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Prostaglandin E2 (PGE2) vaginal gel for cervical ripening.

Cervical ripening prior to oxytocin stimulation is highly desirable to ensure a successful induction. Prostaglandin E2 has been administered by intracervical, intravaginal and extra-amniotic routes with successful ripening of the cervix. The dose of PGE2 administered is under investigation. Use of 3 or 4 mg of PGE2, although effective, has been reported to be accompanied by uterine hypertonus or fetal heart changes. Lower dose of PGE2 at 0.2 mg and 0.4 mg do not have the above-mentioned side effects but necessitate multiple applications. This randomized double-blinded study incorporated the use of 2 mg of PGE2 administered by intravaginal route in a hydroxyethyl cellulose gel medium. A significant increase in Bishop score (40% higher) was achieved in patients receiving PGE2 as compared to placebo patients. There were no adverse side effects, indicating application of 2 mg of PGE2 as a safe method of cervical ripening prior to induction of labor.

Cervix Uteri↗

Vaginal misoprostol for cervical ripening and labour induction in late pregnancy.

BACKGROUND: Although not yet registered for such use, misoprostol has been widely used for obstetric and gynaecological indications, such as induction of abortion and of labour. OBJECTIVES: The objective of this review was to assess the effects of vaginal misoprostol for third trimester cervical ripening or induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and reference lists of articles were searched. SELECTION CRITERIA: Randomised trials comparing vaginal misoprostol with other methods of cervical ripening or labour induction, placebo or no treatment in women due for third trimester induction of labour. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were done by both reviewers. MAIN RESULTS: Twenty-six studies were included. Compared to placebo, misoprostol was associated with increased cervical ripening (relative risk of unfavourable or unchanged cervix after 12 to 24 hours with misoprostol 0.20, 95% confidence interval 0.07 to 0.61). It was also associated with a reduced need for oxytocin (relative risk 0.47, 95% confidence interval 0.23 to 0.96). Misoprostol was more effective than prostaglandin E2 for labour induction (relative risk of failure to achieve vaginal delivery in 24 hours 0.70, 95% confidence interval 0.62 to 0.79). Oxytocin augmentation was used less often with misoprostol than with prostaglandin E2 (relative risk 0.64, 95% confidence interval 0.58 to 0.71). Uterine hyperstimulation and meconium stained liquor were more common with misoprostol than with prostaglandin E2. Lower doses of misoprostol compared to higher doses did not show significant differences except for more need for oxytocin augmentation and less uterine hyperstimulation without fetal heart rate changes. REVIEWER'S CONCLUSIONS: Vaginal misoprostol appears to be more effective in inducing labour than conventional methods of cervical ripening and labour induction. The apparent increase in uterine hyperstimulation is of concern. The studies were not large enough to exclude the possibility of rare but serious adverse effects.

Cervical Ripening↗

The physiology of cervical ripening and cervical dilatation and the effect of abortifacient drugs.

The mechanical properties of the human uterine cervix are determined mainly by the connective tissue component, whereas it is doubtful whether the scanty smooth muscle component is of any physiological importance. Histological and biochemical analyses reveal a fibrous connective tissue similar to that found in skin and tendon. Degradation of the collagen and an increase in some special dermatan sulphate proteoglycans can at least partly explain the pregnancy-associated softening of this connective tissue. Relatively high oestrogen levels seem to be an absolute condition for the process, even when it is induced pharmacologically. Treatment with progesterone-receptor blockers, PGE2, PGF2 alpha or relaxin in pregnancy induce cervical softening as well as histological and biochemical changes which cannot be distinguished from the physiological cervical softening which takes place in late pregnancy. Prostaglandins and relaxin might interact and could include cytokines such as interleukin-1 during the process. The effect of cervical tents cannot be explained only by the radial pressures they exert. Most probably stimulation of local prostaglandin synthesis is also involved.

Abortifacient Agents↗

Nitric oxide metabolites in cervical fluid during pregnancy: further evidence for the role of cervical nitric oxide in cervical ripening.

OBJECTIVE: Cervical tissue expresses all the isoenzymes of nitric oxide synthase. We studied the concentrations of nitric oxide metabolites in the cervical fluid in nonpregnant (n = 11) and pregnant women (n = 106). STUDY DESIGN: Cervical fluid was collected into a Dacron polyester swab, and nitric oxide metabolites were eluted into physiologic saline solution, which was assayed for nitric oxide metabolites with the Griess reaction. The detection limit of the method is 0.2 micromol/L. RESULTS: Cervical fluid nitric oxide metabolite was detectable in 46% of nonpregnant women (median, <0.2 micromol/L; 95% CI, 0-49), in 63% of women in early pregnancy (median, 11 micromol/L; 95% CI, 0-23) and in 82% of women in late pregnancy (median, 128 micromol/L; 95% CI, 21-276). In late pregnancy, the cervical fluid nitric oxide metabolite level was higher in women with Bishop score of > or =6 (median, 163 micromol/L; 95% CI, 105-276) than in women with Bishop score of <6 (median, 86 micromol/L; 95% CI, 21-99). Cervical fluid nitric oxide metabolite concentration before the onset of labor in parous women (median, 97 micromol/L; 95% CI, 78-283) was higher (P =.008) than that in nulliparous women (median, 28 micromol/L; 95% CI, 0-95). Cervical fluid nitric oxide metabolites before the initiation of labor (median, 33 micromol/L; 95% CI, 0-95) rose to 3.5-fold (median, 115 micromol/L; 95% CI, 78-284) after the commencement of uterine contractions and showed a significant relationship to Bishop score (r = 0.39, P =.01). Cervical fluid nitric oxide metabolite concentrations were not relative to simultaneous plasma nitric oxide metabolite levels (n = 41 women, r = 0.14, P =.41). Rupture of fetal membranes tended to decrease cervical fluid nitric oxide metabolite levels, whereas gentle cervical manipulation elevated it 6.6-fold in 1 minute. The administration of glyceryl trinitrate (0.5 mg, nitric oxide donor) intracervically resulted in a significant rise in the cervical fluid nitric oxide metabolite level in 2 minutes. CONCLUSION: Cervical fluid nitric oxide metabolite level rises after cervical ripening, nitric oxide donor administration, or cervical manipulation, which supports a role for cervical nitric oxide in cervical ripening.

Administration, Topical↗

Eosinophils in human cervical ripening.

OBJECTIVE: Cervical ripening has many similarities to an inflammatory reaction. Eosinophil granulocytes are involved in several inflammatory responses. The objective was to investigate the presence of eosinophils in human cervix uteri during different conditions. STUDY DESIGN: Cervical biopsies were obtained from non-pregnant (n = 6), women in early pregnancy (n = 11) and from three groups of women at term: spontaneous vaginal deliveries (n = 5); vaginal deliveries after pretreatment with Prostaglandin E2 (n = 7); and from women who underwent planned Caesarean section (n = 7). Immunohistochemical staining for eosinophil granulocytes (ECP, EG2) were performed. The biopsies were analysed blinded. RESULTS: Eosinophils showing degranulation in the tissue were found in all specimens from vaginal deliveries. No eosinophils, or very few were seen in the biopsies from non-pregnant, early pregnant women or planned caesarean section. Prostaglandin treatment had no effect on the results. CONCLUSION: Eosinophils participate in cervical ripening at term in women, and seem to arise mainly after labour.

Blood Proteins↗

Spontaneous and induced cervical ripening. Natural dilation and effacement process and current cervical ripening techniques.

During gestation, the cervix forms a tight sphincter to ensure the integrity of the pregnancy. Toward the end of the pregnancy, hormone-mediated biochemical changes cause the cervix to ripen and become softer and more pliable to allow passage of the fetus. Failure of the cervix to ripen may result in delayed onset of labor and a prolonged and complicated course, especially if labor is artificially induced. Attempts to induce cervical ripening have involved the use of mechanical methods, estrogen and estrogen precursors, relaxin and prostaglandins. The ideal ripening agent is simple and noninvasive, effective within 24 hours, does not compromise mother or fetus and does not stimulate labor (during the ripening process).

Cervix Uteri↗

Dynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturition.

Cervical epithelia have numerous functions that include proliferation, differentiation, maintenance of fluid balance, protection from environmental hazards, and paracellular transport of solutes via tight junctions (TJs). Epithelial functions must be tightly regulated during pregnancy and parturition as the cervix undergoes extensive growth and remodeling. This study evaluated TJ proteins, as well as markers of epithelial cell differentiation in normal and cervical ripening defective mice to gain insights into how the permeability barrier is regulated during pregnancy and parturition. Although numerous TJ proteins are expressed in the nonpregnant cervix, claudins 1 and 2 are temporally regulated in pregnancy. Claudin 1 mRNA expression is increased, whereas claudin 2 expression declines. The cellular localization of claudin 1 shifts at the end of pregnancy (gestation d 18.75) to the plasma membrane in a lattice pattern, consistent with TJs in the apical cells. The timing of claudin 1-enriched TJs coincides with initiation of terminal differentiation of cervical squamous epithelia as evidenced by the increased expression of genes by differentiated epithelia late on gestation d 18. The cervical ripening defective steroid 5alpha-reductase type 1 deficient mouse, which has an elevated local progesterone concentration, also has aberrant claudin 1 and 2 expressions, fails to form claudin 1-enriched TJs, and lacks normal expression of genes involved in epithelial terminal differentiation. These data suggest that changes in permeability barrier properties during cervical ripening are, in part, negatively regulated by progesterone, and that dynamic changes in barrier properties of the cervix occur during pregnancy and parturition.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Cervico-vaginal foetal fibronectin: a predictor of cervical response at pre-induction cervical ripening.

CONTEXT: Not all pregnant women with an "unripe" cervix can be successfully ripened by the cervical ripening agents; therefore tests with predictive information are justified. OBJECTIVES: To examine the effect of the presence of foetal fibronectin (FFN) in the cervico-vaginal secretions on pre-induction cervical ripening with either intravaginal Misoprostol or transcervical Foley catheter. METHODOLOGY: Twenty (20) patients managed at a tertiary health institution in South-western Nigeria between March and May 2003 were randomised for cervical ripening by either intravaginal Misoprostol or Transcervical Foley catheters. Cervico-vaginal secretions were assessed for presence of FFN with Foetal Fibronectin Enzyme Immunoassay Kit (Adeza Corp.) prior to commencement of cervical ripening. MAIN OUTCOME MEASURES: FFN status, Pre-ripening and Pre-induction modified Bishop scores and duration of cervical ripening. RESULTS: Ten of the fifteen patients with positive membrane immunoassay for FFN achieved ripened cervix (modified Bishop score > or = 6) within 6 - 12 hours of exposure to the agents of cervical ripening. In the FFN negative group, only 2 of the five patients achieved ripe cervix within the >12 - 18 hours period, the rest being in the >18 - 24 hours period. CONCLUSION: Foetal fibronectin test may offer useful predictive information prior to institution of processes of cervical ripening in patients with unfavourable cervices.

Abortifacient Agents, Nonsteroidal↗

Cervical fetal fibronectin correlates to prostaglandin E2-induced cervical ripening and can be identified in cervical tissue.

OBJECTIVE: Our purpose was to investigate whether prostaglandin E2-induced cervical ripening can be related to changes in fetal fibronectin levels and whether fetal fibronectin can be detected by immunohistochemistry in amniotic and cervical tissue. STUDY DESIGN: Fetal fibronectin levels in cervical mucus were quantitated in 28 nulliparous term pregnant women with unfavorable cervical states before and after intracervical application of prostaglandin E2 gel. The concentration of fetal fibronectin was determined with use of an enzyme immunoassay. Cervical biopsy specimens and amniotic tissue for immunohistochemical analysis were obtained from three term pregnant women and after parturition in three women. Cervical biopsy specimens from two nonpregnant women served as controls. Immunohistochemical analysis was performed with antibodies directed toward fetal fibronectin. RESULTS: The fetal fibronectin level in cervical mucus was low in all women before prostaglandin E2 application. In women with a successful prostaglandin E2-induced ripening (i.e., an increase of cervical score with > or =3 points), a tenfold increase in the fetal fibronectin level was registered. In women with an insufficient cervical ripening after prostaglandin E2 treatment no significant increase in the fetal fibronectin level was registered. The immunohistochemical analyses have identified fetal fibronectin in the epithelial cells of the cervix uteri. CONCLUSION: Successful prostaglandin E2-induced cervical ripening seems to be related to a significant increase in cervical fetal fibronectin levels. Fetal fibronectin can be detected immunohistochemically in the pregnant human cervix.

Adult↗

Factors involved in the inflammatory events of cervical ripening in humans.

BACKGROUND: Cervical 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: There 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.

Adult↗

Increased release of cervical nitric oxide in spontaneous abortion before clinical symptoms: a possible mechanism for preabortal cervical ripening.

Nitric oxide (NO) affects cervical ripening. We studied cervical NO release in women with nonviable pregnancy before signs of abortion. Women with missed abortion (n = 56), blighted ovum (n = 36), or tubal pregnancy (n = 7) were selected by means of vaginal ultrasonographic examination from a population seeking early pregnancy termination; 140 women with amenorrhea-matched normal gestation were studied as controls. Cervical fluid samples were assessed for NO metabolites (Nox) by means of Griess reaction. Cervical fluid Nox was more often detectable in women with missed abortion (90%) and blighted ovum (87%) than in the control women (55%; P = 0.01), and Nox levels in women with missed abortion [median, 59.4 mumol/liter; 95% confidence interval (CI), 30.3-81.8] and blighted ovum (25.6 mumol/liter; 95% CI, 14.1-53.0) were 14 and 6 times higher (P < 0.001 and P = 0.002, respectively) than in the control group (4.3 mumol/liter; 95% CI, <3.8 to 6.4). Nox levels in women with tubal pregnancy were normal. In women with nonviable pregnancy, the lower the level of progesterone, expressed as a percentage of that in the control women, the higher (r = -0.69; P < 0.001) the level of cervical fluid Nox, and those with low pretreatment Nox levels failed to abort completely after mifepristone-misoprostol or expectant management more often (P = 0.04) than women with high Nox levels (28% vs. 4%); no such relationship was seen in the control group. Increased preabortal cervical NO release may contribute to cervical ripening and the onset of clinical abortion.

Abortion, Spontaneous↗

Cervical ripening and induction of labour by breast stimulation.

The value of gentle, unilateral breast stimulation in the ripening of cervix and induction of labour was studied. Three hundred patients with uncomplicated term pregnancies, (38-42 weeks) were recruited into the study, consisting of three separate randomised double blind prospective trials. The first trial was to evaluate the effectiveness of breast stimulation in ripening the cervices of 200 term primigravid patients. There was a mean change of 3.90 +/- 2.39 points in cervical score among the study group compared to 0.50 +/- 0.67 among the control group. Thirty-three per cent of the study group went into labour when compared with 4% among the control group. In a second study of cross-over trial involving 78 of the original 200 patients, the study (ex-control) group had a mean change in cervical score of 3.84 +/- 2.24 when compared with the control (ex-study) group, (1.43 +/- 1.08). In a third study involving 100 multiparous patients, a mean change in cervical score of 2.74 +/- 1.16 was observed in the study group when compared with the control group, 0.92 +/- 1.07. Forty-six per cent of the patients went into labour compared with 12% in the control group. All findings were highly significant and there were no maternal or fetal side-effects. The study confirmed the efficacy of breast stimulation in cervical ripening and induction of labour.

Adult↗

[Cervical ripening using misoprostol before hysteroscopy].

Cervical ripening with misoprostol is performed before office or operative hysteroscopy. Aim of this review is to evaluate benefits of cervical ripening with misoprostol before hysteroscopy . Ten studies were selected concerning office or operative hysteroscopy. Cervical ripening with misoprostol seems to be not useful for office hysteroscopy performed with minihysteroscope. Interest of misoprostol in menopausal women with traditional office hysteroscope is debatable. Risk of cervical tear during operative hysteroscopy seems to be reducing with misoprostol. However, interest of misoprostol was not found in all studies. Data were not sufficient to determine adequate dose of misoprostol, time and mode of administration. However, vaginal administration is preferable.

Administration, Intravaginal↗

Human cervical ripening is associated with an increase in cervical inducible nitric oxide synthase expression.

The mechanisms that ultimately regulate cervical ripening during parturition remain largely unknown. A possible role for nitric oxide (NO) has recently emerged; however, the expression of NO synthase (NOS) within the human cervix in the ripening process has not been investigated. The purpose of this study was to identify cell types in the human cervix that contain NOS isoforms and to examine changes in their expression during the ripening process and the nonpregnant state. Inducible NOS (iNOS) immunoreactivity was observed in the epithelial cells and stromal spindle cells in 17 of 20 biopsies from cervices obtained within 10 min postpartum, but in only 4 of 12 nonpregnant controls (p = 0.03). Endothelial NOS (eNOS) immunoreactivity was restricted to vascular endothelia in all sections, whereas neuronal NOS was not detectable. Inducible NOS activity in the postpartum group was 3.2 times that of the control group (p = 0.0005), whereas constitutive NOS activity remained unchanged in both groups (p = 0.222). Competitive reverse transcription-polymerase chain reaction revealed no differences in the expression of iNOS (p = 0.443) or eNOS mRNA (p = 0.409). The existence of iNOS in the human postpartum cervix suggests that increased production of NO, probably induced by cytokines, may be relevant to the process of natural cervical ripening in humans.

Adult↗

Prostaglandin E2 preparations for preinduction cervical ripening.

PGE2 is an effective agent for cervical ripening. It is most effective when administered intravaginally. Patients with unfavorable cervices who begin labor during cervical ripening have greater gestational ages, more baseline uterine activity, more initial uterine activity in response to PGE2, and lesser cesarean delivery rate than those patients who do not begin labor during cervical ripening. However, PGE2 should not be continued or administered when the patient is in active labor because it leads to unacceptable rates of hyperstimulation. Unfortunately, cervical ripening with PGE2 has little or no effect on the overall cesarean delivery rate.

Cervical Ripening↗

Steroid concentrations in human cervical tissue in relation to cervical ripening.

Steroid concentrations in human cervical tissue were measured in order to study the mechanism of cervical ripening at term. Thirty-four women at 37 to 41 weeks of gestation were selected for the study and divided into two groups. Group A consisted of 21 cases with ripened cervix, and Group B consisted of 13 cases with non-ripened cervix. The condition of the cervix was judged by the Bishop's Score. Free and conjugated estrone (E1), estradiol (E2), estriol (E3), and dehydroepiandrosterone (DHA) concentrations in cervical tissue were measured by radioimmunoassay (RIA). Significantly higher concentrations of free E1, conjugated E2, E3 and DHA were found in Group A than in Group B. Cervical tissue during labor showed a further increase in the concentrations of these steroids. Pronounced increases of the steroid concentrations were noted following DHA-Sulfate (DHA-S) administration. These results suggest an intimate relationship between cervical ripening and steroid concentrations in cervical tissue during pregnancy.

Cervix Uteri↗

Cervical fetal fibronectin correlates to cervical ripening.

AIM OF STUDY: It is well established that the cervical ripeness is of great prognostic value at labor induction. The available methods of measuring the cervical ripeness are not satisfactory. This study was therefore initiated to investigate if there is any correlation between cervical fetal fibronectin and cervical ripening at term. METHOD: Three groups were included in this study: women with unripe cervices, women with spontaneous cervical ripening and those with PGE2-induced cervical ripening. Fetal fibronectin was measured by ELIZA after sampling from the cervical canal. RESULTS: The cervical fetal fibronectin was low in women with unripe cervices. In women with favorable cervices a ten fold higher level was found. The fibronectin level was even higher after PGE2-induced ripening. CONCLUSION: Conclusively an increased amount of cervical fetal fibronectin is registered during the cervical ripening process. A level of > 0.80 microgram/ml of cervical fetal fibronectin seems to indicate a favorable cervix.

Adult↗

Mechanical methods of cervical ripening and labor induction.

This article reviews the safety and efficacy of mechanical agents for cervical ripening. Hygroscopic dilators, balloon catheters, and devices designed for cervical ripening have all been shown to be safe and effective for cervical ripening. Mechanical agents are as efficacious as other agents for cervical ripening. However, there is no method that has been conclusively shown to improve mode of delivery or perinatal outcome. The advantages of preinduction cervical ripening with mechanical devices include low cost, low incidence of systemic side effects, and low risk of uterine hyperstimulation.

Abortion, Induced↗