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Congenital diaphragmatic hernia (CDH) can be diagnosed prenatally and its severity assessed by fetal imaging. The prognosis of a fetus with CDH is based on whether or not the hernia is isolated, the measurement of lung volume on ultrasound and MRI, and the position of the liver. The birth of a child with CDH should take place in a center adapted to the care of such children, and in accordance with the recommendations defined by the French National Diagnosis and Care Protocol. It has recently been demonstrated that for moderate and severe forms of CDH, tracheal occlusion using a balloon placed in utero by fetoscopy (FETO) increases survival until discharge from the neonatal unit, but at the cost of an increased risk of prematurity. At the same time, advances in neonatal resuscitation and the standardization of follow-up of these children within the framework of the "Centre de référence maladies rares: hernie de coupole diaphragmatique" have improved the prognosis of these children and young adults., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Temporary fetoscopic endoluminal tracheal occlusion (FETO) promotes lung growth and increases survival in selected fetuses with congenital diaphragmatic hernia (CDH). FETO is performed percutaneously by inserting into the trachea a balloon designed for vascular occlusion. However, reports on the potential postnatal side-effects of the balloon are scarce. This study aimed to evaluate the prevalence of tracheomalacia in infants with CDH managed with and without FETO and other consequences related to the use of the balloon., Methods: In this multicentre, retrospective cohort study, we included infants who were live born with CDH, either with FETO or without, who were managed postnatally at four centres (UZ Leuven, Leuven, Belgium; Antoine Béclère, Clamart, France; BCNatal, Barcelona, Spain; and HCor-Heart Hospital, São Paulo, Brazil) between April 5, 2002, and June 2, 2021. We primarily assessed the prevalence of all (symptomatic and asymptomatic) tracheomalacia as reported in medical records among infants with and without FETO. Secondarily we assessed the prevalence of symptomatic tracheomalacia and its resolution as reported in medical records, and compared tracheal diameters as measured on postnatal x-rays. Crude and adjusted risk ratios (aRRs) and 95% CIs were calculated via modified Poisson regression models with robust error variances for potential association between FETO and tracheomalacia. Variables included in the adjusted model were the side of the hernia, observed-to-expected lung-to-head ratio, and gestational age at birth. Crude and adjusted mean differences and 95% CIs were calculated via linear regression models to assess the presence and magnitude of association between FETO and tracheal diameters. In infants who had undergone FETO we also assessed the localisation of balloon remnants on x-rays, and the methods used for reversal of occlusion and potential complications associated with balloon remnants as documented in clinical records. Finally we investigated whether the presence of balloon remnants was influenced by the interval between balloon removal and delivery., Findings: 505 neonates were included in the study, of whom 287 had undergone FETO and 218 had not. Tracheomalacia was reported in 18 (6%) infants who had undergone FETO and in three (1%) who had not (aRR 6·17 [95% CI 1·83-20·75]; p=0·0030). Tracheomalacia was first reported in the FETO group at a median of 5·0 months (IQR 0·8-13·0). Symptomatic tracheomalacia was reported in 13 (5%) infants who had undergone FETO, which resolved in ten (77%) children by 55·0 months (IQR 14·0-83·0). On average, infants who had undergone FETO had a 31·3% wider trachea (with FETO tracheal diameter 7·43 mm [SD 1·24], without FETO tracheal diameter 5·10 mm [SD 0·84]; crude mean difference 2·32 [95% CI 2·11-2·54]; p<0·0001; adjusted mean difference 2·62 [95% CI 2·35-2·89]; p<0·0001). At birth, the metallic component was visible within the body in 75 (37%) of 205 infants with available thoraco-abdominal x-rays: it was located in the gastrointestinal tract in 60 (80%) and in the lung in 15 (20%). No side-effects were reported for any of the infants during follow-up. The metallic component was more likely to be in the lung than either outside the body or the gastrointestinal tract when the interval between occlusion reversal and birth was less than 24 h., Interpretation: Although FETO was associated with an increased tracheal diameter and an increased probability of tracheomalacia, symptomatic tracheomalacia typically resolved over time. There is a higher risk of retention of metallic balloon components if reversal of the occlusion occurs less than 24 h before delivery. Finally, there were no reported side-effects of the metallic component of the balloon persisting in the body during follow-up. Longer-term follow-up is needed to ensure that no tracheal problems arise later in life., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The treatment of fetuses with a congenital diaphragmatic hernia is challenging, but there is evidence that fetoscopic endoluminal tracheal occlusion has a benefit over expectant care. In addition, standardization and expertism have a great impact on survival and are probably crucial in centers that rely on expectant management with extracorporeal membrane oxygenation after birth., Objective: This study aimed to examine the survival and morbidity rates of fetuses with a severe isolated left-sided congenital diaphragmatic hernia who underwent fetoscopic endoluminal tracheal occlusion vs expectant management in high-volume centers., Study Design: This was a multicenter, retrospective study that included all consecutive fetuses with severe isolated left-sided congenital diaphragmatic hernia who were expectantly managed in a German center or who underwent fetoscopic endoluminal tracheal occlusion in 3 other European centers (Belgium, France, and Italy). Severe congenital diaphragmatic hernia was defined as having an observed to expected total fetal lung volume ≤35% with intrathoracic position of the liver diagnosed with magnetic resonance imaging. All magnetic resonance images were centralized, and lung volumes were measured by 2 experienced operators who were blinded to the pre- and postnatal data. Multiple logistic regression analyses were performed to examine the effect of the management strategy in the 2 groups on the short- and long-term outcomes., Results: A total of 147 patients who were managed expectantly and 47 patients who underwent fetoscopic endoluminal tracheal occlusion were analyzed. Fetuses who were managed expectantly had lower observed to expected total fetal lung volumes (20.6%±7.5% vs 23.7%±6.8%; P=.013), higher gestational age at delivery (median weeks of gestation, 37.4; interquartile range, 36.6-38.00 vs 35.1; interquartile range, 33.1-37.2; P<.001), and more frequent use of extracorporeal membrane oxygenation (55.8% vs 4.3%; P<.001) than the fetuses who underwent fetoscopic endoluminal tracheal occlusion. The survival rates at discharge and at 2 years of age in the expectant management group were higher than the survival rates of the fetoscopic endoluminal tracheal occlusion group (74.3% vs 44.7%; P=.001 and 72.8% vs 42.5%; P=.001, respectively). After adjustment for maternal age, gestational age at birth, observed to expected total fetal lung volume, and birth weight Z-score, the odds ratios were 4.65 (95% confidence interval, 1.9-11.9; P=.001) and 4.37 (95% confidence interval, 1.8-11.0; P=.001), respectively., Conclusion: Fetuses with a severe isolated left-sided congenital diaphragmatic hernia had a higher survival rate when treated in an experienced center in Germany with antenatal expectant management and frequent use of extracorporeal membrane oxygenation during the postnatal period than fetuses who were treated with fetoscopic endoluminal tracheal occlusion in 3 centers in Belgium, France, and Italy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Introduction: One of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to reestablish airway patency. The "Smart-TO" (Strasbourg University-BSMTI, France) is a new balloon for FETO, which spontaneously deflates when positioned near a strong magnetic field, e.g., generated by a magnetic resonance image (MRI) scanner. Translational experiments have demonstrated its efficacy and safety. We will now use the Smart-TO balloon for the first time in humans. Our main objective is to evaluate the effectiveness of prenatal deflation of the balloon by the magnetic field generated by an MRI scanner., Material and Methods: These studies were first in human (patients) trials conducted in the fetal medicine units of Antoine-Béclère Hospital, France, and UZ Leuven, Belgium. Conceived in parallel, protocols were amended by the local Ethics Committees, resulting in some minor differences. These trials were single-arm interventional feasibility studies. Twenty (France) and 25 (Belgium) participants will have FETO with the Smart-TO balloon. Balloon deflation will be scheduled at 34 weeks or earlier if clinically required. The primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the magnetic field of an MRI. The secondary objective is to report on the safety of the balloon. The percentage of fetuses in whom the balloon is deflated after exposure will be calculated with its 95% confidence interval. Safety will be evaluated by reporting the nature, number, and percentage of serious unexpected or adverse reactions., Conclusion: These first in human (patients) trials may provide the first evidence of the potential to reverse the occlusion by Smart-TO and free the airways non-invasively, as well a safety data., Competing Interests: ’Nicolas Sananès is the primary co-inventor of the Smart-TO balloon. None of the authors has any financial interest in BS‐Medical Tech Industry, manufacturing the balloon. There are no other conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Sananès et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Gastro-esophageal reflux disease (GERD) is the most frequent long-term morbidity of congenital diaphragmatic hernia (CDH) survivors. Performing a preventive fundoplication during CDH repair remains controversial. This study aimed to: (1) Analyze the variability in practices regarding preventive fundoplication; (2) Identify predictive factors for fundoplication. (3) Evaluate the impact of preventive fundoplication on gastro-intestinal outcomes in children with a CDH patch repair; METHODS: This prospective multi-institutional cohort study (French CDH Registry) included CDH neonates born in France between January 1st, 2010-December 31st, 2018. Patch CDH was defined as need for synthetic patch or muscle flap repair. Main outcome measures included need for curative fundoplication, tube feed supplementation, failure to thrive, and oral aversion., Results: Of 762 CDH neonates included, 81 underwent fundoplication (10.6%), either preventive or curative. Median follow-up was 3.0 years (IQR: 1.0-5.0). (1) Preventive fundoplication is considered in only 31% of centers. The rates of both curative fundoplication (9% vs 3%, p = 0.01) and overall fundoplication (20% vs 3%, p < 0.0001) are higher in centers that perform preventive fundoplication compared to those that do not. (2) Predictive factors for preventive fundoplication were: prenatal diagnosis (p = 0.006), intra-thoracic liver (p = 0.005), fetal tracheal occlusion (p = 0.002), CDH-grade C-D (p < 0.0001), patch repair (p < 0.0001). After CDH repair, 8% (n = 51) required curative fundoplication (median age: 101 days), for which a patch repair was the only independent predictive factors identified upon multivariate analysis. (3) In neonates with patch CDH, preventive fundoplication did not decrease the need for curative fundoplication (15% vs 11%, p = 0.53), and was associated with higher rates of failure to thrive (discharge: 81% vs 51%, p = 0.03; 6-months: 81% vs 45%, p = 0.008), tube feeds (6-months: 50% vs 21%, p = 0.02; 2-years: 65% vs 26%, p = 0.004), and oral aversion (6-months: 67% vs 37%, p = 0.02; 1-year: 71% vs 40%, p = 0.03)., Conclusions: Children undergoing a CDH patch repair are at high risk of requiring a curative fundoplication. However, preventive fundoplication during a patch repair does not decrease the need for curative fundoplication and is associated with worse gastro-intestinal outcomes in children., Level of Evidence: II - Prospective Study., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: The congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and lung hypoplasia, is a common and severe birth defect that affects around 1 in 4000 live births. However, the etiology of most cases of CDH remains unclear. The aim of this study was to perform a retrospective analysis of copy number variations (CNVs) using a high-resolution array comparative genomic hybridization (array-CGH) in a cohort of fetuses and newborns with CDH., Methods: Forty seven fetuses and newborns with either isolated or syndromic CDH were analyzed by oligonucleotide-based array-CGH Agilent 180K technique., Results: A mean of 10.2 CNVs was detected by proband with a total number of 480 CNVs identified based on five categories: benign, likely benign, of uncertain signification, likely pathogenic, and pathogenic. Diagnostic performance was estimated at 19.15% (i.e., likely pathogenic and pathogenic CNVs) for both CDH types. We identified 11 potential candidate genes: COL25A1, DSEL, EYA1, FLNA, MECOM, NRXN1, RARB, SPATA13, TJP2, XIRP2, and ZFPM2., Conclusion: We suggest that COL25A1, DSEL, EYA1, FLNA, MECOM, NRXN1, RARB, SPATA13, TJP2, XIRP2, and ZFPM2 genes may be related to CDH occurrence. Thus, this study provides a possibility for new methods of a positive diagnosis., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27 +0 to 29 +6 weeks' gestation (referred to as "early") for severe and at 30 +0 to 31 +6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia., Objective: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion., Study Design: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity., Results: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints., Conclusion: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Congenital diaphragmatic hernia can be diagnosed in the prenatal period and its severity can be measured by fetal imaging. There is now level I evidence that, in selected cases, Fetoscopic Endoluminal Tracheal Occlusion with a balloon increases survival to discharge from the neonatal unit as well as the risk for prematurity. Both effects are dependent on the time point of tracheal occlusion. Fetoscopic Endoluminal Tracheal Occlusion may also lead to iatrogenic death when the balloon cannot be timely retrieved. The implementation of the findings from our clinical studies, may also vary based on local conditions. These may be different in terms of available skill set, access to fetal therapy, as well as outcome based on local neonatal management. We encourage prior benchmarking of local outcomes with optimal postnatal management, based on large enough numbers and using identical criteria as in the recent trials. We propose to work further on prenatal prediction methods, and the improvement of fetal intervention. In this manuscript, we describe a research agenda from a fetal medicine perspective. This research should be in parallel with innovation in neonatal and pediatric (surgical) management of this condition., (© 2022 John Wiley & Sons Ltd.)

Objective: To evaluate various signal intensity ratios in isolated congenital diaphragmatic hernia (CDH) and to compare their potential in predicting survival with that of the observed-to-expected (O/E) ratio of total fetal lung volume (TFLV) using magnetic resonance imaging (MRI) measurements. Our second objective was to evaluate the impact of operator's experience in comparing the prediction of postnatal survival by O/E-TFLV., Methods: In 75 conservatively managed CDH fetuses and in 50 who underwent fetoscopic endoluminal tracheal occlusion (FETO), the fetal lung-to-amniotic fluid, lung-to-liver, lung-to-muscle, lung-to-spinal fluid signal intensity ratios, respectively LAFSIR, LLSIR, LMSIR, and LSFSIR, were measured, as was O/E-TFLV. Receiver operating characteristic (ROC) curves were constructed and used to compare the various signal intensity ratios with O/E-TFLV in the prediction of postnatal survival. In 72 MRI lung volumes assessed by the referring radiologists in Paris and Lille and secondarily by our expert radiologist in Brussels (M.M.C.) using the same MRI examinations, ROC curves were constructed and used to compare the value of O/E-TFLV determined by the two centers in the prediction of postnatal survival., Results: In the total cohort of CDH fetuses, O/E-TFLV and LLSIR were predictive of postnatal survival whereas in the conservatively managed group O/E-TFLV, LLSIR, and LMSIR predicted postnatal survival. O/E-TFLV predicted postnatal survival far better than the signal intensity ratios: area under the ROC curve for prediction by O/E-TFLV in the total cohort was 0.866 ( p  < .001; standard error = 0.031). The area under the ROC curve for prediction of postnatal survival using O/E-TFLV by MRI evaluated at the referral centers was 0.640 ( p  = 102; standard error = 0.085), and with O/E-TFLV reevaluated by M.M.C., it was 0.872 ( p  < .001; standard error = 0.061). Pairwise comparison showed a significant difference between the areas under the ROC curves (difference = 0.187, p  = .012; standard error = 0.075)., Conclusion: In fetuses with CDH with/without FETO, LLSIR was significantly correlated with the prediction of postnatal survival. However, measurement of O/E-TFLV was far better in predicting postnatal outcome. Operator experience in measurement of lung volumes using MRI seem to play a role in the predictive value of the technique.

Objective: 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)., Methods: 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., Results: 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., Conclusion: Interrater agreement for stomach position assessment in CDH was poor across NAFTNet and indeed amongst expert reviewers., (© 2021 John Wiley & Sons Ltd.)

Congenital diaphragmatic hernia (CDH) is characterized by a defect in the muscle dividing the thoracic and abdominal cavities. This leads to herniation of the abdominal organs into the thorax and a disturbance of lung development. Two-thirds of cases are identified by prenatal ultrasound in the second trimester, which should prompt referral to a tertiary center for prognosis assessment and counseling by a multidisciplinary team familiar with this condition. In this review, we summarize evidence on prenatal diagnosis and postnatal management of CDH. There is a focus on information that should be provided to expecting parents during prenatal counseling., (© 2020 John Wiley & Sons Ltd.)

Background: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease., Methods: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age., Results: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal., Conclusions: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking., Methods: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women., Results: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09)., Conclusions: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Congenital diaphragmatic hernia (CDH) is, depending of the severity, a birth defect associated with significant mortality and morbidity. Prenatal screening by ultrasound may detect this condition and comprehensive assessment of severity is possible, allowing for in utero referral to an experienced centre for planned delivery. In an effort to improve outcomes, prenatal interventions to stimulate lung development were proposed. Along the same lines, new postnatal management strategies are being developed. In order to enable proper comparison of novel perinatal interventions as well as outcomes, a set of uniform and relevant outcome measures is required. Core outcome sets (COS) are agreed, clearly defined sets of outcomes to be measured in a standardised manner and reported consistently. Herein we aim to describe the methodology we will use to define a COS for perinatal and neonatal outcomes of foetuses and newborns with congenital diaphragmatic hernia and to draft a dissemination and implementation plan., Methods: We will use the methodology described in the Core Outcome Measures in Effectiveness Trials (COMET) Initiative Handbook. An international steering group will be created to guide the development of the COS. We are systematically reviewing the literature to identify all potential relevant pre- and neonatal outcomes previously used in studies on perinatal interventions for CDH. We will build a consensus on these core outcomes in a stakeholder group using the Delphi method. After completion, a stakeholder meeting will decide on a final COS, using a modified Nominal Group Technique. Thereafter, we will review potential definitions and measurements of these outcomes, and again a consensus meeting will be organised, to finalise the COS before dissemination., Discussion: We have started a procedure to develop a COS for studies on perinatal interventions for congenital diaphragmatic hernia, with the purpose of improving the quality of research, guide clinical practice and improve patient care and eventual use in future clinical trials, systematic reviews and clinical practice guidelines., Trial Registration: We prospectively registered this study in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019124399 ) and The Core Outcome Measures in Effectiveness Trials (COMET) Initiative (registration number: 1296 ).

Objectives: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival., Methods: This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care. We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes., Results: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26)., Conclusion: Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH., (© 2020 John Wiley & Sons, Ltd.)

Antenatal ultrasound screening identifies more than 60% of Congenital Diaphragmatic Hernia (CDH) cases and provides the opportunity for in utero referral to a tertiary care center for expert assessment and perinatal management. Prenatal assessment of fetuses with CDH has tremendously improved over the past ten years. The outcome may be predicted prenatally by medical imaging and advanced genetic testing. The combination of lung size and liver position determination by ultrasound measurements and MRI are widely accepted methods to stratify fetuses into groups that correlate not only with neonatal mortality but also with morbidity. Notwithstanding this, prediction of persistent pulmonary hypertension of the newborn still needs to be improved., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To evaluate variability in antenatal sonographic prognostication of congenital diaphragmatic hernia (CDH) within the North American Fetal Therapy Network (NAFTNet)., Methods: NAFTNet centre were invited to complete a questionnaire and participate in videoconference calls, during which participants were observed while measuring lung area by ultrasound using the anteroposterior (AP) method, longest method, and trace method. Each center identified 1-2 experienced fetal medicine specialist(s) or medical imaging specialists locally to participate in the study. Practices were compared among NAFTNet centre within and without the fetal endoscopic tracheal occlusion (FETO) consortium., Results: Nineteen participants from 9 FETO center and 30 participants from 17 non-FETO center completed the survey and 31 participants were interviewed and observed while measuring sonographic lung area. All Centres measured observed-to-expected lung-to-head ratio (o/e LHR) or LHR for CDH prognostication. Image selection criteria for lung area measurement were consistent, including an axial section of the chest with clear lung borders and a 4-chamber cardiac view. Lung area measurement methods varied across NAFTNet, with most centre using longest (4/9 FETO vs. 13/29 non-FETO) or trace (3/9 FETO vs. 11/29 non-FETO) method. Centres differed in expected reference ranges for o/e LHR determination and whether the lowest, highest or average o/e LHR was utilized., Conclusion: Variability in antenatal sonographic prognostication of CDH was identified across NAFTNet, indicating a need for consensus-based standardization., (© 2019 John Wiley & Sons, Ltd.)

Congenital diaphragmatic hernia is characterized by failed closure of the diaphragm, thereby allowing abdominal viscera to herniate into the thoracic cavity and subsequently interfering with normal lung development. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension (PHT), that is lethal in up to 32% of patients. In isolated cases, the outcome may be predicted prenatally by medical imaging and advanced genetic testing. In those fetuses with a predicted poor outcome, fetoscopic endoluminal tracheal occlusion may be offered. This procedure is currently being evaluated in a global randomized clinical trial (www.TOTALtrial.eu). We are currently investigating alternative strategies including transplacental sildenafil administration to reduce the occurrence of persistent PHT., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To determine the antenatal sonographic lung area measurement method in left congenital diaphragmatic hernia (CDH) with the highest interrater agreement among North American Fetal Therapy Network (NAFTNet) centers within and outside the fetoscopic tracheal occlusion (FETO) consortium and in comparison with a European "expert" reviewer (ER)., Methods: Nineteen members from nine FETO consortium centers and 29 reviewers from 17 non-FETO centers reviewed ultrasound clips of the chest from 13 fetuses with isolated left CDH and were asked to select a static plane for lung area measurement using anteroposterior (AP), longest, and trace methods. Interrater agreement in lung area measurements was determined using intraclass correlation coefficient (ICC). Bland-Altman analysis was used to evaluate mean difference (bias) between NAFTNet reviewers and ER., Results: Among FETO centers, agreement was highest using trace (ICC 0.94; 95% CI, 0.83-0.98), followed by longest (ICC 0.89; 95% CI, 0.75-0.97) and lowest for A-P (ICC 0.83; 95% CI, 0.67-0.94). Similar trends were noted in non-FETO centers. When compared with ER, bias was lowest for trace: 14 ± 38 mm 2 and 19 ± 36 mm 2 for FETO and non-FETO centers, respectively., Conclusion: The trace method demonstrated the highest interrater agreement and lowest bias for lung area estimation in left CDH across NAFTNet., (© 2019 John Wiley & Sons, Ltd.)

Background: Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans., Methods: This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/IIb study with as a primary objective to measure the in-vivo transplacental transfer of sildenafil in women in the second and early third trimester of pregnancy (sub-study 1; weeks: 20.0-32.6) and at term (sub-study 2; weeks: 36.6-40). Participants will be randomized to two different sildenafil doses: 25 or 75 mg. In sub-study 1, a single dose of the investigational product will be administered to women undergoing termination of pregnancy, and maternal and fetal blood samples will be collected for determination of sildenafil concentrations. In sub-study 2, sildenafil will be administered three times daily from 3 days before planned delivery until actual delivery, following which maternal and umbilical cord samples will be collected. Proxies of maternal and fetal tolerance as well as markers of fetal pulmonary vasodilation will also be measured., Discussion: This is the first study evaluating in-vivo transplacental passage of sildenafil in humans., Trial Registration: EU Clinical Trials Register 2016-002619-17, validated on 12 August 2016. Trial sponsor: UZ Leuven, Herestraat 49, 3000 Leuven.

Objective: To evaluate neonatal mortality and morbidity up to 6 months in neonates with congenital diaphragmatic hernia (CDH) with or without a hernia sac., Methods: Seventy-two cases of isolated CDH were included in a retrospective single-center study between January 2010 and December 2016. Hernia sac was defined at the time of surgery or at postmortem examination if the neonate died before surgery., Results: Seventeen newborns (23.6%) had a hernia sac. Survival at 6 months was significantly greater for isolated CDH with a hernia sac: 100% versus 63.6% (P = .003). High-frequency oscillatory ventilation was used significantly more in the no hernia sac group (P = .04). At surgery, the need for patch repair was significantly lower in the hernia sac group: 12% versus 50% (P = .005). The prenatal observed/expected lung-to-head ratio was significantly higher in the hernia sac group than in the no hernia sac group: 49.7% versus 38.6% (P < .05)., Conclusion: The presence of a hernia sac in CDH is associated with better outcome, especially survival at 6 months. If the presence of a hernia sac is recognized as a particular entity, which carries a good prognosis, it is necessary to be able to diagnose it prenatally, especially in the era of prenatal fetal surgery., (© 2018 John Wiley & Sons, Ltd.)

Congenital diaphragmatic hernia is a rare disease associated with high mortality and morbidity. Antenatal ultrasound screening identifies more than 70% of cases, providing the opportunity for in utero referral to a tertiary care center for expert assessment and perinatal management. Additional genetic and morphologic assessment may be used to rule out associated anomalies. In isolated cases, the outcome may be predicted prenatally by medical imaging. The combination of lung size and liver herniation is a widely accepted method to stratify fetuses into groups with an increasing degree of pulmonary hypoplasia and corresponding mortality rates. Ultrasound measurement of the observed to expected lung-to-head ratio (o/e LHR) is most widely used. The o/e LHR is an independent predictor of survival and short-term morbidity. Finally, evaluation of stomach position has recently been introduced as an indirect method to estimate severity of the disease in left-sided defects, as it has been shown to correlate with the proportion of intrathoracic liver. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated CDH and individualized prediction of neonatal outcome., (© 2018 John Wiley & Sons, Ltd.)

Rationale: Congenital diaphragmatic hernia (CDH) is associated with a high incidence of respiratory problems, even after initial hospital discharge. These problems are likely to lead to re-hospitalization during infancy, although actual frequency of readmissions is unknown., Objective: We aimed to determine the rate of hospitalization for wheezing in infants with CDH between the time of initial discharge and 24 months of age, and to identify factors associated with readmission., Methods: Data about infants with CDH born in three French reference tertiary centers between January 2009 and March 2013 who were alive at hospital discharge, were extracted from a prospective national database., Results: Ninety-two children were identified, and 86 were included in the analysis. In total, 116 wheezing episodes requiring a doctor's visit occurred in 50 infants (58%) before 24 months of age. Twenty-two children (26%) were readmitted at least once for wheezing exacerbations. RSV was present in 6 of 15 (40%) of children with available nasal samples at first readmission, and 1 of 5 (20%) at second readmission. Thoracic herniation of the liver, low gestational age, longer initial hospitalization, need for oxygen therapy at home, and eczema were all significantly associated with readmission for wheezing exacerbations. Fifty-three infants (62%) received palivizumab prophylaxis, but there was no association with the overall rate of readmission for wheezing exacerbations or RSV-related hospitalization., Conclusions: The rate of readmission for wheezing among infants with CDH is high, and significantly influenced by several prenatal and neonatal factors. Palivizumab prophylaxis was not associated with the rate of readmission.

Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined., (Copyright © 2016 the American Physiological Society.)

Objective: The aim of this study was to describe whether the prophylactic use of a cervical pessary decreases the rate of premature birth in congenital diaphragmatic hernia (CDH) fetuses treated with fetoscopic tracheal occlusion (FETO)., Methods: The study concerns a consecutive series of cases with CDH and FETO and a group of CDH without FETO. In a subgroup of the FETO group, a prophylactic cervical pessary was inserted the day following the procedure. Gestational age (GA) at birth was the primary outcome., Results: Fifty-nine fetuses with FETO and 47 expectantly managed were included. The last 15 FETO had a cervical pessary inserted. The median GA at delivery in the FETO group with pessary was 35.1 weeks and was not different from that in the FETO group without a pessary (34.3 weeks; p = 0.28) but was below that in the expectantly managed group (38.3 weeks; p < 0.001)., Conclusion: Early results suggest that prophylactic use of an Arabin cervical pessary does not prolong gestation of CDH fetuses treated with FETO. © 2015 John Wiley & Sons, Ltd., (© 2015 John Wiley & Sons, Ltd.)

Objective: The objective of the investigation was to study the relationship between gestational age at diagnosis and mortality and morbidity in fetuses with an isolated congenital diaphragmatic hernia., Study Design: Between January 2008 and November 2013, 377 live births with isolated congenital diaphragmatic hernia diagnosed antenatally at a known gestational age were recorded in the database of the French National Center for Rare Diseases. The primary outcome studied was mortality estimated at 28 days and at 6 months. The secondary outcome was morbidity evaluated by pulmonary arterial hypertension at 48 hours, oxygen therapy dependence at 28 days, oral disorders, enteral feeding, and prosthetic patch repair. Analyses were adjusted for the main factors of congenital diaphragmatic hernia severity (side of the hernia, thoracic herniation of the liver, gestational age at birth, lung-to-head ratio, and prenatal treatment by tracheal occlusion., Results: Mortality rates at 28 days decreased significantly (P < .001) when gestational age at diagnosis increased: 61.1%, 39.2%, and 10.4% for a diagnosis in the first, second, and third trimester, respectively. Adjusted odds ratios were 3.12 [95% confidence interval, 1.86-5.25] and 0.35 [95% confidence interval, 0.18-0.66] for a diagnosis in the first and third trimesters, respectively, compared with a diagnosis in the second trimester. Similarly, morbidity decreased significantly when gestational age at diagnosis increased, and the trend remained significant after adjustment for the main factors of congenital diaphragmatic hernia severity (P < .001)., Conclusion: Gestational age at diagnosis is an independent predictor of postnatal prognosis for children presenting an isolated congenital diaphragmatic hernia and should be taken into account when estimating postnatal morbidity and mortality., (Published by Elsevier Inc.)

Objective: To describe a new grading method for stomach position (SP) in fetuses with left-sided congenital diaphragmatic hernia (L-CDH) using ultrasound and to correlate SP to liver position and to liver-to-thoracic cavity volume ratio (LiTR) using magnetic resonance imaging., Methods: SP were graded at the level of the 4-chamber view as following: grade 1-to-4 for stomach not visualised, visualised anteriorly at the apex of the heart, stomach showing abdominal structures anteriorly and stomach with its larger part posterior to the level of the atrial-ventricular heart valves, respectively. The LiTR was calculated and correlated to SP using the Mann-Whitney U test., Results: Seventy-four fetuses were included. Median LiTR for grade 1 SP was 0% and was not different from median LiTR for grade 2 SP (0%, p=NS). Median LiTR for grade 3 SP was 14.9% and was significantly higher than for grade 2 SP (p<0.001). Similarly, median LiTR for grade 4 SP was 20.7% and was significantly higher than for grade 3 SP (p<0.05). When SP was grade 1 or 2, liver was intra-abdominal in 21 (84%) out of 25 fetuses while it was always intrathoracic for SP 3 or 4., Conclusion: In L-CDH, SP as described represents a simple indirect measurement of intrathoracic position and quantification of liver.

Congenital diaphragmatic hernia (CDH) may be isolated or associated with other structural anomalies, the latter with poor prognosis. The defect allows viscera to herniate through the defect into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. When isolated, survival chances can be predicted by antenatal measurement of lung size and liver herniation. Chromosomal microarrays and exome sequencing contribute to understanding genetic factors underlying isolated CDH. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion (FETO) under local anesthesia. The Tracheal Occlusion To Accelerate Lung growth trial (www.totaltrial.eu) is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia. Despite an apparent increase in survival following FETO, the search for lesser invasive and more potent prenatal interventions must continue., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. Observed-to-expected lung-to-head ratio, liver position, and total lung volume measured by magnetic resonance are the prognostic factors most often used, and have been shown to correlate not only with neonatal mortality but also with morbidity. In daily practice, pulmonary hypertension by itself, although most often associated with lung hypoplasia, is more difficult to predict., (Copyright © 2014. Published by Elsevier Ltd.)

Objective: To evaluate the relationship of the liver-to-thoracic volume ratio (LiTR) by MRI with postnatal survival in foetuses with isolated congenital diaphragmatic hernia (CDH)., Methods: In 30 conservatively managed CDH foetuses and in 31 who underwent fetoscopic endoluminal tracheal occlusion (FETO), logistic regression analysis was used to investigate the effect on postnatal survival of the observed-to-expected (O/E) ratio of total foetal lung volume (TFLV), LiTR, gestational age at delivery, CDH side, intrathoracic position of the liver and, for those who underwent FETO, gestational age at FETO and occlusion period. For 19 foetuses undergoing FETO, a post-FETO MRI was available. The proportionate increase in O/E ratio of TFLV at 3-8 weeks after FETO was compared with the pre-FETO value and correlated with pre-FETO LiTR using linear regression analysis., Results: For conservatively managed foetuses, only LiTR provided a significant prediction of postnatal survival. For foetuses undergoing FETO, LiTR and gestational age at delivery provided a significant independent prediction of postnatal survival. There was a significant inverse association between lung response and pre-FETO LiTR., Conclusion: In foetuses with CDH with/without FETO treatment, the LiTR is predictive of postnatal survival at discharge. In foetuses treated with FETO, LiTR is predictive of post-FETO lung response., Key Points: • Congenital diaphragmatic hernia is usually managed conservatively before surgery soon after delivery • Fetoscopic endoluminal tracheal occlusion (FETO) has been introduced for severely affected foetuses • In conservatively managed CDH, the liver-to-thoracic volume ratio (LiTR) predicted postnatal survival best. • In severe CDH with prenatal FETO, LiTR also helped predict postnatal survival. • LiTR should be integrated into the prenatal decision-making for foetuses with CDH.

Objective: The objective of our study was to evaluate the potential of the sonographic fetal lung volume-body weight ratio to predict neonatal deaths and pulmonary hypoplasia in fetuses with isolated congenital diaphragmatic hernia (CDH)., Subjects and Methods: Between January 2002 and December 2004, 40 fetuses with isolated CDH and 450 control subjects were prospectively evaluated in two centers. Fetal lung volumes were estimated on 3D sonography using the rotational technique and fetal weight on 2D sonography using the Hadlock equation. The ratio of sonographic fetal lung volume to body weight was calculated in each case and was correlated with neonatal deaths using the Mann-Whitney U test. Accuracies of the ratio in predicting neonatal deaths and pathologic diagnosis of pulmonary hypoplasia were also evaluated., Results: The ratio of sonographic fetal lung volume to body weight is constant throughout gestation, with a mean value of 0.025. The ratio was significantly lower in neonates that died (median, 0.009; range, 0.004-0.021) than in those that survived (median, 0.011; range, 0.008-0.020) (p = 0.018). Pulmonary hypoplasia was suspected prenatally in 34 of 40 (85.0%) fetuses with CDH, in all cases of death (100%), and in seven of nine (77.8%) neonates that survived. At autopsy, pulmonary hypoplasia was diagnosed in 19 cases (86.4%). Accuracies of the ratio in predicting neonatal deaths and pulmonary hypoplasia were 64.5% (20/31) and 86.4% (19/22), respectively., Conclusion: The sonographic fetal lung volume-body weight ratio can be used more accurately to diagnose pulmonary hypoplasia than to predict neonatal deaths in fetuses with isolated CDH. Further studies are necessary to show the prevalence of pulmonary hypoplasia in fetuses with isolated CDH and its importance for predicting neonatal deaths.

Objective: The aim of the study was to evaluate the potential of fetal pulmonary artery (PA) diameters to predict perinatal death and pulmonary arterial hypertension (PAH) in congenital diaphragmatic hernia (CDH)., Study Design: In this prospective observational study, observed PA (main, right, and left) diameters were measured at the level of the 3 vessels in 21 fetuses with isolated CDH and in 85 controls at 22 to 36 weeks. The observed/expected (o/e) diameters of the main, contralateral, and ipsilateral PAs were calculated by comparing these measurements with reference values obtained in our previous study and correlated with perinatal death and postnatal PAH., Results: The o/e PA diameters were significantly reduced in fetuses with CDH compared to controls (P < .001) and in fetuses with CDH who died (P < .050). However, there was no significant association between PA diameters and PAH (P >or= .050)., Conclusions: The PA diameters might be useful to predict perinatal death in isolated CDH but not postnatal PAH, suggesting that PA diameters are probably related to the severity of pulmonary hypoplasia.

Objective: To evaluate the potential of three-dimensional ultrasound to predict outcome in congenital diaphragmatic hernia., Design: Prospective observational study., Setting: Tertiary care centre., Population: Twelve cases of isolated congenital diaphragmatic hernia (11 left-sided, 1 right-sided) and 109 controls., Methods: Fetal lung volume was assessed by three-dimensional ultrasound using the technique of rotation of the multiplanar imaging. In the control fetuses, a logistic transformation was performed to correlate fetal lung volume with gestational age, and the confidence interval was obtained with a bootstrap resampling. A mathematical equation was then obtained allowing calculation of the expected fetal lung volume as a function of gestational age. In fetuses with congenital diaphragmatic hernia, the observed/expected lung volume ratio was compared with postnatal outcome., Main Outcome Measures: Neonatal mortality and pulmonary hypoplasia, which was defined as lung/body weight ratios less than 0.012., Results: The expected fetal lung volume was derived from the mathematical equation: Fetal lung volume (mL) = exp (4.72/(1 + exp ((20.32 - gestational age in weeks)/6.05))). The observed/expected fetal lung volume ratio was significantly lower in the congenital diaphragmatic hernia group (median: 0.34, range: 0.16-0.66), than in the control group (median: 1.02, range: 0.62-1.97, P < 0.0001). The distribution of this ratio was significantly downshifted in the infants with congenital diaphragmatic hernia who died (median: 0.19, range: 0.18-0.66) compared with survivors (median: 0.44, range: 0.36-0.66, P= 0.04). The observed/expected fetal lung volume ratio was also correlated with the postmortem lung/body weight ratio., Conclusion: In isolated congenital diaphragmatic hernia, fetal lung volume measurement by three-dimensional ultrasound is a potential predictor for pulmonary hypoplasia and postnatal outcome.

We report on 2 fetuses with congenital diaphragmatic hernia (CDH) in whom the fetal lung volumes were estimated by three-dimensional ultrasound and the results compared with the postmortem lung volume measurements. Both examiners (sonographer and pathologist) were blinded to each other's results. The 1st case was a right CDH diagnosed at 20 weeks of gestation. The 2nd case was a left CDH diagnosed at 22 weeks of gestation. Both pregnancies were terminated upon request of the parents. Three-dimensional ultrasound estimation of the fetal lung volume was performed 1 day before termination of pregnancy using the technique of rotation of the three perpendicular planes. The left and right lung volumes estimated by three-dimensional ultrasound were 3.88 and 1.87 cm(3), respectively, in the 1st case and 0 and 5.52 cm(3), respectively, in the 2nd case. On postmortem examination, the left and right lung volumes were 3.0 and 2.2 cm(3), respectively, in case 1 and 1.1 and 5.6 cm(3), respectively, in case 2. This suggests that a three-dimensional estimation of pulmonary volumes may be correlated with postmortem findings in cases with CDH., (Copyright 2004 S. Karger AG, Basel)

Background/purpose: The question of delayed lung maturation in congenital diaphragmatic hernia (CDH) is pending. Data about surfactant proteins (SPs) are sparse in human fetuses and discrepant in the ovine CDH model. The purpose of this study was to investigate, in the ovine surgically created CDH model, the expression of SPs and of thyroid transcription factor 1 (TTF-1), a key regulator of lung development that also controls the expression of surfactant proteins., Methods: Diaphragmatic hernia (DH) was created surgically in lamb fetuses on day 85 of gestation. On day 139, 5 DH and 6 control fetuses were retrieved by cesarean section. The mRNA levels for SPs and TTF-1 were determined by Northern blot analysis; SP-A and SP-B protein levels were assessed by Western blot analysis., Results: In DH lungs, SP-A, SP-B, and SP-C messenger RNAs were diminished by 82%, 67%, and 32%, respectively, compared with control level. SP-A and SP-B protein amounts were decreased consistently. TTF-1 expression was not altered in the surgical model., Conclusions: SP's deficiency appears to be a common feature of the various CDH models. By contrast with the nitrofen model, TTF-1 expression was not altered in the surgical model indicating different underlying molecular mechanisms in both models., (Copyright 2002, Elsevier Science (USA). All rights reserved.)