3 alteration in a prenatal case of ulnar-mammary syndrome: Clinical assessment and functional characterization in Drosophila melanogaster.

Ulnar mammary syndrome (UMS) results from heterozygous variants in the TBX3 gene and impacts limb, tooth, hair, apocrine gland, and genitalia development. The expressivity of UMS is highly variable with no established genotype-phenotype correlations. TBX3 belongs to the Tbx gene family, which encodes transcription factors characterized by the presence of a T-box DNA-binding domain. We describe a fetus exhibiting severe upper limb defects and harboring the novel TBX3:c.400 C > T (p.P134S) variant inherited from the mother who remained clinically misdiagnosed until prenatal diagnosis. Literature revision was conducted to uncover the TBX3 clinical and mutational spectrum. Moreover, we generated a Drosophila humanized model for TBX3 to study the developmental consequences of the p.P134S as well as of other variants targeting different regions of the protein. Phenotypic analysis in flies, coupled with in silico modeling on the TBX3 variants, suggested that the c.400 C > T is UMS-causing and impacts TBX3 localization. Comparative analyses of the fly phenotypes caused by the expression of all variants, demonstrated that missense changes in the T-box domain affect more significantly TBX3 activity than variants outside this domain. To improve the clinicians' recognition of UMS, we estimated the frequency of the main clinical features of the disease. Core features often present pre-pubertally include defects of the ulna and/or of ulnar ray, hypoplastic nipples and/or areolas and, less frequently, genitalia anomalies in young males. These results enhance our understanding of the molecular basis and the clinical spectrum of UMS, shedding light on the functional consequences of TBX3 variants in a developmental context.

Comparative characteristics of the dimensions of the pons with the dimensions of the head in human fetes of different gestational age

Annotation. Malformations of human fetuses brains occur in 2-3 cases per 1000 pregnancies and are one of the most common reasons for termination of pregnancy, therefore prenatal diagnosis is extremely important and is aimed at further genetic testing of the fetus and detailed counseling of parents regarding the risk of recurrence. Anthropometric parameters of human fetuses heads allow monitoring the growth of the fetus, estimating the term of pregnancy and determining the method of birth of a pregnant woman. Therefore, the parameters of the head of human fetuses are one of the most important biological characteristics during prenatal research. The purpose of our scientific work is to determine the dimensions of the pons in human fetuses of different gestational ages and compare them with the dimensions of the head. Anatomical research was conducted on 146 human fetuses from 9-10 to 39-40 weeks of gestation. The material for the study was obtained from the maternity hospitals of the city of Vinnytsia and from the communal non-profit enterprise “Vinnytsia Regional Pathological Bureau of the Vinnytsia Regional Council”, and the study was conducted on stillborns who died from various causes not related to brain diseases in relatively healthy mothers. Head circumference, head height, longitudinal and transverse dimensions of the head, pons height, pons width, pons thickness were measured using a ShTs-125 caliper. Statistical processing of digital values was performed using the standard Statsoft software package “Statistica 6.0” on a personal computer using Microsoft Excel 2016, Kolmagorov-Smirnov and Shapiro-Wilk test indicators were determined and histograms were built based on them for visual assessment of the distribution of features. The head circumference of human fetuses of 39-40 weeks compared to fetuses of 9-10 weeks became 5.2 times larger, the longitudinal size of the head – 5 times, the transverse size of the head – 4.9 times, the height of the head – 3.6 times (p<0.01). The height of the pons in human fetuses of 39-40 weeks compared to fetuses of 9-10 weeks became 3.8 times greater, thickness – 3.6 times, width – 3.1 times (p<0.01).

Innovative study of the fetal heart in monochorionic multiple births

Introduction. Fetal echocardiography is currently one of the main methods of prenatal diagnosis. However, in recent years, attention has shifted towards the use of ultrasound to assess fetal myocardial function.The aim of this study is compare global longitudinal deformation of the myocardium of the left (LV) and right ventricles (RV) of the heart in fetuses with uncomplicated singleton pregnancy, in fetuses from monochorionic twins with transfusion syndrome, selective growth retardation and in uncomplicated monochorionic multiple pregnancy.Material and methods. A prospective cohort study was conducted which included 60 pregnant patients: Group I — patients with an uncomplicated singleton pregnancy (n=25); Group II — 35 patients with monochorionic diamniotic twins, whose pregnancy in 10 cases was complicated by feto-fetal transfusion syndrome (stages I-III according to Quintero R.A.), in 10 cases — selective growth retardation of the second fetus and in 15 cases monochorionic twins without complications. The following parameters were determined: global longitudinal deformation (GLD) of the myocardium of the ventricles of fetal hearts using the speckle tracking method of ejection fraction (EF), end-diastolic and end-systolic volumes of the ventricles of the heart.Results. Significant differences were established in GLD of RV and LV between singleton and monochorionic multiple pregnancies (LV: -21.2 ± 2.03 versus -23.41 ± 0 .25, p = 0.003); RV: — 20.3 ± 2.5 versus -23.3 ± 2.5, p = 0.013). Significant differences were revealed in GLD of the LV and RV in recipient fetuses before and after laser coagulation of placental anastomoses (LPCA) [LV in recipients before LCPA (- 20.4 ± 2.98) versus LV recipient after LCPA (-24.2 ± 3.3), p = 0.018], [RV in recipients before LKPA (- 20.4 ± 2.8) vs. RV in recipients after laser coagulation of placental anastomoses (-23.7 ± 3.4, p = 0.012].Conclusion. Assessment of the cardiac function of fetuses from monochorionic twins using the echocardiographic speckle tracking technique makes it possible to identify early changes in fetal myocardial function in twins from monochorionic diamniotic twins, as well as to carry out reliable testing monitoring changes in cardiac function over time.

The legal issue of prenatal diagnosis

Medical interventions concerning the embryo, such as those involving genetic engineering and, more generally, sperirrientation, artificial insemination, as well as prenatal diagnosis, give rise to a legal problem, the treatment of which requires a preliminary, albeit general, identification of the position recognised by the legal system for the unborn child.

Human Tails and Whole Exome Sequencing Findings: Is There any Association? A Case Report

Introduction: The human tail is a rare congenital condition characterized by a caudal cutaneous appendage, primarily located in the lumbosacral region. These tails are often associated with other congenital malformations, most notably spinal dysraphism. Case Presentation: A 3-week-old male neonate was referred to the Baqiyatallah Pediatric Clinic in Tehran, Iran, due to a 12-cm-long congenital tail-like appendage in his lumbosacral region, which contained only soft tissue upon palpation. There was no apparent neurological deficit on physical examination or magnetic resonance imaging. No other concomitant malformations were present. The parents were consanguineous, and a previous pregnancy had been terminated at 18 weeks of gestation due to a prenatal diagnosis of a neural tube defect. As a result, genetic consultation and whole exome sequencing were performed. Some phenotype-related variants of uncertain significance were detected, and the baby was also found to be heterozygous for oculocutaneous albinism. Conclusions: Although some genetic variants of uncertain significance and a pathogenic variant associated with albinism were identified in this case, the absence of other manifestations beyond the tail and the lack of literature on this topic make the clinical implications of genetic testing in human tails unclear. Further investigation is required to understand these implications.

Second‐Trimester Ultrasound Receipt Mediates the Relationship Between Public Insurance and Prenatal Diagnosis of a Congenital Heart Defect

ABSTRACTObjectiveTo delineate the mechanism behind insurance‐related disparities in the prenatal diagnosis of a congenital heart defect (CHD).MethodsThis was a retrospective analysis of electronic health records of pregnant individuals whose infants received CHD surgery between 2019 and 2020 in the third‐largest United States metropolitan area. The outcome was whether a prenatal diagnosis was received. The exposure was the pregnant individual's insurance status. The mediator was second‐trimester ultrasound receipt. Control variables included sociodemographic and clinical characteristics of the pregnant individual and infant. The relationships between exposure, mediator, and outcome were quantified using mediation analysis with multivariable fixed‐effects regression.ResultsIn total, 496 pregnant individuals met inclusion criteria; 215 (43.3%) were publicly insured and 305 (61.5%) had prenatal diagnosis. In bivariate regressions, public insurance was associated with a 12.6% lower probability (CI 3%–21%) of prenatal diagnosis. In multivariable models, public insurance was associated with 13.2% lower probability (CI 2%–25%) of second‐trimester ultrasound receipt but was no longer associated with prenatal diagnosis after adjusting for second‐trimester ultrasound receipt, suggesting a possible mediation effect. Mediation analysis confirmed that second‐trimester ultrasound receipt mediated 39% of the relationship between public insurance and prenatal diagnosis.ConclusionAn appreciable portion of insurance‐related differences in prenatal CHD diagnosis is due to the lower frequency of second‐trimester ultrasound receipt among those with public insurance.

Advancements in Artificial Intelligence for Fetal Neurosonography: A Comprehensive Review.

The detailed sonographic assessment of the fetal neuroanatomy plays a crucial role in prenatal diagnosis, providing valuable insights into timely, well-coordinated fetal brain development and detecting even subtle anomalies that may impact neurodevelopmental outcomes. With recent advancements in artificial intelligence (AI) in general and medical imaging in particular, there has been growing interest in leveraging AI techniques to enhance the accuracy, efficiency, and clinical utility of fetal neurosonography. The paramount objective of this focusing review is to discuss the latest developments in AI applications in this field, focusing on image analysis, the automation of measurements, prediction models of neurodevelopmental outcomes, visualization techniques, and their integration into clinical routine.

Fetal hemochromatosis: rare case of hepatic and extrahepatic siderosis involving thyroid on fetal MRI

BackgroundNeonatal hemochromatosis (NH) is a rare condition that is characterized by severe neonatal liver disease in association with hepatic and extrahepatic excess iron deposition (siderosis), while sparing the reticuloendothelial system. The most common cause of fetal liver injury leading to the NH phenotype (accounting for over 95% of cases) is gestational alloimmune liver disease. This condition is caused by the transfer of maternal IgG antibodies through the placenta, targeting a fetal hepatocyte antigen. Prenatal diagnosis, particularly the identification of iron overload involving both liver and thyroid, is of significant importance and can have a profound impact on patient care. To our knowledge, no case has been reported on prenatal diagnosis of iron overload involving both liver and thyroid.Case presentationWe present an exceptionally rare case of fetal hemochromatosis in a primigravida, a case that significantly contributes to our understanding of this condition. The diagnosis was made with the presence of hepatic and extrahepatic siderosis involving the thyroid using Ultrasonography (USG) and fetal Magnetic Resonance Imaging (MRI) findings. A 23-year-old primigravida was referred to our center in view of oligohydramnios, Intrauterine Growth Restriction (IUGR) and echogenic bowel at 29 weeks of gestation. USG and fetal MRI showed features of coarse liver echotexture and iron overload involving the liver and thyroid; this is the first case describing iron accumulation in the fetal thyroid gland diagnosed in utero.ConclusionThis case underscores the critical importance of performing MRI in suspected cases of fetal hemochromatosis for early diagnosis and intervention, emphasizing the potential to significantly improve patient outcomes.

Prenatal diagnostic errors in hemoglobin Bart's hydrops fetalis caused by rare genetic interactions of α-thalassemia.

To describe rare genetic interactions of α-thalassemia alleles causing Hb H disease and Hb Bart's hydrops fetalis which could lead to diagnostic errors in a routine practice. Hematological and molecular characterization were carried out in a Thai family with a risk of having fetus with Hb Bart's hydrops fetalis. Both parents were found to be the thalassemia intermedia patients associated with unusual forms of Hb H disease. DNA analysis of common α-thalassemia mutations in Thailand identified α+-thalassemia (-α3.7 kb del) and unknown α0-thalassemia in the father and α0-thalassemia (--SEA) with unknown α+-thalassemia in the mother. Fetal DNA analysis unlikely identified a homozygosity for α0-thalassemia (--SEA/--SEA). Further analysis identified that the father carried a rare South African α0-thalassemia in combination with α+-thalassemia (--SA/-α), whereas the mother was a patient with Hb H-Queens Park disease (--SEA/ααQP). The fetus was, in fact, a compound heterozygote for (--SA/--SEA). As shown in this study, routine screening for α-thalassemia at prenatal diagnosis in the region should include both common and rare α0-thalassemia alleles found in the population to effectively prevent a fatal condition of Hb Bart's hydrops fetalis syndrome.

Fetuses with deceleration of growth improve their growth following maternal rest.

The purpose of this study was to determine if fetuses with deceleration of growth velocity resulting in an EFW <10th percentile increase their growth above the 10th percentile following 2 weeks of maternal rest in the left lateral recumbent position. This was a retrospective observational study of 265 fetuses with the prenatal diagnosis of an EFW <10th percentile. Fetuses were classified by four definitions of abnormal growth velocity: (1) a growth velocity less than 20 g/day, (2) 30 percentile decrease in the EFW, (3) 50 percentile decrease in the EFW, and (4) abnormal growth trajectory. Once the fetuses were identified with an EFW <10th percentile the patient was requested to begin 2 weeks of rest in the left lateral recumbent position during her waking hours following which the EFW was reassessed 2 week later to determine the effect of maternal rest on the EFW. Irrespective of the four types of decreased growth velocity described in the methods section, there was as significant increase (p < 0.001) in the EFW following 2 weeks of maternal rest as follows: (1) growth less than 20 g/day (75%); (2) decrease of 30 or more EFW percentiles (79%); (3) decrease of 50 or more EFW percentiles (64%); and abnormal growth trajectory (77%). This suggests an important role of increased maternal cardiac output as the result of resting in the left lateral recumbent position that may be associated with improved fetal growth. These observations should be the basis for future prospective randomized trials to test this hypothesis.

Reproductive options and genetic testing for patients with an inherited cardiac disease.

In the past decade, genetic testing for cardiac disease has become part of routine clinical care. A genetic diagnosis provides the possibility to clarify risk for relatives. For family planning, a genetic diagnosis provides reproductive options, including prenatal diagnosis and preimplantation genetic testing, that can prevent an affected parent from having a child with the genetic predisposition. Owing to the complex genetic architecture of cardiac diseases, characterized by incomplete disease penetrance and the interplay between monogenic and polygenic variants, the risk reduction that can be achieved using reproductive genetic testing varies among individuals. Globally, disparities, including regulatory and financial barriers, in access to reproductive genetic tests exist. Although reproductive options are gaining a prominent position in the management of patients with inherited cardiac diseases, specific policies and guidance are lacking. Guidelines recommend that prenatal diagnosis and preimplantation genetic testing are options that should be discussed with families. Health-care professionals should, therefore, be aware of the possibilities and feel confident to discuss the benefits and challenges. In this Review, we provide an overview of the reproductive options in the context of inherited cardiac diseases, covering the genetic, technical, psychosocial and equity considerations, to prepare health-care professionals for discussions with their patients.

Study on ultrasound diagnosis and pathological anatomy of fetal complex congenital heart disease in the first trimester.

To assess the feasibility of using the stereo-microscope to identify the pathological anatomy of the congenital heart diseases in the first trimester. Fifteen fetuses of 8-12 weeks aborted due to prevent miscarriage failure and 42 fetuses of 11-14 weeks with congenital heart diseases were included in the study, we dissected their hearts through a stereo-microscope, then compared with the prenatal ultrasonographic diagnosis. Using stereomicroscopy, the positive view of the heart and the great arteries, the long axis view of the aortic arch, the inflow tract view of the bottom heart, the semilunar valve view of the bottom heart, and the transverse section of the ventricle were showed contented and obtained satisfactory images, but the structure of atrioventricular valve and venous system had a lower rate of display. The characteristic pathological changes of cardiac inflow and outflow tract can be obtained by dissecting the heart sequential under the stereo-microscopy. However it is often difficult to obtain satisfactory pathological sections for pulmonary venous abnormalities and Ebstein anomaly.

Impact of isolated fetal congenital heart disease on pregnancy and perinatal outcomes.

The aim of the present study was to evaluate the obstetric complications associated with isolated fetal congenital heart disease (CHD) by comparing pregnancies with and without this condition. In this retrospective matched comparative study at Siriraj Hospital, Thailand, we included 233 postnatally confirmed fetal CHD cases and 466 unaffected fetuses. Controls were selected at a 2:1 ratio, ensuring that they matched the cases in terms of maternal age, parity, and history of preterm deliveries. Fetal CHD was significantly associated with an increased risk of spontaneous preterm labor (30% vs 9.7%; adjusted odds ratio [aOR] 2.42; 95% confidence interval [CI]: 1.35-4.36; P = 0.003), delivery before 34 gestational weeks (11.6% vs 0.6%; aOR 12.33; 95% CI: 3.32-45.78; P < 0.001), and pre-eclampsia (11.6% vs 2.8%; aOR 2.19; 95% CI: 1.01-4.76; P = 0.047). Newborns with CHD were significantly more likely to be small for gestational age (10.7% vs 5.2%; aOR 2.09; 95% CI: 1.11-3.94; P = 0.022). Intriguingly, a prenatal diagnosis of CHD was associated with a reduced risk of preterm delivery in affected pregnancies (P = 0.002). Pregnancies affected by isolated fetal CHD demonstrated a higher propensity for several adverse outcomes. These findings underscore the importance of prenatal CHD detection and tailored perinatal care to potentially improve both pregnancy outcomes and neonatal health.

Descriptive epidemiology of gastroschisis in China from 2007 to 2020: a nationwide surveillance-based study

BackgroundGastroschisis is a common abdominal wall defect that increases infant mortality risk and health care costs. However, recent epidemiological data on gastroschisis in China is limited.MethodsUsing 2007–2020 data from the Chinese Birth Defects Monitoring Network (CBDMN), we analyzed gastroschisis prevalence rates stratified by birth year, maternal age group, residence area, geographical region, and infant sex. We also examined the temporal variations in prevalence, pregnancy outcomes of affected infants, prenatal diagnoses, and co-occurring anomalies.ResultsFrom 2007 to 2020, a total of 6,813 cases of gastroschisis were identified among 25,909,000 births, comprising 4,675 isolated and 2,138 non-isolated cases. Prevalence rates per 10,000 live and still births were 2.63, 1.80, and 0.83 for the overall, isolated, and non-isolated gastroschisis, respectively, all showing a decreasing trend over the study period. The prevalence of overall gastroschisis varied significantly by maternal age (< 20 years, 9.88/10,000; 20–24 years, 4.17/10,000; 25–29 year, 2.08/10,000; 30–34 years, 1.88/10,000;≥35 years, 2.24/10,000), maternal residence (urban, 2.45/10,000; rural, 2.85/10,000), geographic region (central, 2.54/10,000; east, 2.57/10,000; west, 2.80/10,000), and infant sex (male, 2.13/10,000; female, 1.79/10,000). Non-isolated gastroschisis cases had a higher early neonatal mortality rate than isolated cases (41.91% vs. 28.10%) and frequently co-occurred with musculoskeletal anomalies.ConclusionsThis study highlights a declining trend in gastroschisis prevalence in Chinese population, a contrast to previous studies, and underscores the need for improved perinatal management due to adverse pregnancy outcomes associated with this condition.

Mutations in ADAMTSL4 cause a unique form of autosomal-recessive congenital ectopia lentis

Several unique mutations of ADAMTSL4 leading to congenital ectopia lentis (CEL) have been previously reported by our team. The purpose of this study is to find out the possible mechanism of a recurrent novel intronic variant in ADAMTSL4 led to CEL. Twelve novel ADAMTSL4 mutations with a unique form congenital ectopic lentis were detected previously by panel-based NGS. Genetic analysis verified a novel heterozygous ADAMTSL4 variation c.2177+4A > G on Intron 11 in two unrelated patients with iris and lens abnormalities. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon 11 skipping. Construction of wild-type and mutant ADAMTSL4 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of ADAMTSL4 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of ADAMTSL4 in cells transfected with the mutant vectors. 12 novel mutations in ADAMTSL4 gene have been previously reported by our team in 6 CEL patients with a unique series of ocular abnormalities. The recurrent novel ADAMTSL4 mutation c.2177+4A > G triggering the splicing mode of Exon 11 skipping and NMD would cause the decrease of ADAMTSL4 proteins that participate in biosynthesis and assembly of microfibers, which might lead to CEL, and suggest that sequencing of certain intronic splicing varition might be a vital tool for genetic counseling and prenatal diagnoses.

Evolution of the MRT method and current possibilities of its use in prenatal diagnosis of foetal anomalies (literature review)

Evolution of the MRT method and current possibilities of its use in prenatal diagnosis of foetal anomalies (literature review)

Antenatal depression and drug use among deaf and hard-of-hearing birthing parents: results from a U.S. National Survey.

This study aimed to investigate antenatal depression and drug use among deaf and hard-of-hearing (DHH) birthing parents who use American Sign Language (ASL), spoken English, or bilingually both ASL and English. DHH participants in the United States responded to the Survey on Pregnancy Experiences of Deaf and Hard-of-Hearing Women. Respondents self-reported their antenatal depression diagnoses and drug use (i.e., pain relievers, cannabis, or illicit drugs) during their last pregnancy. Poisson regression models were used to estimate prevalence ratios, adjusting for age, race/ethnicity, education, marital status, and parity. The average age of respondents (n = 587) was 35 years. Respondents were predominantly non-Hispanic white (80%), college educated (60%), and married (74%). Relative to DHH English-speakers, DHH ASL-users had lower prevalence of reporting antenatal depression diagnosis (aPR = 0.40, 95% CI: 0.23 to 0.72). DHH people who reported antenatal depression diagnosis had higher prevalence of reporting antenatal drug use (PR = 2.34, 95% CI: 1.65 to 3.33). There were no significant associations between preferred language and antenatal drug use. DHH ASL-users are less likely to report receiving an antenatal depression diagnosis compared to DHH English-speakers. Given well-documented patient-provider communication barriers among DHH ASL-users, it is unclear if the lower prevalence observed in this study is the result of inadequate or inaccessible screening during pregnancy. Future work should consider universal use of linguistically appropriate screening tools for DHH birthing parents in both clinical and research settings.

The onset of coarctation of the aorta before birth: Mechanistic insights from fetal arch anatomy and haemodynamics

Accurate prenatal diagnosis of coarctation of the aorta (CoA) is challenging due to high false positive rate burden and poorly understood aetiology. Despite associations with abnormal blood flow dynamics, fetal arch anatomy changes and alterations in tissue properties, its underlying mechanisms remain a longstanding subject of debate hindering diagnosis in utero. This study leverages computational fluid dynamics (CFD) simulations and statistical shape modelling to investigate the interplay between fetal arch anatomy and blood flow alterations in CoA. Using cardiac magnetic resonance imaging data from 188 fetuses, including normal controls and suspected CoA cases, a statistical shape model of the fetal arch anatomy was built. From this analysis, digital twin models of false and true positive CoA cases were generated. These models were then used to perform CFD simulations of the three-dimensional fetal arch haemodynamics, considering physiological variations in arch shape and blood flow conditions across the disease spectrum. This analysis revealed that independent changes in the shape of.the arch and the balance of left-to-right ventricular output led to qualitatively similar haemodynamic alterations. Transitioning from a false to a true positive phenotype increased retrograde flow through the aortic isthmus. This resulted in the appearance of an area of low wall shear stress surrounded by high wall shear stress values at the flow split apex on the aortic posterior wall opposite the ductal insertion point.Our results suggest a distinctive haemodynamic signature in CoA characterised by the appearance of retrograde flow through the aortic isthmus and altered wall shear stress at its posterior side. The consistent link between alterations in shape and blood flow in CoA suggests the need for comprehensive anatomical and functional diagnostic approaches in CoA. This study presents an application of the digital twin approach to support the understanding of CoA mechanisms in utero and its potential for improved diagnosis before birth.