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Purpose: Amniotic fluid stem cell extracellular vesicles (AFSC-EVs) hold regenerative potential to treat hypoplastic lungs secondary to congenital diaphragmatic hernia (CDH). This study aims to investigate sex-specific differences in pulmonary hypoplasia severity and responses to AFSC-EV administration in an experimental CDH mouse model. Methods: C57BL/6J dams were fed with nitrofen + bisdiamine (left-sided CDH) or olive oil only (control) at embryonic day (E) 8.5. Lungs were dissected (E18.5), grown ex vivo and treated with medium ± AFSC-EVs that were collected via ultracentrifugation and characterized (nanoparticle tracking analysis, electron microscopy, Western blotting). Pulmonary hypoplasia was assessed via mean linear intercept (MLI). Gene and protein expression changes (Cd31, Enos, Il1b, TNFa) were measured via RT-qPCR and immunofluorescence. Pups were genotyped for Sry. Results: Experimental CDH showed a male predominance without sex differences for pulmonary hypoplasia severity, fetal lung vascularization, and inflammation. AFSC-EV administration led to improved lung growth (decreased MLI), improved fetal lung vascularization (increased Cd31 and Enos), and decreased fetal lung inflammation (Il1b, TNFa). There was no sex-specific response to AFSC-EV administration. Conclusion: This study shows sex-independent impaired lung growth, vascularization and fetal lung inflammation in a CDH mouse model. Antenatal administration of AFSC-EVs reverses aspects of pulmonary hypoplasia secondary to CDH independent of the biological sex. [ABSTRACT FROM AUTHOR]

Simple Summary: Pulmonary hypoplasia with anasarca, or hydrops fetalis, is a fatal inherited disease reported in several species. Affected fetuses are stillborn and present with the buildup of fluid within body cavities and tissues and under-developed lungs and lymph tissues. The enlarged size of the fetus frequently results in difficult or obstructed labor. This is the first report of the disease in three flocks of Persian/Persian-cross sheep in Australia. We describe the pathology of affected fetuses and conducted genetic research that identified and validated a variant in the ADAMTS3 gene as the likely cause for this recessive disease in these sheep. A diagnostic DNA test was developed which allows selective breeding to reduce the risk of affected animals being born. Pulmonary hypoplasia with anasarca, or hydrops fetalis, is characterized by stillbirth, diffuse oedema, and generalized lymph node hypoplasia. The enlarged fetus frequently causes dystocia. The disease has been reported in cattle and sheep as an inherited condition with a recessive mode of inheritance. This is the first report of the disease in Persian/Persian-cross sheep in Australia. Affected fetuses were reported from three flocks, and a total of eleven affected, eleven obligate carrier, and 188 related Persian/Persian-cross animals were available for analysis, as well as unrelated control animals. SNP genotyping revealed a region of homozygosity in affected animals on ovine chromosome six, which contained the functional candidate gene ADAMTS3. Whole genome sequencing of two affected fetuses and one obligate carrier ewe revealed a single nucleotide deletion, ENSOARG00000013204:g.87124344delC, located 3 bp downstream from a donor splice site region in the ADAMTS3 gene. Sanger sequencing of cDNA containing this variant further revealed that it is likely to introduce an early splice site in exon 14, resulting in a loss of 6 amino acids at the junction of exon 14 and intron 14/15. A genotyping assay was developed, and the ENSOARG00000013204:g.87124344delC segregated with disease in 209 animals, allowing for effective identification of carrier animals. [ABSTRACT FROM AUTHOR]

Introduction: Fetal magnetic resonance imaging (MRI) lung volume nomograms are increasingly used to prognosticate neonatal outcomes in fetuses with suspected pulmonary hypoplasia. However, pregnancies complicated by fetal anomalies associated with pulmonary hypoplasia may also be complicated by fetal growth restriction (FGR). If a small lung volume is suspected in such cases, it is often unclear whether the lungs are "small" because of underlying lung pathology, or small fetal size. Existing MRI lung volume nomograms have mostly been stratified by gestational age (GA), rather than estimated fetal weight (EFW). Therefore, we aimed to develop a novel fetal lung volume nomogram stratified by EFW. Methods: Consecutive fetal MRIs performed at a quaternary medical center from 2019 to 2021 were analyzed. MRIs performed due to fetal lung anomalies and cases with FGR were excluded. All MRIs were performed without IV contrast on GE 3 or 1.5 Tesla scanners (GE Healthcare). Images were reviewed by three experienced fetal radiologists. Freehand ROI in square centimeter was drawn around the contours of the lungs on consecutive slices from the apex to the base. The volume of the right, left and total lungs were calculated in mL. Lung volumes were plotted by both EFW and GA. Results: Among 301 MRI studies performed during the study period, 170 cases met inclusion criteria and were analyzed. MRIs were performed between 19- and 38-week gestation, and a sonographic EFW was obtained within a mean of 2.9 days (SD ± 5.5 days, range 0–14 days) of each MRI. Nomograms stratified by both EFW and GA were created using 200 g. and weekly intervals respectively. A formula using EFW to predict total lung volume was calculated: LV = 0.07497804 EFW0.88276 (R2 = 0.87). Conclusions: We developed a novel fetal lung volume nomogram stratified by EFW. If validated, this nomogram may assist clinicians predict outcomes in cases of fetal pulmonary hypoplasia with concomitant FGR. [ABSTRACT FROM AUTHOR]

Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a genetically heterogeneous multiple congenital malformation syndrome. Although pathogenic variants in RARB and STRA6 are established causes of PDAC, many PDAC cases remain unsolved at the molecular level. Recently, we proposed biallelic WNT7B variants as a novel etiology based on several families with typical features of PDAC syndrome albeit with variable expressivity. Here, we report three patients from two families that share a novel founder variant in WNT7B (c.739C > T; Arg247Trp). The phenotypic expression of this variant ranges from typical PDAC features to isolated genitourinary anomalies. Similar to previously reported PDAC‐associated WNT7B variants, this variant was found to significantly impair WNT7B signaling activity further corroborating its proposed pathogenicity. This report adds further evidence to WNT7B‐related PDAC and expands its variable expressivity. [ABSTRACT FROM AUTHOR]

We presented a 2.5-year-old boy with a history of the left pulmonary hypoplasia, repaired congenital diaphragmatic hernia and multiple episodes of pyelonephritis was referred to our department for [99mTc]Tc-DMSA and [99mTc]Tc-EC renal scintigraphy. The scans revealed an unusual pattern of renal uptake with horizontally aligned kidneys located high on left lower thoracic region extended to the mid abdomen. SPECT/CT of the [99mTc]Tc-DMSA scan clearly demonstrated the unusual location of the kidneys which was due to crossed fused renal ectopia and elevated diaphragm. Diuretic renal scans showed no evidence of renal obstruction. Additionally, the VCUG scan indicated vesicoureteral reflux in both ureters. [ABSTRACT FROM AUTHOR]

As the pediatric patient with right pulmonary artery agenesis (PAA) matured, she progressively presented symptoms of pulmonary hypertension and hemoptysis. There is limited clinical literature on this condition, and currently, there is no consensus regarding its diagnosis and treatment. This article presents a case study of a 16-year-old female patient with right pulmonary artery hypoplasia, providing a comprehensive summary and analysis of her developmental progression, pathology, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Background: We aimed to conduct a systematic review and meta-analysis to evaluate the fetoscopic tracheal occlusion in patients with isolated severe and left-sided diaphragmatic hernia. Methods: Cochrane Library, Embase, and PubMed (Medline) databases were searched from inception to February 2024 with no filters or language restrictions. We included studies evaluating the outcomes of fetoscopic intervention compared to expectant management among patients with severe congenital diaphragmatic hernia exclusively on the left side. A random-effects pairwise meta-analysis was performed using RStudio version 4.3.1. Results: In this study, we included 540 patients from three randomized trials and five cohorts. We found an increased likelihood of neonatal survival associated with fetoscopic tracheal occlusion (Odds Ratio, 5.07; 95% Confidence Intervals, 1.91 to 13.44; p < 0.01) across general and subgroup analyses. Nevertheless, there were higher rates of preterm birth (OR, 5.62; 95% CI, 3.47–9.11; p < 0.01) and preterm premature rupture of membranes (OR, 7.13; 95% CI, 3.76–13.54; p < 0.01) in fetal endoscopic tracheal occlusion group compared to the expectant management. Conclusions: Our systematic review and meta-analysis demonstrated the benefit of fetoscopic tracheal occlusion in improving neonatal and six-month postnatal survival in fetuses with severe left-sided CDH. Further studies are still necessary to evaluate the efficacy of tracheal occlusion for isolated right-sided CDH, as well as the optimal timing to perform the intervention. [ABSTRACT FROM AUTHOR]

Background: Hydrops fetalis (HF) is fluid accumulation in fetus body cavities and subcutaneous tissue. The condition has been described in various farm and companion animal species, including dogs. Most of cases result from a heart defect. Exact nature of this defect is rarely clarified. Case presentation: A newborn, male French bulldog puppy with severe HF underwent a full anatomopathological examination to diagnose the primary cause of HF. Based on the anatomopathological examination, fetal ultrasound, and micro-computed tomography, transposition of the great arteries with hypoplasia of the ascending aorta, aortic arch interruption, ostium secundum atrial septal defect, severe tricuspid valve dysplasia, as well as hypoplasia of pulmonary vessels and lungs were diagnosed. Conclusions: This is the first report of HF caused by severe, complex congenital heart defects with concurrent pulmonary vessel and lung hypoplasia. [ABSTRACT FROM AUTHOR]

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients. [ABSTRACT FROM AUTHOR]

Restrictive dermopathy is a lethal autosomal recessive disease characterized by tightly adherent skin, distinctive facial dysmorphisms, arthrogryposis, and pulmonary hypoplasia. While clinical findings are unique, histopathology and genetic analysis are critical for early diagnostic confirmation and to initiate appropriate management for this lethal disease. We report on a preterm Hutterite male neonate with biallelic ZMPSTE24 mutations to highlight the clinical and histopathological features of restrictive dermopathy and share our skin‐directed management strategies. [ABSTRACT FROM AUTHOR]

This is a retrospective study investigating biometric measurements using magnetic resonance imaging (MRI) examinations in congenital diaphragmatic hernia (CDH). CDH is one of the more common causes of pulmonary hypoplasia, with grave consequences for the fetus. Inclusion criteria were patients diagnosed with CDH as the only observed anomaly, who underwent MRI examination after the second-trimester morphology ultrasound. The patients came from three university hospitals in Bucharest, Romania. In total, 19 patients were included in the study after applying exclusion criteria. Comparing the observed values of the thoracic transverse diameter, the thoracic anterior–posterior diameter, the thoracic circumference, the thoracic area, and the thoracic volume with values from the literature, we observed a predictive alteration of these parameters, with most showing Gaussian distribution. We observed statistical significance for most of our correlations, except between the observed and expected thoracic anterior–posterior diameters and the observed and expected thoracic volume values. This is very helpful when complex studies that can calculate the pulmonary volume cannot be obtained, as in the case of movement artifacts, and allows the clinicians to better assess the severity of the disease. MRI follow-up in CDH cases is a necessity, as it offers the most accurate thoracic biometry. [ABSTRACT FROM AUTHOR]

Background: The RNA-binding protein Quaking (QKI) increases during epithelial-to-mesenchymal transition and its expression is controlled by microRNA-200 family members. Here, we aimed to describe the expression of QKI in the developing lungs of control and nitrofen-induced congenital diaphragmatic hernia lungs (CDH). Methods: To investigate the expression of QKI, we dissected lungs from control and nitrofen-induced CDH rats on embryonic day 15, 18, 21 (E15, E18, E21). We performed immunofluorescence (IF) and quantitative reverse transcription PCR (RT-qPCR) for QKI expression. Additionally, we assessed Interleukin-6 (IL-6) abundance using IF. Results: On E21, IF showed that the abundance of all three QKI isoforms and IL-6 protein was higher in CDH lungs compared to control lungs (QKI5: p = 0.023, QKI6: p = 0.006, QKI7: p = 0.014, IL-6: p = 0.045, respectively). Furthermore, RT-qPCR data showed increased expression of QKI5, QKI6, and QKI7 mRNA in E21 nitrofen lungs by 1.63 fold (p = 0.001), 1.63 fold (p = 0.010), and 1.48 fold (p = 0.018), respectively. Conclusions: Our data show an increase in the abundance and expression of QKI at the end of gestation in nitrofen-induced CDH lungs. Therefore, a disruption in the regulation of QKI during the late stage of pregnancy could be associated with the pathogenesis of abnormal lung development in CDH. [ABSTRACT FROM AUTHOR]

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with salinetreated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted. NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted. [ABSTRACT FROM AUTHOR]

Backgroud. The results of the Fontan operation, depending on the anatomy of the pulmonary arteries, have been studied quite well. Various indices have been proposed to assess the degree of hypoplasia of the pulmonary arterial bed (Nakata, Reddy, and McGoon indexes). At the same time, an obstruction of pulmonary venous blood return may be considered as a contraindication to Fontan operation. Aim of the Study. To present an optimal method for pulmonary venous index (PVI) calculation based on computed tomography angiography (CTA) enhancement of the heart data in patients with a functional single ventricle. Materials and Methods. 63 patients with a functional single ventricle (SV) underwent CTА (Philips, Brilliance iCT) before the Fontan operation. Axial sections were reconstructed to a thickness of 0.75–3 mm using soft tissue and lung filters, followed by postprocessing of the data (Horos and OsiriX software) and construction of multiplanar and 3D images. The diagnoses were presented by various types of SV of the heart. The age of the patients ranged from 3 to 30 years (median 7 years). Comparison of PVI was carried out in patients of two groups: those who survived the intervention (n = 55 patients) and those who died (n = 8). The evaluation of the pulmonary veins (PV) and the calculation of the pulmonary venous index (PVI) were carried out based on the measurement of each pulmonary vein at 2 levels (at the level of the orifices and bifurcation). The calculation of the PVI was carried out according to the formula: the sum of the cross-sectional area of the main pulmonary veins, related to the body surface area. 3 variants of PVI calculation were compared: taking into account the values of the PV areas at the level of the orifices, the bifurcation, and the sum of the minimum areas of each of the PVs. Results. In the group of survived patients, the median PVI at the level of the PV orifices was 292 mm/m2, and in the group of deceased, it was 242 mm/m2 p = 0.0326 ; at the level of PV bifurcation in the group of survivors, it was 299 mm/m2, and in the group of dead patients, it was 281 mm/m2 p = 0.0776 ; the minimum PVI was 257 mm/m2 in the survivor group and 218 mm/m2 in the deceased group p = 0.006 . An ROC analysis performed to determine the critical value of the minimum PVI affecting survival after Fontan operation revealed that PVI measured taking into account the minimum dimensions of the areas of the PV is a significant risk factor for death after Fontan operation p = 0.00015 , with its value (cutoff) <233.5 mm2/m2. Conclusion. The value of the minimum PVI can be an important morphological indicator of the state of PV blood return and serve as an additional criterion in determining indications for the Fontan operation. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to evaluate the association between fetal cardiac deformation analysis (CDA) and cardiac function with severe adverse perinatal outcomes in fetuses with isolated left congenital diaphragmatic hernia (CDH). Methods: CDA in each ventricle (contractility, size, and shape), evaluated by speckle tracking and novel FetalHQ software, and markers of cardiac function (E/A ratios, pulmonary and aortic peak systolic velocities, and sigmoid annular valve diameters), were evaluated in fetuses with isolated left CDH. Two evaluations were performed: at referral (CDA and function) and within 3 weeks of delivery (CDA). Severe adverse neonatal outcomes were considered neonatal death (ND) or survival with CDH-associated pulmonary hypertension (CDH-PH). Differences and associations between CDA, cardiac function, and severe adverse outcomes were estimated. Results: Fifty fetuses were included, and seventeen (34%) had severe adverse neonatal outcomes (11 ND and 6 survivors with CDH-PH). At first evaluation, the prevalence of a small left ventricle was 34% (17/50) with a higher prevalence among neonates presenting severe adverse outcomes (58.8 [10/17] vs. 21.2% [7/33]; p = 0.01; OR, 5.03 [1.4–19.1; p = 0.01]) and among those presenting with neonatal mortality (8/11 [72.7] vs. 9/39 [23.0%]; p = 0.03; OR, 8.9 [1.9–40.7; p = 0.005]). No differences in cardiac function or strain were noted between fetuses with or without severe adverse outcomes. Within 3 weeks of delivery, the prevalence of small left ventricle was higher (19/34; 55.8%) with a more globular shape (reduced transverse/longitudinal ratio). A globular right ventricle was significantly associated with ND or survival with CDH-PH (OR, 14.2 [1.5–138.3]; p = 0.02). Conclusion: Fetuses with isolated CDH at risk of perinatal death or survival with CDH-PH had a higher prevalence of a small left ventricle and abnormal shape of the right ventricle. [ABSTRACT FROM AUTHOR]

Objective: To systematically evaluate the association of prenatal thoracic ultrasound abnormalities with copy number variants (CNVs). Methods: Chromosomal microarray (CMA) data and clinical characteristics from fetuses with thoracic ultrasound abnormalities were retrieved and analyzed. Results: Thoracic ultrasound findings were mainly isolated except for fetal pleural effusion (FPE) and pulmonary hypoplasia. The diagnostic yield of CMA for thoracic anomaly was 9.66%, and FPE (17/68, 25%), pulmonary hypoplasia (1/8, 12.5%), and congenital diaphragmatic hernia (CDH) (6/79, 7.59%) indicated relatively high pathogenic/likely pathogenic (P/LP) CNV findings. The detection rate for P/LP CNVs was obviously increased in non‐isolated thoracic anomalies (27.91% vs. 1.96%, P < 0.0001), non‐isolated FPE (37.78% vs. 0%, P = 0.0007) and non‐isolated congenital pulmonary airway malformation (CPAM) (27.27% vs. 0%, P < 0.0001), and significantly different among thoracic anomalies. Additionally, the rate of termination of pregnancy in cases with non‐isolated thoracic anomalies (58.49% vs. 12.34%, P < 0.0001) and P/LP CNVs (85.71% vs. 24.15%, P < 0.0001) was obviously increased. Conclusion: The present study expanded phenotype spectrums for particular recurrent CNVs. FPE, CDH, and pulmonary hypoplasia indicated relatively high P/LP CNV findings among common thoracic ultrasound abnormalities, CPAM associated with other ultrasound abnormalities increased the incidence of diagnostic CNVs, while bronchopulmonary sequestration might not be associated with positive CNVs. The present data recommended CMA application for cases with prenatal thoracic ultrasound abnormalities, especially non‐isolated FPE, non‐isolated CPAM, CDH, and pulmonary hypoplasia. Synopsis: The diagnostic yield for CNVs and pregnancy outcomes varied significantly among prenatal thoracic ultrasound abnormalities, and phenotype spectrums for recurrent CNVs were expanded. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypoplasia is the primary cause of perinatal death in lethal skeletal dysplasias. The antenatal ultrasound correlates for lethality are indirect, measuring the thorax (thoracic circumference, TC) or femur compared to the abdomen (TC/AC, FL/AC). A single study has correlated lethality with the observed-to-expected total lung volume (O/E-TFLV) on fetal MRI in 23 patients. Objective: Our aim was to define a cutoff value to predict lethality more specifically using MRI-derived O/E-TFLV. Materials and methods: Two large fetal center databases were searched for fetuses with skeletal dysplasia and MRI; O/E-TFLV was calculated. Ultrasound measures were included when available. Each was evaluated as a continuous variable against lethality (stillbirth or death in the first month of life). Logistic regression and receiver operating characteristic (ROC) curve analyses evaluated the prediction ability. AUC, sensitivity, and specificity were calculated. P < 0.05 was considered statistically significant. Results: A total of 80 fetuses met inclusion criteria. O/E-TFLV < 0.49 was a significant risk factor in predicting lethality, with sensitivity and specificity of 0.63 and 0.93, respectively, and an AUC of 0.81 (P < 0.001). FL/AC < 0.129 was also a strong variable with sensitivity, specificity, and AUC of 0.73, 0.88, and 0.78, respectively (P < 0.001). TC/AC and TC percentile were not significant risk factors for lethality. An O/E-TFLV of < 0.38 defines a specificity for lethality at 1.00. Conclusion: MRI-derived O/E-TFLV and US-derived FL/AC are significant predictors of lethality in fetuses with skeletal dysplasia. When prognosis is uncertain after ultrasound, calculation of MRI-derived O/E-TFLV may provide additional useful information for prognosis and delivery planning. [ABSTRACT FROM AUTHOR]

Introduction: To determine lung hypoplasia in cases with fetal skeletal dysplasia based on the total lung weight at autopsy as the most accountable surrogate marker for pulmonary hypoplasia. Methods: This retrospective cohort study included all pregnancies with antenatal diagnosis of skeletal dysplasia (2012–2018). We included only cases in which information on fetal biometry was available within 2 weeks before delivery and had autopsy and skeletal X-rays + molecular analysis using extracted fetal DNA. We compared the predictive accuracy of fetal sonographic body-proportional ratios (BPRs) including: (1) thoracic circumference-to-abdominal circumference ratio, (2) the femur length-to-abdominal circumference (FL/AC) ratio, (3) head circumference-to-abdominal circumference ratio, and (4) foot length-to-femur length ratio. Lung hypoplasia was defined as total lung weight below −2 SD from the expected mean for gestational age. Results: Fifty three pregnancies with antenatal diagnosis of skeletal dysplasia underwent autopsy included. Lung hypoplasia was determined in 34 (64.1%). Median of gestational age at last sonographic assessment was 21.3 (19.9–24.9) weeks. FL/AC ratio demonstrated the highest area under the curve of 0.817 (95% CI: 0.685–0.949; p < 0.0001). FL/AC ≤0.1550 demonstrated the highest detection rate of 88.2% along with the highest negative predictive value of 75%. Conclusion: Using a novel, more practical approach to predict lung hypoplasia in skeletal dysplasia, fetal sonographic BPRs and, specifically, FL/AC ratio demonstrate a high detection rate of lung hypoplasia. [ABSTRACT FROM AUTHOR]

Purpose: Children with congenital diaphragmatic hernia suffer from long-term morbidity, including lung function impairment. Our study aims to analyze lung morphology characteristics via radiomic-assisted extraction of lung features in patients after congenital diaphragmatic hernia repair. Materials and Methods: 72 patients were retrospectively analyzed after approval by the local research ethics committee. All the image data were acquired using a third-generation dual-source CT (SOMATOM Force, Siemens Healthineers, Erlangen, Germany). Dedicated software was used for image analysis, segmentation, and processing. Results: Radiomics analysis of pediatric chest CTs of patients with status after CDH was possible. Between the ipsilateral (side of the defect) and contralateral lung, three shape features and two higher-order texture features were considered statistically significant. Contralateral lungs in patients with and without ECMO treatment showed significant differences in two shape features. Between the ipsilateral lungs in patients with and without the need for ECMO 1, a higher-order texture feature was depicted as statistically significant. Conclusions: By adding quantitative information to the visual assessment of the radiologist, radiomics-assisted feature analysis could become an additional tool in the future to assess the degree of lung hypoplasia in order to further improve the therapy and outcome of CDH patients. [ABSTRACT FROM AUTHOR]

Key Points: Question: In pregnancies complicated by anhydramnios due to fetal bilateral renal agenesis, do serial amnioinfusions instituted before 26 weeks' gestation mitigate lethal pulmonary hypoplasia in neonates? Findings: In this nonrandomized clinical trial, 82% of live-born infants survived to 14 days of life or longer and placement of dialysis access, but longer-term neonatal survival was reduced. Serial amnioinfusions were not associated with severe maternal complications. Meaning: Prenatal serial amnioinfusions can mitigate neonatal lethal pulmonary hypoplasia in neonates with bilateral renal agenesis, but infants face substantial morbidity independent of lung function. Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P =.01), gestational age greater than 32 weeks (P =.005), and higher birth weight (P =.03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration: ClinicalTrials.gov Identifier: NCT03101891 This prospective, nonrandomized clinical trial assesses neonatal outcomes after serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia in pregnancies complicated by bilateral renal agenesis. [ABSTRACT FROM AUTHOR]

(1) Background: There is no reliable way to assess antenatal fetal pulmonary hypoplasia; however, the biological parameters of the fetal lung can help in evaluating fetal lung development. This study aimed to establish the reference intervals for normal fetal lung biological parameters at 21–40 weeks among the Chinese population. (2) Methods: This was a cross-sectional study of Chinese groups, and included a total of 1388 normal single pregnant women at 21–40 weeks' gestation. We selected 2134 images of a standard four-chamber view (4CV). ImageJ software (Release 2.14.0) was used to measure the left and right lung areas using a manual tracing method; the elliptic function key was used to measure the fetal thoracic circumference (TC), thoracic area (TA), head circumference (HC), heart area (HA), and abdominal circumference (AC). Based on the above measurements, the following parameters were calculated: lung area to head circumference ratio (LHR), total lung area (TLA), TLA/Weight (mm2/g), cardiothoracic ratio (CTR), lung–thoracic area ratio (TLA/TA), lung–heart area ratio (TLA/HA), TC/AC, and TC/HC. (3) Results: The left and right lung areas and LHRs positively correlated with gestational age (R2 = 0.85, 0.88, 0.66, 0.71, p < 0.001). From 21–40 weeks, the left and right lung areas and TLA increased by about 3.33 times, 3.16 times, and 3.22 times, respectively. The means of left and right LHRs increased by about 1.94 times and 1.84 times, respectively. TLA/Weight (mm2/g) was weakly correlated with gestational age, while CTR, TLA/TA, TLA/HA, TC/AC, and TC/HC had no significant correlation with gestational age. There was no statistically significant difference in fetal lung parameters between different genders of newborns, p > 0.05. (4) Conclusions: Our study establishes the reference intervals for normal Chinese fetal lung biological parameters at 21–40 weeks. Moreover, the reference intervals apply to fetuses of different genders. This paper can provide a reference for the prenatal non-invasive assessment of fetal pulmonary hypoplasia. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and treatment response. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37–39 weeks) from women with normal pregnancies (n = 5) or carrying fetuses with CDH (n = 5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, in the MSP–RON signaling in macrophages pathway and in networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Differences in selected proteins, namely pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin-3 were validated by orthogonal testing using ELISA in larger cohorts and showed statistically significant differences aiding in the diagnosis and prediction of CDH. The findings provide potential tools for clinical management of CDH. [ABSTRACT FROM AUTHOR]

Purpose: Lineage tracing is key to study the fate of individual cells and their progeny especially in developmental biology. To conduct these studies, we aimed to establish a reproducible model of CDH in the most commonly used genetic background strain that is C57BL/6J mice. Methods: CDH was induced in C57BL/6J dams by maternal administration of nitrofen + bisdiamine at E8.5. Fetuses from olive oil-gavaged mothers served as controls. Lungs from CDH and control fetuses were compared for (1) growth via radial airspace count (RAC), mean linear intercept (MLI) and gene expression for Fgf10, Nrp1, and Ctnnb1; (2) maturation (Pdpn, Spc, Ager, Abca3, Eln, Acta2, Pdgfra) via gene and protein expression; (3) vascularization via gene and protein expression (CD31, Vegfa, Vegfr1/2, Epas1, Enos). Statistics: unpaired t-test or Mann–Whitney test. Results: Nitrofen + bisdiamine administration resulted in 36% left-sided CDH (31% mortality). CDH fetuses had hypoplastic lungs and impaired growth (lower RAC, higher MLI, lower Fgf10, Nrp1, Ctnnb1), maturation (decreased Pdpn, Ager, Eln gene expression), and vascularization (decreased Cd31, Vegfr1/2; Epas1 and Enos). Lower protein expression was confirmed for PDPN, ELN and CD31. Conclusion: Modeling CDH in C57BL/6J mouse fetuses is effective in reproducing the classical CDH hallmarks. This model will be critical for lineage tracing experiments. [ABSTRACT FROM AUTHOR]

Purpose: Congenital diaphragmatic hernia (CDH) survivors may experience neurodevelopmental impairment, whose etiology remains elusive. Preclinical evidence indicates that amniotic fluid stem cell extracellular vesicle (AFSC-EV) administration promotes lung development but their effects on other organs are unknown. Herein, we investigated the brain of rat fetuses with CDH for signs of inflammation and response to AFSC-EVs. Methods: CDH was induced by maternal nitrofen administration at E9.5. At E18.5, fetuses were injected intra-amniotically with saline or AFSC-EVs (isolated by ultracentrifugation, characterized as per MISEV guidelines). Fetuses from vehicle-gavaged dams served as controls. Groups were compared for: lung hypoplasia, TNFa and IL-1B brain expression, and activated microglia (Iba1) density in the subgranular zone (SGZ). Results: CDH lungs had fewer airspaces compared to controls, whereas AFSC-EV-treated lungs had rescued branching morphogenesis. Fluorescently labeled AFSC-EVs injected intra-amniotically into CDH fetuses had fluorescent signal in the brain. Compared to controls, the brain of CDH fetuses had higher TNFa and IL-1B levels, and increased activated microglia density. Conversely, the brain of AFSC-EV treated fetuses had inflammatory marker expression levels and microglia density similar to controls. Conclusion: This study shows that the brain of rat fetuses with CDH has signs of inflammation that are abated by the intra-amniotic administration of AFSC-EVs. [ABSTRACT FROM AUTHOR]

Hypoplasia of the lung is an uncommon congenital abnormality of the respiratory system in contrast to pulmonary agenesis. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is the congenital absence of the upper two-thirds of the vagina and uterus with normal secondary sexual characteristics, ovary and normal karyotype. We report a 31-year-old female patient who presented in 2022 with cough with expectoration, left-side chest pain and breathlessness for 4 years to tertiary hospital, Puducherry, India. She was evaluated for amenorrhoea and diagnosed as MRKH syndrome and the patient underwent right-side oophorectomy for right ovarian torsion with a tumour. Computed tomography pulmonary angiogram and fiberoptic endoscopy were suggestive of left lung hypoplasia and the patient was advised symptomatic treatment for lung hypoplasia and planned for vaginoplasty for which she refused. [ABSTRACT FROM AUTHOR]

Background: Congenital lower urinary tract obstruction (LUTO) is a rare but significant condition affecting fetal urinary tract development. LUTO has a range of etiologies, with posterior urethral valves (PUV) being the most common cause. The prenatal diagnosis of LUTO plays a crucial role in recognizing the condition and guiding management decisions. Prenatal ultrasound serves as the primary tool for identifying LUTO, with key findings including megacystis, bladder wall thickening, oligohydramnios, hydronephrosis, and the 'keyhole sign' indicating dilatation of the posterior urethra. We present a case of congenital LUTO with a rare complication of spontaneous fetal bladder rupture and urinary ascites, treated by peritoneo-amniotic shunt placement. Case presentation: A 27-year-old pregnant Caucasian women was referred at 28 weeks of pregnancy due to the presence of megacystis and bilateral hydronephrosis on routine ultrasound and suspicion of LUTO. Repeat ultrasound at 29 weeks showed significant fetal ascites, oligohydramnios and resolution of megacystis and hydronephrosis, after which diagnosis of spontaneous bladder rupture was made. Despite ascites aspiration and amnio-infusion, there was persistent ascites and oligohydramnios. A peritoneo-amniotic shunt was placed with resolution of ascites and normalization of the amniotic fluid volume. At 35 weeks, relapse of the megacystis was observed with bilateral pyelectasis and oligohydramnios, possibly due to healing of the bladder rupture, after which elective cesarean section was planned. Cystography confirmed spontaneous healing of the bladder rupture and the presence of posterior urethral valves, which were resected in the neonatal period with cold knife incision. Total follow-up of 8 years continued to show positive ultrasonographic results and good renal function, but the child suffers from bladder dysfunction, manifesting as overactive bladder disease. Conclusions: LUTO might lead to important renal dysfunction and pulmonary hypoplasia in case of increasing disease severity. Spontaneous bladder rupture might improve renal prognosis, acting as a pop-off mechanism by decompression of the urinary tract. However, fetal bladder rupture is rare and only few cases have been reported. Prenatal intervention can be considered for moderate or severe LUTO, but the benefit for long-term outcome remains uncertain and further studies are needed. [ABSTRACT FROM AUTHOR]

Objectives: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival. Design: Retrospective cohort study. Setting: Multicentre study in large referral centres. Population: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020. Methods: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung‐to‐head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV). Main Outcome Measure: Survival to discharge. Results: We included 53 infants born at 30+4 (interquartile range 29+1–31+2) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left‐sided CDH and 33% (2/6) in right‐sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left‐sided CDH and 25% (2/8) in right‐sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07–1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88–1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13). Conclusions: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival. [ABSTRACT FROM AUTHOR]

This article, published in the journal Neuropediatrics, discusses a case study of a late preterm baby who experienced myoclonus (involuntary muscle jerks) after being given lorazepam, a benzodiazepine sedative, in the neonatal intensive care unit. The myoclonus did not respond to phenobarbital treatment, but it ceased after the administration of flumazenil, a medication used to reverse the effects of benzodiazepines. The article suggests that benzodiazepine-induced myoclonus may be more common in preterm infants due to the developmental activity of the GABA receptor. The case study provides videographic documentation to enhance understanding of this phenomenon. [Extracted from the article]

Key Clinical Message: Isolated agenesis of pulmonary arteries with congenital lung hypoplasia is rare. It can be found in childhood or adulthood if asymptomatic. We present a patient with congenital right lung hypoplasia with an absent right pulmonary artery. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and treatment response. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37–39 weeks) from women with normal pregnancies (n = 5) or carrying fetuses with CDH (n = 5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, in the MSP–RON signaling in macrophages pathway and in networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Differences in selected proteins, namely pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin-3 were validated by orthogonal testing using ELISA in larger cohorts and showed statistically significant differences aiding in the diagnosis and prediction of CDH. The findings provide potential tools for clinical management of CDH. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary hypoplasia (PH) is one of the commonest causes of neonatal morbidity and mortality. The suggested diagnostic criteria for PH are the Lung Weight:Body Weight (LW:BW) ratio ≤ 0.012 and/or Radial Alveolar Count (RAC) ≤ 4.1. The present study was done to determine the relative frequency of PH in fetal autopsy study by the LW:BW ratio and RAC along with evaluation of the defects/anomalies associated with PH. Material and Methods: A prospective observational study was done on fetal autopsy specimens in the Department of Pathology. Examination and grossing were done as per the standard format of fetal autopsy study. Evaluation of PH was done using the LW:BW ratio and RAC. Diagnostic criteria for PH were taken as LW:BW ratio <0.012 and/or RAC < 4.1. Chi-square test, Student T test and Kruskal Wallis test were used in statistical analysis. Results: A diagnosis of PH was made in 45 cases. Concordance between the LW:BW ratio and RAC was observed in 33 cases amounting to 73.33%. The mean LW:BW ratio was the lowest in oligohydramnios. The mean RAC was the lowest in congenital cystic adenomatoid malformation. Conclusion: A diagnosis of PH was rendered in a greater number of cases when evaluation was done by considering both the LW:BW ratio and RAC. Hence, evaluation by both the LW:BW ratio and RAC provides a reliable index of lung growth and should be an essential part of fetal autopsy study. [ABSTRACT FROM AUTHOR]

Managing a newborn with lethal congenital anomalies is challenging but handling a parent's request for doctors under oath to terminate the baby's life is another major ethical dilemma requiring cautious evaluation. We present a term male neonate who presented on the 7th day of life, with a dark-blue sclera, multiple limb deformities, long bone fractures, beaded ribs, a flattened forehead, a narrow chest, and respiratory distress. A Diagnosis of Type II Osteogenesis imperfecta was made and he was managed by a multidisciplinary team including neonatologists, geneticists/endocrinologists, orthopaedic surgeons, nurses, and medical social workers. Supplemental oxygen, intravenous fluids and antibiotics, analgesia, and bisphosphonates were offered as supportive care. The main concern was the challenges of managing a newborn with lethal OI and balancing the demand for euthanasia by the parents to end the baby's misery. In providing care, the rights of the child to life, the morals of the physician, the best interests of the baby, and the family's role in decision-making in a setting of out-of-pocket expenditures must be weighed. Following extensive multidisciplinary team meetings, it was ultimately decided to allow nature to take her course. Baby subsequently had progressive respiratory distress from pulmonary hypoplasia and died of respiratory failure on the twelfth day of life. In Conclusion, Osteogenesis imperfecta of the perinatal type is usually a lethal disease, with death often occurring within the perinatal period. The physician must, therefore, balance the parental rights, the oath of office, and the existing legal framework to avoid charges of murder or manslaughter. [ABSTRACT FROM AUTHOR]

Neonates with symptomatic tetralogy of Fallot (sTOF) with hypoplastic pulmonary arteries (hPA) are considered high risk. Data are needed to inform the impact of hPA on outcomes, and the ideal management strategy. The objectives of this study were to quantify the impact of hPA on outcomes in neonates with sTOF and measure the impact of strategy on pulmonary artery (PA) growth in this population. Neonates with sTOF from 2005 to 2017 were reviewed from the Congenital Cardiac Research Collaborative. Criteria for hPA included a unilateral PA z score <−2.0 and contralateral PA z score <0. Primary outcome was mortality. Secondary outcomes included reintervention and PA growth. We included 542 neonates with sTOF, including 188 (35%) with hPA and 354 (65%) with normal PA, with median follow-up of 4.1 years. Median right and left hPA z scores were −2.19 (25th-75th percentile: −2.55 to −1.94) and −2.23 (25th-75th percentile: −2.64 to −1.91), respectively. Staged repair (vs primary TOF repair) was less common in the hPA cohort (36 vs 44%; P = 0.07). Survival was similar between groups (unadjusted P = 0.16; adjusted P = 0.25). Reintervention was more common in the hPA group (HR: 1.28; 95% CI: 1.01-1.63; P = 0.044); there was no difference after definitive repair (HR: 1.21; 95% CI: 0.93-1.58; P = 0.16). PA growth at 1 year was greater in the hPA cohort, particularly for the right PA (P < 0.001). Despite perception, the presence of hPA in neonates with sTOF conferred no increase in overall hazard of mortality or reintervention after definitive repair. PA growth was superior in the hPA cohort. These findings suggest that the presence of hPA does not adversely impact outcomes in sTOF. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: This study describes the fetal and neonatal outcomes and their predictive factors in pregnancies with preterm premature rupture of membranes (PPROM) before 24 weeks of gestation. Methods: A retrospective study was conducted using the patient database of a tertiary university hospital in Lyon, France. All of the medical data of women diagnosed with PPROM before 24 weeks of gestation from 2008 to 2018 were extracted. R software was used for descriptive and analytical statistics. Results: The study included 78 women. Mean gestational age (GA) at PPROM was 19.6 weeks (13.1 to 23.9 weeks). Fifteen (19.2%) pregnancies were terminated, 37 (47.4%) resulted in intrauterine fetal death (IUFD), and 26 (33.3%) children were born alive at an average of 26.9 weeks of gestation. Fourteen children survived and 12 died after birth; 50% of survivors had pulmonary hypoplasia. Within 7 days after PPROM, 46% of IUFD occurred and 36% of pregnancies ended. PPROM before 20 weeks of gestation and chorioamnionitis are statistically associated with IUFD, whereas a latency period of more than 2 weeks is statistically related to live birth. Conclusion: PPROM before 24 weeks of gestation is associated with a high rate of IUFD, preterm birth, and postpartum mortality. Synopsis: Preterm premature rupture of membranes before 24 weeks of gestation is associated with a high rate of intrauterine fetal death, preterm birth, and postpartum mortality. [ABSTRACT FROM AUTHOR]

Pulmonary hypoplasia and respiratory failure are primary causes of death in patients with osteogenesis imperfecta (OI) type II. OI is a genetic skeletal disorder caused by pathogenic variants in genes encoding collagen type I. It is still unknown if the collagen defect also affects lung development and structure, causing lung hypoplasia in OI type II. The aim of this study was to investigate the intrinsic characteristics of OI embryonic lung parenchyma and to determine whether altered collagen type I may compromise airway development and lung structure. Lung tissue from nine fetuses with OI type II and six control fetuses, matched by gestational age, was analyzed for TTF‐1 and collagen type I expression by immunohistochemistry, to evaluate the state of lung development and amount of collagen. The differentiation of epithelium into type 2 pneumocytes during embryonic development was premature in OI type II fetuses compared to controls (p < 0.05). Collagen type I showed no significant differences between the two groups. However, the amount of alpha2(I) chains was higher in fetuses with OI and the ratio of alpha1(I) to alpha2(I) lower in OI compared to controls. Cell differentiation during lung embryonic development in patients with OI type II is premature and impaired. This may be the underlying cause of pulmonary hypoplasia. Altered cell differentiation can be secondary to mechanical chest factors or a consequence of disrupted type I collagen synthesis. Our findings suggest that collagen type I is a biochemical regulator of pulmonary cell differentiation, influencing lung development. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is a neonatal anomaly that includes pulmonary hypoplasia and hypertension. We hypothesized that microvascular endothelial cell (EC) heterogeneity is different in CDH lungs and related to lung underdevelopment and remodeling. To test this, we evaluated rat fetuses at E21.5 in a nitrofen model of CDH to compare lung transcriptomes among healthy controls (2HC), nitrofen-exposed controls (NC) and nitrofen-exposed subjects with CDH. Single-cell RNA sequencing with unbiased clustering revealed 3 distinct microvascular EC clusters: a general population (mvEC), a proliferative population and a population high in hemoglobin. Only the CDH mvEC cluster had a distinct inflammatory transcriptomic signature as compared to the 2HC and NC endothelial cells, e.g. greater activation and adhesion of inflammatory cells and production of reactive oxygen species. Furthermore, CDH mvECs had downregulated Ca4, Apln and Ednrb gene expression. Those genes are markers for ECs important to lung development, gas exchange and alveolar repair (mvCa4+). mvCa4+ ECs were reduced in CDH (2HC [22.6%], NC [13.1%] and CDH [5.3%], p < 0.0001). Overall, these findings identify transcriptionally distinct microvascular endothelial cell clusters in CDH, including the distinctly inflammatory mvEC cluster and the depleted group of mvCa4+ ECs, which together may contribute to pathogenesis. [ABSTRACT FROM AUTHOR]

Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X‐linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans. [ABSTRACT FROM AUTHOR]

Background: Cardiac‐urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin‐related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. Case Presentation: We present case reports of two siblings of unrelated parents in whom whole‐exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. Conclusions: To our knowledge, this is the first published case of familial cardiac‐urogenital syndrome indicating gonadal mosaicism. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia is caused by a defect in the closure of the pericardio-peritoneal canal. It is a real challenge for the anesthetists during the perioperative management as serious complications including hypoxia and hypercarbia may threaten the life of the child. Mortality remains high due to associated pulmonary hypoplasia and pulmonary hypertension. We present a case of a 15-month-old boy, known patient of recurrent congenital diaphragmatic hernia, scheduled to undergo laparotomy to repair his diaphragmatic defect. The patient presented with shortness of breath, and his chest X-ray revealed a diaphragmatic hernia. He was in optimal condition. General anesthesia was chosen with intubation. The patient remained stable and his laboratory tests were within normal limits. We discuss the associated problems during anesthesia and the optimum perioperative management. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is a developmental disorder that results in incomplete diaphragm formation, pulmonary hypoplasia, and pulmonary hypertension. Although a variety of genes have been linked to its etiology, CDH is not a monogenetic disease, and the cause of the condition is still unclear in the vast majority of clinical cases. By comparing human clinical data and experimental rodent data from the literature, we present clear support demonstrating the importance of vitamin A (vitA) during the early window of pregnancy when the diaphragm and lung are forming. Alteration of vitA signaling via dietary and genetic perturbations can create diaphragmatic defects. Unfortunately, vitA deficiency is chronic among people of child-bearing age, and this early window of diaphragm development occurs before many might be aware of pregnancy. Furthermore, there is an increased demand for vitA during this critical period, which exacerbates the likelihood of deficiency. It would be beneficial for the field to further investigate the connections between maternal vitA and CDH incidence, with the goal of determining vitA status as a CDH risk factor. Regular clinical monitoring of vitA levels in child-bearing years is a tractable method by which CDH outcomes could be prevented or improved. [ABSTRACT FROM AUTHOR]

Scimitar syndrome (SS) is a rare congenital condition which includes partial anomalous pulmonary venous return (PAPVR) and a variable degree of pulmonary hypoplasia. We describe the clinical features, therapeutic approach and outcomes of patients who underwent cardiac catheterization and/or surgical repair of the scimitar vein at a single institution in the United States. This retrospective cohort study included all patients with SS who underwent scimitar vein surgical repair or cardiac catheterization from October 1989 through August 2021 in a tertiary care center. A total of 84 patients with SS were included and median follow-up time was 74 months. Patients diagnosed with SS under the age of one year had a significantly greater incidence of congenital heart defects (CHD) (p < 0.001), non-cardiac anomalies (p = 0.02), pulmonary hypertension (p = 0.02), and mortality (p = 0.04) compared to those diagnosed over the age of 1 year. Twenty-eight patients underwent surgical repair of the scimitar vein. Overall, eight (10%) patients died. Compared to surviving patients, deceased patients had a significantly higher incidence of pulmonary hypertension (PH), neonatal SS diagnosis, and extracorporeal membrane oxygenation (ECMO) support. Median scimitar vein pressure (20 mmHg) of deceased patients was significantly higher compared to pressures in surviving patients (11 mmHg; p = 0.02). PH, CHD, neonatal SS diagnosis, ECMO support, and markedly elevated scimitar vein pressure are associated with mortality. Scimitar vein surgical repair during infancy is commonly associated with PH and restenosis that requires re-intervention. [ABSTRACT FROM AUTHOR]

Aim: To perform a systematic literature review to determine the effect of inhaled nitric oxide (iNO) on oxygenation, mortality and morbidity in preterm neonates with preterm prelabour rupture of membranes (PPROM) and early hypoxaemic respiratory failure (HRF). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Science, Zetoc and ProQuest were searched. Studies including neonates <34 weeks' gestation with PPROM, oligohydramnios or pulmonary hypoplasia and HRF in the first 28 days of life treated with iNO were included. Studies were critically appraised and assessed for potential risk of bias using standardised checklists. Results: Six hundred and two records remained after duplicates were removed. Seven studies were included in the critical appraisal process. Quality of available evidence was very low to low. Six studies described an improvement in oxygenation after commencement of iNO. One hundred and three of 284 (36%) neonates exposed to iNO died. Seventy‐seven of 92 (84%) neonates that had an echocardiogram performed before commencement of iNO had pulmonary hypertension (PH) present. Conclusion: iNO may improve oxygenation when standard care fails. Improvement in oxygenation is likely associated with increase in survival. Survival may lead to an increase in morbidity. Efficacy of iNO in this cohort is likely secondary to relatively high prevalence of PH. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and respiratory morbidity. To assess whether respiratory morbidity during the first 2 years of life in infants with left-sided CDH is associated with fetal lung volume (FLV) evaluated by the observed-to-expected FLV ratio (o/e FLV) on antenatal magnetic resonance imaging (MRI). In this retrospective study, o/e FLV measures were collected. Respiratory morbidity in the first 2 years of life was studied according to two endpoints: treatment with inhaled corticosteroids for >3 consecutive months and hospitalization for any acute respiratory disease. The primary outcome was a favorable progression defined by the absence of either endpoint. Forty-seven patients were included. The median o/e FLV was 39% (interquartile range, 33–49). Sixteen (34%) infants were treated with inhaled corticosteroids and 13 (28%) were hospitalized. The most efficient threshold for a favorable outcome was an o/e FLV ≥ 44% with a sensitivity of 57%, specificity of 79%, negative predictive value of 56%, and positive predictive value of 80%. An o/e FLV ≥ 44% was associated with a favorable outcome in 80% of cases. These data suggest that lung volume measurement on fetal MRI may help to identify children at lower respiratory risk and improve information during pregnancy, patient characterization, decisions about treatment strategy and research, and personalized follow-up. [ABSTRACT FROM AUTHOR]

Fetal lower urinary tract obstruction (LUTO) can be mild or severe with oligohydramnios, renal dysplasia and pulmonary hypoplasia. Fetal urine biochemical markers correlate with fetal prognosis and, if favorable, surgical intervention is feasible. We report a patient in her 18th gestational week whose fetus was diagnosed with LUTO and underwent fetal urine sampling for calcium, sodium, chloride, beta2-microglobulin and total protein of the routine LUTO panel, with the addition of creatinine, glucose, phosphate, urea, ammonia, albumin, and NGAL. Although the routine fetal urine biochemistry seemed to be favorably trending favorably, sodium, beta2-microglobulin, glucose, and urea did not decrease to the reference ranges, and ammonia and creatinine were lower than the reference ranges. Ultrasound demonstrated no improvement of the obstruction. This case highlights the need to acquire further experience with biochemical fetal urine markers in order to better manage LUTO. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia is associated with pulmonary hypoplasia, pulmonary hypertension, and significant neonatal morbidity. Although intrathoracic liver herniation (LH) >20% is associated with adverse outcomes, the relationship between LH <20% and outcomes is poorly characterized. A single-center retrospective cohort study was performed from 2011 to 2020 of 80 fetuses with left-sided congenital diaphragmatic hernia that were delivered and repaired at our institution. Perinatal, perioperative, and postoperative data were collected. We evaluated the association of %LH with outcomes as a stratified ordinal variable (0%-10% LH, 10%-19% LH, and >20% LH) and as a continuous variable. Data were analyzed by analysis of variance with Bonferroni post hoc analysis, chi-square analyses, and univariate logistic regression. Extracorporeal membrane oxygenation (ECMO) (P < 0.001), repair on ECMO (P = 0.002), repair with patch (P < 0.001), length of stay (P = 0.002), inhaled nitric oxide use (P < 0.001), and sildenafil use at discharge (P < 0.001), showed significant differences among LH groups. There were no differences among the groups concerning survival (at discharge, 6 mo, and 1 y) and tracheostomy. On further analysis there was no difference between 10% and 19% LH and ≥20% LH patients concerning ECMO (P = 0.55), repair on ECMO (P = 0.54), repair with patch (P = 1.00), length of stay (P = 1.00), and inhaled nitric oxide use (P = 0.33). Logistic regression analysis displayed a significant association with LH and ECMO, repair on ECMO, repair with patch, inhaled nitric oxide use, and sildenafil use. Our analysis displays no significant difference in perinatal management between patients with 10%-19% and ≥20% LH. These findings suggest that the historical cutoff of ≥20% LH may not be sufficient alone to guide perinatal counseling and decision-making. • Assessing percent liver herniation as a continuous variable, rather than an ordinal variable, may better benefit the evaluation of outcomes in CDH and prenatal counseling. [ABSTRACT FROM AUTHOR]

Potter syndrome, first reported in 1946 by Edith Potter, refers to fatal cases of bilateral renal aplasia with pulmonary hypoplasia, peculiar facial features, and limb deformities. Presently, patients with oligohydramnios showing similar pathological manifestations due to oligohydramnios caused by conditions other than bilateral renal aplasia have been reported, and are known as the Potter sequence. There are limited studies and unclear guidelines on the safest delivery time and detailed postpartum management for patients with the Potter sequence. We experienced a case of Potter sequence, in which the patient was born by elective cesarean section at gestational age (GA) of 34 weeks. Fetal ultrasound at GA of 26 weeks 4 days showed oligohydramnios, multilocular cystic lesions in the left kidney, and an absent right kidney. Prenatal fetal MRI at GA of 33 weeks and 3 days showed pulmonary hypoplasia, and the ratio of fetal lung volume (FLV) to fetal body weight (FBW) was 0.0135 ml/g. We suspected that the fetal lung could not grow because of persistent oligohydramnios, which leads to a further decline in the ratio of FLV to FBW during pregnancy. We performed a cesarean section at GA of 34 weeks to prevent the exacerbation of the imbalance between lung volume and physique. We struggled to keep her condition stabilized with strict management of her respiratory condition, dialysis, and nutrition. She was discharged from the hospital at 169 days of age. Elective caesarean section in the term of premature birth prevented the progression of pulmonary hypoplasia and made it possible to save her life. Potter sequence is still relatively unknown, and it is necessary for more studies to be conducted in the future. [ABSTRACT FROM AUTHOR]

We have previously described gestational-age-independent sonographic indices to assess fetal lung size in the right and left lungs: The Quantitative Lung Index for the right lung (QLI-R) and for the left lung (QLI-L), respectively. The purpose of this study was to evaluate the clinical cutoff point of the QLI-R to predict pulmonary hypoplasia and neonatal death. Retrospective assessment of the QLI-R in patients with left-sided congenital diaphragmatic hernia (CDH-L) and other fetal conditions at risk for fetal pulmonary hypoplasia. Cross-section and longitudinal assessment of the behavior of the QLI-R in untreated and treated patients. ROC curve analysis to determine the optimal cutoff point of the QLI-R in predicting neonatal death. One hundred eighteen patients with CDH-L and other fetal conditions at risk for pulmonary hypoplasia had QLI-R measurements done. Seventeen patients were excluded for various reasons. Eleven patients with conditions other than CDH-L but at risk for pulmonary hypoplasia were used for intraclass coefficient measurements of the QLI-R. Ninety patients had CDH-L, of which 78 did not undergo antenatal intervention and in which the cutoff point for pulmonary hypoplasia and neonatal demise was assessed. Stent tracheal occlusion was performed in the remaining 12 patients with CDH-L, in which the behavior of the QLI after surgery was assessed. Analysis of the ICC showed an overall intra-rater reliability of 0.985 (Cronbach's Alpha-based). There was no correlation between gestational age and QLI-R (-0.73, Pearson correlation, p =.72). Twenty-six of the 78 patients (33%) with CDH-L managed expectantly had a neonatal demise. A QLI-R equal to or less than 0.45 was significantly predictive of neonatal demise (area under the curve 0.64, p =.046, sensitivity 77%). Nine of the 12 patients (75%) that underwent tracheal occlusion had neonatal survival. Of these, 10 had serial assessments of the QLI-R after surgery. An increase in the QLI-R of 0.11 was associated with a tendency for neonatal survival (p =.056). Our study confirms that the QLI-R is a gestational-age-independent measurement of fetal lung size, with a high degree of reproducibility. In a population of expectantly managed CDH-L patients, a cutoff value of the QLI-R of 0.45 or lower is predictive of neonatal death from pulmonary hypoplasia. The QLI-R can be used to monitor fetal lung growth after tracheal occlusion, and an increase in the QLI-R is suggestive of neonatal survival. Further prospective studies are needed to confirm these findings and to explore the use of the QLI in other populations at risk for pulmonary hypoplasia and consequent neonatal demise. [ABSTRACT FROM AUTHOR]

BACKGROUND: ppPROM < 24 + 0 weeks of gestation complicates < 1 % of all pregnancies but is responsible for significant maternal and neonatal morbidity. It is associated with 18–20% of perinatal deaths. OBJECTIVE: To evaluate neonatal outcome after expectant management in ppPROM in order to obtain evidence-based information for purposes of future counselling. METHODS: A single-centre, retrospective cohort study of 117 neonates born 1994 to 2012 after ppPROM < 24 weeks of gestation with a latency period > 24 hours and admission to the NICU of the Department of Neonatology, University of Bonn. Data of pregnancy characteristics and neonatal outcome were collected. The results were compared to those found in the literature. RESULTS: The mean gestational age at ppPROM was 20.45±2,9 weeks (range 11 + 2 –22 + 6) with a mean latency period of 44.7±34.8 days (range 1–135). Mean gestational age at birth was 26.77±3.22 weeks (range 22 + 2–35 + 3). 117 newborns were admitted to the NICU, the overall survival rate at discharge was 72.6% (85/117). Non-survivors had a significantly lower gestational age and higher rates of intra-amniotic infections. The most common neonatal morbidities were RDS (76.1%), BPD (22.2%), pulmonary hypoplasia (PH) (14.5%), neonatal sepsis (37.6%), IVH (34.1% all grades, 17.9% grades III/IV), NEC (8.5%) and musculoskeletal deformities (13.7%). Mild growth restriction as a new complication of ppPROM was observed. CONCLUSIONS: Neonatal morbidity after expectant management is similar to that described for infants without ppPROM, but carries a higher risk of pulmonary hypoplasia and mild growth restriction. [ABSTRACT FROM AUTHOR]

To analyze neonatal outcomes in very-low-birthweight (VLBW) infants depending on the presence of preterm premature rupture of membranes (PPROM), oligohydramnios, or both. The electronic medical records of VLBW infants admitted during the study period, January 2013 to September 2018, were reviewed. Neonatal outcomes (primary outcome: neonatal death; secondary outcome: neonatal morbidity) were compared depending on whether the infant was affected by PPROM or oligohydramnios. Logistic regression analysis was performed to assess the association of PPROM and oligohydramnios with neonatal outcomes. Three hundred and nineteen VLBW infants were included: (1) 141 infants in the PPROM group vs. 178 infants in the non-PPROM group, and (2) 54 infants in the oligohydramnios group vs. 265 infants in the non-oligohydramnios group. The infants affected by PPROM were at significantly younger gestational ages at birth with lower 5-min Apgar scores than those not affected by PPROM. Histologic chorioamnionitis was significantly more frequent in the PPROM group than in the non-PPROM group. The proportions of small-for-gestational-age infants and infants affected by multiple births were significantly higher in the non-PPROM group. The median (interquartile range) PPROM latency and onset were 50.5 (9.0 − 103.0) h and 26.6 (24.1 − 28.5) weeks, respectively. Based on the logistic regression analysis assessing the association of PPROM and oligohydramnios with the significant neonatal outcome, oligohydramnios was significantly associated with neonatal death (odds ratio [OR] = 2.831, 95% confidence interval [CI] 1.447 − 5.539), air leak syndrome (OR = 2.692, 95% CI 1.224 − 5.921), and persistent pulmonary hypertension (PPH) (OR = 2.380, 95% CI 1.244 − 4.555). PPROM per se was not associated with any neonatal outcome. However, early onset PPROM and prolonged PPROM latency were associated with neonatal morbidity and mortality. When PPROM was accompanied by oligohydramnios, it was associated with increased odds for PPH (OR = 2.840, 95% CI 1.335 − 6.044), retinopathy of prematurity (OR = 3.308, 95% CI 1.325 − 8.259), and neonatal death (OR = 2.282, 95% CI 1.021 − 5.103). PPROM and oligohydramnios affect neonatal outcomes differently. Oligohydramnios, but not PPROM, is a significant risk factor for adverse neonatal outcomes, which is presumably related to pulmonary hypoplasia. Prenatal inflammation appears to complicate neonatal outcomes in infants affected by early PPROM and prolonged PPROM latency. [ABSTRACT FROM AUTHOR]

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