The Vermian-Crest Angle: A New Method to Assess Fetal Vermis Position within the Posterior Fossa Using 3-Dimensional Multiplanar Sonography.

BACKGROUND: Normal morphometry of the vermis and its relation to the posterior fossa (PF) rule out most major anomalies of the cerebellum. However, accurate categorization of the position and size of the fetal vermis remains a challenge. OBJECTIVE: Our aim was to test a new method to assess the position and size of fetal vermis on 3-dimensional ultrasound (3D-US). METHODS: We measured the vermian-crest angle (VCA) in normal fetuses using multiplanar 3D-US. We also assessed the diameters (superoinferior, anteroposterior, and horizontal) and volume of the vermis. The Spearman rank test and linear and polynomial regression analyses were used for statistical purposes. RESULTS: We included 126 fetuses. Mean ± SD gestational age (GA) was 26.3 ± 4.6 (range 17-35.5) weeks. Mean ± SD superoinferior, anteroposterior, and horizontal diameters were 16.2 ± 4.9, 11.2 ± 3.6, and 5.6 ± 1.6 mm, respectively. Median (range) vermian volume was 0.50 (0.05-2.9) cm3. The VCA was 64.49° ± 11.45. We found no correlation between GA and VCA (r = 0.15; p = 0.13), a linear correlation between GA and vermian diameters, and a quadratic correlation between GA and vermian volume. CONCLUSIONS: We provide a new method to assess vermian position and size within the PF using 3D-US. The combined information may be of value for screening purposes, particularly to differentiate between the various pathological situations encountered within the PF.

Nomograms of the Fetal Sylvian Fissure and Insular Lobe throughout Gestation: A Multicentric, Ultrasonographic Cross-Sectional Study.

INTRODUCTION: Anomalies in cortical development are often associated with an adverse outcome, but prenatal diagnosis is often impeded by the limited knowledge about normal sulci biometries throughout fetal brain development. Our aim was to provide two-dimensional ultrasonographical (2D US) nomograms of the depth of the Sylvian fissure (SF) and insular lobe (IL), as well as of the SF ratio throughout gestation in a large number of fetuses. MATERIALS AND METHODS: This was a prospective cross-sectional study of 329 normal singleton pregnancies. Measurements of the SF, IL, and SF ratio were obtained in a standard transthalamic plane of the fetal head. The SF ratio was defined as SF\SF + IL. All measurements were expressed by regression equations as a function of gestational age (GA) according to the method described by Royston and Wright. The first 38 measurements were repeated twice by 2 examiners to assess the reproducibility through the intraclass correlation coefficient (ICC). RESULTS: A significant correlation was found between GA and SF (r = 0.79; p < 0.0001) as well as IL (r = 0.77; p < 0.0001). Similarly, the SF ratio also showed a significant correlation with GA (r = 0.39; p < 0.0001). When interobserver variability was assessed, ICC was 0.97. CONCLUSIONS: Prenatal 2D US measurements of SF and IL as well as the SF ratio may be feasible and reproducible using a standard view of the fetal head. Our nomograms may be used as a reference for assessing cortical development throughout pregnancy.

Reference Ranges for Fetal Atrioventricular and Ventriculoatrial Time Intervals and Their Ratios during Normal Pregnancy.

BACKGROUND: The diagnostic assessment of fetal arrhythmias relies on the measurements of atrioventricular (AV) and ventriculoatrial (VA) time intervals. Pulsed Doppler over in- and outflow of the left ventricle and tissue Doppler imaging are well-described methods, while Doppler measurements between the left brachiocephalic vein and the aortic arch are less investigated. The aim of this study was to compare these methods of measurement, to find influencing factors on AV and VA times and their ratio, and to create reference ranges. METHODS: Echocardiography was performed between 16 and 40 weeks of gestation in normal singleton pregnancies. Nomograms for the individual measurements were created using quantile regression with Matlab Data Analytics. Statistical analyses were performed with GraphPad version 5.0 for Windows. RESULTS: A total of 329 pregnant women were enrolled. A significant correlation exists between AV and VA times and gestational age (GA) (p = 0.0104 to <0.0001, σ = 0.1412 to 0.3632). No correlation was found between the AV:VA ratio and GA (p = 0.08 to 0.60). All measurements differed significantly amongst the studied methods (p < 0.0001). CONCLUSIONS: AV and VA intervals increase proportionally with GA; no other independent influencing factors could be identified. As significant differences exist between the three methods of assessment, it is crucial to use appropriate reference ranges to diagnose pathologies.

Cervico-isthmic pregnancy successfully treated with bipolar resection following methotrexate administration: case report and literature review.

Cervico-isthmic pregnancy is a rare form of ectopic pregnancy associated with a high morbidity and mortality rate. Recent advances in high-resolution ultrasound have made the diagnosis of early cervico-isthmic pregnancies easier. Early diagnosis allows a more conservative therapeutic approach that avoids hysterectomy and preserves fertility. Here is reported a case of viable cervico-isthmic pregnancy successfully treated with resectoscopy after failed systemic and local (hysteroscopic) methotrexate administration. The resectoscopic excision of the cervico-isthmic pregnancy was carried out with the technique of slicing, using a 27 bipolar resectoscope with a 4-mm loop. The procedure was successful with the complete removal of the ectopic pregnancy, while maintaining satisfactory haemostasis. A literature review shows that no consensus exists for the treatment of cervico-isthmic pregnancies. We report a case of viable cervico-isthmic pregnancy successfully treated with resectoscopy after failed systemic and local (hysteroscopical) methotrexate administration. The resectoscopic excision of cervico-isthmic pregnancy was carried out with the technique of slicing, using a 27 bipolar resectoscope with a 4-mm loop. The procedure was successful with the complete removal of the ectopic pregnancy, while maintaining satisfactory haemostasis.

Pentalogy of Cantrell: embryofetoscopic diagnosis.

Embryofetoscopy is an endoscopic technique that permits a direct visualization and morphologic study of embryos during the first and early second trimester. We report the early prenatal diagnosis of a case of Pentalogy of Cantrell combining data obtained by 2-dimensional and 3-dimensional ultrasonography and embryofetoscopy. Morphologic examination focused on a large omphalocele protruding from the anterior abdominal wall as an oval pulsating mass, measuring approximately 3 cm. The visualization of an omphalocele with ectopia cordis without other malformations confirmed the diagnosis of Pentalogy of Cantrell (class III). Currently, embryofetoscopy allows direct visualization of the embryo in vivo, enabling accurate diagnosis of developmental defects and yielding additional insights into developmental disorders in the embryo.

Hysteroscopic findings in women with menorrhagia.

STUDY OBJECTIVE: To describe the hysteroscopic findings in patients complaining of menorrhagia to establish any significant association between menorrhagia and benign/malignant intrauterine disorders. DESIGN: Prospective cohort study (Canadian Task Force classification II). SETTING: University La Sapienza, Rome, Italy. PATIENTS: One hundred eighteen premenopausal women undergoing office hysteroscopy for menorrhagia (group A) and 344 premenopausal patients undergoing office hysteroscopy for other indications (noncyclic abnormal uterine bleeding, infertility, ultrasonographic abnormalities, etc) (group B). INTERVENTIONS: Office hysteroscopy. MEASUREMENT AND MAIN RESULTS: Data on the prevalence of hysteroscopic findings (cervical polyps, endometrial polyps, submucous myomas, low-grade hyperplasia and high-grade hyperplasia/endometrial carcinoma) were compared between group A and group B. The total prevalence, as well as the prevalence of type 0 and type I myomas (totally or >50% intracavitary, respectively), and the mean number per patients with submucous myomas was significantly higher in group A compared with group B (p = .0001, p = .024, and p = .017, respectively). Multivariable logistic regression analysis showed a statistically significant association between age (odds ratio 4.15, 95% confidence interval 1.55-11.1 in the 40- to 49-year age group), presence of submucous myomas (odds ratio 2.76, 95% confidence interval 1.52-5.00), and menorrhagia. CONCLUSIONS: Menorrhagia seems to be associated with aging, the presence and number of submucous myomas, and with the degree of their intracavitary development.

Repurposing of Bryophyllum pinnatum for dysmenorrhea treatment: a systematic scoping review and case series.

Dysmenorrhea affects women throughout their reproductive years but there has been a lack of effective and well-tolerated treatment options. Pain symptoms mainly result from inflammatory processes and increased contractile activity in the myometrium. The reported use of Bryophyllum pinnatum preparations against inflammation and pain in ethnomedicine as well as current pharmacological data on their inhibition of myometrial contractility led us to hypothesize that this medicinal plant might be a new treatment option for dysmenorrhea. In the first part of the present work, clinical, in vivo, and in vitro studies on the anti-nociceptive and anti-inflammatory, as well as on myometrium relaxing properties of B. pinnatum are reviewed. In the second part, cases of five women with dysmenorrhea who were tentatively treated with a B. pinnatum product are described. The review revealed thirty-three experimental in vivo and in vitro studies, but no clinical study, reporting anti-nociceptive and anti-inflammatory effects of B. pinnatum extracts and compounds in a wide range of conditions. Moreover, sixteen publications on smooth muscle contractility revealed relaxing effects. The latter consisted of clinical evidence, as well as of in vivo and in vitro data. The evidence reviewed therefore provided a rational basis for the use of B. pinnatum in the treatment of dysmenorrhea. We subsequently set out to tentatively treat patients with a well-tolerated B. pinnatum product that is registered (without indication) and commonly used in obstetrics and gynecology in Switzerland. All five treated patients reported a reduction in pain symptoms and 4 out of 5 indicated a reduced intake of painkillers during menstruation. Taken together, the reviewed information on the pharmacological properties and clinical evidence of B. pinnatum extracts and compounds as well as the outcomes of all five patients in the case series support our hypothesis in favor of B. pinnatum as a new, well-tolerated therapeutic approach for dysmenorrhea. Prospective clinical studies are urgently needed.

The use of an oral contraceptive containing estradiol valerate and dienogest before office operative hysteroscopy: a feasibility study.

To investigate the impact of a 3 months preoperative administration of an oral contraceptive, containing dienogest (DNG) and estradiol valerate (E2V) on the outcome of office operative hysteroscopy (OOH). One-hundred and forty-two patients diagnosed at office hysteroscopy as having an asynchronous endometrium associated with either a broad-base sessile endometrial polyp (>1.5, <2.5 cm) or a uterine septum (>1/3 uterine cavity) or scheduled for tubal sterilization were enrolled into a prospective case-control study at University "Federico II" of Naples. 86/142 patients accepted the preoperative hormonal treatment (Group A), while 56/142 refused, thus becoming controls (Group B). Group A underwent OOH during the 10th-20th days of the third cycle of treatment. In Group B OOH was performed at enrolment, together with the diagnostic procedure. The study outcomes were: endometrial pattern, success rate, operating time, degree of surgical difficulty and pain score. An overall improvement of the endometrium was reported in 100% of cases in Group A. A statistically significant difference in success rate could not be demonstrated between two groups. Operative procedures were performed significantly quicker and easier in Group A than Group B (p < 0.001 and p < 0.05, respectively). The mean Visual Analog Scale (VAS) score was significantly lower in Group A (p < 0.001). A short pretreatment with combined oral contraceptive (COC) containing E2V/DNG seems to have a favorable impact on endometrium which in turn may result in an improvement of the overall outcomes of OOH.

Hypertensive disorders of pregnancy share common cfDNA methylation profiles.

Hypertensive disorders of pregnancy (HDP) contribute substantially to perinatal morbidity and mortality. Epigenetic changes point towards cardio-metabolic dysregulation for these vascular disorders. In early pregnancy, epigenetic changes using cell free DNA (cfDNA) are largely unexplored. We aimed to investigate these in HDP between 11 and 14 weeks of gestation by analysis of cfDNA methylation profiles in patients with hypertensive disorders. We identified patients without chronic hypertension but with subsequent development of preeclampsia (PE) (n = 11), with chronic hypertension (HT) but without PE development (n = 14), and lacking both PE and HT (n = 422). We matched patients according to PE risk factors into three groups (n = 5 each group): (1) PE: no HT but PE development, (2) HT: chronic hypertension but no PE and (3) Control: no PE or HT. We successfully optimized our cfDNA isolation process prior to whole genome bisulfite sequencing. Analysis of cfDNA methylation changes indicate a common predisposition in PE and HT groups, chiefly of maternal origin. Assessment of significant differentially methylated regions and annotated genes point towards a common cardiovascular predisposition in preeclampsia and hypertension groups in the first trimester. We postulate the pivotal role of the maternal cardiovascular system in HDP, which is already evident in the first trimester.

Efficacy of a polyethylene oxide-sodium carboxymethylcellulose gel in prevention of intrauterine adhesions after hysteroscopic surgery.

STUDY OBJECTIVES: To assess the efficacy of a polyethylene oxide-sodium carboxymethylcellulose gel (Intercoat; Gynecare, division of Ethicon, Inc., Somerville, NJ) in preventing the development of de novo intrauterine adhesions (IUAs) after hysteroscopic surgery and to rate the patency of the internal uterine ostium at 1-month follow-up diagnostic hysteroscopy. DESIGN: Randomized controlled study (Canadian Task Force classification I). SETTING: University hospital. PATIENTS: One hundred ten patients diagnosed during office hysteroscopy as having single or multiple lesions suitable for surgical treatment or resistant dysfunctional uterine bleeding requiring endometrial ablation. INTERVENTIONS: Patients were randomized to 2 groups. Group 1 underwent hysteroscopic surgery plus intrauterine application of Intercoat gel, and group 2 underwent hysteroscopic surgery only (control group). Follow-up office hysteroscopy was performed at 1 month after surgery to assess the rate and severity of IUA formation and to rate the patency of the internal uterine ostium after the surgical intervention. MEASUREMENTS AND MAIN RESULTS: Compared with the group 2, group 1 demonstrated a significant reduction in the incidence (6% vs 22%; p <.05) of de-novo IUAs. Application of the gel seemed to reduce the severity of IUAs, with fewer moderate and severe IUAs at follow-up in group 1 in comparison with group 2 (33% vs 92%). Furthermore, group 1 demonstrated significant improvement in the degree of patency of the internal uterine ostium (41.9% of cases) in comparison with diagnostic office hysteroscopy performed at enrollment (p <.05). In contrast, in group 2, worsening of patency of the internal uterine ostium was recorded in 18.2% of cases (p <.05). CONCLUSIONS: Intercoat gel seems to prevent de novo formation of IUAs and to improve the patency of the internal uterine ostium at follow-up hysteroscopy. However, larger studies are needed to confirm these findings.

Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2.

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S-adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19/SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes' fate are in part modulated by sPIF and H19. Our results revealed an unexpected mechanism of the H19/SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.

The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction.

In the last decade, the microbiota, i.e., combined populations of microorganisms living inside and on the surface of the human body, has increasingly attracted attention of researchers in the medical field. Indeed, since the completion of the Human Microbiome Project, insight and interest in the role of microbiota in health and disease, also through study of its combined genomes, the microbiome, has been steadily expanding. One less explored field of microbiome research has been the female reproductive tract. Research mainly from the past decade suggests that microbial communities residing in the reproductive tract represent a large proportion of the female microbial network and appear to be involved in reproductive failure and pregnancy complications. Microbiome research is facing technological and methodological challenges, as detection techniques and analysis methods are far from being standardized. A further hurdle is understanding the complex host-microbiota interaction and the confounding effect of a multitude of constitutional and environmental factors. A key regulator of this interaction is the maternal immune system that, during the peri-conceptional stage and even more so during pregnancy, undergoes considerable modulation. This review aims to summarize the current literature on reproductive tract microbiota describing the composition of microbiota in different anatomical locations (vagina, cervix, endometrium, and placenta). We also discuss putative mechanisms of interaction between such microbial communities and various aspects of the immune system, with a focus on the characteristic immunological changes during normal pregnancy. Furthermore, we discuss how abnormal microbiota composition, "dysbiosis," is linked to a spectrum of clinical disorders related to the female reproductive system and how the maternal immune system is involved. Finally, based on the data presented in this review, the future perspectives in diagnostic approaches, research directions and therapeutic opportunities are explored.

Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.

A case of pure uterine lipoma: immunohistochemical and ultrastructural focus.

BACKGROUND: Pure uterine lipoma is a rare clinical event and only a few cases have been reported in literature. The histogenesis of these lesions is still debatable. Preoperative diagnosis is difficult and should be pathologically confirmed postoperatively. CASE: We report the case of a 58-year-old woman who presented with pelvic pain and postmenopausal uterine bleeding. The hysterectomy specimen showed a pure intramural lipoma of the uterus. An immunohistochemical study revealed that the lipomatous tissue was reactive to S-100, vimentin, actin and desmin. Electron microscopy examination revealed bundles of spindle cells with intracytoplasmatic vacuoles and parallel-arranged intermediate filaments in the surrounding zone, in which adipose cells were mixed with muscular cells. DISCUSSION: Clinical and histological diagnosis of pure uterine lipomas are described and a possible involvement of fatty metaplasia of smooth muscle cells in the development of pure uterine lipomas is discussed.

Placental mesenchymal dysplasia: An underdiagnosed placental pathology with various clinical outcomes.

BACKGROUND: Placental mesenchymal dysplasia (PMD) is a rare vascular and connective placental anomaly, which is often associated with severe fetal and/or maternal complications. The diversity of presentation of PMD challenges diagnosis and effective pregnancy management. OBJECTIVE: We aimed to review cases presenting at 7 tertiary centers worldwide over the last decade and to study the occurrence of obstetric and neonatal complications. STUDY DESIGN: Pathology databases from 7 tertiary hospitals were screened for cases of PMD (between 2007-2017). Pregnancy history, outcomes and ultrasound images were then reviewed for each case. RESULTS: Twenty-two cases of PMD were identified. Mean gestational age at diagnosis was 23 weeks (16-39 weeks). Prenatal biochemical screening was abnormal in 8 cases (36%). Of the 12 cases that underwent invasive genetic testing, 4 were abnormal. Six patients (27%) developed maternal complications (preeclampsia/gestational hypertension). Fetal growth restriction was identified in 11 cases (50%) and fetal death in 4 (18%). Four (18%) pregnancies were terminated, 9/14 (64%) delivered preterm and only three (14%) progressed normally. Fourteen babies were born alive; 5 (35%) died in the first sixty-one days after birth, 5 (35%) had transient thrombopenia and 1 (7%) had developmental delay at last follow-up. Our series identified four potential new associations with PMD: placental triploidy mosaicism, CHARGE syndrome, fetal pleuropulmonary blastoma and fetal skeletal dysplasia. CONCLUSIONS: PMD was substantially under-diagnosed before delivery in this cohort. Sonographers, fetal medicine specialists, obstetricians and pathologists should all suspect PMD in cases of an enlarged placenta and should look for fetal abnormalities. Diagnostic genetic testing should be discussed to exclude partial molar pregnancy. Close pregnancy follow-up is indicated due to the high risk of associated fetal or maternal adverse outcomes.

The core sequence of PIF competes for insulin/amyloid ß in insulin degrading enzyme: potential treatment for Alzheimer's disease.

The central pathological feature of Alzheimer's disease (AD) is the sequential proteolytic processing of amyloid precursor protein (APP) to amyloid-ß peptides (Aß) agglomeration. The clearance of Aß may be induced by the large zinc-binding protease insulin degrading enzyme (IDE). IDE is the common link between AD and Type II diabetes as insulin is an IDE target as well. Not surprisingly, the search for safe and effective drugs modulating IDE is ongoing. A new pregnancy derived peptide, PreImplantation Factor (PIF), inhibits neuro-inflammation and crosses the blood-brain-barrier. Importantly, we report that the (R3I4K5P6) core sequence of the PIF peptide modulates IDE function and results in decreased Aß agglomeration in neuronal cells. Using bioinformatics we show that PIF binds to the IDE complex and sterically competes for the same place as insulin or Aß. The predicted RIKP sequence and especially the specific I4 and P6 amino acids are essential for hydrophobic interactions with the IDE complex. In terms of potential AD treatment, PIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval and orphan drug designation for first-in-human trial in autoimmunity.

Extracellular Vesicles Derived from Wharton's Jelly Mesenchymal Stem Cells Prevent and Resolve Programmed Cell Death Mediated by Perinatal Hypoxia-Ischemia in Neuronal Cells.

Hypoxic-ischemic (HI) insult in the perinatal phase harbors a high risk of encephalopathy in the neonate. Brain cells undergo apoptosis, initiating neurodegeneration. So far, therapeutic approaches such as cooling remain limited. Transplantation of mesenchymal stem cells (MSCs) exhibits therapeutic success despite the short-time survival in the host brain, providing strong evidence that their beneficial effects are largely based on secreted factors, including extracellular vesicles (EVs). The aim of this study was to investigate the effects of human Wharton's jelly MSC (hWJ-MSC)-derived EVs on neuroprotection and neuroregeneration, using an in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R) mimicking HI injury in the mouse neuroblastoma cell line neuro2a (N2a). hWJ-MSC-derived EVs were isolated from cell culture supernatants by multistep centrifugation and identified by endosomal marker expression and electron microscopy. OGD/R significantly increased DNA fragmentation and caspase 3 ( Casp3) transcription in N2a cells relative to undamaged cells. OGD/R-mediated DNA fragmentation and Casp3 expression could be prevented as well as resolved by the addition of hWJ-MSC-derived EV before and after OGD, respectively. hWJ-MSC-derived EV also tended to increase the phosphorylation of the B cell lymphoma 2 (Bcl2) family member Bcl-2-antagonist of cell death (BAD) in N2a cells, when added prior or post OGD, thereby inactivating the proapoptotic function of BAD. Fluorescence confocal microscopy revealed the close localization of hWJ-MSC-derived EVs to the nuclei of N2a cells. Furthermore, EVs released their RNA content into the cells. The expression levels of the microRNAs (miRs) let-7a and let-7e, known regulators of Casp3, were inversely correlated to Casp3. Our data suggest that hWJ-MSC-derived EVs have the potential to prevent and resolve HI-induced apoptosis in neuronal cells in the immature neonatal brain. Their antiapoptotic effect seems to be mediated by the transfer of EV-derived let-7-5p miR.