Prenatal treprostinil improves pulmonary arteriolar hypermuscularization in the rabbit model of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a congenital malformation characterized by pulmonary hypoplasia, pulmonary hypertension, and cardiac dysfunction. Pulmonary hypertension represents the major cause of neonatal mortality and morbidity. Prenatal diagnosis allows assessment of severity and selection of foetal surgery candidates.

Development and validation of a novel fetal vesico-amniotic shunt, the vortex shunt.

Fetal lower urinary tract obstruction (LUTO) is a severe malformation associated with an up to 80% mortality risk as well as significant renal and pulmonary morbidity in survivors. Fetal vesico-amniotic shunts (VAS) bypass the bladder obstruction, improve amniotic fluid volume and enhance in-utero pulmonary development. VAS has been shown to reduce respiratory morbidity and mortality in the neonatal period without proven benefit on long-term renal and bladder function.

Lung proliferation is dependent on the duration not the timepoint of tracheal occlusion in nitrofen rats with diaphragmatic hernia.

Objective: Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with congenital diaphragmatic hernia (CDH). Limited data are available regarding the effect of duration versus timepoint of TO. Our objective was to document the impact of TO on lung development in the near-term period in rats with nitrofen-induced CDH.

Cx43 regulates mechanotransduction mechanisms in human preterm amniotic membrane defects.

Objective: The effects of mechanical stimulation in preterm amniotic membrane (AM) defects were explored.

Methods: Preterm AM was collected from women undergoing planned preterm caesarean section (CS) due to fetal growth restriction or emergency CS after spontaneous preterm prelabour rupture of the membranes (sPPROM). AM explants near the cervix or placenta were subjected to trauma and/or mechanical stimulation with the Cx43 antisense.

Survival in very preterm infants with congenital diaphragmatic hernia and association with prenatal imaging markers: A retrospective cohort study.

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.

Challenges and Pitfalls: Performing Clinical Trials in Patients With Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a rare developmental defect of the lungs and diaphragm, with substantial morbidity and mortality. Although internationally established treatment guidelines have been developed, most recommendations are still expert opinions. Trials in patients with CDH, more in particular randomized controlled trials, are rare.

International Urogynecological Consultation (IUC): pathophysiology of pelvic organ prolapse (POP).

Introduction And Hypothesis: This manuscript is the International Urogynecology Consultation (IUC) on pelvic organ prolapse (POP) chapter one, committee three, on the Pathophysiology of Pelvic Organ Prolapse assessing genetics, pregnancy, labor and delivery, age and menopause and animal models.

Materials And Methods: An international group of urogynecologists and basic scientists performed comprehensive literature searches using pre-specified terms in selected biomedical databases to summarize the current knowledge on the pathophysiology of the development of POP, exploring specifically factors including (1) genetics, (2) pregnancy, labor and delivery, (3) age and menopause and (4) non-genetic animal models. This manuscript represents the summary of three systematic reviews with meta-analyses and one narrative review, to which a basic scientific comment on the current understanding of pathophysiologic mechanisms was added.

The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data.

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 to 29 weeks' gestation (referred to as "early") for severe and at 30 to 31 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.

Cx43 mediates changes in myofibroblast contraction and collagen release in human amniotic membrane defects after trauma.

The wound healing capacity of the fetal membranes after spontaneous or iatrogenic membrane rupture is unclear. We examined the healing mechanisms in amniotic membrane (AM) defects after trauma. Traumatised human AM defects were cultured for 4 days.

Fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia: a narrative review of the history, current practice, and future directions.

Fetal intervention for fetuses with congenital diaphragmatic hernia (CDH) has been investigated for over 30 years and is summarized in this manuscript. The review begins with a discussion of the history of fetal intervention for this severe congenital anomaly beginning with open fetal surgery with repair of the anatomical defect, shifting towards tracheal occlusion via open surgery techniques, and finally fetoscopic endoluminal balloon tracheal occlusion using a percutaneous approach. The current technique of fetal endoscopic tracheal occlusion (FETO) is described in detail with steps of the procedure and complementary figures.

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

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.

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

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.

Fetoscopic myelomeningocoele closure: Is the scientific evidence enough to challenge the gold standard for prenatal surgery?

Since the completion of the Management of Myelomeningocoele Study, maternal-fetal surgery for spina bifida has become a valid option for expecting parents. More recently, multiple groups are exploring a minimally invasive approach and recent outcomes have addressed many of the initial concerns with this approach. Based on a previously published framework, we attempt to delineate the developmental stage of the surgical techniques.

Potential sealing and repair of human FM defects after trauma with peptide amphiphiles and Cx43 antisense.

Objective: We examined whether peptide amphiphiles functionalised with adhesive, migratory or regenerative sequences could be combined with amniotic fluid (AF) to form plugs that repair fetal membrane (FM) defects after trauma and co-culture with connexin 43 (Cx43) antisense.

Methods: We assessed interactions between peptide amphiphiles and AF and examined the plugs in FM defects after trauma and co-culture with the Cx43antisense.

Results: Confocal microscopy confirmed directed self-assembly of peptide amphiphiles with AF to form a plug within minutes, with good mechanical properties.

Targeting mechanotransduction mechanisms and tissue weakening signals in the human amniotic membrane.

Mechanical and inflammatory signals in the fetal membrane play an important role in extracellular matrix (ECM) remodelling in order to dictate the timing of birth. We developed a mechanical model that mimics repetitive stretching of the amniotic membrane (AM) isolated from regions over the placenta (PAM) or cervix (CAM) and examined the effect of cyclic tensile strain (CTS) on mediators involved in mechanotransduction (Cx43, AKT), tissue remodelling (GAGs, elastin, collagen) and inflammation (PGE, MMPs). In CAM and PAM specimens, the application of CTS increased GAG synthesis, PGE release and MMP activity, with concomitant reduction in collagen and elastin content.

Neonatal cardiopulmonary transition in an ovine model of congenital diaphragmatic hernia.

Objective: Infants with a congenital diaphragmatic hernia (CDH) are at high risk of developing pulmonary hypertension after birth, but little is known of their physiological transition at birth. We aimed to characterise the changes in cardiopulmonary physiology during the neonatal transition in an ovine model of CDH.

Methods: A diaphragmatic hernia (DH) was surgically created at 80 days of gestational age (dGA) in 10 fetuses, whereas controls underwent sham surgery (n=6).

Effects of tracheal occlusion on the neonatal cardiopulmonary transition in an ovine model of diaphragmatic hernia.

Objective: Fetoscopic endoluminal tracheal occlusion (FETO) aims to reverse pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) and mitigate the associated respiratory insufficiency and pulmonary hypertension after birth. We aimed to determine whether FETO improves the cardiopulmonary transition at birth in an ovine model of CDH.

Methods: In 12 ovine fetuses with surgically induced diaphragmatic hernia (DH; 80 dGA), an endotracheal balloon was placed tracheoscopically at ≈110 dGA and removed at ≈131 dGA (DH+FETO), while 10 were left untreated (DH).

The effects of partial amniotic carbon dioxide insufflation in an ovine model.

Objective: We aim to assess the effect of partial amniotic carbon dioxide insufflation (PACI) at increasing pressures on fetal acid-base, fetal-placental perfusion, and fetal membrane morphology in an ovine model.

Method: Pregnant ewes and fetuses were instrumented under isoflurane anesthesia at 105 days gestation (term 145 days) to monitor utero-placental blood flow, fetal and maternal blood pressure, heart rate, and blood gas status. One group (n = 6) was exposed to PACI (unheated dry CO ), involving 10 mm Hg stepwise increases in insufflation pressure (5 to 25 mm Hg), for 80 minutes followed by 20 minutes of desufflation.

Upregulation of Vascular Endothelial Growth Factor in Amniotic Fluid Stem Cells Enhances Their Potential to Attenuate Lung Injury in a Preterm Rabbit Model of Bronchopulmonary Dysplasia.

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects extremely preterm infants and remains - despite improvements in neonatal intensive care - a major cause of neonatal mortality and morbidity. Cell-therapeutic strategies employing mesenchymal stem cells (MSC) have been shown to modulate lung development in BPD models.

Objective: Herein, we evaluate the potential of human amniotic fluid (hAF)-SC and hAF-SC with upregulated expression of vascular endothelial growth factor (VEGF) as cell-therapeutic agents for BPD.

Trauma induces overexpression of Cx43 in human fetal membrane defects.

Objective: We developed an in vitro model to examine whether trauma induces connexin 43 (Cx43) expression and collagen organisation in the amniotic membrane (AM) of fetal membrane (FM) defects.

Method: Term human FM was traumatised in vitro. Cell morphology and Cx43 were examined in the wound edge AM by immunofluorescence (IMF) confocal microscopy and compared to control AM.

Connexin 43 is overexpressed in human fetal membrane defects after fetoscopic surgery.

Objective: We examined whether surgically induced membrane defects elevate connexin 43 (Cx43) expression in the wound edge of the amniotic membrane (AM) and drives structural changes in collagen that affects healing after fetoscopic surgery.

Method: Cell morphology and collagen microstructure was investigated by scanning electron microscopy and second harmonic generation in fetal membranes taken from women who underwent fetal surgery. Immunofluoresence and real-time quantitative polymerase chain reaction was used to examine Cx43 expression in control and wound edge AM.

A novel translational model for fetoscopic intratracheal delivery of nanoparticles in piglets.

Objectives: The aim of this study was to assess the feasibility of fetal tracheal injection in the late-gestational pig to target the airways.

Methods: Following laparotomy and hysterotomy, fetoscopy was performed in pregnant sows to access the fetal trachea. Two volumes of fluospheres were injected (1 and 3 mL).

Airway tissue engineering for congenital laryngotracheal disease.

Regenerative medicine offers hope of a sustainable solution for severe airway disease by the creation of functional, immunocompatible organ replacements. When considering fetuses and newborns, there is a specific spectrum of airway pathologies that could benefit from cell therapy and tissue engineering applications. While hypoplastic lungs associated with congenital diaphragmatic hernia (CDH) could benefit from cellular based treatments aimed at ameliorating lung function, patients with upper airway obstruction could take advantage from a de novo tissue engineering approach.

The Impact of Entry Technique and Access Diameter on Prelabour Rupture of Membranes Following Primary Fetoscopic Laser Treatment for Twin-Twin Transfusion Syndrome.

Objective: To evaluate the impact of entry method and access diameter at fetoscopic surgery for twin-twin transfusion syndrome in twin pregnancies with at least one survivor. The outcomes evaluated were prelabour rupture of membranes (PROM) and birth <4 weeks, preterm birth (PTB) <28 weeks, and latency to birth.

Methods: A retrospective analysis of prospectively collected data of consecutive laser procedures from 6 centers was performed.