Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish.

Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.

Patent Ductus Arteriosus and Lung Magnetic Resonance Imaging Phenotype in Moderate and Severe Bronchopulmonary Dysplasia-Pulmonary Hypertension.

Rationale: Hemodynamically significant patent ductus arteriosus (hsPDA) in premature infants has been associated with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). However, these associations remain incompletely understood. Objectives: To assess the associations between hsPDA duration and clinical outcomes, PH, and phenotypic differences on lung magnetic resonance imaging (MRI). Methods: In this retrospective cohort study, we identified all infants with BPD at <32 weeks' gestation who also underwent research lung MRI at <48 weeks' postmenstrual age (PMA) from 2014 to 2022. Clinical echocardiograms were reviewed for hsPDA and categorized as no hsPDA, hsPDA 1-60 days, and hsPDA >60 days. Outcome variables included BPD severity, PH at 36 weeks' PMA, PH after 36 weeks' PMA in the absence of shunt (PH-pulmonary vascular disease [PVD]), tracheostomy or death, and lung phenotype by MRI via modified Ochiai score, indexed total lung volume, and whole-lung hyperdensity. Logistic regression and ANOVA were used. Measurements and Main Results: In total, 133 infants born at 26.2 ± 1.9 weeks, weighing 776 ± 276 g, were reviewed (47 with no hsPDA, 44 with hsPDA 1-60 days, and 42 with hsPDA >60 d). hsPDA duration > 60 days was associated with BPD severity (P < 0.01), PH at 36 weeks' PMA (adjusted odds ratio [aOR], 9.7 [95% confidence interval (CI), 3.3-28.4]), PH-PVD (aOR, 6.5 [95% CI, 2.3-18.3]), and tracheostomy or death (aOR, 3.0 [95% CI, 1.0-8.8]). Duration of hsPDA > 60 days was associated with higher Ochiai score (P = 0.03) and indexed total lung volume (P = 0.01) but not whole-lung hyperdensity (P = 0.91). Conclusions: In infants with moderate or severe BPD, prolonged exposure to hsPDA is associated with BPD severity, PH-PVD, and increased parenchymal lung disease by MRI.

Early hybrid cardiac rehabilitation in congenital heart disease: the QUALIREHAB trial.

BACKGROUND AND AIMS: Cardiopulmonary fitness in congenital heart disease (CHD) decreases faster than in the general population resulting in impaired health-related quality of life (HRQoL). As the standard of care seems insufficient to encourage and maintain fitness, an early hybrid cardiac rehabilitation programme could improve HRQoL in CHD. METHODS: The QUALIREHAB multicentre, randomized, controlled trial evaluated and implemented a 12-week centre- and home-based hybrid cardiac rehabilitation programme, including multidisciplinary care and physical activity sessions. Adolescent and young adult CHD patients with impaired cardiopulmonary fitness were randomly assigned to either the intervention (i.e. cardiac rehabilitation) or the standard of care. The primary outcome was the change in HRQoL from baseline to 12-month follow-up in an intention-to-treat analysis. The secondary outcomes were the change in cardiovascular parameters, cardiopulmonary fitness, and mental health. RESULTS: The expected number of 142 patients was enroled in the study (mean age 17.4 ± 3.4 years, 52% female). Patients assigned to the intervention had a significant positive change in HRQoL total score [mean difference 3.8; 95% confidence interval (CI) 0.2; 7.3; P = .038; effect size 0.34], body mass index [mean difference -0.7 kg/m2 (95% CI -1.3; -0.1); P = .022; effect size 0.41], level of physical activity [mean difference 2.5 (95% CI 0.1; 5); P = .044; effect size 0.39], and disease knowledge [mean difference 2.7 (95% CI 0.8; 4.6); P = .007; effect size 0.51]. The per-protocol analysis confirmed these results with a higher magnitude of differences. Acceptability, safety, and short-time effect of the intervention were good to excellent. CONCLUSIONS: This early hybrid cardiac rehabilitation programme improved HRQoL, body mass index, physical activity, and disease knowledge, in youth with CHD, opening up the possibility for the QUALIREHAB programme to be rolled out to the adult population of CHD and non-congenital cardiac disease.

From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease.

NKAP mutations are associated with Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of NKAP mutation-associated disorder for the first time, alongside revealing the relationship between NKAP mutations and congenital heart defect (CHD) in the Chinese population. An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1. Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3. Summarily, our study strengthens NKAP mutations as a cause of CHD and prompts the reclassification of NKAP p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Expanding the phenotypes of ABL1 deficiency syndromes: When mutations in different isoforms Lead to different diseases.

All reported ABL1 gain of function and loss of function (LOF) variants, impact both isoforms 1a and 1b. Our findings suggest that LOF variants affecting solely ABL1 isoform 1b may lead to a distinct autosomal recessive new phenotype.

Infertility treatments and cyanotic congenital heart defects among livebirths in the USA: findings from a contemporary cohort.

STUDY QUESTION: Is there an elevated risk of cyanotic congenital heart defects (CCHD) among livebirths following infertility treatments? SUMMARY ANSWER: In this population-based study of single livebirths, infertility treatment (either ART or non-ART) was associated with a higher prevalence of CCHD among livebirths. WHAT IS KNOWN ALREADY: The use of infertility treatment has been on the rise over the past few decades. However, there are limited studies assessing the risk of major cardiac defects following infertility treatments. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of livebirth data from the National Vital Statistics System (NVSS) was conducted, comprising of 9.6 million singleton livebirths among first-time mothers aged 15-49 years from 2016 to 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information on infertility treatment use and CCHD was obtained from the health and medical information section of birth certificates, which was completed by healthcare staff after reviewing medical records. Logistic regression models were used to estimate odds ratios (OR) and 95% CI. Entropy balancing weighting analysis and probabilistic bias analysis were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of births following infertility treatment increased from 1.9% (27 116) to 3.1% (43 510) during the study period. Overall, there were 5287 cases of CCHD resulting in a prevalence of 0.6 per 1000 livebirths. The prevalence was 1.2 per 1000 live births among infertility treatment users (ART: 1.1 per 1000 livebirths; non-ART: 1.3 per 1000 livebirths) while that for naturally conceived births was 0.5 per 1000 livebirths. Compared to naturally conceived births, the use of any infertility treatment (OR: 2.06, 95% CI: 1.82-2.33), either ART (OR: 2.02, 95% CI: 1.73-2.36) or other infertility treatments (OR: 2.12, 95% CI: 1.74-2.33), was associated with higher odds of CCHD after adjusting for maternal and paternal age, race and ethnicity, and education, as well as maternal nativity, marital status, source of payment, smoking status, and pre-pregnancy measures of BMI, hypertension and diabetes. This association did not differ by the type of infertility treatment (ART versus other infertility treatments) (OR: 1.04, 95% CI: 0.82-1.33, P = 0.712), and was robust to the presence of exposure and outcome misclassification bias and residual confounding. LIMITATIONS, REASONS FOR CAUTION: The findings are only limited to livebirths. We did not have the capacity to examine termination data, but differential termination by mode of conception has not been supported by previous studies designed to consider it. Infertility treatment use was self-reported, leading to the potential for selection bias and misclassification for infertility treatment and CCHD. However, the association persisted when systematic bias as well as exposure and outcome misclassification bias were accounted for in the analyses. Information on the underlying etiology of infertility relating to either maternal, paternal, or both factors, data on specific types of ART and other infertility treatments, as well as information on subtypes of CCHD, were all not available. WIDER IMPLICATIONS OF THE FINDINGS: In light of the increasing trend in the use of infertility treatment in the USA, and elsewhere, the finding of the current study holds significant importance for the clinical and public health of reproductive-aged individuals. The data show that the use of infertility treatment may expose offspring to elevated odds of severe congenital heart defects such as CCHD studied here. These findings cannot be interpreted causally. While our findings can assist in preconception counseling and prenatal care for pregnancies conceived by either ART or other infertility treatments, they also support some current recommendations that pregnancies resulting from infertility treatments undergo fetal echocardiography screening. STUDY FUNDING/COMPETING INTEREST(S): No funding was sought for the study. The authors declare that they have no conflict of interest. TRIAL REGISTRAION NUMBER: N/A.

Epigenomic signature of major congenital heart defects in newborns with Down syndrome.

BACKGROUND: Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. METHODS: We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples. RESULTS: We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples. CONCLUSIONS: A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.

Patent ductus arteriosus (PDA) and coarctation of the aorta (CoA) are relatively common congenital heart defects. Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA. We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.

SF3B2 Haploinsufficiency Associated With Hirschprung Disease and Complex Cardiac Defect Without Craniofacial Microsomia.

Haploinsufficiency of SF3B2 is associated with craniofacial microsomia, characterized by mandibular hypoplasia and microtia, often with preauricular tags or pits, epibulbar dermoids, and cleft palate. In addition, extracraniofacial anomalies may be present, such as skeletal, cardiac renal, and abnormalities of the central nervous system. Variants have been either de novo or inherited, and both inter- and intrafamilial variability has been observed. Here we describe a patient referred for exome sequencing for a complex congenital heart defect and Hirschsprung disease found by exome sequencing to be heterozygous for a loss of function variant, c.945dup (p.Val316SerfsTer5), in SF3B2. This variant was inherited from a parent with an isolated cardiac defect. Interestingly, neither have the defining craniofacial features or other dysmorphisms. This report further illustrates the degree of phenotypic variability seen in SF3B2-related disease and expands the spectrum to include Hirschsprung disease.

The impact of congenital heart disease on treatment and survival of patients with hepatoblastoma: A single-center experience.

BACKGROUND: Patients with hepatoblastoma (HB) have a higher risk of congenital heart defects (CHD). There is limited literature on the management and outcomes of these patients. The purpose of this study was to identify demographics and outcomes of these patients in a single tertiary referral center. METHODS: An Institutional Review Board (IRB)-approved retrospective chart review of patients with newly diagnosed HB from October 2004 to January 2021 was performed. CHD was defined as the presence of a septal defect, patent ductus arteriosus, pulmonary atresia, or bicuspid aortic valve. Chi-square and t-test were utilized for statistical analyses. RESULTS: Of the 151 patients diagnosed with HB during the study timeframe, 29 patients were found to have CHD. Five-year overall survival (OS) for non-CHD HB patients was 81.9% compared to 68.9% in the CHD cohort (p = .12). The 5-year OS for patients without surgically intervened CHD was 63.6% compared to 70.5% for those with surgically repaired CHD (p = .88). Pre-treatment extent of tumor IV was present more often in patients with HB and CHD who passed away (6/9, 66.7%) compared to those who survived (3/16,18.8%, p = .01). CONCLUSIONS: Patients with HB and CHD have similar survival compared to those without CHD. Our data support that patients with HB and CHD should be treated with curative intent including cardiac surgical intervention, medical oncology therapy, and oncological surgery for their HB.

Postnatal outcome following fetal aortic valvuloplasty for critical aortic stenosis.

OBJECTIVE: To report our experience of fetal aortic valvuloplasty (FAV) for critical aortic stenosis (AS), with a focus on the postnatal evolution of the patients. METHODS: This was a retrospective study including all fetuses with critical AS which underwent FAV in a single center between January 2011 and June 2022. FAV was performed under ultrasound guidance. Technical success was based upon balloon inflation across the aortic valve and improvement of the antegrade aortic flow across the aortic valve. At birth, a biventricular circulation (BVC) strategy was decided assuming the left ventricular (LV) systolic and diastolic function would ensure the systemic circulation. RESULTS: Sixty-three FAV procedures were performed in 58 fetuses, at a median (range) gestational age of 26.2 (20.3-32.2) weeks. The procedure was technically successful in 50/58 (86.2%) fetuses. There were 11/58 (19.0%) cases of in-utero demise and 9/58 (15.5%) terminations of pregnancy. No patient was liveborn after an unsuccessful procedure. Thirty-eight (65.5%) infants were liveborn, at a median (range) gestational age of 38.1 (29.0-40.6) weeks, of whom 21 (55.3%) required prostaglandin treatment. Twenty-eight of the 38 (73.7%) liveborn children (48.3% of the study population) entered the BVC pathway at birth. Among them, 20 (71.4%) required an aortic valvuloplasty procedure at birth (11 (55.0%) percutaneous balloon, nine (45.0%) surgical) and eight (28.6%) did not require any treatment at birth, but, of these, five (62.5%) underwent surgical valvuloplasty between day 26 and day 1200 of age. Eleven (39.3%) of the infants with BVC at birth required a second intervention and four (14.3%) of them required a third intervention. Two (7.1%) infants who entered the BVC pathway at birth underwent conversion to univentricular circulation (UVC). None of the surviving children with BVC developed pulmonary hypertension. The overall survival rate in those with BVC at birth was 22/28 (78.6%) at a median (range) follow-up of 23.3 (2.0-112.6) months. Ten of the 58 (17.2%) patients had UVC at birth. Among these, six (60.0%) received compassionate care from birth and four (40.0%) underwent surgery. Three of the 10 patients who had UVC at birth were still alive at the latest follow-up assessment, at a median (range) gestational age of 24.3 (8.3-48.7) months. CONCLUSIONS: FAV for critical AS led to increase of antegrade aortic flow in 86.2% of fetuses, with BVC being achieved in 48.3% (73.7% of the liveborn cases). Among patients with BVC at birth, the rate of reintervention was high, but 78.6% of these children were alive at the latest evaluation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Maternal prepregnancy weight as an independent risk factor for congenital heart defect: systematic review and meta-analysis stratified by subtype and severity of defect.

OBJECTIVE: To assess the association between increased maternal prepregnancy body mass index (BMI) and the risk of congenital heart defect (CHD) in offspring. METHODS: This systematic review and meta-analysis searched PubMed/MEDLINE, Web of Science and Scopus from inception to 20 April 2023. Risk estimates were abstracted or calculated for increased BMI categories (overweight, obesity, moderate obesity and severe obesity) compared with normal weight (reference). Fixed-effects or random-effects models were used to combine individual study risk estimates based on the degree of heterogeneity. Sensitivity analyses were conducted to weight pooled estimates for relevant moderators, particularly diabetes before and during pregnancy. Subgroup analyses for specific CHD subtypes were conducted if there were at least two studies with available data. Findings were presented for groups of defects, categorized using severity and topographic-functional criteria, and for individual defects. The certainty of the evidence for each effect estimate was evaluated according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: Overall, 31 studies comprising 4 861 693 patients and 86 136 CHD cases were included. The risk of CHD increased progressively from moderate to severe obesity (pooled odds ratio (OR), 1.15 (95% CI, 1.11-1.20) and 1.39 (95% CI, 1.27-1.53), respectively). Sensitivity analysis indicated that this effect persisted independently of maternal diabetes status before or during pregnancy. In the subgroup analysis, obesity was associated with up to a 1.5-fold increase in the risk of severe CHD (pooled OR, 1.48 (95% CI, 1.03-2.13)). Severe obesity was associated with an even higher risk, with 1.8-times higher odds compared with the reference group for specific CHD subtypes, including tetralogy of Fallot (pooled OR, 1.72 (95% CI, 1.38-2.16)), pulmonary valve stenosis (pooled OR, 1.79 (95% CI, 1.39-2.30)) and atrial septal defect (pooled OR, 1.71 (95% CI, 1.48-1.97)). CONCLUSIONS: Maternal weight is a crucial modifiable risk factor for CHD, particularly for severe forms of defect. Further research is needed to investigate whether weight management before pregnancy might serve as a preventive measure against CHD. In pregnant women with obesity, fetal echocardiography should be a routine diagnostic procedure. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Angiogenic imbalance in maternal and cord blood is associated with neonatal birth weight and head circumference in pregnancies with major fetal congenital heart defect.

OBJECTIVES: To ascertain whether abnormalities in neonatal head circumference and/or body weight are associated with levels of angiogenic/antiangiogenic factors in the maternal and cord blood of pregnancies with a congenital heart defect (CHD) and to assess whether the specific type of CHD influences this association. METHODS: This was a multicenter case-control study of women carrying a fetus with major CHD. Recruitment was carried out between June 2010 and July 2018 at four tertiary care hospitals in Spain. Maternal venous blood was drawn at study inclusion and at delivery. Cord blood samples were obtained at birth when possible. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in maternal and cord blood. Biomarker concentrations in the maternal blood were expressed as multiples of the median (MoM). RESULTS: PlGF, sFlt-1 and sEng levels were measured in the maternal blood in 237 cases with CHD and 260 healthy controls, and in the cord blood in 150 cases and 56 controls. Compared with controls, median PlGF MoM in maternal blood was significantly lower in the CHD group (0.959 vs 1.022; P < 0.0001), while median sFlt-1/PlGF ratio MoM was significantly higher (1.032 vs 0.974; P = 0.0085) and no difference was observed in sEng MoM (0.981 vs 1.011; P = 0.4673). Levels of sFlt-1 and sEng were significantly higher in cord blood obtained from fetuses with CHD compared to controls (mean ± standard error of the mean, 447 ± 51 vs 264 ± 20 pg/mL; P = 0.0470 and 8.30 ± 0.92 vs 5.69 ± 0.34 ng/mL; P = 0.0430, respectively). Concentrations of sFlt-1 and the sFlt-1/PlGF ratio in the maternal blood at study inclusion were associated negatively with birth weight and head circumference in the CHD group. The type of CHD anomaly (valvular, conotruncal or left ventricular outflow tract obstruction) did not appear to alter these findings. CONCLUSIONS: Pregnancies with fetal CHD have an antiangiogenic profile in maternal and cord blood. This imbalance is adversely associated with neonatal head circumference and birth weight. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Automated analysis of heart sound signals in screening for structural heart disease in children.

Our aim was to investigate the ability of an artificial intelligence (AI)-based algorithm to differentiate innocent murmurs from pathologic ones. An AI-based algorithm was developed using heart sound recordings collected from 1413 patients at the five university hospitals in Finland. The corresponding heart condition was verified using echocardiography. In the second phase of the study, patients referred to Helsinki New Children's Hospital due to a heart murmur were prospectively assessed with the algorithm, and then the results were compared with echocardiography findings. Ninety-eight children were included in this prospective study. The algorithm classified 72 (73%) of the heart sounds as normal and 26 (27%) as abnormal. Echocardiography was normal in 63 (64%) children and abnormal in 35 (36%). The algorithm recognized abnormal heart sounds in 24 of 35 children with abnormal echocardiography and normal heart sounds with normal echocardiography in 61 of 63 children. When the murmur was audible, the sensitivity and specificity of the algorithm were 83% (24/29) (confidence interval (CI) 64-94%) and 97% (59/61) (CI 89-100%), respectively. CONCLUSION: The algorithm was able to distinguish murmurs associated with structural cardiac anomalies from innocent murmurs with good sensitivity and specificity. The algorithm was unable to identify heart defects that did not cause a murmur. Further research is needed on the use of the algorithm in screening for heart murmurs in primary health care. WHAT IS KNOWN: • Innocent murmurs are common in children, while the incidence of moderate or severe congenital heart defects is low. Auscultation plays a significant role in assessing the need for further examinations of the murmur. The ability to differentiate innocent murmurs from those related to congenital heart defects requires clinical experience on the part of general practitioners. No AI-based auscultation algorithms have been systematically implemented in primary health care. WHAT IS NEW: • We developed an AI-based algorithm using a large dataset of sound samples validated by echocardiography. The algorithm performed well in recognizing pathological and innocent murmurs in children from different age groups.

Neurodevelopmental outcomes of preterm and growth-restricted neonate with congenital heart defect: a systematic review and meta-analysis.

The purpose of the study is to assess the risks of neurodevelopmental morbidity among preterm and growth restricted youth with congenital heart defects (CHD). This systematic review and meta-analysis included observational studies assessing neurodevelopmental outcomes among children with CHD born preterm (i.e., before 37 weeks of gestation) or growth restricted (small-for-gestational age (SGA) with a birthweight < the 10th percentile or with low birthweight (LBW) < 2500 g). Studies were identified in Medline and Embase databases from inception until May 2022, with data extracted by two blinded reviewers. Risk of bias was assessed using the Critical Appraisal Skills Programme cohort checklist. Meta-analysis involved the use of random-effects models. Main outcome measures were neurodevelopmental outcomes including overall cognitive impairment and intellectual disability, IQ, communication, and motor skills scores. From 3573 reports, we included 19 studies in qualitative synthesis and 6 meta-analysis studies. Risk of bias was low in 8/19 studies. Cognitive impairment and intellectual disability were found in 26% (95% CI 20-32, I2 = 0%) and 19% (95% CI 7-35, I2 = 82%) of preterm children with CHD, respectively. Two studies documented a lower IQ score for SGA children who underwent CHD operations in comparison to non-SGA children who also underwent CHD operations. Two studies have reported lower IQ, communication, and motor skills in children with hypoplastic left heart syndrome (HLHS) and low birth weight compared to those with HLHS and expected birth weight. CONCLUSIONS: Based on a low level of evidence, prematurity and/or growth retardation appear to accentuate specific neurodevelopmental outcomes in certain CHD subgroups. Further evidence is needed to confirm these findings. TRIAL REGISTRATION: PROSPERO [CRD42020201414]. WHAT IS KNOWN: • Children born with CHD, preterm birth, or growth restriction at birth are independently at higher risk for neurodevelopmental impairment. • The additional effect of preterm birth and/or growth restriction on neurodevelopmental outcomes in children with CHD remains unclear. WHAT IS NEW: • Prematurity and/or growth retardation appear to accentuate specific neurodevelopmental outcomes in certain CHD subgroups. • Children with CHD, particularly those born preterm or with growth restriction, should undergo lifelong systematic comprehensive neurodevelopmental assessment.

Clinical characteristics of congenital heart defects in mild congenital anorectal malformation: single-centre experience.

OBJECTIVE: To analyze the clinical characteristics and types of congenital heart defect (CHD) in mild congenital anorectal malformation (CARM), namely the rectoperineal and rectovestibular fistulas. METHODS: The retrospective study of 183 patients with mild CARM was conducted with assessments of demographic information, color Doppler echocardiography results, and follow-up data. We performed an analysis of the clinical characteristics of CHD, grouping them based on sex and type of mild CARM. RESULTS: Of the 183 patients, rectoperineal fistula occurred in 133 patients (72.7%), while the frequency of CHD was 79.8% (146/183). Ventricular septal defects (VSDs) occur more frequently in patients with rectoperineal fistula compared to those with rectovestibular fistula (1.5% vs. 10%), while the opposite trend was observed for patent ductus arteriosus (PDAs) (39.8% vs. 22.0%). Additionally, males presented higher frequency of PDA (42.7% vs. 26.4%) and self-healing (6 months: 87.2% vs. 42.6%; 12 months: 91.0% vs. 63.2%) than females. However, males had a lower rate of undergoing cardiac surgery (6.4% vs. 17.6%) and a younger median diagnosis age (1 day vs. 9 days). CONCLUSION: Our study indicates that there is a necessity for meticulous cardiac assessment and follow-up in neonates diagnosed with mild CARM.

Major congenital heart defects are rarely diagnosed after newborns' hospital discharge with modern screening.

AIM: Our aim was to assess undiagnosed congenital heart defects (CHD) after newborns' hospital discharge in patients with a murmur or CHD suspicion, to find out the signs that predict CHDs and to estimate the costs of the examinations. METHODS: We reviewed retrospective medical records of patients (n = 490) referred for the evaluation of CHD suspicion during 2017-2018. RESULTS: The median age of the patients was 2.5 (IQR 0.5-7.4) years. Sixty-three (13%) patients had an abnormal echocardiography. Neither ductal-dependent nor cyanotic CHDs were found. Cardiac interventions were performed for 14 out of 63 (22%) patients. Clinical signs indicating CHDs were murmur grade ≥3 (10/11 [91%] vs. 53/479 [11%], p < 0.001) and harsh murmur (15/44 [34%] vs. 48/446 [11%], p < 0.001). Abnormal electrocardiography did not indicate CHD (8/40 [20%] vs. 55/447 [12%], p = 0.165). The total cost of the examinations was 259 700€. The share of the cost of studies assessed as benign was 59%. CONCLUSION: Only a few CHDs were found after newborn hospital discharge among patients who received foetal and newborn screening and were examined due to CHD suspicion. The high number of benign murmurs in children leads to many referrals, resulting in unnecessary healthcare costs.