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Background Oxytocin is one of the most widely used treatments in obstetrics. French guidelines favour low-dose protocols to avoid excessive uterine activity. Therefore, there is no recommendation for the maximum total dose to be administered. Several investigations exist about oxytocin dosage during spontaneous labour and induction. They have rarely reported total doses or analysed their association with maternal and neonatal factors. Methods We assessed the association between cumulative doses of oxytocin and maternal complications such as post-partum haemorrhage and emergency cesarean in the context of labour induction. We conducted an observational, retrospective, monocentric study in a tertiary care centre. We recruited single pregnancies with induction of labour and oxytocin administration during labour at term. The exclusion criteria were previous cesarean and foetus with identified pathology requiring immediate post-partum transfer. We recorded socio-demographic characteristics, obstetrical and neonatal data. Results In all, 3598 women receiving induction of labour after 37 +0 WG were recorded. After equivalent sampling over four years, 504 patients were included. Increasing total dose of oxytocin was associated with a greater risk of cesarean and post-partum haemorrhage. Excess risk of cesarean was found from 5 IU of oxytocin (cumulative dose). Nulliparous patients and those who had undergone cervical ripening had a greater risk of morbidity. We found no association with neonatal morbidity factors. Conclusion This study alerts to potential morbidity at oxytocin cumulative doses of 5 IU or greater, and so more likely at 10 IU, administered during induction of labour. Obstetric considerations and decisions should be guided by the co-factors of morbidity, in particular parity and need for cervical ripening.

A number of intrinsic, maternal and environmental factors have been linked to the risk of fetal developmental anomalies. In a previous study, we showed that telomere length (TL) was notably reduced in amniotic fluid when the fetus exhibited a developmental anomaly. In this new study, we measured the fetal and maternal TL for 75 evolutive pregnancies with congenital malformation. We also measured the TL of 50 pregnant women without fetal anomalies and 50 non-pregnant control women who had at least one child with normal development. In fetal samples, telomeres were significantly shortened in cases with congenital anomalies compared to controls (n  =  93) (P  <  0.0001). Interestingly, age-adjusted maternal TL was also significantly reduced in these cases (P  <  0.01). Receiver operating characteristic (ROC) analysis showed that maternal TL, at the optimal cut-off value, identified cases of congenital anomalies with 92% specificity and 73% sensitivity. In addition, fetal and maternal TL were correlated, with 15% to 38% of the variance in fetal TL attributable to maternal TL. Telomere shortening can lead to increased sensitivity to various maternal exposure factors and may contribute to compromised organogenesis, possibly due to inadequate cell proliferation or genomic instability. Measuring maternal TL during the periconceptional period could serve as a useful predictive biomarker for assessing the risk of fetal developmental anomalies.

IntroductionThis trial evaluates whether daily low-dose aspirin initiated before 16 weeks of gestation can reduce preeclampsia and fetal growth restriction in nulliparous women identified by first-trimester uterine artery Dopplers as at high risk of preeclampsia.MethodsThis randomized, blinded, placebo-controlled, parallel-group trial took place in 17 French obstetric departments providing antenatal care. Pregnant nulliparous women aged ≥ 18 years with a singleton pregnancy at a gestational age < 16 weeks of gestation with a lowest pulsatility index ≥ 1.7 or a bilateral protodiastolic notching for both uterine arteries on an ultrasound performed between 11+0 and 13+6 weeks by a certified sonographer were randomized at a 1:1 ratio to 160 mg of low-dose aspirin or to placebo to be taken daily from inclusion to their 34th week of gestation. The main outcome was preeclampsia or a birthweight ≤ 5th percentile. Other outcomes included preeclampsia, severe preeclampsia, preterm preeclampsia, preterm delivery before 34 weeks, mode of delivery, type of anesthesia, birthweight ≤ 5th percentile and perinatal death.ResultsThe trial was interrupted due to recruiting difficulties. Between June 2012 and June 2016, 1104 women were randomized, two withdrew consent, and two had terminations of pregnancies. Preeclampsia or a birthweight ≤ 5th percentile occurred in 88 (16.0%) women in the low-dose aspirin group and in 79 (14.4%) in the placebo group (proportion difference 1.6 [-2.6; 5.9] p = 0.45). The two groups did not differ significantly for the secondary outcomes.ConclusionLow-dose aspirin was not associated with a lower rate of either preeclampsia or birthweight ≤ 5th percentile in women identified by their first-trimester uterine artery Doppler as at high risk of preeclampsia.Trial registration(NCT0172946).

Enterovirus D68 (EV-D68) has emerged as an agent of epidemic respiratory illness and acute flaccid myelitis in the paediatric population but data are lacking in adult patients. We performed a 4.5-year single-centre retrospective study of all patients who tested positive for EV-D68 and analysed full-length EV-D68 genomes of the predominant clades B3 and D1. Between 1 June 2014, and 31 December 2018, 73 of the 11,365 patients investigated for respiratory pathogens tested positive for EV-D68, of whom 20 (27%) were adults (median age 53.7 years [IQR 34.0–65.7]) and 53 (73%) were children (median age 1.9 years [IQR 0.2–4.0]). The proportion of adults increased from 12% in 2014 to 48% in 2018 (p = 0.01). All adults had an underlying comorbidity factor, including chronic lung disease in 12 (60%), diabetes mellitus in six (30%), and chronic heart disease in five (25%). Clade D1 infected a higher proportion of adults than clades B3 and B2 (p = 0.001). Clade D1 was more divergent than clade B3: 5 of 19 amino acid changes in the capsid proteins were located in putative antigenic sites. Adult patients with underlying conditions are more likely to present with severe complications associated with EV-D68, notably the emergent clade D1.

The integrity of human fetal membranes is crucial for harmonious fetal development throughout pregnancy. Their premature rupture is often the consequence of a physiological phenomenon that has been exacerbated. Beyond all the implied biological processes, inflammation is of primary importance and is qualified as ‘sterile’ at the end of pregnancy. In this study, complementary methylomic and transcriptomic strategies on amnion and choriodecidua explants obtained from the altered (cervix zone) and intact fetal membranes at term and before labour were used. By cross-analysing genome-wide studies strengthened by in vitro experiments, we deciphered how the expression of toll-like receptor 4 (TLR4), an actor in pathological fetal membrane rupture, is controlled. Indeed, it is differentially regulated in the altered zone and between both layers by a dual mechanism: (1) the methylation of TLR4 and miRNA promoters and (2) targeting by miRNA (let-7a-2 and miR-125b-1) acting on the 3’-UTR of TLR4. Consequently, this study demonstrates that fine regulation of TLR4 is required for sterile inflammation establishment at the end of pregnancy and that it may be dysregulated in the pathological premature rupture of membranes.

Inflammation is the leading mechanism involved in both physiological and pathological rupture of fetal membranes. Our aim was to obtain a better characterization of the inflammasome-dependent inflammation processes in these tissues, with a particular focus on the nucleotide-binding oligomerization domain (NOD)-like receptor, pyrin domain containing protein 7 (NLRP7) inflammasome. The presence of NLRP7 inflammasome actors [NLRP7, apoptosis-associated speck-like protein containing a CARD domain (ASC), and caspase-1] was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) in human amnion and choriodecidua at the three trimesters and at term. The protein concentrations were then determined by enzyme-linked immunosorbent assay in term tissues, with or without labor. The presence of and in human fetal membranes was investigated using a PCR approach. Human amnion epithelial cells (AECs) were treated for 4 or 20 h with fibroblast-stimulating lipopeptide-1 (FSL-1), a -derived ligand. Transcripts and proteins quantity was then measured by RT-quantitative PCR and Western blotting, respectively. NLRP7 and ASC colocalization was confirmed by immunofluorescence. Western blots allowed analysis of pro-caspase-1 and gasdermin D cleavage. NLRP7, ASC, and caspase-1 transcripts were expressed in both sheets of human fetal membranes during all pregnancy stages, but only ASC protein expression was increased with labor. In addition, and were detected for the first time in human fetal membranes. NLRP7 and caspase-1 transcripts, as well as NLRP7, ASC, and pro-caspase-1 protein levels, were increased in FSL-1-treated AECs. The NLRP7 inflammasome assembled around the nucleus, and pro-caspase-1 and gasdermin D were cleaved into their mature forms after FSL-1 stimulation. Two new mycoplasmas, and , were identified in human fetal membranes, and a lipopeptide derived from was found to induce NLRP7 inflammasome formation in AECs.

Mammalian airways are highly ramified tree-like structures that develop by the repetitive branching of the lung epithelium into the surrounding mesenchyme through reciprocal interactions. Based on a morphometric analysis of the epithelial tree, it has been recently proposed that the complete branching scheme is specified early in each lineage by a programme using elementary patterning routines at specific sites and times in the developing lung. However, the coupled dynamics of both the epithelium and mesenchyme have been overlooked in this process. Using a qualitative and quantitative in vivo morphometric analysis of the E11.25 to E13.5 mouse whole right cranial lobe structure, we show that beyond the first generations, the branching stereotypy relaxes and both spatial and temporal variations are common. The branching pattern and branching rate are sensitive to the dynamic changes of the mesoderm shape that is in turn mainly dependent upon the volume and shape of the surrounding intrathoracic organs. Spatial and temporal variations of the tree architecture are related to local and subtle modifications of the mesoderm growth. Remarkably, buds never meet after suffering branching variations and continue to homogenously fill the opening spaces in the mesenchyme. Moreover despite inter-specimen variations, the growth of the epithelial tree and the mesenchyme remains highly correlated over time at the whole lobe level, implying a long-range regulation of the lung lobe morphogenesis. Together, these findings indicate that the lung epithelial tree is likely to adapt in real time to fill the available space in the mesenchyme, rather than being rigidly specified and predefined by a global programme. Our results strongly support the idea that a comprehensive understanding of lung branching mechanisms cannot be inferred from the branching pattern or behavior alone. Rather it needs to be elaborated upon with the reconsideration of mesenchyme-epithelium coupled growth and lung tissues mechanics.

Background Pregnancy may have a beneficial effect on disease activity in rheumatoid arthritis (RA) but the evidence is more conflicting in spondyloarthritis (SpA). The aim of this study was to analyse disease activity and relapse during pregnancy in women with RA and SpA. Methods Consecutive pregnant women with RA or SpA were enrolled in this French multicentre observational cohort from 2014 to 2022. Women who had at least two prenatal visits (including one in the first trimester) were included in the analysis. Disease relapse was defined as treatment intensification (initiation or switch of a DMARD) or increase in disease activity scores (DAS28-CRP for RA patients; ASDAS-CRP and/or BASDAI for SpA patients). Results Of the 124 pregnant women included, 53 had RA and 71 had SpA. A total of 18 (35%) RA and 44 (62%) SPA received a TNF inhibitor during pregnancy. At the group level, disease activity indexes remained stable in the 1st, 2nd and 3rd trimesters. Disease relapse during pregnancy occurred in 17 (32%) RA patients and 28 (39%) SpA patients, among whom 30 (24%) requiring a treatment intensification. In multivariable analysis, factors associated with disease relapse were nulliparity (odds ratio, OR: 6.5, 95%CI: 1.1 to 37.9) and a disease flare in the 12 months prior to conception (OR: 8.2, 95%CI: 1.6 to 42.7) for RA patients, and a history of bDMARD use (OR: 5.4, 95%CI: 1.1 to 27.3) for SpA patients. Conclusion Disease activity remained stable during pregnancy in women with RA and SpA but almost a quarter required major changes to their treatment.

IntroductionPremature rupture of membranes (PROM) occurs at term in 8% of pregnancies. Several studies have demonstrated that the risk of chorioamnionitis and neonatal sepsis increases with duration of PROM. Decreasing the time interval between PROM and delivery is associated with lower rates of maternal infections. In case of an unfavourable cervix, the use of prostaglandin for cervical maturation demonstrates some advantages over oxytocin. The use of double balloon catheter in reduction of PROM duration has not been evaluated in the literature.Methods and analysisWe are conducting a prospective, monocentric, randomised clinical trial on pregnant women with an unfavourable cervix showing PROM at term (RUBAPRO).After 12–24 hours of PROM, women are randomly assigned to one group treated with a double balloon catheter for 12 hours, with oxytocin administered after 6 hours or to the control group treated with 24 hours of vaginal prostaglandin followed by oxytocin infusion alone. Patients (n=80) are randomised at a 1:1 ratio with stratification on parity.The inclusion criteria are a Bishop score of <6, cephalic presentation at term and confirmed PROM. Women with suspected chorioamnionitis; group B streptococcus (GBS) carrier; a history of caesarean delivery or any contraindication for vaginal delivery are excluded.The time from induction to delivery is the primary outcome. Secondary outcomes were mode of delivery, maternofetal morbidity and the effect of parity on strategies for reduction of PROM duration.To sufficiently demonstrate a difference (10 hours) between groups—with a statistical power of 90% and a two-tailed α of 5%—40 patients per group will be required.Ethics and disseminationWritten informed consent is required from participants.National Ethics Committee approval was obtained in August 2017. The results will be published in a peer-reviewed journal and presented at relevant conferences. Access to raw data will be available only to members of the research team.Trial registration number NCT03310333.

In recent decades, preterm birth (PTB) has become a significant research focus in the healthcare field, as it is a leading cause of neonatal mortality worldwide. Using five independent study cohorts including 1290 vaginal samples from 561 pregnant women who delivered at term ( n  = 1029) or prematurely ( n  = 261), we analysed vaginal metagenomics data for precise microbiome structure characterization. Then, a deep neural network (DNN) was trained to predict term birth (TB) and PTB with an accuracy of 84.10% and an area under the receiver operating characteristic curve (AUROC) of 0.875 ± 0.11. During a benchmarking process, we demonstrated that our DL model outperformed seven currently used machine learning algorithms. Finally, our results indicate that overall diversity of the vaginal microbiota should be taken in account to predict PTB and not specific species. This artificial-intelligence based strategy should be highly helpful for clinicians in predicting preterm birth risk, allowing personalized assistance to address various health issues. DeepMPTB is open source and free for academic use. It is licensed under a GNU Affero General Public License 3.0 and is available at https://deepmptb.streamlit.app/ . Source code is available at https://github.com/oschakoory/DeepMPTB and can be easily installed using Docker ( https://www.docker.com/ ).