Cervical length and quantitative fetal fibronectin in the prediction of spontaneous preterm birth in asymptomatic women with congenital uterine anomaly.

BACKGROUND: Congenital uterine anomalies are associated with late miscarriage and spontaneous preterm birth. OBJECTIVE: Our aim was 1) to determine the rate of spontaneous preterm birth in each type of congenital uterine anomaly, and 2) to assess the performance of quantitative fetal fibronectin and cervical length measurement by transvaginal ultrasound in asymptomatic women with congenital uterine anomalies for the prediction of spontaneous preterm birth at <34 and <37 weeks of gestation. MATERIALS AND METHODS: This was a retrospective cohort of women with congenital uterine anomalies asymptomatic for spontaneous preterm birth, from 4 tertiary referral centers in the United Kingdom (2001-2016). Congenital uterine anomalies were categorized into fusion (unicornuate, didelphic, and bicornuate uteri) or resorption defects (septate, with or without resection, and arcuate uteri), based on prepregnancy diagnosis. All women underwent serial transvaginal ultrasound cervical length assessment in the second trimester (16 to 24 weeks' gestation); a subgroup underwent quantitative fetal fibronectin testing from 18 weeks' gestation. We investigated the relationship between congenital uterine anomalies and predictive test performance for spontaneous preterm birth at <34 and <37 weeks' gestation. RESULTS: A total of 319 women were identified as having congenital uterine anomalies in our high-risk population. Of the women, 7% (23/319) delivered spontaneously at <34 weeks' gestation and 18% (56/319) at <37 weeks' gestation. Rates of spontaneous preterm birth by type were as follows: 26% (7/27) for unicornuate, 21% (7/34) for didelphic, 16% (31/189) for bicornuate, 13% (7/56) for septate, and 31% (4/13) for arcuate. In all, 80% (45/56) of women who had spontaneous preterm birth at <37 weeks did not develop a short cervical length (<25 mm) during the surveillance period (16-24 weeks). The diagnostic accuracy of short cervical length had a low sensitivity (20.3) for predicting spontaneous preterm birth at <34 weeks. Cervical length had an area under the receiver operating curve of 0.56 (95% confidence interval, 0.48-0.64) and 0.59 (95% confidence interval, 0.55-0.64) for prediction of spontaneous preterm birth at <34 and <37 weeks, respectively. The area under the curve for cervical length to predict spontaneous preterm birth at <34 weeks was 0.48 for fusion defects (95% confidence interval, 0.39-0.57) but 0.78 (95% confidence interval, 0.66-0.91) for women with resorption defects. Overall quantitative fetal fibronectin had an area under the curve of 0.63 (95% confidence interval, 0.49-0.77) and 0.58 (95% confidence interval, 0.49- 0.68) for prediction of spontaneous preterm birth at <34 and <37 weeks, respectively. The area under the curve for prediction of spontaneous preterm birth at <37 weeks with quantitative fetal fibronectin for fusion defects was 0.52 (95% confidence interval, 0.41-0.63) but 0.79 (95% confidence interval, 0.63-0.95) for women with resorption defects. Results were similar when women with intervention were excluded. CONCLUSION: The commonly used markers cervical length and quantitative fetal fibronectin have utility in prediction of spontaneous preterm birth in resorption congenital uterine defects but not in fusion defects. This is contrary to findings in other high-risk populations. These findings need to be accounted for when planning antenatal care, and have potential implications for predictive tests used in spontaneous preterm birth surveillance and intervention.

Exogenous oxytocin modulates human myometrial microRNAs.

OBJECTIVE: MicroRNAs (miRNAs) play a modulatory role in pathways that lead to labor onset, although oxytocin is known to modulate gene expression within the myometrium. We aimed to identify miRNAs whose expression is regulated by oxytocin in pregnant human myometrium. STUDY DESIGN: Myometrial miRNA expression profiles were compared between samples collected from women at term before the onset of labor (no labor; n = 8) and after labor onset after early exogenous oxytocin treatment (n = 8). Multivariate modelling was used to assess differences in miRNA profiles. Biologic validation was undertaken on 3 independent patient cohorts (no labor, n = 10; labor induced with oxytocin, n = 8; and spontaneous labor with no oxytocin treatment, n = 10). In vitro studies that used primary myocytes were undertaken to assess target miRNA expression after oxytocin treatment. Target genes of candidate miRNAs were identified in silico and cross-referenced with genes that are known to be associated with labor or expressed in myometrium. RESULTS: In total, 1309 miRNAs were analyzed by microarray, of which 494 were detected in human myometrium. Multivariate modeling identified 12 target miRNAs the differential expression of which was most responsible for the observed separation of the 2 patient populations in the primary discovery cohorts. Biologic validation in the independent secondary sample cohorts showed that oxytocin independently regulated 5 miRNAs (hsa-miR-146b-3p, hsa-miR-196b-3p, hsa-miR-223-3p, hsa-miR-873-5p, and hsa-miR-876-5p). Additionally, hsa-miR-146b-3p was increased both in labor that was induced with oxytocin and in myometrium from spontaneous labor with no oxytocin treatment compared with no labor samples. Four of the validated miRNAs (hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR-196b-3p, and hsa-miR-876-5p) were expressed in primary human myocytes; oxytocin treatment of these cells replicated the directional changes that were observed in vivo. CONCLUSION: Oxytocin alters the expression of a unique set of myometrial miRNAs. These results suggest a further role for oxytocin as a signaling molecule that is involved in the regulation of gene expression during parturition.

Cerclage position, cervical length and preterm delivery in women undergoing ultrasound indicated cervical cerclage: A retrospective cohort study.

OBJECTIVE: The objectives were to assess whether anatomical location of ultrasound (USS) indicated cervical cerclage and/or the degree of cervical shortening (cervical length; CL) prior to and following cerclage affects the risk of preterm birth (PTB). METHOD: A retrospective cohort study of 179 women receiving cerclage for short cervix (≤25mm) was performed. Demographic data, CL before and after cerclage insertion, height of cerclage (distance from external os) and gestation at delivery were collected. Relative risk (RR) and odds ratio (OR) of preterm delivery were calculated according to the anatomical location of the cerclage within the cervix and the CL before and after cerclage as categorical and continuous variables. Partition tree analysis was used to identify the threshold cerclage height that best predicts PTB. RESULTS: 25% (n = 45) delivered <34 weeks and 36% (n = 65) delivered <37 weeks. Risk of PTB was greater with cerclage in the distal 10mm (RR2.37, 95% CI 1.45-3.87) or the distal half of a closed cervix (RR2.16, 95% CI 1.45-3.87). Increasing absolute cerclage height was associated with a reduction in PTB (OR 0.87, 95% CI 0.82-0.94). A cerclage height <14.5 mm best predicts PTB (70.8%). Increasing CL following cerclage was associated with a reduction in PTB (OR0.87, 95% CI 0.82-0.94). Conversely, the risk of PTB was increased where CL remained static or shortened further following cerclage (RR2.34, 95% CI 1.04-5.25). CONCLUSION: The higher a cerclage was placed within a shortened cervix, the lower the subsequent odds of PTB. Women whose cerclage is placed in the distal 10mm of closed cervix or whose cervix fails to elongate subsequently, should remain under close surveillance as they have the highest risk of PTB.

Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage.

Preterm birth, the leading cause of death in children under 5 years, may be caused by inflammation triggered by ascending vaginal infection. About 2 million cervical cerclages are performed annually to prevent preterm birth. The procedure is thought to provide structural support and maintain the endocervical mucus plug as a barrier to ascending infection. Two types of suture material are used for cerclage: monofilament or multifilament braided. Braided sutures are most frequently used, although no evidence exists to favor them over monofilament sutures. We assessed birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in five UK university hospitals and showed that braided cerclage was associated with increased intrauterine death (15% versus 5%; P = 0.0001) and preterm birth (28% versus 17%; P = 0.0006) compared to monofilament suture. To understand the potential underlying mechanism, we performed a prospective, longitudinal study of the vaginal microbiome in women at risk of preterm birth because of short cervical length (≤25 mm) who received braided (n = 25) or monofilament (n = 24) cerclage under comparable circumstances. Braided suture induced a persistent shift toward vaginal microbiome dysbiosis characterized by reduced Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the vaginal microbiome and its interactions with the host. These data provide in vivo evidence that a dynamic shift of the human vaginal microbiome toward dysbiosis correlates with preterm birth.