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Labour classified by cervical dilatation & fetal membrane rupture demonstrates differential impact on RNA-seq data for human myometrium tissues

ABSTRACT: High throughput sequencing has previously identified differentially expressed genes (DEGs) and enriched signalling networks in human myometrium for term (≥37 weeks) gestation labour, when defined as a singular state of activity at comparison to the non-labouring state. However, transcriptome changes that occur during transition from early to established labour (defined as ≤3 and >3 cm cervical dilatation, respectively) and potentially altered by fetal membrane rupture (ROM), when adapting from onset to completion of childbirth, remained to be defined. In the present study, we assessed whether differences for these two clinically observable factors of labour are associated with different myometrial transcriptome profiles. Analysis of our tissue (‘bulk’) RNA-seq data (NCBI Gene Expression Omnibus: GSE80172) with classification of labour into four groups, each compared to the same non-labour group, identified more DEGs for early than established labour; ROM was the strongest up-regulator of DEGs. We propose that lower DEGs frequency for early labour and/or ROM negative myometrium was attributed to bulk RNA-seq limitations associated with tissue heterogeneity, as well as the possibility that processes other than gene transcription are of more importance at labour onset. Integrative analysis with future data from additional samples, which have at least equivalent refined clinical classification for labour status, and alternative omics approaches will help to explain what truly contributes to transcriptomic changes that are critical for labour onset. Lastly, we identified five DEGs common to all labour groupings; two of which (AREG and PER3) were validated by qPCR and not differentially expressed in placenta and choriodecidua.

SUBMITTER: Lai P

PROVIDER: S-EPMC8604334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe call for women-centred approaches to reduce labour interventions, particularly primary caesarean section, has renewed an interest in gaining a better understanding of natural labour progression.ObjectiveTo synthesise available data on the cervical dilatation patterns during spontaneous labour of 'low-risk' women with normal perinatal outcomes.Search strategyPubMed, EMBASE, CINAHL, POPLINE, Global Health Library, and reference lists of eligible studies.Selection criteriaObservational studies and other study designs.Data collection and analysisTwo authors extracted data on: maternal characteristics; labour interventions; the duration of labour centimetre by centimetre; and the duration of labour from dilatation at admission through to 10 cm. We pooled data across studies using weighted medians and employed the Bootstrap-t method to generate the corresponding confidence bounds.Main resultsSeven observational studies describing labour patterns for 99 971 women met our inclusion criteria. The median time to advance by 1 cm in nulliparous women was longer than 1 hour until a dilatation of 5 cm was reached, with markedly rapid progress after 6 cm. Similar labour progression patterns were observed in parous women. The 95th percentiles for both parity groups suggest that it was not uncommon for some women to reach 10 cm, despite dilatation rates that were much slower than the 1-cm/hour threshold for most part of their first stage of labours.ConclusionAn expectation of a minimum cervical dilatation threshold of 1 cm/hour throughout the first stage of labour is unrealistic for most healthy nulliparous and parous women. Our findings call into question the universal application of clinical standards that are conceptually based on an expectation of linear labour progress in all women.FundingUNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, and the United States Agency for International Development (USAID).Tweetable abstractCervical dilatation threshold of 1 cm/hour throughout labour is unrealistic for most women, regardless of parity.

Project description:Pre-labour uterine contractions, occurring throughout pregnancy, are an important phenomenon involving the placenta in addition to the myometrium. They alter the uterine environment and thus potentially the blood supply to the fetus and may thus provide crucial insights into the processes of labour. Assessment in-vivo is however restricted due to their unpredictability and the inaccessible nature of the utero-placental compartment. While clinical cardiotocography (CTG) only allows global, pressure-based assessment, functional magnetic resonance imaging (MRI) provides an opportunity to study contractile activity and its effects on the placenta and the fetus in-vivo. This study aims to provide both descriptive and quantitative structural and functional MR assessments of pre-labour contractions in the human uterus. A total of 226 MRI scans (18-41 weeks gestation) from ongoing research studies were analysed, focusing on free-breathing dynamic quantitative whole uterus dynamic T2* maps. These provide an indirect measure of tissue properties such as oxygenation. 22 contractile events were noted visually and both descriptive and quantitative analysis of the myometrial and placental changes including volumetric and T2* variations were undertaken. Processing and analysis was successfully performed, qualitative analysis shows distinct and highly dynamic contraction related characteristics including; alterations in the thickness of the low T2* in the placental bed and other myometrial areas, high intensity vessel-like structures in the myometrium, low-intensity vessel structures within the placental parenchyma and close to the chorionic plate. Quantitative evaluation shows a significant negative correlation between T2* in both contractile and not-contractile regions with gestational age (p < 0.05) as well as a significant reduction in T2* during contractions. The T2* values in the myometrium were however not correlated to gestational age (p > 0.5). The quantitative and qualitative description of uterine pre-labour contractions including dynamic changes and key characteristics aims to contribute to the sparsely available in-vivo information and to provide an in-vivo tool to study this important phenomenon. Further work is required to analyse the origins of these subclinical contractions, their effects in high-risk pregnancies and their ability to determine the likelihood of a successful labour. Assessing T2* distribution as a marker for placental oxygenation could thus potentially complement clinically used cardiotocography measurements in the future.

Project description:BackgroundThe transition of the myometrium from a quiescent to a contractile state during labour is known to involve inflammation, which is characterized by the infiltration of immune cells and the secretion of cytokines. However, the specific cellular mechanisms underlying inflammation in the myometrium during human parturition are not yet fully understood.MethodsThrough the analysis of transcriptomics, proteomics, and cytokine arrays, the inflammation in the human myometrium during labour was revealed. By performing single-cell RNA sequencing (scRNA-seq) and spatiotemporal transcriptomic (ST) analyses on human myometrium in term in labour (TIL) and term in non-labour (TNL), we established a comprehensive landscape of immune cells, their transcriptional characteristics, distribution, function and intercellular communications during labour. Histological staining, flow cytometry, and western blotting were applied to validate some results from scRNA-seq and ST.ResultsOur analysis identified immune cell types, including monocytes, neutrophils, T cells, natural killer (NK) cells and B cells, present in the myometrium. TIL myometrium had a higher proportion of monocytes and neutrophils than TNL myometrium. Furthermore, the scRNA-seq analysis showed an increase in M1 macrophages in TIL myometrium. CXCL8 expression was mainly observed in neutrophils and increased in TIL myometrium. CCL3 and CCL4 were principally expressed in M2 macrophages and neutrophils-6, and decreased during labour; XCL1 and XCL2 were specifically expressed in NK cells, and decreased during labour. Analysis of cytokine receptor expression revealed an increase in IL1R2, which primarily expressed in neutrophils. Finally, we visualized the spatial proximity of representative cytokines, contraction-associated genes, and corresponding receptors in ST to demonstrate their location within the myometrium.ConclusionsOur analysis comprehensively revealed changes in immune cells, cytokines, and cytokine receptors during labour. It provided a valuable resource to detect and characterize inflammatory changes, yielding insights into the immune mechanisms underlying labour.

Project description:INTRODUCTION:Labour induction in women with a previous caesarean delivery currently uses vaginal prostaglandin E2 (PGE2), which carries the risks of uterine hyperstimulation and scar rupture. We aim to compare the efficacy of mechanical labour induction using a transcervically applied Foley catheter balloon (FCB) with PGE2 in affected women attempting trial of labour after caesarean (TOLAC). METHODS AND ANALYSIS:This single-centre non-inferiority prospective, randomised, open, blinded-endpoint study conducted at an academic maternity unit in Singapore will recruit a total of 100 women with one previous uncomplicated caesarean section and no contraindications to vaginal delivery. Eligible consented participants with term singleton pregnancies and unfavourable cervical scores (?5) requiring labour induction undergo stratified randomisation based on parity and are assigned either FCB (n=50) or PGE2 (n=50). Treatments are applied for up to 12?hours with serial monitoring of the mother and the fetus and serial assessment for improved cervical scores. If the cervix is still unfavourable, participants are allowed a further 12?hours' observation for cervical ripening. Active labour is initiated by amniotomy at cervical scores of ?6. The primary outcome is the rate of change in the cervical score, and secondary outcomes include active labour within 24?hours of induction, vaginal delivery, time-to-delivery interval and uterine hyperstimulation. All analyses will be intention-to-treat. The data generated in this trial may guide a change in practice towards mechanical labour induction if this proves efficient and safer for women attempting TOLAC compared with PGE2, to improve labour management in this high-risk population. ETHICS AND DISSEMINATION:Ethical approval is granted by the Domain Specific Review Board (Domain D) of the National Healthcare Group, Singapore. All adverse events will be reported within 24?hours of notification for assessment of causality. Data will be published and will be available for future meta-analyses. TRIAL REGISTRATION NUMBER:NCT03471858; Pre-results.

Project description:BackgroundRupture of membranes (ROM) before the onset of uterine contractions, particularly in pregnancies less than 37 weeks gestational age, is a common diagnostic problem in obstetrical practice. Timely detection of ROM is vital to support gestational age-specific interventions to optimize perinatal outcomes and minimize the risk of serious complications such as preterm delivery, fetal distress and maternal/fetal infections. Rapid bedside immunoassay tests designed to detect amniotic fluid proteins in cervicovaginal fluids have emerged as valuable clinical tools to provide timely ROM diagnosis.MethodsIn this prospective observational study, two commercially-available immunoassay tests (ROM Plus®, AmniSure®) were evaluated concurrently in 111 pregnant women who presented with the chief complaint of ROM. Immunoassay results were compared to clinical parameters for determining ROM via comprehensive, retrospective clinical chart review. Diagnostic performance characteristics were calculated including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy.ResultsOverall, diagnostic performance characteristics were robust and similar between ROM Plus® and AmniSure®, respectively: sensitivity (96.4 and 89.3%), specificity (98.8 and 100%), PPV (96.4 and 100%), NPV (98.8% and 96.5) and accuracy (98.2 and 97.3%). For term patients (≥37 weeks gestation), the sensitivities were 93.8 and 81.3% and specificities were 97.1 and 100% for ROM Plus® and AmniSure®, respectively. For preterm patients (<37 weeks gestation), both immunoassay tests provided exact concordance with clinical confirmation of ROM resulting in 100% diagnostic accuracy.ConclusionsBoth rapid immunoassay tests provided similarly excellent diagnostic accuracy for the rapid detection of ROM with only two discrepant results for ROM Plus® and three discrepant results for AmniSure® compared to clinical confirmation. The findings from this study recommend these tests for pregnant women presenting with suspected ROM to guide correct clinical management decisions to improve obstetrical and neonatal outcomes.Trial registrationClinicalTrials.gov, NCT02208011 (1 August 2014).

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Labour classified by cervical dilatation & fetal membrane rupture demonstrates differential impact on RNA-seq data for human myometrium tissues

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