Congenital heart disease (CHD) is a leading cause of neonatal morbidity and mortality, whose underlying pathogenesis remains largely unclear, and lacks reliable biomarkers or therapeutic targets for early detection and treatment during pregnancy. In this study, we investigated the role of endogenous peptide ELABELA (ELA) in fetal CHD. Our findings reveal that ELA levels are significantly reduced in human fetal cardiac tissues with CHD. In mouse models, ELA deletion in cardiac progenitor cells disrupted mitochondrial function, directly contributing to cardiac malformations. Mechanistically, ELA deficiency caused mitochondrial swelling by inhibiting the APJ-AKT-BCL2/BAX signaling pathway. Notably, exogenous ELA administration reduced both CHD severity and incidence in mice. Furthermore, plasma ELA levels were markedly down-regulated in human pregnancies with fetal CHD. These findings establish ELA as a crucial regulator of cardiac development and highlight its potential as both a biomarker and therapeutic target for the prevention and management of fetal CHD during gestation.

This study aims to evaluate the effect of maternal antiseizure medication (ASM) exposure on fetal malformations, accounting for specific periods of medication use during pregnancy and differentiating between monotherapy and dual therapy. Using data from the Korean National Health Insurance Service between 2010 and 2020, we conducted a population-based retrospective cohort study of pregnant women with epilepsy who were administered ASMs during pregnancy and those who were not, to assess the associated risk of congenital malformations. Participants were divided into four subgroups based on ASM exposure: Subgroup 1, first trimester (T1) exposure (first 12 weeks); Subgroup 2, exposure limited to the first 140 days; Subgroup 3, exposure only after day 141; Subgroup 4, continuous exposure. Each subgroup was analyzed separately to compare the effects of monotherapy and dual therapy. The primary outcome was the relative risk (RR) of congenital malformations associated with ASM monotherapy and dual therapy. Between 2012 and 2020, 1 916 583 women gave birth. Among these, 8939 (.47%) were diagnosed with epilepsy and required continuous ASM therapy for part or all of the observation period, whereas 4968 women with epilepsy had no ASM exposure during pregnancy and served as the unexposed comparator group. Subgroup 2 showed lower adjusted RR of congenital malformations with monotherapy and dual therapy. In dual therapy, lamotrigine was linked to an increased risk of overall malformations in Subgroups 1 (adjusted RR = 1.81, 95% confidence interval [CI] = 1.22-2.70, p = .0033) and 4 (adjusted RR = 1.81, 95% CI = 1.21-2.70, p = .0039). Valproate dual therapy in Subgroup 4 showed higher risk of overall malformations (adjusted RR = 3.40, 95% CI = 1.36-8.48, p = .0086) and cardiac malformations (adjusted RR = 5.50, 95% CI = 1.29-23.51, p = .0214). Prolonged ASM exposure throughout pregnancy was associated with a significantly increased risk of malformations compared with exposure limited to T1 or to the first half of pregnancy.

ERα-mediated endoplasmic reticulum stress drives 4-tert-octylphenol-induced cardiac developmental toxicity in zebrafish.

Exome sequencing (ES) and gene panels can be considered for fetal anomalies. Whether ES offers substantial benefit over targeted panels is not clear. Secondary analysis of a prospective cohort study of pregnancies with fetal anomalies undergoing ES. We included cases with isolated or multisystem skeletal dysplasias, CNS anomalies, and/or cardiac anomalies. Participants underwent ES, and pathogenic (P) and likely pathogenic (LP) variants were reported. The primary outcome was the percentage of P/LP variants found on ES that would have been identified on panels available prenatally in the United States. 109 cases with relevant anomalies were included in the primary analysis. Of these, 20 (18%) had P/LP variant(s) identified on ES-4 multisystem, 4 isolated CNS, 6 isolated cardiac, and 6 isolated skeletal dysplasia. Gene panels would have detected 50 (88%) of the variants identified by ES. Yield was highest for isolated skeletal anomalies (100%) compared to CNS and cardiac malformations (75% and 67%, p=0.02). Yield was higher for isolated anomalies than multisystem anomalies (median 91.5% vs. 50%, p<0.01). In cases of fetal anomalies with genetic etiologies identified on ES, commercial gene panels had variable diagnostic yields. Panels performed worst for multisystem anomalies.

Recurrent idiopathic severe fetal structural anomalies present major challenges for reproductive decision-making and genetic counselling. A non-consanguineous healthy Estonian couple had experienced two electively terminated pregnancies at 12-13 weeks' gestation due to unexplained major fetal malformations and one early miscarriage. Their three pregnancies had resulted in unaffected newborns. Exome sequencing of fetal tissues from both terminated pregnancies identified a homozygous rare missense variant in MGRN1 (mahogunin ring finger 1), c.881G>A, p.(Arg294His) (Genome Aggregation Database V.4.1.0 allele frequency<8×10⁻⁵; no homozygotes reported in any population database). MGRN1 functions as an E3 ubiquitin ligase critical for protein homeostasis and developmental signalling. The detected substitution compromises a conserved residue within the RING (Really Interesting New Gene) finger domain. Cascade testing revealed that the parents and one unaffected child were heterozygous carriers, while two healthy siblings were homozygous for the reference allele. Both affected fetuses displayed congenital malformations closely mirroring prenatal phenotypes reported in Mgrn1 homozygous mutant mice, including cardiac malformations (ventricular septal defect, outflow tract malposition, pulmonary artery hypoplasia) and abnormal left-right axis patterning. These findings provide the first evidence implicating MGRN1 in human congenital disease and support its role in early embryonic patterning.

NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations.

O-phenylphenol induces cardiac injury by regulating cardiac progenitor cells in zebrafish (Danio rerio).

Abstract Pregnancy is a period of heightened vulnerability to toxic exposures, with each trimester representing distinct developmental stages. In Nigeria and across sub-Saharan Africa, pregnant women are commonly exposed to various pharmaceuticals such as antidepressants, antibiotics, contraceptives, antiemetics, vitamins, and antidiabetics, as well as chemicals including alcohol, pesticides, and industrial pollutants like lead and mercury. This narrative review summarizes trimester-specific outcomes and mechanisms of toxicity based on published studies from Nigeria and Africa. Evidence shows that many pregnant women self-medicate or inadvertently consume hazardous substances. About 22.6% of Nigerian women report alcohol use during pregnancy, and nearly 30% self-medicate with drugs such as paracetamol, antimalarials, and antibiotics. First-trimester exposures, when organogenesis occurs, are most strongly linked to structural anomalies like neural tube and cardiac defects, whereas later exposures impair fetal growth and neurodevelopment. Prenatal selective serotonin reuptake inhibitors (particularly paroxetine and fluoxetine) are associated with cardiac and cranial malformations, while antibiotics such as tetracyclines and fluoroquinolones may cause skeletal or cartilage toxicity. Alcohol is a potent teratogen causing fetal alcohol spectrum disorders at any stage. Pesticide exposure in early pregnancy is linked to neural and limb malformations, and lead exposure contributes to miscarriage, preterm birth, low birth weight, and neurodevelopmental deficits. Regional statistics and study data are summarized in tables, with case reports highlighting Nigerian infants affected by fetal alcohol syndrome and lead poisoning. The findings emphasize an urgent need for improved education, regulation, and prenatal screening to reduce these risks in Africa.

Respiratory infections are a leading cause of pediatric hospitalization and impose a significant burden on health care systems. To evaluate clinical outcomes and risk factors for severe disease in hospitalized children with viral respiratory infections, focusing on the role of etiologies, comorbidities, age, and coinfections. This multicenter observational cohort study is part of an active pediatric surveillance system established in September 2023, within the framework of the European Union-funded National Recovery and Resilience Plan. The One Health Basic and Translational Actions Addressing Unmet Needs on Emerging Infectious Diseases (INF-ACT) network, which includes 12 pediatric infectious disease referral centers across Italy, is designed to enable early detection of emerging infectious threats in children. The network is based on 3 pillars: monthly online meetings, a register of cases of unusual severity or induced by unusual pathogens, and a sample repository to investigate microbiology or host-related risk factors. Hospitalized children with respiratory symptoms and confirmed or suspected viral infection between September 2023 and December 2024 were eligible. Type of respiratory virus, viral or bacterial coinfections, and presence of chronic comorbidities. Severity was assessed using a clinical severity score (CSS), with a score greater than 3 indicating severe disease. The CSS considered mechanical ventilator support, hospital admission, length of hospital stay, oxygen saturation level, and use of supplemental oxygen. Length of hospital stay, intensive care unit admission, and the need for oxygen therapy were also considered as individual outcomes. Of 516 children hospitalized with respiratory symptoms (median [IQR] age, 13.3 [4.0-43.0] months; 288 male [55.8%]), 34 (6.6%) had severe disease (CSS >3). In multivariable analysis, among patients with respiratory symptoms, infection with respiratory syncytial virus (10 of 67 [14.9%]; adjusted odds ratio [AOR], 4.26 [95% CI, 1.80-10.10]) or influenza (14 of 104 [13.5%]; AOR, 4.13 [95% CI, 1.88-9.04]) and the presence of cardiac or pulmonary diseases (4 of 18 [22.2%]; AOR, 5.25 [95% CI, 1.47-18.78]) or congenital malformations (3 of 14 [21.4%]; AOR, 4.94 [95% CI, 1.23-19.93]) were associated with increased risk of severe infection. A higher ICU admission rate was observed in children with influenza infection (12 of 104 [11.5%] vs 9 of 412 [2.2%]; P < .001) and preexisting comorbidities (9 of 69 [13.0%] vs 12 of 447 [2.7%]; P < .001). Age and coinfections were not significantly associated with worse outcomes. In this cohort study of hospitalized children, respiratory syncytial virus and influenza infections, as well as the presence of chronic comorbidities, were significantly associated with severe disease. These findings support the need for targeted prevention and vaccination strategies, as well as early identification of children at risk for severe disease. The INF-ACT network offered a scalable model for real-time infectious disease monitoring in pediatric populations.

Aortopulmonary window is an uncommon CHD that often coexists with additional cardiovascular anomalies. Criss-cross heart, defined by rotation of the ventricular mass with crossed atrioventricular inflow streams, is exceedingly rare. The coexistence of aortopulmonary window and criss-cross heart is exceptional and markedly increases diagnostic and therapeutic complexity. We report a full-term neonate with prenatal suspicion of aortopulmonary window. Postnatal echocardiography and CT demonstrated situs solitus, concordant atrioventricular and ventriculoarterial connections, rotational malalignment of the ventricles consistent with criss-cross heart, an inferior sinus venosus atrial septal defect, and a large type III aortopulmonary window. There was marked right-sided dilation and evolving right ventricular dysfunction, although no interrupted aortic arch was identified. At 17 days of life, the patient underwent early surgical repair with reconstruction of the aortic pathway. Despite anatomically successful correction, the immediate postoperative course was complicated by severe ventricular dysfunction and refractory low cardiac output syndrome, requiring venoarterial extracorporeal membrane oxygenation for haemodynamic stabilisation. Extracorporeal membrane oxygenation was discontinued on day nine, and follow-up imaging showed preserved biventricular systolic function and no residual aortopulmonary window. This case illustrates an exceptionally rare association between aortopulmonary window and criss-cross heart, underscoring the value of prenatal detection and detailed postnatal imaging to delineate complex anatomical relationships. Early surgical intervention was mandatory, and the need for extracorporeal membrane oxygenation highlights the high intrinsic risk of this anatomical combination. Reporting such cases expands the limited literature on rare congenital cardiac malformations and may inform future refinements in diagnostic evaluation and perioperative management.

The cardiac conduction system (CCS) develops asymmetrically along the body axes. In heterotaxy syndrome - resulting from aberrant left-right axis formation - atrial and atrioventricular conduction defects can cause life-threatening arrhythmias. However, the developmental mechanisms regulating the atrioventricular conduction system (AVCS) disposition and integrity remain unclear. To investigate the etiology of AVCS malformations in laterality defects, we analyzed CCS development and function in mouse mutants for Cryptic and Lefty1, which are key regulators of Pitx2 in the left-right axis formation. Cryptic-/- embryos exhibited bilateral sinoatrial nodes and an ectopic anterior AV node and bundle accompanied by reduced Pitx2 expression. In contrast, Lefty1-/- embryos showed a hypoplastic sinoatrial node and AV node-bundle dissociation with ectopic Pitx2 expression. Single-cell transcriptomic analysis of Pitx2-/- hearts revealed expansion of AV node and bundle populations, consistent with a repressive role of Pitx2 in AVCS specification. Genetic lineage tracing indicated that Pitx2-expressing cells from the left lateral plate mesoderm populate cranioventral cardiac regions, where AVCS development is suppressed. Together, these findings clarify how global left-right axis information is locally integrated to shape AVCS disposition and integrity, providing a mechanistic model for AVCS abnormalities in laterality-associated congenital heart disease.

Quadricuspid pulmonary valve (QPV) is a rare congenital anomaly with limited reports. This study characterizes QPV morphology and function by multimodal imaging, evaluates predictors of moderate-to-severe pulmonary regurgitation (PR), and assesses mid-term prognosis. Retrospective search of the imaging database at a tertiary medical center identified patients diagnosed with QPV between October 2004 and September 2024. Multimodal imaging was utilized to assess the characteristics of QPV and associated abnormalities. Among 1,367,280 cardiac CT and MR exams, 16 patients were diagnosed with QPV (38% male; mean age 43.4 ± 19.7 years). The most common morphology was type D (38%, one larger, two equal intermediate, and one smaller cusps), with cusp fusion in 25% and Becker's type Ⅲ in 13%. Associated congenital heart disease (CHD) occurred in 6 patients (38%). Moderate-to-severe PR was observed in 11 patients (69%), severe pulmonary valve stenosis (PS) in one, and pulmonary artery aneurysm (PAA) in eight (50%). Both regurgitant orifice area (ROA) and main pulmonary artery (PA) dilation increased the risk of moderate-to-severe PR (OR = 2.33, p = 0.048; OR = 1.57, p = 0.041; each 0.25-unit increase). No significant difference was found between QPV classification and PR severity or clinical outcomes. During a median follow-up of 16 (IQR: 2-66) months, no deaths occurred, and 5 patients (31%) underwent surgery. QPV is a rare congenital cardiac malformation with diverse morphologies, predominantly associated with PR and PAA. Approximately one-third of patients required surgery. Multimodal imaging is essential for diagnosis, functional assessment, and management planning for QPV.

Congenital heart disease (CHD) is the most common birth defect, and its pathogenesis is closely related to the abnormal establishment of the left-right (LR) body axis, which highly depends on the ciliary function of the left-right organizer (LRO). This review systematically expounds the molecular pathways by which ciliary structural and functional abnormalities cause cardiac malformations by integrating multi-species model evidence. We believe that defects in multiple conserved genes (including CFAP45, ZIC3, FOXJ1, NEK3, APLNR, and microRNAs) disrupt ciliary assembly, motility, or signaling capacity, leading to the disappearance of the leftward nodal flow or mechanical sensing failure within the LRO. This further interrupts the left-specific calcium ion flicker and the activation of the Nodal-Pitx2 signaling cascade, ultimately resulting in failed cardiac looping and structural defects (such as ventricular septal defect and transposition of the great arteries). This review integrates transcriptional regulation, protein stability, miRNA-mediated fine regulation, and the planar cell polarity (PCP) pathway into a unified "cilia-LRO-heart" network and explores the molecular mechanisms of cilia in valve diseases and cardiac fibrosis. This not only deepens the understanding of the fundamental biological processes of heart development but also provides new molecular targets and theoretical frameworks for the genetic diagnosis and counseling of related congenital heart diseases.

To understand characteristics associated with additional operative encounters following tracheostomy to inform the timing of gastrostomy tube (GT) placement in neonates. Retrospective cohort study utilizing the Pediatric Health Information System (PHIS) and including neonates who underwent tracheostomy with either concurrent or subsequent GT from 1/2015-12/2022. The primary outcome was the number of subsequent operative encounters following tracheostomy. Bivariate analysis and logistic regression assessed for patient characteristics associated with subsequent operative encounters. Of 2395 neonates, 1693 (71%) underwent concurrent procedures, and 702 (29%) underwent initial tracheostomy alone with subsequent GT (p < 0.001). The median number of operative encounters for the entire cohort following tracheostomy was 3 events (IQR 1-6). Infants with prematurity, cardiac valve malformations, and pulmonary hypertension were more likely to have additional operative encounters. Neonates born prematurely with cardiovascular comorbidities will likely return to the operating room after tracheostomy placement, presenting an opportunity for GT placement.

Background: Pregnancy induces a hyperglycemic state, which frequently results in gestational diabetes. Maternal hyperglycemia impacts the fetus by causing hyperplasia of pancreatic islet cells and fetal hyperinsulinemia. This condition, coupled with increased oxidative stress and irregular development of cardiac neural crest cells, may lead to a range of fetal anomalies. Furthermore, newborns born to diabetic mothers ought to be screened for possible cardiac malformations. Aims and Objective: This study aimed to investigate cardiovascular malformations in the infants of diabetic mothers. Materials and Methods: A total of 50 newborns were enrolled in the study. Following the initial stabilization of the newborns, a routine echocardiographic examination was conducted on all 40 newborns born to mothers with gestational diabetes mellitus (GDM) and 10 newborns born to mothers with pre-GDM (pGDM). Only pGDM mothers who were receiving insulin were included in the study; those on other medications were excluded. Statistical analysis was carried out using the Statistical Package for the Social Sciences version 24, and significance levels were defined as P≤0.05. Results: The distribution of sex among the newborns was nearly equal, with only a few exhibiting cyanosis or congestive heart failure. The most prevalent echocardiographic finding was asymmetric septal hypertrophy, whereas the most common heart defects identified were atrial septal defect and ventricular septal defect. All the babies born to diagnosed pGDM mothers exhibited some sort of positive echocardiographic findings in this study. The risk of developing cardiovascular anomalies is significantly higher in the offspring of mothers with pGDM compared to those with GDM (P=0.002). Conclusion: The significant association between maternal hyperglycemia and cardiovascular anomalies highlights the necessity for echocardiographic evaluation in infants born to diabetic mothers.

Assess prenatal ultrasound's diagnostic value in fetal cardiac anomalies using an abnormal number of pulmonary artery (PA) branches as an initial clue. Retrospective analysis of 20 fetuses with an abnormal number of PA branches on ultrasound, comparing prenatal ultrasonic findings with postnatal echocardiography, computed tomography (CT), surgery, autopsy, and genetic tests. Summarized ultrasonographic characteristics and occurrence frequencies in 3-vessel trachea (3VT), 3-vessel PA branch, and innominate artery (INA) coronary section. In total, abnormal PA branches included: 1 branch (15 cases: 7 pulmonary artery sling [PAS], 4 unilateral absence of pulmonary artery [UAPA], 4 anomalous origin of 1 pulmonary artery from ascending aorta [AOPA]); 3 branches (2 cases: 1 isolated left subclavian artery [ILSA], 1 isolated left innominate artery [ILINA], absent right ductus arteriosus); 4 branches (3 cases: 2 ILSA, 1 ILINA, double ductus arteriosus). Associated anomalies: tetralogy of Fallot, persistent left superior vena cava, ventricular septal defect, Berry syndrome, and nasal bone dysplasia. Postnatal confirmations were achieved via autopsy (9 cases), imaging/surgery (10 cases), or lost (1 case). Genetic tests (14 cases) were normal. Detection: 63.2% (3VT section), 100% (3-vessel PA branch section), 57.9% (INA coronary section). The 3VT, 3-vessel PA branch, and INA coronary section are key for the diagnosis of fetal cardiac malformations with abnormal PA branches. The spatiotemporal image correlation with high-definition (STIC-HD) live flow sonography can aid in visualizing the vascular connection linked to these anomalies. Identifying features of 1/3/4 PA branches facilitates a systematic assessment of fetal cardiac defects primarily characterized by aberrant PA branching.

Antibiotic residues in wastewater treatment plant (WWTP) effluents are a matter of global environmental health concern. This study combined global WWTP monitoring data with epidemiological modeling and zebrafish embryo assays to assess developmental risks. A meta-analysis of 121 studies identified amoxicillin, trimethoprim and norfloxacin as high priority contaminants. Ecological modeling using generalized additive models (GAM) revealed a statistical association between effluent antibiotic levels and neonatal disease incidence. Zebrafish exposed to environmentally relevant concentrations exhibited dose-dependent developmental toxicity, including pericardial edema, oxidative stress, and impaired cardiac function. Molecular analysis indicated dysregulation of the Wnt/β-catenin signaling pathway, with Wnt1 upregulation mediating toxic effects. Functional validation using CRISPR interference targeting wnt1 attenuated cardiac malformations and apoptosis, while docking simulations confirmed strong antibiotic-Wnt1 binding. These findings establish a mechanistic link between environmental antibiotic exposure and developmental toxicity and underscore the potential of Wnt1 as a biomarker for ecological risk assessment. This work supports the need for advanced tertiary treatment strategies and molecular-based monitoring frameworks.

HFPO-TA induces cardiac developmental damage in zebrafish by disrupting mitochondrial dynamics through FABP3.

Introduction: Since the first description of Turner syndrome (TS), both genotypic spectrum and phenotypic presentation have evolved. This study aimed to examine trends in this evolution over the past three decades and provides an overview of current genetic and clinical features in a large nationwide multicenter cohort of girls with TS. Methods: We analyzed data from growth hormone (GH)-treated girls with TS included in BELGROW, the national GH registry of the BELux Society for Pediatric Endocrinology and Diabetology, between 1985 and 2022. Karyotype, age at diagnosis, and phenotype were studied in 716 girls. Two periods were compared: 1991–2002 (group 1, n = 250) and 2003–2017 (group 2, n = 270). Results: The annual number of girls with TS starting GH remained stable (mean n = 19/year). In the entire cohort, monosomy 45,X was the most frequent karyotype (44%), followed by structural anomalies of the X chromosome (27%), 45,X/46,XX mosaicism (13%), triple X mosaicism (4%), 45,X/46,XY or complex Y anomalies (6%), and others (6%). The proportion of 45,X decreased between the two periods (46%–38%, p < 0.05). Overall, median age at diagnosis was 6.4 years with 7.6% of girls diagnosed prenatally, 24% before age 1, 49% in childhood, and 19% after 12 years. Prenatal diagnoses increased from 2.5% (group 1) to 15% (group 2) (p < 0.001). Girls with a 45,X karyotype were diagnosed earlier than girls with other genotypes (median 2.2 vs. 8 years, p < 0.001). Skeletal (73%), neurosensory (60%), and cardiac (29%) systems were most affected. Skeletal and cardiac malformations were more frequent in girls with a 45,X karyotype (p < 0.05 and p < 0.01, respectively). Conclusion: Genotype distribution and timing of TS diagnosis have significantly changed since 1991, while the annual number of girls starting GH therapy has remained stable. A 45,X karyotype is associated with earlier diagnosis and more comorbidities.

Background: Congenital cardiac malformations constitute one of the leading causes of perinatal morbidity and mortality, accounting for nearly one-third of all major structural fetal anomalies. Despite advances in prenatal imaging, particularly fetal echocardiography, accurate delineation of complex cardiac defects often remains challenging. Autopsy studies continue to play a pivotal role in confirming prenatal diagnoses, understanding embryopathogenesis, and identifying associated extracardiac abnormalities. Objectives: To study the spectrum and frequency of congenital cardiac malformations in perinatal deaths, assess their gestational and sex distribution, correlate with mode of death and fetal weight, and identify associated extracardiac anomalies. Materials and Methods: A retrospective descriptive study comprising 20 perinatal autopsy cases with major congenital cardiac malformations was conducted over a one-year period. Each case was analyzed for gestational age, sex, estimated birth weight, associated malformations, and mode of death. Statistical analysis included descriptive measures and correlation between gestational age and fetal weight. Results: The mean gestational age was 21.5 weeks and mean fetal weight was 447 g. Males constituted 65%, females 30%, and 5% had ambiguous genitalia (M: F = 2.1:1). The predominant mode of death was therapeutic termination (60%), followed by spontaneous abortion (30%) and intrauterine death (10%). The most frequent cardiac malformations were Double Outlet Right Ventricle (DORV) and Hypoplastic Left or Right Heart Syndromes, often associated with Congenital Cystic Adenomatoid Malformation (CCAM) or chromosomal syndromes such as Down and Mermaid Syndrome. A strong positive correlation (r = 0.95) was observed between gestational age and fetal weight. Conclusion: Perinatal autopsy remains a cornerstone for confirming and characterizing congenital cardiac malformations. Comprehensive autopsy evaluation enhances the understanding of associated extracardiac defects and aids in accurate genetic counseling, thereby contributing significantly to perinatal care and prevention strategies.