Maternal and perinatal outcomes in women aged 42 years or older.

OBJECTIVE: To describe maternal and fetal outcomes of pregnancies after 42 years and to compare maternal and fetal morbidities according to the conception mode; comparing pregnancies obtained spontaneously and those resulting from assisted reproductive technology (ART). METHODS: This retrospective cohort study was conducted in a level 3 maternity hospital. This study covered all women, aged 42 years or older, who gave birth between January 1, 2014 and December 31, 2019. Univariate and multivariate analyses with logistic regression models were used to compare maternal and perinatal outcomes depending on conception mode: spontaneous or using ART. RESULTS: A sample of 532 women, including 335 spontaneous pregnancies (63%) and 147 pregnancies after ART (27.6%) were studied. Conception mode was missing for 50 (9.4%). We found increased rates not only of maternal complications such as maternal overweight and obesity, pre-eclampsia, and gestational diabetes, but also of interventions such as hospitalization during pregnancy, cesarean section, postpartum hemorrhage, and perinatal outcome like preterm birth. There were also more maternal and perinatal negative outcomes among the ART group. After multivariate analysis, pre-eclampsia was predominant in the ART group (odds ratio 0.25, 95% confidence interval 0.07-0.85, P = 0.02). CONCLUSION: While maternal and fetal risks increase for late pregnancies, there also appears to be a difference depending on the conception mode, with pregnancies resulting from ART having more pregnancy-related complications than those obtained spontaneously.

Successful Elective Thoracoscopic Resection of Complicate Extralobar Bronchopulmonary Sequestration after Intrafoetal Vascular Laser Ablation: The Paediatric Surgeon's Point of View.

Few reports of laser coagulation for foetal bronchopulmonary sequestration (BPS), a rare congenital malformation characterised by the absence of tracheobronchial connection and the presence of a systemic feeding artery, have been published. Additionally, very few of them focus also on the postnatal management, with results limited and controversial. Postnatal treatment of residual malformation remains debated, hence the need to share our experience of a combined pre- and postnatal approach to complicated extra-lobar BPS. We report the case of a female foetus with the diagnosis of a pulmonary lesion. Due to mediastinal shift, unilateral compressive hydrothorax, ascites, and hydrops, a foetal treatment with ultrasound-guided laser coagulation of the anomalous vessel was performed. At birth, due to the persistence of the malformation, an elective delayed thoracoscopical surgery was performed. Prenatal laser ablation for complicated BPS is a life-saving procedure not always resulting in lesion disappearance. Thoracoscopical surgical exploration in case of persistent lesions at birth offers the possibility of a minimally invasive sequestrectomy feasible and safe.

Oral and periodontal assessment at the first trimester of pregnancy: The PERISCOPE longitudinal study.

INTRODUCTION: Periodontal diseases (gingivitis and periodontitis) are chronic non-communicable inflammatory diseases. The risk of developing gingivitis and periodontitis increases during pregnancy. Also, periodontitis increases the risk of developing adverse pregnancy outcomes such as preterm birth and preeclampsia. Early diagnosis of adverse pregnancy outcomes is essential and periodontitis could be an early sign to take into consideration. MATERIAL AND METHODS: We conducted a longitudinal observational study (PERISCOPE study: CNIL, no. 1 967 084 v 0; CER, no. 01-0416) on 121 pregnant women in the first trimester to determine their oral and periodontal health status. We explored the relations between oral and periodontal health status and sociodemographic and behavior characteristics, as well as their course and outcome of pregnancy. RESULTS: A total of 47.1% of the women had periodontitis, of which only 66.7% presented clinical manifestations associated with the disease such as gingival bleeding. These women had a poorer oral and periodontal health, and a higher body mass index, and more of them developed gestational diabetes during the course of pregnancy. The remaining 33.3% showed only discreet and isolated inflammatory signs and, unless thoroughly examined, would have gone undiagnosed for periodontitis. Interestingly these women were more often primiparous, still active professionally and had had a recent oral examination. CONCLUSIONS: The PERISCOPE study is one of the few studies that reports the oral and periodontal health status of pregnant women in the first trimester. Furthermore, the results highlight the need for early oral and periodontal assessment and treatment, even in the absence of exterior clinical signs, in order to prevent periodontal disease aggravation and also, by reducing low grade systemic inflammation, possibly adverse pregnancy outcomes.

Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro.

Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.

Arabin pessary to prevent adverse perinatal outcomes in twin pregnancies with a short cervix: a multicenter randomized controlled trial (PESSARONE).

BACKGROUND: The number of twin pregnancies continues to increase worldwide as both the number of pregnancies obtained by medically assisted reproduction and age at first pregnancy keep rising. Preterm delivery is the major complication associated with twin pregnancies. The effectiveness of preventive treatments such as progesterone or cervical cerclage for women with a short cervix is doubtful in twin pregnancies. The effectivity of cervical pessaries in preventing preterm birth and its associated morbidity and mortality is also controversial. OBJECTIVE: We sought to investigate if the Arabin pessary reduces adverse neonatal outcomes in twin pregnancies with a short cervix. STUDY DESIGN: This open-label, multicenter, randomized controlled trial on twin pregnancies with a cervical length of <35 mm compared pessary placement at 16+0 to 24+0 weeks' gestation with standard care alone. The primary endpoint was a composite of adverse neonatal outcomes, namely peripartum or neonatal death or significant neonatal morbidity before hospital discharge, defined as at least 1 of the following complications: bronchopulmonary dysplasia, intraventricular hemorrhage grade III to IV, periventricular leukomalacia, necrotizing enterocolitis grade II or higher, culture-proven sepsis, and retinopathy requiring treatment. A sample size of 308 pregnancies was planned to ensure 80% power to compare the proportions of women with at least 1 infant with an adverse neonatal outcome. The intention-to-treat analysis after multiple imputation of missing data, was supplemented with a secondary analysis that controlled for gestational age and cervical length, both at inclusion. The primary endpoint was also compared between randomization groups in the per-protocol population, which excluded patients with prespecified major protocol violations (mostly cervical cerclage and/or progesterone after inclusion). Secondary endpoints included preterm birth, spontaneous preterm birth, and pessary side effects. RESULTS: In total, 315 women were randomized to either receive a pessary (n=157) or standard management (n=158). Overall, 10.8% (34 women) of participants had a missing value for the primary endpoint, mostly (79%) because of the lack of paternal consent for neonatal data collection. In the intention-to-treat analysis, the adverse neonatal outcome occurred in 16.8% of the pessary group vs in 22.5% of the control group (risk ratio, 0.69; 95% confidence interval, 0.39-1.23; P=.210). The per-protocol analysis did not show any significant difference between groups (risk ratio, 0.78; 95% confidence interval, 0.47-1.28; P=.320). The occurrence of preterm birth or spontaneous preterm birth did not differ significantly between groups. No serious side effects were associated with pessary use. CONCLUSION: Pessary use in our study did not significantly reduce adverse neonatal outcomes in twin pregnancies with a short cervix.

Severe placental lesions due to maternal SARS-CoV-2 infection associated to intrauterine fetal death.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause severe placental lesions leading rapidly to intrauterine fetal death (IUFD). From August 2020 to September 2021, in the pathology department of Toulouse Oncopole, we analyzed 50 placentas from COVID-19-positive unvaccinated mothers. The purpose of our study is to describe the clinicopathological characteristics of these placental damages and to understand the pathophysiology. Ten of them (20%) showed placental lesions with positive immunohistochemistry for SARS-CoV-2 in villous trophoblasts. In five cases (10%), we observed massive placental damage associating trophoblastic necrosis, fibrinous deposits, intervillositis, as well as extensive hemorrhagic changes due to SARS-CoV-2 infection probably responsible of IUFD by functional placental insufficiency. In five other cases, we found similar placental lesions but with a focal distribution that did not lead to IUFD but live birth. These lesions are independent of maternal clinical severity of COVID-19 infection because they occur despite mild maternal symptoms and are therefore difficult to predict. In our cases, they occurred 1-3 weeks after positive SARS-CoV-2 maternal real-time polymerase chain reaction testing and were observed in the 2nd and 3rd trimesters of pregnancies. When these lesions are focal, they do not lead to IUFD and can be involved in intrauterine growth restriction. Our findings, together with recent observations, suggest that future pregnancy guidance should include stricter pandemic precautions such as screening for a wider array of COVID-19 symptoms, enhanced ultrasound monitoring, as well as newborn medical surveillance.

Human Cytomegalovirus Infection Changes the Pattern of Surface Markers of Small Extracellular Vesicles Isolated From First Trimester Placental Long-Term Histocultures.

Extracellular vesicles (EVs) have increasingly been recognized as key players in a wide variety of physiological and pathological contexts, including during pregnancy. Notably, EVs appear both as possible biomarkers and as mediators involved in the communication of the placenta with the maternal and fetal sides. A better understanding of the physiological and pathological roles of EVs strongly depends on the development of adequate and reliable study models, specifically at the beginning of pregnancy where many adverse pregnancy outcomes have their origin. In this study, we describe the isolation of small EVs from a histoculture model of first trimester placental explants in normal conditions as well as upon infection by human cytomegalovirus. Using bead-based multiplex cytometry and electron microscopy combined with biochemical approaches, we characterized these small EVs and defined their associated markers and ultrastructure. We observed that infection led to changes in the expression level of several surface markers, without affecting the secretion and integrity of small EVs. Our findings lay the foundation for studying the functional role of EVs during early pregnancy, along with the identification of new predictive biomarkers for the severity and outcome of this congenital infection, which are still sorely lacking.

Prenatal features and neonatal management of severe hyperparathyroidism caused by the heterozygous inactivating calcium-sensing receptor variant, Arg185Gln: A case report and review of the literature.

BACKGROUND: Loss-of-function variants in the calcium-sensing receptor (CASR) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH.NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs.Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype. CASE PRESENTATION: We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful. DISCUSSION: An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.

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

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

Combination of the fetal urinary metabolome and peptidome for the prediction of postnatal renal outcome in fetuses with PUV.

Most of biomarker panels, extracted from single omics traits, still need improvement since they display a gray zone where prediction is uncertain. Here we verified whether a combination of omics traits, fetal urinary metabolites and peptides analyzed in the same sample, improved prediction of postnatal renal function in fetuses with posterior urethral valves (PUV) compared to individual omics traits. Using CE-MS, we explored the urinary metabolome of 13 PUV fetuses with end stage renal disease (ESRD) and 12 PUV fetuses without postnatal ESRD at 2 years postnatally. This allowed the selection of 24 differentially abundant metabolite features which were modelled into predictive classifiers, alone or in combination with 12 peptides previously identified as predictive of ESRD. Validation in 35 new fetuses showed that the combination of peptides and metabolites significantly outperformed the 24 metabolite features with increased AUC (0.987 vs 0.905), net reclassification improvement (36%) and better sensitivity accuracy (86% vs 60%). In addition, the two trait combination tended to improve, but without reaching statistical significance, the already high performances of the 12 peptide biomarkers (AUC 0.967, accuracy 80%). In conclusion, this study demonstrates the potential of cumulating different omics traits in biomarker research where single omics traits fall short. SIGNIFICANCE: Although increasingly proposed in disease-diagnosis and -prognosis because of their improved efficacy over single markers, panels of body fluid biomarkers based on single omics analysis still fail to display perfect accuracy, probably due to biological variability. Here, we hypothesized that combination of different omics traits allowed to better capture this biological variability. As proof of concept, we studied the added value of fetal urine metabolites and peptides using CE-MS, starting from the same urine sample, to predict postnatal renal outcome in fetuses with posterior urethral valves. We observed that the prognostic power of combined metabolite and peptide markers was clearly higher than that of metabolites alone and slightly, but non-significantly, improved compared to the peptides alone. To our knowledge, this report is the first to demonstrate that combining multiomics traits extracted from (fetal) urine samples displays clear promise for kidney disease stratification.

Mortality, morbidity and 2-years neurodevelopmental prognosis of twin to twin transfusion syndrome after fetoscopic laser therapy: a prospective, 58 patients cohort study.

OBJECTIVE: To describe the morbidity and mortality and long-term neurodevelopmental outcomes in children born from a Twin-to-Twin Transfusion Syndrome (TTTS) pregnancy treated using laser fetoscopy in Toulouse. POPULATION AND METHOD: All pregnancies with TTTS treated by laser fetoscopy in our centre were included. Antenatal and postnatal morbidity and neonatal morbidity were identified in the medical records retrospectively. The neurodevelopmental outcome was studied using Ages and Stages Questionnaires (ASQ) sent to the parents, an oral interview with the parents and with the child's doctor (last objective neurological examination, rehabilitation needs, learning disabilities). RESULTS: Seventy-one pregnancies, or 144 foetuses, were included from 2008 to 2014, overall survival at 2 years was 72.9% and the survival of at least one child at 2 years was 91.5%, severe neonatal morbidity was 11.2% of the children, severe brain damage accounted for 3.6% of children admitted to the hospital unit. It was possible to study the neurodevelopmental outcome for 58 children (55.3%), with a corrected age from 24 to 95 months. Five children (8.6%) had severe neurological abnormalities and 17 (29.3%) had moderate neurological abnormalities. DISCUSSION: The mortality, neonatal morbidity and long-term neurological morbidity of our cohort are higher than those of premature infants (EPIPAGE-2 French cohort), which confirms the severity of this syndrome, and are comparable to those of the TTTS cohorts described in the literature.

Real-time three-dimensional foetal echocardiography using a new transabdominal xMATRIX array transducer.

BACKGROUND: Foetal echocardiography has been used to diagnose congenital heart disease. However, conventional echocardiography can only display two-dimensional (2D) structural images of the intricate three-dimensional (3D) foetal heart. AIM: The purpose of this study was to report the first use of a new transabdominal xMATRIX array transducer and to describe its ability to perform all 3D modalities: intelligent spatiotemporal image correlation (iSTIC) acquisition, xPlane imaging and 3D surface imaging. METHODS: Eighty foetuses without congenital heart disease were included consecutively, with a gestational age between 20 and 37 weeks. 2D and 3D scans were performed with a transabdominal xMATRIX array transducer. Cardiac-STIC volume datasets were acquired and postprocessed with new automatic software (the 'Fetal Heart Navigator'). RESULTS: A total of 224 iSTIC acquisitions were performed (mean time for each, 2 seconds). Only 78 iSTIC acquisitions (35%) were able to detect the ductal arch automatically. 'Fetal Heart Navigator' feasibility varied according to foetal position, including the descending aorta. Live xPlane imaging had excellent feasibility regardless of foetal position; using rotation, lateral and vertical tilts, all cardiac structures were identified from a unique reference plane. Live 3D surface imaging had variable feasibility depending on the target structure. Only 10% of the volume dataset offered comprehensive imaging of intracardiac views. CONCLUSION: The new xMATRIX transabdominal transducer allows a multimodality approach to the foetal heart. Further studies that include foetuses with cardiac malformations are required.

Rupture of a splenic artery aneurysm in the first trimester of pregnancy.

BACKGROUND: Rupture of a splenic artery aneurysm during pregnancy is a rare and serious event, occurring mainly during the third trimester. The risk of rupture for an existing splenic artery aneurysm is very high during pregnancy (from 20% to 50%). When it does rupture, the maternal mortality rate is around 75% and the fetal mortality rate 95%. Of 110 cases reported in the literature, only one ruptured during the first trimester. OBJECTIVES: The aim of this case report is to make emergency physicians aware of this diagnosis, because only if it is considered can it be managed rapidly and appropriately. CASE REPORT: We report the case of a 6-weeks pregnant patient referred to our institution in hemorrhagic shock who died of a ruptured splenic artery aneurysm shortly after surgery. The initial diagnosis considered was a ruptured ectopic pregnancy. CONCLUSION: We report this case to increase awareness of splenic artery rupture during pregnancy, even during the first trimester.