Mirror syndrome is a rare maternal-fetal condition associated with fetal hydrops and a high risk of adverse maternal and fetal perinatal outcomes. Its diagnosis is challenging due to the lack of standardized diagnostic criteria and its clinical and biochemical overlap with preeclampsia. This narrative review summarizes current evidence on mirror syndrome, with a focus on prenatal diagnosis, placental pathophysiology and the role of targeted fetal therapy. Mirror syndrome is most frequently associated with non-immune causes of fetal hydrops and available evidence supports a central role for the placenta in disease pathogenesis. Recent data suggest that angiogenic biomarkers, including sFlt-1 and PlGF, may be useful in the differential diagnosis from preeclampsia. Resolution of fetal hydrops through in utero therapy can lead to rapid maternal improvement and pregnancy prolongation in selected cases. Early recognition and multidisciplinary management are essential to optimize maternal and fetal outcomes.
Celocentesis represents a novel form of invasive pregnancy test that allows the genetic material of the embryo to be tested during the embryonic stage at 6-9 weeks of gestation. The purpose of this narrative review is to present the latest available literature on celocentesis, including its biological basis, technical aspects, diagnostic performance, safety profile, clinical applications, and future perspectives. Available evidence from selected studies conducted in highly specialized centers suggests that the diagnosis of monogenic diseases by celocentesis can achieve high accuracy, with reported success rates ranging from 93% to 99% when combined with molecular testing and selective fetal cell isolation. Similarly, a high level of concordance with conventional prenatal and postnatal diagnostic methods has been reported. The pregnancy loss associated with celocentesis appears to be low and comparable to baseline early pregnancy loss, although current evidence is derived primarily from observational studies and limited clinical series. One of the main benefits of celocentesis is the capability to perform prenatal diagnosis at an early stage of pregnancy, which facilitates more informed decisions about treatment options, minimizes parental anxiety, and allows earlier intervention when required. Moreover, experimental evidence suggests that celocentesis may provide a future platform for intrauterine therapeutic approaches, including stem cells and gene-based therapies, although these applications remain investigational. Despite these promising findings, celocentesis should currently be considered an experimental procedure, as its use remains largely confined to specialized centers and further multicenter studies are required to establish its safety, reproducibility, and broader clinical utility.
Congenital portosystemic shunts are rare vascular anomalies of the fetal venous system caused by abnormal connections between the portal and systemic circulation. Although prenatal diagnosis is challenging, it is essential for appropriate counseling and management. A 34-year-old pregnant woman was referred at 26 weeks of gestation with suspected early-onset fetal growth restriction. Ultrasonography revealed severe fetal growth restriction, with all biometric parameters below the 1st percentile, while Doppler findings remained normal. Targeted evaluation demonstrated an abnormal vascular connection between the left portal vein and the left hepatic vein, consistent with an intrahepatic portosystemic shunt, without additional structural anomalies. The pregnancy was closely monitored, and a female infant weighing 1410 g was delivered at 37 weeks of gestation. The neonatal course was uneventful except for low birth weight. Intrahepatic portosystemic shunts should be considered in the differential diagnosis of unexplained early-onset fetal growth restriction, even when conventional Doppler findings are normal.
Background and Objectives: Posterior fossa anomalies (PFAs) represent a heterogeneous group of congenital malformations involving the cerebellum and adjacent structures. Prenatal counseling remains challenging because neurodevelopmental outcomes vary substantially according to the specific anomaly. This study aimed to evaluate ultrasonographic and fetal magnetic resonance imaging (MRI) characteristics, associated anomalies, genetic test results, and perinatal and neurodevelopmental outcomes of prenatally diagnosed PFAs in a tertiary care population. Materials and Methods: This retrospective study included 115 fetuses diagnosed with PFAs between 2020 and 2024. PFAs were categorized into "simple" (mega cisterna magna, Blake's pouch cyst [BPC], and arachnoid cyst) and "complex" (Dandy-Walker malformation [DWM], vermian agenesis/hypoplasia, cerebellar hypoplasia, Joubert syndrome, Walker-Warburg syndrome, and pontocerebellar hypoplasia). Maternal characteristics, associated cerebral and extracerebral anomalies, fetal MRI findings, genetic test results, and pregnancy and postnatal outcomes were analyzed. Results: Among 115 cases, 44.3% were isolated, and 55.6% were non-isolated. Ventriculomegaly was detected in 35.6% of cases and was significantly more frequent in the complex group (47.9% vs. 14.2%). Fetal MRI was performed in 35.6% (n = 41) of cases and demonstrated a 24.3% discrepancy rate with ultrasound, mainly in differentiating DWM from BPC. Genetic testing was performed in 66.9% of cases, revealing chromosomal abnormalities in 15.6% of the total cohort. Complex anomalies, including cerebellar hypoplasia and vermian agenesis/hypoplasia, were more frequently associated with pathogenic copy-number variants and monogenic disorders. The simple group (n = 42) had favorable outcomes, with an 89.2% survival rate and neurodevelopmental delay in 15.2% of survivors. In contrast, the complex group (n = 73) had significantly poorer outcomes (p < 0.001), with a 38.1% survival rate, 42.5% rate of pregnancy termination, and neurodevelopmental delay in 56.3% of survivors. Conclusions: This study highlights the persistent diagnostic challenges associated with PFAs and underscores the importance of multimodal imaging and comprehensive genetic evaluation. The proposed simple-complex classification provides a clinically meaningful framework for prognostication and parental counseling. Future research should prioritize prospective multicenter studies with higher rates of comprehensive genetic testing coupled with standardized long-term neurodevelopmental follow-up to refine the understanding of the natural history and prognostic trajectory of these complex brain malformations.
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Red blood cell (RBC) alloimmunization remains a relevant cause of hemolytic disease of the fetus and newborn (HDFN). Although RhD immunization has significantly decreased since the implementation of systematic prophylaxis, it is still the main cause of alloimmunization in pregnancy. Clinically significant non-RhD alloantibodies, particularly those of the Rh (c, C, E), Kell, Kidd, Duffy, and MNS systems, are associated with variable risk of fetal anemia and account for an increasing proportion of alloimmunized pregnancies requiring specialized prenatal care. Most diagnostic algorithms and management protocols are based on evidence derived from RhD alloimmunization. Although these frameworks are often extrapolated to other alloantibodies, important differences exist regarding antibody titration and critical thresholds, the diagnostic accuracy of non-invasive fetal antigen genotyping, and the risk and timing of fetal and neonatal interventions. These differences underscore the need for antibody-specific considerations in the prenatal diagnosis and management of non-RhD alloimmunization. Though advances in non-invasive diagnostic techniques have improved risk stratification and optimized prenatal management, individualized care pathways in alloimmunized pregnancies are needed. This review will focus on the current strategies for prenatal diagnosis and risk assessment in pregnancies complicated by non-RhD red cell alloimmunization.
Objectives: Prenatal diagnosis of horseshoe kidney (HSK), a common congenital renal fusion anomaly of the upper urinary tract, remains challenging. Most cases are identified only after birth; however, the clinical significance of prenatal detection and its impact on postnatal outcomes remains unknown. Methods: We investigated infants with postnatally confirmed HSK born at a tertiary referral center between January 2009 and August 2025. Prenatal ultrasonographic findings and postnatal outcomes were reviewed. Patients were classified into three groups according to prenatal detection status: missed HSK (group 1), prenatally detected renal abnormalities without recognition of HSK (group 2), and prenatally identified HSK (group 3). Perinatal outcomes, postnatal urological complications, renal function, and associated anomalies were compared. Results: Overall, 29 infants were included in this study. Perinatal outcomes, including gestational age at delivery, birth weight, preterm birth, Apgar scores, need for ventilatory support, and neonatal sex, did not differ significantly among the groups. Hydronephrosis and renal scarring were more frequently observed in group 2 than in the other groups. Other urological outcomes, renal function parameters, and mortality rates were comparable between the groups. Conclusions: This adds to the limited longitudinal evidence linking the prenatal to postnatal period and evaluating the full spectrum of prenatal detection in HSK, as well as its association with postnatal outcomes. Postnatal outcomes are closely associated with the presence of renal abnormalities. Therefore, prenatal imaging is more appropriate for identifying associated renal abnormalities than for establishing a definitive diagnosis of HSK.
RNA sequencing (RNA-seq) provides transcript-level evidence for interpreting variants of uncertain significance in monogenic disorders, but its prenatal application is limited by sample availability and processing time. This study evaluated uncultured amniocytes as a practical substrate for prenatal RNA-seq. We performed RNA-seq on 15 matched paired cultured and uncultured amniocyte samples and compared their transcriptomic profiles using principal component analysis, differential expression analysis, and pathway enrichment. We then analyzed 77 uncultured amniocyte samples collected between 16+6 and 29+6 weeks of gestation to disease-related gene expression coverage and gestational-age-associated variation. Five selected cases were further analyzed to evaluate transcript-level findings relevant to variant interpretation. Cultured and uncultured amniocytes showed distinct transcriptomic profiles, with 11,234 differentially expressed genes and culture-associated transcriptional and pathway changes. Uncultured amniocytes expressed an average of 63.4% of genes across disease-associated panels, and most disease-related genes were consistently expressed across gestational stages, although stage-associated differences in gene detectability were observed. In selected cases, uncultured amniocyte RNA-seq detected aberrant expression, aberrant splicing, allelic imbalance, and expressed sequence variants. These findings support the feasibility of prenatal RNA-seq using uncultured amniocytes and further evaluation of this approach as a complementary functional assay for prenatal variant interpretation.
To evaluate the potential value of peak velocity at the vertical vein obstruction site (Vmax), proximal vertical vein velocity (Vp), and their ratio (Vmax/Vp) in the prenatal diagnosis of fetal total anomalous pulmonary venous connection (TAPVC) with pulmonary venous obstruction (PVO) and in early neonatal risk assessment. This was a retrospective cohort study. A total of 8 fetuses with TAPVC and PVO (14 examinations), 6 fetuses with TAPVC without PVO (11 examinations), and 50 normal fetuses were enrolled. Peak velocities of the vertical vein (or pulmonary vein) were compared across the three groups. In the PVO group, the correlations between indicators such as Vmax, Vmin, Vmean, PVVI, Vp, and Vmax/Vp and clinical outcomes (including neonatal acidosis, hypoxemia, severity of pulmonary hypertension, and death) were analyzed. Vmax was higher in the PVO group than in the TAPVC without PVO and normal groups (p < 0.001). Vp was lower in the PVO group than the corresponding pulmonary venous velocity in normal fetuses (p < 0.001). Vmax was not significantly correlated with Vmax/Vp (rs = 0.43, p = 0.126), suggesting that the ratio may provide additional hemodynamic information beyond Vmax alone. Lower Vp was associated with acidosis, hypoxemia, more severe pulmonary hypertension, more severe obstruction, and mortality (all p ≤ 0.03). Vmax/Vp was associated with the severity of pulmonary hypertension (p = 0.045). In this small exploratory cohort, Vp and Vmax/Vp appeared to provide complementary information to Vmax in fetuses with TAPVC and PVO. These preliminary findings suggest that combined assessment of proximal and stenotic-site velocities may help identify atypical obstruction and support prenatal risk stratification.
Cobalamin C (Cbl-C) disease, the most common inborn error of cobalamin metabolism caused by biallelic pathogenic MMACHC variants, leads to multisystem involvement from methylmalonic acid and homocysteine accumulation. When diagnosed early, it is treatable. Rapid genome sequencing (GS) is becoming increasingly accessible and enables timely diagnosis and prompt treatment. We report a neonate who had severely decreased prenatal and postnatal biventricular function requiring inotropic support. Given the critically ill condition and unclear etiology, rapid GS was obtained and revealed homozygous pathogenic MMACHC variants, confirming a diagnosis of Cbl-C disease. This prompted the early initiation of treatment with high-dose hydroxocobalamin, betaine, levocarnitine, and folic acid. His cardiac function gradually improved, and he was discharged at 28 days of life. Critical care providers should suspect treatable inherited metabolic disorders in patients with unexplained presentations and recognize rapid GS as a powerful tool for early identification and treatment in critically ill patients.
This study aims to delineate the prenatal ultrasound characteristics of four cases of Rubinstein-Taybi syndrome type 2 (RSTS2) and explore potential associations with this condition as detected through prenatal ultrasound. Whole exome sequencing (WES) and Sanger sequencing were conducted on four fetuses diagnosed with RSTS2. Prenatal ultrasound data were systematically collected and analyzed. All four fetuses were found to have previously unreported EP300 variants, which were absent from ClinVar and the Human Gene Mutation Database (HGMD). The prenatal ultrasound findings were diverse; in the second trimester, two fetuses exhibited growth parameters below minus two standard deviations (M-2SD). One fetus showed an abnormal foot posture and thickened plantar skin, another was found to have exencephaly in the first trimester, and one case presented with fetal rhabdomyoma. This study prenatal ultrasound phenotypes associated with EP300 variants may add to the phenotypic profile of RSTS2 and could serve as a reference for prenatal diagnosis and counseling.
Down syndrome (DS) is the most common chromosomal abnormality in the human population, most frequently caused by trisomy 21 due to meiotic nondisjunction. Rarely, DS may result from an isochromosome or a Robertsonian translocation, this being the least common variant. We present a rare prenatal case of Down syndrome caused by a derivative chromosome 21, together with a case-based review of previously reported prenatal der(21;21)/i(21q) rearrangements. We report a case of prenatal diagnosis of DS in a 13-week female fetus, characterized by a derivative chromosome 21, der(21;21)(q10;q10), identified by conventional karyotyping and subsequently confirmed by fluorescence in situ hybridization (FISH). First-trimester ultrasonography showed bilateral jugular lymphatic sacs, marked tricuspid regurgitation, and a single umbilical artery. Quantitative fluorescence polymerase chain reaction (QF-PCR) failed to detect the structural chromosomal abnormality. The rearrangement was considered likely de novo based on normal parental karyotypes. Consequently, the empirical recurrence risk is 1% for de novo cases, whereas in families with a parental 21q;21q rearrangement the recurrence risk may approach 100%. This case highlights the importance of integrating detailed ultrasound screening with molecular and cytogenetic techniques, including QF-PCR, conventional karyotyping, and FISH, for accurate prenatal diagnosis of DS. Precise determination of the underlying chromosomal abnormality is essential for providing accurate genetic counseling, estimating recurrence risk, and facilitating informed reproductive planning for the parents.
Organoids are three-dimensional structures derived from a single stem cell. They self-organize in vitro and mature to recreate microarchitecture and characteristics of their tissues of origin. Since the first culture of mouse intestinal epithelial organoids and the translation to human, this technology has shown vast potential. Applications include developmental biology, disease modelling, drug testing and regenerative medicine making it increasingly relevant to clinical practice. Organoids can now be generated from tissues such as lung, intestine, kidney and brain using adult and fetal stem cells, pluripotent stem cells and cancer samples. Whether to study fetal development, disease physiopathology, regenerative medicine or to develop new therapies in a faster, more ethical and cost-effective way than animal models, organoids represent a powerful new tool. First described in 1999, personalised medicine aims to fine-tune diagnostic, prognosis and treatment to each patient. Nowadays, personalised medicine is spreading to most areas of clinical management, becoming the gold standard for the adoption of new interventions. More recently, these concepts have been applied to fetal medicine for prevention and therapy with initial reports appearing in literature in 2020. By recapitulating patient-specific disease mechanisms, prenatal organoids represent a unique bridge between in vitro-based approaches and personalised fetal medicine. This review presents fetal diseases for which organoids were explored, focusing on the implications of their derivation from prenatal sources such as the amniotic fluid, and discusses their advantages, challenges, and perspectives for prenatal counselling, prognosis or diagnosis, regenerative therapy, in utero surgery, disease modelling and prenatal drug testing.
This study aimed to evaluate whether peak systolic velocity (PSV) in the fetal extra-abdominal superior mesenteric artery (SMA) is a useful prenatal marker of bowel inflammation in gastroschisis (GS), which manifests postnatally as bowel matting. This case-control study included 30 fetuses with gastroschisis who underwent standardized bowel assessment and Doppler measurement of the extra-abdominal SMA-PSV. Postnatal bowel status was classified as normal or inflamed. The primary analysis examined the association between fetal SMA-PSV and bowel inflammation, using linear models and generalized estimating equations for repeated measurements. Among 30 fetuses, bowel matting was identified postnatally in 10 cases (33.3%). These neonates had significantly lower birthweight percentiles (5.5 vs. 50.5; p = 0.002) and more frequent ultrasound inflammatory signs such as bowel wall oedema (80% vs. 15%; p = 0.002), bowel wall stiffness (50% vs. 5%; p = 0.004), and corrugation wall (60% vs. 5%; p = 0.004). PSV was strongly correlated with bowel wall thickness (r = 0.81) and significantly higher in fetuses with postnatally diagnosed bowel matting (p < 0.001). GEE models showed that higher prenatal PSV independently predicted the later occurrence of bowel matting. Incorporating the time × bowel matting interaction significantly improved model fit (adjusted R2 = 0.460). Fetal SMA-PSV is significantly associated with prenatal/ultrasound and postnatal signs of bowel inflammation in gastroschisis, such as bowel wall thickening and bowel matting. This association appears independent of the simple/complex GS surgical classification, suggesting PSV as a functional marker of intestinal compromise. Although technically demanding, SMA-PSV assessment may aid prenatal evaluation and perinatal planning, particularly in detecting evolving intestinal inflammatory cases.
Cell-free DNA (cfDNA) screening is a highly accurate method of genetic screening that relies on the presence of placenta-derived DNA circulating in maternal plasma. The widespread availability of this screening, also known as non-invasive prenatal testing, has transformed prenatal genetic screening for fetal chromosome disorders, including trisomies 21, 18, and 13. Despite the increased accuracy of the cfDNA approach, false-positive results remain a possibility. Such results have distinct biological causes and clinical implications. In this article, we review the most common causes of false-positive screening results: confined placental mosaicism; vanishing twin syndrome; and maternal factors, including maternal mosaicism and malignancies. We also review unexplained false-positive and nonreportable cfDNA results and appropriate follow-up. Clinical vignettes demonstrate scenarios that nurses and other providers may encounter in the delivery of prenatal care.
Cytomegalovirus (CMV) remains one of the most relevant congenital and early-life infections in pediatrics because of its high global seroprevalence, lifelong latency, and potential for reactivation or reinfection. Biologically, the virus poses a particular threat during pregnancy, when maternal primary infection carries a substantially higher risk of transplacental transmission than non-primary infection, with fetal and neonatal consequences that vary according to gestational timing and host vulnerability. In children, CMV infection is common in the first years of life and may contribute to a broad spectrum of outcomes, ranging from asymptomatic infection to severe multisystem disease, neurodevelopmental impairment, and sensorineural hearing loss. Clinically, the document highlights the importance of timely maternal diagnosis, differentiation between primary and recurrent infection, and integration of prenatal, neonatal, radiological, and audiological assessment. Attention is given to symptomatic and asymptomatic newborns, preterm infants, and infants exposed through breast milk. The availability of antiviral strategies in pregnancy and infancy strengthens the rationale for early identification and risk stratification. Universal newborn screening emerges as a potentially valuable approach to improve case detection, enable prompt follow-up, and reduce long-term disability. Overall, a multidisciplinary and early-intervention framework is essential to optimize prevention, diagnosis, treatment, and long-term outcomes in pediatric CMV infections.
Conventional methods for α-thalassemia gene diagnosis, such as Gap-PCR, are primarily designed for common deletions. However, their limitations in detecting complex rearrangements that maintain the total copy number of α-globin genes can lead to misdiagnosis, as exemplified by the misinterpretation of "-α3.7 heterozygous" carriers. This study aimed to evaluate the application of single-molecule real-time (SMRT) sequencing in addressing these diagnostic challenges. From January 2023 to April 2025, 9180 individuals from Dongguan were enrolled. Peripheral blood samples underwent routine thalassemia genetic testing. Samples identified as -α3.7/αα by Gap-PCR were further analyzed using multiplex ligation-dependent probe amplification (MLPA) and SMRT sequencing. SMRT sequencing demonstrated high precision in distinguishing genotypes that are difficult to differentiate by traditional methods. It accurately identified benign variants like HKαα and pathogenic triplications such as αααanti4.2, which is crucial for assessing the risk of offspring developing intermediate β-thalassemia. Furthermore, the technology successfully revealed "hidden" balanced complex rearrangements (e.g., -α3.7/αααanti3.7) within the blind spots of conventional techniques. Notably, a specific genotype, -α3.7/αα12, was reported for the first time in the Chinese population. Additionally, the sequencing process concurrently enabled the detection of point variants, achieving a comprehensive "one-stop" assessment. This study demonstrates that SMRT sequencing technology, leveraging its advantages of long reads, single-molecule resolution, and haplotype phasing, can significantly improve the diagnostic accuracy for complex α-thalassemia genotypes. It effectively corrects misdiagnoses and omissions associated with conventional methods, thereby providing a reliable basis for precise genetic counseling and risk assessment.
Posterior fossa anomalies (PFAs) encompass a spectrum of central nervous system malformations affecting the cerebellum, brainstem, and surrounding cerebrospinal fluid spaces. This study evaluates the prenatal diagnosis, genetic findings, and pregnancy outcomes of PFAs in a tertiary care setting in India. A retrospective analysis was conducted on 35 cases of PFAs diagnosed via prenatal ultrasound and fetal MRI between January 2023 and May 2024. Anomalies were classified based on standard criteria, and genetic testing (karyotypte, chromosomal microarray analysis and whole exome sequencing) was offered. Pregnancy outcomes, including termination, live birth, and neonatal survival, were documented, with short-term neurodevelopmental follow-up conducted via telephonic inquiries. The most common PFAs identified were Vermian Agenesis/Hypoplasia (VA/VH) and Cerebellar Hypoplasia (CH), each accounting for 25.71% of cases, followed by Dandy-Walker Malformation (20%). Isolated PFAs were observed in 37.14% of cases, while 62.85% had additional anomalies. Genetic testing was performed in 74.2% of cases, revealing variants in 5.71%. Karyotyping was performed in all tested cases and yielded normal results, while additional molecular testing with chromosomal microarray analysis (5 cases) and whole-exome sequencing (3 cases) detected clinically relevant variants in selected fetuses with posterior fossa anomalies. Among the 35 pregnancies, 65.71% opted for termination, facilitated by the Medical Termination of Pregnancy (MTP) Act, particularly for cases diagnosed beyond 24 weeks of gestation. Of the 9 live births, 2 neonates with vermian hypoplasia (5.71%) died within one month, while 6 (17.14%) had normal developmental milestones at 6 months including 6 babies with mega cisterna magna and one with an arachnoid cyst. One infant exhibited delayed milestones. PFAs present with diverse prognostic implications, necessitating detailed imaging, genetic evaluation, and individualized counseling. The MTP Amendment Act, played a crucial role in providing extended access to termination in pregnancies with severe PFAs and poor prognoses.
Prenatal cannabis use is associated with adverse pregnancy and neonatal outcomes, but research on its association with child anxiety and depressive disorders is limited. This study aimed to test the hypothesis that prenatal cannabis use is associated with child anxiety or depressive disorder diagnoses. Population-based retrospective birth cohort study of children (N = 115,553) born between 1/1/2011-12/31-2017 to pregnant individuals (N = 97,376) universally screened for prenatal cannabis use. Cox proportional hazards regression models examined associations between cannabis use during early pregnancy (at ∼8-10 weeks gestation based on self-reported use or a positive urine toxicology test for delta-9-tetrahydrocannabinol [THC]) and child anxiety and depressive disorders from ages 6 to 13 years based on diagnosis codes, adjusting for maternal sociodemographic and clinical characteristics. The median age at pregnancy onset was 31 (inter quartile range [IQR] = 6) years. Most pregnancies (61.4%) were to non-White individuals; 4.4% screened positive for any cannabis use; 3.7% had a positive toxicology test and 1.9% self-reported use. Overall, 9,230 children were diagnosed with an anxiety disorder at median age of 8 (IQR = 3) years and 1,224 with depressive disorder at median age of 9 (IQR = 3) years. Prenatal cannabis use was associated with a lower risk of child anxiety disorders (aHR:0.84, 95%CI: 0.75-0.95), which remained significant when defined by a toxicology test but not by self-report. Maternal prenatal cannabis use was not associated with child depressive disorders (aHR:1.15, 95%CI: 0.85-1.54). Prenatal cannabis use during early pregnancy was not associated with an increased risk of offspring early onset anxiety or depressive disorders.