Publications by authors named "Vassilis Tsatsaris"

120 Publications

Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study.

Am J Obstet Gynecol 2021 May 29. Epub 2021 May 29.

Department of Obstetrics and Gynaecology, Antoine Béclère Hospital, AP-HP, Paris Saclay University, Clamart, France.

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
Results: Of 682 referred fetuses diagnosed with isolated fetal growth restriction, both karyotype and chromosomal microarray analysis were performed in 146 fetuses. Overall, the detection rate of genetic anomalies found by chromosomal microarray analysis was estimated to be 7.5% (11 of 146 [95% confidence interval, 3.3-11.8]), including 10 copy number variants classified as pathogenic and 1 copy number variant classified as likely pathogenic. Among the 139 fetuses with normal karyotype, 5 were detected with pathogenic and likely pathogenic copy number variants, resulting in an incremental yield of 3.6% (95% confidence interval, 0.5-6.6) in chromosomal microarray analysis compared with karyotype. All fetuses detected with pathogenic or likely pathogenic copy number variants resulted in terminations of pregnancy. In addition, 3 fetuses with normal karyotype were detected with a variant of unknown significance (2.1%). Among the 7 fetuses with abnormal karyotype, chromosomal microarray analysis did not detect trisomy 18 mosaicism in all fetuses.

Conclusion: Our study found that compared with karyotype, chromosomal microarray analysis improves the detection of genetic anomalies in fetuses diagnosed with isolated fetal growth restriction. These results support the use of chromosomal microarray analysis in addition to karyotype for isolated fetal growth restriction.
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http://dx.doi.org/10.1016/j.ajog.2021.05.035DOI Listing
May 2021

Prevalence of hypertensive disorders during pregnancy in France (2010-2018): The nationwide CONCEPTION study.

J Clin Hypertens (Greenwich) 2021 May 27. Epub 2021 May 27.

Paris-Descartes University, Paris, France.

Hypertensive disorders of pregnancy (HDP) are one of the leading causes of maternal and fetal morbidity and mortality. We aimed to estimate the prevalence of each HDP in France and to study their associations. All pregnant women who delivered in France between 2010 and 2018 were included in a cohort and followed during their pregnancy and 6 weeks of postpartum. Each HDP occurring during the follow-up was identified. Prevalence of each HDP and cumulative incidence by gestational age were estimated. Incidence rate ratio (IRR) and 95% confidence interval (CI) for preeclampsia among women with preexisting or gestational hypertension (GH) were estimated using Poisson regression and adjusted for age were estimated. Between 2010 and 2018, 6 302 810 deliveries were included. HDP complicated 7.4% of pregnancies. Preeclampsia and GH complicated 2.0% and 4.2% of pregnancies, respectively. Most of preeclampsia cases occurred without a prior HDP. HELLP syndrome represented 10.4% of preeclampsia cases. Compared to nulliparous pregnancies without HDP prior preeclampsia, the age-adjusted IRR of preeclampsia was 6.2 [95% CI: 6.1-6.4] in nulliparous pregnancies with preexisting hypertension and 2.9 [95% CI: 2.8-3.0] in nulliparous pregnancies with GH. In France, HDP occurred in 7.4% of all pregnancies. Women with preexisting chronic hypertension are at high risk to present preeclampsia during pregnancy. Preeclampsia complicated 2.0% of pregnancies in France. Tailoring management of women according to the HDP is a major challenge to avoid complications related to these disorders.
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http://dx.doi.org/10.1111/jch.14254DOI Listing
May 2021

Evaluation of the severe preeclampsia classification criterion for antiphospholipid syndrome in a study of 40 patients.

Arthritis Res Ther 2021 05 4;23(1):134. Epub 2021 May 4.

AP-HP, Cochin Hospital, Internal Medicine Department, Centre de référence maladies auto-immunes et systémiques rares d'Ile de France, Paris, France.

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.
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http://dx.doi.org/10.1186/s13075-021-02518-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094564PMC
May 2021

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.

Genet Med 2021 May 3. Epub 2021 May 3.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.

Methods: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.

Results: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2's folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants.

Conclusion: NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch-Steindl syndrome after the delineators of this phenotype.
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http://dx.doi.org/10.1038/s41436-021-01158-1DOI Listing
May 2021

Cancer during pregnancy: Factors associated with termination of pregnancy and perinatal outcomes.

Eur J Obstet Gynecol Reprod Biol 2021 Jun 21;261:110-115. Epub 2021 Apr 21.

Maternité Port-Royal, AP-HP, Hôpital Cochin, FHU PREMA, F-75014, Paris, France; Curie Institute, Department of Medical Oncology, 26 rue d'Ulm, 75248, Paris Cedex 05, France; Université de Paris, INSERM UMR -S 1139, Physiopathologie et pharmacotoxicologie placentaire humaine, F-75006, Paris, France.

Background: Cancer during pregnancy is rare (about 1/1000 pregnancies) and its diagnosis raises the question of whether or not to continue the pregnancy.

Objectives: 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.

Study Design: 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.

Results: 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, p < 0.01). 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 %) (p < 0.01). 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 %).

Conclusion: 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.
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http://dx.doi.org/10.1016/j.ejogrb.2021.04.020DOI Listing
June 2021

Safety of Omalizumab During Pregnancy and Breast-Feeding With Assessment of Placental Transfer: A Case Report.

Allergy Asthma Immunol Res 2021 May;13(3):515-516

Centre Régional de Pharmacovigilance, Service de Pharmacologie, Hôpital Cochin, AP-HP. Centre - Université de Paris, Paris, France.

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http://dx.doi.org/10.4168/aair.2021.13.3.515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984957PMC
May 2021

Placenta Accreta Spectrum: A Continuously Evolving Challenge for Radiologists.

Can Assoc Radiol J 2020 Dec 29:846537120984124. Epub 2020 Dec 29.

Department of Radiology, 26935Hôpital Cochin, AP-HP Centre, Paris, France.

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http://dx.doi.org/10.1177/0846537120984124DOI Listing
December 2020

SARS-COV-2 IgG antibody response in pregnant women at delivery.

J Gynecol Obstet Hum Reprod 2020 Dec 10;50(7):102041. Epub 2020 Dec 10.

Université Paris-Saclay, 94804 Villejuif, France; Laboratoire de Virologie, AP-HP, Hôpital Paul-Brousse, F-94804 Villejuif, France.

Background: The prevalence of COVID-19 infection during pregnancy is not known. COVIPREG is a prospective French multicenter study to assess the seroprevalence at the time of delivery and the maternal and neonatal impact of COVID-19 infection during pregnancy. In order to study factors associated with poor outcomes after COVID-19 Infection during pregnancy and adapt the sample size of the study, a preliminary assessment of the prevalence of SARS-CoV-2 IgG was planned after 500 inclusions in a one perinatal center of Paris area.

Objectives: To assess the prevalence of SARS-CoV-2 IgG antibody response in pregnant women at the time of delivery during the COVID-19 pandemia.

Study Design: A prospective observational study at Cochin hospital (Level III maternity). Patients admitted for delivery were offered to participate to the study. Each patient participating to the study was tested for anti-SARS-CoV-2-IgG antibodies using a commercially available ELISA.

Results: Among the 529 patients included in the COVIPREG study between April 29 and June 26, 529 were assessed for SARS-CoV-2 IgG antibody response and 25 had a positive test, ie 4.7 % with a confidence interval at 95 % [3.0 %-6.9 %]).

Conclusions: Four months after the beginning of the infection in Paris, the seroprevalence of SARS-CoV-2 IgG in pregnant women at the time of delivery is low. Studies evaluating the impact of COVID-19 infection during pregnancy should take this information in account in order to adapt the sample size.
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http://dx.doi.org/10.1016/j.jogoh.2020.102041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831450PMC
December 2020

Preeclampsia before 26 weeks of gestation: Obstetrical prognosis for the subsequent pregnancy.

J Gynecol Obstet Hum Reprod 2021 Mar 19;50(3):102000. Epub 2020 Nov 19.

Department of Obstetrics Gynecology and Reproductive Medicine, University Paris Est Créteil, Centre Hospitalier Inter-Communal de Créteil, 94000, CRETEIL, France.

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 <3rd percentile or <10 percentile with Doppler abnormalities, maternal death and fetal death.

Results: Among the 107 patients who met the criteria, 48 were analyzed for a subsequent pregnancy. Seventeen women (35.4 %) developed an adverse composite outcome, occurring for 15 women (31.2 %) before 34 weeks. Ten women (20.8 %) developed a recurrent preeclampsia occurring for 5 women (10.4 %) before 34 weeks. We related 3 HELLP syndromes, 1 placental abruption, 9 fetal growth restrictions, 3 fetal deaths and no maternal death. Compared to baseline normotensive women, chronic hypertension was significantly associated with an increased risk of adverse composite outcome (19.3 vs 58.8 %, p-value 0.014).

Conclusion: In our population, preeclampsia with delivery before 26 weeks is associated with 35.4 % of adverse composite outcomes and 20.8 % of recurrent preeclampsia during the immediate subsequent pregnancy. These results justify the importance of an ongoing monitoring of these patients during subsequent pregnancy.
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http://dx.doi.org/10.1016/j.jogoh.2020.102000DOI Listing
March 2021

The cause of birth is associated with neonatal prognosis in late preterm singletons.

J Gynecol Obstet Hum Reprod 2020 Sep 22:101920. Epub 2020 Sep 22.

Université de Paris, INSERM U1153, Equipe de recherche en Epidémiologie Obstétricale, Périnatale et Pédiatrique (EPOPé), Centre de Recherche Epidémiologie et Biostatistique Sorbonne Paris Cité (CRESS), Paris, France; Sorbonne Université, AP-HP, Department of Gynaecology and Obstetrics, Trousseau Hospital, Paris, France.

Introduction: Recent studies have shown that the cause of very preterm births may be related to neonatal morbidity and mortality. Even though these risks are lower among late preterm births, this group accounts for the vast majority of all preterm births. The objective of this study was to evaluate the relation of neonatal morbidity and mortality to the cause of late preterm birth.

Materials And Methods: This retrospective observational cohort study included all women who gave birth to liveborn singletons from 34 to 36 weeks+6 days of gestation in a French level III maternity hospital in the 5-year period 2013-2017. The causes of preterm delivery were divided into 6 mutually exclusive groups. The main outcome was a composite neonatal morbidity criterion, defined by at least one among the following criteria: neonatal respiratory distress, neurological complications, neonatal sepsis, severe necrotizing enterocolitis, and neonatal hypoglycemia. We analyzed the association between cause of preterm delivery and neonatal morbidity after adjustment for gestational age and antenatal corticosteroid therapy. The reference group was preterm labor, defined by spontaneous preterm labor with intact membranes.

Results: During the study period, there were a total of 27 110 births, including 1114 singleton births at 34 to 36 weeks of gestation + 6 days (4.1%). Among the 968 late preterm births included, the risk of neonatal morbidity in the group with preterm premature rupture of membranes (PPROM) was similar to that in the preterm labor (reference) group: adjusted odds ratio (aOR) 1.2 (95% CI, 0.8-1.8). All the other causes of late preterm birth were associated with a higher risk of neonatal morbidity than the reference group: aOR 2.0 [95% CI, 1.1-3.5] for hypertensive disorders without suspected fetal growth restriction (FGR) (9.1% of cases), aOR 2.4 [95% CI, 1.4-4.2] for hypertensive disorders with suspected FGR (8.9%), aOR 4.2 [95% CI, 2.2-8.0] for suspected FGR without hypertensive disorders (5.8%), and aOR 4.4 [95% CI, 2.2-8.8] for vaginal bleeding related to abnormal placental insertion (4.7%).

Conclusion: Among infants born from 34 to 36 weeks + 6 days of gestation, PPROM and preterm labor had similar risks of neonatal morbidity, while the other causes were associated with a risk of neonatal morbidity at least twice that with preterm labor.
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http://dx.doi.org/10.1016/j.jogoh.2020.101920DOI Listing
September 2020

Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group.

Blood 2020 11;136(19):2103-2117

Maternité Port-Royal, Hôpital Cochin, Université de Paris/AP-HP, Fighting Prematurity University Hospital Federation (FHU PREMA), INSERM UMR 1139, Paris, France.

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.
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http://dx.doi.org/10.1182/blood.2020005221DOI Listing
November 2020

Evidence for contamination as the origin for bacteria found in human placenta rather than a microbiota.

PLoS One 2020 10;15(8):e0237232. Epub 2020 Aug 10.

Université de Paris, INSERM UMR-S 1139 (3PHM), Paris, France.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237232PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416914PMC
October 2020

Vitamin D and pregnancy outcomes: Overall results of the FEPED study.

J Gynecol Obstet Hum Reprod 2020 Oct 27;49(8):101883. Epub 2020 Jul 27.

Service de Gynécologie-Obstétrique, Hôpital Antoine Béclère, Assistance Publique des Hôpitaux de Paris, Université Paris Saclay, Clamart, France.

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 <20 ng/mL in 46.5 % of patients. After matching 83 cases of preeclampsia with 319 controls, a significant decrease in the risk of preeclampsia was associated with maternal vitamin D levels ≥ 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.
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http://dx.doi.org/10.1016/j.jogoh.2020.101883DOI Listing
October 2020

Influenza immunisation in pregnancy is efficacious and safe, but questions remain.

Lancet Respir Med 2020 06;8(6):533-534

Inserm, F-CRIN, Réseau Innovative Clinical Research in Vaccinology, Paris, France; FHU PREMA, Hôpital Cochin, Paris 75014, France; Inserm, CIC Cochin Pasteur, Hôpital Cochin, Paris 75014, France; Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris 75014, France; Université de Paris, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30034-5DOI Listing
June 2020

Relationship between vitamin D status in the first trimester of pregnancy and gestational diabetes mellitus - A nested case-control study.

Clin Nutr 2021 01 25;40(1):79-86. Epub 2020 Apr 25.

Gynécologie-Obstétrique, Hôpital Antoine-Béclère, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud, Clamart, France; Fondation PremUp, Paris, France.

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 <20 ng/mL (OR = 1∙42, 95% CI 1∙06-1∙91; p = 0∙021). However, there was no significant relationship with other thresholds. The study of 25OHD levels with the more precise cutting of 5 units intervals showed a variable relationship with GDM risk, as the risk was low for very low 25OHD levels, increased for moderated levels, decreased for normal levels, and finally increased for higher levels.

Conclusion: According to our study, there seems to be no linear relationship between GDM and 25OHD levels in the first trimester of pregnancy since GDM risk does not continuously decrease as 25OHD concentrations increase. Our results most probably highlight the absence of an association between 25OHD levels and GDM risk.
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http://dx.doi.org/10.1016/j.clnu.2020.04.028DOI Listing
January 2021

Beetroot juice lowers blood pressure and improves endothelial function in pregnant eNOS mice: importance of nitrate-independent effects.

J Physiol 2020 09 27;598(18):4079-4092. Epub 2020 May 27.

Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Key Points: Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, the effects of nitrate-containing BRJ were compared with both 'placebo' (nitrate-depleted) BRJ as well as water to control for potential nitrate-independent effects. Our data show novel, nitrate-independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS ) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasize the importance of accounting for nitrate-independent effects of BRJ in study design and interpretation.

Abstract: Maternal hypertension is associated with adverse pregnancy outcomes, including fetal growth restriction (FGR), due in part to reductions in nitric oxide (NO) bioavailability. We hypothesized that maternal dietary nitrate administration would increase NO bioavailability to reduce systolic blood pressure (SBP), improve vascular function and increase fetal growth in pregnant endothelial NO synthase knockout (eNOS ) mice, which exhibit hypertension, endothelial dysfunction and FGR. Pregnant wildtype (WT) and eNOS mice were supplemented with nitrate-containing beetroot juice (BRJ+) from gestational day (GD) 12.5. Control mice received an equivalent dose of nitrate-depleted BRJ (BRJ-) or normal drinking water. At GD17.5, maternal SBP was measured; at GD18.5, maternal nitrate/nitrite concentrations, uterine artery (UtA) blood flow and endothelial function were assessed, and pregnancy outcomes were determined. Plasma nitrate concentrations were increased in both WT and eNOS mice supplemented with BRJ+ (P < 0.001), whereas nitrite concentrations were increased only in eNOS mice (P < 0.001). BRJ- did not alter nitrate/nitrite concentrations. SBP was lowered and UtA endothelial function was enhanced in eNOS mice supplemented with either BRJ+ or BRJ-, indicating nitrate-independent effects of BRJ. Improvements in endothelial function in eNOS mice were abrogated in the presence of 25 mm KCl, implicating enhanced EDH signalling in BRJ- treated animals. At GD18.5, eNOS fetuses were significantly smaller than WT animals (P < 0.001), but BRJ supplementation did not affect fetal weight. BRJ may be a beneficial intervention in pregnancies associated with hypertension, endothelial dysfunction and reduced NO bioavailability. Our data showing biological effects of non-nitrate components of BRJ have implications for both interpretation of previous findings and in the design of future clinical trials.
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http://dx.doi.org/10.1113/JP279655DOI Listing
September 2020

Dolutegravir and neural tube defects: a new insight.

Lancet Infect Dis 2020 04;20(4):405-406

Centre Regional de Pharmacovigilance, Assistance Publique-Hopitaux de Paris, Université de Paris, Hopital Cochin, Paris 75014, France.

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http://dx.doi.org/10.1016/S1473-3099(20)30117-1DOI Listing
April 2020

Placental Overexpression of Soluble CORIN in Preeclampsia.

Am J Pathol 2020 05 19;190(5):970-976. Epub 2020 Feb 19.

Université de Paris, National Institute of Health and Medical Research (INSERM), UMR-S1139, 3PHM, Paris, France; PremUp Foundation, Paris, France; University Hospital Federations (FHU) PREMA, Paris, France; Department of Gynaecology-Obstetrics, Port-Royal Hospital, AP-HP, Paris, France.

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.
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http://dx.doi.org/10.1016/j.ajpath.2019.12.012DOI Listing
May 2020

Lack of consensus in the choice of termination of pregnancy for Turner syndrome in France.

BMC Health Serv Res 2019 Dec 23;19(1):994. Epub 2019 Dec 23.

Maternité de Port Royal, Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Assistance-Publique Hôpitaux de Paris, Paris, France.

Background: The 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.

Methods: We 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.

Results: Overall 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%.

Conclusion: Our 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.
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http://dx.doi.org/10.1186/s12913-019-4833-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929477PMC
December 2019

First Trimester Maternal Vitamin D Status and Risks of Preterm Birth and Small-For-Gestational Age.

Nutrients 2019 Dec 13;11(12). Epub 2019 Dec 13.

Department of Obstetrics and Gynaecology, Antoine Béclère Hospital, AP-HP, University Paris Saclay, F-92140 Clamart, France.

Maternal 25-hydroxyvitamin D (25-OHD) deficiency during pregnancy may increase the risk of preterm and small-for-gestational age (SGA) birth, but studies report conflicting results. We used a multicenter prospective cohort of 2813 pregnant women assessed for 25-OHD levels in the first trimester of pregnancy to investigate the association between maternal 25-OHD concentrations and risks of preterm birth (<37 weeks) and SGA (birthweight <10th percentile). Odds ratios were adjusted (aOR) for potential cofounders overall and among women with light and dark skin separately, based on the Fitzpatrick scale. 25-OHD concentrations were <20 ng/mL for 45.1% of the cohort. A total of 6.7% of women had a preterm birth. The aOR for preterm birth associated with the 1st quartile of 25-OHD concentrations compared to the 4th quartile was 1.53 (95% confidence interval (CI): 0.97-2.43). In stratified analyses, an association was observed for women with darker skin (aOR = 2.89 (95% CI: 1.02-8.18)), and no association with lighter skin. A total of 11.9% of births were SGA and there was no association overall or by skin color. Our results do not provide support for an association between maternal first trimester 25-OHD deficiency and risk of preterm or SGA birth overall; the association with preterm birth risk among women with darker skin requires further investigation.
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http://dx.doi.org/10.3390/nu11123042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950733PMC
December 2019

Association of serum angiogenic factors with bronchopulmonary dysplasia. The ANGIODYS cohort study.

Pregnancy Hypertens 2019 Oct 29;18:82-87. Epub 2019 Sep 29.

Service de Médecine et Réanimation néonatales de Port Royal, 53 avenue de l'Observatoire, 75014 Paris, France; INSERM, U1141, Hopital Robert Debré, 75019 Paris, Île-de-France, France.

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 β [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, TGF-beta) 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 = 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-β 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.
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http://dx.doi.org/10.1016/j.preghy.2019.09.015DOI Listing
October 2019

SOX3 duplication: A genetic cause to investigate in fetuses with neural tube defects.

Prenat Diagn 2019 10 9;39(11):1026-1034. Epub 2019 Aug 9.

Department of Histology Embryology and Cytogenetics, Necker-Enfants Malades Hospital, APHP, Paris, France.

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.
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http://dx.doi.org/10.1002/pd.5523DOI Listing
October 2019

VEGF (Vascular Endothelial Growth Factor) Functionalized Magnetic Beads in a Microfluidic Device to Improve the Angiogenic Balance in Preeclampsia.

Hypertension 2019 07 13;74(1):145-153. Epub 2019 May 13.

Université Paris Est Créteil, France (E.L.).

Preeclampsia is a hypertensive pregnancy disease associated with a massive increase in sFlt-1 (soluble form of the vascular endothelial growth factor 1) in the maternal circulation, responsible for angiogenic imbalance and endothelial dysfunction. Pilot studies suggest that extracorporeal apheresis may reduce circulating sFlt-1 and prolong pregnancy. Nonspecific apheresis systems have potential adverse effects because of the capture of many other molecules. Our concept is based on a specific and competitive apheresis approach using VEGF (vascular endothelial growth factor) functionalized magnetic beads to capture sFlt-1 while releasing endogenous PlGF (placental growth factor) to restore a physiological angiogenic balance. Magnetic beads were functionalized with VEGF to capture sFlt-1. Experiments were performed using PBS, conditioned media from human trophoblastic cells, and human plasma. The proof of concept was validated in dynamic conditions in a microfluidic device as an approach mimicking real apheresis. Magnetic beads were functionalized with VEGF and characterized to evaluate their surface ligand density and recognition capabilities. VEGF-coated magnetic beads proved to be an efficient support in capturing sFlt-1 and releasing PlGF. In static conditions, sFlt-1 concentration decreased by 33±13%, whereas PlGF concentration increased by 27±10%. In dynamic conditions, the performances were improved, with 40% reduction of sFlt-1 and up to 2-fold increase of free PlGF. The sFlt-1/PlGF ratio was reduced by 63% in the plasma of preeclamptic patients. Apheresis was also associated with VEGF release. A ligand-based approach using VEGF-coated beads is an effective approach to the capture of sFlt-1 and the release of endogenous PlGF. It offers new perspectives for the treatment of preeclampsia.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12380DOI Listing
July 2019

Post-partum acute kidney injury: sorting placental and non-placental thrombotic microangiopathies using the trajectory of biomarkers.

Nephrol Dial Transplant 2020 09;35(9):1538-1546

Sorbonne Université, Urgences Néphrologiques et Transplantation Rénale, Assistance Publique-Hôpital de Paris (APHP), Hôpital Tenon, Paris, France.

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.
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http://dx.doi.org/10.1093/ndt/gfz025DOI Listing
September 2020

Relationship between vitamin D status in pregnancy and the risk for preeclampsia: A nested case-control study.

Clin Nutr 2020 02 15;39(2):440-446. Epub 2019 Feb 15.

Laboratoire d'Explorations Fonctionnelles, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Background & Aims: Vitamin D is thought to be involved in the pathogenesis of preeclampsia. To evaluate the relationship between vitamin D insufficiency in the first trimester of pregnancy and preeclampsia.

Methods: Nested case-control study (FEPED study) in type 3 obstetrical units. Pregnant women from 10 to 15 WA. For each patient with preeclampsia, 4 controls were selected from the cohort and matched by parity, skin color, maternal age, season and BMI. The main outcome measure was serum 25(OH)D status in the first trimester.

Results: 83 cases of preeclampsia were matched with 319 controls. Mean 25(OH)D levels in the first trimester were 20.1 ± 9.3 ng/mL in cases and 22.3 ± 11.1 ng/mL in controls (p = 0.09). The risk for preeclampsia with 25(OH)D level ≥30 ng/mL in the first trimester was decreased, but did not achieve statistical significance (OR, 0.57; 95% CI, 0.30-1.01; p = 0.09). High 25(OH)D during the 3rd trimester was associated with a significantly decreased risk of preeclampsia (OR, 0.43; 95%CI, 0.23-0.80; p = 0.008). When women with 25(OH)D levels <30 ng/mL both in the first and 3rd trimesters ("low-low") were taken as references, OR for preeclampsia was 0.59 (95% CI, 0.31-1.14; p = 0.12) for "low-high" or "high-low" women and 0.34 (95% CI, 0.13-0.86; p = 0.02) for "high-high" women.

Conclusions: No significant association between preeclampsia and vitamin D insufficiency in the first trimester was evidenced. However, women with vitamin D sufficiency during the 3rd trimester and both in the first and 3rd trimesters had a significantly lower risk of preeclampsia.
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http://dx.doi.org/10.1016/j.clnu.2019.02.015DOI Listing
February 2020

[Aspirin and preeclampsia].

Presse Med 2019 Jan 18;48(1 Pt 1):34-45. Epub 2019 Jan 18.

Assistance publique-Hôpital de Paris, centre hospitalier universitaire Cochin Broca Hôtel-Dieu, groupe hospitalier universitaire Ouest, département de gynécologie-obstétrique, maternité de Port-Royal, 53, avenue de l'Observatoire, 75014 Paris, France; PRES Sorbonne Paris Cité, université Paris Descartes, Paris, France; Fondation PremUP, Paris, France; DHU Risques et grossesse, Paris, France.

Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.
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http://dx.doi.org/10.1016/j.lpm.2018.11.022DOI Listing
January 2019

Sildenafil for the treatment of preeclampsia, an update: should we still be enthusiastic?

Nephrol Dial Transplant 2019 11;34(11):1819-1826

Department of Nephrology and Kidney Transplantation, Hôpital Tenon, Assistance publique - Hôpitaux de Paris, Paris, France.

Preeclampsia is a hypertensive disorder of pregnancy and the clinical manifestation of severe endothelial dysfunction associated with maternal and foetal morbidity and mortality. The primum movens of the disease is the defect of invasion of the uterine arteries by foetal syncytiotrophoblasts, which causes a maladaptive placental response to chronic hypoxia and the secretion of the soluble form of type 1 vascular growth endothelial factor receptor, also called soluble fms-like tyrosine kinase 1 (sFlt-1), the major player in the pathophysiology of the disease. Among its different effects, sFlt-1 induces abnormal sensitivity of the maternal vessels to the vasoconstrictor angiotensin II. This leads to the hypertensive phenotype, recently shown to be abrogated by the administration of sildenafil citrate, which can potentiate the vasodilatory mediator nitrite oxide. This review focuses on the mechanisms of maternal endothelial dysfunction in preeclampsia and discusses the therapeutic window of sildenafil use in the context of preeclampsia, based on the results from preclinical studies and clinical trials. Safety issues recently reported in neonates have considerably narrowed this window.
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http://dx.doi.org/10.1093/ndt/gfy328DOI Listing
November 2019

Intrauterine fetal deaths related to antiphospholipid syndrome: a descriptive study of 65 women.

Arthritis Res Ther 2018 Nov 6;20(1):249. Epub 2018 Nov 6.

AP-HP, Cochin Hospital, Internal Medicine Department, Centre de référence maladies auto-immunes et systémiques rares d'île de France, 27 Rue du Faubourg Saint Jacques, 75014, Paris, France.

Objective: Although one of the three obstetric manifestations of antiphospholipid syndrome (APS) is intrauterine fetal death (IUFD), little is known about it in this context. We report the first large series of patients with APS and IUFD.

Methods: We retrospectively analyzed the history and clinical data of women at four French hospitals. All had (1) APS diagnosis (Sydney criteria) and (2) IUFD at or after 10 weeks of gestation (weeks) between 2000 and 2016.

Results: The study included 65 women. Their median age at the index IUFD was 29 years (IQR 26-33); 38 (58%) were primigravidas. The index IUFD was the first APS clinical manifestation in 48 women (74%). Overall, 35% had a triple-positive antibody profile. IUFD occurred at a median gestational age of 24 weeks (IQR 18-27) and was associated with maternal obstetric complications in 16 women (25%), namely, preeclampsia (n = 12), hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP) (n = 6), and/or placental abruption (n = 5). Half of the 50 women with available data had a small-for-gestational-age fetus. Overall, including during the follow-up period of 4 years (IQR 2-9), 28 women (43%) had at least one thrombosis, and 29% were diagnosed with systemic lupus erythematosus (SLE). Ultimately, 54 women (83%) had at least one live birth. Only one woman had three consecutive early miscarriages.

Conclusion: IUFD was most often the inaugural sign of APS. Of the APS classification criteria, IUFD, preeclampsia, and thromboses were common in this cohort, while the "3 consecutive early miscarriages" criterion was met only once. With treatment, most of the women successfully had at least one live birth.
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http://dx.doi.org/10.1186/s13075-018-1745-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235231PMC
November 2018

Placenta Imaging Workshop 2018 report: Multiscale and multimodal approaches.

Placenta 2019 04 31;79:78-82. Epub 2018 Oct 31.

Dept. of Medical Physics and Biomedical Engineering, University College London, UK; King's College London, UK.

The Centre for Medical Image Computing (CMIC) at University College London (UCL) hosted a two-day workshop on placenta imaging on April 12th and 13th 2018. The workshop consisted of 10 invited talks, 3 contributed talks, a poster session, a public interaction session and a panel discussion about the future direction of placental imaging. With approximately 50 placental researchers in attendance, the workshop was a platform for engineers, clinicians and medical experts in the field to network and exchange ideas. Attendees had the chance to explore over 20 posters with subjects ranging from the movement of blood within the placenta to the efficient segmentation of fetal MRI using deep learning tools. UCL public engagement specialists also presented a poster, encouraging attendees to learn more about how to engage patients and the public with their research, creating spaces for mutual learning and dialogue.
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http://dx.doi.org/10.1016/j.placenta.2018.10.010DOI Listing
April 2019

Chemotherapy in pregnancy: exploratory study of the effects of paclitaxel on the expression of placental drug transporters.

Invest New Drugs 2019 10 26;37(5):1075-1085. Epub 2018 Oct 26.

INSERM, UMR-S1139, Paris, France.

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.
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http://dx.doi.org/10.1007/s10637-018-0677-7DOI Listing
October 2019