Objective To evaluate the neonatal outcome of fetuses with isolated right‐sided congenital diaphragmatic hernia (iRCDH) based on prenatal severity indicators and antenatal management. Methods This was a retrospective review of prospectively collected data on consecutive cases diagnosed with iRCDH before 30 weeks' gestation in four fetal therapy centers, between January 2008 and December 2018. Data on prenatal severity assessment, antenatal management and perinatal outcome were retrieved. Univariate and multivariate logistic regression analysis were used to identify predictors of survival at discharge and early neonatal morbidity. Results Of 265 patients assessed during the study period, we excluded 40 (15%) who underwent termination of pregnancy, two cases of unexplained fetal death, two that were lost to follow‐up, one for which antenatal assessment of lung hypoplasia was not available and six cases which were found to have major associated anomalies or syndromes after birth. Of the 214 fetuses with iRCDH included in the neonatal outcome analysis, 86 were managed expectantly during pregnancy and 128 underwent fetal endoscopic tracheal occlusion (FETO) with a balloon. In the expectant‐management group, lung size measured by ultrasound or by magnetic resonance imaging was the only independent predictor of survival (observed‐to‐expected lung‐to‐head ratio (o/e‐LHR) odds ratio (OR), 1.06 (95% CI, 1.02–1.11); P = 0.003). Until now, stratification for severe lung hypoplasia has been based on an o/e‐LHR cut‐off of 45%. In cases managed expectantly, the survival rate was 15% (4/27) in those with o/e‐LHR ≤ 45% and 61% (36/59) for o/e‐LHR > 45% (P = 0.001). However, the best o/e‐LHR cut‐off for the prediction of survival at discharge was 50%, with a sensitivity of 78% and specificity of 72%. In the expectantly managed group, survivors with severe pulmonary hypoplasia stayed longer in the neonatal intensive care unit than did those with mildly hypoplastic lungs. In fetuses with an o/e‐LHR ≤ 45% treated with FETO, survival rate was higher than in those with similar lung size managed expectantly (49/120 (41%) vs 4/27 (15%); P = 0.014), despite higher prematurity rates (gestational age at birth: 34.4 ± 2.7 weeks vs 36.8 ± 3.0 weeks; P < 0.0001). In fetuses treated with FETO, gestational age at birth was the only predictor of survival (OR, 1.25 (95% CI, 1.04–1.50); P = 0.02). Conclusions Antenatal measurement of lung size can predict survival in iRCDH. In fetuses with severe lung hypoplasia, FETO was associated with a significant increase in survival without an associated increase in neonatal morbidity. © 2020 International Society of Ultrasound in Obstetrics and Gynecology

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Objective: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Herein we report on prenatal changes in biometry and brain perfusion in fetuses with isolated CDH.Study Design: This retrospective study evaluated fetuses with isolated, left-sided CDH in three European referral centers. Abdominal circumference (AC), femur length (FL), head circumference (HC), transcerebellar diameter (TCD), middle cerebral artery (MCA) Doppler, and ventricular width (VW) were assessed during four gestational periods (<24 weeks, 25-28 weeks, 29-32 weeks, >33 weeks). Z-scores were calculated, and growth curves were created based on longitudinal data. Results:In 367 fetuses, HC, AC and FL were within normal ranges throughout gestation. The TCD diminished with advancing gestational age to fall below the fifth percentile after 32 weeks. A less pronounced but similar trend was seen in VW. The peak systolic velocity of the MCA was consistently approximately 10% lower than normal. Disease severity was correlated to TCD (p = 0.002) and MCA doppler values (p = 0.002). There were no differences between fetuses treated with FETO and those managed expectantly.

The novel 'Smart-TO' balloon for fetal endoscopic tracheal occlusion (FETO) deflates both ex vivo and in vivo when exposed to the peripheral magnetic field around a magnetic resonance scanner. Occlusiveness and tracheal effects are similar to those of the clinical standard Goldbal2 system. What are the clinical implications of this work? This study provides proof of efficacy and safety of the Smart-TO balloon, both in a simulated in-utero environment and in the fetal lamb model. It is part of a series of experiments required before clinical implementation. Introduction of this device should reduce the burden for patients undergoing FETO.

Objectives In fetuses with isolated left‐sided congenital diaphragmatic hernia (LCDH), prenatal detection of severe pulmonary hypoplasia is important, as fetal therapy can improve survival. Cases with mild or moderate lung hypoplasia still carry a considerable risk of mortality and morbidity, but there has been less interest in the accurate prediction of outcome in these cases. In this study of fetuses with mild or moderate isolated LCDH, we aimed to investigate: (1) the association between intrapulmonary artery (IPA) Doppler findings and mortality at discharge; (2) whether adding IPA Doppler findings improves the prediction of mortality based on lung size and liver herniation; and (3) the association between IPA Doppler findings and early neonatal morbidity. Methods This was a retrospective study of all consecutive fetuses assessed at the BCNatal and UZ Leuven hospitals between 2008 and 2020 with a prenatal diagnosis of isolated, non‐severe LCDH, defined as observed‐to‐expected lung‐to‐head ratio (o/e‐LHR) > 25%, that were managed expectantly during pregnancy followed by standardized neonatal management. An additional inclusion criterion was the availability of IPA Doppler measurements. The primary outcome was the association between IPA Doppler findings and mortality at discharge. Other predictors included o/e‐LHR, liver herniation and gestational age at birth. Secondary outcomes were the association between IPA Doppler findings and the presence of pulmonary hypertension (PHT), need for supplemental oxygen at discharge and need for extracorporeal membrane oxygenation. IPA pulsatility index (PI) values were converted into Z‐scores. Logistic regression analysis was performed to investigate the associations between predictor variables and outcome, and the best model was chosen based on the Nagelkerke R2. Results Observations for 70 non‐severe LCDH cases were available. Fifty‐four (77%) fetuses survived until discharge. On logistic regression analysis, higher IPA‐PI was associated with an increased risk of mortality (odds ratio (OR), 3.96 (95% CI, 1.62–9.70)), independently of o/e‐LHR (OR, 0.87 (95% CI, 0.79–0.97)). An IPA‐PI Z‐score cut‐off of 1.8 predicted mortality with a detection rate of 69% and specificity of 93%. Adding IPA‐PI to o/e‐LHR improved significantly the model's performance (Nagelkerke R2, 46% for o/e‐LHR + IPA‐PI vs 28% for o/e‐LHR (P < 0.002)), with a detection rate of 81% at a 10% false‐positive rate. IPA‐PI was associated with PHT (OR, 2.20 (95% CI, 1.01–4.59)) and need for oxygen supplementation at discharge (OR, 1.90 (95% CI, 1.10–3.40)), independently of lung size. Conclusions In fetuses with mild or moderate LCDH, IPA‐PI was associated with mortality and morbidity, independently of lung size. A model combining o/e‐LHR with IPA‐PI identified up to four in five cases that eventually died, despite being considered to have non‐severe pulmonary hypoplasia. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

In fetal lambs with diaphragmatic hernia (DH), tracheal occlusion using the 'smart' tracheal occlusion (Smart-TO) device is effective and safe. The occlusion could be effectively reversed non-invasively and the deflated intact balloon was expelled spontaneously out of the fetal upper airways. What are the clinical implications of this work? This study proves the efficacy and safety of the Smart-TO balloon in the DH lamb model. This study is the last preclinical step before a first-in-woman study. Clinical use of this device would obviate the need for a second invasive intervention to re-establish airway patency, thus reducing the risks for the mother and fetus.

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.

Congenital diaphragmatic hernia (CDH) is a complex malformation characterised by a triad of pulmonary hypoplasia, pulmonary hypertension (PH) and cardiac ventricular dysfunction. Much of the mortality and morbidity in CDH is largely accounted for by PH, especially when persistent beyond the neonatal period and refractory to available treatment. Gentle ventilation, haemodynamic optimisation and pulmonary vasodilation constitute the foundations of neonatal treatment of CDH-related PH (CDH-PH). Moreover, early prenatal diagnosis, the ability to assess severity and the developmental nature of the condition generate the perfect rationale for fetal therapy. Shortcomings of currently available clinical therapies in combination with increased understanding of CDH pathophysiology have spurred experimental drug trials, exploring new therapeutic mechanisms to tackle CDH-PH. We herein discuss clinically available neonatal and fetal therapies specifically targeting CDH-PH and review the most promising experimental treatments and future research avenues.