Fetal Diaphragmatic Hernia Research Articles

Clinical characteristics and genetic counseling for a three-generation Chinese pedigree with recurrent fetal Kabuki syndrome due to variant of KDM6A gene

To explore the genetic basis for a pregnant woman with a history of adverse pregnancy outcomes. A woman with an adverse history of pregnancies including one fetal demise and two induced abortions due to fetal diaphragmatic hernia and complex cardiac anomalies was selected as the study subject. Muscle tissue from the induced abortus was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the couple and other family members. Genetic sequencing revealed that the fetus has harbored a frameshift variant of the KDM6A gene (NM_001291415.2), namely c.1228_1229del (p.Gln410GlufsTer2), which was inherited from the woman and her mother. The variant was unreported previously, and the woman was found to have short stature, sparse eyebrows in the outer third, peculiar facial features, but normal intelligence in addition with female congenital genital malformation, like incomplete vaginal septum, double cervix, double uterus, and unilateral ovary absence. mostly similar phenotypes observed in her mother. The hemizygous c.1228_1229del variant of the KDM6A gene probably underlay the abnormalities in the fetus. All findings have enabled genetic counseling for this family featuring X-linked inheritance, and the woman had given birth to a healthy girl with appropriate prevention and intervention.

Radiomics of fetal magnetic resonance imaging in congenital diaphragmatic hernia

Objectives. Analysis of possibilities of radiomics as a source of additional diagnostic information about the structural maturity of the lungsMaterials and methods. A retrospective study included 72 pregnant women: 35 with congenital fetal diaphragmatic hernia (group 1) and 37 without fetal lung pathology (group 2). Frontal or co-frontal T2 images (T2 FSE) were obtained. Segmentation of regions of interest at the fetal lung level was performed manually with ITK-Snap. A total of 107 radiomic features were extracted using pyradiomics. The statistical analysis was performed using the STATISTICA 10 statistical analysis package (USA) to detect correlation between trait values and the target variable (presence of lung pathology in CDH), and to show differences in the comparison groups according to the detected parameters.Results. Statistically significant features were identified for 2D and 3D segmentations (p < 0.05). For 2D and 3D segmentations, the number of significant features was 14 and 73, respectively. After exclusion of features with cross-correlations, their number decreased to 6 and 8 for single slices and 3D images, respectively. Correlation coefficients between the features and the presence of lung pathology were also calculated. In the case of 3D images, the number of features with significant correlation coefficients (r > 0.4, p < 0.05) equaled 20, while for single-slice images this number was 3.Conclusion. The data obtained allow to conclude that it is reasonable to use texture analysis of the 3D MRI images as a source of additional diagnostic information concerning the structural maturity of the lungs.

Methodology of prenatal ultrasound examinations in congenital diaphragmatic hernia

Background. Congenital diaphragmatic hernia is a complex malformation with high anatomical and clinical variability. Prenatal ultrasound examinations allow one to assess the severity of pathological process in a particular case in order to determine the management of pregnancy, labor and neonatal period. However, the rarity of this pathology and some features of ultrasound imaging can lead to low informative value of the examination. Purpose – to present a detailed methodology of prenatal ultrasound examinations in fetal congenital diaphragmatic hernia, taking into account anatomical variants of pathology and features of US imaging at different terms of pregnancy, and to characterize the preconditions for diagnostic errors. Materials and methods. The data on prenatal ultrasound examinations of 265 high-risk pregnant women with fetal diaphragmatic hernia conducted during the period of 2007–2020 in the Department of Fetal Medicine of State Institution «Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova of National Academy of Medical Sciences of Ukraine», were systemized. US examinations were performed on systems HDI 4000, ACCUVIX V20EX-EXP, ACCUVIX V10LV-EX. Isolated anomaly was detected in 192 (72.5 %) cases, associated congenital malformations in 65 (24.5 %), chromosomal pathology in 8 (3.0 %). Left-sided hernia was diagnosed in 85.7 % of cases (n = 227), right-sided – in 12.1% (n = 32), central in 1.1 % (n = 3), bilateral in 1.1 % (n = 3). Location of abdominal, retroperitoneal and thoracic organs was determined, as well as specifics of their US imaging in different terms of pregnancy. Results. Methodology of prenatal ultrasound examination of fetuses with congenital diaphragmatic hernia was developed taking into account the specifics of pathological anatomy and ultrasound imaging. Typical and rare variants of thoracic and abdominal organs’ localization in the standard cross section plane at the level of the four chambers of the heart were characterized, preconditions and variants of diagnostic errors were determined. The methods of correct measurement of the thorax, lungs, liver, and also methods of prognostic indices’ calculation for determining the degree of pulmonary hypoplasia and the degree of liver herniation were presented. Conclusions. Prenatal ultrasound semiotics of congenital diaphragmatic hernia is characterized by considerable variability, and contains significant risks of diagnostic errors. The presented methodology of unified ultrasound examinations allows for systematic assessment, which results in correct prenatal diagnosis, determination of the pathology severity, and prognosis – for the correct choice of pregnancy and labor management.

A novel surgical toxicological-free model of diaphragmatic hernia in fetal rats.

Teratogen-induced congenital diaphragmatic hernia (CDH) rat models are commonly used to study the pathophysiology. We have created a new and reliable surgically induced diaphragmatic hernia (DH) model to obtain a purely mechanical DH rat model, and avoid the confounding teratogen-induced effects on the lung development. Fetal DH was surgically created on fetuses at E18.5 and harvested at E21.5 in rats. Four groups were evaluated (n = 16): control (CONT), control exposed to Nitrofen (CONT NIT), DH surgically created (DH SURG), and CDH Nitrofen (CDH NIT). Body weight, total lung weights, and their ratio (BW, TLW, and TLBR) were compared. Air space (AS), parenchyma (PA), total protein, and DNA contents were measured to verify lung hypoplasia. Medial wall thickness (MWT) of pulmonary arterioles was also analyzed. DH SURG showed significant hypoplasia (decreased in total protein and DNA) vs CONT (p < 0.05); DH SURG vs CDH NIT were similar in TLW and TLBR. DH SURG has less AS than CONT (p < 0.05) and similar PA compared to CONT NIT and CDH NIT, MWT were similarly increased in CONT NIT, DH SURG, and CDH NIT. This novel surgical model generates fetal lung hypoplasia contributing to the study of the mechanical compression effect on fetal lung development in DH. There is a critical need to develop a surgical model in rat to complement the findings of the well-known Nitrofen-induced CDH model. This experimental study is pioneer and can help to understand better the CDH pathophysiological changes caused by herniated abdominal viscera compression against the lung during the final stage of gestation in CDH fetuses, and also to develop more efficient treatments in near future.

Interrater agreement for sonographic stomach position classification in fetal diaphragmatic hernia across the North American Fetal Therapy Network.

To evaluate inter-rater agreement for sonographic classification of stomach position (as a surrogate for liver herniation) in fetal left congenital diaphragmatic hernia (LCDH) among: (i) fetal medicine specialists from the North American Fetal Therapy Network (NAFTNet) centers within and without the fetal endoscopic tracheal occlusion (FETO) consortium and in comparison to an expert external reviewer (ER1); and (iii) among two expert ERs (ER1 and ER2). Forty-eight physicians from 26 NAFTNet centers and 2 ERs were asked to assess 13 sonographic clips of isolated LCDH and classify stomach position as "intra-abdominal," "anterior left chest," "mid to posterior left chest," or "retro-cardiac" based on the classification published by Basta et al.8 Interrater agreement was assessed by determining proportion of stomach position ratings concordant amongst NAFTNet participants and ER1. Agreement for stomach position between ERs was calculated using kappa statistics. Agreement for stomach position was 69% (39%-85%; n=19) and 54% (23%-92%; n=29) among FETO and non-FETO NAFTNet participants, respectively, when compared to ER1. Most disagreement in stomach position was related to a discrepancy of one position. ERs were in agreement for stomach position in 5 of 13 cases (38.5%) and inter-rater agreement was highest for "anterior" stomach position. Interrater agreement for stomach position assessment in CDH was poor across NAFTNet and indeed amongst expert reviewers.

Top 100 Most Influential Manuscripts in Congenital Abdominal Pediatric Surgery: A Bibliometric Analysis.

Bibliometric analysis identifies the most influential manuscripts that shape our understanding of various congenital gastrointestinal pathologies. This study sets out to analyse the 100 most cited manuscripts on congenital gastrointestinal surgery. The Thomson Reuters Web of Science database was searched for all manuscripts relevant to paediatric congenital gastrointestinal surgery. The number of citations, authorship, publication date, journal of publication, institution and country were recorded for each paper. Eigenfactor and impact factor rankings were obtained for each journal of publication. 971 eligible manuscripts were returned by the search. Within the top 100 manuscripts, the most cited paper (by Metkus et al.) investigated fetal diaphragmatic hernia and was cited 413 times. University of Indianapolis had the most publications (n=5) and Journal of Pediatric Surgery had the most citations (n=3231). The country with the most publications in top 100 were the USA (n=39). The most commonly published topics were diaphragmatic hernia (n=23), abdominal wall defect (n=20) and atresia (n=6). The most cited manuscripts include various topics with a primary focus on the aetiology, diagnosis, management and outcome of diaphragmatic hernia and abdominal wall defects. Additionally, by collecting the most influential works, this study serves to reference what makes a manuscript 'citable'.

Heterogeneous Response in Rabbit Fetal Diaphragmatic Hernia Lungs After Tracheal Occlusion

BackgroundFetal tracheal occlusion (TO) is an experimental therapeutic approach to stimulate lung growth in the most severe congenital diaphragmatic hernia (CDH) cases. We have previously demonstrated a heterogeneous response of normal fetal rabbit lungs after TO with the appearance of at least two distinct zones. The aim of this study was to examine the fetal lung response after TO in a left CDH fetal rabbit model. MethodsFetal rabbits at 25 d gestation underwent surgical creation of CDH followed by TO at 27 d and harvest on day 30. Morphometric analysis, global metabolomics, and fluorescence lifetime imaging microscopy (FLIM) were performed to evaluate structural and metabolic changes in control, CDH, and CDH + TO lungs. ResultsRight and left lungs were different at the baseline and had a heterogeneous pulmonary growth response in CDH and after TO. The relative percent growth of the right lungs in CDH + TO was higher than the left lungs. Morphometric analyses revealed heterogeneous tissue-to-airspace ratios, in addition to size and number of airspaces within and between the lungs in the different groups. Global metabolomics demonstrated a slower rate of metabolism in the CDH group with the left lungs being less metabolically active. TO stimulated metabolic activity in both lungs to different degrees. FLIM analysis demonstrated local heterogeneity in glycolysis, oxidative phosphorylation (OXPHOS), and FLIM “lipid-surfactant” signal within and between the right and left lungs in all groups. ConclusionsWe demonstrate that TO leads to a heterogeneous morphologic and metabolic response within and between the right and left lungs in a left CDH rabbit model.

A new approach using image analysis to assess pulmonary hypoplasia in the fetal lamb diaphragmatic hernia model.

In congenital diaphragmatic hernia (CDH), there is pulmonary hypoplasia (PH) and also pulmonary vascular and bronchial abnormalities. Few studies have investigated bronchial maldevelopment in CDH. We evaluated bronchial area (BA) by bronchography in a fetal lamb DH model to develop a measure of PH. We created DH in fetal lambs at 75days gestation, delivering by cesarean section and killing them at term (DH, n = 12). Normal term fetuses provided controls (C, n = 5). We measured total lung volume (TLV) and performed barium bronchography. Using image analysis, BA, total lung area (TLA) and bronchial area/lung area ratio (B/L ratio) were calculated. Student's T test (p < 0.05; significant) and Spearman's correlation coefficient were performed. TLV (ml) was 133.3 ± 41.2 in DH and 326 ± 22.5 in C (p = 0.0000001). TLA (cm2) was 78.8 ± 17.4 in DH and 107.1 ± 10.3 in C (p = 0.006). BA (cm2) was 39.6 ± 11.9 in DH and 52.2 ± 7.7 in C (p = 0.019). The B/L ratio was 0.45 ± 0.06 in DH and 0.49 ± 0.05 in C (p = 0.28). There are correlations in DH between TLV and TLA (r = 0.79), TLV and BA (r = 0.73) and in C between TLV and TLA (r = 0.97) and TLV and BA (r = 0.67). It may be possible to assess PH on fetal MRI, given the correlation between TLV and TLA, and TLV and BA.

OC03.03: Interrater agreement for sonographic stomach position classification in fetal diaphragmatic hernia across the North American Fetal Therapy Network

OC03.03: Interrater agreement for sonographic stomach position classification in fetal diaphragmatic hernia across the North American Fetal Therapy Network

Prenatal Diagnosis of Tetrasomy 12P Mosaicism: A Case Report

Tetrasomy 12p mosaicism (also Pallister–Killian syndrome or Pallister mosaic aneuploidy syndrome) is an extremely rare genetic disorder caused by the presence of two extra copies of the chromosome 12 short arm. The signs and symptoms vary, although most people with this disorder have severe to profound intellectual disability and other serious health problems. The ever reported anomalies include varying degrees of developmental disability, epilepsy, hypotonia, distinctive facial structure, characterized by a high, rounded forehead; a broad nasal bridge; a short nose; widely spaced eyes; low-set ears; rounded cheeks. Patients may also exhibit congenital heart defects, cataracts and diaphragmatic hernia. Case report and literature review. A 40 years old pregnant women, gravida3,para 2 had unremarkable medical history. The previous two pregnancies were uneventful. She received routine prenatal examinations in other local clinics and the report of non-invasive prenatal testing (NIPT) was low risk for trisom13,18 and 21 .She first came to our hospital when 24 weeks’ gestation for the fetal diaphragmatic hernia. The detailed ultrasound scan showed fetal left side diaphragmatic hernia, polyhydramnios (AFI:25cm), bilateral ventriculomegaly(1.04/1.06cm) and short long bones. The amniocentesis was then arranged for chromosome survey. The final report of karyotypes Giemsa banding was 47,XY,+i(12)(p10)[11]/46,XY[6] .No mutation defects were noted in the FGFR3 genes. The array-CGH showed a 33.99Mb-duplication at chromosome 12p12.33-12p11.1 and the report was arr[GRCh37]12p13.33p11.1(230,450- 34,217.,434)x4[0.78],(XY)x1. Tetrasomy 12p mosaicism is an extremely rare genetic disorder.The role of array CGH is important to make clear diagnosis when two or or more fetal anomalies were noted in the prenatal sonography.

The Fetal Diaphragmatic Hernia, Diagnosis and Therapy

The objective. early prenatal diagnosis signs of the congenital fetal diaphragmatic hernia determination by using ultrasound. Patients and мethods. 46 publications analysis by Ukrainian and foreign researchers. Results. The ultrasound diagnosis of the diaphragmatic hernia at 24–26 weeks of gestation dependends on the damaged side and a copathology presence (in 60–70%). Conclusion. A co-pathology, intrathoracic liver location, lungs hypoplasia degree and heart compression index are main predictive signs which correlate with fetal survival.

Prenatal ultrasound diagnosis of fetal diaphragmatic hernia

Objective : To evaluate the prenatal ultrasound detection in the diagnosis of fetal diaphragmatic hernia. Methods : After routine prenatal ultrasonic examination in pregnant women, the suspected fetal diaphragmatic hernia cases were taken thoracic and abdominal multidetector continuous scanning, focus on the following ultrasonic appearance: abnormal echo in thoracic cavity, image features and the blood supply of the echo, displacement of the heart, position and structure of abdominal organs. In order to determine the existence and the type of diaphragmatic hernia, other malformations screening was practiced simultaneously. Results : 25 cases with fetal diaphragmatic hernia were detected by ultrasonography and clinic approved with 26 cases, only 1 case missed. Among the 26 cases of fetal diaphragmatic hernia,there were 23 cases of left side diaphragmatic hernia（88.5%,23/26), 3 cases of right side diaphragmatic hernia（11.5%, 3/26）. 11 cases of fetal diaphragmatic hernia complicated with other organ abnormal(42.3%，11/26). 17 cases of fetaldiaphragmatic hernia complicated with polyhydramnios (65.4％，17/26）. Conclusions : Prenatal ultrasound can accurately diagnose the fetal diaphragmatic hernia, it is indeed valuable in clinical application.

P28.01: The value of liver herniation volume as assessed by MRI in the prediction of outcome in fetal right congenital diaphragmatic hernia

P28.01: The value of liver herniation volume as assessed by MRI in the prediction of outcome in fetal right congenital diaphragmatic hernia

447: Quantification of ultrasound umbilical vein changes in fetal diaphragmatic hernia

changes in fetal diaphragmatic hernia Douglas Richards, David Kays Intermountain Medical Center and the University of Utah, Maternal Fetal Medicine, Murray, UT, University of Florida, Pediatric Surgery, Gainesville, FL OBJECTIVE: Deviation of the intraabdominal umbilical vein has been described as a marker of congenital diaphragmatic hernia and has been shown to help identify liver prolapse into the fetal chest. Deviation has previously been described only as a subjective finding. The purpose of this study is to quantify the degree of deviation in affected fetuses and to determine the accuracy of measurements for determining liver prolapse. STUDY DESIGN: In patients undergoing prenatal sonography for CDH the mid-hepatic portion of the umbilical vein was identified, and the distance between the lateral edge of the vein and the inner rib margin was measured. The same was done on the right, and the ratio of left to right measurement was termed the umbilical vein ratio (UVR). For this analysis, deviation of the UV, as quantified by the UVR, was used to predict the presence and side of the hernia, as well as to diagnose liver prolapse. The 5th and 95th confidence limits for the normal UVR were determined from 80 unaffected fetuses. Of 160 cases of CDH seen at our center between 11/1995 and 9/2010, 56 fetuses were studied prospectively, and 76 had adequate images available for retrospective measurements. The first sonogram at our center was used for analysis. RESULTS: The gestational age at the time of the ultrasound was 29.4 / 6.2 weeks. Of the 132 patients, 14 had a right-sided and 118 had a left-side hernia. All but one of the cases with right-sided hernias had an UVR above the normal range, and all had liver prolapse. Of those with a left-sided hernia, only 2 had a ratio within the normal range. Of those with a left-sided hernia, an UVR of 0.4 was shown by ROC analysis to be the best predictor of liver prolapse. This cut off had a sensitivity of 0.89 for predicting prolapse, with a false positive rate of 0.14. CONCLUSION: 93% of right-sided CDH and 98% of left-sided lesions have an UVR outside of the normal range. This demonstrates that deviation may a useful indicator of CDH in screening ultrasound examinations. A UVR less 0.4 is predictive of liver prolapse.

Association of Intrathoracic Herniation of the Liver with Left Heart Hypoplasia in Fetuses with a Left Diaphragmatic Hernia but not in Fetuses with a Right Diaphragmatic Hernia

Predominant left heart hypoplasia is commonly observed in human fetuses with left diaphragmatic hernia and intrathoracic liver herniation ("liver-up"). In contrast, marked left/right heart disproportion has not been described in fetuses with right diaphragmatic hernia, despite intrathoracic herniation of large parts of the liver. We analyzed the data of 15 fetuses with left diaphragmatic hernia and 10 fetuses with right diaphragmatic hernia and all with intrathoracic liver herniation ("liver-up") that were examined with fetal echocardiography between 21 weeks + 1 day and 35 weeks + 0 days of gestation. The inflow and outflow dimensions and Z-scores of the two groups were statistically compared. In addition, ductus venosus streaming patterns were examined. Despite the presence of intrathoracic liver herniation, predominant left heart hypoplasia, defined as a mitral valve Z-score < - 2 in combination with a tricuspid valve Z-score that was at least 2 Z larger than the mitral valve Z-score in an individual fetus, was observed in 11 of the 15 fetuses with left diaphragmatic hernia but in none of the 10 fetuses (p < 0.001) with right diaphragmatic hernia. Preferential streaming to the right heart was observed in 14 of the 15 fetuses with left hernia but in none of the 7 fetuses with right diaphragmatic hernia in whom this flow information was available (p < 0.0001). Intrathoracic herniation of the liver ("liver-up") is associated with predominant left heart hypoplasia in left diaphragmatic hernia but not right fetal diaphragmatic hernia. Our observations indicate that this difference may result from different ductus venosus streaming sites in these conditions.

Intrathoracic Herniation of the Liver ("Liver-Up") is Associated with Predominant Left Heart Hypoplasia in Left but not Right Fetal Diaphragmatic Hernia

Predominant left heart hypoplasia is commonly observed in human fetuses with left diaphragmatic hernia and intrathoracic liver herniation (“liver-up”). In contrast, marked left/right heart dysproportion has not been described in fetuses with right diaphragmatic hernia, despite intrathoracic herniation of large parts of their liver.

Prenatal Ultrasonographic Diagnosis of Congenital Diaphragmatic Hernia at 11 Weeks Gestation

Congenital diaphragmatic hernia is a major malformation. Early diagnosis is in itself an important factor for the prediction of the outcome. The authors present a case of left-sided fetal diaphragmatic hernia diagnosed by transvaginal ultrasound examination at 10 weeks, 5 days gestation.

Insulin-like growth factor-I gene expression in three models of accelerated lung growth

Background/Purpose : We have learned previously that in utero tracheal ligation reverses the structural and physiological effects of surgically created congenital diaphragmatic hernia. In addition, we have discovered that postnatal lung growth similarly can be accelerated using liquid-based airway distension with perfluorocarbon. Another model of accelerated lung growth is that of compensatory growth seen after neonatal pneumonectomy. In all of these models, growth has occurred because of an increase in alveolar number rather than enlargement of preexisting alveoli. However, the molecular mechanisms underlying these processes remain unknown. The purpose of this study was to determine if gene expression could be altered by changes in physical forces in the prenatal and postnatal lung. Methods : The three models of accelerated lung growth studied were the following: (1) The prenatal group, consisted of fetal lambs (n = 12) that underwent the surgical creation of a left diaphragmatic hernia at 90 days' gestation. Six of these animals also underwent simultaneous tracheal ligation. (2) The PFC group consisted of five neonatal animals that underwent isolation of the superior segment of the right upper lobe, with intrabronchial distension with perfluorocarbon to 7 to 10 mm Hg pressure for a 3-week period. (3) The postpneumonectomy group consisted of four neonatal animals that underwent left pneumonectomy. In the fetal study, lungs were retrieved at term (130 days), and in the postnatal study, lungs were retrieved 3 weeks after initial intervention. In all cases, RNA was extracted from snap-frozen lung samples and Northern blot analysis performed. Results : Insulinlike growth factor-I, insulinlike growth factor-II, and vascular endothelial growth factor gene expression were analyzed by densitometry. Insulinlike growth factor-I gene expression was found to be decreased in association with experimental diaphragmatic hernia ( P = .005), but restored to normal with tracheal ligation. Insulinlike growth factor-I gene expression was significantly increased in both postnatal models of accelerated lung growth ( P = .022, P = .016). No significant differences were found in insulinlike growth factor-II or vascular endothelial growth factor gene expression. Conclusions : The authors conclude from these preliminary data that (1) insulin like growth factor-I gene expression is reduced in experimental fetal diaphragmatic hernia and restored to normal by tracheal ligation, and (2) insulinlike growth factor-I gene expression is increased in both the liquid-based airway distension and postpneumonectomy models of accelerated postnatal lung growth. The authors speculate that all of these manipulations exploit a natural pathway essential for normal lung growth.

Fetal surgery: a brief review.

Fetal therapy is a logical extension of fetal diagnosis. Fetal surgery has been performed in humans for the past 10 years. During this time, technical obstacles have been overcome and the natural history of many fetal disorders has been defined. A select group of disorders amenable to potential improvement by fetal treatment has been identified including fetal urinary tract obstruction, fetal diaphragmatic hernia, fetal congenital cystic adenomatoid malformation and fetal sacrococcygeal teratoma. The fetal surgical experience with each of these lesions is reviewed and the maternal risk of fetal surgery is discussed.

Morphometric Analysis of Pulmonary Development in the Sheep Following Creation of Fetal Diaphragmatic Hernia

Morphometric Analysis of Pulmonary Development in the Sheep Following Creation of Fetal Diaphragmatic Hernia