PURPOSE:To investigate whether women with a short cervical length (CL), but delivered at term in the first pregnancy might have increased risks of having short cervix and spontaneous preterm birth (sPTB) in the subsequent pregnancies. METHODS:This is a retrospective cohort study including singleton gestations who were delivered between Jan 2011 and Dec 2018, who had had one childbirth experience and who had transvaginal sonographic CL assessment performed at mid-trimester (18 ~ 30 weeks) in both pregnancy. The women were divided into four group according to the history of preterm birth and a short cervix (< 25 mm before 30 weeks of gestation): (1) the Preterm-short cervix group, (2) the Preterm-no shortening group, (3) the Term-short cervix group, and (4) the Term-no shortening group. We compared the risk of having short cervix and sPTB during the second pregnancy of women. Secondary outcomes were threatened preterm labor, need for tocolytics, and cerclage placement. RESULTS:A total of 804 women met our inclusion criteria. The rate of having short cervix (< 25 mm before 28 weeks of gestation) during the second pregnancy in women in the Term-short cervix group (43.2%) was significantly higher than those in women in the Term-no shortening group (6.6%), and in the Preterm-no shortening group (8.8%) (all p < 0.001 with Bonferroni correction), but not higher than those in women with the Preterm-short cervix group (30.8%, p > 0.05 with Bonferroni correction). When compared with women in the Preterm-no shortening group, women in the Term-short cervix group were also at an increased risk of need for need of tocolytics (60.2% vs. 26.5%) and cerclage placement (15.9% vs. 6.1%, all p < 0.001). Women in the Term-short cervix group had an increased risk of sPTB (< 37 weeks) during the second pregnancy, as compared to those in the Term-no shortening group (adjusted odds ratio 5.098, 95% CI 2.107-11.874). CONCLUSION:Women with a history of short cervix in their first pregnancy, but who delivered at term, were at increased risk of having a short cervix and sPTB in their second pregnancy, as compared to women with a history of term delivery without cervical shortening. Thus, short cervix of the previous pregnancy might be a predictive factors for preterm birth in the subsequent pregnancy.

BACKGROUND:A short cervix is a risk factor for preterm birth. The molecular drivers of a short cervix remain elusive. Metabolites may function as mediators of pathologic processes. OBJECTIVE:We sought to determine if a distinct cervicovaginal metabolomic profile is associated with a short cervix (<25 mm) to unveil the potential mechanisms by which premature cervical remodeling leads to a short cervix. STUDY DESIGN:This was a secondary analysis of a completed prospective pregnancy cohort. Cervicovaginal fluid was obtained between 20 and 24 weeks' gestation. The participants selected for metabolomic profiling were frequency-matched by birth outcome and cervicovaginal microbiota profile. This analysis included 222 participants with cervical length measured. A short cervix was defined as one having length <25 mm, as measured by transvaginal ultrasound. Unpaired t-tests were performed with a Bonferroni correction for multiple comparisons. RESULTS:There were 27 participants with a short cervix, and 195 with normal cervical length. Of the 637 metabolites detected, 26 differed between those with a short cervix and those with normal cervical lengths; 22 were decreased, of which 21 belonged to the lipid metabolism pathway (all P<.000079). Diethanolamine, erythritol, progesterone, and mannitol or sorbitol were increased in the cases of short cervix. Among participants with Lactobacillus-deficient microbiota, only diethanolamine and mannitol or sorbitol differed between short cervix (n=17) and normal cervical length (n=75), both increased. CONCLUSION:A short cervix is associated with decreased cervicovaginal lipid metabolites, particularly sphingolipids. This class of lipids stabilizes cell membranes and protects against environmental exposures. Increased diethanolamine-an immunostimulatory xenobiotic-is associated with a short cervix. These observations begin to identify the potential mechanisms by which modifiable environmental factors may invoke cell damage in the setting of biological vulnerability, thus promoting premature cervical remodeling in spontaneous preterm birth.

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.

OBJECTIVES:We compared the pregnancy prolongation effect attributable to cervical cerclage to that achieved by conservative management, and determined the cervical length for which cervical cerclage is effective. METHODS:We retrospectively examined medical records of 281 women admitted to our hospital between January 2013 and December 2017 for management of threatened preterm birth at 22-28 weeks of gestation. Obstetricians determined suitability for cervical cerclage, which was performed using the McDonald procedure in all cases. Of the 281 subjects, 71 underwent cervical cerclage (cerclage group); the other 210 received conservative therapy (non-cerclage group). We recorded maternal and neonatal characteristics of all patients. The two groups were compared in terms of length of extension of pregnancy and weeks of gestation at delivery. Multivariate analysis was performed to identify factors associated with extension of time to delivery. RESULTS:Our analyses revealed that the cerclage group was hospitalized earlier in pregnancy than the non-cerclage group (23.7 ± 1.5 weeks vs. 26.4 ± 1.9 weeks,  < .001) and had shorter cervixes (6.0 ± 9.4 mm vs. 16.9 ± 13.0 mm,  < .001). The two groups did not differ significantly in terms of gestational weeks at delivery. Multivariate analysis regarding extension of pregnancy revealed significant differences in extension of pregnancy related with cervical cerclage (26.65 days, 95% CI 17.0 - 36.3,  < .001) and cervical length <10 mm (-27.4 days, 95% CI -36.0--18.8,  < .001). While the time to delivery was extended by cervical cerclage in women with short cervixes (<25 mm), the two groups did not differ when cervical length was ≥15 mm. CONCLUSIONS:Cervical cerclage was a significant positive factor and short cervix was a significant negative factor for elongating pregnancy. In primigravida and multigravida women with no history of preterm birth, when the cervix is short (<10 mm), cervical cerclage should be recommended.

OBJECTIVE: The present study aims to determine if the use of cervical pessary plus progesterone in short-cervix (≤ 25 mm) dichorionic-diamniotic (DC-DA) twin pregnancies is equivalent to the rate of preterm births (PBs) with no intervention in unselected DC-DA twin pregnancies. METHODS: A historical cohort study was performed between 2010 and 2018, including a total of 57 pregnant women with DC-DA twin pregnancies. The women admitted from 2010 to 2012 ( = 32) received no treatment, and were not selected by cervical length (Non-Treated group, NTG), whereas those admitted from 2013 to 2018 ( = 25), were routinely submitted to cervical pessary plus progesterone after the diagnosis of short cervix from the 18th to the 27th weeks of gestation (Pessary-Progesterone group, PPG). The primary outcome analyzed was the rate of PBs before 34 weeks. RESULTS: There were no statistical differences between the NTG and the PPG regarding PB < 34 weeks (18.8% versus 40.0% respectively;  = 0.07) and the mean birthweight of the smallest twin (2,037 ± 425 g versus 2,195 ± 665 g;  = 0.327). The Kaplan-Meyer Survival analysis was performed, and there were no differences between the groups before 31.5 weeks. Logistic regression showed that a previous PB (< 37 weeks) presented an odds ratio (OR) of 15.951 (95% confidence interval [95%CI]: 1.294-196.557;  = 0.031*) for PB < 34 weeks in the PPG. CONCLUSION: In DC-DA twin pregnancies with a short cervix, (which means a higher risk of PB), the treatment with cervical pessary plus progesterone could be considered equivalent in several aspects related to PB in the NTG, despite the big difference between these groups.

INTRODUCTION:This study aimed to investigate amniotic fluid (AF) proteins that were differentially expressed between patients with cervical insufficiency (CI) and asymptomatic short cervix (SCX, ≤ 25 mm), and whether these proteins could be predictive of spontaneous preterm birth (SPTB) in these patients. METHOD:This was a retrospective cohort study of 129 singleton pregnant women with CI (n = 80) or SCX (n = 49) at 17 to 26 weeks who underwent amniocentesis. An antibody microarray was used to perform comparative proteomic profiling of AF from matched CI (n = 20) and SCX (n = 20) pregnancies. In the total cohort, an ELISA validation study was performed for 15 candidate proteins of interest. Subgroup analyses of patients with CI and SCX were conducted to evaluate the association between the 15 proteins and SPTB at < 32 weeks of gestation. RESULTS:Eighty-six proteins showed intergroup differences. ELISA validation confirmed significantly higher levels of AF EN-RAGE, IL-8, lipocalin-2, MMP-9, S100A8/A9, thrombospondin-2, and TNFR2 in patients with CI than in those with SCX. Multivariable analysis showed that increased AF levels of EN-RAGE, S100A8/A9, and uPA were independently associated with SPTB at < 32 weeks in patients with CI; whereas in patients with SCX, high AF levels of APRIL, EN-RAGE, LBP, and TNFR2 were independently associated with SPTB at < 32 weeks. CONCLUSIONS:Multiple AF proteins show altered expression in patients with CI compared with SCX controls. Moreover, several novel mediators involved in inflammation were identified as potential biomarkers for predicting SPTB after the diagnosis of CI and SCX. These results provide new insights into target-specific molecules for targeted therapies to prevent SPTB in patients with CI/SCX.

We aimed to determine the maternal characteristics (demographics, an obstetric history, and prior cervical excisional procedure) associated with a short mid-trimester cervical length (CL, defined as a CL of ≤ 25 mm) and whether having a short cervix explains the association between these maternal characteristics and spontaneous preterm delivery (SPTD, defined as a delivery before 34 weeks). This is a single-center retrospective cohort study of 3,296 consecutive women with a singleton pregnancy who underwent routine CL measurement between 20 and 24 weeks. Data were collected on maternal age, weight, height, parity, obstetric history (nulliparity; a history of at least 1 SPTD; and at least 1 term birth and no preterm birth [low-risk history group]), and prior cervical excisional procedure. In the multivariate regression analysis, an obstetric history, prior cervical excisional procedure, and gestational age at measurement were the variables significantly associated with short CL. In contrast, maternal weight, height, age, and parity were not significantly associated with short CL. By using the likelihood of SPTD as an outcome variable, logistic regression indicated that short CL and obstetric history, but not prior cervical excisional procedure, were significantly associated with SPTD after adjustment for potential confounders. A history of SPTD and prior cervical excisional procedure were associated with an increased risk of a short mid-trimester CL. A history of SPTD, but not prior cervical excisional procedure, is associated with an increased risk of SPTD, independent of a short CL.

Importance:Cervical cerclage (CC) represents one of the few effective measures currently available for the prevention of preterm delivery caused by cervical insufficiency, thus contributing in the reduction of neonatal morbidity and mortality rates. Objective:The aim of this study was to review and compare the most recently published major guidelines on the indications, contraindications, techniques, and timing of placing and removal of CC. Evidence Acquisition:A descriptive review of guidelines from the American College of Obstetricians and Gynecologists (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), the Society of Obstetricians and Gynaecologists of Canada (SOGC), and the International Federation of Gynecology and Obstetrics (FIGO) on CC was carried out. Results:There is a consensus among the reviewed guidelines regarding the recommended techniques, the indications for rescue CC, the contraindications, as well as the optimal timing of CC placement and removal. All medical societies also agree that ultrasound-indicated CC is justified in women with history of prior spontaneous PTD or mid-trimester miscarriage and a short cervical length detected on ultrasound. In addition, after CC, serial sonographic measurement of the cervical length, bed rest, and routine use of antibiotics, tocolysis, and progesterone are unanimously discouraged. In case of established preterm labor, CC should be removed, according to ACOG, RCOG, and SOGC. Furthermore, RCOG and SOGC agree on the prerequisites that should be met before attempting CC. These 2 guidelines along with FIGO recommend history-indicated CC for women with 3 or more previous preterm deliveries and/or second trimester pregnancy miscarriages, whereas the ACOG suggests the use of CC in singleton pregnancies with 1 or more previous second trimester miscarriages related to painless cervical dilation or prior CC due to painless cervical dilation in the second trimester. The role of amniocentesis in ruling out intra-amniotic infection before rescue CC remains a matter of debate. Conclusions:Cervical cerclage is an obstetric intervention used to prevent miscarriage and preterm delivery in women considered as high-risk for these common pregnancy complications. The development of universal international practice protocols for the placement of CC seems of paramount importance and will hopefully improve the outcomes of such pregnancies.

OBJECTIVE:The aim of the study was to determine the relationships between short cervical length (CL) and levels of cervical fluid neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), and interleukin 8 (IL-8) in the second trimester of pregnancy of women who underwent ultrasound-indicated cervical cerclage. MATERIALS AND METHODS:CL of <25 mm or cervical funneling were included in the short CL group (n = 26) and the normal CL group (n = 22) included women who had CL of ≥25 mm and had no cervical funneling in women between 17 + 0 and 24 + 6 weeks of gestation. Levels of NE, SLPI, and IL-8 were measured by using enzyme-linked immunosorbent assay kits. Mann-Whitney U tests and Spearman's correlation analysis were used for statistical analyses. RESULTS:Compared with the normal CL group, the short CL group had significantly higher median NE levels (P < 0.001) and higher, though not significant, median IL-8 levels by approximately three times (2107.0 vs. 798.3 pg/mL, P = 0.132). The median SLPI levels in cervical fluid was similar between the two groups (107.6 vs. 103.2 ng/mL, P = 0.499). Short CL had a significant correlations with cervical fluid NE levels (r = -0.475, P = 0.001). CONCLUSION:Increased cervical fluid NE associated with cervical shortening in second trimester of pregnancy, whereas cervical fluid SLPI had constant levels.

AIM:We hypothesized that elevated vaginal levels of matrix metalloproteinase-8 (MMP-8), interleukin-8 (IL-8) and the 70kDa heat shock protein (hsp70), compounds involved in inflammatory responses, correlated with a short cervix in pregnant women. METHODS:This prospective cohort study used a convenience sample of 64 women in their early third trimester with a singleton pregnancy. A short cervical length was present in 35 women (54.7 %). Vaginal fluid was tested for levels of MMP-8, IL-8 and hsp70 by enzyme-linked immunosorbent assay (ELISA). A receiver operating charasteristic (ROC) analysis was used to calculate the area under the curve (AUC) for each mediator in predicting short cervical length. RESULTS:MMP-8 (109 vs 29.6 ng/ml, p=0.014), IL-8 (689 vs 330 pg/ml, p=0.007) and hsp70 (4.4 vs 2.9 ng/ml, p=0.036) were all elevated in vaginal samples from women with a short cervix. In addition, there was a negative association between the concentration of each compound in vaginal fluid and cervical length p≤0.026). The vaginal IL-8 concentration had the highest negative correlation with a short cervix (AUC=0.7, p=0.007). CONCLUSION:MMP-8, hsp70 and IL-8 contribute to a pro-inflammatory cervico-vaginal milieu that weakens cervical integrity and leads to a shortening in cervical length (Tab. 4, Fig. 1, Ref. 27).