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OBJECTIVE: Women with a history of spontaneous preterm birth (sPTB) face an increased risk of recurrence. Yet, the factors contributing to the increased risk are unknown, hampering the development of targeted interventions. Noninvasive quantitative ultrasound (QUS) has been validated in the characterization of cervical tissue and has the potential to provide information about postpartum cervical remodeling. The objective of this study was to determine the postpartum cervical remodeling trajectories of women over 12 mo post-delivery and to determine whether there were differences between women who delivered full-term and spontaneous preterm that were sensitive to QUS biomarkers. METHODS: Data were collected prospectively from 55 women: 41 who delivered full-term and 14 who delivered spontaneously preterm at 6 wk, 3, 6, 9 and 12 mo (±2 wk) postpartum. Data from QUS biomarkers: Attenuation Coefficient; Backscatter Coefficient; Shear Wave Speed; and Lizzi-Feleppa Slope, Intercept and Midband were analyzed from the acquired radiofrequency data using a Siemens S2000 ultrasound system with a transvaginal MC 9-4 MHz probe. The biomarkers were analyzed using descriptive statistics and linear mixed-effects models. RESULTS: QUS biomarkers, Backscatter Coefficient and Lizzi-Feleppa Intercept showed significant differences during the year after delivery between women who had a full-term birth and sPTB (p < 0.05), suggesting that there are differences in the cervical remodeling trajectories between the two groups. All QUS biomarkers demonstrated significant variations between the full-term birth and sPTB groups over time (p < 0.05), indicating ongoing cervical remodeling for both groups during the 12-mo postpartum period. CONCLUSION: QUS biomarkers identified cervical microstructure differences and trajectories in the year after delivery between women who delivered full-term and spontaneous preterm.
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BACKGROUND: Historically, clinicians have relied on medical risk factors and clinical symptoms for preterm birth risk assessment. In nulliparous women, clinicians may rely solely on reported symptoms to assess for the risk of preterm birth. The routine use of ultrasound during pregnancy offers the opportunity to incorporate quantitative ultrasound scanning of the cervix to potentially improve assessment of preterm birth risk. OBJECTIVE: This study aimed to investigate the efficiency of quantitative ultrasound measurements at relatively early stages of pregnancy to enhance identification of women who might be at risk for spontaneous preterm birth. STUDY DESIGN: A prospective cohort study of pregnant women was conducted with volunteer participants receiving care from the University of Illinois Hospital in Chicago, Illinois. Participants received a standard clinical screening followed by 2 research screenings conducted at 20±2 and 24±2 weeks. Quantitative ultrasound scans were performed during research screenings by registered diagnostic medical sonographers using a standard cervical length approach. Quantitative ultrasound features were computed from calibrated raw radiofrequency backscattered signals. Full-term birth outcomes and spontaneous preterm birth outcomes were included in the analysis. Medically indicated preterm births were excluded from the analysis. Using data from each visit, logistic regression with Akaike information criterion feature selection was conducted to derive predictive models for each time frame based on historical clinical and quantitative ultrasound features. Model evaluations included a likelihood ratio test of quantitative ultrasound features, cross-validated receiver operating characteristic curve analysis, sensitivity, and specificity. RESULTS: On the basis of historical clinical features alone, the best predictive model had an estimated receiver operating characteristic area under the curve of 0.56±0.03. By the time frame of Visit 1, a predictive model using both historical clinical and quantitative ultrasound features provided a modest improvement in the area under the curve (0.63±0.03) relative to that of the predictive model using only historical clinical features. By the time frame of Visit 2, the predictive model using historical clinical and quantitative ultrasound features provided significant improvement (likelihood ratio test, P<.01), with an area under the curve of 0.69±0.03. CONCLUSION: Accurate identification of women at risk for spontaneous preterm birth solely through historical clinical features has been proven to be difficult. In this study, a history of preterm birth was the most significant historical clinical predictor of preterm birth risk, but the historical clinical predictive model performance was not statistically significantly better than the no-skill level. According to our study results, including quantitative ultrasound yields a statistically significant improvement in risk prediction as the pregnancy progresses.
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BACKGROUND: Spontaneous preterm birth occurs more frequently in multiple pregnancies. This syndrome has multiple triggers that result in a unified downstream pathway of cervical remodeling, uterine activity, and progressive cervical dilatation. Whilst the triggers for labor in multiple pregnancy may be different from singletons, the downstream changes will be the same. Identifying patients at risk of preterm birth is a priority as interventions to delay delivery and optimize the fetus can be initiated. Methods for screening for risk of preterm birth which focus on the detection of cervical remodeling may therefore have potential in this population. METHODS: This review explores the evidence for the predictive utility for preterm birth of several published techniques that assess the physical, biomechanical, and optical properties of the cervix, with a focus on those which have been studied in multiple pregnancies and highlighting targets for future research in this population. RESULTS: Fifteen techniques are discussed which assess the physical, biomechanical, and optical properties of the cervix in pregnancy. Of these, only three techniques that evaluated the predictive accuracy of a technique in patients with multiple pregnancies were identified: uterocervical angle, cervical consistency index, and cervical elastography. Of these, measurement of the uterocervical angle has the strongest evidence. Several techniques have shown predictive potential in singleton pregnancies, but have not yet been studied in multiple pregnancies, which would be a logical expansion of research. CONCLUSION: Research on techniques with predictive utility for PTB in patients with multiple pregnancies is limited but should be a research priority. Overall, the theory supports the investigation of cervical remodeling as a predictor of PTB, and there are numerous techniques in development that may have potential in this field.
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Nacimiento Prematuro , Embarazo , Femenino , Humanos , Recién Nacido , Nacimiento Prematuro/epidemiología , Cuello del Útero/diagnóstico por imagen , Medición de Longitud Cervical/métodos , Embarazo MúltipleRESUMEN
The latent phase of labor extends from the initiation of labor to the onset of the active phase. Because neither margin is always precisely identifiable, the duration of the latent phase often can only be estimated. During this phase, the cervix undergoes a process of rapid remodeling, which may have begun gradually weeks before. As a consequence of extensive changes in its collagen and ground substance, the cervix softens, becomes thinner and dramatically more compliant, and may dilate modestly. All of these changes prepare the cervix for the more rapid dilatation that will occur during the active phase to follow. For the clinician, it is important to recognize that the latent phase may normally extend for many hours. The normal limit for the duration of the latent phase should be considered to be approximately 20 hours in a nullipara and 14 hours in a multipara. Factors that have been associated with a prolonged latent phase include deficient prelabor or intrapartum cervical remodeling, excessive maternal analgesia or anesthesia, maternal obesity, and chorioamnionitis. Approximately 10% of women with a prolonged latent phase are actually in false labor, and their contractions eventually abate spontaneously. The management of a prolonged latent phase involves either augmenting uterine activity with oxytocin or providing a sedative-induced period of maternal rest. Both are equally effective in advancing the labor to active phase dilatation. A very long latent phase may be a harbinger of other labor dysfunctions.
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Corioamnionitis , Trabajo de Parto , Embarazo , Femenino , Humanos , Trabajo de Parto Inducido , Factores de Tiempo , Oxitocina , Primer Periodo del Trabajo de PartoRESUMEN
OBJECTIVE: Predicting women at risk for spontaneous pre-term birth (sPTB) has been medically challenging because of the lack of signs and symptoms of pre-term birth until interventions are too late. We hypothesized that prediction of the sPTB risk level is enhanced when using both historical clinical (HC) data and quantitative ultrasound (QUS) data compared with using only HC data. HC data defined herein included birth history prior to that of the current pregnancy as well as, from the current pregnancy, a clinical cervical length assessment and physical examination data. METHODS: The study population included 248 full-term births (FTBs) and 26 sPTBs. QUS scans (Siemens S2000 and MC9-4) were performed by registered diagnostic medical sonographers using a standard cervical length approach. Two cervical QUS scans were conducted at 20 ± 2 and 24 ± 2 wk of gestation. Multiple QUS features were evaluated from calibrated raw radiofrequency backscattered ultrasonic signals. Two statistical models designed to determine sPTB risk were compared: (i) HC data alone and (ii) combined HC and QUS data. Model comparisons included a likelihood ratio test, cross-validated receiver operating characteristic area under the curve, sensitivity and specificity. The study's birth outcomes were only FTBs and sPTBs; medically induced pre-term births were not included. DISCUSSION: Combined HC and QUS data identified women at risk of sPTB with better AUC (0.68, 95% confidence interval [CI]: 0.57-0.78) compared with HC data alone (0.53, 95% CI: 0.40-0.66) and HC data + cervical length at 18-20 wk of gestation (average AUC = 0.51, 95% CI: 0.38-0.64). A likelihood ratio test for significance of QUS features in the classification model was highly statistically significant (p < 0.01). CONCLUSION: Even with only 26 sPTBs among 274 births, value was added in predicting sPTB when QUS data were included with HC data.
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Nacimiento Prematuro , Nacimiento a Término , Embarazo , Humanos , Femenino , Nacimiento Prematuro/diagnóstico por imagen , Nacimiento Prematuro/epidemiología , Medición de Longitud Cervical/efectos adversos , Cuello del Útero/diagnóstico por imagen , Sensibilidad y EspecificidadRESUMEN
The remodeling of the cervix from a closed rigid structure to one that can open sufficiently for passage of a term infant is achieved by a complex series of molecular events that in large part are regulated by the steroid hormones progesterone and estrogen. Among hormonal influences, progesterone exerts a dominant role for most of pregnancy to initiate a loss of tissue strength yet maintain competence in a phase termed softening. Equally important are the molecular events that abrogate progesterone function in late pregnancy to allow a loss of tissue competence and strength during cervical ripening and dilation. In this review, we focus on current understanding by which progesterone receptor signaling for the majority of pregnancy followed by a loss/shift in progesterone receptor action at the end of pregnancy, collectively ensure cervical remodeling as necessary for successful parturition.
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Cuello del Útero , Progesterona , Maduración Cervical , Cuello del Útero/fisiología , Estrógenos , Femenino , Humanos , Embarazo , Receptores de ProgesteronaRESUMEN
BACKGROUND: Spontaneous preterm birth remains the main driver of childhood morbidity and mortality. Because of an incomplete understanding of the molecular pathways that result in spontaneous preterm birth, accurate predictive markers and target therapeutics remain elusive. OBJECTIVE: This study sought to determine if a cell-free RNA profile could reveal a molecular signature in maternal blood months before the onset of spontaneous preterm birth. STUDY DESIGN: Maternal samples (n=242) were obtained from a prospective cohort of individuals with a singleton pregnancy across 4 clinical sites at 12-24 weeks (nested case-control; n=46 spontaneous preterm birth <35 weeks and n=194 term controls). Plasma was processed via a next-generation sequencing pipeline for cell-free RNA using the Mirvie RNA platform. Transcripts that were differentially expressed in next-generation sequencing cases and controls were identified. Enriched pathways were identified in the Reactome database using overrepresentation analysis. RESULTS: Twenty five transcripts associated with an increased risk of spontaneous preterm birth were identified. A logistic regression model was developed using these transcripts to predict spontaneous preterm birth with an area under the curve =0.80 (95% confidence interval, 0.72-0.87) (sensitivity=0.76, specificity=0.72). The gene discovery and model were validated through leave-one-out cross-validation. A unique set of 39 genes was identified from cases of very early spontaneous preterm birth (<25 weeks, n=14 cases with time to delivery of 2.5±1.8 weeks); a logistic regression classifier on the basis of these genes yielded an area under the curve=0.76 (95% confidence interval, 0.63-0.87) in leave-one-out cross validation. Pathway analysis for the transcripts associated with spontaneous preterm birth revealed enrichment of genes related to collagen or the extracellular matrix in those who ultimately had a spontaneous preterm birth at <35 weeks. Enrichment for genes in insulin-like growth factor transport and amino acid metabolism pathways were associated with spontaneous preterm birth at <25 weeks. CONCLUSION: Second trimester cell-free RNA profiles in maternal blood provide a noninvasive window to future occurrence of spontaneous preterm birth. The systemic finding of changes in collagen and extracellular matrix pathways may serve to identify individuals at risk for premature cervical remodeling, with growth factor and metabolic pathways implicated more often in very early spontaneous preterm birth. The use of cell-free RNA profiles has the potential to accurately identify those at risk for spontaneous preterm birth by revealing the underlying pathophysiology, creating an opportunity for more targeted therapeutics and effective interventions.
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Ácidos Nucleicos Libres de Células , Nacimiento Prematuro , Ácidos Nucleicos Libres de Células/genética , Cuello del Útero , Femenino , Humanos , Recién Nacido , Embarazo , Nacimiento Prematuro/genética , Estudios Prospectivos , ARNRESUMEN
Appropriate timing of cervical remodeling (CR) is key to normal term parturition. To date, mechanisms behind normal and abnormal (premature or delayed) CR remain unclear. Recent studies show regional differences exist in human cervical tissue structure. While the entire cervix contains extracellular matrix (ECM), the internal os is highly cellular containing 50-60% cervical smooth muscle (CSM). The external os contains 10-20% CSM. Previously, we reported ECM rigidity and different ECM proteins influence CSM cell function, highlighting the importance of understanding not only how cervical cells orchestrate cervical ECM remodeling in pregnancy, but also how changes in specific ECM proteins can influence resident cellular function. To understand this dynamic process, we utilized a systematic proteomic approach to understand which soluble ECM and cellular proteins exist in the different regions of the human cervix and how the proteomic profiles change from the non-pregnant (NP) to the pregnant (PG) state. We found the human cervix proteome contains at least 4548 proteins and establish the types and relative abundance of cellular and soluble matrisome proteins found in the NP and PG human cervix. Further, we report the relative abundance of proteins involved with elastic fiber formation and ECM organization/degradation were significantly increased while proteins involved in RNA polymerase I/promoter opening, DNA methylation, senescence, immune system, and compliment activation were decreased in the PG compared to NP cervix. These findings establish an initial platform from which we can further comprehend how changes in the human cervix proteome results in normal and abnormal CR.
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Cuello del Útero , Nacimiento Prematuro , Cuello del Útero/metabolismo , Matriz Extracelular/metabolismo , Femenino , Humanos , Embarazo , Nacimiento Prematuro/metabolismo , Proteoma/metabolismo , ProteómicaRESUMEN
Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. The ability to predict patients at risk for preterm birth remains a major health challenge. The currently available clinical diagnostics such as cervical length and fetal fibronectin may detect only up to 30% of patients who eventually experience a spontaneous preterm birth. This paper reviews ongoing efforts to improve the ability to conduct a risk assessment for preterm birth. In particular, this work focuses on quantitative methods of imaging using ultrasound-based techniques, magnetic resonance imaging, and optical imaging modalities. While ultrasound imaging is the major modality for preterm birth risk assessment, a summary of efforts to adopt other imaging modalities is also discussed to identify the technical and diagnostic limits associated with adopting them in clinical settings. We conclude the review by proposing a new approach using combined photoacoustic, ultrasound, and elastography as a potential means to better assess cervical tissue remodeling, and thus improve the detection of patients at-risk of PTB.
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Diagnóstico por Imagen de Elasticidad , Nacimiento Prematuro , Medición de Longitud Cervical , Cuello del Útero/diagnóstico por imagen , Femenino , Fibronectinas , Humanos , Recién Nacido , Embarazo , Nacimiento Prematuro/diagnóstico por imagenRESUMEN
OBJECTIVE: The aim: To evaluate the prevalence of preterm birth and to determine the role of cervicitis as a cause of preterm birth in women in Ukraine. PATIENTS AND METHODS: Materials and methods: We conducted a retrospective multicentre cohort study from January 1st, 2019 to December 31st, 2021. This study included pregnant women aged 17-50 years admitted to the labor ward at the 13 hospitals from 10 regions of Ukraine. RESULTS: Results: Of the 8151 participants, the prevalence of preterm birth was 2226 (27.3%, [95% CI 26.8 - 27.8]) whereas 5925 (72.7% [95% CI 72.2-73.2]) delivered at term. Preterm birth associated with cervicitis was 76.3% (4,388/2666). History of cervicitis, maternal age, previous preterm labor or premature birth, and pregnancy with twins, triplets or other multiples were identified as independent risk factors of preterm birth. CONCLUSION: Conclusions: Preterm birth in Ukraine is widespread, the number of which tends to increase. Infection and inflammation of the cervix seem to play a significant role for preterm birth. Early detection and treatment of cervicitis can reduce the risk of preterm birth. Women who have a history of poor pregnancy outcomes are at greater risk of poor outcomes in following pregnancies. Health providers should be aware of this risk when treating patients with a history of poor pregnancy outcomes.
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Trabajo de Parto Prematuro , Nacimiento Prematuro , Cervicitis Uterina , Embarazo , Femenino , Recién Nacido , Humanos , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/etiología , Cervicitis Uterina/complicaciones , Cervicitis Uterina/epidemiología , Estudios de Cohortes , Trabajo de Parto Prematuro/epidemiología , Trabajo de Parto Prematuro/etiología , Resultado del Embarazo/epidemiologíaRESUMEN
The cervix acts as a dynamic barrier between the uterus and vagina, retaining the fetus during pregnancy and allowing birth at term. Critical to this function, the physical properties of the cervix change, or remodel, but abnormal remodeling can lead to preterm birth (PTB). Although cervical remodeling has been studied, the complex 3D cervical microstructure has not been well-characterized. In this complex, dynamic, and heterogeneous tissue microenvironment, the microstructural changes are likely also heterogeneous. Using quantitative, 3D, second-harmonic generation microscopy, we demonstrate that rat cervical remodeling during pregnancy is not uniform across the cervix; the collagen fibers orient progressively more perpendicular to the cervical canals in the inner cervical zone, but do not reorient in other regions. Furthermore, regions that are microstructurally distinct early in pregnancy become more similar as pregnancy progresses. We use a finite element simulation to show that heterogeneous regional changes influence cervical funneling, an important marker of increased risk for PTB; the internal cervical os shows â¼6.5x larger radial displacement when fibers in the inner cervical zone are parallel to the cervical canals compared to when fibers are perpendicular to the canals. Our results provide new insights into the microstructural and tissue-level cervical changes that have been correlated with PTB and motivate further clinical studies exploring the origins of cervical funneling. STATEMENT OF SIGNIFICANCE: Cervical funneling, or dilation of the internal cervical os, is highly associated with increased risk of preterm birth. This study explores the 3D microstructural changes of the rat cervix during pregnancy and illustrates how these changes influence cervical funneling, assuming similar evolution in rats and humans. Quantitative imaging showed that microstructural remodeling during pregnancy is nonuniform across cervical regions and that initially distinct regions become more similar. We report, for the first time, that remodeling of the inner cervical zone can influence the dilation of the internal cervical os and allow the cervix to stay closed despite increased intrauterine pressure. Our results suggest a possible relationship between the microstructural changes of this zone and cervical funneling, motivating further clinical investigations.
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Cuello del Útero , Nacimiento Prematuro , Animales , Cuello del Útero/diagnóstico por imagen , Simulación por Computador , Femenino , Embarazo , Nacimiento Prematuro/etiología , Ratas , ÚteroRESUMEN
The cervical remodeling process during pregnancy is characterized by progressive compositional and structural changes in the tissues extra-cellular matrix (ECM). Appropriately timed remodeling is critical for healthy gestation and prevention of premature cervical softening leading to preterm birth (PTB). Modification of the ECM glycosaminoglycans (GAGs) content with advancing pregnancy, especially the non-sulfated GAG hyaluronan (HA), is a fundamental change associated with cervical remodeling. While GAGs have numerous physiological roles, the mechanical consequence of evolving GAG content on cervical structure-function behavior remains an open question. Additionally, an understanding of cervical swelling properties, postulated to be regulated in part by GAGs, is required for the appropriate definition of a reference configuration for mechanical tests and to enhance biological understanding. To investigate cervical swelling, osmotic loading tests are conducted on isolated wild type mouse cervices throughout pregnancy. These tests are performed in various osmolarity solutions to assess the influence of the media on swelling kinetics. A genetically altered strain of mice with depletion of cervical HA is also tested to elucidate the contribution of HA to tissue swelling. Results show ex vivo cervical swelling is significant with volume changes ranging from 20 to 100% after 3h of free swelling. The swelling kinetics depend highly on osmolarity of the media and is altered with advancing pregnancy. The contribution of HA to swelling is only significant in hypo-osmotic solution when HA cervical content is high at the end of pregnancy. In summary, it is critical to account for swelling deformation mechanisms after excision in mechanical experiments. STATEMENT OF SIGNIFICANCE: The cervical extracellular matrix (ECM) undergoes drastic changes to fulfill the functional change of the cervix during pregnancy. Inappropriate timing for this transformation can result in preterm birth, a severe clinical challenge. One of the fundamental changes of the cervical ECM is the significant modification of the glycosaminoglycan content, especially hyaluronan (HA), which is thought to contribute significantly to the swelling and mechanical properties of the cervix. This study aims to measure the swelling kinetics of cervical tissue during pregnancy and to investigate the role of HA in these swelling tendencies. Results show the significant swelling of cervical tissue, which evolves as pregnancy progresses, highlighting a key material property feature of the remodeled cervix. Using a mouse strain with a cervical HA depletion, this work shows HA contributes to the swelling trends of late-term cervical tissue, in a hypo-osmotic solution.
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Ácido Hialurónico , Nacimiento Prematuro , Animales , Cuello del Útero , Femenino , Cinética , Ratones , Concentración Osmolar , EmbarazoRESUMEN
During gestation, the female reproductive tract must maintain pregnancy while concurrently preparing for parturition. Here, we explore the transitions in gene expression and protein turnover (fractional synthesis rates [FSR]) by which the cervix implements a transition from rigid to compliant. Shifts in gene transcription to achieve immune tolerance and alter epithelial cell programs begin in early pregnancy. Subsequently, in mid-to-late pregnancy transcriptional programs emerge that promote structural reorganization of the extracellular matrix (ECM). Stable isotope labeling revealed a striking slowdown of overall FSRs across the proteome on gestation day 6 that reverses in mid-to-late pregnancy. An exception was soluble fibrillar collagens and proteins of collagen assembly, which exhibit high turnover in nonpregnant cervix compared with other tissues and FSRs that continue throughout pregnancy. This finding provides a mechanism to explain how cross-linked collagen is replaced by newly synthesized, less cross-linked collagens, which allows increased tissue compliance during parturition. The rapid transition requires a reservoir of newly synthesized, less cross-linked collagens, which is assured by the high FSR of soluble collagens in the cervix. These findings suggest a previously unrecognized form of "metabolic flexibility" for ECM in the cervix that underlies rapid transformation in compliance to allow parturition.
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Cuello del Útero/fisiología , Matriz Extracelular/metabolismo , Preñez/metabolismo , Proteoma , Transcriptoma , Animales , Femenino , Ratones , EmbarazoRESUMEN
Approximately 40% of cases of spontaneous preterm birth (sPTB) are associated with ascending intrauterine infections. The cervix serves as a physical and immunological gatekeeper, preventing the ascent of microorganisms from the vagina to the amniotic cavity. The cervix undergoes remodeling during pregnancy. It remains firm and closed from the start until the late third trimester of pregnancy and then dilates and effaces to accommodate the passage of the fetus during delivery. Remodeling proceeds appropriately and timely to maintain the pregnancy until term delivery. However, risk factors, such as acute and chronic infection and local inflammation in the cervix, may compromise cervical integrity and result in premature remodeling, predisposing to sPTB. Previous clinical studies have established bacterial (i.e., chlamydia, gonorrhea, mycoplasma, etc.) and viral infections (i.e., herpesviruses and human papillomaviruses) as risk factors of PTB. However, the exact mechanism leading to PTB is still unknown. This review focuses on: (1) the epidemiology of cervical infections in pregnant patients; (2) cellular mechanisms that may explain the association of cervical infections to premature cervical ripening and PTB; (3) endogenous defense mechanisms of the cervix that protect the uterine cavity from infection and inflammation; and (4) potential inflammatory biomarkers associated with cervical infection that can serve as prognostic markers for premature cervical ripening and PTB. This review will provide mechanistic insights on cervical functions to assist in managing cervical infections during pregnancy.
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Spontaneous preterm birth (sPTB), a major cause of infant morbidity and mortality, must involve premature cervical softening/dilation for a preterm vaginal delivery to occur. Yet, the mechanism behind premature cervical softening/dilation in humans remains unclear. We previously reported the non-pregnant human cervix contains considerably more cervical smooth muscle cells (CSMC) than historically appreciated and the CSMC organization resembles a sphincter. We hypothesize that premature cervical dilation leading to sPTB may be due to (1) an inherent CSMC contractility defect resulting in sphincter failure and/or (2) altered cervical extracellular matrix (ECM) rigidity which influences CSMC contractility. To test these hypotheses, we utilized immunohistochemistry to confirm this CSMC phenotype persists in the human pregnant cervix and then assessed in vitro arrays of contractility (F:G actin ratios, PDMS pillar arrays) using primary CSMC from pregnant women with and without premature cervical failure (PCF). We show that CSMC from pregnant women with PCF do not have an inherent CSMC contractility defect but that CSMC exhibit decreased contractility when exposed to soft ECM. Given this finding, we used UPLC-ESI-MS/MS to evaluate collagen cross-link profiles in the cervical tissue from non-pregnant women with and without PCF and found that women with PCF have decreased collagen cross-link maturity ratios, which correlates to softer cervical tissue. These findings suggest having soft cervical ECM may lead to decreased CSMC contractile tone and a predisposition to sphincter laxity that contributes to sPTB. Further studies are needed to explore the interaction between cervical ECM properties and CSMC cellular behavior when investigating the pathophysiology of sPTB.
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Cuello del Útero/patología , Matriz Extracelular/patología , Miocitos del Músculo Liso/patología , Miometrio/patología , Nacimiento Prematuro/patología , Contracción Uterina , Actinas/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Cuello del Útero/metabolismo , Cuello del Útero/fisiopatología , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Femenino , Humanos , Miocitos del Músculo Liso/metabolismo , Miometrio/metabolismo , Miometrio/fisiopatología , Fenotipo , Embarazo , Nacimiento Prematuro/metabolismo , Nacimiento Prematuro/fisiopatologíaRESUMEN
Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R2 = 0.75) and interleukin-8 (R2 = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.
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Cuello del Útero/patología , Nacimiento Prematuro/inmunología , Progranulinas/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Adulto , Animales , Moco del Cuello Uterino/inmunología , Moco del Cuello Uterino/metabolismo , Cuello del Útero/inmunología , Modelos Animales de Enfermedad , Femenino , Antagonistas de Hormonas/administración & dosificación , Humanos , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Edad Materna , Ratones , Mifepristona/administración & dosificación , Modelos Animales , Embarazo , Segundo Trimestre del Embarazo/inmunología , Nacimiento Prematuro/inducido químicamente , Nacimiento Prematuro/patología , Progesterona/administración & dosificación , Progesterona/antagonistas & inhibidores , Progesterona/metabolismo , Progranulinas/análisis , Inhibidor Secretorio de Peptidasas Leucocitarias/análisis , Regulación hacia Arriba/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: Accurate prediction of spontaneous preterm labor/preterm birth in asymptomatic women remains an elusive clinical challenge because of the multi-etiological nature of preterm birth. OBJECTIVE: The aim of this study was to develop and validate an immunoassay-based, multi-biomarker test to predict spontaneous preterm birth. MATERIALS AND METHODS: This was an observational cohort study of women delivering from December 2017 to February 2019 at 2 maternity hospitals in Melbourne, Australia. Cervicovaginal fluid samples were collected from asymptomatic women at gestational week 16+0-24+0, and biomarker concentrations were quantified by enzyme-linked immunosorbent assay. Women were assigned to a training cohort (n = 136) and a validation cohort (n = 150) based on chronological delivery dates. RESULTS: Seven candidate biomarkers representing key pathways in utero-cervical remodeling were discovered by high-throughput bioinformatic search, and their significance in both in vivo and in vitro studies was assessed. Using a combination of the biomarkers for the first 136 women allocated to the training cohort, we developed an algorithm to stratify term birth (n = 124) and spontaneous preterm birth (n = 12) samples with a sensitivity of 100% (95% confidence interval, 76-100%) and a specificity of 74% (95% confidence interval, 66-81%). The algorithm was further validated in a subsequent cohort of 150 women (n = 139 term birth and n = 11 preterm birth), achieving a sensitivity of 91% (95% confidence interval, 62-100%) and a specificity of 78% (95% confidence interval, 70-84%). CONCLUSION: We have identified a panel of biomarkers that yield clinically useful diagnostic values when combined in a multiplex algorithm. The early identification of asymptomatic women at risk for preterm birth would allow women to be triaged to specialist clinics for further assessment and appropriate preventive treatment.
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Trabajo de Parto Prematuro , Nacimiento Prematuro , Australia , Biomarcadores , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Trabajo de Parto Prematuro/diagnóstico , Embarazo , Nacimiento Prematuro/diagnósticoRESUMEN
The cervix plays an integral part in ensuring the proper timing of pregnancy and parturition. It maintains the fetus within the uterus and protects it from pathogens present in the vaginal canal. The cervix undergoes extensive remodeling during pregnancy and parturition. This process is associated with collagen degradation, an increase in immune cell response and inflammation in the cervix. However, our understanding of the role of cervical smooth muscles and their contribution to cervical remodeling is still lacking. In this paper, we propose that the active contractile function of the cervix influences cervical remodeling during pregnancy and parturition. Contraction of the cervical smooth muscles helps the cervix to remain firm and closed during early pregnancy, while relaxation of the cervical smooth muscles help facilitate cervical dilatation during labor. This contractile function of the cervix can be influenced by endocrine signals, such as estrogen, progesterone, and oxytocin; local paracrine signals, such as inflammatory chemokines and cytokines, as well as extracellular vesicles, such as exosomes and ectosomes; and by pharmacological agents used for cervical ripening and the induction of labor. A deeper understanding of the role of smooth muscles in cervical remodeling can help us elucidate the cellular processes in the cervix during pregnancy and parturition. This can also help in finding critical signaling pathways and therapeutic targets in the cervix that may decrease the rates of premature cervical ripening and preterm birth.
Asunto(s)
Cuello del Útero , Nacimiento Prematuro , Maduración Cervical , Femenino , Humanos , Recién Nacido , Parto , Embarazo , ProgesteronaRESUMEN
Preterm birth, defined as delivery at less than 37 weeks' gestation, increases maternal-fetal morbidity and mortality and places heavy financial and emotional burdens on families and society. Although premature cervical remodeling is a major factor in many preterm deliveries, how and why this occurs is poorly understood. This review describes existing and emerging imaging techniques and their advantages and disadvantages in assessing cervical remodeling. Brightness mode (B-mode) ultrasound is used to measure the cervical length, currently the gold standard for determining risk of preterm birth. Several new B-mode ultrasound techniques are being developed, including measuring attenuation, cervical gland area, and the cervical consistency index. Shear wave speed can differentiate between soft (ripe) and firm (unripe) cervices by measuring the speed of ultrasound through a tissue. Elastography provides qualitative information regarding cervical stiffness by compressing the tissue with the ultrasound probe. Raman spectroscopy uses a fiber optic probe to assess the biochemical composition of the cervix throughout pregnancy. Second harmonic generation microscopy uses light to quantify changes in collagen fiber structure and size during cervical maturation. Finally, photoacoustic endoscopy records light-induced sound to determine optical characteristics of cervical tissue. In the long term, a combination of several imaging approaches, combined with consideration of clinical epidemiologic characteristics, will likely be required to accurately predict preterm birth.
Asunto(s)
Cuello del Útero , Nacimiento Prematuro , Cuello del Útero/diagnóstico por imagen , Femenino , Humanos , Recién Nacido , Embarazo , Nacimiento Prematuro/diagnóstico por imagenRESUMEN
PROBLEM: A breakdown of the cervical epithelial barrier has been associated with preterm cervical remodeling. It is unknown if Replens, the vehicle for vaginal progesterone, alters cervical epithelial junctional proteins impacting cervical remodeling and preterm birth. METHOD OF STUDY: E17 CD-1 pregnant mice received an intrauterine injection of saline or lipopolysaccharide (LPS). Effect of intravaginal Replens given on day E16 and on E17 coincident with LPS was tested. A second experiment determined if an antibody to the interferon receptor (IFNaR) blocked the effects of LPS. Mice were killed after six hours, the preterm birth rate was recorded, and the serum and cervices were collected for analysis. Additionally, the epithelial cell barrier was assessed using an in vitro permeability assay. RESULTS: Replens decreased the rate of LPS-induced preterm birth within six hours, from 87.5% to 37.5% (P < .005). LPS + IFNaR antibody decreased the rate of preterm birth or vaginal bleeding compared to LPS + control antibody mice, 43.8% vs 87%, respectively (P < .01). E-Cadherin in the mouse serum was increased by LPS, an effect mitigated by treatment with Replens (P < .0001) or the IFNaR antibody (P < .01). Replens + LPS decreased the expression of IFN-ß (P < .01). The anti-IFNaR, as well as Replens, decreased the expression of MMP13 (P < .05) compared to LPS mice. Replens also prevented the LPS-induced increase in permeability (P < .001). CONCLUSION: Replens prevents preterm birth by decreasing the interferon-induced upregulation of MMP13 and the degradation of the cell adhesion protein E-Cadherin. Further studies are needed to determine if Replens can be useful as treatment for preterm birth.