Management and outcome of fetal abdominal cysts in first trimester: systematic review of the literature.

OBJECTIVES: The finding of an abdominal cyst during pregnancy has an estimated prevalence of 1 in 1000 pregnancies, mostly in second and third trimester. The detection of a fetal abdominal cyst during the first trimester scan is a rare event, whose natural history and prognosis are often unknown and unpredictable as these anomalies can be related to various underlying conditions and originate from different structures. The aim of this study is to evaluate the outcome of fetal abdominal cysts detected in the first trimester in order to understand their possible clinical significance and to offer the proper management according to the available data. METHODS: We present a case report of a first trimester fetal abdominal cyst detected with subsequent diagnosis of congenital multiple arthrogryposis and we performed a systematic review of the literature to identify the incidence and the outcomes of similar cases. The systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 25 and registered with PROSPERO (CRD42023491729). RESULTS: A total of 60 cases of first trimester abdominal cysts were included. Of these, 35% were associated with concurrent or late onset structural anomalies, as in our case report, and 65% were isolated. In pregnancies with isolated fetal abdominal cysts, 56% had a completely normal outcome. CONCLUSIONS: The finding of an abdominal cyst during the first trimester of pregnancy is in most cases an isolated event with a moderate to good prognosis but it could also be an early sign of other associated abnormalities, including arthrogryposis. Increased ultrasound surveillance and additional genetic testing to rule out possible associated anomalies are pivotal to assess the risk of adverse pregnancy outcomes and to provide appropriate counselling to the patient. This article is protected by copyright. All rights reserved.

Performance of a targeted cell-free DNA prenatal test for 22q11.2 deletion in a large clinical cohort.

OBJECTIVE: 22q11.2 deletion is more common than trisomies 18 and 13 combined, yet no routine approach to prenatal screening for this microdeletion has been established. This study evaluated the clinical sensitivity and specificity of a targeted cell-free DNA (cfDNA) test to screen for fetal 22q11.2 deletion in a large cohort, using blinded analysis of prospectively enrolled pregnancies and stored clinical samples. METHODS: In order to ensure that the analysis included a meaningful number of cases with fetal 22q11.2 deletion, maternal plasma samples were obtained by prospective, multicenter enrolment of pregnancies with a fetal cardiac abnormality and from stored clinical samples from a research sample bank. Fetal genetic status, as evaluated by microarray analysis, karyotyping with fluorescence in-situ hybridization or a comparable test, was available for all cases. Samples were processed as described previously for the Harmony prenatal test, with the addition of DANSR (Digital Analysis of Selected Regions) assays targeting the 3.0-Mb region of 22q11.2 associated with 22q11.2 deletion syndrome. Operators were blinded to fetal genetic status. Sensitivity and specificity of the cfDNA test for 22q11.2 deletion were calculated based on concordance between the cfDNA result and fetal genotype. RESULTS: The final study group consisted of 735 clinical samples, including 358 from prospectively enrolled pregnancies and 377 stored clinical samples. Of 46 maternal plasma samples from pregnancies with a 22q11.2 deletion, ranging in size from 1.25 to 3.25 Mb, 32 had a cfDNA result indicating a high probability of 22q11.2 deletion (sensitivity, 69.6% (95% CI, 55.2-80.9%)). All 689 maternal plasma samples without a 22q11.2 deletion were classified correctly by the cfDNA test as having no evidence of a 22q11.2 deletion (specificity, 100% (95% CI, 99.5-100%)). CONCLUSIONS: The results of this large-scale prospective clinical evaluation of the sensitivity and specificity of a targeted cfDNA test for fetal 22q11.2 deletion demonstrate that this test can detect the common and smaller, nested 22q11.2 deletions with a low (0-0.5%) false-positive rate. Although the positive predictive value (PPV) observed in this study population was 100%, the expected PPV in the general pregnant population is estimated to be 12.2% at 99.5% specificity and 41.1% at 99.9% specificity. The use of this cfDNA test to screen for 22q11.2 deletion could enhance identification of pregnancies at risk for 22q11.2 deletion syndrome without significantly increasing the likelihood of maternal anxiety and unnecessary invasive procedures related to a false-positive result. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Treatment and outcome of 370 cases with spontaneous or post-laser twin anemia-polycythemia sequence managed in 17 fetal therapy centers.

OBJECTIVE: To investigate the antenatal management and outcome in a large international cohort of monochorionic twin pregnancies with spontaneous or post-laser twin anemia-polycythemia sequence (TAPS). METHODS: This study analyzed data of monochorionic twin pregnancies diagnosed antenatally with spontaneous or post-laser TAPS in 17 fetal therapy centers, recorded in the TAPS Registry between 2014 and 2019. Antenatal diagnosis of TAPS was based on fetal middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) in the TAPS donor and < 1.0 MoM in the TAPS recipient. The following antenatal management groups were defined: expectant management, delivery within 7 days after diagnosis, intrauterine transfusion (IUT) (with or without partial exchange transfusion (PET)), laser surgery and selective feticide. Cases were assigned to the management groups based on the first treatment that was received after diagnosis of TAPS. The primary outcomes were perinatal mortality and severe neonatal morbidity. The secondary outcome was diagnosis-to-birth interval. RESULTS: In total, 370 monochorionic twin pregnancies were diagnosed antenatally with TAPS during the study period and included in the study. Of these, 31% (n = 113) were managed expectantly, 30% (n = 110) with laser surgery, 19% (n = 70) with IUT (± PET), 12% (n = 43) with delivery, 8% (n = 30) with selective feticide and 1% (n = 4) underwent termination of pregnancy. Perinatal mortality occurred in 17% (39/225) of pregnancies in the expectant-management group, 18% (38/215) in the laser group, 18% (25/140) in the IUT (± PET) group, 10% (9/86) in the delivery group and in 7% (2/30) of the cotwins in the selective-feticide group. The incidence of severe neonatal morbidity was 49% (41/84) in the delivery group, 46% (56/122) in the IUT (± PET) group, 31% (60/193) in the expectant-management group, 31% (57/182) in the laser-surgery group and 25% (7/28) in the selective-feticide group. Median diagnosis-to-birth interval was longest after selective feticide (10.5 (interquartile range (IQR), 4.2-14.9) weeks), followed by laser surgery (9.7 (IQR, 6.6-12.7) weeks), expectant management (7.8 (IQR, 3.8-14.4) weeks), IUT (± PET) (4.0 (IQR, 2.0-6.9) weeks) and delivery (0.3 (IQR, 0.0-0.5) weeks). Treatment choice for TAPS varied greatly within and between the 17 fetal therapy centers. CONCLUSIONS: Antenatal treatment for TAPS differs considerably amongst fetal therapy centers. Perinatal mortality and morbidity were high in all management groups. Prolongation of pregnancy was best achieved by expectant management, treatment by laser surgery or selective feticide. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Postmortem fetal imaging: prospective blinded comparison of two-dimensional ultrasound with magnetic resonance imaging.

OBJECTIVE: To compare the diagnostic rate and accuracy of 3-Tesla (T) postmortem magnetic resonance imaging (PM-MRI) and postmortem ultrasound (PM-US) in an unselected fetal population. METHODS: We performed prospectively, in a blinded manner, 3-T PM-MRI and PM-US on 160 unselected fetuses at 13-41 weeks of gestation. All imaging was reported according to a prespecified template, for five anatomical regions: brain, thorax, heart, abdomen and spine. The rates of non-diagnostic results for PM-US and PM-MRI were compared and, for results that were diagnostic, we calculated sensitivity, specificity and concordance rates for each anatomical region, using conventional autopsy as the reference standard. RESULTS: 3-T PM-MRI performed significantly better than did PM-US overall and in particular for fetuses ≥ 20 weeks' gestation. Specifically, the non-diagnostic rates for PM-MRI vs PM-US were 4.4% vs 26.9% (7/160 vs 43/160; P < 0.001) for the brain, 5.2% vs 17.4% (8/155 vs 27/155; P < 0.001) for the thorax, 3.8% vs 30.6% (6/157 vs 48/157; P < 0.001) for the heart and 3.2% vs 23.6% (5/157 vs 37/157; P < 0.001) for the abdomen. For the spine, both techniques showed an equally low non-diagnostic rate. When both postmortem imaging techniques were diagnostic, they had similar accuracy, with no difference in sensitivity or specificity, and similar concordance with autopsy (PM-US, 79.5-96.5%; PM-MRI, 81.6-99.1%). CONCLUSIONS: PM-MRI performed significantly better than PM-US in this unselected population, due mainly to a lower non-diagnostic rate. PM-MRI should remain the first-line imaging investigation for perinatal autopsy, but PM-US could be considered if MRI is not available, albeit with a higher non-diagnostic rate. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Postmortem examination of human fetuses: comparison of two-dimensional ultrasound with invasive autopsy.

OBJECTIVE: To assess the diagnostic accuracy of postmortem ultrasound performed by operators blinded to prenatal findings and to invasive autopsy results in fetuses at different gestational ages and to investigate the effect of various parameters on its diagnostic success. METHODS: We performed postmortem two-dimensional ultrasound examination, blinded to clinical details, on 163 fetuses at 13-42 weeks' gestation. Logistic regression analysis was used to investigate the effect of: (i) gestational age at postmortem ultrasound, (ii) presence of maceration and (iii) mode of death, on whether the exam succeeded or failed to reach a diagnosis. In 123 cases in which invasive autopsy was available, the diagnostic accuracy of ultrasound in detecting major organ abnormalities was evaluated, using invasive autopsy as the gold standard. RESULTS: For the fetal brain, postmortem ultrasound exam was non-diagnostic in significantly more fetuses with maceration (39.5%; 17/43) vs those without maceration (20.0%; 24/120) (P = 0.013). For the fetal thorax, the exam was non-diagnostic in 34.1% (15/44) of fetuses < 20 weeks of gestation and in 10.9% (13/119) of fetuses ≥ 20 weeks (P < 0.001). For the heart and abdominal organs, there was no association between non-diagnostic postmortem ultrasound and the variables tested. For fetuses < 20 weeks, specificity of postmortem ultrasound examination was 83.3% for detection of anomalies of the brain, 68.6% for the thorax and 77.4% for the heart. For fetuses ≥ 20 weeks, sensitivity and specificity were, respectively, 61.9% and 74.2% for detection of anomalies of the brain, 29.5% and 87.0% for the thorax and 65.0% and 83.1% for the heart. For the fetal abdominal organs, sensitivity was 60.7% and specificity 75.8%, and postmortem ultrasound was particularly useful for detection of abnormalities of the kidneys, irrespective of gestational age. CONCLUSION: Although maceration may lead to failure of postmortem ultrasound examination in some cases, this technique achieves diagnostically acceptable levels of accuracy for fetal brain and abdominal organs, compared with conventional autopsy. It may therefore play a role as a first-line examination before other virtual autopsy techniques are indicated. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Impact of chlorpyrifos on human villous trophoblasts and chorionic villi.

Placental barrier regulates maternal-fetal interchange protecting the baby from damage caused by substances found in the uterine environment or circulating in the vascular system. Organophosphate (OP) pesticides are a paramount group of environmental pollutants used in intensive agriculture for protection against diseases and pests. While many studies have reported an increased risk of pregnancy alterations in pregnant women exposed to OPs, few have analyzed the effects caused by these pesticides in the placenta. Herein, we evaluated the effects of chlorpyrifos (CPF), one of the most widely used OP insecticides, on human placenta using in vitro and ex vivo exposure models. Villous cytotrophoblast cells isolated from normal human term placentas maintained their cell viability, differentiated into syncytiotrophoblast-like structures, and increased the expression of ß-hCG, ABCG2, and P-gp in the presence of CPF at concentrations of 10 to 100µM. The same doses of CPF induced marked changes in chorionic villi samples. Indeed, CPF exposure increased stroma cell apoptosis, altered villi matrix composition, basement membrane thickness, and trophoblastic layer integrity. Histomorphological and ultrastructural alterations are compatible with those found in placentas where maternal-placenta injury is chronic and able to impair the placental barrier function and nutrient transport from mother to the fetus. Our study shows that placental ex vivo exposure to CPF produces tissue alterations and suggest that human placenta is a potential target of CPF toxicity. In addition, it highlights the importance of using different models to assess the effects of a toxic on human placenta.

Low oxygen tension induces Krüppel-Like Factor 6 expression in trophoblast cells.

The transcription factor Krüppel-Like Factor 6 (KLF6) has important roles in cell differentiation, angiogenesis, apoptosis, and proliferation. Furthermore, there is evidence that KLF6 is required for proper placental development. While oxygen is a critical mediator of trophoblast differentiation and function, the involvement of oxygen in the regulation of KLF6 expression remains unexplored. In the present study we examined the expression of KLF6 in placental tissue from uncomplicated and preeclamptic pregnancies, the latter often characterized by an inadequately perfused placenta. We also determined the effect of hypoxia and the involvement of Hypoxia-Inducible Factor 1α (HIF-1α) on the expression of KLF6 in cultured trophoblast cells and placental tissues. Results revealed that villous, interstitial and endovascular extravillous cytotrophoblasts from placentas from normal and preeclamptic pregnancies express KLF6. In addition, KLF6 immunoreactivity was higher in the placental bed of preeclamptic pregnancies than in those of uncomplicated pregnancies. We demonstrated that hypoxia induced an early and transient increase in KLF6 protein levels in HTR8/SVneo extravillous cytotrophoblast cells and in placental explants. Reoxygenation returned KLF6 protein to basal levels. Moreover, hypoxia-induced up-regulation of KLF6 expression was dependent on HIF-1α as revealed by siRNA knockdown in HTR8/SVneo cells. These results indicate that KLF6 may mediate some of the effects of hypoxia in placental development. The regulation of KLF6 protein levels by oxygen has significant implications for understanding its putative role in diseases affected by tissue hypoxia.

Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies.

OBJECTIVES: To report clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood in screening for trisomies 21, 18 and 13 in twin pregnancies and examine variables that could influence the failure rate of the test. METHODS: cfDNA testing was performed in 515 twin pregnancies at 10-28 weeks' gestation. The failure rate of the test to provide results was compared with that in 1847 singleton pregnancies, and logistic regression analysis was used to determine which factors among maternal and pregnancy characteristics were significant predictors of test failure. RESULTS: Failure rate of the cfDNA test at first sampling was 1.7% in singletons and 5.6% in twins. Of those with a test result, the median fetal fraction in twins was 8.7% (range, 4.1-30.0%), which was lower than that in singletons (11.7% (range, 4.0-38.9%)). Multivariable regression analysis demonstrated that twin pregnancy, higher maternal weight and conception by in-vitro fertilization provided significant independent prediction of test failure. Follow-up was available in 351 (68.2%) of the twin pregnancies and comprised 334 with euploid fetuses, 12 discordant for trisomy 21 and five discordant for trisomy 18. In all 323 euploid cases with a result, the risk score for each trisomy was < 1:10 000. In 11 of the 12 cases with trisomy 21 and in the five with trisomy 18, the cfDNA test gave a high-risk result, but in one case of trisomy 21, the score was < 1:10 000. CONCLUSION: In twin pregnancies screening by cfDNA testing is feasible, but the failure rate is higher and detection rate may be lower than in singletons.

Review: putative roles for the macrophage migratory inhibitory factor at the maternal fetal interface.

Complex and dynamic networks of molecules participate in the essential interactions between maternal organism, placenta and fetus in a healthy and successful pregnancy. Macrophage migratory inhibitory factor (MIF) is one of several molecules produced at implantation sites; MIF is mostly expressed by trophoblast cells. This has led to expectations of MIF's relevance as a partner in the maternal/fetal dialog. MIF is known by its biological interactions and functional roles as an activator of innate immunity, regulating subsequent adaptive responses, which include inhibition of migration of mononuclear cells in vitro, antagonism of glucocorticoids, and regulation of expression of Toll-like receptor 4. Beyond roles in the inflammatory response, MIF can interfere with proliferative activities in different cell types, as well as with cell death pathways. This intriguing factor found at the human, porcine, ovine, bovine and rodent maternal-fetal interfaces is present in a time- and spatially-dependent manner, indicating regulatory roles in the process of embryo implantation, placental development, maintenance of pregnancy and birth. Here, we will review MIF participation in placental physiology, including new evidence for a dialog with uterine cells, and a potential role in protection of uterine decidual cells.

Matrix array transducer for the examination of fetal heart.

The X6-1 xmatrix array transducer allows a completely new approach to the diagnostic ultrasound: it permits visualization of fetal heart in real time, without the need for gating, and it is unaffected by motion artefacts. It is obtained in real time, without any spatial reconstruction. The authors compared this technology with the traditional one in two case reports: a diagnostic doubt of small muscular ventricular septal defect was solved using this new technique; a diagnosis of complete atrioventricular septal defect was confirmed. Three-dimensional real-time imaging would seem very precise in the study of fetal heart: the defects were fully visualized from any angulations. This new technology is promising but from the authors' limited experience, there is no evidence to use it in routine practice. It should be very useful to commence a prospective study on fetuses at risk while testing the superiority of this technique.

A case of uterine rupture in mid-trimester spontaneous abortion: a complication of gemeprost vaginal administration.

The only prostaglandin analogue licensed in Italy for induction of labour in spontaneous and therapeutic abortion is gemeprost. The authors report a case of spontaneous uterine rupture of a scarred uterus, for previous caesarean sections, in a woman at 20 weeks of gestation with a diagnosis of spontaneous abortion. She received a pessary of gemeprost every three hours. After the fifth pessary, she complained of severe pain. At the ultrasound examination, uterine cavity appeared empty and the dead fetus was dislocated in the abdomen. Emergency laparotomy was performed and uterine tear was repaired. To induce labour for fetal demise or therapeutic abortion in second trimester in women with scarred uterus, the authors decided to lengthen the time between administrations of pessary from four to five hours depending on patient's symptoms. However the appropriate drug regimen has still to be found and more data are necessary.

Ultrasound management and clinical outcome of twin pregnancies.

The rate of multiple pregnancies is showing a significant increase in Western countries. Twin gestations should be considered a high-risk condition because they are responsible for a disproportionate amount of overall perinatal morbidity and mortality. We used a specialised ultrasound protocol based on chorionicity to monitor 44 twin pregnancies (61% dichorionic diamniotic (DD) and 39% monochorionic diamniotic (MD)). Adverse pregnancy outcomes and pre-term deliveries were more common in MD pregnancies than in DD pregnancies; the rate of extreme pre-term delivery (< 32 weeks) was almost three-times higher in MD than in DD pregnancies (41% vs 15%) and perinatal complications were more frequent in MD than in DD pregnancies (59% vs 22%), but fetal anomalies were more frequent in DD than in MD pregnancies (30% vs 24%). Periodic ultrasound follow-up would predict the pregnancies that are at greater risk for fetal and neonatal complications and these should be monitored more closely.

Mediastinal masses: a case of fetal teratoma and literature review.

Fetal mediastinal masses are rare congenital formations that could complicate pregnancy. They are usually discovered as space occupying lesions in the fetal chest during routine ultrasound scan. The most important prognostic factors of mediastinal masses are mass location, compressing effect causing pulmonary hypoplasia and/or heart failure, and the presence or absence of hydrops. We report a case of fetal mediastinal teratoma and a review of the literature. A 32-year-old woman carrying a fetus with hydrops due to a mediastinal mass underwent cesarean section at 32 1/7 weeks' gestation. A well encapsulated tumor was excised by surgery at one day of life. The baby is now eight months old without respiratory difficulty. To our knowledge, this is the fourth case report of a mediastinal teratoma associated with nonimmune hydrops in a fetus that survived the neonatal period. Fetal mediastinal teratoma requires close surveillance and multidisciplinary management by obstetricians, neonatologists, and pediatric surgeons.

Localization of cathepsins D and B at the maternal-fetal interface and the invasiveness of the trophoblast during the postimplantation period in the mouse.

A survey of existing data suggests that trophoblast cells produce factors involved in extracellular matrix degradation. In this study, we correlated the expression of cathepsins D and B in the murine ectoplacental cone with the ultrastructural progress of decidual invasion by trophoblast cells. Both proteases were immunolocalized at implantation sites in lysosome-endosome-like compartments of trophoblast giant cells. Cathepsin D, but not cathepsin B, was also detected ultrastructurally in extracellular compartments surrounded by processes of the invading trophoblast containing extracellular matrix components and endometrial cell debris. The expression of cathepsins D and B by trophoblast cells was confirmed by RT-PCR in ectoplacental cones isolated from implantation chambers at gestation day 7.5. Our data addressed a positive relationship between the expression and presence of cathepsin D at the extracellular compartment of the maternal-fetal interface and the invasiveness of the trophoblast during the postimplantation period, suggesting a participation of invading trophoblast cells in the cathepsin D release. Such findings indicate that mouse trophoblast cells might exhibit a proteolytic ability to partake in the decidual invasion process at the maternal-fetal interface.

Asthma related to Alternaria sensitization: an analysis of skin-test and serum-specific IgE efficiency based on the bronchial provocation test.

BACKGROUND: It is difficult to find a causal relationship between exposure to Alternaria spores and the development of asthma symptoms in sensitized individuals due to the complexity of clinical situations in which positive diagnostic tests are often found. OBJECTIVE: To analyse the diagnostic efficiency of skin testing (ST) and serum-specific IgE to Alternaria, based on the results of a bronchial specific challenge with Alternaria extracts. METHODS: Seventy-four asthmatic patients sensitized to Alternaria underwent a specific bronchial challenge with this mould. Skin-testing weal sizes, serum-specific IgE values (CAP-system) and bronchial challenge results were analysed by receiver operating characteristics curves (ROC curves) and logistic regression. The sensitivity, specificity, positive and negative predictive values were calculated for different cut-off points. RESULTS: Bronchial challenges to Alternaria elicited a positive result in 45 patients (61%). Skin prick testing almost perfectly predicted the outcome of bronchoprovocation tests (area under the ROC curve of 0.957), whereas intradermal skin testing had moderate efficacy. A negative result for skin prick test (SPT) showed a 4% probability of a positive bronchial challenge in the logistic regression analysis. However, weals around 5.5 mm in diameter had 90% probability of a positive challenge. Quantification of serum-specific IgE correctly classified 86% of the cases. In the logistic regression analysis, a CAP value 16 kU(A)/L predicted a positive bronchial challenge result with 99% accuracy, whereas for a CAP value <0.35 kU(A)/L, this probability was 33%. CONCLUSIONS AND CLINICAL RELEVANCE: Most asthmatic patients with positive SPT results to Alternaria would have a positive bronchial challenge. As atmospheric mould levels may vary significantly with the weather conditions, sensitized patients should be instructed on the risk situations, environmental control measures and the importance of correct medication compliance. Immunotherapy with Alternaria could also be taken into account as a valid therapeutic option.