Multicentre randomised trial of screening with sFlt1/PlGF and planned delivery to prevent pre-eclampsia at term: protocol of the PE37 study.

INTRODUCTION: Pre-eclampsia affects ~5%-7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term pre-eclampsia accounts for 70% of all cases and a large proportion of maternal-fetal morbidity related to this condition. Unlike in preterm pre-eclampsia, the prediction and prevention of term pre-eclampsia remain unsolved. Previously proposed approaches are based on combined third-trimester screening and/or prophylactic drugs, but these policies are unlikely to be widely implementable in many world settings. Recent evidence shows that the soluble fms-like tyrosine kinase-1 (s-Flt-1) to placental growth factor (PlGF) ratio measured at 35-37 weeks' gestation predicts term pre-eclampsia with an 80% detection rate. Likewise, recent studies demonstrate that induction of labour beyond 37 weeks is safe and well accepted by women. We hypothesise that a single-step universal screening for term pre-eclampsia based on sFlt1/PlGF ratio at 35-37 weeks followed by planned delivery beyond 37 weeks reduces the prevalence of term pre-eclampsia without increasing the caesarean section rates or worsening the neonatal outcomes. METHODS AND ANALYSIS: We propose an open-label randomised clinical trial to evaluate the impact of a screening of term pre-eclampsia with the sFlt-1/PlGF ratio followed by planned delivery in asymptomatic nulliparous women at 35-37 weeks. Women will be assigned 1:1 to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cut-off of >90th centile is used to define the high risk of subsequent pre-eclampsia and offer planned delivery from 37 weeks. The efficacy variables will be analysed and compared between groups primarily following an intention-to-treat approach, by ORs and their 95% CI. This value will be computed using a Generalised Linear Mixed Model for binary response (study group as fixed effect and the centre as intercept random effect). ETHICS AND DISSEMINATION: The study is conducted under the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 20 November 2020. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04766866.

Vaginal changes after ovariectomy in ewes: A large animal model for genitourinary syndrome of menopause.

OBJECTIVE: To evaluate the effect of iatrogenic menopause on the physiology of the vagina of the ewe and to evaluate if vaginal changes in ewes can be translated to women with genitourinary syndrome of menopause (GSM). METHODS: Preclinical research with Dohne Merino ewes. Iatrogenic menopause was induced by bilateral ovariectomy (OVX). Animals were randomized for surgery, blinded for allocation and outcome assessment. Differences between groups were determined by linear regression analyses at 5 months after OVX. Outcome measures were vaginal epithelial thickness, pH, vaginal maturation value, vaginal maturation index, epithelial glycogen accumulation, content of elastin fibers, collagen, and vascularity. RESULTS: OVX ewes (n = 20) showed epithelial thinning of the vaginal wall from 146 µm to 47 µm (mean, P < 0.001). Furthermore, epithelial glycogen accumulation and vascularity of the vaginal wall significantly decreased (43% and 23%, respectively) as compared with the control group (no intervention; n = 5). No significant differences were found for other outcome measures. CONCLUSION: This study established the ewe as a suitable large animal model for GSM. Furthermore, the similar relevant outcomes in humans and ewes hold great value for future translational research for the evaluation and optimization of different treatment modalities for GSM.

VEGF overexpressed mesoangioblasts enhance urethral and vaginal recovery following simulated vaginal birth in rats.

Vaginal birth causes pelvic floor injury which may lead to urinary incontinence. Cell therapy has been proposed to assist in functional recovery. We aim to assess if intra-arterial injection of rat mesoangioblasts (MABs) and stable Vascular Endothelial Growth Factor (VEGF)-expressing MABs, improve recovery of urethral and vaginal function following simulated vaginal delivery (SVD). Female rats (n = 86) were assigned to either injection of saline (control), allogeneic-MABs (MABsallo), autologous-MABs (MABsauto) or allogeneic-MABs transduced to stably expressed VEGF (MABsallo-VEGF). One hour after SVD, 0.5 × 106 MABs or saline were injected into the aorta. Primary outcome was urethral (7d and 14d) and vaginal (14d) function; others were bioluminescent imaging for cell tracking (1, 3 and 7d), morphometry (7, 14 and 60d) and mRNAseq (3 and 7d). All MABs injected rats had external urethral sphincter and vaginal function recovery within 14d, as compared to only half of saline controls. Functional recovery was paralleled by improved muscle regeneration and microvascularization. Recovery rate was not different between MABsallo and MABsauto. MABsallo-VEGF accelerated functional recovery and increased GAP-43 expression at 7d. At 3d we detected major transcriptional changes in the urethra of both MABsallo and MABsallo-VEGF-injected animals, with upregulation of Rho/GTPase activity, epigenetic factors and dendrite development. MABSallo also upregulated transcripts that encode proteins involved in myogenesis and downregulated pro-inflammatory processes. MABsallo-VEGF also upregulated transcripts that encode proteins involved in neuron development and downregulated genes involved in hypoxia and oxidative stress. At 7d, urethras of MABsallo-VEGF-injected rats showed downregulation of oxidative and inflammatory response compared to MABSallo. Intra-arterial injection of MABsallo-VEGF enhances neuromuscular regeneration induced by untransduced MABs and accelerates the functional urethral and vaginal recovery after SVD.

Distinct patterns of interictal intracranial EEG in focal cortical dysplasia type I and II.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common malformation causing refractory focal epilepsy. Surgical removal of the entire dysplastic cortex is crucial for achieving a seizure-free outcome. Precise presurgical distinctions between FCD types by neuroimaging are difficult, mainly in patients with normal magnetic resonance imaging findings. However, the FCD type is important for planning the extent of surgical approach and counselling. METHODS: This study included patients with focal drug-resistant epilepsy and definite histopathological FCD type I or II diagnoses who underwent intracranial electroencephalography (iEEG). We detected interictal epileptiform discharges (IEDs) and their recruitment into repetitive discharges (RDs) to compare electrophysiological patterns characterizing FCD types. RESULTS: Patients with FCD type II had a significantly higher IED rate (p < 0.005), a shorter inter-discharge interval within RD episodes (p < 0.003), sleep influence on decreased RD periodicity (p < 0.036), and longer RD episode duration (p < 0.003) than patients with type I. A Bayesian classifier stratified FCD types with 82% accuracy. CONCLUSION: Temporal characteristics of IEDs and RDs reflect the histological findings of FCD subtypes and can differentiate FCD types I and II. SIGNIFICANCE: Presurgical prediction of FCD type can help to plan a more tailored surgical approach in patients with normal magnetic resonance findings.

Endometriosis in postmenopause.

In our review article, we focused on the rare topic of endometriosis in postmenopause. Endometriosis is primarily a disease of women of reproductive age. In postmenopause, atrophy of endometriosis foci usually occurs. However, recurrence or even de novo occurrence of endometriosis in postmenopause has also been described. The prevalence in postmenopause has been reported to be around 2-5%. Factors that may account for the recurrence of endometriosis are exogenously administered estrogens, self-production of estrogens in peripheral adipose tissue, or activation of aromatase in the focus of endometriosis. When hormonal therapy is required, the best results are achieved by administration of Tibolone. Risk factors for recurrence and subsequent difficulties are the extent of endometriosis, the retained uterus and adnexa. Pain was the most common symptom in 43.5% and palpable finding in 28%. Endometriotic cells are capable of proliferation, survival in an ectopic localization and metastasis to distant locations. The risk of malignant transformation is around 1% and the most common are ovarian tumors. Endometriosis-associated ovarian tumors are typically low-grade disease, histologically endometrioid or clear cell carcinomas. Dia-gnosis is based on ultrasound and magnetic resonance imaging. The basis of therapy for newly developed endometriosis or when symptoms associated with the risk of endometriosis appear is a surgical solution, primarily to exclude the cancerous process.

Cesarean scar pregnancy - a retrospective analysis of cases in the years 2012-2021.

INTRODUCTION: With the increasing number of caesarean sections, the number of cesarean scar pregnancies (CSP) is also increasing. This is a relatively new entity of an ectopic pregnancy, which is risky mainly because of its possible association with placenta accreta spectrum. CSP is thought to represent about 6% of the total number of ectopic pregnancies in all women who have a history of at least one caesarean section. The estimated incidence of CSP is about 1/1,688 of all pregnancies and about 1/2,000 of all caesarean sections. MATERIAL AND METHODS: Retrospective analysis of individual cases of cesarean scar pregnancies managed in our health care facility in the years 2012-2021. RESULTS: In total, we managed 16 cases of pregnancy in the caesarean scar in 15 women. In one woman, we recorded CSP twice. The mean age of the women was 36.6 years (27-41). The mean number of caesarean sections was 1.6 (1-3) and gestational week was 7 (4-10). The average time since the caesarean section was 3.6 years (2-11). The management was methotrexate administration once, hysteroscopic resection once and 11times primarily vacuum aspiration only, when in two cases we had to attach laparoscopic uterine artery ligation due to postoperative bleeding. We performed primary ligature of uterine arteries twice before performing vacuum aspiration. In pregnancies above 10 weeks of gestation, we observed more bleeding complications requiring surgical management. Bleeding complications were also related to the presence of fetal cardiac action. CONCLUSION: Early correct dia-gnosis is essential in the management of CSP. Pregnancies up to the 10th week of gestation are managed by simple vacuum aspirations under ultrasound guidance. If the pregnancy is over the 10th week of gestation and especially with cardiac activity, we add laparoscopic uterine artery ligation before vacuum aspiration. All patients are subsequently advised to undergo laparoscopic resuturing of the lower uterine segment.

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

INTRODUCTION AND HYPOTHESIS: This manuscript is the International Urogynecology Consultation (IUC) on pelvic organ prolapse (POP) chapter one, committee three, on the Pathophysiology of Pelvic Organ Prolapse assessing genetics, pregnancy, labor and delivery, age and menopause and animal models. MATERIALS AND METHODS: An international group of urogynecologists and basic scientists performed comprehensive literature searches using pre-specified terms in selected biomedical databases to summarize the current knowledge on the pathophysiology of the development of POP, exploring specifically factors including (1) genetics, (2) pregnancy, labor and delivery, (3) age and menopause and (4) non-genetic animal models. This manuscript represents the summary of three systematic reviews with meta-analyses and one narrative review, to which a basic scientific comment on the current understanding of pathophysiologic mechanisms was added. RESULTS: The original searches revealed over 15,000 manuscripts and abstracts which were screened, resulting in 202 manuscripts that were ultimately used. In the area of genetics the DNA polymorphisms rs2228480 at the ESR1 gene, rs12589592 at the FBLN5 gene, rs1036819 at the PGR gene and rs1800215 at the COL1A1 gene are significantly associated to POP. In the area of pregnancy, labor and delivery, the analysis confirmed a strong etiologic link between vaginal birth and symptoms of POP, with the first vaginal delivery (OR: 2.65; 95% CI: 1.81-3.88) and forceps delivery (OR: 2.51; 95% CI: 1.24-3.83) being the main determinants. Regarding age and menopause, only age was identified as a risk factor (OR : 1.102; 95% CI: 1.02-1.19) but current data do not identify postmenopausal status as being statistically associated with POP. In several animal models, there are measurable effects of pregnancy, delivery and iatrogenic menopause on the structure/function of vaginal support components, though not on the development of POP. CONCLUSIONS: Genetics, vaginal birth and age all have a strong etiologic link to the development of POP, to which other factors may add or protect against the risk.

Animal models for pelvic organ prolapse: systematic review.

INTRODUCTION AND HYPOTHESIS: We aimed to summarize the knowledge on the pathogenesis of pelvic organ prolapse (POP) generated in animal models. METHODS: 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. RESULTS: 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. CONCLUSION: In several species there are measurable effects of pregnancy, delivery and iatrogenic menopause. Squirrel monkeys can develop spontaneous prolapse.

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

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.

Video Summary:http://links.lww.com/MENO/A672.

Effects of non-ablative Er:YAG laser on the skin and the vaginal wall: systematic review of the clinical and experimental literature.

INTRODUCTION AND HYPOTHESIS: Er:YAG laser is frequently used in dermatology and gynecology. Clinical studies document high satisfaction rates; however, hard data on the effects at the structural and molecular levels are limited. The aim of this systematic review was to summarize current knowledge about the objective effects of non-ablative Er:YAG laser on the skin and vaginal wall. METHODS: We searched MEDLINE, Embase, Cochrane, and the Web of Science. Studies investigating objectively measured effects of non-ablative Er:YAG laser on the skin or vaginal wall were included. Studies of any design were included. Owing to the lack of methodological uniformity, no meta-analysis could be performed and therefore results are presented as a narrative review. RESULTS: We identified in vitro or ex vivo studies on human cells or tissues, studies in rats, and clinical studies. Most studies were on the skin (n = 11); the rest were on the vagina (n = 4). The quality of studies is limited and the settings of the laser were very diverse. Although the methods used were not comparable, there were demonstrable effects in all studies. Immediately after application the increase in superficial temperature, partial preservation of epithelium and subepithelial extracellular matrix coagulation were documented. Later, an increase in epithelial thickness, inflammatory response, fibroblast proliferation, an increase in the amount of collagen, and vascularization were described. CONCLUSIONS: Er:YAG laser energy may induce changes in the deeper skin or vaginal wall, without causing unwanted epithelial ablation. Laser energy initiates a process of cell activation, production of extracellular matrix, and tissue remodeling.

Functional supramolecular bioactivated electrospun mesh improves tissue ingrowth in experimental abdominal wall reconstruction in rats.

Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Therefore, we aimed to develop a functionalized electrospun mesh that promotes tissue ingrowth and provides adequate mechanical strength and compliance during degradation. We describe the in vivo function of a new supramolecular bioactivated polycarbonate (PC) material based on fourfold hydrogen bonding ureidopyrimidinone (UPy) units (UPy-PC). The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Morphometric analysis of the musculofascial content during wound healing showed that cRGD functionalization promotes myogenesis with inhibition of collagen deposition at 14 days. It also prevents muscle atrophy at 90 days and exerts an immunomodulatory effect on infiltrating macrophages at 14 days and foreign body giant cell formation at 14 and 90 days. Additionally, the bioactivated material promotes neovascularization and connective tissue ingrowth. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in the rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. Our results provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP. STATEMENT OF SIGNIFICANCE: Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Ureidopyrimidinone-polycarbonate is a elastomeric and biodegradable electrospun mesh, which could mimic physiological compliance. The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. These data provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP.

The importance of developing relevant animal models to assess existing and new materials.

PURPOSE OF REVIEW: We summarize the recent literature on the use of different animal models for testing existing and new materials for treatment of pelvic organ prolapse. RECENT FINDINGS: A wide spectrum of animal models is being used in urogynecology, both for the study of physiologic and pathophysiologic processes, training in surgical procedures, yet mainly to study the host response to implant materials. The quality of studies is variable, and procedures, read-outs, and reporting are not standardized. This makes comparison very difficult. The research community is experimenting with different knitting patterns, novel polymers, bioactivation, as well as resorbable rather than durable implants. Outcomes of the experiments are dependent on the location of implantation. Lighter polypropylene constructs seem to induce a less vigorous host response than elder heavier products. Modification of the surface yields contradictory findings. Resorbable acellular collagen matrices may be reintroduced as prophylactically inserted support structures. SUMMARY: Although animal experimentation with novel candidate implants is advocated, there is a lack of standardization in reporting. The concept of resorbable construct is being revived, as durable materials have caused clinical graft-related complications. Large animal experiments seem to provide interesting and more comprehensive information, yet their use may be contested.

Morphological and Functional Changes in the Vagina following Critical Lifespan Events in the Ewe.

BACKGROUND/AIMS: The ewe is increasingly being used as an animal model for pelvic floor disorders. The aim was to further characterize changes in the vaginal properties during its entire lifespan. METHODS: Vaginal tissues were collected at different stages of reproductive life (neonatal, prepubescence, nulliparous, primiparous, multiparous, and menopausal; ≥6 ewes/group). Vaginal size, as well as active and passive biomechanics, was measured. Microscopy included thickness of glycogen, epithelium, lamina propria and muscularis thickness, densities of collagen, elastin, smooth muscle, and nerves. RESULTS: Vaginal dimensions increase during adolescence, peak at reproductive levels, and decrease sharply after ovariectomy. One year after first delivery, the distal vagina gets more compliant, yet this is reversed later in life. The thickness of glycogen staining epithelial layers changed with puberty and menopause. The epithelium was markedly thicker after multiple deliveries. The thickness of lamina propria and muscularis increased in puberty and in nulliparous. Semi-quantitative collagen assessment demonstrated a lower collagen and higher elastin content after first and multiple deliveries. CONCLUSION: The changes in the ovine vaginal wall during representative moments of her lifespan parallel those observed in women.