Equine cervical remodeling during placentitis and the prepartum period: a transcriptomic approach.

Cervical remodeling is a critical component in both term and preterm labor in eutherian mammals. However, the molecular mechanisms underlying cervical remodeling remain poorly understood in the mare. The current study compared the transcriptome of the equine cervix (cervical mucosa (CM) and stroma (CS)) during placentitis (placentitis group, n = 5) and normal prepartum mares (prepartum group, n = 3) to normal pregnant mares (control group, n = 4). Transcriptome analysis identified differentially expressed genes (DEGs) during placentitis (5310 in CM and 907 in CS) and during the normal prepartum period (189 in CM and 78 in CS). Our study revealed that cervical remodeling during placentitis was dominated by inflammatory signaling as reflected by the overrepresented toll-like receptor signaling, interleukin signaling, T cell activation, and B cell activation pathways. These pathways were accompanied by upregulation of several proteases, including matrix metalloproteinases (MMP1, MMP2, and MMP9), cathepsins (CTSB, CTSC, and CTSD) and a disintegrin and metalloproteinase with thrombospondin type 1 motifs (ADAMTS1, ADAMTS4, and ADAMTS5), which are crucial for degradation of cervical collagens during remodeling. Cervical remodeling during placentitis was also associated with upregulation of water channel-related transcripts (AQP9 and RLN), angiogenesis-related transcripts (NOS3, ENG1, THBS1, and RAC2), and aggrecan (ACAN), a hydrophilic glucosaminoglycan, with subsequent cervical hydration. The normal prepartum cervix was associated with upregulation of ADAMTS1, ADAMTS4, NOS3 and THBS1, which might reflect an early stage of cervical remodeling taking place in preparation for labor. In conclusion, our findings revealed the possible key regulators and mechanisms underlying equine cervical remodeling during placentitis and the normal prepartum period.

Chlamydia muridarum infection differentially alters smooth muscle function in mouse uterine horn and cervix.

Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum (Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi; P < 0.001 and P < 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi (P < 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF2α) by 53-83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice (P < 0.01 to P < 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE2 in mouse uterine horn and cervix.

Evaluation of Cervical Elastography for Prediction of Spontaneous Preterm Birth in Low-Risk Women: A Prospective Study.

OBJECTIVES: The aim of this study was to determine whether cervical elastographic parameters in addition to cervical length (CL) during the 3 trimesters of pregnancy would be predictive of spontaneous preterm birth (sPTB) among low-risk women. METHODS: This work was a prospective nested case-control study evaluating cervical elastographic parameters and CL in low-risk women during the 3 trimesters of pregnancy. A binary logistic regression analysis was used to calculate significant covariates for prediction of sPTB. The area under the curve of the prediction model was calculated by using a receiver operating characteristic curve. RESULTS: There were 286 women (26 cases and 260 controls) included in the analysis. The parameters of cervical elasticity became softened and heterogeneous during the 3 trimesters of pregnancy in both women with and without sPTB. The differences in the mean strain value at the internal os of the cervix (IOS), ratio (strain ratio of the internal os to the external os) during the second trimester and the IOS during the third trimester between the groups had statistical significance (P < .01; P = .01; P < .01, respectively). The CL had no association with sPTB during the 3 trimesters. The IOS during the second trimester was a better predictor of sPTB, with an area under the curve of 0.730, and sensitivity was 72.73%. CONCLUSIONS: We observed multiple elastographic parameters and demonstrated the physiologic changes in the cervix during the 3 trimesters of pregnancy. Furthermore, we found that the IOS during the second trimester can be helpful in predicting sPTB. However, the CL had no association with sPTB during the 3 trimesters of pregnancy.

Influence of epidemiological characteristics (age, parity and other factors) in the assessment of healthy uterine cervical stiffness evaluated through shear wave elastography as a prior step to its use in uterine cervical pathology.

PURPOSE: The purpose of this study was to evaluate stiffness changes occurring in the healthy uterine cervix according to age, parity, phase of the menstrual cycle and other factors by shear wave elastography (SWE). METHODS: Evaluations of cervical speed and stiffness measurements were performed in 50 non-pregnant patients without gynaecological pathology using SWE transvaginal ultrasound. We performed the evaluation in the midsagittal plane of the uterine cervix with measurements at 0.5, 1 and 1.5 cm from external cervical os, at both anterior and posterior cervical lips. RESULTS: We evaluated 44 patients by SWE and obtained a total average velocity of 3.48 ± 1.08 m/s and stiffness of 42.39 ± 25.33 kPa. We found differences in speed and stiffness according to the cervical lip and depth evaluated; thus, we observed a velocity of 2.70 m/s at 0.5 cm of depth in the anterior lip and 3.53 m/s at 1.5 cm of depth in the posterior lip (p < 0.05). We observed differences according to parity, obtaining a wave transmission speed of 2.67 m/s and 4.41 m/s at the cervical canal of nulliparous and multiparous patients, respectively (p < 0 0.002). We observed differences according to patient age (from a speed of 2.75 m/s at the cervical canal in the age group of 20-35 years to 5.05 m/s in the age group > 50 years) (p < 0.008). We did not observe differences in speed or stiffness according to the phase of the menstrual cycle, BMI, smoking status or the presence or absence of non-HPV infections. CONCLUSIONS: The wave transmission speed and stiffness of the uterine cervix evaluated by SWE varies according to the cervical lip and depth of the evaluation as well as according to the parity and age of the patient.

Surgical resection based on ontogenetic cancer field theory for cervical cancer: mature results from a single-centre, prospective, observational, cohort study.

BACKGROUND: Previous findings from our centre suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. We aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumour control without the need for adjuvant radiotherapy. METHODS: We did the final clinical and histopathological evaluation of data from, the single-centre, observational, cohort study, the Leipzig School Mesometrial Resection Study. Patients of any age with stage IB1, IB2, IIA1, IIA2, or IIB cervical cancer (according to 2009 International Federation of Gynecology and Obstetrics [FIGO]) had total mesometrial resection or extended mesometrial resection and therapeutic lymph node dissection, done on the basis of ontogenetic cancer fields. We defined sentinel node, first-line, second-line, and third-line lymph node regions as progressive regional cancer fields. Primary outcomes were disease-specific survival and recurrence-free survival, and treatment-related morbidity (assessed with the Franco-Italian glossary). Applying Cox proportional hazard models, ontogenetic local (T) and regional (N) tumour staging was compared with pathological T and N staging. This trial is registered with the German Clinical Trials Register, number DRKS00015171. FINDINGS: Between Oct 16, 1999, and June 27, 2017, 523 patients were treated per protocol and followed up for a median of 61·8 months (IQR 49·3-94·8). In 495 patients with cervical cancer treated with cancer field surgery, 5-year disease-specific survival was 89·4% (95% CI 86·5-92·4) and recurrence-free survival was 83·1% (79·7-86·6). In the per-protocol population of 523 patients, treatment-related morbidity comprised 112 (21%) grade 2 and 15 (3%) grade 3 complications. The most common moderate and severe treatment-related complications and sequelae were wound dehiscence (17 [3%]), hydronephrosis (17 [3%]), bowel obstruction (26 [5%]), and lymph oedema (33 [6%]). One patient (<1%), who received total mesometrial resection, died from postoperative brain infarction. INTERPRETATION: Total or extended mesometrial resection with therapeutic lymph node dissection based on ontogenetic cancer fields results in good survival outcomes of patients with cervical cancer in our institution, but needs to be investigated further in multicentre trials. FUNDING: Leipzig School of Radical Pelvic Surgery, University of Leipzig Medical School, and the Gynecologic Oncology Research Foundation.

History-indicated cervical cerclage in management of twin pregnancy.

OBJECTIVE: Cervical cerclage, when performed in twin gestation, has been reported to be associated with poor outcome. However, the role of first-trimester history-indicated cerclage among women with a twin pregnancy and a history of preterm birth has not been evaluated. The aim of this study was to assess pregnancy outcomes among women with a twin pregnancy who underwent first-trimester history-indicated cervical cerclage compared with outcomes in those managed expectantly. METHODS: This was a retrospective matched case-control study. The study group comprised all women with a twin pregnancy who had undergone first-trimester history-indicated cerclage during the period 2006 to 2017 at Hadassah-Hebrew University Medical Center. A control group of women with a twin pregnancy who were managed expectantly was established by matching age, history of spontaneous preterm birth (20-36 weeks' gestation) and year of delivery. Pregnancy and delivery characteristics and neonatal outcomes were compared between the two groups. RESULTS: Data from 82 women with a twin gestation were analyzed, of whom 41 underwent first-trimester history-indicated cerclage and 41 were matched controls who were managed expectantly. Gestational age at delivery was higher in the cerclage group than in those managed expectantly (median 35 vs 30 weeks; P < 0.0001). Rates of spontaneous preterm birth before 24 weeks (2.4% vs 19.5%; odds ratio (OR), 0.10 (95% CI, 0.01-0.87); P = 0.03), before 28 weeks (12.2% vs 34.1%; OR, 0.27 (95% CI, 0.09-0.84); P = 0.03), before 32 weeks (22.0% vs 56.1%; OR, 0.22 (95% CI, 0.08-0.58); P = 0.003) and before 34 weeks (34.1% vs 82.9%; OR, 0.11 (95% CI, 0.04-0.30); P < 0.0001) were significantly lower in the cerclage group than in the control group. Median birth weight was higher in the cerclage group (2072 g vs 1750 g; P = 0.003), with lower rates of low birth weight (< 2500 g) (65.0% vs 89.4%; P = 0.001) and very low birth weight (< 1500 g) (21.3% vs 37.9%; P = 0.03) than in the group managed expectantly. Rates were also lower in the cerclage group for stillbirth, admission to the neonatal intensive care unit, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, neonatal mortality and composite adverse neonatal outcome. CONCLUSIONS: History-indicated cerclage performed in the first trimester, as compared with expectant management, in women with a twin pregnancy had an overall positive effect on pregnancy and neonatal outcomes. These findings suggest the need for adequate randomized trials on cerclage placement in this subset of women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Predicting asymptomatic cervical dilation in pregnant patients with short mid-trimester cervical length: A secondary analysis of a randomized controlled trial.

INTRODUCTION: Second trimester asymptomatic cervical dilation is a significant risk factor for early preterm birth. The objective of this study is to evaluate whether transvaginal ultrasound cervical length (CL) predicts asymptomatic cervical dilation on physical exam in women with short cervix (CL ≤25 mm) and no prior preterm birth. MATERIAL AND METHODS: Secondary analysis of a randomized trial on pessary in asymptomatic singletons without prior preterm birth diagnosed with CL ≤25 mm between 18+0/7 and 23+6/7  weeks. Participants had transvaginal ultrasound and physical cervical exam and were randomized to pessary or no pessary with all patients with cervical length ≤20 mm offered vaginal progesterone. The primary outcome was to determine whether CL was predictive of asymptomatic physical cervical dilation ≥1 cm using receiver operating characteristic curve. RESULTS: In all, 119 women were included. Based on receiver operating characteristic curve, CL ≤11 mm was best predictive of cervical dilation ≥1 cm, with 75% sensitivity, 80% specificity, and area under the curve 0.73 (0.55-0.91), P = 0.009. Cervical length ≤11 mm had increased incidence of cervical dilation ≥1 cm on physical exam (30% vs 3%, odds ratio 12.29 (3.05-49.37) P < 0.001) with a negative predictive value of 97%. Patients with ≥1 cm dilation had increased preterm birth <37 weeks (75% vs 39%, P = 0.03) compared to those not dilated. Women with a CL ≤11 mm had increased preterm birth <37 weeks (77% vs 31%, P < 0.001), preterm birth <34 weeks (63% vs 22%, P < 0.001), and lower birthweight (1552 ± 1047 vs 2560 ± 1072 g, P < 0.001) compared to women with CL >11 mm. CONCLUSIONS: Among singletons without prior preterm birth diagnosed with short cervix (≤25 mm), CL ≤11 mm may identify a subgroup of patients at high risk for asymptomatic cervical dilation and poor perinatal outcome. Physical exam should be considered and adjunctive preterm birth prevention measures should be studied in singletons with CL ≤11 mm.

Cervical shear wave elastography as a predictor of preterm delivery during 18-24 weeks of pregnancy.

AIM: The aim of this study was to compare shear wave cervical elasticity between term and preterm delivery group. METHODS: A prospective cohort study was conducted in enrolled 158 pregnant women at 18-24 weeks of gestation who come for second trimester scan consecutively. Transvaginal ultrasonography for cervical length as well as cervical elasticity in five regions of interest was performed. Intraobserver and interobserver reproducibility were evaluated. Gestational age at deliveries was followed, and cervical shear wave elasticity between term and preterm group was compared. RESULTS: A total of 158 pregnant women were enrolled in this study while 120 pregnancies data were collected for subsequent analysis, 10 pregnancies spontaneously delivered during the preterm period and 110 pregnancies delivered at term. Intraobserver and interobserver reproducibility were high; however, cervical shear wave elasticity in both groups were not significantly different (external anterior lip 2.29 ± 0.66 and 2.45 ± 0.58 m/s, P value 0.30, internal anterior lip 2.74 ± 0.96 and 2.80 ± 0.61 m/s, P value 0.83). Nonsignificant correlations of cervical shear wave elasticity with gestational age and cervical length (r = -0.1 and r = 0.02, respectively) were demonstrated. CONCLUSION: Cervical shear wave elasticity in preterm and term groups was not significantly different when measured at 18-24 weeks of gestation. There are nonsignificant correlations between cervical shear wave elasticity, gestational age and cervical length. Cervical shear wave elastography alone should not be used as a predictor for preterm delivery.

Cervical Ectopic Pregnancy: A Rare Site of Implantation.

BACKGROUND: Cervical ectopic pregnancies are rare, comprising < 1% of ectopic pregnancies, and life threatening if there is a delay in treatment or a misdiagnosis. CASE REPORT: This case report describes a presentation of cervical ectopic pregnancy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case report reviews nonsurgical and surgical treatment options for patients with cervical ectopic pregnancies.

In Vivo Measurement of Cervical Elasticity on Pregnant Women by Torsional Wave Technique: A Preliminary Study.

A torsional wave (TW) sensor prototype was employed to quantify stiffness of the cervix in pregnant women. A cross-sectional study in a total of 18 women between 16 weeks and 35 weeks + 5 days of gestation was performed. The potential of TW technique to assess cervical ripening was evaluated by the measurement of stiffness related to gestational age and cervical length. Statistically significant correlations were found between cervical stiffness and gestational age ( R 2 = 0.370 , p = 0.0074 , using 1 kHz waves and R 2 = 0.445 , p = 0.0250 , using 1.5 kHz waves). A uniform decrease in stiffness of the cervical tissue was confirmed to happen during the complete gestation. There was no significant correlation between stiffness and cervical length. A stronger association between gestational age and cervical stiffness was found compared to gestational age and cervical length correlation. As a conclusion, TW technique is a feasible approach to objectively quantify the decrease of cervical stiffness related to gestational age. Further research is required to evaluate the application of TW technique in obstetric evaluations, such as prediction of preterm delivery and labor induction failure.

[Clinical outcome of therapeutic cervical cerclage in short cervix syndrome].

Objective: To investigate the clinical effect of therapeutic cervical cerclage on short cervix syndrome for anti-premature birth in the second trimester. Methods: Totally 44 singleton pregnant patients were diagnosed as short cervix syndrome, which was cervical length ≤2.5 cm without cervical dilatation, and received treatment from January 2008 and July 2015 in Peking University Third Hospital were collected. Among them, 30 patients who received therapeutic cervical cerclage were defined as cerclage group and another 14 cases who received conservative treatment were defined as un-cerclage group. The days of conservative treatment, delivery rate of different gestational weeks, birth weight of newborns, neonatal survival rate within 7 days of birth were analyzed between the two groups. Results: There were no significant differences between the two groups in days of pregnancy conservative treatment [103 (84-141) vs 105 (85-114) days], delivery weeks [38.0 (35.5-39.4) vs 38.5 (37.3-39.5) weeks], birth weight of newborns [3 120 (2 750-3 400) vs 3 130 (2 760-3 545) g], and survival rate of newborns [100% (30/30) vs 13/14]. The fetuses of both groups were all delivered after 28 weeks. There was no significant difference in accumulated delivery rate between the two groups after 32 weeks, 34 weeks, and 37 weeks, respectively (all P>0.05) . Conclusions: The treatment of cervical cerclage is not superior to conservative means in single pregnancy of cervical length ≤2.5 cm without cervical dilatation. For such patients with short cervix syndrome, the treatment of cervical cerclage may not be necessary, but dynamic monitoring and search for the causing factors and prompt treatment are more important.

CERVICAL RIPENING BALLOON AS A METHOD OF PREINDUCTION - ONE CENTER STUDY.

- Cervical ripening can be promoted in many ways, but mechanical methods are among the oldest. Like all other methods, this one also has its pros and cons. Disadvantages compared to pharmacological methods include some maternal discomfort upon manipulation of the cervix, a theoretical increase in the risk of maternal and neonatal infection from the introduction of a foreign body, potential disruption of a low-lying placenta, and increase in the need of oxytocin induction of labor. The aim of the study was to evaluate the effect of using cervical ripening balloon in preinduction on the mode of delivery. This was a longitudinal, cohort, intervention, non-randomized one center study. Inclusion criteria were term pregnancies with gestational diabetes, oligohydramnios, intrauterine growth restriction, gestational hypertension/preeclampsia and pregnancies after 41 weeks of pregnancy. Preinduction of labor was performed in term pregnancies at Sestre milosrdnice University Hospital Center. Results in the first 150 women having undergone labor preinduction with cervical ripening balloon were included. Two-sided p values <0.05 were considered significant. Statistical analysis was done using SPSS Version 20.0. The study included 150 women; one woman was excluded from further analyses due to conversion of fetal presentation (head to breech). Indications for labor preinduction were as follows: gestational diabetes, oligohydramnios, intrauterine growth restriction, gestational hypertension/preeclampsia and pregnancies after 41 weeks of pregnancy. Women with normal vaginal delivery (96/149) had lower rates of gestational diabetes and oligohydramnios and used epidural analgesia more frequently. Women with dystocia (32/53) had a significantly longer labor duration and higher neonatal birth weight. In multivariate analysis, multiparity, greater cervical dilatation after balloon removal and use of epidural analgesia were associated with a decreased risk of cesarean section, while the presence of gestational diabetes and oligohydramnios was associated with an increased risk of cesarean section. We found this preinduction method safe and efficient, with a potential to increase the rate of vaginal deliveries.

Intraoperative cervix location and apical support stiffness in women with and without pelvic organ prolapse.

BACKGROUND: It is unknown how initial cervix location and cervical support resistance to traction, which we term "apical support stiffness," compare in women with different patterns of pelvic organ support. Defining a normal range of apical support stiffness is important to better understand the pathophysiology of apical support loss. OBJECTIVE: The aims of our study were to determine whether: (1) women with normal apical support on clinic Pelvic Organ Prolapse Quantification, but with vaginal wall prolapse (cystocele and/or rectocele), have the same intraoperative cervix location and apical support stiffness as women with normal pelvic support; and (2) all women with apical prolapse have abnormal intraoperative cervix location and apical support stiffness. A third objective was to identify clinical and biomechanical factors independently associated with clinic Pelvic Organ Prolapse Quantification point C. STUDY DESIGN: We conducted an observational study of women with a full spectrum of pelvic organ support scheduled to undergo gynecologic surgery. All women underwent a preoperative clinic examination, including Pelvic Organ Prolapse Quantification. Cervix starting location and the resistance (stiffness) of its supports to being moved steadily in the direction of a traction force that increased from 0-18 N was measured intraoperatively using a computer-controlled servoactuator device. Women were divided into 3 groups for analysis according to their pelvic support as classified using the clinic Pelvic Organ Prolapse Quantification: (1) "normal/normal" was women with normal apical (C < -5 cm) and vaginal (Ba and Bp < 0 cm) support; (2) normal/prolapse had normal apical support (C < -5 cm) but prolapse of the anterior or posterior vaginal walls (Ba and/or Bp ≥ 0 cm); and (3) prolapse/prolapse had both apical and vaginal wall prolapse (C > -5 cm and Ba and/or Bp ≥ 0 cm). Demographics, intraoperative cervix locations, and apical support stiffness values were then compared. Normal range of cervix location during clinic examination and operative testing was defined by the total range of values observed in the normal/normal group. The proportion of women in each group with cervix locations within and outside the normal range was determined. Linear regression was performed to identify variables independently associated with clinic Pelvic Organ Prolapse Quantification point C. RESULTS: In all, 52 women were included: 14 in the normal/normal group, 11 in the normal/prolapse group, and 27 in the prolapse/prolapse group. At 1 N of traction force in the operating room, 50% of women in the normal/prolapse group had cervix locations outside the normal range while 10% had apical support stiffness outside the normal range. Of women in the prolapse/prolapse group, 81% had cervix locations outside the normal range and 8% had apical support stiffness outside the normal range. Similar results for cervix locations were observed at 18 N of traction force; however the proportion of women with apical support stiffness outside the normal range increased to 50% in the normal/prolapse group and 59% in the prolapse/prolapse group. The prolapse/prolapse group had statistically lower apical support stiffness compared to the normal/normal group with increased traction from 1-18 N (0.47 ± 0.18 N/mm vs 0.63 ± 0.20 N/mm, P = .006), but all other comparisons were nonsignificant. After controlling for age, parity, body mass index, and apical support stiffness, cervix location at 1 N traction force remained an independent predictor of clinic Pelvic Organ Prolapse Quantification point C, but only in the prolapse/prolapse group. CONCLUSION: Approximately 50% of women with cystocele and/or rectocele but normal apical support in the clinic had cervix locations outside the normal range under intraoperative traction, while 19% of women with uterine prolapse had normal apical support. Identifying women whose apical support falls outside a defined normal range may be a more accurate way to identify those who truly need a hysterectomy and/or an apical support procedure and to spare those who do not.

The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes.

BACKGROUND: Premature prelabor rupture of fetal membranes accounts for 30% of all premature births and is associated with detrimental long-term infant outcomes. Premature cervical remodeling, facilitated by matrix metalloproteinases, may trigger rupture at the zone of the fetal membranes overlying the cervix. The similarities and differences underlying cervical remodeling in premature prelabor rupture of fetal membranes and spontaneous preterm labor with intact membranes are unexplored. OBJECTIVES: We aimed to perform the first transcriptomic assessment of the preterm human cervix to identify differences between premature prelabor rupture of fetal membranes and preterm labor with intact membranes and to compare the enzymatic activities of matrix metalloproteinases-2 and -9 between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. STUDY DESIGN: Cervical biopsies were collected following preterm labor with intact membranes (n = 6) and premature prelabor rupture of fetal membranes (n = 5). Biopsies were also collected from reference groups at term labor (n = 12) or term not labor (n = 5). The Illumina HT-12 version 4.0 BeadChips microarray was utilized, and a novel network graph approach determined the specificity of changes between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. Quantitative reverse transcription-polymerase chain reaction and Western blotting confirmed the microarray findings. Immunofluorescence was used for localization studies and gelatin zymography to assess matrix metalloproteinase activity. RESULTS: PML-RARA-regulated adapter molecule 1, FYVE-RhoGEF and PH domain-containing protein 3 and carcinoembryonic antigen-ralated cell adhesion molecule 3 were significantly higher, whereas N-myc downstream regulated gene 2 was lower in the premature prelabor rupture of fetal membranes cervix when compared with the cervix in preterm labor with intact membranes, term labor, and term not labor. PRAM1 and CEACAM3 were localized to immune cells at the cervical stroma and NDRG2 and FGD3 were localized to cervical myofibroblasts. The activity of matrix metalloproteinase-9 was higher (1.22 ± 4.403-fold, P < .05) in the cervix in premature prelabor rupture of fetal membranes compared with preterm labor with intact membranes. CONCLUSION: We identified 4 novel proteins with a potential role in the regulation of cervical remodeling leading to premature prelabor rupture of fetal membranes. Our findings contribute to the studies dissecting the mechanisms underlying premature prelabor rupture of fetal membranes and inspire further investigations toward the development of premature prelabor rupture of fetal membranes therapeutics.

Cervical collagen is reduced in non-pregnant women with a history of cervical insufficiency and a short cervix.

INTRODUCTION: Preterm cervical shortening and cervical insufficiency may be caused by a constitutional weakness of the cervix. The aim of this study was to assess the cervical collagen concentration in non-pregnant women with a history of cervical insufficiency or of a short cervix in the second trimester of pregnancy. MATERIAL AND METHODS: In this case-control study we included non-pregnant women one year or more after pregnancy: 55 controls with a history of normal delivery; 27 women with a history of cervical insufficiency; and 10 women with a history of a short cervix (<5th percentile) and 10 women with a history of a long cervix (>95th percentile) at gestational weeks 18-20. We obtained biopsies (3 × 3-4 mm) from the ectocervix and determined the collagen concentration by measuring the hydroxyproline concentration. RESULTS: Women with cervical insufficiency had lower collagen concentrations (63.5 ± 5.1%; mean ± SD) compared with controls (68.2 ± 5.4%; p = 0.0004); area under the ROC curve 0.73 (95% CI 0.62-0.84). A cut-off value at 67.6% collagen resulted in a positive likelihood ratio of 3.2, a sensitivity of 60%, and a specificity of 81%. Also, women with a short cervix in the second trimester had lower collagen concentrations in a non-pregnant state (62.1% ± 4.9%) compared with women with a long cervix (67.8% ± 5.0%; p = 0.02). CONCLUSIONS: Both cervical insufficiency and a short cervix in the second trimester of pregnancy are associated with low cervical collagen concentrations in a non-pregnant state more than one year after pregnancy.

Cervical Pessary for Preventing Preterm Birth in Singleton Pregnancies With Short Cervical Length: A Systematic Review and Meta-analysis.

OBJECTIVES: To evaluate the effectiveness of cervical pessary for preventing spontaneous preterm birth (SPTB) in singleton gestations with a second trimester short cervix. METHODS: Electronic databases were searched from their inception until February 2016. We included randomized clinical trials (RCTs) comparing the use of the cervical pessary with expectant management in singletons pregnancies with transvaginal ultrasound cervical length (TVU CL) ≤25 mm. The primary outcome was incidence of SPTB <34 weeks. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). RESULTS: Three RCTs (n = 1,420) were included. The mean gestational age (GA) at randomization was approximately 22 weeks. The Arabin pessary was used as intervention in all three trials, and was removed by vaginal examination at approximately 37 weeks. Cervical pessary was not associated with prevention of SPTB <37 (20.2% vs 50.2%; RR 0.50, 95% CI 0.23 to 1.09), <34, <32, and <28 weeks, compared to no pessary. No differences were found in the mean of GA at, interval from randomization to delivery, incidence of preterm premature rupture of membranes and of cesarean delivery, and in neonatal outcomes. The Arabin pessary was associated with a significantly higher risk of vaginal discharge. CONCLUSIONS: In singleton pregnancies with a TVU CL ≤25mm at 200 -246 weeks, the Arabin pessary does not reduce the rate of spontaneous preterm delivery or improve perinatal outcome. Individual patient data meta-analysis may clarify whether cervical pessary may be beneficial in subgroups, such as only singleton gestations without prior SPTB or by different CL cutoffs.

The impact of postpartum cervical tear on the occurrence of preterm birth in subsequent pregnancy.

PURPOSE: To examine the occurrence of subsequent preterm birth (PTB) among women who experienced a cervical tear during prior delivery. METHODS: A retrospective study conducted at a single teaching hospital on data from January 1994 to March 2014. The study group included all women who had a cervical tear detected at uterine and cervical examination, performed due to early postpartum hemorrhage. The control group consisted of women who delivered vaginally, experienced an early postpartum hemorrhage, and had an intact cervix at uterine and cervical examination. The control group was matched for maternal age and ethnicity at a ratio of 1:2. Women who had a cervical tear but then did not have a subsequent delivery, or had multiple fetal gestations or cervical cerclage at subsequent pregnancies were excluded. Primary outcome was spontaneous PTB rate (<37 weeks) in the subsequent pregnancy. Secondary outcomes included any PTBs in other subsequent pregnancies. RESULTS: Overall, 389 women were included. Of all cases of cervical tear, 129 were identified eligible and included in the final analysis. The control group included 260 women with an intact cervix. No significant differences were found between the study and control groups in the incidence of spontaneous PTB in the immediate subsequent pregnancy [1.6% (2/129) vs. 3.8% (10/260), respectively, p = 0.35]. The incidence of any spontaneous PTBs in all subsequent pregnancies did not differ also [4.7% (6/129) vs. 7.3% (19/260), respectively, p = 0.31]. CONCLUSION: Cervical tear detected after delivery does not increase the risk of spontaneous PTB in subsequent pregnancies.

Cervical Strain Elastography in Pregnancy and Association with Maternal Factors.

Purpose To assess cervical elasticity in different regions by sonoelastography, to compare the results to the Bishop score, cervical length, week of pregnancy and other maternal factors (age, weight, parity) and to evaluate the reproducibility of the method. Materials and Methods 131 patients between 17 - 41 gestational weeks were examined by transvaginal cervical strain elastography. In the sagittal view strain values were calculated in 7 regions of interest (ROI; external and internal os anterior/posterior, middle part anterior/posterior, cervical canal). In the cross sectional views strain values in 3 ROIs were evaluated at the level of the internal and external cervical os (anterior/posterior, cervical canal). The intra- and interobserver variance was tested. Results Strain values differed highly significantly in different parts of the cervix (p < 0.001). The anterior parts and the cervical canal were significantly softer with increasing gestational age and Bishop score, and the posterior parts were significantly harder with increasing maternal age, weight, parity. Cervical length showed an inverse relationship to cervical softness. The intra- and interobserver variance was low. Conclusion Elastography is a reproducible method for the evaluation of cervical elasticity in pregnancy. It showed a significant association with the Bishop score and other maternal factors and could provide additional information about changes in cervical stiffness in pregnancy.

A new paradigm for the role of smooth muscle cells in the human cervix.

BACKGROUND: Premature cervical remodeling resulting in spontaneous preterm birth may begin with premature failure or relaxation at the internal os (termed "funneling"). To date, we do not understand why the internal os fails or why funneling occurs in some cases of premature cervical remodeling. Although the human cervix is thought to be mostly collagen with minimal cellular content, cervical smooth muscle cells are present in the cervix and can cause cervical tissue contractility. OBJECTIVE: To understand why the internal os relaxes or why funneling occurs in some cases of premature cervical remodeling, we sought to evaluate cervical smooth muscle cell content and distribution throughout human cervix and correlate if cervical smooth muscle organization influences regional cervical tissue contractility. STUDY DESIGN: Using institutional review board-approved protocols, nonpregnant women <50 years old undergoing hysterectomy for benign indications were consented. Cervical tissue from the internal and external os were immunostained for smooth muscle cell markers (α-smooth muscle actin, smooth muscle protein 22 calponin) and contraction-associated proteins (connexin 43, cyclooxygenase-2, oxytocin receptor). To evaluate cervical smooth muscle cell morphology throughout the entire cervix, whole cervical slices were obtained from the internal os, midcervix, and external os and immunostained with smooth muscle actin. To correlate tissue structure with function, whole slices from the internal and external os were stimulated to contract with 1 µmol/L of oxytocin in organ baths. In separate samples, we tested if the cervix responds to a common tocolytic, nifedipine. Cervical slices from the internal os were treated with oxytocin alone or oxytocin + increasing doses of nifedipine to generate a dose response and half maximal inhibitory concentration. Student t test was used where appropriate. RESULTS: Cervical tissue was collected from 41 women. Immunohistochemistry showed cervical smooth muscle cells at the internal and external os expressed mature smooth muscle cell markers and contraction-associated proteins. The cervix exhibited a gradient of cervical smooth muscle cells. The area of the internal os contained 50-60% cervical smooth muscle cells that were circumferentially organized in the periphery of the stroma, which may resemble a sphincter-like pattern. The external os contained approximately 10% cervical smooth muscle cells that were randomly scattered in the tissue. In organ bath studies, oxytocin stimulated the internal os to contract with more than double the force of the external os (1341 ± 693 vs 523 ± 536 integrated grams × seconds, respectively, P = .009). Nifedipine significantly decreased cervical tissue muscle force compared to timed vehicle control (oxytocin alone) at doses of 10(-5) mol/L (vehicle 47% ± 15% vs oxytocin + nifedipine 24% ± 16%, P = .007), 10(-4) mol/L (vehicle 46% ± 16% vs oxytocin + nifedipine -4% ± 20%, P = .003), and 10(-3) mol/L (vehicle 42% ± 14% vs oxytocin + nifedipine -15% ± 18%, P = .0006). The half maximal inhibitory concentration for nifedipine was 1.35 × 10(-5) mol/L. CONCLUSION: Our findings suggest a new paradigm for cervical tissue morphology-one that includes the possibility of a specialized sphincter at the internal os. This new paradigm introduces novel avenues to further investigate potential mechanisms of normal and premature cervical remodeling.

Prediction of Spontaneous Preterm Birth Among Nulliparous Women With a Short Cervix.

OBJECTIVES: The purpose of this study was to evaluate whether demographic and sonographic factors associated with spontaneous preterm birth among nulliparous women with a cervical length of less than 30 mm could be combined into an accurate prediction model for spontaneous preterm birth. METHODS: We conducted a secondary analysis of a trial of nulliparous women with a singleton gestation and a cervical length of less than 30 mm on transvaginal sonography between 16 and 22 weeks who lacked other risk factors for spontaneous (eg, prior cervical excisional procedure) or medically indicated (eg, chronic hypertension) preterm birth, who were randomized to either 17α-hydroxyprogesterone caproate treatment or a placebo. Risk factors associated with spontaneous preterm birth within the entire cohort were identified by univariable analysis. Factors significantly associated (P < .05) with spontaneous preterm birth were included in a multivariable logistic regression analysis to determine whether an accurate prediction model could be developed. RESULTS: Of the 657 randomized patients, 109 (16.6%) had spontaneous preterm birth before 37 weeks' gestation. Logistic regression analysis revealed only cervical length (odds ratio, 1.06 per 1-mm decrease; 95% confidence interval, 1.02-1.10) to be associated with spontaneous preterm birth. The area under the receiver operating characteristic curve based on this regression was low (0.63; 95% confidence interval, 0.58-0.69). Results were similar for the outcome of spontaneous preterm birth before 34 weeks. CONCLUSIONS: An accurate prediction model for spontaneous preterm birth among nulliparous women with a short cervix could not be developed.