Showing papers by "Jan Deprest published in 2021"

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia

Abstract: Background Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital ...

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

Abstract: 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.

Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation.

Abstract: Extreme prematurity remains a major cause of neonatal mortality and severe long-term morbidity. Current neonatal care is associated with significant morbidity due to iatrogenic injury and developmental immaturity of extreme premature infants. A more physiologic approach, replacing placental function and providing a womb-like environment, is the foundational principle of artificial placenta (AP) and womb (AW) technology. The concept has been studied during the past 60 years with limited success. However, recent technological advancements and a greater emphasis on mimicking utero-placental physiology have improved the success of experimental models, bringing the technology closer to clinical translation. Here, we review the rationale for and history of AP and AW technology, discuss the challenges that needed to be overcome, and compare recent successful models. We conclude by outlining some remaining challenges to be addressed on the path towards clinical translation and opportunities for future research.

Fetal endoscopic tracheal occlusion reverses the natural history of right-sided congenital diaphragmatic hernia: European multicenter experience

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

Pregnancy, labour and delivery as risk factors for pelvic organ prolapse: a systematic review.

Abstract: Pregnancy and childbirth are considered risk factors for pelvic organ prolapse (POP). The long latency between obstetric events and morbidity hinders the establishment of cause-effect relationships. Recently, intermediate outcomes such as organ descent and levator avulsion (LA) have been identified. We aimed to assess the effect of obstetric events on symptoms and signs of POP and on LA. We systematically reviewed the literature by searching PubMed/MEDLINE, Embase and Cochrane Library. We included studies in women examining associations between obstetric events and symptoms and signs of POP and LA, assessed through questionnaires, clinical examination and pelvic floor imaging. Two reviewers evaluated the studies for eligibility and for methodological quality/susceptibility to bias. We extracted study results and clustered them by outcome: symptoms of POP (sPOP), clinical findings of POP (cPOP) and LA. When appropriate, we performed a random-effect meta-analysis and reported the summary odds ratios (OR) with 95% confidence intervals. Heterogeneity across studies was assessed using the I2 statistic. The first vaginal delivery was a risk factor for POP as measured by sPOP (OR: 2.65 [1.81–3.88]), cPOP (OR: 4.85 [2.15–10.94]) and in association with LA (OR: 41.6 [4.13– 419.41]). Forceps delivery was a risk factor for POP as measured by sPOP (OR: 2.51 [1.34–4.69]), cPOP (OR: 1.68 [1.21–2.34]) and in association with LA (OR: 5.92 [3.75–9.34]). Birth exclusively by caesarean was protective for sPOP (OR: 0.38 [0.29–0.51]) and for cPOP (OR: 0.29 [0.20–0.41]) and it did not confer any additional risk compared to nulliparity. This review confirms a strong aetiological link between vaginal birth and POP, with the first vaginal and forceps delivery being the main determinants.

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

Abstract: 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

Safety and efficacy of smart tracheal occlusion device in diaphragmatic hernia lamb model.

Abstract: Objective To investigate the efficacy and safety of the 'smart' tracheal occlusion (Smart-TO) device in fetal lambs with diaphragmatic hernia (DH). Methods DH was created in fetal lambs on gestational day 70 (term, 145 days). Fetuses were allocated to either pregnancy continuation until term (DH group) or fetoscopic endoluminal tracheal occlusion (TO), performed using the Smart-TO balloon on gestational day 97 (DH + TO group). On gestational day 116, the presence of the balloon was confirmed on ultrasound, then the ewe was walked around a 3.0-Tesla magnetic resonance scanner for balloon deflation, which was confirmed by ultrasound immediately afterwards. At term, euthanasia was performed and the fetus retrieved. Efficacy of occlusion was assessed by the lung-to-body-weight ratio (LBWR) and lung morphometry. Safety parameters included tracheal side effects assessed by morphometry and balloon location after deflation. The unoccluded DH lambs served as a comparator. Results Six fetuses were included in the DH group and seven in the DH + TO group. All balloons deflated successfully and were expelled spontaneously from the airways. In the DH + TO group, in comparison to controls, the LBWR at birth was significantly higher (1.90 (interquartile range (IQR), 1.43-2.55) vs 1.07 (IQR, 0.93-1.46); P = 0.005), while on lung morphometry, the alveolar size was significantly increased (mean linear intercept, 47.5 (IQR, 45.6-48.1) vs 41.9 (IQR, 38.8-46.1) μm; P = 0.03); whereas airway complexity was lower (mean terminal bronchiolar density, 1.56 (IQR, 1.0-1.81) vs 2.23 (IQR, 2.14-2.40) br/mm2 ; P = 0.005). Tracheal changes on histology were minimal in both groups, but more noticeable in fetal lambs that underwent TO than in unoccluded lambs (tracheal score, 2 (IQR, 1-3) vs 0 (0-1); P = 0.03). Conclusions In fetal lambs with DH, TO using the Smart-TO balloon is effective and safe. Occlusion can be reversed non-invasively and the deflated intact balloon expelled spontaneously from the fetal upper airways. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Obstetric risk factors for anorectal dysfunction after delivery: a systematic review and meta-analysis.

Abstract: Pregnancy and childbirth are considered risk factors for pelvic floor dysfunction, including anorectal dysfunction. We aimed to assess the effect of obstetric events on anal incontinence and constipation after delivery. We systematically reviewed the literature by searching MEDLINE, Embase and CENTRAL. We included studies in women after childbirth examining the association between obstetric events and anorectal dysfunction assessed through validated questionnaires. We selected eligible studies and clustered the data according to the type of dysfunction, obstetric event and interval from delivery. We assessed risk of bias using the Newcastle Ottawa Scale and we performed a random-effects meta-analysis and reported the results as odds ratios (ORs) with their 95% confidence intervals. Heterogeneity across studies was assessed using I2 statistics. Anal sphincter injury (OR: 2.44 [1.92–3.09]) and operative delivery were risk factors for anal incontinence (forceps—OR :1.35 [1.12–1.63]; vacuum—OR: 1.17 [1.04–1.31]). Spontaneous vaginal delivery increased the risk of anal incontinence compared with caesarean section (OR: 1.27 [1.07–1.50]). Maternal obesity (OR:1.48 [1.28–1.72]) and advanced maternal age (OR: 1.56 [1.30–1.88]) were risk factors for anal incontinence. The evidence on incontinence is of low certainty owing to the observational nature of the studies. No evidence was retrieved regarding constipation after delivery because of a lack of standardised validated assessment tools. Besides anal sphincter injury, forceps delivery, maternal obesity and advanced age were associated with higher odds of anal incontinence, whereas caesarean section is protective. We could not identify obstetric risk factors for postpartum constipation, as few prospective studies addressed this question and none used a standardised validated questionnaire.

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

Abstract: 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.

The TOTAL trial dilemma: A survey among professionals on equipoise regarding fetal therapy for severe congenital diaphragmatic hernia

Abstract: Objective Running randomized clinical trials (RCT) in fetal therapy is challenging. This is no different for fetoscopic endoluminal tracheal occlusion (FETO) for severe left-sided Congenital Diaphragmatic Hernia (CDH). We assessed the knowledge, attitude and practice (KAP) of maternal-fetal medicine specialists toward the antenatal management of CDH, and the randomized controlled clinical (RCT) "Tracheal Occlusion To Accelerate Lung growth-trial." Methods A cross-sectional KAP-survey was conducted among 311 registrants of the 18th World Congress in Fetal Medicine. Results The overall knowledge of CDH and FETO was high. Remarkably only 45% considers prenatal prediction of neonatal outcome reliable. Despite, in their clinical practice they perform severity assessment (80%) and refer families for FETO either within the context of an RCT (43%) or on patient request (32%). Seventy percent perceives not offering FETO on patient demand seems as if no treatment is provided to a fetus with predicted poor outcome. Only 20% of respondents considers denying access to FETO on patient demand not as a psychological burden. Conclusion Often the views of individual respondents contradicted with their clinical practice. It seems that, for severe CDH, clinicians face personal and practical dilemmas that undermine equipoise. To us, this indicates the tension between the clinical and scientific obligations physicians experience.

Globally Optimal Fetoscopic Mosaicking Based on Pose Graph Optimisation With Affine Constraints

Abstract: Fetoscopic laser ablation surgery could be guided using a high-quality panorama of the operating site, representing a map of the placental vasculature. This can be achieved during the initial inspection phase of the procedure using image mosaicking techniques. Due to the lack of camera calibration in the operating room, it has been mostly modelled as an affine registration problem. While previous work mostly focuses on image feature extraction for visual odometry, the challenges related to large-scale reconstruction (re-localisation, loop closure, drift correction) remain largely unaddressed in this context. This letter proposes using pose graph optimisation to produce globally optimal image mosaics of placental vessels. Our approach follows the SLAM framework with a front-end for visual odometry and a back-end for long-term refinement. Our front-end uses a recent state-of-the-art odometry approach based on vessel segmentation, which is then managed by a key-frame structure and the bag-of-words (BoW) scheme to retrieve loop closures. The back-end, which is our key contribution, models odometry and loop closure constraints as a pose graph with affine warpings between states. This problem in the special Euclidean space cannot be solved by existing pose graph algorithms and available libraries such as G2O. We model states on affine Lie group with local linearisation in its Lie algebra. The cost function is established using Mahalanobis distance with the vectorisation of the Lie algebra. Finally, an iterative optimisation algorithm is adopted to minimise the cost function. The proposed pose graph optimisation is first validated on simulation data with a synthetic trajectory that has different levels of noise and different numbers of loop closures. Then the whole system is validated using real fetoscopic data that has three sequences with different numbers of frames and loop closures. Experimental results validate the advantage of the proposed method compared with baselines.

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

Abstract: A retrospective study was performed to study the effect of fetal surgery on brain development measured by MRI in fetuses with myelomeningocele (MMC). 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. MMC ventricular volume/week (mm3/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 (mm3) and VW (mm) (r = 0.64), cerebellar volume and TCD (r = 0.56) were moderately correlated. 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.

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

Abstract: 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.

Animal models for pelvic organ prolapse: systematic review.

Abstract: We aimed to summarize the knowledge on the pathogenesis of pelvic organ prolapse (POP) generated in animal models. We searched MEDLINE, Embase, Cochrane and the Web of Science to establish what animal models are used in the study of suggested risk factors for the development of POP, including pregnancy, labor, delivery, parity, aging and menopause. Lack of methodologic uniformity precluded meta-analysis; hence, results are presented as a narrative review. A total of 7426 studies were identified, of which 51 were included in the analysis. Pregnancy has a measurable and consistent effect across species. In rats, simulated vaginal delivery induces structural changes in the pelvic floor, without complete recovery of the vaginal muscular layer and its microvasculature, though it does not induce POP. In sheep, first vaginal delivery has a measurable effect on vaginal compliance; measured effects of additional deliveries are inconsistent. Squirrel monkeys can develop POP. Denervation of their levator ani muscle facilitates this process in animals that delivered vaginally. The models used do not develop spontaneous menopause, so it is induced by ovariectomy. Effects of menopause depend on the age at ovariectomy and the interval to measurement. In several species menopause is associated with an increase in collagen content in the longer term. In rodents there were no measurable effects of age apart of elastin changes. We found no usable data for other species. In several species there are measurable effects of pregnancy, delivery and iatrogenic menopause. Squirrel monkeys can develop spontaneous prolapse.

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

Abstract: 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.

Effects of Maternal Abdominal Surgery on Fetal Brain Development in the Rabbit Model.

Abstract: Introduction Anesthesia during pregnancy can impair fetal neurodevelopment, but effects of surgery remain unknown. The aim is to investigate effects of abdominal surgery on fetal brain development. Hypothesis is that surgery impairs outcome. Methods Pregnant rabbits were randomized at 28 days of gestation to 2 h of general anesthesia (sevoflurane group, n = 6) or to anesthesia plus laparoscopic appendectomy (surgery group, n = 13). On postnatal day 1, neurobehavior of pups was assessed and brains harvested. Primary outcome was neuron density in the frontal cortex, and secondary outcomes included neurobehavioral assessment and other histological parameters. Results Fetal survival was lower in the surgery group: 54 versus 100% litters alive at birth (p = 0.0442). In alive litters, pup survival until harvesting was 50 versus 69% (p = 0.0352). No differences were observed for primary outcome (p = 0.5114) for surviving pups. Neuron densities were significantly lower in the surgery group in the caudate nucleus (p = 0.0180), but not different in other regions. No differences were observed for secondary outcomes. Conclusions did not change after adjustment for mortality. Conclusion Abdominal surgery in pregnant rabbits at a gestational age corresponding to the end of human second trimester results in limited neurohistological changes but not in neurobehavioral impairments. High intrauterine mortality limits translation to clinical scenario, where fetal mortality is close to zero.

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

Abstract: 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. Furthermore, we discuss the barriers of performing randomized controlled trials comparing two surgical interventions and suggest that data collection through registries is an alternative method to gather high-grade evidence.

A spatio-temporal atlas of the developing fetal brain with spina bifida aperta

Abstract: Background: Spina bifida aperta (SBA) is a birth defect associated with severe anatomical changes in the developing fetal brain. Brain magnetic resonance imaging (MRI) atlases are popular tools for studying neuropathology in the brain anatomy, but previous fetal brain MRI atlases have focused on the normal fetal brain. We aimed to develop a spatio-temporal fetal brain MRI atlas for SBA. Methods: We developed a semi-automatic computational method to compute the first spatio-temporal fetal brain MRI atlas for SBA. We used 90 MRIs of fetuses with SBA with gestational ages ranging from 21 to 35 weeks. Isotropic and motion-free 3D reconstructed MRIs were obtained for all the examinations. We propose a protocol for the annotation of anatomical landmarks in brain 3D MRI of fetuses with SBA with the aim of making spatial alignment of abnormal fetal brain MRIs more robust. In addition, we propose a weighted generalized Procrustes method based on the anatomical landmarks for the initialization of the atlas. The proposed weighted generalized Procrustes can handle temporal regularization and missing annotations. After initialization, the atlas is refined iteratively using non-linear image registration based on the image intensity and the anatomical land-marks. A semi-automatic method is used to obtain a parcellation of our fetal brain atlas into eight tissue types: white matter, ventricular system, cerebellum, extra-axial cerebrospinal fluid, cortical gray matter, deep gray matter, brainstem, and corpus callosum. Results: An intra-rater variability analysis suggests that the seven anatomical land-marks are sufficiently reliable. We find that the proposed atlas outperforms a normal fetal brain atlas for the automatic segmentation of brain 3D MRI of fetuses with SBA. Conclusions: We make publicly available a spatio-temporal fetal brain MRI atlas for SBA, available here: https://doi.org/10.7303/syn25887675. This atlas can support future research on automatic segmentation methods for brain 3D MRI of fetuses with SBA.

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

Abstract: 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. 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. 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]; i2 = 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], i2 = 0%, p = 0.076). Age is a risk factor for POP; postmenopausal status was not statistically associated with POP, prompting the need for further studies addressing this factor.

Dimensionless squared jerk: An objective differential to assess experienced and novice probe movement in obstetric ultrasound.

Abstract: OBJECTIVE Widely accepted, validated and objective measures of ultrasound competency have not been established for clinical practice. Outcomes of training curricula are often based on arbitrary thresholds, such as the number of clinical cases completed. We aimed to define metrics against which competency could be measured. METHOD We undertook a prospective, observational study of obstetric sonographers at a UK University Teaching Hospital. Participants were either experienced in fetal ultrasound (n = 10, >200 ultrasound examinations) or novice operators (n = 10, <25 ultrasound examinations). We recorded probe motion data during the performance of biometry on a commercially available mid-trimester phantom. RESULTS We report that Dimensionless squared jerk, an assessment of deliberate hand movements, independent of movement duration, extent, spurious peaks and dimension differed significantly different between groups, 19.26 (SD 3.02) for experienced and 22.08 (SD 1.05, p = 0.01) for novice operators, respectively. Experienced operator performance, was associated with a shorter time to task completion of 176.46 s (SD 47.31) compared to 666.94 s (SD 490.36, p = 0.0004) for novice operators. Probe travel was also shorter for experienced operators 521.23 mm (SD 27.41) versus 2234.82 mm (SD 188.50, p = 0.007) when compared to novice operators. CONCLUSION Our results represent progress toward an objective assessment of technical skill in obstetric ultrasound. Repeating this methodology in a clinical environment may develop insight into the generalisability of these findings into ultrasound education.

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

Abstract: 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 Terminology (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 (MFAET) version 1.0. allows systematic consistent AE assessment in pregnancy trials to improve safety. This article is protected by copyright. All rights reserved.

The Detection, Outcome, and Presentation of Twin-Twin Transfusion Syndrome in Monochorionic Diamniotic Twin Pregnancies Followed with a Protocol of Fortnightly Ultrasound Examination.

Abstract: BACKGROUND Evidence to support a fortnightly scan protocol for monochorionic diamniotic (MCDA) pregnancies to detect twin-twin transfusion syndrome (TTTS) is scarce. Also, TTTS-related mortality in an unselected cohort is not well documented. Finally, common knowledge suggests that a more frequent follow-up may pick up the disease at a milder stage, but little is known on the ultrasound findings before the diagnosis. OBJECTIVES We examine if a fortnightly ultrasound scan from 16 weeks onward detects TTTS in time. Also, we document the outcomes in a large unselected cohort of MCDA twins and examine the ultrasound findings within 14 days before diagnosis. METHODS Retrospective cohort of 675 MCDA twin pregnancies followed with a fortnightly scan protocol from 16 weeks onward. Timely detection of TTTS was defined as before fetal demise (stage V), ruptured membranes, or a dilated cervix. We compared the ultrasound findings before the diagnosis between stage I-II and stage III-IV. RESULTS A total of 82/675 (12%) pregnancies developed TTTS, of which 74/82 (90%) were detected in time. In 8/82 (10%), TTTS was diagnosed in stage V: 5 before 16 weeks and 2 after 26 weeks. Fetoscopic laser photocoagulation (FLP) of the placental anastomoses was performed in 48/82 (59%). The survival of TTTS in the entire cohort was 105/164 (64%). In contrast, survival after FLP was 77/96 (80%). In 16/19 (84%) of stage III-IV TTTS, abnormal Doppler findings preceded the diagnosis of TTTS. CONCLUSIONS A scheme of fortnightly ultrasound scans from 16 weeks onward detects 9 out of ten TTTS pregnancies in time. Most stage V cases presented outside the typical time window of 16 and 26 weeks. Survival rates after FLP underestimate the mortality of TTTS. Most stage III-IV cases have abnormal Doppler findings before the diagnosis of TTTS.

Preclinical stem cell therapy in fetuses with myelomeningocele: A systematic review and meta-analysis.

Abstract: Objective We performed a systematic review to summarize the efficacy and safety of in utero stem cells application in preclinical models with myelomeningocele (MMC). Methods The study was registered with PROSPERO (CRD42019160399). We searched MEDLINE, Embase, Web of Science, Scopus and CENTRAL for publications articles on stem cell therapy in animal fetuses with MMC until May 2020. Publication quality was assessed by the SYRCLE's tool. Meta-analyses were pooled if studies were done in the same animal model providing similar type of stem cell used and outcome measurements. Narrative synthesis was performed for studies that could not be pooled. Results Nineteen and seven studies were included in narrative and quantitative syntheses, respectively. Most used mesenchymal stem cells (MSCs) and primarily involved ovine and rodent models. Both intra-amniotic injection of allogeneic amniotic fluid (AF)-MSCs in rat MMC model and the application of human placental (P)-MSCs to the spinal cord during fetal surgery in MMC ovine model did not compromise fetal survival rates at term (rat model, relative risk [RR] 1.03, 95% CI 0.92-1.16; ovine model, RR 0.94, 95% CI 0.78-1.13). A single intra-amniotic injection of allogeneic AF-MSCs into rat MMC model was associated with a higher rate of complete defect coverage compared to saline injection (RR 16.35, 95% CI 3.27-81.79). The incorporation of human P-MSCs as a therapeutic adjunct to fetal surgery in the ovine MMC model significantly improved sheep locomotor rating scale after birth (mean difference 5.18, 95% CI 3.36-6.99). Conclusions Stem cell application during prenatal period in preclinical animal models is safe and effective.

What should we tell parents? Congenital diaphragmatic hernia.

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

The ewe as an animal model of vaginal atrophy and vaginal Er:YAG laser application.

Abstract: Objective In sheep of reproductive age, we aimed to document decrease in epithelial thickness, glycogen amount, and other vaginal changes after castration and the effect of Er:YAG laser as used clinically. Methods On day 0, 16 sheep underwent ovariectomy. They were randomized to sham or three vaginal Er:YAG laser applications at monthly intervals. Primary outcome was vaginal epithelial thickness (d60, d71, d73, d77, and d160). Secondary outcomes included indicators of atrophy (vaginal health index = VHI), pH, cytology, morphology at the above time points, microcirculation focal depth (FD; d70 and d160), and at sacrifice (d160) vaginal dimensions and active and passive biomechanical testing. Results Menopausal changes between 60 and 160 days after ovariectomy included a progressive decrease in epithelial thickness, in VHI, FD, glycogen, elastin content and vasculature, and an increase in pH and collagen content. In lasered animals, the first day a few white macroscopic foci were visible and an increase in pH was measured. Both disappeared within 3 days. Seven days after laser the epithelial thickness increased. At sacrifice (d160), there were no differences between sham and laser group in vaginal dimensions, morphometry, mitotic and apoptotic activity, active contractility, vaginal compliance, except for a lower blood vessel density in the lamina propria of the midvagina in the laser group. Conclusions In reproductive sheep, ovariectomy induces vaginal atrophy evidenced in different outcome measurements. Vaginal Er:YAG laser induced visual impact, a short-term increase in epithelial thickness yet no long-term changes compared to sham therapy in menopausal controls.