Cervical Ripening

Major clinical challenges for obstetricians and neonatologists result from early cervix remodeling and preterm birth. Complications related to cervix remodeling or delivery account for significant morbidity in newborns and peripartum mothers. Understanding morphology and structure of the cervix in pregnant women is limited mostly to the period soon before and after birth. However, evidence in rodent models supports a working hypothesis that a convergence of factors promotes a physiological inflammatory process that degrades the extracellular collagen matrix and enhances biomechanical distensibility of the cervix well before the uterus develops the contractile capabilities for labor. Contributing factors to this remodeling process include innervation, mechanical stretch, hypoxia, and proinflammatory mediators. Importantly, the softening and shift to ripening occurs while progesterone is near peak concentrations in circulation across species. Since progesterone is required to maintain pregnancy, the premise of this review is that loss of responsiveness to progesterone constitutes a common final mechanism for remodeling the mammalian cervix in preparation for birth at term. Various inputs are suggested to promote signaling between stromal cells and resident macrophages to drive proinflammatory processes that advance the soft cervix into ripening. With infection, pathophysiological processes may prematurely drive components of this remodeling mechanism and lead to preterm birth. Identification of critical molecules and pathways from studies in various rodent models hold promise for novel endpoints to assess risk and provide innovative approaches to treat preterm birth or promote the progress of ripening at term.

BackgroundCervical ripening is an inflammatory reaction. The glucocorticoid receptor (GR) mediates glucocorticoid anti-inflammatory reactions, whereas nuclear factor (NF)kappaB is a key pro-inflammatory transcription factor. Prostaglandins as well as platelet activating factor (PAF) are inflammatory mediators. Inducible nitric oxide synthase (iNOS) regulates the level of nitric oxide (NO) in response to various inflammatory stimuli. We hypothesize that a changed biological response to glucocorticoids could be a mechanism regulating the inflammatory events resulting in cervical ripening.MethodsWe monitored GR and NFkappaB, prostaglandin synthases cyclooxygenase (COX)-1 and -2, iNOS, as well as the PAF-receptor (PAF-R) in the uterine cervix from term pregnant women (with unripe cervices) before the onset of labor (TP), immediately after parturition (PP), as compared to non-pregnant (NP), using immunohistochemistry and RT-PCR.ResultsThe GR protein was detected by immunohistochemistry in the nuclei of stroma and squamous epithelium (SQ). Stromal GR staining was increased in TP as compared to the NP group and decreased again after parturition. GR staining in SQ was decreased after parturition as compared to term. NFkappaB was present in SQ and glandular epithelium (GE), stroma and vascular endothelium. Increased nuclear NFkappaB staining was observed postpartum as compared to term pregnancy in stroma and GE. Stromal immunostaining for COX-1 as well as COX-2 was increased in the TP and PP groups as compared to the NP, and GE displayed an intensely increased COX-2 immunostaining at term and postpartum. Stromal PAF-R immunostaining was highest at term, while it was greatly increased in GE postpartum. No difference in the immunostaining for iNOS was found between the groups. RT-PCR showed a predominance of GRalpha to GRbeta mRNA in cervical tissue. The COX-2 mRNA level was increased in the PP group as compared to the TP group.ConclusionsThere is a decrease in GR levels in human cervix at parturition. Concomitantly there is an increase of factors such as NFkappaB, PAF-R, COX-1 and COX-2, suggesting that they may participate in the sequence of events leading to the final cervical ripening.

BackgroundOne in four Australian births are induced. If cervical ripening using a prostaglandin is required, a pre-labour overnight hospitalisation and separation from family and support companions is necessary. Recent evidence shows that balloon catheter cervical ripening is just as effective as prostaglandins, but does not cause uterine stimulation. For women with low risk pregnancies, this offers the possibility of undergoing the overnight ripening process in their own home. We conducted a pilot randomised trial to assess the outcomes, clinical pathways and acceptability to both women and clinicians of outpatient balloon catheter ripening compared with usual inpatient care.MethodsForty-eight women with low risk term pregnancies were randomised (2:1) to either outpatient (n = 33) or inpatient double-balloon catheter (n = 15) cervical ripening. Although not powered for statistically significant differences, the study explored potential direction of effect for key clinical outcomes such as oxytocin use, caesarean section and morbidities. Feedback on acceptability was sought from women at catheter insertion and 4 weeks after the birth, and from midwives and doctors, at the end of the study.ResultsClinical and perinatal outcomes were similar. Most women required oxytocin (77 %). The outpatient group were 24 % less likely to require oxytocin (risk difference -23.6 %, 95 % CI -43.8 to -3.5). There were no failed inductions, infections or uterine hyperstimulation attributable to the catheter in either group. Most women in both groups reported discomfort with insertion and wearing the catheter, but were equally satisfied with their care and felt the baby was safe (91 % both groups). Outpatient women reported feeling less isolated or emotionally alone. Most midwives and doctors (n = 90) agreed that they are more comfortable in sending home a woman with a catheter than prostaglandins and 90 % supported offering outpatient ripening to eligible women.ConclusionsOutpatient balloon catheter ripening should be further investigated as an option for women in an adequately powered randomised trial.Trial registrationProspectively registered, Australian New Zealand Clinical Trials Registry ACTRN12612001184864 .

BackgroundCervical ripening in labor induction using a combination of methods is gaining popularity, but the effectiveness and safety of this approach are not clear. The assessment of study trustworthiness has recently been raised for evidence synthesis.ObjectiveTo compare the effectiveness, perinatal and maternal safety of cervical ripening in the induction of labor (IOL) using a balloon catheter with concurrent low-dose vaginal misoprostol (combined group) versus low-dose vaginal misoprostol alone.Search strategyMEDLINE, Embase, Emcare, Scopus, Cochrane Library, WHO ICTRP and clinicaltrials.gov.Selection criteriaRandomized controlled trials (RCTs), viable singleton gestation, no language restrictions, published and unpublished data.Data collection and analysisA systematic search, screening for trustworthiness and study quality, and an individual participant data (IPD) meta-analysis were conducted.Main resultsA total of eight of 22 (36.4%) trials provided individual participant data, of which three (604 participants) were excluded due to trustworthiness concerns after data checking. A total of 13 of 22 trials (59.1%) were identified as "not meeting trustworthiness criteria." This individual participant data meta-analysis included five trials (649 participants): two had prospective, another two had retrospective trial registrations, and one trial was unregistered. Vaginal delivery rate (adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI]: 0.30; 3.12, very low certainty of evidence as downgraded due to imprecision, inconsistency and data completeness), composite adverse perinatal (aOR 0.88, 95% CI: 0.62; 1.24, very low certainty of evidence as downgraded due to imprecision, inconsistency and data completeness) and maternal outcomes (aOR 0.70, 95% CI: 0.33; 1.50, very low certainty of evidence as downgraded due to imprecision, inconsistency and data completeness) were comparable between the two groups in the individual participant data meta-analysis. Women in the combined group reported significantly less uterine hyperstimulation (aOR 0.20, 95% CI: 0.10; 0.41) and less meconium-stained liquor (aOR 0.23, 95% CI 0.07; 0.77). Based on aggregate data from eight trials meeting trustworthiness criteria (IPD and non-IPD), combined methods had an OR of 1.07 (95% CI: 0.68; 1.68) for vaginal delivery. In comparison, data from 13 trials not meeting trustworthiness criteria (IPD and non-IPD) showed an OR of 1.25 (95% CI: 0.88; 1.77) for vaginal birth.ConclusionsBased on trustworthy data, the current evidence does not suggest that one method is superior to the other for the effectiveness of the combined balloon catheter with concurrent low-dose vaginal misoprostol versus low-dose vaginal misoprostol alone. At present, we are uncertain about the safety of using the combined method due to low data retrieval and trustworthiness concerns among the underlying trials. The results could slightly favor the combined method due to reduced hyperstimulation and meconium-stained liquor.