Publications by authors named "Jan Deprest"

467 Publications

Evaluation of the short term host response and biomechanics of an absorbable poly-4-hydroxybutyrate scaffold in a sheep model following vaginal implantation.

BJOG 2021 Dec 5. Epub 2021 Dec 5.

Department of Obstetrics and Gynaecology, Amsterdam Reproduction and Development, Amsterdam UMC - location AMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Objective: To evaluate the host- and biomechanical response to a fully absorbable poly-4-hydroxybutyrate (P4HB) scaffold in comparison with the response to polypropylene (PP) mesh.

Design: In vivo animal experiment.

Setting: KU Leuven Center for Surgical Technologies.

Population: Fourteen parous female Mule sheep.

Methods: P4HB scaffolds were surgically implanted in the posterior vaginal wall of sheep. The comparative PP mesh data were obtained from an identical study protocol performed previously.

Main Outcome Measures: Gross necropsy, host response and biomechanical evaluation of explants, and the in vivo P4HB scaffold degradation were evaluated at 60- and 180-days post-implantation. Data are reported as mean ± standard deviation (SD) or standard error of the mean (SEM).

Results: Gross necropsy revealed no implant-related adverse events using P4HB scaffolds. The tensile stiffness of the P4HB explants increased at 180-days (12.498 ± 2.66 N/mm SEM (P=0.019)) as compared to 60-days (4.585 ± 1.57 N/mm) post-implantation, while P4HB degraded gradually. P4HB scaffolds exhibited excellent tissue integration with dense connective tissue and a moderate initial host response. P4HB scaffolds induced a significantly higher M2/M1 ratio (1.70 ± 0.67 SD, score 0-4), as compared to PP mesh(0.99 ± 0.78 SD, score 0-4) at 180-days.

Conclusions: P4HB scaffold facilitated a gradual load transfer to vaginal tissue over time. The fully absorbable P4HB scaffold, in comparison to PP mesh, has a favorable host response with comparable load-bearing capacity. If these results are also observed at longer follow-up in-vivo, a clinical study using P4HB for vaginal POP surgery may be warranted to demonstrate efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1471-0528.17040DOI Listing
December 2021

Fetal Surgery for Severe Left Diaphragmatic Hernia. Reply.

N Engl J Med 2021 11;385(22):2112

Hospital Antoine Béclère, Clamart, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc2115673DOI Listing
November 2021

The randomized TOTAL-trials on fetal surgery for congenital diaphragmatic hernia: re-analysis using pooled data.

Am J Obstet Gynecol 2021 Nov 19. Epub 2021 Nov 19.

Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium; Clinical Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.

Background: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion (FETO) with expectant prenatal management in fetuses with moderate and severe isolated congenital diaphragmatic hernia (CDH), respectively. FETO 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. Reported absolute increase in survival to discharge were 13% (95% confidence interval, -1-28; P=.059), and 25% (95% confidence interval, 6-46; P=.0091) for moderate and hypoplasia CDH, respectively.

Objectives: Data from the two trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of the gestational age at balloon insertion.

Study Design: Individual participant data from the two trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced FETO centers, and were randomized in a 1:1 ratio to either expectant management or FETO. All received standardized postnatal management. The combined data involved 287 patients (196 moderate and 91 severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. 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 (FETO 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 observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity.

Results: For survival to discharge, the adjusted odds ratio of FETO was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was positive but highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these two effects, the adjusted odds ratio of FETO with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). 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% CI, 1.1-2.3) following FETO with late insertion and 3.2 weeks earlier (95% CI, 2.3-4.1) following FETO with early insertion, as compared to expectant management. There was no evidence that the effect of FETO depended on the observed over expected lung-to-head ratio for any of the endpoints.

Conclusions: This analysis suggests that FETO increases survival both for moderate and severe lung hypoplasia. The difference between the results for the TOTAL trials, when considered apart, may be due to the difference in the time point of balloon insertion. However, the effect of time point of balloon insertion could not be robustly assessed due to small sample size and the confounding effect of disease severity. FETO, in particular with early balloon insertion, strongly increases the risk for preterm delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2021.11.1351DOI Listing
November 2021

Authors' reply re: 'Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial'.

BJOG 2021 Nov 20. Epub 2021 Nov 20.

Department of Development and Regeneration, Cluster Urogenital, Abdominal and Plastic Surgery, KU Leuven, Leuven, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1471-0528.16998DOI Listing
November 2021

What brain abnormalities can magnetic resonance imaging detect in foetal and early neonatal spina bifida: a systematic review.

Neuroradiology 2021 Nov 18. Epub 2021 Nov 18.

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.

Purpose: Open spina bifida (OSB) encompasses a wide spectrum of intracranial abnormalities. With foetal surgery as a new treatment option, robust intracranial imaging is important for comprehensive preoperative evaluation and prognostication. We aimed to determine the incidence of infratentorial and supratentorial findings detected by magnetic resonance imaging (MRI) alone and MRI compared to ultrasound.

Methods: Two systematic reviews comparing MRI to ultrasound and MRI alone were conducted on MEDLINE, EMBASE, and Cochrane databases identifying studies of foetal OSB from 2000 to 2020. Intracranial imaging findings were analysed at ≤ 26 or > 26 weeks gestation and neonates (≤ 28 days). Data was independently extracted by two reviewers and meta-analysis was performed where possible.

Results: Thirty-six studies reported brain abnormalities detected by MRI alone in patients who previously had an ultrasound. Callosal dysgenesis was identified in 4/29 cases (2 foetuses ≤ 26 weeks, 1 foetus under any gestation, and 1 neonate ≤ 28 days) (15.1%, CI:5.7-34.3%). Heterotopia was identified in 7/40 foetuses ≤ 26 weeks (19.8%, CI:7.7-42.2%), 9/36 foetuses > 26 weeks (25.3%, CI:13.7-41.9%), and 64/250 neonates ≤ 28 days (26.9%, CI:15.3-42.8%). Additional abnormalities included aberrant cortical folding and other Chiari II malformation findings such as lower cervicomedullary kink level, tectal beaking, and hypoplastic tentorium. Eight studies compared MRI directly to ultrasound, but due to reporting inconsistencies, it was not possible to meta-analyse.

Conclusion: MRI is able to detect anomalies hitherto underestimated in foetal OSB which may be important for case selection. In view of increasing prenatal OSB surgery, further studies are required to assess developmental consequences of these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00234-021-02853-1DOI Listing
November 2021

Super-resolution Reconstruction MRI Application in Fetal Neck Masses and Congenital High Airway Obstruction Syndrome.

OTO Open 2021 Oct-Dec;5(4):2473974X211055372. Epub 2021 Oct 25.

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.

Objective: Reliable airway patency diagnosis in fetal tracheolaryngeal obstruction is crucial to select and plan ex utero intrapartum treatment (EXIT) surgery. We compared the clinical utility of magnetic resonance imaging (MRI) super-resolution reconstruction (SRR) of the trachea, which can mitigate unpredictable fetal motion effects, with standard 2-dimensional (2D) MRI for airway patency diagnosis and assessment of fetal neck mass anatomy.

Study Design: A single-center case series of 7 consecutive singleton pregnancies with complex upper airway obstruction (2013-2019).

Setting: A tertiary fetal medicine unit performing EXIT surgery.

Methods: MRI SRR of the trachea was performed involving rigid motion correction of acquired 2D MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume. SRR, 2D MRI, and paired data were blindly assessed by 3 radiologists in 3 experimental rounds.

Results: Airway patency was correctly diagnosed in 4 of 7 cases (57%) with 2D MRI as compared with 2 of 7 cases (29%) with SRR alone or paired 2D MRI and SRR. Radiologists were more confident ( = .026) in airway patency diagnosis when using 2D MRI than SRR. Anatomic clarity was higher with SRR ( = .027) or paired data ( = .041) in comparison with 2D MRI alone. Radiologists detected further anatomic details by using paired images versus 2D MRI alone ( < .001). Cognitive load, as assessed by the NASA Task Load Index, was increased with paired or SRR data in comparison with 2D MRI.

Conclusion: The addition of SRR to 2D MRI does not increase fetal airway patency diagnostic accuracy but does provide improved anatomic information, which may benefit surgical planning of EXIT procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2473974X211055372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549475PMC
October 2021

Fetal surgery has no additional effect to general anesthesia on brain development in neonatal rabbits.

Am J Obstet Gynecol MFM 2021 Oct 24;4(1):100513. Epub 2021 Oct 24.

Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, Catholic University of Leuven, Leuven, Belgium (Drs Van der Veeken, Emam, and Valenzuela, Dr Van der Merwe, and Dr Deprest); Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium (Drs Van der Veeken and Valenzuela, Dr Van der Merwe, and Dr Deprest); Institute for Women's Health, University College London, London, United Kingdom (Dr Deprest). Electronic address:

Background: Fetal surgery is part of modern fetal medicine, and some procedures, such as fetal spina bifida repair, are performed under general anesthesia. Fetuses are operated on in a time window when the developing brain is extremely vulnerable to external, potentially harmful factors. To date, little is known about the effect of fetal surgery on fetal brain development.

Objective: This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model.

Study Design: This was a randomized, sham-controlled study in time-mated pregnant does at 28 days' gestation (term, 31 days), which corresponds to the start of the peak of brain development and end of the second trimester of pregnancy in humans. We included 4 different groups in this experiment: no-surgery, general anesthesia, general anesthesia+hysterotomy, and general anesthesia+fetal surgery. In 11 does, anesthesia was induced using propofol and maintained for 75 minutes with 3.6 vol% (4% is the equivalent of 1 minimum alveolar concentration) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO were continuously monitored. For each operated doe, 6 fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac were assigned to fetal surgery: hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision, and suturing. Only hysterotomy was performed on the opposing cornual and third amniotic sacs of the does. The fetus in these experimental sacs was used as internal unmanipulated control (general anesthesia). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no-surgery). At term, the does were delivered by cesarean delivery under ketamine-medetomidine sedation and local anesthesia. The pups underwent standardized motoric and sensory neurologic testing on day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation, and glial cells.

Results: Maternal vital signs were stable during surgery. Survival was similar in the 4 groups (75%-94%), and brain-to-body weight ratio was comparable; only the no-surgery pups had a higher brain weight. On postnatal day 1, the pups in the 4 groups had a comparable neurobehavioral outcome on both motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significantly higher neuron density than pups who underwent maternal surgery, but there was no difference among pups that underwent general anesthesia, hysterotomy, or fetal surgery. The measurements of proliferation had a similar outcome: a higher proliferation rate in the prefrontal cortex of no-surgery pups. Moreover, synaptic density values were higher in the no-surgery pups, but there was no difference observed among pups who underwent general anesthesia, hysterotomy, and fetal surgery. Lastly, there was no difference in gliosis among the 4 groups.

Conclusion: In rabbits, fetal surgery through hysterotomy under maternal general anesthesia did not affect brain development, in addition to the effects of general anesthesia per se.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajogmf.2021.100513DOI Listing
October 2021

Prenatal ultrasonographic markers for prediction of complex gastroschisis and adverse perinatal outcomes: a systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2021 Oct 4. Epub 2021 Oct 4.

Division of Fetal Therapy and Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA

Objective: We sought to perform a meta-analysis of the predictive value of antenatal ultrasonographic markers of bowel dilation, gastric dilation, polyhydramnios and abdominal circumference that predict complex gastroschisis and adverse perinatal outcomes DATA SOURCES: PubMed, Web of Science, Scopus and Embase were searched for relevant articles up to December 2020. Studies reporting prenatal ultrasonographic markers including intra-abdominal bowel dilation (IABD), extra-abdominal bowel dilation (EABD), bowel wall thickness, polyhydramnios, abdominal circumference <5th percentile, gastric dilation (GD) and bowel dilation not otherwise specified (BD-NOS) were included. The primary outcome was prediction of complex gastroschisis; secondary outcomes were length of hospital stay for newborn, time to full enteral feeding, postnatal mortality rate, incidence of necrotising enterocolitis and short bowel syndrome.

Results: Thirty-six studies were included in this meta-analysis. We found significant associations between complex gastroschisis and IABD (OR=5.42; 95% CI 3.24 to 9.06), EABD (OR=2.27; 95% CI 1.40 to 3.66), BD-NOS (OR=6.27; 95% CI 1.97 to 19.97), GD (OR=1.88; 95% CI 1.22 to 2.92) and polyhydramnios (OR=6.93; 95% CI 3.39 to 14.18). Second trimester IABD and EABD have greater specificity for the prediction of complex gastroschisis than third trimester values with specificity of 95.6% (95% CI 58.1 to 99.7) and 94.6% (95% CI 86.7 to 97.9) for the second trimester IABD and EABD, respectively.

Conclusion: Prenatal ultrasonographic markers, especially the second trimester IABD and EABD, can identify fetuses that develop complex gastroschisis. Furthermore, these specific ultrasonographic markers can identify those babies at the highest risk for severe complications of this congenital anomaly and hence selected for future antenatal interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/archdischild-2021-322612DOI Listing
October 2021

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

Prenat Diagn 2021 Sep 22. Epub 2021 Sep 22.

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.

Objective: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions.

Method: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives.

Results: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus.

Conclusions: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.6047DOI Listing
September 2021

Automatic Extraction of Hiatal Dimensions in 3-D Transperineal Pelvic Ultrasound Recordings.

Ultrasound Med Biol 2021 Dec 15;47(12):3470-3479. Epub 2021 Sep 15.

Department of Development and Regeneration, Cluster Urogenital Surgery, Biomedical Sciences, KU Leuven; Clinical Department of Obstetrics and Gynaecology, UZ Leuven, Leuven, Belgium.

The aims of this work were to create a robust automatic software tool for measurement of the levator hiatal area on transperineal ultrasound (TPUS) volumes and to measure the potential reduction in variability and time taken for analysis in a clinical setting. The proposed tool automatically detects the C-plane (i.e., the plane of minimal hiatal dimensions) from a 3-D TPUS volume and subsequently uses the extracted plane to automatically segment the levator hiatus, using a convolutional neural network. The automatic pipeline was tested using 73 representative TPUS volumes. Reference hiatal outlines were obtained manually by two experts and compared with the pipeline's automated outlines. The Hausdorff distance, area, a clinical quality score, C-plane angle and C-plane Euclidean distance were used to evaluate C-plane detection and quantify levator hiatus segmentation accuracy. A visual Turing test was created to compare the performance of the software with that of the expert, based on the visual assessment of C-plane and hiatal segmentation quality. The overall time taken to extract the hiatal area with both measurement methods (i.e., manual and automatic) was measured. Each metric was calculated both for computer-observer differences and for inter-and intra-observer differences. The automatic method gave results similar to those of the expert when determining the hiatal outline from a TPUS volume. Indeed, the hiatal area measured by the algorithm and by an expert were within the intra-observer variability. Similarly, the method identified the C-plane with an accuracy of 5.76 ± 5.06° and 6.46 ± 5.18 mm in comparison to the inter-observer variability of 9.39 ± 6.21° and 8.48 ± 6.62 mm. The visual Turing test suggested that the automatic method identified the C-plane position within the TPUS volume visually as well as the expert. The average time taken to identify the C-plane and segment the hiatal area manually was 2 min and 35 ± 17 s, compared with 35 ± 4 s for the automatic result. This study presents a method for automatically measuring the levator hiatal area using artificial intelligence-based methodologies whereby the C-plane within a TPUS volume is detected and subsequently traced for the levator hiatal outline. The proposed solution was determined to be accurate, relatively quick, robust and reliable and, importantly, to reduce time and expertise required for pelvic floor disorder assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ultrasmedbio.2021.08.009DOI Listing
December 2021

Pharmacokinetics and pharmacodynamics of sildenafil in fetal lambs on extracorporeal support.

Biomed Pharmacother 2021 Nov 16;143:112161. Epub 2021 Sep 16.

MyFetUZ, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Background: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil.

Methods: Five fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3-0.5-0.7 mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response.

Findings: The target concentration range (47-500 ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose.

Interpretation: Immediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5 mg/kg/24 h dose balancing rapid attainment of target concentrations with short-lived systemic effects.

Research In Context: None.

Search Strategy Before Undertaking The Study: A literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work.

Evidence Before This Study: Prenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model.

Added Value Of This Study: We therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference.

Implications Of All The Available Evidence: We demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5 mg/kg/24 h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2021.112161DOI Listing
November 2021

Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap/Taz pathway.

Am J Physiol Lung Cell Mol Physiol 2021 11 25;321(5):L814-L826. Epub 2021 Aug 25.

Division Organ Systems, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Accurate fluid pressure in the fetal lung is critical for its development, especially at the beginning of the saccular stage when alveolar epithelial type 1 (AT1) and type 2 (AT2) cells differentiate from the epithelial progenitors. Despite our growing understanding of the role of physical forces in lung development, the molecular mechanisms that regulate the transduction of mechanical stretch to alveolar differentiation remain elusive. To simulate lung distension, we optimized both an ex vivo model with precision cut lung slices and an in vivo model of fetal tracheal occlusion. Increased mechanical tension showed to improve alveolar maturation and differentiation toward AT1. By manipulating ROCK pathway, we demonstrate that stretch-induced Yap/Taz activation promotes alveolar differentiation toward AT1 phenotype via ROCK activity. Our findings show that balanced ROCK-Yap/Taz signaling is essential to regulate AT1 differentiation in response to mechanical stretching of the fetal lung, which might be helpful in improving lung development and regeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00484.2020DOI Listing
November 2021

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

Sci Rep 2021 08 18;11(1):16975. Epub 2021 Aug 18.

Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, UK.

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. Markers for nuclear (DAPI), cell type (vimentin, αSMA) and healing (Cx43, TGFβ, collagen) were examined by immunofluorescence (IMF) confocal microscopy, Second Harmonic Generation (SHG) imaging and RT-qPCR. After trauma, AMCs and myofibroblasts migrated to the AM wound edge. Within four days, αSMA expressing myofibroblasts showed abundant Cx43 localized in the cytoplasmic processes. The highly contractile spindle-shaped myofibroblasts were present in the defect site and released collagen. In contrast, AMCs expressed vimentin and formed Cx43 plaques between cells found in the outer edges of the wound. Whilst AMCs were absent in the defect site, αSMA expressing myofibroblasts continued to elongate and polarize the collagen fibres. Both TGFβ and Cx43 gene expression were significantly increased after trauma. Cx43 has differential effects on AM cell populations that increase cellularity, contraction and potentially migration to the wound edge resulting in collagen polarisation in the AM defect site. Establishing how Cx43 regulates AM cell function could be an approach to repair defects in the membranes after trauma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-94767-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373966PMC
August 2021

Age and/or postmenopausal status as risk factors for pelvic organ prolapse development: systematic review with meta-analysis.

Int Urogynecol J 2021 Aug 5. Epub 2021 Aug 5.

Department of Gynecology, Federal University of Sao Paulo, São Paulo, Brazil.

Introduction And Hypothesis: Age is named as a risk factor for pelvic organ prolapse (POP), despite not being the primary outcome for many observational studies. Postmenopausal status is another associated factor but has many confounders. We aimed to systematically review the role of age and/or postmenopausal status in POP development.

Methods: Systematic review addressing age and hormones, more specifically by postmenopausal status, from inception to March 2020 in four databases (PubMed, Embase, WOS, Cochrane Library). Quality of evidence was classified by the ROBINS-I classification for non-randomized studies. Experimental studies, animal studies, studies linking age with recurrent POP and case series were excluded. Effect estimates were collected from adjusted odds ratio plus 95% confidence intervals. Significance level was 5%. A discussion exploring mechanistic factors was also included.

Results: Nineteen studies (11 cross sectional, 6 cohort and 2 case control) were included for quantitative analysis. Only two studies presented a low overall risk of bias for age; most of the domains were of moderate risk. Every additional year was responsible for a 10% increase in the risk to develop POP (OR = 1.102 [1.021-1.190]; i = 80%, random analysis, p = 0.012). This trend was confirmed when age was dichotomized into a cutoff of 35 (p = 0.035) and 50 (p < 0.001) years. Although an increase in the risk for POP was noted in postmenopausal women, this did not reach statistical significance (OR = 2.080 [0.927-4.668], i = 0%, p = 0.076).

Conclusion: Age is a risk factor for POP; postmenopausal status was not statistically associated with POP, prompting the need for further studies addressing this factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00192-021-04953-1DOI Listing
August 2021

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Sci Rep 2021 07 6;11(1):13898. Epub 2021 Jul 6.

Department of Obstetrics & Gynecology, University of Campinas, Campinas, Brazil.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-92357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260739PMC
July 2021

'We did everything we could'- a qualitative study exploring the acceptability of maternal-fetal surgery for spina bifida to parents.

Prenat Diagn 2021 Jul 18;41(8):910-921. Epub 2021 Jul 18.

Department of Development and Regeneration Cluster Woman and Child, Biomedical Sciences, KU Leuven, Leuven, Belgium.

Objective: To explore the concepts and strategies parents employ when considering maternal-fetal surgery (MFS) as an option for the management of spina bifida (SB) in their fetus, and how this determines the acceptability of the intervention.

Methods: A two-centre interview study enrolling parents whose fetuses with SB were eligible for MFS. To assess differences in acceptability, parents opting for MFS (n = 24) were interviewed at three different moments in time: prior to the intervention, directly after the intervention and 3-6 months after birth. Parents opting for termination of pregnancy (n = 5) were interviewed only once. Themes were identified and organised in line with the framework of acceptability.

Results: To parents opting for MFS, the intervention was perceived as an opportunity that needed to be taken. Feelings of parental responsibility drove them to do anything in their power to improve their future child's situation. Expectations seemed to be realistic yet were driven by hope for the best outcome. None expressed decisional regret at any stage, despite substantial impact and, at times, disappointing outcomes. For the small group of participants, who decided to opt for termination of pregnancy (TOP), MFS was not perceived as an intervention that substantially could improve the quality of their future child's life.

Conclusion: Prospective parents opting for MFS were driven by their feelings of parental responsibility. They recognise the fetus as their future child and value information and care focusing on optimising the child's future health. In the small group of parents opting for TOP, MFS was felt to offer insufficient certainty of substantial improvement in quality of life and the perceived severe impact of SB drove their decision to end the pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5996DOI Listing
July 2021

Prenatal cerebellar growth is altered in congenital diaphragmatic hernia on ultrasound.

Prenat Diagn 2021 Jul 3. Epub 2021 Jul 3.

Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Leuven, Belgium.

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.

Conclusion: Fetuses with isolated left-sided CDH have a small cerebellum and reduced MCA peak systolic velocity. Follow up studies are necessary to determine the impact of these changes on neurodevelopment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5993DOI Listing
July 2021

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

Transl Pediatr 2021 May;10(5):1448-1460

Clinical Department of Obstetrics and Gynecology, Academic Department of Development and Regeneration, Woman and Child, Leuven, Belgium.

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. The main outcomes of single-institutional studies and multiple systematic reviews are examined and discussed. Despite these studies, the fetal community agrees that FETO remains investigational at this time as there is insufficient evidence to recommend it as the standard of care for CDH. A randomized controlled trial, The Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial, has been designed to attempt to answer this question in an elaborate, international, multi-institutional study and is described in the text. Finally, future directions of fetal intervention for antenatally diagnosed CDH are discussed, including options for non-isolated CDH, the Smart-TO balloon for nonoperative reversal of occlusion, and transplacental sildenafil for treatment of pulmonary hypertension prior to birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tp-20-130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192998PMC
May 2021

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

Fetal Diagn Ther 2021 16;48(6):411-420. Epub 2021 Jun 16.

Department of Development and Regeneration, Katholieke Universiteit, Leuven, Belgium.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000515435DOI Listing
November 2021

Risk Factors Associated with Preterm Prelabor Rupture of Membranes after Cord Occlusion in Monochorionic Diamniotic Twins.

Fetal Diagn Ther 2021 15;48(6):457-463. Epub 2021 Jun 15.

BCNatal Fetal Medicine Research Center, Hospital Clínic and Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.

Introduction: Preterm prelabor rupture of membranes (PPROM) is a common complication after fetal surgeries. The aim of this study was to assess risk factors for and outcomes after PPROM following cord occlusion (CO) in monochorionic diamniotic (MCDA) pregnancies.

Methods: This was a retrospective cohort study of 188 consecutive MCDA pregnancies treated by bipolar or laser CO, either primarily because of discordant malformation (dMF) or severe selective fetal growth restriction (sFGR), or secondarily when complete bichorionization was not possible in case of twin-to-twin transfusion syndrome (TTTS) or sFGR. Intentional septostomy was performed when needed. The procedure-related PPROM was defined as rupture of membranes <32 weeks' gestation (PROM <32 weeks). Selected pre-, intra-, and early postoperative variables were analyzed by univariate and binomial logistic regression to determine they are correlated to PROM <32 weeks after CO.

Results: Between 2006 and 2017, 188 cases underwent CO. Diagnosis was TTTS in 28.2% (n = 53), severe sFGR in 49.5% (n = 93), and dMF in 22.3% (n = 42). PROM <32 weeks occurred in 21.3% (n = 40), resulting in worse perinatal outcomes, as preterm birth <32 weeks occurred in 80.7% (vs. 8.3%, p = 0.000), procedure-to-delivery interval was 47.5 days (vs. 125, p = 0.000), gestational age (GA) at birth 30.0 weeks (vs. 37.7 weeks, p = 0.000), and survival 65.0% (vs. 91.1%, p = 0.000). In univariate analysis, indication, anterior placenta, cervical length, GA at surgery, operation time, amniodistention and drainage fluid volumes, chorioamniotic membrane separation, and septostomy were selected as relevant factors to be included in the regression model. In a multivariate analysis, TTTS was the only factor associated to PROM <32 weeks (OR 3.5 CI 95% 1.5-7.9).

Conclusions: PROM <32 weeks after CO increases the risk of preterm delivery. In this cohort, the membrane rupture was more likely when CO was done in the context of TTTS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000516513DOI Listing
November 2021

MIDeepSeg: Minimally interactive segmentation of unseen objects from medical images using deep learning.

Med Image Anal 2021 08 18;72:102102. Epub 2021 May 18.

School of Mechanical and Electrical Engineering, University of Electronic Science and Technology of China, Chengdu, China; SenseTime Research, Shanghai, China.

Segmentation of organs or lesions from medical images plays an essential role in many clinical applications such as diagnosis and treatment planning. Though Convolutional Neural Networks (CNN) have achieved the state-of-the-art performance for automatic segmentation, they are often limited by the lack of clinically acceptable accuracy and robustness in complex cases. Therefore, interactive segmentation is a practical alternative to these methods. However, traditional interactive segmentation methods require a large number of user interactions, and recently proposed CNN-based interactive segmentation methods are limited by poor performance on previously unseen objects. To solve these problems, we propose a novel deep learning-based interactive segmentation method that not only has high efficiency due to only requiring clicks as user inputs but also generalizes well to a range of previously unseen objects. Specifically, we first encode user-provided interior margin points via our proposed exponentialized geodesic distance that enables a CNN to achieve a good initial segmentation result of both previously seen and unseen objects, then we use a novel information fusion method that combines the initial segmentation with only a few additional user clicks to efficiently obtain a refined segmentation. We validated our proposed framework through extensive experiments on 2D and 3D medical image segmentation tasks with a wide range of previously unseen objects that were not present in the training set. Experimental results showed that our proposed framework 1) achieves accurate results with fewer user interactions and less time compared with state-of-the-art interactive frameworks and 2) generalizes well to previously unseen objects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.media.2021.102102DOI Listing
August 2021

WITHDRAWN: Phosphodiesterase-5 inhibitors in Pregnancy: Systematic review and meta-analysis of maternal and perinatal safety and clinical outcomes.

Am J Obstet Gynecol 2021 06 8. Epub 2021 Jun 8.

Mater Research Institute - University of Queensland, Level 3 Aubigny Place, Raymond Terrace, South Brisbane, Queensland 4101, Australia; Faculty of Medicine, University of Medicine, Whitty Building, Annerley Road, South Brisbane, Queensland 4101, Australia; NHMRC Stillbirth Centre For Research Excellence, Mater Research Institute, South Brisbane, Queensland 4101, Australia. Electronic address:

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2021.06.006DOI Listing
June 2021

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

N Engl J Med 2021 07 8;385(2):107-118. Epub 2021 Jun 8.

From the Department of Obstetrics and Gynecology, KU Leuven (J.A.D., F.M.R.) and Academic Department of Development and Regeneration, Biomedical Sciences, University Hospitals KU Leuven, Leuven, Belgium (J.A.D., B.V.C., F.M.R.); King's College Hospital (K.H.N.) and the Institute for Women's Health, University College London Hospital (J.A.D.) - both in London; Hospital Antoine-Béclère, Université Paris-Saclay, Clamart, France (A.B.); Hospital Clinic and Sant Joan de Déu, Barcelona (E.G.); Mount Sinai Hospital, Toronto (G.R.); Hospital Maggiore Policlinico, Milan (N.P.); the National Center for Child Health and Development, Tokyo (H.S.); Children's Memorial Hermann Hospital, Houston (A.J.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and University Hospital Bonn, Bonn, Germany (C.B.).

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.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2027030DOI Listing
July 2021

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

N Engl J Med 2021 07 8;385(2):119-129. Epub 2021 Jun 8.

From the Department of Obstetrics and Gynecology, University Hospitals KU Leuven (J.A.D., P.L.J.D.) and Academic Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium (J.A.D., B.V.C., P.L.J.D.); Hospital Antoine-Béclère, Université Paris-Saclay, Clamart (A.B.), and Necker-Enfants Malades Hospital, Paris (Y.V.) - both in France; Hospital Clinic and Sant Joan de Déu, Barcelona (E.G.); Institute for Women's Health, University College London Hospital (J.A.D.) and King's College Hospital(K.H.N.) - both in London; the University Hospital Bonn, Bonn, Germany (C.B.); Hospital Maggiore Policlinico, Milan (N.P.), and Bambino Gesù Children's Hospital, Rome (F.M.) - both in Italy; Baylor College of Medicine and Texas Children's Hospital (M.B.) and Children's Memorial Hermann Hospital (A.J.) - all in Houston; Mater Mothers' Hospital, Brisbane, QLD, Australia (G.J.G.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands (P.L.J.D.).

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.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2026983DOI Listing
July 2021

The effect of xenon on fetal neurodevelopment following maternal sevoflurane anesthesia and laparotomy in rabbits.

Neurotoxicol Teratol 2021 Sep-Oct;87:106994. Epub 2021 May 5.

Department of Anesthesiology, University Hospitals of the KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address:

Background: There is concern that maternal anesthesia during pregnancy impairs brain development of the human fetus. Xenon is neuroprotective in pre-clinical models of anesthesia-induced neurotoxicity in neonates. It is not known if xenon also protects the developing fetal brain when administered in addition to maternal sevoflurane-anesthesia during pregnancy.

Objective: To investigate the effects of sevoflurane and xenon on neurobehaviour and neurodevelopment of the offspring in a pregnant rabbit model.

Methods: Pregnant rabbits on post-conception day 28 (term = 31d) underwent two hours of general anesthesia with 1 minimum alveolar concentration (MAC) of sevoflurane in 30% oxygen (n = 17) or 1 MAC sevoflurane plus 50-60 % xenon in 30% oxygen (n = 10) during a standardized laparotomy while receiving physiological monitoring. A sham-group (n = 11) underwent monitoring alone for two hours. At term, the rabbits were delivered by caesarean section. On the first postnatal day, neonatal rabbits underwent neurobehavioral assessment using a validated test battery. Following euthanasia, the brains were harvested for neurohistological analysis. A mixed effects-model was used for statistical analysis.

Results: Maternal cardiopulmonary parameters during anesthesia were within the reference range. Fetal survival rates were significantly higher in the sham-group as compared to the sevoflurane-group and the fetal brain/body weight ratio was significantly lower in the sevoflurane-group as compared with the sham- and xenon-group. Pups antenatally exposed to anesthesia had significantly lower motor and sensory neurobehavioral scores when compared to the sham-group (mean ± SD; sevo: 22.70 ± 3.50 vs. sevo+xenon: 22.74 ± 3.15 vs. sham: 24.37 ± 1.59; overall p = 0.003; sevo: 14.98 ± 3.00 vs. sevo+xenon: 14.80 ± 2.83 vs. sham: 16.43 ± 2.63; overall p = 0.006; respectively). Neuron density, neuronal proliferation and synaptic density were reduced in multiple brain regions of the exposed neonates. The co-administration of xenon had no measurable neuroprotective effects in this model.

Conclusions: In rabbits, sevoflurane anesthesia for a standardized laparotomy during pregnancy resulted in impaired neonatal neurobehavior and a decreased neuron count in several regions of the neonatal rabbit brain. Co-administration of xenon did not prevent this effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ntt.2021.106994DOI Listing
May 2021

Cortical spectral matching and shape and volume analysis of the fetal brain pre- and post-fetal surgery for spina bifida: a retrospective study.

Neuroradiology 2021 Oct 1;63(10):1721-1734. Epub 2021 May 1.

School of Biomedical Engineering & Imaging Sciences (BMEIS), King's College London, London, UK.

Purpose: A retrospective study was performed to study the effect of fetal surgery on brain development measured by MRI in fetuses with myelomeningocele (MMC).

Methods: MRI scans of 12 MMC fetuses before and after surgery were compared to 24 age-matched controls without central nervous system abnormalities. An automated super-resolution reconstruction technique generated isotropic brain volumes to mitigate 2D MRI fetal motion artefact. Unmyelinated white matter, cerebellum and ventricles were automatically segmented, and cerebral volume, shape and cortical folding were thereafter quantified. Biometric measures were calculated for cerebellar herniation level (CHL), clivus-supraocciput angle (CSO), transverse cerebellar diameter (TCD) and ventricular width (VW). Shape index (SI), a mathematical marker of gyrification, was derived. We compared cerebral volume, surface area and SI before and after MMC fetal surgery versus controls. We additionally identified any relationship between these outcomes and biometric measurements.

Results: MMC ventricular volume/week (mm/week) increased after fetal surgery (median: 3699, interquartile range (IQR): 1651-5395) compared to controls (median: 648, IQR: 371-896); P = 0.015. The MMC SI is higher pre-operatively in all cerebral lobes in comparison to that in controls. Change in SI/week in MMC fetuses was higher in the left temporal lobe (median: 0.039, IQR: 0.021-0.054), left parietal lobe (median: 0.032, IQR: 0.023-0.039) and right occipital lobe (median: 0.027, IQR: 0.019-0.040) versus controls (P = 0.002 to 0.005). Ventricular volume (mm) and VW (mm) (r = 0.64), cerebellar volume and TCD (r = 0.56) were moderately correlated.

Conclusions: Following fetal myelomeningocele repair, brain volume, shape and SI were significantly different from normal in most cerebral layers. Morphological brain changes after fetal surgery are not limited to hindbrain herniation reversal. These findings may have neurocognitive outcome implications and require further evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00234-021-02725-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460513PMC
October 2021

Fetally-injected drugs for immobilization and analgesia do not modify fetal brain development in a rabbit model.

Prenat Diagn 2021 Aug 16;41(9):1164-1170. Epub 2021 May 16.

Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven, Belgium.

Objective: During fetal surgery, fetuses receive medication (atropine-fentanyl-curare) to prevent fetal pain, movement and bradycardia. Although essential there has been no detailed review of potential side effects. Herein we aimed to assess the effects of this medication cocktail on fetal brain development in a rabbit model.

Methods: Pregnant does underwent laparotomy at 28 days of gestation. Two pups of each horn were randomized to an ultrasound guided injection with medication (atropine-cisatracurium-fentanyl, as clinically used) or saline (sham). The third pup was used as control. At term, does were delivered by cesarean. Outcome measures were neonatal biometry, neuromotoric functioning and neuro-histology (neuron density, synaptic density and proliferation).

Results: Maternal vital parameters remained stable during surgery. Fetal heart rates did not differ before and after injection, and were comparable for the three groups. At birth, neonatal body weights and brain-to-body weight ratios were also comparable. Both motor and sensory neurobehavioral scores were comparable. There were no differences in neuron density or proliferation. Sham pups, had a lower synaptic density in the hippocampus as compared to the medication group, however there was no difference in the other brain areas.

Conclusion: In the rabbit model, fetal medication does not appear to lead to short-term neurocognitive effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5954DOI Listing
August 2021

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.

Br J Anaesth 2021 Jun 6;126(6):1128-1140. Epub 2021 Apr 6.

Department of Anaesthesiology, UZ Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, Group Biomedical Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Background: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning.

Methods: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses.

Results: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine.

Conclusion: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed.

Prospero Registration Number: CRD42018115194.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2021.02.026DOI Listing
June 2021

Incidence and patterns of abnormal corpus callosum in fetuses with isolated spina bifida aperta.

Prenat Diagn 2021 Jul 8;41(8):957-964. Epub 2021 Apr 8.

Department of Development and Regeneration, Cluster Woman and Child, Biomedical Sciences, KU Leuven, Leuven, Belgium.

Objective: To determine the incidence and characterise corpus callosum (CC) abnormalities in fetuses with spina bifida aperta (SBA) between 18 and 26 weeks of gestation.

Methods: This was a retrospective study on fetuses with isolated SBA and who were assessed for fetal surgery. Digitally stored ultrasound images of the brain were reviewed for the presence/absence of the CC, and the length and diameter of its constituent parts (rostrum, genu, body and splenium). We used regression analysis to determine the relationship between CC abnormalities and gestational age, head circumference, ventricle size, lesion level and lesion type.

Results: Nearly three-quarters of fetuses with isolated SBA had an abnormal CC (71.7%, 76/106). Partial agenesis was most common in the splenium (18.9%, 20/106) and the rostrum (13.2%, 14/106). The most common abnormal pattern was of a short CC with normal diameter throughout. Of note, 20.8% (22/106) had a hypoplastic genu and 28.3% (30/106) had a thick body part. Larger lateral ventricle size was associated with partial agenesis of the CC (odds ratio [OR]: 0.14, p < 0.001) and inversely associated with a shorter CC (OR: 2.60, p < 0.01).

Conclusion: An abnormal CC is common in fetuses with isolated SBA who are referred for fetal surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5945DOI Listing
July 2021
-->