Self-reported respiratory and gastrointestinal outcomes in children with isolated congenital diaphragmatic hernia: A prospective multicentre study.

OBJECTIVE: To evaluate medium-term self-reported respiratory and gastrointestinal (GI) outcomes in children with congenital diaphragmatic hernia (CDH). DESIGN: Self-reported respiratory and GI outcomes correlated with prenatal severity indicators. SETTING: Prospective study at three fetal medicine units. POPULATION: Families of children prenatally diagnosed with isolated, left-sided CDH surviving for >1 year. METHODS: Families received validated questionnaires for GI outcomes (Infant Gastroesophageal Reflux Questionnaire Revised, I-GERQ-R, for infants aged <2 years, or Paediatric Gastro-oesophageal Symptom and Quality of Life Questionnaire, PGSQ, for children aged aged 2-8 years or >9 years) and respiratory outcomes (preschool respiratory outcome questionnaire, for children aged ≤5 years, or the International Study of Asthma and Allergies in Childhood asthma questionnaire, for children aged 6-8 years or ≥9 years). Prenatal data collected from the medical records included lung size (percentage observed/expected lung-to-head ratio, O/E LHR %), liver position, fetal endoluminal tracheal occlusion (FETO) gestational age (GA) at delivery, and perinatal data included birthweight, location, patch repair and respiratory support. MAIN OUTCOME MEASURES: The GI and respiratory scores were correlated with O/E LHR using linear and logistic regression models. Univariate analysis was used to evaluate associations with perinatal variables. RESULTS: We obtained 142 responses from 342 families (representing a response rate of 45%). The baseline characteristics of participants and non-participants were comparable. No correlations between perinatal variables and respiratory or GI scores were identified. Children aged ≤5 years with lower O/E LHR values reported higher respiratory scores (P = 0.0175); this finding was not reported in older children. Overall, the children who underwent FETO (n = 51) had GI (P = 0.290) and respiratory (P = 0.052) scores that were comparable with those of children who were expectantly managed. CONCLUSIONS: Families and children with prenatally diagnosed CDH reported fewer respiratory symptoms with increasing age. There was no correlation between O/E LHR or the use of FETO and self-reported outcomes.

Have the results of the TOTAL-trials changed the attitude and practice of maternal-fetal medicine specialists?

OBJECTIVE: To explore the views and practices of maternal-fetal medicine specialists on offering fetoscopic endoluminal tracheal occlusion (FETO) for left- and right-sided congenital diaphragmatic hernia (LCDH, RCDH) in the post Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trial era. METHOD: Cross-sectional knowledge, attitude and practice survey was conducted among 105 attendees of the 19th World Congress of Fetal Medicine. RESULTS: On average, respondents were knowledgeable about CDH, involved in research, and provided antenatal treatment options. Four out of five (82%) agreed that neonatal survival in LCDH can be reliably predicted in the prenatal period. Few respondents considered the exact risks and benefits of FETO for severe LCDH as being unclear (16%), yet half were uncertain about this for moderate LCDH (57%) and severe RCDH (45%). Most respondents offer FETO for severe LCDH (97%) and RCDH (79%), but only 59% offer it for moderate LCDH. However, half of respondents (58%) stated that not offering FETO for moderate LCDH would be a psychological burden for parents. CONCLUSION: Respondents consider the risk-benefit ratio of FETO for severe LCDH clear and consistently offer FETO, but not for moderate LDCH and severe RCDH. However, not offering the option of FETO to parents was considered a psychological burden.

Patient-reported outcomes for congenital diaphragmatic hernia: A qualitative study.

OBJECTIVE: To identify Patient-reported outcomes (PROs) for parents with a lived experience of a prenatal diagnosis of isolated congenital diaphragmatic hernia (CDH). METHOD: Thematic analysis of in-depth interview transcripts. RESULTS: Interviews (n = 26) identified 11 PROs for given time points throughout the CDH trajectory. At the time of diagnosis, acceptable quality of life was selected as relevant PRO to decide whether to continue or terminate the pregnancy. During pregnancy, (neonatal) survival chances and the eligibility for foetal therapy were prominent outcomes with foetal and maternal complications adding distress. After birth, postnatal management options became the next milestone. When survival was deemed likely, post-hospital discharge complications and future care for infant and child became important. In retrospect, impact on family, bonding, parental mental health, and parental satisfaction with care were reported as relevant outcomes. CONCLUSION: PROs are relevant in addition to hard medical outcomes, as they help parents to make decisions suiting their unique needs and personal situation. Given the knowledge inherently related to the parent's perspective, our findings provide relevant directions for clinicians to support parents and their family in facing challenging decisions in healthcare. The outcomes impacting parents are essential to prepare parents for the steep journey ahead.

Brain development is altered in rabbit fetuses with congenital diaphragmatic hernia.

INTRODUCTION: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Some changes are already present prenatally. Herein, we further examined how the brain develops in fetal rabbits with surgically created DH. METHODS: Two fetuses underwent surgical DH creation on day 23 (term = d31). DH pups and littermate controls were harvested at term. Ten DH pups and 11 controls underwent transcardial perfusion for brain fixation and measurement of brain volume, brain folding, neuron and synaptic density, pre-oligodendrocyte count, proliferation, and vascularization. Twelve other DH and 11 controls had echocardiographic assessment of cardiac output and aortic and cerebral blood flow, magnetic resonance imaging (9.4 T) for cerebral volumetry, and molecular assessment of vascularization markers. RESULTS: DH pups had lower lung-to-body weight ratio (1.3 ± 0.3 vs. 2.4 ± 0.3%; p < 0.0001) and lower heart-to-body weight ratio (0.007 ± 0.001 vs. 0.009 ± 0.001; p = 0.0006) but comparable body weight and brain-to-body weight ratio. DH pups had a lower left ventricular ejection fraction, aortic and cerebral blood flow (39 ± 8 vs. 54 ± 15 mm/beat; p = 0.03) as compared to controls but similar left cardiac ventricular morphology. Fetal DH-brains were similar in volume but the cerebellum was less folded (perimeter/surface area: 25.5 ± 1.5 vs. 26.8 ± 1.2; p = 0.049). Furthermore, DH brains had a thinner cortex (143 ± 9 vs. 156 ± 13 µm; p = 0.02). Neuron densities in the white matter were higher in DH fetuses (124 ± 18 vs. 104 ± 14; p = 0.01) with comparable proliferation rates. Pre-oligodendrocyte count was lower, coinciding with the lower endothelial cell count. CONCLUSION: Rabbits with DH had altered brain development compared to controls prenatally, indicating that brain development is already altered prenatally in CDH.

Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH). BACKGROUND: Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO. METHODS: CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls. RESULTS: The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ±â€Š0.3% vs 2.3 ±â€Š0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ±â€Š0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ±â€Š0.8 br/mm2 vs 3.5 ±â€Š0.9 br/mm2, P=0.043) and lung mechanics (static elastance 61 ±â€Š36 cmH2O /mL vs 113 ±â€Š40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ±â€Š0.8 br/mm2, P=0.001 and 31 ±â€Š9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ±â€Š2.9% and 41.8 ±â€Š3.2%, vs 24.0 ±â€Š2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ±â€Š2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil. CONCLUSION: In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.

Pulmonary hypertension in congenital diaphragmatic hernia: Antenatal prediction and impact on neonatal mortality.

OBJECTIVE: To determine the prevalence of pulmonary hypertension (PAH) in left-sided congenital diaphragmatic hernia (CDH); how we could predict it; and how PAH contributed to the model for mortality prediction. STUDY DESIGN: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day (d) 1, 7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio (o/e LHR), liver-herniation, fetoscopic endoluminal tracheal occlusion (FETO), and gestational age (GA) at delivery. The combined effect of pre- and postnatal variables on mortality was modeled by Cox regression. RESULTS: Of the 197 neonates, 56 (28.4%) died. At d1, 67.5% (133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge. At d1, o/e LHR (odds ratio (OR) 0.96) and FETO (OR 2.99) independently correlated to PAH (areas under the curve [AUC]: 0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9; AUC: 0.65). None were significant for PAH at discharge. Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction (p = 0.02), in a model including o/e LHR (HR: 0.94), FETO (HR: 0.35), liver herniation (HR: 16.78), and PAH (HR: 15.95). CONCLUSIONS: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH.

Outcomes of Monoamniotic Twin Pregnancies from the First Trimester Onward.

INTRODUCTION: Monochorionic monoamniotic (MCMA) twins are rare, and information is lacking on pregnancy outcomes from the first trimester onward. This study compares the pregnancy and neonatal outcomes between MCMA and monochorionic diamniotic (MCDA) twin pregnancies from the first trimester onward. We also report on the outcomes of MCMA twin pregnancies continuing after 28 weeks and on the neurodevelopmental outcomes of MCMA twins. METHODS: A retrospective single-center cohort study of MCMA and MCDA twin pregnancies followed from the first trimester with a fortnightly ultrasound scan. We excluded pregnancies with a major anomaly diagnosed on the first-trimester ultrasound scan. MCMA twin pregnancies were offered inpatient monitoring from 28 weeks onward, and an elective cesarean section was advised between 32 and 33 weeks. MCDA pregnancies were managed as inpatients only if medically indicated, and an elective birth between 36 and 37 weeks was recommended. RESULTS: We analyzed the outcomes of 52 MCMA and 671 MCDA twin pregnancies. In MCMA twins, the fetal and neonatal survival rate was 81/104 (78%) versus 1,192/1,342 (89%) in MCDA twins (p = 0.016). Double intrauterine demise (IUD) was more common in MA than in DA pairs (13% vs. 3%) (p = 0.002). No IUD occurred in the 40 MCMA pregnancies that continued after 28 weeks, but five women (13%) required an urgent cesarean section for fetal distress. Thirty-eight of 52 eligible infants (73%) underwent a neurodevelopmental assessment. Thirty-three (87%) had cognitive and motor development scores within normal limits. Four infants had mild cognitive or motor impairment, and one infant was diagnosed with spastic diplegia. CONCLUSION: MCMA twins are associated with decreased survival rates compared to MCDA due to increased rates of double IUD. After 28 weeks, about one in eight women required an urgent delivery for fetal distress. Most infants had normal neurodevelopmental outcomes.

Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model.

BACKGROUND: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects. METHODS: Twelve fetal lambs (127-133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored. RESULTS: The transplacental sildenafil transfer was 2.9% (range: 1.4-7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38-78%) and increased both pulmonary blood flow (32-132%) and heart rate (13-49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion. CONCLUSION: In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe.

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia.

OBJECTIVE: Profiling of miR-200b expression and its targets (transforming growth factor [TGF]-ß2 and ZEB2) in the surgical rabbit congenital diaphragmatic hernia (DH) model before and after tracheal occlusion (TO). METHODS: Thirty-eight timed-pregnant rabbits had left DH creation on gestational day (GD) 23. On GD28, 17 randomly selected fetuses had TO. We harvested fetuses at GD23, GD28, or GD30. We calculated lung-to-body weight ratios, processed lungs for miR-200b in situ hybridization and real-time quantitative polymerase chain reaction, and evaluated effects on downstream targets TGF-ß2 or ZEB2. RESULTS: We obtained 16 DH fetuses (n = 7 GD28 and n = 9 GD30), 13 TO fetuses (GD30), and 38 control fetuses (n = 15 GD23, n = 11 GD28, and n = 12 GD30). Diaphragmatic hernia lungs were hypoplastic, and TO resulted in control lung-to-body weight ratio levels. Term miR-200b-3p levels were significantly upregulated in the hypoplastic compared with control ipsilateral lung (1.906 ± 0.90 vs 0.7429 ± 0.44) (P < .01). Fetal TO ipsilateral lungs displayed a variable miR-200b response on in situ hybridization and polymerase chain reaction, with levels similar to control and congenital DH lungs. The TGF-ß2 was unchanged in hypoplastic and TO lungs, and ZEB2 tended to be reduced in TO compared with DH lungs (1.79 [0.4-2.9] vs 0.73 [0.5-1.4]). CONCLUSIONS: Hypoplastic fetal rabbit lungs display upregulation of miR-200b expression although downstream targets are not different from controls. Following TO, fetal rabbit lungs display a variable miR-200b response.

Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA).

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.

Antenatal Medical Therapies to Improve Lung Development in Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.

Fetal Tracheal Occlusion for Severe Pulmonary Hypoplasia in Isolated Congenital Diaphragmatic Hernia: A Systematic Review and Meta-analysis of Survival.

OBJECTIVE: To evaluate fetal survival after tracheal occlusion in fetuses with severe pulmonary hypoplasia and isolated congenital diaphragmatic hernia (CDH). BACKGROUND: Despite recent advances in neonatal intensive care, CDH still has a high mortality and morbidity. Fetoscopic endoluminal tracheal occlusion (FETO) stimulates lung growth and improves gas exchange in animal models of CDH, but the effects in humans are still under investigation. METHODS: We searched Pubmed, Cochrane, EMBASE, and Scopus databases for clinical studies on tracheal occlusion and CDH. All studies comparing FETO and a contemporary control group were included. The primary outcome was survival, with the need for oxygen on discharge the secondary outcome. Meta-analysis of outcome measures was performed and odds ratios, relative risk ratios, and 95% confidence intervals were estimated with a fixed-effects model and were reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. RESULTS: Between 1997 and 2015, five eligible studies describing 211 patients were included (101 control and 110 FETO). All studies selected isolated severe CDH fetuses with a lung-to-head ratio 1.0 or less and liver herniation into the thoracic cavity. FETO favored survival outcome (odds ratio 13.32; 95% confidence interval, 5.40-32.87). Meta-analysis of the secondary outcome oxygen need at discharge could not be calculated, because it was not reported in all included studies. CONCLUSIONS: FETO improves survival in isolated CDH with severe pulmonary hypoplasia compared with the standard perinatal management.

The use of human amniotic fluid stem cells as an adjunct to promote pulmonary development in a rabbit model for congenital diaphragmatic hernia.

OBJECTIVE: This study aimed to evaluate the potential benefit of intra-tracheal injection of human amniotic fluid stem cells (hAFSC) on pulmonary development combined with TO in a rabbit model for CDH. METHODS: In time-mated pregnant does a left diaphragmatic defect was created at d23 (term = 31). At d28, previously operated fetuses were assigned to either TO and injection with 70 µL of phosphate buffered saline (PBS) or 1.0 × 10(6) c-Kit positive hAFSC expressing LacZ or were left untouched (CDH). Harvesting was done at d31 to obtain their lung-to-body weight ratio (LBWR), airway and vascular lung morphometry, X-gal staining and immunohistochemistry for Ki67 and surfactant protein-B (SP-B). RESULTS: CDH-induced pulmonary hypoplasia is countered by TO + PBS, this reverses LBWR, mean terminal bronchiole density (MTBD) and medial thickness to normal. The additional injection of hAFSC decreases MTBD and results in a non-significant decrease in muscularization of intra-acinary vessels. There were no inflammatory changes and LacZ positive hAFSC were dispersed throughout the lung parenchyma 4 days after injection. CONCLUSION: HAFSC exert an additional effect on TO leading to a decrease in MTBD, a measure of alveolar number surrounding the terminal bronchioles, without signs of toxicity. © 2015 John Wiley & Sons, Ltd.

Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential.

BACKGROUND AIMS: Cord blood (CB) and amniotic fluid (AF) could represent new and attractive mesenchymal stromal cell (MSC) sources, but their potential therapeutic applications are still limited by lack of standardized protocols for isolation and differentiation. In particular, chondrogenic differentiation has never been deeply investigated. METHODS: MSCs were obtained from CB and AF samples collected during cesarean sections at term and compared for their biological and differentiation properties, with particular interest in cartilage differentiation, in which quantitative real-time polymerase chain reaction and immunohistochemical analyses were performed to evaluate the expression of type 2 collagen, type 10 collagen, SRY-box9 and aggrecan. RESULTS: We were able to isolate MSCs from 12 of 30 (40%) and 5 of 20 (25%) CB and AF units, respectively. Fluorescence in situ hybridization analysis indicated the fetal origin of isolated MSC strains. Both populations expressed mesenchymal but not endothelial and hematopoietic markers, even though we observed a lower expression of human leukocyte antigen (HLA) I in CB-MSCs. No differences in proliferation rate and cell cycle analysis could be detected. After osteogenic induction, both populations showed matrix mineralization and typical marker expression. Under chondrogenic conditions, pellets derived from CB-MSCs, in contrast with AF-MSCs pellets, were significantly larger, showed cartilage-like morphology and resulted positive for chondrocyte-associated markers, such as type 2 collagen, type 10 collagen, SRY-box9 and aggrecan. CONCLUSIONS: Our results show that CB-MSCs and AF-MSCs collected at term differ from each other in their biological and differentiation properties. In particular, only CB-MSCs showed a clear chondrogenic potential and thus could represent an ideal candidate for cartilage-tissue engineering.

Tracheomalacia and tracheomegaly in infants and children with congenital diaphragmatic hernia managed with and without fetoscopic endoluminal tracheal occlusion (FETO): a multicentre, retrospective cohort study.

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.

Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids.

Isolation of tissue-specific fetal stem cells and derivation of primary organoids is limited to samples obtained from termination of pregnancies, hampering prenatal investigation of fetal development and congenital diseases. Therefore, new patient-specific in vitro models are needed. To this aim, isolation and expansion of fetal stem cells during pregnancy, without the need for tissue samples or reprogramming, would be advantageous. Amniotic fluid (AF) is a source of cells from multiple developing organs. Using single-cell analysis, we characterized the cellular identities present in human AF. We identified and isolated viable epithelial stem/progenitor cells of fetal gastrointestinal, renal and pulmonary origin. Upon culture, these cells formed clonal epithelial organoids, manifesting small intestine, kidney tubule and lung identity. AF organoids exhibit transcriptomic, protein expression and functional features of their tissue of origin. With relevance for prenatal disease modeling, we derived lung organoids from AF and tracheal fluid cells of congenital diaphragmatic hernia fetuses, recapitulating some features of the disease. AF organoids are derived in a timeline compatible with prenatal intervention, potentially allowing investigation of therapeutic tools and regenerative medicine strategies personalized to the fetus at clinically relevant developmental stages.

Seasonal impact in the frequency of isolated spina bifida.

OBJECTIVES: To evaluate whether a relationship exists between season at conception and occurrence of isolated spina bifida (ISB). STUDY DESIGN: All fetuses with prenatal diagnosis of ISB were analyzed according to date of conception. We compared the seasonal rates of conception between ISB fetuses and a control group consisting of a cohort of fetuses delivered during the same period from 1992 to 2009. RESULTS: In the control group, conceptions were equally distributed among the four seasons. Chi-square analysis showed a significantly higher rate of ISB conceptions in the fall compared with the control group (16/36, 44% vs. 12467/50533, 25%, Odds Ratio (OR) 2.44, 95% confidence interval 1.21-4.92). Not a single woman with a fetus affected by ISB took preconceptional supplement of folic acid. CONCLUSIONS: Seasonality affects the frequency of ISB. We hypothesize that the seasonal differences may reflect dietary and climate changes with reduced intake of folic acid in the fall.

Perinatal complications in twin pregnancies after 34 weeks: effects of gestational age at delivery and chorionicity.

OBJECTIVE: To evaluate the perinatal outcome of twins approaching term in relation to chorionicity and gestational age at delivery. STUDY DESIGN: We accessed data pertaining to a cohort of 471 twin pregnancies with certain chorionicity delivered at > 34.0 weeks' gestation. Twin gestation per se, estimated fetal weight below the 10th percentile, or any intertwin discordance was not an indication for delivery before 40.0 weeks. Predictors of adverse perinatal outcome were identified using logistic regression analysis. RESULTS: There were no stillbirths. Adverse neonatal outcome occurred in 27% of monochorionic versus 16% of dichorionic gestations. At multivariate analysis, lower gestational age at delivery (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.57 to 0.87), monochorionicity (OR 2.06, 95% CI 1.16-3.63), and either twin being growth-restricted (OR 2.35, 95% CI 1.22 to 4.54) were independent predictors of adverse neonatal outcome. Analysis of adverse neonatal outcome stratified by gestational age and chorionicity identified 36 to 37 weeks as optimal timing for delivery of monochorionic twins, and dichorionic twin pregnancies should be allowed to continue until term. CONCLUSION: Among twin gestations delivered after 34 weeks with appropriate fetal growth, reassuring fetal status at weekly assessment, and absence of obstetric complications, delivery after 36 weeks for monochorionic twins and at term for dichorionic twins minimizes the risk of stillbirths and neonatal morbidity.

Fetoscopic endoluminal tracheal occlusion with Smart-TO balloon: Study protocol to evaluate effectiveness and safety of non-invasive removal.

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.

Are there differences between monochorionic twin placentas after spontaneous and assisted conception?

INTRODUCTION: No data are available on the placental characteristics of monochorionic twin pregnancies conceived by in vitro fertilization (IVF). This study investigates the differences between placentas from monochorionic diamniotic (MCDA) twin pregnancies conceived spontaneously and those conceived after IVF. METHODS: This is a retrospective analysis of placental data from a consecutive series of MCDA twin pregnancies followed from the first trimester. The following placental characteristics were compared between IVF versus spontaneous MCDA pregnancies: placental sharing and birth weight discordance relative to placental sharing, the placental angioarchitecture (number, type, and size of anastomoses), and the umbilical cord insertion types. RESULTS: Of the 256 MCDA placentas included in this analysis, 32 (12%) were conceived through IVF and 224 (88%) spontaneously. MCDA twin placentas after IVF did not differ significantly from MCDA twin placentas after spontaneous conception regarding placental sharing, birthweight discordance relative to sharing discordance, and angioarchitecture. There was a trend toward more discordant cord insertions (combination eccentric and velamentous) in IVF (25%) than in spontaneously conceived placentas (12%) (P = 0.05). DISCUSSION: No differences could be demonstrated between MCDA placentation after spontaneous conception and IVF. Any differences in pregnancy outcome between spontaneous and IVF conceived MCDA twins may not be related to differences in placental sharing, angioarchitecture and cord insertion type.