Research question: What part do maternal context and medically assisted reproduction (MAR) techniques play in the risk of fetal growth disorders? Design: This retrospective nationwide cohort study uses data available in the French National Health System database and focuses on the period from 2013 to 2017. Fetal growth disorders were divided into four groups according to the origin of pregnancy: fresh embryo transfer (n = 45,201), frozen embryo transfer (FET, n = 18,845), intrauterine insemination (IUI, n = 20,179) and natural conceptions (n = 3,412,868). Fetal growth disorders were defined from the percentiles of the weight distribution according to gestational age and sex: small and large for gestational age (SGA and LGA) if <10th and >90th percentiles, respectively. Analyses were performed using univariate and multivariate logistic models. Results: Compared with births following natural conception, multivariate analysis showed that the risk of SGA was higher for births following fresh embryo transfer and IUI (adjusted odds ratio [aOR] 1.26 [1.22-1.29] and 1.08 [1.03-1.12], respectively) and

BackgroundRisks of maternal morbidity are known to be reduced in pregnancies resulting from frozen embryo transfer (FET) compared to fresh-embryo transfer (fresh-ET), except for the risk of pre-eclampsia, reported to be higher in FET pregnancies compared to fresh-ET or natural conception. Few studies have compared the risk of maternal vascular morbidities according to endometrial preparation for FET, either with ovulatory cycle (OC-FET) or artificial cycle (AC-FET). Furthermore, maternal pre-eclampsia could be associated with subsequent vascular disorders in the offspring.MethodsA 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies was conducted: FET with either OC or AC preparation, and fresh-ET. Data were extracted from the French National Health System database. Results were adjusted for maternal characteristics and infertility (age, parity, smoking, obesity, history of diabetes or hypertension, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency).ResultsA total of 68025 single deliveries were included: fresh-ET (n=48152), OC-FET (n=9500), AC-FET (n=10373). The risk of pre-eclampsia was higher in AC-FET compared to OC-FET and fresh-ET groups in univariate analysis (5.3% vs. 2.3% and 2.4%, respectively, P<0.0001). In multivariate analysis the risk was significantly higher in AC-FET compared to fresh-ET: aOR=2.43 [2.18-2.70], P<0.0001). Similar results were observed for the risk of other vascular disorders in univariate analysis (4.7% vs. 3.4% and 3.3%, respectively, P=0.0002) and in multivariate analysis (AC-FET compared to fresh-ET: aOR=1.50 [1.36-1.67], P<0.0001). In multivariate analysis, the risk of pre-eclampsia and other vascular disorders were comparable in OC-FET and fresh-ET: aOR=1.01 [0.87-1.17, P= 0.91 and aOR=1.00 [0.89-1.13], P=0.97, respectively).Within the group of FET, the risks of pre-eclampsia and other vascular disorders in multivariate analysis were higher in AC-FET compared to OC-FET (aOR=2.43 [2.18-2.70], P<0.0001 and aOR=1.5 [1.36-1.67], P<0.0001, respectively).ConclusionThis nationwide register-based cohort study highlights the possibly deleterious role of prolonged doses of exogenous estrogen-progesterone supplementation on gestational vascular pathologies and the protective role of the corpus luteum present in OC-FET for their prevention. Since OC-FET has been demonstrated not to strain the chances of pregnancy, OC preparation should be advocated as first-line preparation in FET as often as possible in ovulatory women.

Research question: What are the risk factors for prematurity other than intrauterine growth restriction in singletons after IVF?Design: Data were collected from a national registry, based on an observational prospective cohort of 30,737 live births after assisted reproductive technology (fresh embryo transfers: n = 20,932 and frozen embryo transfer [FET] n = 9805) between 2014 and 2015. A population of not-small for gestational age singletons conceived after fresh embryo transfers and FET, and their parents, was selected. Data on a number of variables were collected, including type of infertility, number of oocytes retrieved and vanishing twins.Results: Preterm birth occurred in 7.7% (n = 1607) of fresh embryo transfers and 6.2% (n = 611) of frozen-thawed embryo transfers (P < 0.0001; adjusted odds ratio [aOR] =1.34 [1.21-1.49]). Endometriosis and vanishing twin increased the risk of preterm birth after fresh embryo transfer (P < 0.001; aOR 1.32 and 1.78, respectively). Polycystic ovaries or more than 20 oocytes retrieved also increased preterm birth risk (aOR 1.31 and 1.30; P = 0.003 and P = 0.02, respectively); large oocyte cohort (>20) was no longer associated with the risk of prematurity in FET.Conclusion: Endometriosis remains a risk for prematurity even in the absence of intrauterine growth retardation, which suggests a dysimmune effect. Large oocyte cohorts obtained by stimulation, without clinical polycystic ovary syndrome diagnosed before attempts, do not affect FET outcomes, reinforcing the idea of a phenotypic difference in the clinical presentation of polycystic ovary syndrome.

Background To the best of our knowledge, no study has exhaustively evaluated the association between maternal morbidities and Coronavirus Disease 2019 (COVID-19) during the first wave of the pandemic in pregnant women. We investigated, in natural conceptions and assisted reproductive technique (ART) pregnancies, whether maternal morbidities were more frequent in pregnant women with COVID-19 diagnosis compared to pregnant women without COVID-19 diagnosis during the first wave of the COVID-19 pandemic. Methods and findings We conducted a retrospective analysis of prospectively collected data in a national cohort of all hospitalizations for births ≥22 weeks of gestation in France from January to June 2020 using the French national hospitalization database (PMSI). Pregnant women with COVID-19 were identified if they had been recorded in the database using the ICD-10 (International Classification of Disease) code for presence of a hospitalization for COVID-19. A total of 244,645 births were included, of which 874 (0.36%) in the COVID-19 group. Maternal morbidities and adverse obstetrical outcomes among those with or without COVID-19 were analyzed with a multivariable logistic regression model adjusted on patient characteristics. Among pregnant women, older age (31.1 (±5.9) years old versus 30.5 (±5.4) years old, respectively, p < 0.001), obesity (0.7% versus 0.3%, respectively, p < 0.001), multiple pregnancy (0.7% versus 0.4%, respectively, p < 0.001), and history of hypertension (0.9% versus 0.3%, respectively, p < 0.001) were more frequent with COVID-19 diagnosis. Active smoking (0.2% versus 0.4%, respectively, p < 0.001) and primiparity (0.3% versus 0.4%, respectively, p < 0.03) were less frequent with COVID-19 diagnosis. Frequency of ART conception was not different between those with and without COVID-19 diagnosis (p = 0.28). When compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to ICU (5.9% versus 0.1%, p < 0.001), mortality (0.2% versus 0.005%, p < 0.001), preeclampsia/eclampsia (4.8% versus 2.2%, p < 0.001), gestational hypertension (2.3% versus 1.3%, p < 0.03), postpartum hemorrhage (10.0% versus 5.7%, p < 0.001), preterm birth at <37 weeks of gestation (16.7% versus 7.1%, p < 0.001), <32 weeks of gestation (2.2% versus 0.8%, p < 0.001), <28 weeks of gestation (2.4% versus 0.8%, p < 0.001), induced preterm birth (5.4% versus 1.4%, p < 0.001), spontaneous preterm birth (11.3% versus 5.7%, p < 0.001), fetal distress (33.0% versus 26.0%, p < 0.001), and cesarean section (33.0% versus 20.2%, p < 0.001). Rates of pregnancy terminations ≥22 weeks of gestation, stillbirths, gestational diabetes, placenta praevia, and placenta abruption were not significantly different between the COVID-19 and non-COVID-19 groups. The number of venous thromboembolic events was too low to perform statistical analysis. A limitation of this study relies in the possibility that asymptomatic infected women were not systematically detected. Conclusions We observed an increased frequency of pregnant women with maternal morbidities and diagnosis of COVID-19 compared to pregnant women without COVID-19. It appears essential to be aware of this, notably in populations at known risk of developing a more severe form of infection or obstetrical morbidities and in order for obstetrical units to better inform pregnant women and provide the best care. Although causality cannot be determined from these associations, these results may be in line with recent recommendations in favor of vaccination for pregnant women.

Research question: Does endometriosis increase obstetric and neonatal complications, and does assisted reproductive technology (ART) cause additional risk of maternal or fetal morbidity? Design: A nationwide cohort study (2013-2018) comparing maternal and perinatal morbidities in three groups of single pregnancies: spontaneous pregnancies without endometriosis; spontaneous pregnancies with endometriosis; and ART pregnancies in women with endometriosis. Results: Mean maternal ages were 30.0 (SD = 5.3), 31.7 (SD = 4.8) and 33.1 years (SD = 4.0), for spontaneous conceptions, spontaneous conceptions with endometriosis and ART pregnancies with endometriosis groups, respectively (P < 0.0001). Comparison of spontaneous conceptions with endometriosis and spontaneous conceptions: endometriosis independently increased the risk of venous thrombosis (adjusted OR [aOR] 1.51, P < 0.001), pre-eclampsia (aOR 1.29, P < 0.001), placenta previa (aOR 2.62, P < 0.001), placental abruption (aOR 1.54, P < 0.001), premature birth (aOR 1.37, P < 0.001), small for gestational age (aOR 1.05, P < 0.001) and malformations (aOR 1.06, P = 0.049). Comparison of ART pregnancies with endometriosis and spontaneous conceptions with endometriosis: ART increased the risk of placenta previa (aOR 2.43, 95% CI 2.10 to 2.82, P < 0.001), premature birth (aOR 1.42, 95% CI 1.29 to 1.55, P < 0.001) and small for gestational age (aOR 1.18, 95% CI 1.10 to 1.27, P < 0.001), independently from the effect of endometriosis. Risk of pre-eclampsia, placental abruption or congenital malformations was not increased with ART. Conclusion: Endometriosis is an independent risk factor for mother and child morbidities. Maternal morbidity and perinatal morbidity were significantly increased by ART in addition to endometriosis; however, some perinatal and maternal morbidity risks were increasingly linked to pathologies related to infertility.

STUDY QUESTION:Do IVF, IUI or female infertility (i.e. endometriosis, polycystic ovary syndrome [PCOS] and primary ovarian insufficiency [POI]) lead to an increased risk of congenital anomalies in singletons?SUMMARY ANSWER:After multivariable adjustments, the increased risks of congenital defects associated with IUI were no longer significant, but the underlying maternal infertility presented a potential emental risk, in addition to the risk associated with IVF.WHAT IS KNOWN ALREADY:Most epidemiological studies suggest that singletons born from ART have a higher risk of birth defects, specifically musculoskeletal, cardiovascular and urogenital disorders. However, most of these studies were established on data obtained at birth or in the neonatal period and from relatively small populations or several registries. Moreover, to our knowledge, female infertility, which is a potential confounder, has never been included in the risk assessment.STUDY DESIGN, SIZE, DURATION:Using data from the French National Health System database, we conducted a comparative analysis of all singleton births (deliveries ≥22 weeks of gestation and/or >500 g of birthweight) in France over a 5-year period (2013-2017) resulting from fresh embryo or frozen embryo transfer (fresh-ET or FET from IVF/ICSI cycles), IUI and natural conception (NC). Data were available for this cohort of children at least up to early childhood (2.5 years old).PARTICIPANTS/MATERIALS, SETTING, METHODS:A total of 3 501 495 singleton births were included (3 417 089 from NC, 20 218 from IUI, 45 303 from fresh-ET and 18 885 from FET). Data were extracted from national health databases and used to identify major birth defects. Malformations were classified according to the 10th revision of the International Classification of Disease. To analyse the effect of mode of conception, multivariable analyses were performed with multiple logistic regression models adjusted for maternal age, primiparity, obesity, smoking, history of high blood pressure or diabetes and female infertility.MAIN RESULTS AND THE ROLE OF CHANCE:In our cohort of children, the overall prevalence of congenital malformations was 3.78% after NC, 4.53% after fresh-ET, 4.39% after FET and 3.91% after IUI (132 646 children with major malformations). Compared with infants conceived naturally, children born after fresh-ET and after FET had a significantly higher prevalence of malformations, with an adjusted odds ratio (aOR) of 1.15 [95% CI 1.10-1.20, P < 0.0001] and aOR of 1.13 [95% CI 1.05-1.21, P = 0.001], respectively. Among the 15 relevant subgroups of malformations studied, we observed a significantly increased risk of eight malformations in the fresh-ET group compared with the NC group (i.e. musculoskeletal, cardiac, urinary, digestive, neurological, cleft lip and/or palate and respiratory). In the FET group, this increased risk was observed for digestive and facial malformations. The overall risk of congenital malformations, and the risk by subtype, was similar in the IUI group and the NC group (overall risk: aOR of 1.01 [95% CI 0.94-1.08, P = 0.81]). In addition, there was an overall independent increase in the risk of congenital defects when the mothers were diagnosed with endometriosis (1.16 aOR [95% CI 1.10-1.22], P < 0.0001), PCOS (1.20 aOR [95% CI 1.08-1.34], P = 0.001) or POI (1.52 aOR [95% CI 1.23-1.88], P = 0.0001). Chromosomal, cardiac and neurological anomalies were more common in the three maternal infertility groups.LIMITATIONS, REASONS FOR CAUTION:Male infertility, the in vitro fertilization method (i.e. in vitro fertilization without or with sperm injection: conventional IVF vs ICSI) and embryo stage at transfer could not be taken into account. Furthermore, residual confounding cannot be excluded as well as uncertainties regarding the diagnostic criteria used for the three female infertilities. Findings for specific malformations should be interpreted with caution because the number of cases was small in some sub-groups (potentially due to the Type I error or multiple testing).WIDER IMPLICATIONS OF THE FINDINGS:In this large study, after multivariable maternal adjustments, a moderately increased risk of defects subsisted after IVF, while those associated with IUI were no longer significant. In addition, our results showed that underlying maternal infertility could contribute to the increased risk of defects associated with IVF. These novel findings highlight the importance of taking into account the ART treatment methods and the type of infertility.STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the National Agency of Biomedicine. The authors have no competing interests to disclose.TRIAL REGISTRATION NUMBER:NA.

Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility. From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013–2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed. Compared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13–1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43–2.70], p < 0.001). There was an overall independent increase in risk of imprinting diseases for children with mothers diagnosed with endometriosis (1.38 aOR [95% CI 1.06–1.80], p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk. This prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).

The objective of this large cohort study is to identify by univariate and multivariate analysis whether there is an excess of maternal morbidity (MM) in ongoing pregnancies and deliveries after IVF and fresh transfer techniques, when compared to spontaneous conceptions (SC). This is an observational, exposed-unexposed cohort study comparing pregnancies, deliveries and births following IVF, standard or using Intra Cytoplasmic injection (ICSI), and fresh transfers to non-IVF controls. The study included all 2,832,578 national deliveries registered between 2013 and 2016 in France, among which 1.5% (43,084) resulted from IVF and immediate fresh transfer. Pregnancies and deliveries were analyzed by extracting the Information Systems Medicalization Program (PMSI) French database. The main identified maternal morbidity indicators for the 43084 IVF and 2 789 494 non-IVF pregnancies were: venous and arterial thrombosis (VT, AT), gestational diabetes mellitus (GDM), pre-eclampsia (PE), Placenta Previa (PP), placenta abruption (PA) hemorrhage at delivery (HD). The risks of MM in IVF were estimated in multivariate analysis after adjustment for maternal age, smoking and obesity, and multiple deliveries. The mean maternal age was 33.2 and 29.9 years in the IVF and control groups (p <0.0001). The rate of multiple deliveries was 1.68%, of which 13% if IVF conception. Diabetes and hypertensive disorders during pregnancy were more common in the IVF vs non-IVF group: 1.01% vs 0.9% (p = 0.01) and 1.04% vs 0.9% (p <0.001). Tobacco dependence and obesity were less common in the IVF vs non-IVF group (2.2% vs 4.5%, and 3.9% vs 4.3%, p <0.001). The frequency of premature deliveries was higher in IVF vs non-IVF: 19.3% vs 6.9% (p <0.0001), persistent for single births (9.0% vs 5.7%, p <0.001). The risk of MM (VT, GDM, PE, PP, PA, HD) was higher in IVF vs non-IVF (20.9% vs 14.3%, p <0.0001), even if single pregnancies (19.6% vs 14.1%, p <0.0001) except arterial thrombosis. The risk of MM increased significantly with age for all events except for PE. In multivariate analysis, IVF is a significant risk factor for all MM events except arterial thrombosis. The adjusted risk of the occurrence of at least one concern after IVF is 1.29 [1.26-1.32] at all and 1.32 [1.28-1.35] in single deliveries. This risk is stable over the four years. Large observational studies identified that IVF pregnancies are associated with a significant risk of complications, initially attributed to multiple pregnancies, as compared with pregnancies after SC. The strength of this large national exposed-unexposed cohort study lies in the number and completeness of subjects studied. Our data provide in turn evidence for increased adjusted risk of premature delivery and maternal morbidity (VT, GDM, PE, PP, PA, and HD) after IVF, including in single pregnancies. The knowledge of the excess risk is an essential tool for informing without worrying couples candidate for IVF, and analyzing neonatal health of IVF-children. Future developments should allow to refine the knowledge of more or less at-risk subgroups.

The purpose of this study is to establish whether babies born after In Vitro Fertilization (IVF) and fresh transfer are at higher risk of low birthweight (LBW) for gestational age (SGA). This is an observational, exposed-unexposed national cohort study comparing pregnancies, births and neonatal data, focused on birth weight by gestational age, in births following IVF standard or using Intra Cytoplasmic injection (ICSI) and fresh transfers versus (vs) non-IVF controls data. The study included all 2,922,718 births from 2,832,578 deliveries registered between 2013 and 2016 in France, among which 1.7% (49,224) from IVF conception and immediate fresh transfer. Neonate's data from births 2013-2016 in France were analyzed by extracting the Information Systems Medicalization Program (PMSI) French database. Premature birth < 37 gestational weeks (WG), SGA and malformations were the main neonatal data investigated for the 49,224 IVF and 2,873,474 non-IVF neonates. SGA is defined as birth weight less than the 10th percentile of gestational age (GA), its frequency related to maternal characteristics, fetal sex, and single / multiple births. Mean maternal age was 33.2 +/- 4.3 and 29.9 +/- 5.3 years in the IVF and non-IVF groups (p <0.0001). The frequency of multiple deliveries was 1.68% (48,425), including 13% from IVF. The frequency of premature deliveries was higher in IVF vs non-IVF group, 19.3% vs 6.9% (p <0.0001), as it was for single deliveries (9.0% vs 5.7%, p <0.001). The SGA rate was increased in IVF compared to non-IVF group, in all neonates, 21.6% vs 12.1%, (p <0.0001); in singletons, 14.9% vs 11.4% (OR = 1.37 [1.33-1.14], p <0.001), as in born >37 WG singletons, 13.6% vs 10.6% (OR = 1.33 [1.29-1.38], p <0.001). Univariate analysis indicated that the risk was identical according to sex, higher in multiple births (OR = 4.8) and premature births (OR = 2.9), if maternal smoking (OR = 2.2), and other maternal morbidity (MM) events except diabetes, and congenital malformation (OR = 1.7). In multivariate analysis, the added risk of SGA in IVF group was 2.1 [2.07-2.016] after adjustment for age, smoking, maternal obesity; 1.37 [1.34-1.40] if adjusted in addition to multiple births; 1.34 [1.30-1.37] if adjusted in addition to MM; 1.33 [1.30-1.36] if further adjusted for prematurity. Large observational studies identified that IVF pregnancies are associated with a significant risk of concerns for babies. SGA babies are known to be at increased risks of perinatal morbidity and mortality. The results of this large cohort, whose strength is the completeness of IVF and controls neonates data, provide evidence that the proportion of SGA birth post-IVF, including singletons, is increased compared to general population in multivariate analysis, after adjustment for age, smoking, maternal obesity, multiple births, maternal morbidity and prematurity. This is important to inform without worrying candidates for IVF, and understand possible concerns in IVF-children development. Further studies should allow to define more or less at-risk subgroups.

Background. In France, the need for continuous monitoring of transplant center performance has recently become apparent. Cumulative sum (CUSUM) monitoring of transplantation is already been used to monitor transplant outcomes in the United Kingdom and in the United States. Because CUSUM monitoring can be applied by different methods, the objective was to assess and compare the performance of different CUSUM methods for detecting higher than expected (ie, excessive) graft failure rates. Methods. Data come from the French transplant registry. Lung and kidney transplants in 2011-2013 constituted the control cohort, and those in 2014-2016 the observed cohort. The performance of CUSUM monitoring, according to center type and predefined control limits, was measured by simulation. The outcome monitored was 3-month graft failure. Results. In a low-volume center with a low failure rate, 3 different types of control limits produced successful detection rates of excessive graft failures of 15%, 62%, and 73% and false alarm rates of 5%, 40%, and 52%, with 3, 1, and 1 excess failures necessary before a signal occurred. In a high-volume center with a high failure rate, successful detection rates were 83%, 93%, and 100% and false alarm rates were 5%, 16%, and 69%, with 6, 13, and 17 excess failures necessary before a signal occurred. Conclusions. CUSUM performances vary greatly depending on the type of control limit used. A new control limit set to maximize specificity and sensitivity of detection is an appropriate alternative to those commonly used. Continued attention is necessary for centers with characteristics making it difficult to obtain adequate sensitivity or sufficiently prompt response.

Le but de cette étude est d'évaluer le parcours prénatal des femmes qui ont donné naissance à un enfant atteint de trisomie 21 afin de connaître la part des grossesses non classées parmi le groupe à risque élevé lors du dépistage par les différentes stratégies utilisant les marqueurs sériques maternels (MSM) (avec ou sans mesure de la clarté nucale) et celle des femmes qui ne souhaitaient pas de dépistage ou de diagnostic prénatal de la trisomie 21. Le dépistage de la trisomie 21 est en effet un choix personnel de chaque femme enceinte (de chaque couple). Cette étude couvre la période de mise en place et de montée en charge du dépistage combiné au 1er trimestre et permet d'obtenir aussi une comparaison d'efficacité entre les différents dépistages par les marqueurs sériques maternels. Une enquête a été réalisée auprès de tous les laboratoires de cytogénétique français pour documenter le parcours prénatal des mères vis-à-vis du dépistage de la trisomie 21 pour tous les enfants âgés de moins de un an, nés en France, avec un diagnostic postnatal de trisomie 21 entre janvier 2010 et juillet 2013. Cette étude a permis le recueil de 1253 cas de diagnostics de trisomie 21 réalisés dans l'année qui suivait leur naissance chez des enfants dont les mères n'avaient pas eu de diagnostic prénatal quelle qu'en soit la raison (y compris le refus de la mère d'avoir recours à un prélèvement invasif). Parmi les 861 femmes avec un dépistage prénatal renseigné, 72 % avaient eu recours à un dépistage de la trisomie 21 par les marqueurs sériques et/ou l'échographie fœtale, avec pour 28 % d'entre elles un résultat de dépistage par marqueurs sériques maternels (MSM) positif (score ≥ 1/250), pour 5 % des signes d'appels échographiques et pour 67 % un dépistage par MSM négatif (toute stratégie confondue). Le taux de détection sur l'ensemble de la période était de 82 %. Une analyse par type de dépistage montre que les taux de détection de la trisomie 21 avec les tests combinés du 1er trimestre et des tests avec MSM du 2e trimestre sont très proches (83 %), mais significativement inférieurs avec les tests séquentiels combinant les marqueurs sériques du 2e trimestre avec la mesure de la clarté nucale au 1er trimestre (70 %). Les objectifs de santé publique visant à réduire le nombre de prélèvements invasifs sans altérer les performances globales du dépistage ont été atteints. L'analyse fine du dépistage par l'étude des différents parcours obstétricaux des femmes qui ont donné naissance à un enfant atteint permet d'obtenir des informations qui seront utiles pour bâtir la stratégie d'introduction du dépistage par l'analyse de l'ADN fœtal circulant dans le sang maternel. The main objective of this study was to screen the prenatal follow-up of women with live birth trisomy 21 child in order to evaluate the proportion of prenatal screening failure versus cases where the women refused either the screening or the prenatal diagnosis of Down syndrome. This study covers the period of time from 2009 to 2012 when the national prenatal screening policy changed from second to first trimester and allows for a comparative assessment of the nationwide efficiency of the various maternal serum marker based strategies. All authorized cytogenetic laboratories sent required data for all cases of trisomy 21 diagnosed in FRANCE in new-borns (less than 1-year-old) from January 2010 to July 2013. A total of 1253 cases of trisomy 21 were diagnosed before 1 year of age whose mother did not had prenatal diagnosis. For 861 of them, information on the prenatal follow-up was available, with 72% of cases where a prenatal screening was organized either by maternal serum marker or by ultrasound. Results of the screening strategy was positive with maternal serum marker in 28% of cases (calculated risk ≥ 1/250), positive because of abnormal ultrasound in 5% and negative with maternal marker screening (whatever the strategy used) in 67% of cases. Detection rate over the period of the study was 82%, with similar efficiency of first and second trimester strategies (83%) but significantly lower with sequential association of first trimester Nuchal translucency measurement and second trimester serum screening (70%). Switching from second trimester to first trimester screening strategy, with as many trisomy 21 foetuses diagnosed with half invasive procedures fulfilled national health policy objectives. Analysis of these data gives useful insights to elaborate a future screening policy involving cell-free foetal DNA sequencing.

Une analyse rétrospective de l’accès à la greffe rénale des malades selon leur nationalité ou leur lieu de résidence outre-mer, portant sur la période 2004–2008, a été menée dans la continuité d’une évaluation précédemment réalisée en 2006. Parmi les 14 732 patients inscrits en liste d’attente pendant cette période, 15,3 % sont de nationalité étrangère (3,4 % européenne, 5,9 % d’Afrique du Nord, 3,9 % d’Afrique subsaharienne et 2,9 % autres). Parmi les patients de nationalité française, 3,3 % sont domiciliés dans les départements d’outre-mer. Les malades inscrits en liste d’attente de greffe rénale et non originaires de la France métropolitaine présentent toujours des difficultés d’accès à la greffe, marquées par des durées d’attente prolongées, et ce, malgré l’amélioration constante des règles de répartition des greffons. Par comparaison à la médiane d’attente globale de cette cohorte de 17,6 mois, la médiane d’attente diffère de façon significative entre les différents groupes, allant de 15,7 mois pour les patients français à 36 mois pour les patients d’Afrique subsaharienne. Ces inégalités ne sont que partiellement expliquées par les difficultés d’appariement immunologique liées au groupe sanguin ABO ou à la difficulté d’appariement HLA. Il conviendrait dans l’avenir d’orienter la recherche vers d’autres facteurs explicatifs non médicaux et une approche sur les conditions socioéconomiques et l’accès au système de soins de ces patients.

BACKGROUND & AIMS:The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC).METHODS:Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively.RESULTS:α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria.CONCLUSIONS:Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

In France, foreign patients, whether resident or not in France, can register on the national waiting list under administrative and financial conditions. We performed a retrospective analysis to evaluate the access to kidney transplantation on a cohort 2004-2008, using the national registry. Among the 14,732 patients registered during this period, 15.3% are of non-French nationality (3.4% other European, 5.9% North African, 3.9% sub-Saharan African, 2.9% other). Among the 84.6% of French nationality, 3.3% are living in French overseas territories. Compared to the 17.6-month median waiting time of the cohort, median waiting time differs significantly between groups, from 15.7 months for mainland French patients to 36 months for sub-Saharan African patients. Despite the regular development of the allocation rules, these disparities in access to transplantation are mainly, but not completely, explained by blood group or HLA matching difficulties. After adjustment for the other factors known to be significantly linked to a difficult access to transplantation, North and sub-Saharan African patients have the worst difficulties. Future research should consider nonmedical factors, such as socio-economic or socio-cultural factors, potentially relevant to avoid disparities in access to transplantation and should aim at developing specific interventions.

En France, l’amélioration de l’accès à la greffe passe en premier par une augmentation du prélèvement des donneurs d’organes hospitalisés dans les services d’urgence et de réanimation. En effet, dans ces services, le profil des donneurs a évolué au cours des dix dernières années vers des sujets de plus en plus âgés et vers des critères de prélèvement étendus (antécédents d’hypertension, de diabète) loin de l’image du donneur « idéal ». La méthode Cristal action proposée par l’Agence de la biomédecine, s’appuyant sur des recommandations européennes, permet d’analyser en continu la situation du prélèvement dans chaque hôpital. Un recueil des grandes étapes de la prise en charge des patients décédés est réalisé par les coordinations hospitalières de prélèvement, dans le but de connaître les motifs éventuels de non-prélèvement. Un retour d’information est présenté aux équipes des services d’urgence et de réanimation, dans l’objectif de valoriser leur travail et de proposer des actions correctrices et des formations. Le but est d’arriver à mettre en place ou consolider entre médecins urgentistes, médecins réanimateurs et coordination hospitalière un dialogue et des procédures communes. La méthode propose également la possibilité de réaliser des enquêtes sur les connaissances, les attitudes et les pratiques de tous les personnels concernés. L’ensemble s’intègre parfaitement dans une démarche d’amélioration de la qualité et d’évaluation des pratiques professionnelles. À terme, il sera possible de croiser les données de Cristal action avec les informations globales du système de santé pour mieux analyser l’activité de prélèvement.

antiviral strategies.The tight junction protein claudin-1 (CLDN1) has been shown to be essential for HCV entry.Using genetic immunization, we produced six monoclonal antibodies efficiently inhibiting HCV infection by targeting host entry factor CLDN1.Monoclonal anti-CLDN1 antibodies bound to human CLDN1 on the cell surface of primary human hepatocytes and Huh7.5.1 with high affinity.Competition and binding studies demonstrated that antibodies target conformational epitopes of the first extracellular loop.Using an infectious HCV cell culture system we demonstrate that monoclonal anti-CLDN1 antibodies efficiently inhibit HCV Jc1-Luc and Con1-Luc infection of Huh7.5.1 cells in a dose-dependent manner.Anti-CLDN1 antibodies efficiently cross-neutralize infection of primary human hepatocytes by HCV pseudotypes (HCVpp) derived from genotypes 1-6.In patients with chronic HCV infection, anti-CLDN1 antibodies broadly crossinhibit entry of HCVpp bearing envelope glycoproteins of the viral quasispecies population.Furthermore, anti-CLDN1 antibodies markedly inhibit entry of HCV escape variants isolated from six patients undergoing liver transplantation which were resistant to autologous host responses.In conclusion, these results suggest that targeting HCV entry factor CLDN1 using monoclonal anti-CLDN1 antibodies constitutes a novel antiviral approach to prevent primary HCV infection, such as after liver transplantation and might also restrain virus spread in chronically infected patients.I.F and S.K. contributed equally to this work.