Fetal Congenital Diaphragmatic Hernia Research Articles

Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment.

Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs. We identified that intra-amniotically injected AFSC-EVs reach the fetal lung in rats with CDH, where they promote lung branching morphogenesis and epithelial cell differentiation. Moreover, snRNA-seq revealed that rat fetal CDH lungs have a multilineage inflammatory signature with macrophage enrichment, which is reversed by AFSC-EV treatment. Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses.

Bias in the prenatal lung measurements in fetal congenital diaphragmatic hernia with intrauterine growth restriction.

The failure of a fetus to develop to its full potential due to maternal or placental factors is known as intrauterine growth restriction (IUGR). Fetal head growth is usually preserved in that situation producing a potential discordance between head and body size. Our goal is to discover if IUGR has an impact on the prenatal ultrasound measurements taken to assess pulmonary development in congenital diaphragmatic hernia (CDH). A retrospective chart review (IRB#2017-6361) was performed on all prenatally diagnosed CDH patients from 2007 to 2016. Patient demographics, fetal and neonatal anthropometric measurements, and fetal lung parameters were the main subjects of the data that were gathered. Fetal growth was assessed by the curves based on US data by Olsen etal. and by Peleg etal. Of 147 CDH patients, 19 (12.9 %) patients were diagnosed with IUGR before the 30th gestational week while there were 20 (13.6 %) patients after the 30th gestational week. Patients with IUGR and the observed-to-expected lung-to-head ratio (O/E LHR) less than 25 % had better survival rates both to discharge and date compared to non IUGR group (p=0.226, OR 2.25 95 % CI 0.60-1.08 and p=0.175, OR 2.40 95 % CI 0.66-1.17, respectively). Moreover, the ECMO need of the patients who had IUGR and O/E LHR less than 25 % was significantly less than the patients without IUGR (38.5 vs. 80.0 %, p=0.005). This study confirms that the intrauterine measurements to predict pulmonary hypoplasia in CDH patients are misleading in the presence of IUGR and cause an overestimation.

Management advances for congenital diaphragmatic hernia: integrating prenatal and postnatal perspectives.

In congenital diaphragmatic hernia (CDH), abdominal organs are displaced into the chest, compress the lungs, and cause mediastinal shift. This contributes to development of pulmonary hypoplasia and hypertension, which is the primary determinant of morbidity and mortality for affected newborns. The severity is determined using prenatal imaging as early as the first trimester and is related to the laterality of the defect, extent of lung compression, and degree of liver herniation. Comprehensive evaluation of fetal CDH includes imaging-based severity assessment, severity assessment, and evaluation for structural or genetic abnormalities to differentiate isolated from complex cases. Prenatal management involves multispecialty counseling, consideration for fetal therapy with fetoscopic endoluminal tracheal occlusion (FETO) for severe cases, monitoring and intervention for associated polyhydramnios or signs of preterm labor if indicated, administration of antenatal corticosteroids in the appropriate setting, and planned delivery to optimize the fetal condition at birth. Integrated programs that provide a smooth transition from prenatal to postnatal care produce better outcomes. Neonatal care involves gentle ventilation to avoid hyperinflation and must account for transitional physiology to avoid exacerbating cardiac dysfunction and decompensation. Infants who have undergone and responded to FETO have greater pulmonary capacity than expected, but cardiac dysfunction seems unaffected. In about 25-30% of CDH neonates extracorporeal life support is utilized, and this provides a survival benefit for patients with the highest predicted mortality, including those who underwent FETO. Surgical repair after initial medical management for the first 24-48 hours of life is preferred since later repair is associated with delayed oral feeding, increased need for tube feeds, and increased post-repair ventilation requirement and supplemental oxygen at discharge. With overall survival rates >70%, contemporary care involves management of chronic morbidities in the context of a multidisciplinary clinic setting.

Intra-Amniotic Sildenafil and Rosiglitazone Late in Gestation Ameliorate the Pulmonary Hypertension Phenotype in Congenital Diaphragmatic Hernia

BackgroundPulmonary hypertension remains difficult to manage in congenital diaphragmatic hernia (CDH). Prenatal therapy may ameliorate postnatal pulmonary hypertension. We hypothesized that intra-amniotic (IA) injection of either sildenafil, a phosphodiesterase 5 inhibitor, or rosiglitazone, a PPAR-γ agonist, or both late in gestation would decrease the detrimental pulmonary vascular remodeling seen in CDH and improve peripheral pulmonary blood flow. MethodsPregnant rats were gavaged with nitrogen on embryonic day (E) 9.5 to induce fetal CDH. Sildenafil and/or rosiglitazone were administered to each fetus via an intra-amniotic injection after laparotomy on the pregnant dam at E19.5, and fetuses delivered at E21.5. Efficacy measures were gross necropsy, histology, peripheral blood flow assessment using intra-cardiac injection of a vascular tracer after delivery, and protein expression analysis. ResultsIntra-amniotic injections did not affect fetal survival, the incidence of CDH, or lung weight-to-body weight ratio in CDH fetuses. IA sildenafil injection decreased pulmonary vascular muscularization, and rosiglitazone produced an increase in peripheral pulmonary blood flow distribution. The combination of sildenafil and rosiglitazone decreased pulmonary artery smooth muscle cell proliferation. These intra-amniotic treatments did not show any negative effects in either CDH fetuses or control fetuses. ConclusionIA injection of sildenafil and rosiglitazone late in gestation ameliorates the pulmonary hypertensive phenotype of CDH and may have utility in clinical translation. Level of EvidenceNot applicable.

Konjenital Diyafragma Hernisi Tanılı Fetüslerde Prognostik Marker Olarak Mide Pozisyonu

Aim: To examine the relationship between stomach position and neonatal survival in congenital diaphragmatic hernia (CDH). 
 Materials and Method: A total of 36 pregnant women with a diagnosis of fetal CDH, aged between 18-45 years and 22-39 weeks of gestation, who applied Ankara City Hospital Perinatology clinic between December 2019 and December 2022, were analyzed retrospectively. Pregnancies were classified into two categories based on neonatal survival. Demographic characteristics, clinical features and contralateral lung size/head circumference (LHR) ratio, stomach position, and other prognostic indicators were evaluated among the survivor (n=8) and non-survivor (n=22) groups. 
 Results: The mean maternal age was 29.30 ± 1.02 (range 17-40), and 36% (13/36) of the patients were primigravid. The median gestational week at diagnosis was 25.10 (13.5-37.6). There was no statistically significant difference between the survivor and non-survivor groups in terms of CDH type, liver position, gestational week at diagnosis, and median LHR. Grade 2 stomach position was found to be statistically significantly higher in the survivor group (p=0.01). Operation rate and 1st-5th minute Apgar scores were higher than in the non-survivor group (p=0.02, p=0.01, and p=0.00, respectively). 
 Conclusion: Stomach position grading in CDH is a practical and applicable method associated with neonatal survival, and grade 2 stomach position may be a marker associated with increased survival in fetuses with CDH regardless of LHR. It may be useful in assessing neonatal prognosis and planning perinatal management, such as maternal transfer to a tertiary center where fetal interventions are available.

Overactivated Epithelial NF-κB Disrupts Lung Development in Congenital Diaphragmatic Hernia.

Abnormal lung development is the main cause of morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH), a common birth defect (1:2500) of largely unknown pathobiology. Recent studies discovered that inflammatory processes, and specifically NF-κB associated pathways are enriched in human and experimental CDH. However, the molecular signaling of NF-κB in abnormal CDH lung development and its potential as a therapeutic target requires further investigation. Using sections and hypoplastic lung explant cultures from the nitrofen rat model of CDH and human fetal CDH lungs, we demonstrate that NF-κB and its downstream transcriptional targets are hyperactive during abnormal lung formation in CDH. NF-κB activity was especially elevated in the airway epithelium of nitrofen and human CDH lungs at different developmental stages. Fetal rat lung explants had impaired pseudoglandular airway branching after exposure to nitrofen, together with increased phosphorylation and transcriptional activity of NF-κB. Dexamethasone, the broad and clinically applicable anti-inflammatory NF-κB antagonist, rescued lung branching and normalized NF-κB signaling in hypoplastic lung explants. Moreover, specific NF-κB inhibition with curcumenol similarly rescued ex vivo lung hypoplasia and restored NF-κB signaling. Lastly, we showed that prenatal intraperitoneal dexamethasone administration to pregnant rat dams carrying fetuses with hypoplastic lungs, significantly improves lung branching and normalizes NF-κB in vivo. Our results indicate that NF-κB is aberrantly activated in human and nitrofen CDH lungs. Anti-inflammatory treatment with dexamethasone and/ or specific NF-κB inhibition should be investigated further as a therapeutic avenue to target lung hypoplasia in CDH.

Fetal lung hypoxia and energetic cell failure in the nitrofen-induced congenital diaphragmatic hernia rat model.

Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development. To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1. The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase. Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.

Additive value of fetal MRI to different ultrasound modalities in diagnosis of fetal GIT and abdominal wall anomalies

BackgroundFetal MRI is a valuable supplementary study to the prenatal US in accurate diagnosis of fetal gastrointestinal anomalies and ventral abdominal wall anomalies, which has an impact on the postnatal outcome.Aim of workTo establish the additive role of fetal MRI to the prenatal US in the identification of complex fetal GIT anomalies.MethodsThis prospective study involved 36 pregnant patients with age range from 19 to 41 years (mean ± SD of 27.8 ± 5.3 years). Thirty-six fetuses (19 males and 17 females). All cases underwent dedicated 2D obstetric ultrasound assessment with a focus on the fetal abdomen and some cases required additional 3D and 4D assessment. Twenty-seven patients underwent fetal MRI procedures.ResultsIn our study, fetal MRI was significantly more accurate than US in the confirmation and accurate delineation of the level of small bowel obstruction and differentiation of complete obstruction from luminal stenosis. In cases of anorectal malformations, prenatal US and fetal MRI were equally sensitive in the detection of their associated findings. While fetal MRI was superior to the US in the case of congenital chloride diarrhea. MRI images added the presence of distended oropharynx in esophageal atresia cases while other findings were detected with the same accuracy with both US and MRI. In cases of ventral abdominal wall defects, fetal MRI added fine details about the true size of the defect, the actual content of the abdominal wall defect as well as the detection of the presence of large bowel loops and related complications. In the category of fetal abdominal cysts, fetal MRI was superior to the US owing to its greater soft tissue characterization. In the case of sacrococcygeal teratoma (SCT), fetal MRI detected an additional intra-pelvic extension upgrading the tumor and detecting the true size of the intra-spinal component. In the category of congenital diaphragmatic hernia, MRI was superior in the detection of hernia capsule, herniated liver, and associated complications as well as accurate estimation of fetal lung volume. Studying the cases of cloacal malformations showed that owing to better tissue characterization by MRI the anomaly and its associated abnormal genitourinary communication were better delineated by MRI. The sensitivity of MRI to detect congenital anomalies concerning postnatal findings was 100%, the specificity was 50% and diagnostic accuracy was 96.6%. The sensitivity of ultrasound to detect congenital anomalies concerning postnatal findings was 85.3%, the specificity was 89%, and diagnostic accuracy was 80.6%. The sensitivity of combined US and MRI to detect congenital anomalies concerning postnatal findings was 100%, the specificity was 89%, and diagnostic accuracy was 93.1%.ConclusionsFetal MRI is a valuable supplementary study to the prenatal US in accurate diagnosis of fetal obstructive gastrointestinal anomalies, ventral abdominal wall anomalies, fetal abdominal cysts, masses, and congenital diaphragmatic hernia. Fetal MRI is equally sensitive to the prenatal US in anorectal malformations.

A Tracheal Aspirate-derived Airway Basal Cell Model Reveals a Proinflammatory Epithelial Defect in Congenital Diaphragmatic Hernia.

Rationale: Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. Objectives: To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing. Methods: We developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells (BSCs) from patients with CDH and preterm and term non-CDH control subjects were derived and analyzed by bulk RNA sequencing, assay for transposase accessible chromatin with sequencing, and air-liquid interface differentiation. Lung sections from fetal human CDH samples and the nitrofen rat model of CDH were subjected to histological assessment of epithelial defects. Therapeutics to restore epithelial differentiation were evaluated in human epithelial cell culture and the nitrofen rat model of CDH. Measurements and Main Results: Transcriptomic and epigenetic profiling of CDH and control BSCs reveals a proinflammatory signature that is manifested by hyperactive nuclear factor kappa B and independent of severity and hernia size. In addition, CDH BSCs exhibit defective epithelial differentiation invitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, blockade of nuclear factor kappa B hyperactivity normalizes epithelial differentiation phenotypes of human CDH BSCs invitro and in nitrofen rat tracheas invivo. Conclusions: Our findings have identified an underlying proinflammatory signature and BSC differentiation defects as a potential therapeutic target for airway epithelial defects in CDH.

Termination of pregnancy after a prenatal diagnosis of congenital diaphragmatic hernia: Factors influencing the parental decision process.

To evaluate the incidence of termination of pregnancies (TOP) and factors associated with the decision for TOP in prenatally detected congenital diaphragmatic hernia (CDH). Single-centre retrospective cohort includes all prenatally detected CDH cases born between January 2009 and December 2021. Parental factors, such as parity, and fetal characteristics, such as disease severity, were collected. Descriptive statistics were used to present the data. Differences between terminated and continued pregnancies were analysed. The study population consisted of 278 prenatally detected CDH cases of which 80% detected <24weeks of gestation. The TOP rate was 28% in cases that were detected <24weeks of gestation. Twenty continued pregnancies resulted in either intrauterine fetal demise (n=6), preterm birth <24weeks (n=2), or comfort care after birth (n=12). The survival rate was 70% in the remaining 195 live born cases. Factors associated with the decision for TOP were additional fetal genetic or anatomical abnormalities (p<0.0001) and expected severity of pulmonary hypoplasia in left-sided CDH (p=0.0456). The decision to terminate a pregnancy complicated by fetal CDH depends on the severity of pulmonary hypoplasia and the presence of additional abnormalities. This emphasises the importance of early referral to expertise centres for detailed evaluation and multidisciplinary counselling.

Multimodality Evaluation of Fetal Congenital Diaphragmatic Hernia and Its Mimics

Multimodality Evaluation of Fetal Congenital Diaphragmatic Hernia and Its Mimics

Early functional analysis on the pulmonary hemodynamic effects of Transamniotic Stem Cell Therapy (TRASCET) in the nitrofen model of congenital diaphragmatic hernia

PurposeTransamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) has been shown to impact pulmonary vascular development and remodeling in experimental congenital diaphragmatic hernia (CDH), with secondary structural cardiac effects. We sought to determine whether TRASCET has any functional impact on term fetal pulmonary hemodynamics in the nitrofen model. MethodsTime-dated pregnant rat dams (n = 13) received nitrofen on gestational day 9 (E9) to induce fetal CDH. Fetuses (n = 155) were divided into three groups: untreated (n = 45), and two groups receiving volume-matched intra-amniotic injections on E17 of either saline (sham; n = 46), or a suspension of amniotic fluid-derived MSCs (afMSCs) (TRASCET; n = 64). Donor afMSCs were syngeneic, phenotyped by flow cytometry, and “primed” by exposure to interferon-gamma and interleukin-1beta prior to administration in vivo. At term (E21), fetuses underwent Doppler flow assessment at the mid-pulmonary artery and 4-chamber echocardiogram. Pulmonary vascular resistance was estimated by pulmonary artery acceleration time (PAAT), max velocity (MaxV) and velocity time integral (VTI). Cardiac function was assessed by global longitudinal strain (GLS) and ejection fraction (EF) using speckle analyses. Healthy fetuses (n = 11) served as additional controls. Statistical analysis was by the Mann-Whitney U test ResultsHigh resolution ultrasound data could be obtained from 8 to 13 fetuses per group. The PAAT and the PAAT normalized to cardiac cycle time were significantly improved by TRASCET compared to both untreated and sham-treated CDH (p = 0.004 to <0.001 in all pairwise comparisons). The flow profile sharpness (MaxV:VTI) was increased in untreated (p = 0.06) and sham (p = 0.01) groups but normalized by TRASCET (p<0.01). There was no difference in GLS between TRASCET and either the untreated or sham groups (p = 0.25 to p = 0.93). ConclusionTransamniotic stem cell therapy improves pulmonary vascular resistance in early term fetuses in the Nitrofen model of congenital diaphragmatic hernia. Further focus on the functional pulmonary hemodynamic impact of this therapy is justified. Level of EvidenceN/A (animal and laboratory study)

Neuraxial anesthesia in ex utero intrapartum therapy for parturients with fetal congenital diaphragmatic hernia: a prospective observational study

BackgroundCongenital diaphragmatic hernia (CDH) is characterized by defects in the fetal diaphragm and thoracic herniation of the abdominal viscera. The ex utero intrapartum treatment (EXIT) procedure is used to establish the fetal airway while on placental support. These EXIT procedures are commonly performed under general anesthesia, which increases maternal bleeding and the risk of insufficient placental perfusion subsequently. This study investigated the feasibility of performing neuraxial anesthesia for the EXIT procedure for fetal congenital diaphragmatic hernia to improve outcomes. MethodsParturients with fetal CDH who underwent an EXIT procedure between January 2019 and May 2021 in our institution were recruited. Variables evaluated included gestational age, surgical time, intra-operative blood loss, peri-operative hemoglobin, maternal complications, fetal lung-to-head ratio, time on placental bypass, and postnatal outcome. ResultsTwenty-two cases were included. All procedures were performed under neuraxial anesthesia. The median gestational age at the time of the EXIT procedure was 37 weeks. The median estimated blood loss was 200 mL. There was no report of an adverse maternal event. The placental bypass time was 142.9 ± 72.6 s, and access to the airway was successfully established within the bypass time. Twenty-one neonates reached an Apgar score of 9 at 5 min. In the first two hours after birth, the average pH of neonatal peripheral arterial blood was 7.35 ± 0.07 (n=19), and lactate level 1.85 ± 0.71 mmol/L (n=19). ConclusionsIn the EXIT procedure to establish an airway for fetal CDH, neuraxial anesthesia proved a feasible technique for maternal anesthesia.

Anaesthetic management of fetal congenital diaphragmatic hernia by EXIT: A case report

We present a case of congenital diaphragmatic hernia (CDH) diagnosed in the second trimester of pregnancy, with most of the stomach and part of the liver occupying half of the left hemithorax. Severe pulmonary hypoplasia is associated with reduced survival in patients with CDH. The pregnant woman was treated with Exutero intrapartum treatment (EXIT) at 38 weeks of gestation. Open fetal and EXIT procedures require maternal general anesthesia with volatile anesthetic and other medications to maintain uterine relaxation. Through this case, our team summarized some experience in perioperative period anesthetic management of EXIT. Keywords: CDH; EXIT procedure; fetal surgery; maternal anaesthesia.

Ретроспективный анализ результатов диагностики и лечения врожденной диафрагмальной грыжи плода, по данным перинатального консилиума

Study Objective: Analysis of the detection of congenital diaphragmatic hernia (CDH) in the fetus at the antenatal stage and perinatal outcomes of newborns with CDH in the Russian Federation in a sample of women who applied to the perinatal consultation of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after academician V.I. Kulakov. Study Design: Retrospective study. Materials and Methods. The study included 235 cases of CDH in fetuses and newborns were selected by the federal perinatal consultation of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after academician V.I. Kulakov. The following were retrospectively analyzed: medical and social characteristics of pregnant women, results of ultrasound and MRI examination of fetuses, delivery features and perinatal outcomes. Study Results. The number of women with fetal CDH in the perinatal consultation of the Center continues to grow every year. In 3/4 of the treated patients, fetal CDH was detected in the 2nd trimester of pregnancy, which exceeds the European level of detection. But against this background, an extremely low level of invasive prenatal diagnosis was noted. Detection using ultrasound and MRI of liver infection in the chest, including a group with a prognosis of high neonatal survival of 2.2–4 times. The perinatal mortality rate with CDH in the Centers detection is 43.4%. The most common method of delivery is the natural birth. The optimal term of delivery with the least increase in postnatal loss should be considered the period of 38–39 weeks of pregnancy. Forecast of survival of newborns. At the same time, the Apgar score does not have statistical indicators of differences in surviving and deceased newborns, regardless of the method of delivery, which is associated with a violation of child development. Conclusion. The level of detection of CDH and perinatal mortality of newborns is similar to the data of foreign perinatal centers that provide assistance to mothers and their newborns. Increasing the survival rate of newborns with CDH is possible with the development and implementation of an integrated system for diagnosing the severity of CDH, as this will open up the possibility of a personalized approach to the treatment of CDH. Keywords: congenital diaphragmatic hernia, perinatal mortality, perinatal consultation, pulmonary hypoplasia, cardiac compression.

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.

Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia.

Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H2), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain reaction analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveolarization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2′-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of protein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.

Influence of Gestational Age and Mode of Delivery on Neonatal Outcomes in Prenatally Diagnosed Isolated Congenital Diaphragmatic Hernia

Aim: The optimal gestational age (GA) at delivery and mode of delivery (MoD) for pregnancies with fetal congenital diaphragmatic hernia (CDH) is undetermined. The impact of early term (37–38 weeks 6 days) versus full term (39–40 weeks 6 days) and MoD on immediate neonatal outcomes in prenatally diagnosed isolated CDH cases was evaluated. Material and Methods: A retrospective chart review of pregnancies evaluated and delivered with the prenatal diagnosis of CDH between July 1, 2008, and December 31, 2018. The primary outcome was survival to hospital discharge. Secondary outcomes included neonatal intensive care unit (NICU) length of stay (LOS), extracorporeal membrane oxygenation (ECMO) requirement and need for supplemental oxygen at day 30 of life. Results: A total of 296 patients were prenatally evaluated for CDH and delivered in a single center during the study period. After applying exclusion criteria, data were available on 113 women who delivered early term and 72 women who delivered full term. Survival to hospital discharge was comparable between the 2 groups – 83.2% in the early term versus 93.1% in the full term (p = 0.07; 95% CI of 0.13–1.04). No difference was observed in any other secondary outcomes. MoD was stratified into spontaneous vaginal, induced vaginal, unplanned cesarean and scheduled cesarean delivery with associated neonatal survival rates of 74.2, 90.6, 89.7 and 88.2%, respectively, p = 0.13. The 5-min Apgar score was higher in the elective cesarean group (7.94) followed by the induced vaginal delivery group (7.8) compared to 7.17 and 7.18 in the spontaneous vaginal and unplanned cesarean groups, respectively (p = 0.03). The GA and MoD did not influence survival to hospital discharge nor NICU LOS in multivariate analysis. Conclusions: Though there were no significant differences in neonatal outcomes for early term compared to full term deliveries of CDH neonates, a trend toward improved survival rates and lower ECMO requirements in the full term group may suggest an underlying importance GA at delivery. Further studies are warranted to validate these findings.

Prenatal stomach position predicts gastrointestinal morbidity at 2 years in fetuses with left-sided congenital diaphragmatic hernia.

The long-term morbidity associated with isolated left-sided congenital diaphragmatic hernia (CDH) has been described previously. However, antenatal criteria impacting gastrointestinal morbidity (GIM) are not yet defined. The objective of this study was to evaluate the effect of fetal stomach position on the risk of GIM at 2 years of age in children with left-sided CDH. This was a retrospective, observational multicenter cohort study of data obtained from January 2010 to January 2014, that included patients whose fetus had isolated left-sided CDH, with or without fetal endoscopic tracheal occlusion (FETO). Prenatal maternal, fetal and pediatric data were collected. Fetal stomach position was evaluated a posteriori by two observers, using ultrasound images at the level of the four-chamber view of the heart that had been obtained to calculate the observed-to-expected lung-area-to-head-circumference ratio (O/E-LHR). Fetal stomach position was graded as follows: Grade 1, stomach not visualized; Grade 2, stomach visualized anteriorly, next to the apex of the heart, with no structure in between the stomach and the sternum; Grade 3, stomach visualized alongside the left ventricle of the heart, and abdominal structures anteriorly; or Grade 4, as Grade 3 but with stomach posterior to the level of the atrioventricular heart valves. The primary outcome was GIM at 2 years of age, assessed in a composite manner, including the occurrence of gastroesophageal reflux disease, need for gastrostomy, duration of parenteral and enteral nutrition and persistence of oral aversion. Regression analysis was performed in order to investigate the effect of O/E-LHR, stomach position and FETO on various GIM outcome variables. Forty-seven patients with fetal left-sided CDH were included in the analysis. Thirteen (27.7%) infants did not meet the criterion of exclusive oral feeding at 2 years of age. Fetal stomach position grade was associated significantly and independently with the duration of parenteral nutrition (odds ratio (OR), 19.86; P = 0.031) and persistence of oral aversion at 2 years (OR, 3.40; P = 0.006). On multivariate analysis, O/E-LHR was predictive of the need for prosthetic patch repair, but not for GIM. FETO did not seem to affect the risk of GIM at 2 years. In isolated left-sided CDH, fetal stomach position is the only factor that is predictive of GIM at 2 years of age. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

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.