The predictive value of prenatal cell-free DNA testing for rare autosomal trisomies: a systematic review and meta-analysis.

OBJECTIVE: The diagnostic accuracy of cell-free fetal DNA in screening for rare autosomal trisomies is uncertain. We conducted a systematic review and meta-analysis aiming to determine the predictive value of cell-free DNA in screening for rare autosomal trisomies. DATA SOURCES: PubMed, Embase, and Web of Science were searched from inception to January 2022. STUDY ELIGIBILITY CRITERIA: All studies that reported on the diagnostic accuracy of cell-free DNA in the detection of rare autosomal trisomies were included. Case series were included if they contained at least 10 cases with diagnostic test results or postnatal genetic testing. METHODS: Study appraisal was completed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Statistical analysis was performed using random-effects meta-analysis of double-arcsine transformed proportions of confirmed results in the fetus out of the positive tests to obtain a pooled estimate of the positive predictive value. RESULTS: The search identified 7553 studies, of which 1852 were duplicates. After screening 5701 titles and abstracts, 380 studies proceeded to the full-text screen; 206 articles were retrieved for data extraction, of which another 175 articles were excluded. A total of 31 studies, with a total of 1703 women were included for analysis. The pooled positive predictive value of cell-free DNA for the diagnosis of rare autosomal trisomies was 11.46% (95% confidence interval, 7.80-15.65). Statistical heterogeneity was high (I2=82%). Sensitivity analysis restricted to 5 studies at low risk of bias demonstrated a pooled positive predictive value of 9.13% (95% confidence interval, 2.49-18.76). There were insufficient data to provide accurate ascertainment of sensitivity and specificity because most studies only offered confirmatory tests to women with high-risk results. CONCLUSION: The positive predictive value of cell-free DNA in diagnosing rare autosomal trisomies is approximately 11%. Clinicians should provide this information when offering cell-free DNA for screening of conditions outside of common autosomal trisomies.

The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis.

BACKGROUND: The performance of cell-free DNA (cfDNA) screening for microscopic copy number variants (CNVs) is unclear. OBJECTIVES: This was a systematic review and meta-analysis to investigate the sensitivity, specificity and positive predictive value (PPV) of cfDNA screening for CNVs. SEARCH STRATEGY: Articles published in EMBASE, PubMed or Web of Science before November 2022 were screened for inclusion. This protocol was registered with PROSPERO (23 March 2021, CRD42021250849) prior to initiation. SELECTION CRITERIA: Articles published in English, detailing diagnostic outcomes for at least 10 high-risk CNV results with cfDNA were considered for inclusion. DATA COLLECTION AND ANALYSIS: The PPV was calculated and pooled with random-effects models for double-arcsine transformed proportions, using cases with diagnostic confirmation. Overall sensitivity, specificity and a summary receiver-operating characteristics (ROC) curve were calculated using bivariate models. The risk of bias was assessed using QUADAS-2. MAIN RESULTS: In all, 63 articles were included in the final analysis, detailing 1 591 459 cfDNA results. The pooled PPV was 37.5% (95% confidence interval [CI] 30.6-44.8), with substantial statistical heterogeneity (I2  = 93.9%). Bivariate meta-analysis estimated sensitivity and specificity to be 77.4% (95% CI 65.7-86.0) and 99.4% (95% CI 98.0-99.8), respectively, with an area under the summary ROC curve of 0.947 (95% CI 0.776-0.984). CONCLUSIONS: Approximately one-third of women who screen high-risk for CNVs with cfDNA will have an affected fetus. This value is of importance for screening counselling.

The clinical impact of the first-trimester nuchal translucency between the 95th-99th percentiles.

OBJECTIVES: To evaluate the clinical significance of nuchal translucency (NT) between the 95th-99th percentile in terms of typical and atypical chromosomal abnormalities (ACAs), associated fetal congenital defects and postnatal outcome. METHODS: A retrospective cohort study of fetuses with NT between the 95th-99th percentile. Data regarding the rate of associated fetal defects, genetic abnormalities and postnatal outcome were collected. RESULTS: A total of 306 cases of fetuses with an NT between the 95th-99th percentiles were included. The overall rate of genetic abnormalities was 12.1% (37/306). Chromosomal abnormalities were found in 10.1% (31/306) of cases and 2% were ACA (6/306). Within this group, two were pathogenic Copy Number Variants (CNVs) and four were single gene disorders. The overall rate of fetal congenital defects was 13.7% (42/306). All ACAs were found in fetuses with congenital defects. Postnatally, a new diagnosis of a single gene disorder was made in 0.85% of cases (2/236). CONCLUSIONS: The presence of an NT between the 95th-99th percentiles carries a 10-fold increased risk of fetal defects, representing an indication for referral for a detailed fetal anatomy evaluation. The risk of ACA is mainly related to the presence of fetal defects, irrespective of the combined test risk.

Cotyledonoid Leiomyoma Clinical Characteristics, Imaging Features, and Review of the Literature.

Cotyledonoid leiomyoma of the uterus is a rare variant of benign uterine leiomyoma. It has a favorable attitude, despite some ultrasound presentations. A bulky uterus with a heterogeneous mass with irregular margins, high vascularity, and infiltration of the myometrium can induce the suspicion of a malignant mesenchymal tumor and lead to a radical surgical treatment. If present, some imaging features may suggest this rare type of leiomyoma, thus avoiding extensive surgery, especially in young nulliparous women. We report 13 cases of cotyledonoid leiomyoma with clinical characteristics, imaging features, and a literature review.

The accuracy of prenatal cell-free DNA screening for sex chromosome abnormalities: A systematic review and meta-analysis.

OBJECTIVE: Although cell-free DNA screening for sex chromosome abnormalities is increasingly used in clinical practice, its diagnostic accuracy and clinical utility remain unclear. This systematic review and meta-analysis aimed to determine the performance of cell-free DNA in the detection of sex chromosome abnormalities. DATA SOURCES: Medline and PubMed, Embase, and Web of Science were searched from inception to January 2022 for articles relating to cell-free DNA screening for sex chromosome abnormalities. STUDY ELIGIBILITY CRITERIA: Original articles, randomized control trials, conference abstracts, cohort and case-control studies, and case series with more than 10 cases with diagnostic confirmation were considered for inclusion. METHODS: Quality assessment of each included publication was performed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. The positive predictive value was calculated as the proportion of true positive cases among those who tested positive and underwent diagnostic testing. Sensitivity and specificity were pooled, and a summary receiver operating characteristic curve was produced using bivariate models that included studies that had diagnostic confirmation for high- and low-risk women. RESULTS: The search identified 7553 results. Of these, 380 proceeded to the full-text screening, of which 94 articles were included in the meta-analysis with a total of 1,531,240 women tested. All studies reported a confirmatory genetic test. The pooled positive predictive value was 49.4% (95% confidence interval, 45.8-53.1). The pooled positive predictive value was 32.0% (95% confidence interval, 27.0%-37.3%) for monosomy X, 67.6% (95% confidence interval, 62.5%-72.5%) for XXY, 57.5% (95% confidence interval, 51.7%-63.1%) for XXX, and 70.9% (95% confidence interval, 63.9%-77.1%) for XYY. The pooled sensitivity and specificity of cell-free DNA for sex chromosome abnormalities were 94.1% (95% confidence interval, 90.8%-96.3%) and 99.5% (95% confidence interval, 99.0%-99.7%), respectively, with an area under the summary receiver operating characteristic curve of 0.934 (95% confidence interval, 0.907-0.989). CONCLUSION: Although the sensitivity and specificity of cell-free DNA for sex chromosome abnormalities are high, the positive predictive value was approximately 50%. The positive predictive value was higher for sex chromosome abnormalities with a supernumerary Y chromosome and lower for monosomy X. Clinicians should inform couples about these findings when offering cell-free DNA for sex chromosome abnormalities.

Exploring the Needs and Expectations of Expectant and New Parents for an mHealth Application to Support the First 1000 Days of Life: Steps toward a Co-Design Approach.

To improve maternal and child health, it is essential to adhere to health-promoting and preventive measures. However, reliable information as well as effective tools are not easy to identify in this field. Our cross-sectional study investigated the needs and expectations of expectant and new mothers and fathers as potential primary users of a hypothetical application supporting the first 1000 days of life. Between May and August 2022, we recruited expectant and new parents by administering an 83-item 5-point Likert scale questionnaire related to the content, functionalities, and technical features of the hypothetical app. We stratified responses using sociodemographic characteristics and then performed ward hierarchical clustering. The 94 women and 69 men involved in our study generally agreed with the proposed content, but expressed low interest in certain app functionalities or features, including those related to the interaction mechanism and interactivity. Women were generally more demanding than men. Our findings, resulting from the engagement of end-users, may be useful for designers and technology providers to implement mHealth solutions that, in addition to conveying reliable information, are tailored to the needs and preferences of end-users in the first 1000 days of life.

What do hospital-based health professionals need and expect from an mHealth app to support the first 1000 days of life? Results from a cross sectional study.

BACKGROUND: Several attempts have been made to introduce mHealth solutions to support maternal, newborn, and child health (MNCH). However, most of the available apps do not meet the needs of end-users, underscoring the urgency of involving them in the co-design of telehealth interventions. OBJECTIVE: With this in mind, we investigated the needs and expectations of hospital-based health professionals (i.e., secondary users) providing care to pregnant women and new mothers with their babies for a hypothetical mHealth app to support the first 1000 days of life. METHODS: From November 2021 to March 2022, we surveyed health professionals using a questionnaire that explored the perceived importance of specific content, functionalities, and technical features of the proposed app. We also collected sociodemographic information from secondary users. We performed descriptive analysis and then used Ward hierarchical clustering method to classify respondents according to their response patterns. RESULTS: We recorded the needs and expectations of 145 hospital-based health professionals from obstetrics/gynecology, nursery/neonatology, and pediatrics. We found general agreement with the proposed content of the app, particularly general information about health during pregnancy (92%) and potential risky infections during pregnancy (91%). Three clusters emerged from the analysis, with the high and medium demanding clusters rating the importance of app content and technical features as very high and high, respectively, while low demanding cluster expressing more skepticism, especially about some of the proposed functionalities of the app. CONCLUSIONS: Assessing the needs and expectations of end-users is an essential process for developing tailored and effective mHealth solutions. This study has shown that hospital-based health professionals generally recognize the value of the proposed app, suggesting their propensity to integrate such a telehealth solution into mainstream clinical practice.

The role of melatonin in pregnancies complicated by placental insufficiency: A systematic review.

Placental insufficiency affects about 10% of pregnancies and can lead to pre-eclampsia, fetal growth restriction, and preterm birth. Despite significant advances in early prediction and prevention of preterm pre-eclampsia with aspirin, the effects of prophylaxis on fetal growth restriction are less certain, and the rates of late-onset pre-eclampsia are not influenced by aspirin treatment. Pregnancies complicated by placental insufficiency are characterized by increased oxidative stress, and recent studies suggest that melatonin has antioxidant properties and contributes to maintaining placental homeostasis. We aimed to systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. PubMed (Medline) and Scopus were searched until December 2020. Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in qualitative evidence synthesis. The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency reflected by lower production of melatonin, with consequent lower systemic and placental concentrations and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Small intervention studies also suggest that treatment is safe and may lead to prolongation of pregnancy and better outcomes, but double-blind, randomized placebo-controlled trials are lacking.

Ultrasound-Guided Tru-Cut Biopsy in Gynecological and Non-Gynecological Pelvic Masses: A Single-Center Experience.

AIM: The aim of this study was to evaluate the feasibility of adequacy, accuracy, and safety of ultrasound-guided tru-cut biopsy in managing malignant and benign abdominopelvic masses in a selected population and critically discuss some issues in different situations, which deserve some reflections on those practices. MATERIALS AND METHODS: This is a retrospective study involving 42 patients who underwent transvaginal or transabdominal tru-cut biopsy between August 2017 and November 2021. The inclusion criteria were poor health status or primary inoperable advanced tumor, suspicion of recurrence or metastasis to the ovaries or peritoneum in gynecological and non-gynecological pelvic malignancies. Tissue samples were considered adequate if it was possible to determine the origin of the tumor, and immunohistochemistry could be performed. Diagnostic accuracy was assessed considering the agreement between tru-cut biopsy histology and final postoperative histology. RESULTS: It total, 44 biopsies were obtained from 42 patients (2 patients had repeat biopsies). The pathologist considered all pathological samples adequate (adequacy 100%). The final histology was consistent with tru-cut biopsy diagnosis in all but 2 cases (diagnostic accuracy 88.2%). If we consider only the cases that have carried out at least two diagnostic samples, accuracy rose to 94.1%. Pathological examinations from tru-cut samples showed 2 benign lesions (4.8%) and 40 malignant tumors (95.2%), divided into 19 advanced primary inoperable ovarian cancers, 7 primary advanced cervical cancers, 4 recurrent endometrial cancers, 3 recurrent cervical cancers, 3 recurrent ovarian cancers, 1 case of primitive peritoneal malignancy (leiomyosarcoma), and 3 non-gynecological cancers with a strong suspicion of metastases at ultrasound (2 cases of ovarian, colorectal cancer metastasis, and 1 case of pelvic site type B lymphoma metastasis). However, one case of minor complication related to the procedure was reported but not significant. CONCLUSIONS: The diagnostic adequacy, accuracy of the tru-cut biopsy, and safety were high. Pathological samples are representative of the disease and suitable for histological and immunohistochemical analysis.

Accuracy and clinical utility of standard postmortem radiological imaging after early second trimester termination of pregnancy.

OBJECTIVE: This study aims to assess accuracy and clinical utility of postmortem radiological exams [Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Radiography (XR)] after termination of pregnancy at <23 weeks' gestation for congenital fetal malformations in comparison to autopsy. STUDY DESIGN: This a prospective single-center study on fetuses underwent termination of pregnancy for fetal defects. Overall concordance between any radiological exam and autopsy was evaluated. For postmortem MRI only, the following subgroups were analyzed: 1) total agreement; 2) agreement for main findings; 3) agreement for main findings but major relevant additional findings at autopsy; 4) total disagreement. RESULTS: 174 cases were collected. The overall concordance with autopsy for main findings was 71% (115/163) for postmortem MRI and 99% (173/174) for prenatal ultrasound (US). Postmortem MRI detection rate was high for central nervous system (CNS) defects (98%), gastrointestinal, genitourinary and respiratory defects (100%), while it was poor for cardiovascular and musculoskeletal defects (25% and 42%, respectively). For musculoskeletal abnormalities, the performance of postmortem XR and postmortem CT exams improved the detection rate from 42% for postmortem MRI alone to 92%. CONCLUSIONS: Postmortem MRI has a good overall concordance for fetal defects after termination of pregnancy performed at <23 weeks. Along with autopsy, postmortem MRI may be offered for all cases of CNS defects in order to prevent inconclusive exams due to autolysis of the brain tissue, while postmortem CT and postmortem XR are indicated for musculoskeletal defects. In the presence of multiple abnormalities or cardiac defects the couple should be counseled on the poor performance of radiological investigations.

CARE 1000: randomized controlled trial for the evaluation of the effectiveness of a mHealth app for supporting the first 1000 days of life.

BACKGROUND: Recent developments in eHealth and mobile health (mHealth), as well as the introduction of information and communication technology innovations in clinical practice, such as telemedicine, telemonitoring, and remote examinations, are already changing the current scenario and will continue to generate innovations in the coming decades. The widespread use of mobile devices, with an estimated nearly 30 billion devices and more than 325,000 apps worldwide, will provide various opportunities for people to take control of their own health. Already in 2017, most of the apps available were focused on pregnancy support, more than any other medical field. There have been some reported experiences with social media and mHealth that could benefit the promotion of maternal physical and mental health during pregnancy. However, many apps targeting the first 1000 days of a child's life do not consider the continuity between the prenatal and postnatal periods and their joint impact on maternal and child health. The aim of this study is to evaluate the effectiveness of this mHealth app to support women during the first 1000 days (from conception to 24 months of age) and to improve health prevention behaviours such as immunizations during pregnancy, weight gain during pregnancy, abstinence from smoking and alcohol consumption, and adherence to the routine childhood immunization schedule. In addition, the study aims to understand the level of appreciation of this mHealth app as a tool to overcome information and communication gaps between patients and institutions. METHODS: Conduction of a randomized controlled trial. DISCUSSION: Our results will be relevant for improving this mHealth app to promote health and prevention and to support the first 1000 days of life for both mother and child. Our results will be relevant to the future expansion of such an mHealth app to promote positive health-related outcomes in patients and co-user satisfaction and to support the organization of health services. TRIAL REGISTRATION: ClinicalTrials.gov NCT05500339.

Ultrasound Imaging of Acquired Myometrial Pseudoaneurysm: The Role of Manipulators as an Unusual Cause during Laparoscopic Surgery.

An acquired uterine artery myometrial pseudoaneurysm can occur due to inflammation, trauma, or iatrogenic causes, such as surgical procedures, and can lead to profuse bleeding. The efficacy of uterine manipulators in gynecological surgery, particularly as a cause of a pseudoaneurysm, has been poorly discussed in the literature. In this paper, we discuss a case of a 39-year-old woman with profuse uterine bleeding that occurred seven days after operative laparoscopic surgery for endometriosis. The color Doppler ultrasound better evoked the arterial-like turbulent blood flow inside this cavity. These sonographic features were highly suggestive of uterine artery pseudoaneurysm, presumably related to a secondary trauma caused by the manipulator. The diagnosis was subsequently re-confirmed by angiography, and the patient was treated conservatively with uterine artery embolization. Ultrasound has been shown to be a valuable and safe tool for imaging pseudoaneurysm and guiding subsequent interventional procedures. Accordingly, we briefly review the most suitable manipulators used in benign gynecological surgeries to verify if the different types in use can guide the surgeon towards the correct choice according to surgical needs and thus prevent potentially dangerous trauma.

The Management of the Cotyledonoid Leiomyoma of the Uterus: A Narrative Review of the Literature.

Cotyledonoidleiomyoma is an unusual uterine myoma due to some ultrasound features that mimic a malignant lesion facilitating the choice of radical surgery. This study aims to summarize the ultrasound and the magnetic resonance imaging aspects of this atypical lesion, and also discuss surgical treatment and pathological exam. It included all English case reports or case series until August 2021 found through PubMed, Google Scholar, and Scopus. A total of 94 cotyledonoid leiomyomas were reported, with a median tumor size of 12 cm. The typical ultrasound image is characterized by a large solid heterogeneous mass, with high vascularity, no shadowing, and indistinct margins within the myometrium. Magnetic resonance imaging shows the presence of merging isointense nodules to the myometrium in T1-weighted images, hyperintense in T2-weighted images, and contrast agent enhancement. Surgical treatment consists of hysterectomy (75 cases, 80%) or myomectomy (19 cases, 20%), without evidence of recurrence if complete. The placenta-like appearance observed during surgery supports this rare fibroid hypothesis. The intraoperative frozen section can be considered. Microscopically, no atypical cells, signs of mitotic activity or cell necrosis are found. To conclude, some preoperative and intraoperative aspects of this lesion are distinctive and may lead surgeons to opt for conservative surgery.