Early first-trimester transvaginal ultrasound screening for Cesarean scar pregnancy in patients with previous Cesarean delivery: analysis of the evidence.

Obstetric hemorrhage is a leading cause of maternal morbidity and mortality. An important etiology of obstetric hemorrhage is placenta accreta spectrum. In the last two decades, there has been increased clinical experience of the devastating effect of undiagnosed, as well as late diagnosed, cases of Cesarean scar pregnancy. There is a growing body of evidence suggesting that Cesarean scar pregnancy is an early precursor of second- and third-trimester placenta accreta spectrum. As such, Cesarean scar pregnancy should be diagnosed in the early first trimester. This early diagnosis could be achieved by introducing regimented sonographic screening in pregnancies of patients with previous Cesarean delivery. This Opinion article evaluates the scientific and clinical basis of whether Cesarean scar pregnancy, with special focus on its early first-trimester discovery, complies with the accepted requirements of a screening test. Each of the 10 classical screening criteria of Wilson and Jungner were systematically applied to evaluate if the criteria were met by Cesarean scar pregnancy, to analyze if it is possible and realistic to carry out screening in a population-wide fashion.

First-trimester cesarean scar pregnancy: a comparative analysis of treatment options from the international registry.

BACKGROUND: A cesarean scar pregnancy is an iatrogenic consequence of a previous cesarean delivery. The gestational sac implants into a niche created by the incision of the previous cesarean delivery, and this carries a substantial risk for major maternal complications. The aim of this study was to report, analyze, and compare the effectiveness and safety of different treatments options for cesarean scar pregnancies managed in the first trimester through a registry. OBJECTIVE: This study aimed to evaluated the ultrasound findings, disease behavior, and management of first-trimester cesarean scar pregnancies. STUDY DESIGN: We created an international registry of cesarean scar pregnancy cases to study the ultrasound findings, disease behavior, and management of cesarean scar pregnancies. The Cesarean Scar Pregnancy Registry collects anonymized ultrasound and clinical data of individual patients with a cesarean scar pregnancy on a secure, digital information platform. Cases were uploaded by 31 participating centers across 19 countries. In this study, we only included live and failing cesarean scar pregnancies (with or without a positive fetal heart beat) that received active treatment (medical or surgical) before 12+6 weeks' gestation to evaluate the effectiveness and safety of the different management options. Patients managed expectantly were not included in this study and will be reported separately. Treatment was classified as successful if it led to a complete resolution of the pregnancy without the need for any additional medical interventions. RESULTS: Between August 29, 2018, and February 28, 2023, we recorded 460 patients with cesarean scar pregnancies (281 live, 179 failing cesarean scar pregnancy) who fulfilled the inclusion criteria and were registered. A total of 270 of 460 (58.7%) patients were managed surgically, 123 of 460 (26.7%) patients underwent medical management, 46 of 460 (10%) patients underwent balloon management, and 21 of 460 (4.6%) patients received other, less frequently used treatment options. Suction evacuation was very effective with a success rate of 202 of 221 (91.5%; 95% confidence interval, 87.8-95.2), whereas systemic methotrexate was least effective with only 38 of 64 (59.4%; 95% confidence interval, 48.4-70.4) patients not requiring additional treatment. Overall, surgical treatment of cesarean scar pregnancies was successful in 236 of 258 (91.5%, 95% confidence interval, 88.4-94.5) patients and complications were observed in 24 of 258 patients (9.3%; 95% confidence interval, 6.6-11.9). CONCLUSION: A cesarean scar pregnancy can be managed effectively in the first trimester of pregnancy in more than 90% of cases with either suction evacuation, balloon treatment, or surgical excision. The effectiveness of all treatment options decreases with advancing gestational age, and cesarean scar pregnancies should be treated as early as possible after confirmation of the diagnosis. Local medical treatment with potassium chloride or methotrexate is less efficient and has higher rates of complications than the other treatment options. Systemic methotrexate has a substantial risk of failing and a higher complication rate and should not be recommended as first-line treatment.

The use of pressure balloons in the treatment of first trimester cesarean scar pregnancy.

Cesarean scar pregnancy (CSP) is among the most severe complications of cesarean delivery. CSP refers to the abnormal implantation of the gestational sac in the area of the prior cesarean delivery (CD), potentially leading to severe hemorrhage, uterine rupture, or development of placenta accreta spectrum disorders (PAS). The management of women with CSP has not been standardized yet. In women who opted for termination, discussion about the treatments should consider maternal symptoms, gestational age at intervention, and the future reproductive risk. A multitude of treatments, either medical or surgical, for CSP has been reported in the published literature. The present review aims to provide up-to-date information on a recently introduced minimally invasive treatments for CSP, including the single and double balloon catheter. The methodology of using the single or double catheter is described in a step-by-step fashion illustrated by pictures as well as video recordings. Both catheters have their deserved place to be used as a primary method for terminating scar pregnancies as well as using them as adjuncts to other treatments. They were successfully used by multiple individual practitioners and institutions due to their simplicity and low complication rates. The rare, but possible post-procedure complications such as recurrent CSP and enhanced myometrial vascularity are also mentioned.

Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients.

Background: Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the ATP7B gene. WD is characterized by heterogeneous clinical presentations expressed by hepatic and neuropsychiatric phenotypes. The disease is difficult to diagnose, and misdiagnosed cases are commonly seen. Methods: In this study, the presented symptoms of WD, the biochemical parameters as well as its natural history are described based on cases collected in Mohammed VI Hospital University of Marrakech (Morocco). We screened and sequenced 21 exons of ATP7B gene from 12 WD patients that confirmed through biochemical diagnosis. Results: Mutational assessment of the ATP7B gene showed six homozygous mutations in 12 individuals however, 2 patients had no evidence of any mutation in promoter and exonic regions. All mutations are pathogenic and most were missense mutations. c.2507G > A (p.G836E), c.3694A > C (p.T1232P) and c.3310 T > C (p.C1104R) that were identified in 4 patients. The other mutations were a non-sense mutation (c.865C > T (p.C1104R)) detected in 2 patients, a splice mutation (c.51 + 4A > T) detected in 2 patients and a frameshift mutation (c.1746 dup (p.E583Rfs*25) detected in 2 patients. Conclusion: Our study is the first molecular analysis in Moroccan patients with Wilson's disease, the ATP7B mutational spectrum in the Moroccan population is diverse and still unexplored.

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

Extreme enhanced myometrial vascularity following cesarean scar pregnancy: a new diagnostic entity.

OBJECTIVE: To define, illustrate and to follow-up the diagnosis, pathophysiology and treatment of a subset of the known enhanced myometrial vascularity (EMV): its extreme form, associated with cesarean scar pregnancies (CSP) and with some cases pf placenta accreta spectrum being at increased risk of significant bleeding complications. We also aim to provide guidance to the management of such cases. MATERIAL AND METHODS: This is an IRB-approved retrospective observational study of thirteen patients with an extreme form of EMV complicating CSPs. Patient's age, parity, number of cesarean deliveries, initial and time to negative serum hCG levels, primary and secondary diagnoses, blood flow peak systolic velocities, primary and secondary treatments, uterine artery embolization and outcomes were recorded. RESULTS: Gestational ages ranged 6-11 weeks at initial presentation. Initial serum hCG was 20.0-102.48 mIU/L (mean 44.4 mIU/L). Diameter of EMV reached 20-75 mm (mean 46.8 mm). The mean peak systolic velocity (PSV) was 84.2 cm/s (range 46.7-118.0). Primary treatments were: systemic methotrexate (MTX) alone; D&C alone; MTX and D&C; local and systemic intra-gestational MTX injection; double cervical ripening balloon with systemic MTX; misoprostol and D&C; emergent UAE. UAE and hysterectomy were the two main secondary treatments in 10 women except 1 having a D&C after UAE, and in 1 the lesion regressed without secondary treatment. Mean time to nonpregnant hCG levels was 21-122 days (mean 67.2). Mean follow-up was 110.2 days (range 26-160). Ten women were treated with UAE, 6 had one, 3 had two embolizations. Two women had hysterectomies, one of these for persistent bleeding. Based upon the common denominators of the clinical and the US pictures, our definition of extreme EMV is sustained form of EMV associated with treated or untreated CSP, with peak systolic velocities of blood flow over 50 cm/s, slow return or plateauing serum hCG, with or without clinically significant vaginal bleeding, unresponsive to initial or secondary treatment requiring uterine artery embolization or hysterectomy. CONCLUSION: The EMV developing in the background of retained placental tissue associated with CSP differs following the normal regression of the physiologically re-modelled, dilated vascular bed from the faulty "disrepair" of the vessel wall in in treated or untreated CSPs. The "threatening" appearance of the above EMVs warranted the term "extreme", creating their separate new sub-category." Extreme forms of CSP-related EMV pose significant diagnostic and management challenges. Prompt recognition and intervention, the proactive use of UAE, can maximize the outcome of women affected by this "extreme" form of EMV enabling to preserve reproductive potential. Obstetricians, gynecologists and interventional radiologists should be aware of this form of severe vascular complication.

Wilson's Disease: Facing the Challenge of Diagnosing a Rare Disease.

Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD's phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.

Expanding the ß-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration.

(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by ß-III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical spinocerebellar ataxia type 5 (SCA5). (2) Methods: In-depth phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modeling and protein expression. An extensive review of the literature was conducted in order to better characterize the SPTBN2-associated NPCA. (3) Results: Patients exhibited an NPCA with hypotonia, developmental delay, cerebellar syndrome, and cognitive deficits. Both probands presented with progressive global cerebellar volume loss in consecutive cerebral magnetic resonance imaging studies, characterized by decreasing midsagittal vermis relative diameter measurements. Cortical hyperintensities were observed on fluid-attenuated inversion recovery (FLAIR) images, suggesting a neurodegenerative process. Each patient carried a novel de novo SPTBN2 substitution: c.193A > G (p.K65E) or c.764A > G (p.D255G). Modeling and protein expression revealed that both mutations might be deleterious. (4) Conclusions: The reported findings contribute to a better understanding of the SPTBN2-associated phenotype. The mutations may preclude proper structural organization of the actin spectrin-based membrane skeleton, which, in turn, is responsible for the underlying disease mechanism.

Beta-blocker therapy in elderly patients with renal dysfunction and heart failure.

OBJECTIVE: To assess the role of beta-blockers (BB) in patients with chronic kidney disease (CKD) aged ≥ 75 years. METHODS AND RESULTS: From January 2008 to July 2014, we included 390 consecutive patients ≥ 75 years of age with ejection fraction ≤ 35% and glomerular filtration rate (GFR) ≤ 60 mL/min per 1.73 m2. We analyzed the relationship between treatment with BB and mortality or cardiovascular events. The mean age of our population was 82.6 ± 4.1 years. Mean ejection fraction was 27.9% ± 6.5%. GFR was 60-45 mL/min per 1.73 m2 in 50.3% of patients, 45-30 mL/min per 1.73 m2 in 37.4%, and < 30 mL/min per 1.73 m 2 in 12.3%. At the conclusion of follow-up, 67.4% of patients were receiving BB. The median follow-up was 28.04 (IR: 19.41-36.67) months. During the study period, 211 patients (54.1%) died and 257 (65.9%) had a major cardiovascular event (death or hospitalization for heart failure). BB use was significantly associated with a reduced risk of death (HR = 0.51, 95% CI: 0.35-0.74;P < 0.001). Patients receiving BB consistently showed a reduced risk of death across the different stages of CKD: stage IIIa (GFR = 30-45 mL/min per 1.73 m 2; HR = 0.47, 95% CI: 0.26-0.86,P < 0.0001), stage IIIb (GFR 30-45 mL/min per 1.73 m 2; HR = 0.55, 95% CI: 0.26-1.06,P = 0.007), and stages IV and V (GFR < 30 mL/min per 1.73 m 2; HR = 0.29, 95% CI: 0.11-0.76;P = 0.047). CONCLUSIONS: The use of BB in elderly patients with HFrEF and renal impairment was associated with a better prognosis. Use of BB should be encouraged when possible.

Outcome of cesarean scar pregnancy according to gestational age at diagnosis: A systematic review and meta-analysis.

OBJECTIVE: The association between the most severe types of placenta accreta spectrum disorders and caesarean scar pregnancy (CSP) poses the question of whether early diagnosis may impact the clinical outcome of these anomalies. The aim of this study is to report the outcome of cesarean scar pregnancy (CSP) diagnosed in the early (≤9 weeks) versus late (>9 weeks) first trimester of pregnancy. STUDY DESIGN: Medline, Embase and Clinicaltrail.gov databases were searched. Studies including cases of CSP with an early (≤9 weeks of gestation) compared to a late (>9 weeks) first trimester diagnosis of CSP, followed by immediate treatment, were included in this systematic review. The primary outcome was a composite measure of severe maternal morbidity including either severe first trimester bleeding, need for blood transfusion, uterine rupture or emergency hysterectomy. The secondary outcomes were the individual components of the primary outcome. Random-effect meta-analyses were used to combine data. RESULTS: Thirty-six studies (724 women with CSP) were included. Overall, composite adverse outcome complicated 5.9 % (95 % CI 3.5-9.0) of CSP diagnosed ≤9 weeks and 32.4 % (95 % CI 15.7-51.8) of those diagnosed >9 weeks. Massive hemorrhage occurred in 4.3 % (95 % CI 2.3-7.0) of women with early and in 28.0 % (95 % CI 14.1-44.5) of those with late first trimester diagnosis of CSP, while the corresponding figures for the need for blood transfusion were 1.5 % (95 % CI 0.6-2.8) and 15.8 % (95 % CI 5.5-30.2) respectively. Uterine rupture occurred in 2.5 % (95 % CI 1.2-4.1) of women with a prenatal diagnosis of CSP ≤ 9 weeks and in 7.5 % (95 % CI 2.5-14.9) of those with CSP > 9 weeks, while an emergency intervention involving hysterectomy was required in 3.7 % (95 % CI 2.2-5.4) and 16.3 % (95 % CI5.9-30.6) respectively. When computing the risk, early diagnosis of CSP was associated with a significantly lower risk of composite adverse outcome, (OR: 0.14; 95 % CI 0.1-0.4 p < 0.001). CONCLUSIONS: Early first trimester diagnosis of CSP is associated with a significantly lower risk of maternal complications, thus supporting a policy of universal screening for these anomalies in women with a prior cesarean delivery although the cost-effectiveness of such policy should be tested in future studies.

Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation.

BACKGROUND AND PURPOSE: Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only 15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%. METHODS: In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next-generation sequencing and subsequent Sanger sequencing of SORD. RESULTS: Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals. CONCLUSIONS: This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.

Change in cervical length and spontaneous preterm birth in nulliparous women with a history of loop electrosurgical excision procedure.

BACKGROUND: Prior studies have shown an association between history of loop electrode procedures (LEEP) and spontaneous preterm delivery (SPTD) independent of mid-trimester cervical length. These studies suggest that there may be other factors beyond an individual cervical length, which contribute to identifying at-risk pregnancies. OBJECTIVE: The objective of this study is to determine the association between change in cervical length and SPTD in women with a history of LEEP. STUDY DESIGN: This is a retrospective cohort study of singleton nulliparous women with a history of LEEP who received serial cervical length measurements at a single institution between 2012 and 2016. Women with serial cervical lengths and available outcome data were included. The cervical length at different gestational ages and the rate of change in length were compared with the risk for SPTD <37 weeks using Student's t-test. RESULTS: One-hundred-thirty subjects met the inclusion criteria for the study. The mean cervical length (35.3 versus 39.8 mm, p = .042 at 16 weeks; 32.2 versus 37.8 mm, p < .01 at 20 weeks; 29.9 versus 35.6 mm, p = .027 at 24 weeks; 21.6 versus 33.4 mm, p < .01 at 28 weeks) was significantly different between women who had an SPTD <37 weeks compared to women who did not. The average rate of change in transvaginal cervical length between 16 to 28 weeks was significantly different between women who had an SPTD <37 weeks compared to women who did not (-1.4 versus 0.4 mm/week, p < .01). CONCLUSION: Women with a history of LEEP who had an SPTD <37 weeks had a shorter cervical length at 16, 20, 24, and 28 weeks' gestation and a higher rate of change in cervical length between 16 and 28 weeks than women without a history of SPTD. Our findings support the concept of the preterm birth syndrome as an evolving biophysical process rather than a distinct event, suggesting improved prediction in the setting of prior history of a LEEP with serial imaging.

Three-Dimensional Coronal Plane of the Uterus: A Critical View for Diagnostic Accuracy.

Two-dimensional transvaginal and transabdominal ultrasound (US) examinations are the suggested methods for examining the uterus. Three-dimensional (3D) US, which is not compulsory by society guidelines, provides additional uterine views, reassuring users of pathologic conditions not evident on customary sagittal and transverse views. The 3D coronal plane is rarely seen by 2-dimensional US transducers, let alone in extremely retroverted or axial uteri. Ultrasound machines nowadays feature 3D US capability. Our experience is that the coronal uterine view is a problem solver, helping diagnostic abilities of pelvic imaging. We advocate its liberal use and its acquisition in every pelvic scan. In this Pictorial Essay we present examples to demonstrate its use.

Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity.

BACKGROUND: Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. METHODS: A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. RESULTS: Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 µg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. CONCLUSION: Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.