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1.
J Matern Fetal Neonatal Med ; : 1-9, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34549687

RESUMO

PURPOSE: The cervix undergoes a dynamic remodeling process throughout pregnancy. Appropriate timing of cervical remodeling is essential in maintaining the fetus inside the uterus and ensuring cervical dilatation for safe delivery of the fetus at term. This study aims to determine the characteristics and trends of published articles in the field of cervical remodeling during pregnancy through a bibliometric analysis. MATERIALS AND METHODS: A systematic review of the literature on cervical remodeling during pregnancy was performed on using the Scopus database from inception to 2020. The following information was obtained for each article: authors, year of publication, title, journal, institution, country, title, keywords, citation frequency, and relative citation ratio. The visualization of collaboration networks of countries and keywords related to cervical remodeling during pregnancy was conducted using VOSviewer software. RESULTS: A total of 1979 bibliographic records were obtained from Scopus database. The number of publications increased in the 1980s and peaked in 2010. A total of 80 countries produced research in cervical remodeling during pregnancy. The USA contributed the greatest number of publications (n= 541), total citations (n= 11,971), and number of international collaborations (n= 28 countries). The American Journal of Obstetrics and Gynecology, Obstetrics and Gynecology, and BJOG: An International Journal of Obstetrics and Gynaecology are the top three contributors in this field in terms of number of publications and total citations. The Karolinska Institutet produced the greatest number of publications while UT Southwestern Medical Center was the most cited institution in this field. The topics of the top cited articles were studies regarding the role of collagen degradation in cervical remodeling during pregnancy; dynamics, anatomy, and physiology of cervical remodeling; and the use of misoprostol for cervical ripening and labor induction. CONCLUSIONS: Our bibliometric analysis shows the trends and development, scientific impact, and collaboration in the field of cervical remodeling research. These results show the important discoveries in the past and provided new avenues for scientific and clinical investigations in the field.

2.
Eur J Obstet Gynecol Reprod Biol ; 266: 23-30, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34560330

RESUMO

OBJECTIVE: Our objective was to examine if US obstetrician-gynecologists (OBGYNs) practice outside of evidenced-based guidelines and use a combination of interventions to prevent spontaneous preterm birth (sPTB). STUDY DESIGN: An electronic survey was distributed to members of the Pregnancy-Related Care Research Network (PRCRN), and also to members of the Society of Maternal-Fetal Medicine (SMFM). The survey consisted of questions regarding physician demographics, and the use of interventions to prevent sPTB in women with 1) a prior sPTB, 2) an incidental short cervix (no prior sPTB), and 3) a history of cervical insufficiency. RESULTS: The PRCRN response rate was 58.6% (283/483) with an additional 143 responses from SMFM members. Among PRCRN responders, 82.7% were general OBGYNs and 17.3% were Maternal-Fetal Medicine subspecialists. Respondents were from all geographic regions of the country; most practiced in a group private practice (42.6%) or academic institution (31.4%). In women with prior sPTB, 45.2% of respondents would consider combination therapy, most commonly weekly intramuscular progesterone (IM-P) and serial cervical length (CL) measurements. If the patient then develops a short cervix, 33.7% would consider adding an ultrasound-indicated cerclage. In women with an incidental short cervix, 66.8% of respondents were likely to recommend single therapy with daily vaginal progesterone (VP). If a patient developed an incidentally dilated cervix, 40.8% of PRCRN respondents would recommend dual therapy, most commonly cerclage + VP, whereas 64.3% of SMFM respondents were likely to continue with VP only. In women with a history of cervical insufficiency, 47% of PRCRN respondents indicated they would consider a combination of IM-P, history-indicated cerclage and serial CL measurements. CONCLUSION: Although not currently supported by evidence-based medicine, combination therapy is commonly being used by U.S. OBGYNs to prevent sPTB in women with risk factors such as prior sPTB, short or dilated cervix or more than one of these risks.


Assuntos
Cerclagem Cervical , Nascimento Prematuro , Administração Intravaginal , Medida do Comprimento Cervical , Colo do Útero/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/prevenção & controle , Progesterona
3.
Mol Cell Endocrinol ; 529: 111276, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33823217

RESUMO

The cervix undergoes extensive remodeling throughout pregnancy and parturition. This process involves both ECM collagen degradation and cellular remodeling, which includes cell proliferation, transition and migration. Progesterone (P4) has been used clinically to delay cervical ripening and prevent preterm birth (PTB). However, the mechanisms by which progesterone affects cell transition and the migration of cervical epithelial and stromal cells are not yet fully known. In this study, we documented the role of a gestational level of P4 in the cellular transition (epithelial-mesenchymal transition [EMT] and mesenchymal-epithelial transition [MET]), cell migration, and inflammatory responses of endocervical epithelial cells (EEC) and cervical stromal cells (CSC). EEC and CSC were treated with LPS and P4 for 6 days. The epithelial:mesenchymal ratio (regular microscopy and cell shape index analysis), shift in intermediate filaments (immunofluorescence microscopy and western blot analyses for cytokeratin [CK]-18 and vimentin), adhesion molecules and transcription factors (western blot analyses for E-cadherin, N-cadherin and SNAIL), were used to determine growth characteristics and EMT and MET changes in EEC and CSC under the indicated conditions. To test cell remodeling, scratch assays followed by cellular analyses as mentioned above were performed. Inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor α [TNFα]) and matrix metallopeptidase 9 (MMP9) were measured by ELISA. LPS promoted EMT (decreased cell shape index, decreased CK-18 and E-cadherin, increased vimentin, N-cadherin, and SNAIL), and increased IL-6 and MMP9 production by EEC. A gestational level of P4 prevented LPS-induced EMT in EEC and exhibited anti-inflammatory effect in both EEC and CSC. LPS slowed down wound healing in CSC but P4 treatment prevented the negative impact of LPS in CSC wound healing. These results may explain the cellular mechanisms by which P4 helps to stabilize the cervical epithelial barrier and preserve the mechanical and tensile strength of the cervical stromal layer, which are important in normal cervical remodeling processes during pregnancy.

4.
Ann Biomed Eng ; 49(8): 1923-1942, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33880632

RESUMO

The mechanical function of the uterus is critical for a successful pregnancy. During gestation, uterine tissue grows and stretches to many times its size to accommodate the growing fetus, and it is hypothesized the magnitude of uterine tissue stretch triggers the onset of contractions. To establish rigorous mechanical testing protocols for the human uterus in hopes of predicting tissue stretch during pregnancy, this study measures the anisotropic mechanical properties of the human uterus using optical coherence tomography (OCT), instrumented spherical indentation, and video extensometry. In this work, we perform spherical indentation and digital image correlation to obtain the tissue's force and deformation response to a ramp-hold loading regimen. We translate previously reported fiber architecture, measured via optical coherence tomography, into a constitutive fiber composite material model to describe the equilibrium material behavior during indentation. We use an inverse finite element method integrated with a genetic algorithm (GA) to fit the material model to our experimental data. We report the mechanical properties of human uterine specimens taken across different anatomical locations and layers from one non-pregnant (NP) and one pregnant (PG) patient; both patients had pathological uterine tissue. Compared to NP uterine tissue, PG tissue has a more dispersed fiber distribution and equivalent stiffness material parameters. In both PG and NP uterine tissue, the mechanical properties differ significantly between anatomical locations.

5.
Biol Reprod ; 105(1): 204-216, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-33760067

RESUMO

A physiologic increase in reactive oxygen species throughout pregnancy is required to remodel the cervix. Oxidative stress can cause cellular damage that contributes to dysfunctional tissue. This study determined the oxidative stress-induced cell fate of human cervical epithelial and cervical stromal cells. We treated the ectocervical and endocervical epithelial cells and cervical stromal cells with cigarette smoke extract, an oxidative stress inducer, for 48 h. Cell viability (crystal violet assay); cell cycle, apoptosis, and necrosis (flow cytometry); senescence (senescence-associated ß-galactosidase staining); autophagy (staining for autophagosome protein, microtubule-associated protein 1 light chain 3B); stress signaler p38 mitogen-activated protein kinases pathway activation (western blot analyses); and inflammation by measuring interleukin-6 (enzyme-linked immunosorbent assay) were conducted after 48 h of cigarette smoke extract treatment. Oxidative stress induced reactive oxygen species production in cervical cells, which was inhibited by N-acetylcysteine. Oxidative stress promoted cell cycle arrest and induced necrosis in cervical cells. High senescence and low autophagy were observed in cervical stromal cells under oxidative stress. Conversely, senescence was low and autophagy was high in endocervical epithelial cells. Oxidative stress induced p38 mitogen-activated protein kinases (p38MAPK) activation in all cervical cells but only increased interleukin-6 production by the ectocervical epithelial cells. Inhibition of interleukin-6 production by a p38 mitogen-activated protein kinases inhibitor confirmed the activation of an oxidative stress-induced pathway. In conclusion, oxidative stress can promote cell death and sterile inflammation that is mediated by p38 mitogen-activated protein kinases activation in the cellular components of the cervix. These cellular damages may contribute to the normal and premature cervical ripening, which can promote preterm birth.

6.
J Physiol Sci ; 71(1): 7, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33618673

RESUMO

BACKGROUND: Currently available tocolytic agents are not effective treatment for preterm labor beyond 48 h. A major reason is the development of maternal side effects which preclude the maintenance of an effective steady-state drug concentration. One strategy that can mitigate these side effects is utilizing synergistic drug combinations to reduce the drug concentrations necessary to elicit a clinical effect. We have previously shown that three anoctamin 1 (ANO1) antagonists mediate potent relaxation of precontracted human uterine smooth muscle (USM). In this study, we aimed to determine whether a combination of sub-relaxatory doses of tocolytic drugs in current clinical use [the L-type voltage-gated calcium channel (VGCC) blocker, nifedipine (NIF); and the ß2-adrenergic (ß2AR) agonist, terbutaline (TRB)] will potentiate USM relaxation with two ANO1 antagonists [benzbromarone (BB) and MONNA (MN)]. OBJECTIVE: This study sought to examine the synergistic potency and mechanistic basis of two ANO1 antagonists with currently available tocolytic drugs. Functional endpoints assessed included relaxation of pre-contracting pregnant human USM tissue, inhibition of intracellular calcium release, and reduction of spontaneous transient inward current (STIC) recordings in human uterine smooth muscle cells. METHODS: Human myometrial strips and primary human USM cells were used in organ bath and calcium flux experiments with different combinations of sub-threshold doses of ANO1 antagonists and terbutaline or nifedipine to determine if ANO1 antagonists potentiate tocolytic drugs. RESULTS: The combination of sub-threshold doses of two ANO1 antagonists and current tocolytic drugs demonstrate a significant degree of synergy to relax human pregnant USM compared to the effects achieved when these drugs are administered individually. CONCLUSION: A combination of sub-threshold doses of VGCC blocker and ß2AR agonist with ANO1 antagonists potentiates relaxation of oxytocin-induced contractility and calcium flux in human USM ex vivo. Our findings may serve as a foundation for novel tocolytic drug combinations.


Assuntos
Anoctamina-1/antagonistas & inibidores , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Terbutalina/farmacologia , Útero/fisiologia , Benzobromarona/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Gravidez , Técnicas de Cultura de Tecidos , Tocolíticos/farmacologia , Uricosúricos/farmacologia , ortoaminobenzoatos/farmacologia
7.
PLoS One ; 16(1): e0242118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33507927

RESUMO

Tissue mechanics is central to pregnancy, during which maternal anatomic structures undergo continuous remodeling to serve a dual function to first protect the fetus in utero while it develops and then facilitate its passage out. In this study of normal pregnancy using biomechanical solid modeling, we used standard clinical ultrasound images to obtain measurements of structural dimensions of the gravid uterus and cervix throughout gestation. 2-dimensional ultrasound images were acquired from the uterus and cervix in 30 pregnant subjects in supine and standing positions at four time points during pregnancy (8-14, 14-16, 22-24, and 32-34 weeks). Offline, three observers independently measured from the images of multiple anatomic regions. Statistical analysis was performed to evaluate inter-observer variance, as well as effect of gestational age, gravity, and parity on maternal geometry. A parametric solid model developed in the Solidworks computer aided design (CAD) software was used to convert ultrasonic measurements to a 3-dimensional solid computer model, from which estimates of uterine and cervical volumes were made. This parametric model was compared against previous 3-dimensional solid models derived from magnetic resonance frequency images in pregnancy. In brief, we found several anatomic measurements easily derived from standard clinical imaging are reproducible and reliable, and provide sufficient information to allow biomechanical solid modeling. This structural dataset is the first, to our knowledge, to provide key variables to enable future computational calculations of tissue stress and stretch in pregnancy, making it possible to characterize the biomechanical milieu of normal pregnancy. This vital dataset will be the foundation to understand how the uterus and cervix malfunction in pregnancy leading to adverse perinatal outcomes.


Assuntos
Colo do Útero , Idade Gestacional , Imageamento Tridimensional , Modelos Biológicos , Gravidez/fisiologia , Ultrassonografia Pré-Natal , Adulto , Colo do Útero/diagnóstico por imagem , Colo do Útero/fisiologia , Feminino , Humanos , Estudos Longitudinais
8.
Reprod Sci ; 28(1): 237-251, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32700284

RESUMO

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.

9.
Reprod Sci ; 27(9): 1802, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32671689

RESUMO

This article was updated to correct Joy Y. Vink's name in the author listing.

10.
Reprod Sci ; 27(9): 1791-1801, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32166706

RESUMO

Spontaneous preterm birth (sPTB) remains a worldwide healthcare challenge. Preterm labor (PTL) is thought to be the largest reversible cause of sPTB, but current tocolytic therapies are ineffective and associated with systemic side effects from chronic use. Therefore, identifying novel mechanisms that promote human uterine smooth muscle (hUSM) relaxation is essential to improving clinical management of PTL. Here, we aimed to determine if an extraocular opsin receptor (OPN 3,4,5) system is expressed in pregnant hUSM and to characterize how photo-mediated relaxation of pre-contracting hUSM may be facilitated by external application of light. Translational studies were performed with hUSM from healthy late gestation patients (n = 8) and non-pregnant, similarly aged patients undergoing hysterectomy (n = 4). First, RT-PCR screened for mRNA coding for components of the classical extraocular light receptors (OPN 3,4,5). We found a restricted repertoire of opsin receptors (OPN3) expressed in pregnant hUSM tissue. Immunohistochemistry was performed to confirm protein expression. Pre-contracting late gestation hUSM strips were studied in functional organ bath studies to determine if photo-mediated relaxation is intensity or wavelength dependent. Functional organ bath studies revealed acute photo-mediated relaxation occurring in an intensity- and wavelength-dependent manner. Finally, coimmunoprecipitation of OPN3 with Gs following light activation suggests that a component of photo-relaxation occurs via G protein-coupled receptor machinery. This is the first report of light-mediated relaxation of pre-contracted human myometrium. Activation of endogenous light receptors on human myometrium may become a novel, non-invasive tocolytic strategy.


Assuntos
Miométrio/metabolismo , Opsinas de Bastonetes/metabolismo , Contração Uterina/metabolismo , Útero/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Relaxamento Muscular/fisiologia , Nascimento Prematuro/metabolismo
11.
J Matern Fetal Neonatal Med ; 33(17): 2865-2871, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30572777

RESUMO

Objective: To examine the utility of fetal fibronectin (fFN) for predicting spontaneous preterm birth (PTB) in asymptomatic women with a cervical length (CL) ≤10 mm compared to those with a CL 11-25 mm.Methods: Data was collected on all women with nonanomalous singleton and twin gestations who underwent transvaginal CL at a single institution between 2009 and 2012. Women with an incidental short cervix (CL ≤ 25 mm) between 22 and 32 weeks who had an fFN result within 7 days thereafter were included. Indicated preterm deliveries at <14 days of fFN, women who underwent cerclage placement, and terminations of pregnancy were excluded. The primary outcome was spontaneous PTB within 7 and 14 days of the fFN. Sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) of fFN for a CL ≤ 10 mm was calculated for singletons and twins and compared to those with a CL 11-25 mm.Results: Of the 213 women included, 117 (54.9%) were singletons and 96 (45%) were twins. Baseline characteristics were similar between those with a CL ≤ 10 mm and with a CL 11-25 mm in both singletons and twins. The NPV of fFN for delivery within 7 days in singletons and twins with a CL ≤ 10 mm was 100%, similar to those with a CL 11-25 mm (93-100%). The NPV of fFN for delivery within 14 days in singletons and twins with a CL ≤ 10 mm remained high (87.5-100%) when compared to those with a CL 11-25 mm (93-100%). The PPV of fFN for delivery within 7 and 14 days in both singletons and twins with a CL ≤ 10 mm was low (10-25%) and similar to those with a CL 11-25 mm (7.1-24.4%).Conclusions: The NPV of fFN in asymptomatic singleton and twin pregnancies with a CL ≤ 10 mm is high and comparable to the NPV of fFN in women with a longer CL. Routine fFN collection in this select population should be considered as it may avoid unnecessary and costly admissions, as well as assist with timing of antenatal corticosteroids.


Assuntos
Gravidez de Gêmeos , Nascimento Prematuro , Medida do Comprimento Cervical , Colo do Útero/diagnóstico por imagem , Feminino , Fibronectinas , Humanos , Recém-Nascido , Gravidez
12.
Ultrasound Med Biol ; 46(1): 149-155, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31668428

RESUMO

The cervix has two biomechanical functions: to remain closed while the fetus develops throughout pregnancy, and to open for delivery of the fetus at full term. This dual function is principally attributed to collagen within the extracellular matrix (ECM). However, recent evidence suggests that other ECM, and non-ECM, components play a role as well. One component is smooth muscle cells arranged circumferentially near the internal os. In this study, we investigate correlations between cervical smooth muscle cell force generation and the effective scatterer diameter (ESD), a quantitative ultrasound parameter directly related to the acoustic impedance distribution and, therefore, a potential biomarker of muscle contractility. Using whole cervical slices (N = 5), we determined significant positive correlations (quantified with Pearson's r) between muscle force generation and ESD immediately after administration of oxytocin (median r = 0.90). In summary, the ESD may prove a useful biomarker for studying structure and function of cervical smooth muscle in vivo.


Assuntos
Colo do Útero/diagnóstico por imagem , Colo do Útero/fisiologia , Músculo Liso/diagnóstico por imagem , Músculo Liso/fisiologia , Contração Uterina , Feminino , Humanos , Técnicas In Vitro , Ultrassonografia/métodos
13.
J Biomech Eng ; 141(9)2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374123

RESUMO

The cervix is essential to a healthy pregnancy as it must bear the increasing load caused by the growing fetus. Preterm birth is suspected to be caused by the premature softening and mechanical failure of the cervix. The objective of this paper is to measure the anisotropic mechanical properties of human cervical tissue using indentation and video extensometry. The human cervix is a layered structure, where its thick stromal core contains preferentially aligned collagen fibers embedded in a soft ground substance. The fiber composite nature of the tissue provides resistance to the complex three-dimensional loading environment of pregnancy. In this work, we detail an indentation mechanical test to obtain the force and deformation response during loading which closely matches in vivo conditions. We postulate a constitutive material model to describe the equilibrium material behavior to ramp-hold indentation, and we use an inverse finite element method based on genetic algorithm (GA) optimization to determine best-fit material parameters. We report the material properties of human cervical slices taken at different anatomical locations from women of different obstetric backgrounds. In this cohort of patients, the anterior internal os (the area where the cervix meets the uterus) of the cervix is stiffer than the anterior external os (the area closest to the vagina). The anatomic anterior and posterior quadrants of cervical tissue are more anisotropic than the left and right quadrants. There is no significant difference in material properties between samples of different parities (number of pregnancies reaching viable gestation age).


Assuntos
Colo do Útero/citologia , Análise de Elementos Finitos , Teste de Materiais , Fenômenos Mecânicos , Adulto , Anisotropia , Fenômenos Biomecânicos , Colo do Útero/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Imagem Molecular , Estresse Mecânico
14.
AJP Rep ; 8(4): e315-e324, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30393580

RESUMO

Objective In 2017, the Society for Maternal-Fetal Medicine (SMFM) Guideline Committee reaffirmed that 17 α -hydroxyprogesterone caproate (17-OHPC) to prevent preterm birth (PTB) is underutilized. We sought to determine what drove progestogen treatment choice of obstetricians managing pregnant women with histories of 1+ singleton spontaneous PTBs (< 37 weeks) who then delivered singleton gestations within the previous 12 months. Subjects We recruited a nationally representative random sample of obstetricians to abstract medical records of study-qualified patients. Of the 423 study-qualified physicians contacted, 358 (85%) participated; 56 (16%) maternal fetal medicine specialists and 302 (84%) general obstetrician/gynecologists (OB/GYNs) extracted data from 991 eligible patient charts. Results Almost three-fourths of patients (73.6%) were treated with 17-OHPC; 18.6% received vaginal progesterone, and 11.8% were not treated. Key drivers of physicians' choice to (1) prescribe branded 17-OHPC were "FDA (Food and Drug Administration) approval" (52% relative influence [RI]) and "SMFM guidelines" (24% RI); (2) prescribe vaginal progesterone were "ease of administration" (32% RI) and "shortened cervix" (16% RI); and (3) not provide prophylaxis were "patient not informed of risk" (35% RI) and "no shortened cervix" (29% RI). Conclusion Study findings support SMFM's contention of continued 17-OHPC underutilization to prevent PTB. Need for additional physician education merits assessment along with appropriate follow-up actions.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30314740

RESUMO

Spontaneous preterm birth (SPTB), defined as delivery before 37 weeks' gestation, remains a significant obstetric dilemma even after decades of research in this field. Although trends from 2007 to 2014 showed the rate of preterm birth slightly decreased, the CDC recently reported the rate of preterm birth has increased for two consecutive years since 2014. Currently, 1 in 10 pregnancies in the US still end prematurely. In this chapter, we focus on the "compartment" of the cervix. The goal is to outline the current knowledge of normal cervical structure and function in pregnancy and the current knowledge of how the cervix malfunctions lead to SPTB. We review the mechanisms by which our current interventions are hypothesized to work. Finally, we outline gaps in knowledge and future research directions that may lead to novel and effective interventions to prevent premature cervical failure and SPTB.


Assuntos
Colo do Útero/fisiologia , Nascimento Prematuro/prevenção & controle , Animais , Cerclagem Cervical , Colo do Útero/diagnóstico por imagem , Colo do Útero/fisiopatologia , Feminino , Humanos , Pessários , Gravidez , Nascimento Prematuro/etiologia , Progesterona/farmacologia , Progesterona/uso terapêutico , Progestinas/farmacologia , Progestinas/uso terapêutico , Fatores de Risco
16.
J Smooth Muscle Res ; 54(0): 28-42, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29937453

RESUMO

BACKGROUND: Pre-term birth is a major health care challenge throughout the world, and preterm labor represents a potentially reversible component of this problem. Current tocolytics do not improve preterm labor beyond 48 h. We have previously shown that anoctamin 1 (ANO1) channel blockade results in relaxation of pre-contracted human uterine smooth muscle (USM). Three drug classes with reported medicinal effects in humans also have members with ANO1 antagonism. In this study, we compared the ability of representatives from these 3 classes to reduce human USM contractility and excitability. OBJECTIVE: This study sought to examine the comparative potency of 3 ANO1 antagonists on pregnant human USM relaxation, contraction frequency reduction, inhibition of intracellular calcium release and membrane hyperpolarization. METHODS: Experiments were performed using: 1) Ex vivo organ bath (human pregnant tissue), 2) Oxytocin-induced calcium flux (in vitro human USM cells) and 3) Membrane potential assay (in vitro human USM cells). RESULTS: Benzbromarone (BB) demonstrated the greatest potency among the compounds tested with respect to force, frequency inhibition, reducing calcium elevation and depolarizing membrane potential. CONCLUSION: While all 3 ANO1 antagonists attenuate pregnant human uterine tissue contractility and excitability, BB is the most potent tocolytic drug. Our findings may serve as a foundation for future structure-function analyses for novel tocolytic drug development.


Assuntos
Anoctamina-1/antagonistas & inibidores , Atividade Motora/fisiologia , Relaxamento Muscular/fisiologia , Miócitos de Músculo Liso/fisiologia , Miométrio/fisiologia , Proteínas de Neoplasias/antagonistas & inibidores , Tocolíticos/farmacologia , Contração Uterina/fisiologia , Feminino , Humanos , Atividade Motora/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miométrio/efeitos dos fármacos , Ocitócicos/farmacologia , Ocitocina/farmacologia , Gravidez , Contração Uterina/efeitos dos fármacos
17.
Reproduction ; 156(1): 71-79, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29712877

RESUMO

The cervix shortens and softens as its collagen microstructure remodels in preparation for birth. Altered cervical tissue collagen microstructure can contribute to a mechanically weak cervix and premature cervical dilation and delivery. To investigate the local microstructural changes associated with anatomic location and pregnancy, we used second-harmonic generation microscopy to quantify the orientation and spatial distribution of collagen throughout cervical tissue from 4 pregnant and 14 non-pregnant women. Across patients, the alignment and concentration of collagen within the cervix was more variable near the internal os and less variable near the external os. Across anatomic locations, the spatial distribution of collagen within a radial zone adjacent to the inner canal of the cervix was more homogeneous than that of a region comprising the middle and outer radial zones. Two regions with different collagen distribution characteristics were found. The anterior and posterior sections in the outer radial zone were characterized by greater spatial heterogeneity of collagen than that of the rest of the sections. Our findings suggest that the microstructural alignment and distribution of collagen varies with anatomic location within the human cervix. These observed differences in collagen microstructural alignment may reflect local anatomic differences in cervical mechanical loading and function. Our study deepens the understanding of specific microstructural cervical changes in pregnancy and informs investigations of potential mechanisms for normal and premature cervical remodeling.


Assuntos
Colo do Útero/diagnóstico por imagem , Colo do Útero/metabolismo , Colágeno/metabolismo , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Nascimento Prematuro , Tomografia de Coerência Óptica , Adulto Jovem
18.
Reprod Sci ; 25(11): 1589-1600, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29471754

RESUMO

BACKGROUND: Spontaneous preterm labor leading to preterm birth is a significant obstetric problem leading to neonatal morbidity and mortality. Current tocolytics are not completely effective and novel targets may afford a therapeutic benefit. OBJECTIVE: To determine whether the anoctamin (ANO) family, including the calcium-activated chloride channel ANO1, is present in pregnant human uterine smooth muscle (USM) and whether pharmacological and genetic modulation of ANO1 modulates USM contraction. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR), quantitative RT-PCR, and immunohistochemical staining were done to determine which members of the ANO family are expressed in human USM. Uterine smooth muscle strips were studied in an organ bath to determine whether ANO1 antagonists inhibit oxytocin-induced USM contractions. Anoctamin 1 small interfering RNA (siRNA) knockdown was performed to determine its effect on filamentous-/globular (F/G)-actin ratio, a measurement of actin polymerization's role in promoting smooth muscle contraction. RESULTS: Messenger RNA (mRNA) encoding all members of the ANO family (except ANO7) are expressed in pregnant USM tissue. Anoctamin 1 mRNA expression was decreased 15.2-fold in pregnant USM compared to nonpregnant. Anoctamin 1 protein is expressed in pregnant human USM tissue. Functional organ bath studies with pregnant human USM tissue demonstrated that the ANO1 antagonist benzbromarone attenuates the force and frequency of oxytocin-induced contractions. In human USM cells, siRNA knockdown of ANO1 decreases F-/G-actin ratios. CONCLUSION: Multiple members of the ANO family, including the calcium-activated chloride channel ANO1, are expressed in human USM. Antagonism of ANO1 by pharmacological inhibition and genetic knockdown leads to an attenuation of contraction in pregnant human USM. Anoctamin 1 is a potentially novel target for tocolysis.


Assuntos
Anoctamina-1/metabolismo , Miométrio/metabolismo , Proteínas de Neoplasias/metabolismo , Tocólise , Contração Uterina , Actinas/metabolismo , Anoctamina-1/antagonistas & inibidores , Anoctaminas/metabolismo , Feminino , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Ocitocina/administração & dosagem , Gravidez , Cultura Primária de Células , RNA Mensageiro/metabolismo
19.
Am J Obstet Gynecol ; 218(3): 368, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29175251
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