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Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1. The uncertainty of pathogenicity of MEN1 variants complexifies the selection of the patients likely to benefit from specific care. Objective MEN1-mutated patients should be offered tailored tumor screening and genetic counseling. We present a patient with hyperparathyroidism for whom genetic analysis identified a variant of uncertain significance in the MEN1 gene (NM_130799.2): c.654G > T p.(Arg218=). Additional functional genetic tests were performed to classify the variant as pathogenic and allowed prenatal testing. Design Targeted next generation sequencing identified a synonymous variant in the MEN1 gene in a 26-year-old male with symptomatic primary hyperparathyroidism. In silico and in vitro genetic tests were performed to assess variant pathogenicity. Results Genetic testing of the proband’s unaffected parents showed the variant occurred de novo. Transcript study showed a splicing defect leading to an in-frame deletion. The classification of the MEN1 variant as pathogenic confirmed the diagnosis of MEN1 and recommended an adapted medical care and follow-up. Pathogenic classification also allowed to propose a genetic counseling to the proband and his wife. Noninvasive prenatal diagnosis was performed with a personalized medicine-based protocol by detection of the paternally inherited variant in maternal plasmatic cell free DNA, using digital PCR. Conclusion We showed that functional genetic analysis can help to assess the pathogenicity of a MEN1 variant with crucial consequences for medical care and genetic counseling decisions.

To evaluate the use of cervical dilators concurrently with misoprostol to shorten labor in second-trimester medical termination of pregnancy.This multicenter randomized controlled trial compared the efficacy of cervical dilators inserted concurrently with misoprostol with that of misoprostol, alone, to shorten labor for women undergoing termination of pregnancy between 15 0/7 and 27 6/7 weeks of gestation. The primary outcome was the proportion of women with a duration of labor exceeding 12 hours. Secondary outcomes included median duration of labor, time to amniotomy, side effects, complications, NPRS (Numeric Pain Rating Scale) score, and women's distress as measured by the IES-R (Impact of Event Scale-Revised). These outcomes also were studied separately in the nulliparous subgroup. To demonstrate a reduction of 50% of the proportion of women with a duration of labor exceeding 12 hours in the dilator group, with a power of 80% and a 2-sided 0.05 significance level, a sample of 268 women (134 in each group) was required.Between December 2017 and September 2019, this study enrolled and analyzed 347 women: 174 in the dilator group and 173 in the control group, including 87 and 93 nulliparous patients, respectively. Sociodemographic and obstetric characteristics were similar between groups. The proportion of women with labor exceeding 12 hours was not different between groups (49/174 [28.2%] in the dilator group vs 53/173 [30.6%] in the control group [ P =.61] for the whole population, and 37/87 [42.5%] vs 42/93 [45.2%] [ P =.72], respectively, among nulliparous patients). Median duration of labor was 8.5 hours in the dilator group compared with 9.2 hours in the control group ( P =.65) for the whole population, and 10.5 hours compared with 11.8 hours, respectively, among nulliparous patients ( P =.33). Median time to amniotomy was 3.6 hours in the dilator group compared with 5.0 hours in the control group ( P =.08) for the whole population, and 3.5 hours compared with 6.7 hours, respectively, among nulliparous patients ( P =.003). Side effects, complications, NPRS score, and IES-R score were similar between groups.Cervical dilators inserted concurrently with misoprostol did not reduce the proportion of women whose labor exceeded 12 hours compared with misoprostol alone.ClinicalTrials.gov , NCT03194230.

Background and ObjectivesDespite the potentially devastating effects of pregnancy-related stroke, few studies have examined its incidence by type of stroke. We aimed to study the nationwide incidence rates and recent temporal trends for all types of pregnancy-related stroke and to compare these incidences with stroke incidence in nonpregnant women.MethodsWe conducted a study of 6,297,698 women aged 15–49 years who gave birth in France between 2010 and 2018 with no history of stroke before pregnancy by collecting data from the French National Health Insurance Information System database. Poisson regression was used to estimate the incidence by types of strokes for the different pregnancy periods and the incidence rate ratio of stroke in pregnant vs nonpregnant French women.ResultsAmong the 6,297,698 women, 1,261 (24.0 per 100,000 person-years) experienced a first ever stroke during, antepartum peripartum, or the first 6 weeks of postpartum. Of the pregnancy-related strokes, 42.9% were ischemic (IS), 41.9% were hemorrhagic (with similar proportion of intracerebral and subarachnoid hemorrhage), and 17.4% were cerebral venous thrombosis (CVT). Compared with nonpregnant women, incidence rates of stroke were similar during pregnancy for IS (adjusted incidence risk ratio [IRR] 0.9 [0.8–1.1]), slightly higher for all hemorrhagic strokes (IRR 1.4 [1.2–1.8]), and considerably increased for CVT (IRR 8.1 [6.5–10.1]). Pregnancy-related stroke incidence rose between 2010 and 2018 for IS and HS but was stable for CVT.DiscussionThe risk of pregnancy-related CVT was more than 8-fold higher than that observed in nonpregnant women. The incidence of pregnancy-related IS and HS is increasing over time, and efforts should be made for prevention considering treatable cardiovascular risk factors and hypertensive disorders in pregnant women.

Polyhydramnios is a common feature diagnosed by ultrasound in the second half of pregnancy. Biochemical analysis of amniotic fluid can be useful when suspecting Bartter syndrome or digestive atresia but in most of cases, no etiology of polyhydramnios is found because of the complex regulation of amniotic fluid. Aquaporins (AQP) are transmembrane channel proteins contributing to water transfers. Some of them are expressed in fetal membranes and placenta. Their expression has been shown to be disrupted in some pathological conditions such as maternal diabetes, often associated with polyhydramnios. AQP-1, 3 and 8 levels in amniotic fluid were retrospectively measured in patients suffering from polyhydramnios (n=21) from 23 weeks of gestation (WG). They were compared to the levels observed in control subjects (n=96) and their relationship with maternal factors and neonatal issues was analyzed. AQP-1, 3, 8 levels were physiologically fluctuating, AQP-1 levels always being the lowest and AQP-3 the highest, with a significant decrease at the end of pregnancy. AQPs/AFP ratios increased about 8 folds during pregnancy, their kinetic profiles reflecting physiological dynamic evolution of amniotic fluid volume. In polyhydramnios, AQP-3 level tended to be decreased whereas AQP-8 level was decreased from mid-gestation whatever the etiology of polyhydramnios. No significant relationship was found between AQPs levels and either the fetal prematurity degree or macrosomia. No specific pattern was observed in idiopathic polyhydramnios, limiting the interest of AQPs dosage in amniotic fluid in the management of those complicated pregnancies.

Cancer during pregnancy is rare (about 1/1000 pregnancies) and its diagnosis raises the question of whether or not to continue the pregnancy.The primary objective of our study was to evaluate associated factors with termination of pregnancy in cases of cancer during pregnancy. Secondary objectives were to evaluate maternal and neonatal outcomes when pregnancy is continued.We conducted a retrospective, single-center study between January 2009 and December 2019 including 2 groups of patients those who underwent termination of pregnancy and those who continued pregnancy. Patients were distributed in 3 categories breast cancer, blood cancer and other cancers.A total of 71 pregnancies associated with cancer were included. Twenty patients (28.16 %) underwent termination of pregnancy. The median gestational age at diagnosis was significantly earlier in the termination of pregnancy group compared with the ongoing pregnancy group (9 vs 22 weeks, p0.01). Blood cancer was more frequent in the termination group 7 (35 %) compared to continuous pregnancy 8 (15.7 %) as other cancers 8 (40 %) in the termination group vs 5 (9,8 %). Conversely breast cancer what was less frequent in the termination group 5 (25 %) vs 38 (74,5 %) (p0.01). In the continued pregnancy group, there was a high rate of induced prematurity (35.5 %) and scheduled delivery to optimize maternal oncologic management (78.4 %).The rate of termination of pregnancy remains high particularly in case of non-breast cancer and early pregnancy detection. Scheduled preterm birth is frequent when pregnancy is continued in order to optimize of cancer management.

Background The criteria for antiphospholipid syndrome (APS) include severe preeclampsia and/or placental insufficiency leading to preterm delivery before 34 weeks of gestation, but this APS manifestation has been rarely studied. Thus, we report a series of severe preeclampsia occurred in patients with APS. Methods We retrospectively analysed data of women with APS (Sydney criteria) who experienced severe preeclampsia with delivery before 34 weeks’ gestation between 2000 and 2017 at five French internal medicine departments and one Italian rheumatology unit. Results The 40 women had a mean age of 30.5 ± 4.6 years at their first episode of preeclampsia; 21 were nulligravid (52.5%), 12 (30%) had already been diagnosed with APS, and 21 (52.5%) had a triple-positive antiphospholipid (aPL) antibody test. Preeclampsia occurred at a median gestational age of 25.5 weeks (IQR 23-29). It was associated with HELLP in 18 cases (45%), eclampsia in 6 (15%), placental abruption in 3 (7.5%), catastrophic APS in 3 (7.5%), and foetal and neonatal death in 11 and 15 cases. Overall, 14 (35%) children survived, born at a median gestational age of 31 weeks. Among other APS criteria, 16 women (40%) experienced at least one thrombosis, 17 (42.5%) an intrauterine foetal death, and 19 (47.5%) at least one episode of HELLP during follow-up (median 5 years, IQR = 2-8). None had three or more consecutive miscarriages. Notably, 12 women (30%) had systemic lupus erythematosus. Conclusions Severe preeclampsia led to high mortality in the offspring. Almost half of these women experienced other APS features, but not three consecutive miscarriages. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-021-02518-7.

Approccio multidisciplinare ai tumori maligni del vestibolo del naso: verso la definizione di nuovi standard.I tumori maligni del vestibolo del naso, principalmente SCC, sono considerati neoplasie rare. Nel presente lavoro, rivediamo lo stato attuale dell’arte per quanto riguarda la classificazione e il trattamento, e descriviamo le evidenze attuali a supporto di un cambiamento di paradigma. Nell’attuale classificazione AJCC il vestibolo del naso è considerato parte della cavità nasale/etmoide. Nella pratica clinica quotidiana, le lesioni del vestibolo del naso sono spesso erroneamente classificate come primarie della pelle. Questo porta a una sottovalutazione della reale incidenza e a una cattiva gestione. Quando i tumori primitivi del vestibolo del naso sono correttamente classificati come a origine dal naso/seni paranasali, l’attuale AJCC TNM appare inadeguato per la stratificazione prognostica e un vecchio sistema di stadiazione descritto 4 decenni fa da Wang ha dimostrato di essere più affidabile ed è preferito nei centri con il maggior volume di casi trattati. I principi della classificazione di Wang dovrebbero essere applicati e il vestibolo del naso dovrebbe essere riconosciuto dall’AJCC/UICC come una nuova sottosede distinta di naso e seni paranasali. La chirurgia, la radioterapia a fasci esterni (EBRT) e la radioterapia interventistica (IRT, BrachyTherapy BT) sono le attuali opzioni terapeutiche per il carcinoma del vestibolo del naso (NVSCC). Sempre più evidenze dimostrano che la IRT, da effettuarsi in un contesto rigorosamente multidisciplinare, è almeno equivalente alla chirurgia e all’EBRT per il trattamento delle lesioni primarie in termini di esiti oncologici, ma nettamente superiore in termini di risultati estetici e funzionali, supportando l’HDR (high dose rate) IRT come nuovo standard per il trattamento della lesione primaria in questi tumori maligni. Per ottimizzare i vantaggi della IRT come modalità terapeutica primaria abbiamo impostato un nuovo approccio alla fase di impianto della IRT sfruttando i piani anatomici della chirurgia estetica e funzionale del naso e le potenzialità della brachiterapia a intensità modulata e guidata dalle immagini, per evitare la perforazione del setto e dell’ala (impianto anatomico).Nose vestibule malignancies, mainly SCCs, are considered rare neoplasms. In the present paper, we review the current state of the art concerning classification and treatment, and describe current evidence supporting a paradigm shift. In the current AJCC classification nose vestibule is considered part of nasal cavity/ethmoid. In daily clinical practice, nose vestibule lesions are often misclassified as skin primaries. This leads to an underestimation of the real incidence and to a mis-management. When nose vestibule primaries are correctly classified as nose primaries, the current AJCC TNM appears inadequate for prognostic stratification and an old staging system described 4 decades ago by Wang has been demonstrated to be more reliable in the literature and is preferred in centers with the largest volume of cases treated. The principles of Wang classification should be applied and nose vestibule acknowledged as a new distinct subsite of nose and paranasal sinuses by the AJCC/UICC. Surgery, External Beam RadioTherapy (EBRT) and Interventional RadioTherapy (IRT, BrachyTherapy BT) are the current therapeutic options for nose vestibule (NV) SCC.Increasing evidence demonstrates that IRT, with a proper multidisciplinary approach, is at least equivalent to surgery and EBRT for treatment of the primary lesions in terms of oncological outcomes, but markedly superior in terms of cosmetic and functional results, supporting HDR (high dose rate) IRT as the new standard for the treatment of the primary lesion in these malignancies. To optimize the advantages of IRT as primary therapeutic modality we set up a new approach to the implantation phase of IRT exploiting the anatomic planes of esthetic and functional nose surgery and the potential of intensity modulated and image guided brachytherapy to avoid septal and alar perforation (anatomic implantation).

In a three-dimensional (3D) representation, each protein molecule displays a specific pattern of chemical and topological features, which are altered during its misfolding and aggregation pathway. Generating a recognizable fingerprint from such features could provide an enticing approach not only to identify these biomolecules but also to gain clues regarding their folding state and the occurrence of pathologically lethal misfolded aggregates. We report here a universal strategy to generate a fluorescent fingerprint from biomolecules by employing the pan-selective molecular recognition feature of a cucurbit[7]uril (CB[7]) macrocyclic receptor. We implemented a direct sensing strategy by covalently tethering CB[7] with a library of fluorescent reporters. When CB[7] recognizes the chemical and geometrical features of a biomolecule, it brings the tethered fluorophore into the vicinity, concomitantly reporting the nature of its binding microenvironment through a change in their optical signature. The photophysical properties of the fluorophores allow a multitude of probing modes, while their structural features provide additional binding diversity, generating a distinct fluorescence fingerprint from the biomolecule. We first used this strategy to rapidly discriminate a diverse range of protein analytes. The macrocyclic sensor was then applied to probe conformational changes in the protein structure and identify the formation of oligomeric and fibrillar species from misfolded proteins. Notably, the sensor system allowed us to differentiate between different self-assembled forms of the disease-specific amyloid-β (Aβ) aggregates and segregated them from other generic amyloid structures with a 100% identification accuracy. Ultimately, this sensor system predicted clinically relevant changes by fingerprinting serum samples from a cohort of pregnant women.

The objective of this study was to assess the performance of ultrasound and magnetic resonance imaging (MRI) features in helping to classify the type of placenta accreta spectrum (PAS; accreta/increta vs percreta), alone or combined in a predictive score.We conducted a retrospective study in 82 pregnant women with PAS who underwent ultrasound and MRI examination of the pelvis before delivery (from an initial cohort of 185 women with PAS). We estimated the sensitivity, specificity and accuracy of MRI and ultrasound in the diagnosis of the type of PAS. We analyzed cesarean and imaging features using univariable logistic regression analysis. We constructed a nomogram to predict the risk of placenta percreta and validated it with bootstrap resampling, then used receiver operating characteristic curves to assess the performance of the model in distinguishing between placenta percreta and placenta accreta/increta.Among the 82 patients, 29 (35%) had placenta accreta/increta and 53 (65%) had placenta percreta. The best features to discriminate between placenta accreta/increta and placenta percreta with ultrasound were increased vascularization at the uterine serosa-bladder wall interface (odds ratio [OR] 7.93; 95% confidence interval [CI] 2.78-24.99; p 0.01) and the number of lacunae without a hyperechogenic halo (OR 1.36; 95% CI 1.14-1.67; p = 0.012). Concerning MRI markers, heterogeneous placenta (OR 12.89; 95% CI 3.05-89.16; p = 0.002), dark intraplacental bands (OR 12.89; 95% CI 3.05-89.16; p = 0.002) and bladder wall interruption (OR 15.89; 95% CI 4.78-73.33; p 0.001) had a higher OR in discriminating placenta accreta/increta from placenta percreta. The nomogram yielded areas under the curve of 0.841 (95% CI 0.754-0.927) and 0.856 (95% CI 0.767-0.945), after bootstrap resampling, for the accurate prediction of placenta percreta.The nomogram we developed to predict the risk of placenta percreta among patients with PAS had good discriminative capabilities. This performance and its impact on maternal morbidity should be confirmed by future prospective studies.

Prevention and treatment of infertility remains a priority for developed countries where a large proportion of women undergo in vitro fertilization (IVF) after ovarian stimulation. Latest data suggest that, in the USA alone, almost eight million women of fertile age will have sought medical advice for fertility problems by 2025. However, over the last years, attention has been increasingly focused, and questions have risen, on the long-term health effects in women who underwent assisted reproductive technologies (ARTs). Since the emergence of ART, reports highlight a possible connection of ovarian stimulation and several types of gynaecological cancer, including ovarian, endometrial and cervical types, but due to limited scientific evidence, such a speculation is still under investigation. The objective of this review is to summarize the latest data of ovarian hyperstimulation and IVF, associated with the risk of gynecological tract cancer development.

International audience; Purpose: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC).Methods: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered.Results: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy.Conclusion: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.

Cancer is a medical condition which has a molecular basis. Proto-oncogenes are the first regulatory factors of this biological process. They act in transmitting signals, resulting as growth factors. Modifications of these genes, called oncogenes, lead to the appearance of cancer cells. The activation process leading to proto-oncogenes are chromosomal translocation, point mutation, and gene amplification. Concerning the clonal theory of oncogenesis, it is believed that a tumor starts from a cell. Furthermore, there is close association between tumor development and inhibition of apoptosis or programmed cell death, providing cell immortality. Angiogenesis and angiogenic factors found to be expressed in tumors and may play a key role in tumor formation and development. Tumor-suppressor genes block the growth of cancer and contribute to the normal development of cells. This article highlights the evidence that neoplasms develop as the after-effect of the increase of acquired and physical genetic variations in proto-oncogenes and tumor-suppressor genes; these form a target group in the cells of neoplasms. Tumor formation and development are characterized by individual processes, working synergistically, and an understanding of each individual process may provide a better basis for further anticancer research.

International audience; Background: Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction.Objective: This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction.Study design: This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of

In the context of a medical termination of pregnancy, prolonged labor may accentuate the difficulty of women's experience and increase the risk of associated complications. The factors associated with prolonged labor are not known. Reducing the duration of labor could limit these complications. Determining the relevant factors associated with prolonged labor defined as a delay between the onset of induction and delivery greater than or equal to 12hours and comparing the complications rates between the two groups.We conducted a retrospective study at Port Royal Maternity Hospital from 2017 to 2019, including medical terminations of pregnancy by vaginal delivery in the 2nd and 3rd trimesters for fetal or maternal reasons.Two hundred twenty-seven patients were included and divided into two comparative groups based on the duration of labor: labor12h (n=173) and labor ≥12h (n=54). The mean maternal age was 33.7 years. Forty-four percent of patients were nulliparous, 15.8 % had a history of cesarean section. The average gestational age was 20+2 weeks of gestation. The average duration of labor was 9.7hours. The duration of labor was greater than 24hours in 3% of cases (7/227). Advanced gestational age (22+3 vs. 20+5 p=0,04) and nulliparity (p=0.01) were associated with prolonged labor. Two other intermediate factors, not independent of the duration of labor, were significant: long time to rupture of membranes (239min vs. 427min p0,01) and an unfavorable Bishop score at rupture (p=0,003). In both groups, the complications were placental retention and the occurrence of fever during labor.Two main factors affecting labor duration were identified in this study (term and nulliparity). This knowledge could allow women to be better informed about the expected time of labor and the potential associated risks.

Objective Rathkes cleft cysts are benign, embryological remnants in the pituitary gland. The majority of them are small and asymptomatic but a few may become large, and cause mass effects, pituitary hormone deficiencies and visual impairment. Recommendations for the follow-up of Rathkes cleft cysts vary since data on the natural history are sparse. Patients and Design Data at diagnosis and at 1, 5 and 10 years for patients with a Rathkes cleft cyst (434 at diagnosis, 317 females) were retrieved from the Swedish Pituitary Registry. Cysts = 10 mm that were not operated (n = 174) decreased in size over the years (p < .01). Pituitary hormone deficiencies and visual impairments were more frequent (18% and 5.7%, respectively) but were stable over time. Transphenoidal surgery was performed in 56 patients of whom 51 underwent surgery before the 1-year follow-up. The mean cyst diameter at diagnosis was 18 mm (range: 930 mm), 36% had pituitary hormone deficiency, 45% had visual field defects and 20% had impaired visual acuity. One year after surgery 60% had no cyst remnants, 50% had a pituitary deficiency, 26% had visual field defects and 12% had impaired visual acuity. No major changes were observed after 5 years. Twelve of the operated patients had a follow-up at 10 years, in eight the cyst remnants or recurrences increased in size over time (p < .05). Conclusions Rathkes cleft cysts with a size less than 10 mm rarely grow and our results indicate that radiological follow-up can be restricted to 5 years. In contrast, progression of postoperative remnants or recurrent cysts is more likely and require long-term follow-up.

ObjectiveTo determine whether bladder size is associated with an unfavorable neonatal outcome, in the case of first-trimester megacystis.Materials and methodsThis was a retrospective observational study between 2009 and 2019 in two prenatal diagnosis centers. The inclusion criterion was an enlarged bladder (> 7 mm) diagnosed at the first ultrasound exam between 11 and 13+6weeks of gestation. The main study endpoint was neonatal outcome based on bladder size. An adverse outcome was defined by the completion of a medical termination of pregnancy, the occurrence of in utero fetal death, or a neonatal death. Neonatal survival was considered as a favorable outcome and was defined by a live birth, with or without normal renal function, and with a normal karyotype.ResultsAmong 75 cases of first-trimester megacystis referred to prenatal diagnosis centers and included, there were 63 (84%) adverse outcomes and 12 (16%) live births. Fetuses with a bladder diameter of less than 12.5 mm may have a favorable outcome, with or without urological problems, with a high sensitivity (83.3%) and specificity (87.3%), area under the ROC curve = 0.93, 95% CI (0.86–0.99), p< 0.001. Fetal autopsy was performed in 52 (82.5%) cases of adverse outcome. In the 12 cases of favorable outcome, pediatric follow-up was normal and non-pathological in 8 (66.7%).ConclusionBladder diameter appears to be a predictive marker for neonatal outcome. Fetuses with smaller megacystis (7–10 mm) have a significantly higher chance of progressing to a favorable outcome. Urethral stenosis and atresia are the main diagnoses made when first-trimester megacystis is observed. Karyotyping is important regardless of bladder diameter.

Objective Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus. Methods The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC. Results In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected. Conclusion Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.

OBJECTIVE To validate and evaluate the performance metrics of the high-throughput semiconductor sequencing platform, Ion Proton®, in non-invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting. METHODS This prospective cohort study included 2505 pregnant women from eight academic genetics laboratories (695 high risk for trisomy 21 (risk ≥ 1/250) pregnancies in a validation study, and 1810 such pregnancies, without ultrasound anomalies, in a real-life NIPS clinical setting). Outcome was available for all cases in the validation cohort and for 521 in the clinical cohort. Cell-free DNA from plasma samples was sequenced using the Ion Proton sequencer, and sequencing data were analyzed using the open-access software, WISECONDOR. Performance metrics for detection of trisomies 21, 18 and 13 were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, and DEFRAG and SANEFALCON software). RESULTS Results from both cohorts were consistent and their gestational age was not significantly different so their data were combined to increase the sample size for analysis. Sensitivities and specificities, respectively, were as follows: for trisomy 21, 98.3% (95% CI, 93.5-99.7%) and 99.9% (95% CI, 99.4-100%); for trisomy 18, 96.7% (95% CI, 80.9-99.8%) and 100% (95% CI, 99.6-100%); and for trisomy 13, 94.1% (95% CI, 69.2-99.7%) and 100% (95% CI, 99.6-100%). Our failure rate was 1.2% initially and as low as 0.6% after retesting some of the failed samples. Fetal fraction estimation by the RASSF1A assay was consistent with DEFRAG results, and both were adequate for routine diagnosis. CONCLUSIONS We describe one of the largest studies evaluating Ion Proton-based NIPS and the first clinical study reporting pregnancy outcome in a large series of patients. This platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be implemented easily in any medical genetics laboratory. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Background In early terminations of pregnancy for fetal anomaly (TOPFA) without identified cytogenetic abnormality, a fetal autopsy is recommended for diagnostic purposes, to guide genetic counseling. Medical induction, which allows analysis of a complete fetus, is generally preferred over surgical vacuum aspiration. Our objective was to assess the diagnostic value of fetal autopsies in these early terminations, relative to the first-trimester ultrasound, overall and by termination method. Materials For this retrospective study at the Port Royal Maternity Hospital, we identified all TOPFA performed from 11 weeks to 16 weeks diagnosed at the first-trimester ultrasound in cases with a normal karyotype. The principal endpoint was the additional value of the autopsy over /compared to the ultrasound and its impact on genetic counseling, globally and by termination method. The secondary objective was to compare the complication rate by method of termination. Results The study included 79 women during period of 2013–2017: 42 with terminations by medical induction and 37 by aspiration. Fetal autopsy found additional abnormalities in 54.4% of cases, more frequently after medical induction (77.5%) than after aspiration (21.4%, p < .01). Genetic counseling was modified in 20.6% of cases, more often after induction (32.5% vs 3.6%, p < .01). The length of stay was significantly longer and a secondary aspiration was required in 16,7% of case in the medical induction group (p < .01). Conclusion Medically induced vaginal expulsion appears preferable and can change genetic counseling for subsequent pregnancies.

Aims Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and foetal morbidity and mortality. We aimed to estimate the impact of HDP on the onset of chronic hypertension in primiparous women in the first years following childbirth. Methods and results This nationwide cohort study used data from the French National Health Data System (SNDS). All eligible primiparous women without pre-existing chronic hypertension who delivered between 2010 and 2018 were included. Women were followed up from six weeks post-partum until onset of hypertension, a cardiovascular event, death, or the study end date (31 December 2018). The main outcome was a diagnosis of chronic hypertension. We used Cox models to estimate hazard ratios (HRs) of chronic hypertension for all types of HDP. Overall, 2 663 573 women were included with a mean follow-up time of 3.0 years. Among them, 180 063 (6.73%) had an HDP. Specifically 66 260 (2.16%) had pre-eclampsia (PE) and 113 803 (4.27%) had gestational hypertension (GH). Compared with women who had no HDP, the fully adjusted HRs of chronic hypertension were 6.03 [95% confidence interval (CI) 5.89–6.17] for GH, 8.10 (95% CI 7.88–8.33) for PE (all sorts), 12.95 (95% CI 12.29–13.65) for early PE, 9.90 (95% CI 9.53–10.28) for severe PE, and 13.17 (95% CI 12.74–13.60) for PE following GH. Hypertensive disorders of pregnancy exposure duration was an additional risk factor of chronic hypertension for all PE subgroups. Women with HDP consulted a general practitioner or cardiologist more frequently and earlier. Conclusion Hypertensive disorders of pregnancy exposure greatly increased the risk of chronic hypertension in the first years following delivery.

Breast cancer represents one of the three most common gynecological cancers, with each subtype having distinct risk profile and treatment strategies. Optimal therapy for each case depends not only on tumor subtype and cancer stage, but also on patient preferences. Thus, the final therapeutic choice seems complicated to be reached. In addition, frequent relapses and the aesthetic effects have led to the search for more effective and less invasive methods. Surgical interventions have become less complex and new hormonal and chemotherapeutic drugs are established, that promise great results, either combined to surgical treatment or used exclusively. Luteolin is a representative of natural flavonoid that has proven to modulate various signaling pathways involved in cancer development. Recent data demonstrate that luteolin induces apoptotic cell death via antioxidant activity, acting as an anticancer agent against various types of human malignancies including breast cancer. The aim of this review is to summarize latest data considering the therapeutic role of luteolin in breast cancer.

International audience; Introduction: Gestational age at delivery seems to be a risk factor of recurrence of preeclampsia. The objective of this study was to analyze adverse pregnancy outcomes and recurrence of preeclampsia during the subsequent pregnancy in women with a history of pre-eclampsia delivered before 26 weeks of gestation.Material and method: We performed a retrospective study in two French tertiary care hospitals between 2000 and 2018. Patients with a history of pre-eclampsia delivered before 26 weeks of gestation were analyzed. Information on the immediate subsequent pregnancy was collected. Adverse composite outcome was defined as recurrent preeclampsia, HELLP syndrome, placental abruption, fetal growth restriction

International audience; Background: The number of twin pregnancies continues to increase worldwide as both the number of pregnancies obtained by medically assisted reproduction and age at first pregnancy keep rising. Preterm delivery is the major complication associated with twin pregnancies. The effectiveness of preventive treatments such as progesterone or cervical cerclage for women with a short cervix is doubtful in twin pregnancies. The effectivity of cervical pessaries in preventing preterm birth and its associated morbidity and mortality is also controversial.Objective: We sought to investigate if the Arabin pessary reduces adverse neonatal outcomes in twin pregnancies with a short cervix.Study design: This open-label, multicenter, randomized controlled trial on twin pregnancies with a cervical length of

Background: In the ATLANTIC (Administration of Ticagrelor in the catheterization laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery) trial the early use of aspirin, anticoagulation, and ticagrelor coupled with very short medical contact-to-balloon times represent good indicators of optimal treatment of ST-elevation myocardial infarction and an ideal setting to explore which factors may influence coronary reperfusion beyond a well-established pre-hospital system. Methods: This study sought to evaluate predictors of complete ST-segment resolution after percutaneous coronary intervention in ST-elevation myocardial infarction patients enrolled in the ATLANTIC trial. ST-segment analysis was performed on electrocardiograms recorded at the time of inclusion (pre-hospital electrocardiogram), and one hour after percutaneous coronary intervention (post-percutaneous coronary intervention electrocardiogram) by an independent core laboratory. Complete ST-segment resolution was defined as ≥70% ST-segment resolution. Results: Complete ST-segment resolution occurred post-percutaneous coronary intervention in 54.9% ( n=800/1456) of patients and predicted lower 30-day composite major adverse cardiovascular and cerebrovascular events (odds ratio 0.35, 95% confidence interval 0.19–0.65; pConclusions: This study confirmed that post-percutaneous coronary intervention complete ST-segment resolution is a valid surrogate marker for cardiovascular clinical outcomes. In the current era of ST-elevation myocardial infarction reperfusion, patients’ delay and diabetes mellitus are independent predictors of poor reperfusion and need specific attention in the future.

International audience; Background & aims: Gestational diabetes mellitus (GDM) is one of the most frequent medical complications during pregnancy. It has been associated with many adverse pregnancy, fetal and neonatal outcomes, as well as with an increased risk for mothers and children in the long term. There is a growing interest in vitamin D and its potential role in the development of metabolic disorders. However, the medical literature is not consensual. The aim of this study was to assess the risk of GDM according to vitamin D status during the first trimester.Methods: This study is a nested case-control study performed from a multicenter prospective observational cohort of pregnant women assessed for 25-hydroxyvitamin D levels (25OHD). Three hundred ninety-three patients were included in the initial cohort. After applying exclusion criteria, a total of 1191 pregnant women were included. Two hundred fifty women with GDM (cases) were matched to 941 women without GDM (controls) for parity, age, body mass index before pregnancy, the season of conception, and phototype. This study was funded by a grant from the "Programme Hospitalier de Recherche Publique 2010".Results: The GDM risk was significantly greater for patients with 25OHD levels

International audience

International audience; Vitamin D insufficiency is highly prevalent in children and adults including pregnant women. During pregnancy, maternal vitamin D insufficiency could increase risks of several pregnancy complications and adverse birth outcomes. The FEPED study was designed to assess the effects of maternal vitamin D status in the first trimester during pregnancy on risks of preeclampsia, gestational diabetes mellitus (GDM), preterm birth and small-for-gestational age (SGA) at birth. This observational prospective cohort included 3129 women with a singleton pregnancy between April 2012 and July 2014 in six maternity units in France and Belgium. The aim of this review is to summarize the results of the FEPED study. At the first trimester the mean 25(OH)D concentration was 21.9 +/- 10.4 ng/mL and 25(OH)D concentration was = 30 ng/mL in the third trimesters (OR = 0.34; 95 % CI: 0.13-0.86. P = 0.023). In the first trimester, the risk for preeclampsia was decreased in these patients, but did not achieve statistical significance (OR = 0.57 95 % CI, 0.30-1.01; p = 0.09). For the 250 cases with GDM matched with 941 controls, no linear relationship was found between GDM and 25OHD levels in the first trimester of pregnancy. Finally, 2813 pregnant women were included in analyses of risks of preterm and SGA birth. No association was found between low maternal vitamin D levels in the first trimester and the risks of preterm birth (aOR = 1.53; 95 % CI: 0.97-2.43) or SGA (aOR = 1.07; 95 % CI: 0.75-1.54). Further investigation is needed to understand the mechanisms behind the association between vitamin D and birth outcomes

International audience; Until recently the in utero environment of pregnant women was considered sterile. Recent high-sensitivity molecular techniques and high-throughput sequencing lead to some evidence for a low-biomass microbiome associated with the healthy placenta. Other studies failed to reveal evidence for a consistent presence of bacteria using either culture or molecular based techniques. Comparing conflicting "placental microbiome" studies is complicated by the use of varied and inconsistent protocols. Given this situation, we undertook an evaluation of the in utero environment sterility using several controlled methods, in the same study, to evaluate the presence or absence of bacteria and to explain contradictions present in the literature. Healthy pregnant women (n = 38) were recruited in three maternity wards. Placenta were collected after cesarean section with or without Alexis ® and vaginal delivery births. For this study we sampled fetal membranes, umbilical cord and chorionic villi. Bacterial presence was analyzed using bacterial culture and qPCR on 34 fetal membranes, umbilical cord and chorionic villi samples. Shotgun metagenomics was performed on seven chorionic villi samples. We showed that the isolation of meaningful quantities of viable bacteria or bacterial DNA was possible only outside the placenta (fetal membranes and umbilical cords) highlighting the importance of sampling methods in studying the in utero environment. Bacterial communities described by metagenomics analysis were similar in chorionic villi samples and in negative controls and were dependent on the database chosen for the analysis. We conclude that the placenta does not harbor a specific, consistent and functional microbiota.

To investigate the possible association between maternal and paternal age and breast cancer in Greek women.This study enrolled 238 women with breast cancer and 153 healthy women as control group. All participants were examined clinically and with breast ultrasound and those older than 40 years, also with digital mammography.A statistically significant positive correlation was observed between the age of the father (x2=52.985, p0.001) and the mother (x2=34.838, p=0.001). More specifically, in breast cancer patients, the majority of their mothers (45.4%) was over 30 years of age and their fathers' age (48.3%) was over 37 years of age.Our study found that as the age of the father and mother increases, the incidence of breast cancer increases in parallel. Further studies with larger number of patients are necessary in order to clarify the real role of parental age as a risk factor of breast cancer.

Purpose to present our experience in the management of pathological nipple discharge using the procedure D.DL.DB: "ductoscopy" (D) coupled to "duct lavage" (DL) plus "duct brushing" (DB) for etiologic diagnosis. Also to compare the diagnosis obtained with D.DL.DB to the final histology. Material and method Eighty-five patients with organic unilateral nipple discharge were enrolled in two Breast Units. 82 of 85 patients were investigated successfully with D.DL.DB. Results:: The final histological results were: papilloma 46.3%, duct ectasia 36.5%, breast cancer 8.5%, precancer lesions 4.9%, and mixed benign lesions 3.8%. Pyramidectomy and radical ductectomy were performed in 76 and 6 cases respectively. In 80% of the cases, DLDB cytology results were identical to the final histology. (Kappa=0;69 CI=[0.56 -0.82]. The sensitivity of D.DL.DB versus pathology, for cancer or precancer lesions was 81.8% (CI=0.59 -1) and the specificity was 97.1% (CI=0.93 -1). Using Koch scale, the concordance between the two methods D.DL.DB and surgery was high and the sensitivity was in the upper range regarding the literature (58% to 90%). Conclusion Our experience confirms the high value of D.DL.DB in the management of organic nipple discharge.

Background Among the severe complications of preeclampsia (PE), acute kidney injury (AKI) is problematic if features of thrombotic microangiopathy (TMA) are present. Although a haemolysis enzyme liver low-platelets syndrome is considerably more frequent, it is vital to rule out a flare of atypical haemolytic and uraemic syndrome (aHUS). Our objective was to improve differential diagnosis procedures in post-partum AKI. Methods A total of 105 cases of post-partum AKI, admitted to nine different regional French intensive care units from 2011 to 2015, were analysed. Analysis included initial and final diagnosis, renal features, haemostasis and TMA parameters, with particular focus on the dynamics of each component within the first days following delivery. A classification and regression tree (CART) was used to construct a diagnostic algorithm. Results AKI was attributed to severe PE (n = 40), post-partum haemorrhage (n = 33, including 13 renal cortical necrosis) and ‘primary’ TMA (n = 14, including 10 aHUS and 4 thrombotic thrombocytopenic purpura). Congruence between initial and final diagnosis was low (63%). The dynamics of haemoglobin, haptoglobin and liver enzymes were poorly discriminant. In contrast, the dynamic pattern of platelets was statistically different between primary TMA-related AKI and other groups. CART analysis independently highlighted the usefulness of platelet trajectory in the diagnostic algorithm. Limitations of this study include that only the most severe cases were included in this retrospective study, and the circumstantial complexity is high. Conclusion Trajectory of platelet count between admission and Day 3 helps to guide therapeutic decisions in cases of TMA-associated post-partum AKI. Our study also strongly suggests that during the post-partum period, there may be a risk of transient, slowly recovering TMA in cases of severe endothelial injury in women without a genetic mutation known to induce aHUS.

AT-rich interaction domain 1A gene (ARID1A) encodes for a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, a chromatin remodeling complex, and it has been implicated in the pathogenesis of various cancer types. In this review, we discuss how ARID1A is linked to endometrial cancer and what molecular pathways are affected by mutation or inhibition of ARID1A. We also discuss the potential use of ARID1A not only as a prognostic biomarker, but also as a target for therapeutic interventions.

International audience; Objective: Severe preeclampsia may require the delivery of the placenta to avoid life-threatening complications for the mother. Before 26 weeks of gestation, this often results in perinatal death. A decrease in soluble fms-like tyrosine kinase 1 (sFlt1), an anti-angiogenic factor central to the pathophysiology of the maternal syndrome, has been reported after LDL- apheresis. The present study tested whether LDL-apheresis could be used to allow women with early and severe preeclampsia to reach a gestational age where the baby had a viable chance of survival.Study Design: A phase II prospective study. Adult women were included if they had very early (

Cell-free DNA (cfDNA) as a primary screening test has been available for years but few studies have addressed this option in a prospective manner. The question is of interest after reports that maternal serum screening (MSS) is less accurate for pregnancies resulting from assisted reproduction technologies (ART) than for spontaneous pregnancies (SP). A prospective interventional study was designed to address the performances of cfDNA compared with MSS in pregnancies with or without ART. Each patient was offered both MSS and cfDNA testing. The primary analysis cohort ultimately included 794 patients with a spontaneous pregnancy (SP) (n = 472) or pregnancy obtained after ART (n = 322). Overall, the false-positive rate and positive predictive value were 6.6% and 8.8% for MSS but 0% and 100% for cfDNA. MSS false-positive rate and positive predictive values were clearly poorer in the ART group (11.7% and 2.6%) than in the SP group (3.2% and 21.1%). The global rates of invasive procedures were 1.9% (15/794) with cfDNA but 8.4% (65/794) if MSS alone was proposed. cfDNA achieved better performance than MSS in both spontaneous and ART pregnancies, thus decreasing the number of invasive procedures. Our findings suggest that cfDNA should be considered for primary screening, especially in pregnancies obtained after ART.

International audience; Introduction The use of paclitaxel in pregnant cancer patients is feasible in terms of fetal safety, but little is known about the effects of paclitaxel on the placenta. Using three experimental models, we aimed to assess the effects of paclitaxel on the expression of placental drug transporters. Methods In the in vitro model (human primary trophoblast culture), trophoblasts were isolated from normal term placentas and subsequently exposed to paclitaxel. The transcriptional regulation of 84 genes encoding for drug transporters, and the protein expression of ABCB1/P-gp and ABCG2/BCRP were assessed. In the in vivo model, placental tissues isolated from pregnant cancer patients treated with paclitaxel were analyzed to assess the protein expression of ABCB1/P-gp and ABCG2/BCRP. The same parameters were assessed in extracts from human placental cotyledons perfused ex vivo with paclitaxel. Results In the in vitro model, the expression of twelve drug-transporters genes was found to be significantly down-regulated after exposure to paclitaxel, including ABCC10, SLC28A3, SLC29A2, and ATP7B (involved in the transport of taxanes, antimetabolites, and cisplatin, respectively). The protein expression of ABCB1/P-gp increased by 1.3-fold after paclitaxel administration. Finally, the protein expression of ABCB1/P-gp and ABCG2/BCRP was higher in cotyledons from mothers treated with multiple doses of paclitaxel during pregnancy than in cotyledons perfused with a single dose of paclitaxel. Discussion Paclitaxel modulates the expression of placental drug transporters involved in the disposition of various anticancer agents. Further studies will be needed to assess the impact of repeated or prolonged exposure to paclitaxel on the expression and function of placental drug transporters.

International audience; Preeclampsia is a serious pregnancy disorder characterized by the onset of high blood pressure and proteinuria. Although the understanding of the disease is increasing, it remains without treatment, other than the delivery of the baby and the placenta. This review sets out to discuss some new developments and strategies in the treatment of preeclampsia. We briefly review the current knowledge on the preeclamptic pathophysiology. We then examine the recent trends in preeclampsia treatment and, in particular, the tracks of potential therapeutic targets. Finally, we focus on the possibilities nanocarriers could offer in the management of preeclampsia. Indeed, nanocarriers could help to prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. Tendencies are then drawn from the available studies on the optimal characteristics of a nanocarrier to deliver drugs to the placenta.

Background: To limit risks of miscarriages associated with invasive procedures of current prenatal diagnosis practice, we aim to develop a personalized medicine-based protocol for non-invasive prenatal diagnosis (NIPD) of monogenic disorders relying on the detection of paternally inherited mutations in maternal blood using droplet digital PCR (ddPCR). Methods: This study included four couples at risk of transmitting paternal neurofibromatosis type 1 (NF1) mutations and four couples at risk of transmitting compound heterozygous CFTR mutations. NIPD was performed between 8 and 15 weeks of gestation, in parallel to conventional invasive diagnosis. We designed specific hydrolysis probes to detect the paternal mutation and to assess the presence of cell-free fetal DNA by ddPCR. Analytical performances of each assay were determined from paternal sample, an then fetal genotype was inferred from maternal plasma sample. Results: Presence or absence of the paternal mutant allele was correctly determined in all the studied plasma DNA samples. Conclusions: We report an NIPD protocol suitable for implementation in an experienced laboratory of molecular genetics. Our proof-of-principle results point out a high accuracy for early detection of paternal NF1 and CFTR mutations in cell-free DNA, and open new perspectives for extending the technology to NIPD of many other monogenic diseases.

Background Brucellosis remains a disease that is very difficult to control and eradicate in Greece. Information exchange between the responsible authorities is crucial in order to support public health infrastructure in the sense of the 'One-Health' strategy model. Methods The data for 2007-2012 were retrieved from the notifiable diseases system and analysed statistically for correlations between human brucellosis cases and the disease in small ruminants. Disease-related risk factors were also estimated with parallel exploitation mapping software. Results In Greece the dominant strain for brucellosis is Brucella melitensis. The average incidence in Greece was estimated to be 1.43/100,000. The majority of human cases were males (67.60%). The age distribution of brucellosis patients differs significantly between men and women. Brucellosis in male patients was related to high risk jobs and animal contact, while brucellosis in females was related to recent consumption of dairy products. Seasonality of the disease was different in relation to the European countries an observation attributed to the traditional customs. There was a statistically significant difference in human brucellosis incidence between the eradication and vaccination zones. Conclusion The updated information on brucellosis in Greece revealed differences in seasonality and transmission patterns. A more active cooperation between the involved public health-related sectors should be followed in order to effectively fight brucellosis as there are still foci of brucellosis in Greece.

Background CMV infections are the most frequent congenital infections worldwide. Aim Assess the cost-effectiveness of vaccination strategies of adolescent girls vs. current practice (hygiene counseling) to prevent CMV seroconversions during pregnancy in France. Method A Markov decision-tree model simulated overtime the trajectory of a single fictive cohort of 390,000 adolescent women aged 14 years old, living in France. Impact of vaccination was explored until the end of their reproductive live 40 years later. Strategies compared “S1: No vaccination” (current practice); “S2: Routine vaccination”; “S3: Screening and vaccination of the seronegative”. Model parameters Seroconversion rate without vaccination (0.035%/pregnant woman-week); fetal transmission risk (41%). Vaccine vs. no vaccination: a 50% decrease in maternal seroconversions. Outcomes Quality-Adjusted Life-Years (QALYs) of the cohort-born babies; discounted costs; Incremental Cost-Effectiveness Ratio (ICER). Results S2 was the most effective strategy (with 35,000 QALYs gained) and the most expensive (€211,533,000); S1 was the least effective and least costly (€75,423,000). ICERs of strategy S3 vs. S1, and S2 vs. S3 were 6,000€/QALY gained (95% uncertainty range [2700–13,300]) and 16,000€/QALY [negative ICER (S3 dominated by S2) – 94,000] gained, respectively; highly cost-effective because ICER Sensitivity analysis If the seroprevalence was >62% (vs. 20% in the base case), S3 would become the most efficient strategy. Conclusion In France, systematic vaccination of adolescent girls was the most efficient strategy to prevent maternal seroconversions. If the population was less than 62% immune, systematic screening and vaccination of susceptibles would become the most cost-effective approach.

BACKGROUND: Among patients with STEMI in the ATLANTIC study, pre-hospital administration of ticagrelor improved post-PCI ST-segment resolution and 30-day stent thrombosis. We investigated whether this clinical benefit with pre-hospital ticagrelor differs by ischemic duration.METHODS: In a post hoc analysis we compared absence of ST-segment resolution post-PCI and stent thrombosis at 30 days between randomized treatment groups (pre- versus in-hospital ticagrelor) stratified by symptom onset to first medical contact (FMC) duration [≤1 hour (n = 773), >1 to ≤3 hours (n = 772), and >3 hours (n = 311)], examining the interaction between randomized treatment strategy and duration of symptom onset to FMC for each outcome.RESULTS: Patients presenting later after symptom onset were older, more likely to be female, and have higher baseline risk. Patients with symptom onset to FMC >3 hours had the greatest improvement in post-PCI ST-segment elevation resolution with pre- versus in-hospital ticagrelor (absolute risk difference: ≤1 hour, 2.9% vs. >1 to ≤3 hours, 3.6% vs. >3 hours, 12.2%; adjusted p for interaction = 0.13), while patients with shorter duration of ischemia had greater improvement in stent thrombosis at 30 days with pre- versus in-hospital ticagrelor (absolute risk difference: ≤1 hour, 1.3% vs. >1 hour to ≤3 hours, 0.7% vs. >3 hours, 0.4%; adjusted p for interaction = 0.55). Symptom onset to active ticagrelor administration was independently associated with stent thrombosis at 30 days (adjusted OR 1.89 per 100 minute delay, 95%CI 1.20-2.97, P < .01), but not post-PCI ST-segment resolution (P = .41).CONCLUSIONS: The effect of pre-hospital ticagrelor to reduce stent thrombosis was most evident when given early within 3 hours after symptom onset, with delay in ticagrelor administration after symptom onset associated with higher rate of stent thrombosis. These findings re-emphasize the need for early ticagrelor administration in primary PCI treated STEMI patients.

Objective(s) Every year in France, 10% to 20% of the 600 000 women given epidural analgesia during labor experience hypotension, which in 15% of cases is associated with fetal heart rate abnormalities. The efficiency of lower limbs venous compression in preventing the occurrence of maternal hypotension after neuraxial anesthesia has already been demonstrated, but only in the context of scheduled cesarean section. We assessed the preventive effect of medical lower limbs venous compression on the incidence of maternal hypotension after epidural analgesia during spontaneous term labor. Study design This before/after, single-center study in a university hospital included 93 women in spontaneous labor at term who between 1 January and 31 March 2015 with epidural analgesia plus lower limbs compression and 202 women in spontaneous labor at term who delivered between 1 and 31 December 2014 with epidural analgesia without lower limbs compression (control group). The main outcome was maternal hypotension (systolic blood pressure 20%) in the 15 min after epidural analgesia. Results In the lower limbs compression group the incidence of hypotension 15 min after epidural analgesia was significantly lower than in the control group (3.23% versus 23.3%, adjusted odds ratio = 0.1 [0.03; 0.35]). The incidence of fetal heart rate abnormalities was unsignificantly lower in the lower limbs compression group than in the control group (10.7% versus 16.34%, p = 0.22). Conclusion The results suggest that medical lower limbs compression (20–36 mmHg) in women in spontaneous labor at term, could significantly reduce the incidence of maternal hypotension following epidural analgesia. A prospective, randomized, open trial would allow confirmation of these preliminary results.

Aspirin is currently the most widely prescribed treatment in the prevention of cardiovascular complications. The indications for the use of aspirin during pregnancy are, however, the subject of much controversy. Since the first evidence of the obstetric efficacy of aspirin in 1985, numerous studies have tried to determine the effect of low-dose aspirin on the incidence of preeclampsia, with very controversial results. Large meta-analyses including individual patient data have demonstrated that aspirin is effective in preventing preeclampsia in high-risk patients, mainly those with a history of preeclampsia. However, guidelines regarding the usage of aspirin to prevent preeclampsia differ considerably from one country to another. Screening modalities, target population, and aspirin dosage are still a matter of debate. In this review, we report the pharmacodynamics of aspirin, its main effects according to dosage and gestational age, and the evidence-based indications for primary and secondary prevention of preeclampsia.

Objective The objective of this study is to assess progress made in the ultrasound (US) measurement of femur length (FL) by students after one hour of training on US obstetric simulators. Materials and methods Medical residents and midwives registered for the 2016 French national foetal US diploma were invited to a 1-hour US training course with simulators. The time to acquire the FL plane with changing foetal presentation was prospectively measured before and after the training. Every image was recorded, and quality criteria were assessed. Results Thirty new learners trained in foetal US were evaluated. The time needed to measure the FL was significantly shorter in the post-test versus the pre-test (86s versus 125, P = 0.015). The quality criteria were statistically similar before and after training regarding the angle to horizontal (10.0° versus 9.6°, P = 0.84) and FL (31.3 mm versus 32.0 mm, P = 0.15). Conclusion The time needed to obtain the FL plane was reduced by 30% after a 1-hour US simulation training session.

The aim of this study is to assess if the presence of bilateral absent or reverse end-diastolic velocity (AREDV) indicates a poorer prognosis than unilateral AREDV in dichorionic-diamniotic twin pregnancies complicated by intrauterine growth restriction.A prospective observational study of 36 dichorionic-diamniotic twin pregnancies complicated by intrauterine growth restriction. One hundred and fifty seven ultrasound (US) examinations were performed. The pulsatility indexes (PI) of the two umbilical arteries (UA-perivesical site), the middle cerebral artery (MCA) and the ductus venosus (DV) were recorded. The fetal hemodynamic status was represented by the existence of a bilateral positive end-diastolic velocity (PEDV), a unilateral AREDV or a bilateral AREDV in the umbilical arteries.Bilateral PEDV, unilateral AREDV and bilateral AREDV represented respectively 66.0%, 10.6% and 23.4% of the US examinations. Intervals between Doppler examinations and delivery were significantly longer (P0.005) in the bilateral PEDV group (26.5 days±19.7) than in the unilateral AREDV group (11.8 days±11.7) and in the bilateral AREDV group (11.0 days±8.6). MCA-PI, DV-PI, IFI and early neonatal outcomes did not differ between the unilateral and bilateral AREDV groups.The routine measurement of the Doppler indices of the two umbilical arteries seems to be no more relevant than unilateral measurement in fetuses of dichorionic-diamniotic twin pregnancies complicated by intrauterine growth restriction.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

To investigate the possible association between ABO blood types and breast cancer in Greek women.202 female patients with breast cancer and 139 healthy women as control group were examined clinically and with breast ultrasound and those older than 40 years, also with bilateral digital mammography.In the case-group, 26.7% had blood group O, 5.5% had blood group B, 61.9% had blood group A and 5.9% had blood group AB. In the control-group, 47.5% had blood group O, 13.7% had blood group B, 31.6% had blood group A and 7.2% had blood group AB. Usage of diagrams with the percentages of frequency, the average control, Pearson, Spearman, Student's t-tests analyzed with SPSS statistical software showed a significant correlation between breast cancer and blood group A (p0.01).Although in the literature it is controversial whether ABO/Rh blood groups have association with breast cancer, the results of our study show a significant correlation between breast cancer and blood group A.

BackgroundThe observed rate of termination of pregnancy (TOP) for Turner syndrome varies worldwide and even within countries. In this vignette study we quantified agreement among ten multidisciplinary prenatal diagnosis centers in Paris.MethodsWe submitted online three cases of Turner syndrome (increased nuchal translucency, normal ultrasound, aortic coarctation) to fetal medicine experts: one obstetrician, one pediatrician and one geneticist in each of the ten Parisian centers. Each case was presented in the form of a progressive clinical history with conditional links dependent upon responses. The background to each case was provided, along with the medical history of the parents and the counseling they got from medical staff. The experts indicated online whether or not they would accept the parents’ request for TOP. We assessed the percentage of agreement for acceptance or refusal of TOP. We also used a multilevel logistic regression model to evaluate differences among obstetrician-gynecologists, pediatricians and cytogeneticists.ResultsOverall agreement among the experts to accept or refuse TOP was, respectively, 25 and 28%. The percentage of disagreement was 47%. The percentage of agreement to accept TOP was 33, 8 and 33% for obstetrician-gynecologists, pediatricians and cytogeneticists, respectively. The respective percentages of agreement to refuse TOP were 19, 47 and 26%.ConclusionOur results show the lack of consensus with regard to decisions related to termination of pregnancy for Turner Syndrome. This lack of consensus in turn underscores the importance of multidisciplinary management of these pregnancies in specialized fetal medicine centers.

Objectives: Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cord blood angiogenic factors (sFlt-1, placental growth factor [PlGF], soluble endogline [sEng], transforming growth factor beta [TGF-beta]) and their association with moderate and severe bronchopulmonary dysplasia (BPD) in very preterm growth-restricted infants.Study design: Prospective monocentric cohort study. Twenty-four mother-child dyads featuring antepartum preeclampsia, intra-uterine growth restriction (IUGR) and birth before 30 weeks' gestation were included. This ensured a 80% power to test whether sFlt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD.Main outcome measures: Four pro/anti-angiogenic factors from two pathways (sFlt-1, PlGF and sEng, TGFbeta) were measured in maternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates' cord blood. Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks' postmenstrual age.Results: sFlt-1 levels were positively correlated in maternal serum and cord blood (r(s) = 0.83, p < .001) but levels of PlGF and TGF-beta and its receptor sEng were not. Among all the factors studied in cord and maternal blood, none was associated with BPD.Conclusions: In IUGR preterm babies born before 30 weeks' gestation from preeclamptic mothers, serum sFlt-1, PlGF and sEng, TGF-beta levels were not correlated with BPD. The increased BPD risk in preterm neonates born from preeclamptic mothers cannot be related to high sFlt-1 levels.

Preeclampsia (PE) is a hypertensive disease of pregnancy associated with substantial maternal and fetal morbidity and mortality. CORIN is a transmembrane type II serine protease expressed in cardiomyocytes that converts pro-atrial natriuretic peptide into atrial natriuretic peptide, a cardiac hormone that regulates blood pressure. High levels of soluble CORIN have been reported in PE and are supposed to be cardiac in origin. We hypothesized that during pregnancy soluble CORIN is released by the syncytiotrophoblast and that increased levels of soluble CORIN in preeclampsia originate from placenta. A total of 375 patients (181 PE patients and 194 controls) were analyzed. High levels of soluble CORIN were confirmed in maternal blood from preeclamptic pregnancies compared with controls. Differentiated primary villous cytotrophoblasts showed that CORIN was expressed (mRNA and protein levels) and secreted by trophoblastic cells, mostly by the syncytiotrophoblast. Finally, placental explants showed a significant increase in CORIN production and secretion in PE cases compared with controls. This study showed that CORIN is secreted by trophoblastic cells and that high levels of soluble CORIN in preeclampsia have a placental origin.