Intracervical instillation of PGE2-gel in patients with missed abortion or intrauterine fetal death

A single intracervical instillation of prostaglandin E2 (1.0 mg or 0.5 mg in viscous gel) was given to dilate the cervix before dilatation and evacuation in patients with missed abortion or intrauterine fetal death in late pregnancy. The 1.0-mg dose of PGE2 gave more prominent cervical dilatation in early pregnancy. In late pregnancy 1.0 mg PGE2 induced labor in the majority of patients and with shorter induction delivery time than in patients given 0.5 mg PGE2. There was no uterine hypertonus and no patients complained of gastrointestinal symptoms. We conclude that intracervical instillation of 1.0 mg of PGE2 in viscous gel is a safe and effective method both for dilating the cervix before dilatation and evacuation and as a method of inducing labor in patients with intrauterine fetal death.     

Prostaglandin E2 cervical ripening without subsequent induction of labor.

OBJECTIVE: To determine whether outpatient administration of intracervical prostaglandin (PG) E2 gel decreases the interval to delivery and duration of labor. METHODS: A randomized, double-blind, placebo-controlled trial compared the intracervical placement of 0.5 mg PGE2 gel with placebo in 61 pregnant women at 38 weeks' or greater gestation with Bishop scores less than 9. Transvaginal cervical length, fetal fibronectin, and Bishop score were assessed before gel placement. Subjects were then allowed to go into spontaneous labor unless an indication for induction developed. RESULTS: Thirty women were assigned to PGE2 and 31 to placebo. There were no significant demographic differences between the groups and there were no differences in cervical length, fetal fibronectin status, or Bishop scores. Fifteen women in the PGE2 group and five in the placebo group went into labor and delivered within the first 2 days after gel placement (P = .007). The median interval to delivery was significantly shorter in the PGE2 group, at 2.5 days, compared with placebo, at 7 days (P = .02). Nulliparas in the PGE2 group had a median interval to delivery of 2 days, compared with 7 days for nulliparas receiving placebo (P = .03). Active phases of labor were significantly shorter in the PGE2 group and for women with a negative fetal fibronectin test who received PGE2. CONCLUSION: Outpatient administration of intracervical PGE2 gel shortened intervals to delivery and shortened labor.     

Sequential outpatient application of intravaginal prostaglandin E2 gel in the management of postdates pregnancies

A randomized blinded investigation was undertaken to determine the efficacy and safety of sequentially applied intravaginal prostaglandin E2 (PGE2) gel for accelerating cervical ripening in an outpatient setting in low-risk prolonged pregnancies. Fifty women with uncomplicated pregnancies at or beyond 41 weeks' gestation and Bishop scores below 9 received twice-weekly outpatient administration of gel containing 2.0 mg of PGE2 or placebo. Thirty nulliparas and 20 multiparas were enrolled. The PGE2 gel failed to improve cervical ripening over placebo, as judged by Bishop scores. There was no difference between the groups in gestational age on admission to the labor and delivery suite, number of gel applications, requirement for oxytocin, incidence of cesarean delivery, or neonatal outcome. Only two patients (4%) experienced regular uterine contractions after gel insertion; these subsided spontaneously in both. None of the subjects experienced labor, tetanic contractions, evidence of fetal distress, or any other side effects related to gel insertion. We conclude that PGE2 gel in this dosage may be used safely in an outpatient setting, but more frequent application or earlier initiation may be required to produce a clinical effect.     

Intracervical application of prostaglandin gel for induction of term labor

A new gel for local application of prostaglandins has been elaborated. The new gel, based on a lyophilized prostaglandin E2 (PGE2) starch powder, seems to have solved most of the pharmaceutical and clinical problems associated with local administration of prostaglandins. In a randomized double-blind study, 50 nulliparous patients with an unfavorable cervical state at term were given 2 ml gel containing 0.5 mg PGE2 (PGE2 gel) or gel without PGE2 (placebo gel). The gel was deposited into the cervical canal. Among patients given PGE2 gel, 11 of 25 had induced labor, delivering without further stimulation within 24 hours. In patients given placebo gel, 2 of 25 were delivered with 24 hours. This difference is statistically significant (P less than .01). Patients undelivered after treatment with PGE2 gel achieved a considerable and statistically significant improvement of cervical score, whereas in patients in whom labor was not induced successfully by placebo gel treatment no significant changes in cervical score were registered. In a subsequent open study another 70 term patients of varied parity were given 0.5 mg PGE2 gel. Thirty-eight patients (54%) had successfully induced labor. Among the remaining undelivered patients, considerable ripening of the cervix occurred. Thus, the cervical score changed from a mean of 3.2 prior to treatment to a mean of 6.5 by 24 hours after treatment. Gastrointestinal discomforts were not observed. Signs of uterine hyperstimulation were registered in 1 patient.     

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.     

Open randomized comparison of prostaglandin E2 given by intracervical gel or vagitory for preinduction cervical ripening and induction of labor.

Intracervical application of prostaglandin E2 (PGE2) in a viscous gel was compared with conventional wax-based PGE2 vagitories (pessaries) for ripening of the cervix prior to induction of labor. A total of 226 healthy pregnant women at term were randomly allocated to receive intracervical gel with an effective dose of 0.5 mg (n = 116) or vagitories containing 2.5 mg PGE2 (n = 110). All women had a modified cervical score of less than or equal to 4. The numbers of cases contributed by each of the three centers were similar. There was no significant difference in parity, gestational length, maternal characteristics, indications for induction or preinduction cervical scores between the treatment groups. The rate of spontaneous birth was 71% in the gel group, compared with 69% in the vagitory group. Successful treatment was defined as active labor within 24 h or a change in cervical dilatation allowing artificial rupture of the membranes with subsequent progressive labor. The success rate was not significantly different in the gel group (82%) compared with the vagitory group (80%). There were no differences in the frequency of fetal distress, outcome of labor, assisted delivery rates or maternal side effects. The cervical scores were not different at 12 and 24 h after application. Intracervical gel and intravaginal application of PGE2 were similar in their efficacy and safety for ripening of the cervix and inducing labor at term.     

Intracervical versus intravaginal PGE2 for induction of labor at term in patients with an unfavorable cervix

In a randomized double-blind study we evaluated the effects on cervical ripening and labor induction of 0.5 mg PGE2 in gel given intracervically and 2.0 mg PGE2 given as a vaginal suppository. All patients were at term with unfavorable cervical scores. The indications for induction were toxemia, diabetes mellitus, Rh-immunization, or intrauterine growth retardation. Significantly better results for both cervical priming and labor induction were obtained after intracervical PGE2-gel application than after treatment with placebo or vaginal suppositories. Eleven out of 19 patients (58%) were delivered within 24 h after intracervical PGE2-gel compared to two out of 19 patients given placebo (p less than 0.01). In patients not delivered 24 h after the start of treatment, the mean cervical score had changed from 3.7 to 6.0 (p less than 0.05) after PGE2-gel application compared to a change from 3.9 to 4.3 after placebo treatment (n.s.). The outcome after treatment with PGE2 suppositories did not differ significantly from that with placebo treatment. In a subsequent study 25 patients were given 0.5 mg PGE2-gel intracervically. The results were consistent with those obtained in patients receiving PGE2-gel intracervically in the double-blind study. Few side effects were noted. No patient complained of gastro-intestinal discomfort but increased myometrial activity was observed in two patients; one after placebo and the other after active intracervical PGE2-gel treatment. The hyperactivity was readily countered with the beta 2-agonist, terbutaline. All infants were born in good condition with Apgar scores of 7 or more within 5 min. At pediatric examinations at 1 week and at 6 months of age all children seemed healthy.     

Intracervical administration of prostaglandin E2-gel prior to therapeutic abortion: a prospective randomized double-blind study

Forty primigravid women due to undergo first trimester termination of pregnancy were randomly selected for intracervical application of 1 mg prostaglandin E2 in gel or gel only as placebo. In the PGE2-gel group, a marked dilatation of the cervical canal was obtained, with post-gel treatment mean Hegar dilatation of 11.18 mm in that group, compared to 4.4 mm in the control group (P 0.001). Moreover, 16 (80%) patients in the PGE2-gel group had a complete abortion, one (5%) patient had an incomplete abortion and in the remaining three (15%) patients, fetal demise was observed. The mean induction-abortion interval in this group was 7.5 h. In the placebo group, none of the above effects were observed. The only side effect noted was vomiting, which occurred in five (25%) of the patients in the PGE2-gel group. Termination of pregnancy was found to be easier in the PGE2-gel group, compared to the placebo group.     

Intracervical prostaglandin in postdate pregnancy. A randomized trial

A study was designed to see if incorporating intracervical administration of prostaglandin could affect the outcome of postdate pregnancies. All patients with verified dates, at least 41 6/7 weeks pregnant and enrolled in an antepartum testing schedule were randomized in a double-blind fashion to receive either 0.5 mg of prostaglandin E2 (PGE2) suspended in methylcellulose or a placebo of the gel alone. The gel was inserted directly into the cervical canal after the patient had a reactive/negative contraction stress test. The patient was then observed on an external fetal monitor for an hour before going home. A total of 23 patients received PGE2, and 20 received the placebo. Results were analyzed for the following: change in the Bishop score, lag time from dosage to delivery, spontaneous versus induced labor, cesarean section rate, length of labor and neonatal outcome. There were no significant differences between the groups except in the incidence of patients going into labor within 72 hours. The results indicate that, in general, 0.5 mg of intracervical PGE administered at greater than or equal to 41 6/7 weeks without subsequent oxytocin induction of labor did not appear to significantly alter the obstetric outcome.     

Pre-induction intracervical application of a highly viscous prostaglandin E2 gel in pregnant women with an unripe uterine cervix: a double-blind placebo-controlled trial.

Intracervical application of prostaglandin E2 (PGE2) gel has shown to be an effective method for pre-induction cervical ripening in pregnant women with an unripe uterine cervix. Side effects are minimal, provided that the instillation is carefully restricted to the cervical canal. This requires--apart from a proper technique--an optimal gel formulation. For this reason a newly developed highly viscous PGE2 gel was evaluated in a randomized, double-blind, placebo-controlled multicentre trial. Within a 9-h study period, successful cervical ripening (increase in Bishop score to 6 or more) was achieved in 39 (56%) of the 70 patients in the PGE2 groups and in 23 (34%) of the 68% patients in the placebo group (P = 0.04). During the first 12 h after gel application, 25 (35%) of the women in the PGE2 group and 2 (3%) in the placebo group had a spontaneous delivery. No serious adverse reactions were observed. The data suggest that the use of this highly viscous PGE2 gel may be advantageous if strictly intracervical application is the primary objective.     

Ripening of the uterine cervix and induction of labour at term with prostaglandin E2 in viscous gel.

In order to achieve ripening of the uterine cervix or induce labour in patients at term with an unfavourable cervical state, 1 mg of prostaglandin E2 (PGE2), suspended in a viscous gel, was instilled into the cervical canal. In a pilot study, 41 patients received the PGE2-gel. Twenty-three of these, (56%), went into labour, and delivery occurred without further stimulation within 15 hours. In the remaining 18 patients, there was a marked improvement of the cervical state, which changed from an average (modified) Bishop score of 2.5 to 6.1 within 24 hours. In a double-blind study comprising 20 nulliparae, 10 received gel containing PGE2 and 10 gel without prostaglandin. Cervical state did not change significantly (Bishop score 3.6 and 4.0) after 24 hours in patients receiving placebo gel. In those receiving PGE2 gel, 8 went into labour and were delivered without further induction within 13 hours. Two patients showed an increase in Bishop score from 3 to 6 and 7, respectively, after 24 hours. They were then induced by oxytocin and delivery occurred after 8 and 10 hours. The results suggest that administration of PGE2 intracervically can induce ripening of the cervix in patients at term with an unfavourable cervical state, and thus facilitate delivery.     

A comparison of prostaglandin E2 gel and prostaglandin F2 alpha gel for preinduction cervical ripening

The unfavorable cervix remains a major obstacle to the successful induction of labor. Reported are results from an ongoing study of topical prostaglandin preparations used to effect preinduction cervical ripening. The current study compares the efficacy of 40 mg of prostaglandin (PG) F2 alpha versus 5 mg of PGE2, applied to the cervix in a methyltylose gel the night before attempted induction of labor. A prospective double-blind protocol was used similar to that which previously established the efficacy of the 5 mg of PGE2 preparation versus placebo at this institution. Results indicate the superiority of the PGE2 preparation as measured by change in Bishop score, Pitocin requirement, rate of cervical dilatation, and percentage of failed inductions. Cesarean section rates were similar in the two study groups, and no fetal or maternal morbidity was attributable to the preinduction ripening technique.     

Intracervical application of PGE2-gel combined with early intravenous infusion of oxytocin for induction of term labor in women with unripe cervix

Fifty-four women with an unripe cervix at term were given 0.5 mg intracervical prostaglandin E2 (PGE2) gel. In 37 of them (70%) the cervix ripened within 5 h and seven of them were in labor at that time. Of the remaining 30 patients, 15 were randomly given an i.v. oxytocin infusion and 13 were delivered within 12 h. In 17 women (30%) the cervix was still unfavorable 5 h after PGE2-gel application but seven of them had a favorable cervix when reassessed 24 h after PGE2-gel instillation. All these patients went into labor with an i.v. infusion of oxytocin. The remaining 10 patients required another dose of PGE2-gel and subsequent i.v. oxytocin. Only in two of these patients did induction fail so that delivery by Caesarean sections was required. All infants were born in good condition.     

Effects of induction of labor with prostaglandin E2 on fetal breathing and body movements: controlled, randomized, double-blind study.

OBJECTIVE: To evaluate the effects of prostaglandin (PG) E2, given for induction of labor at term, on fetal breathing and body movements. METHODS: Eighteen women with term pregnancies, mild gestational hypertension, intact membranes, and unripe cervices who were not in labor participated in this study. After a 60-minute baseline ultrasound examination of fetal chest and body movements, recorded on videotape, the patients were randomly assigned to either 3 mg intravaginal PGE2 tablets or controls (placebo intravaginal tablets). Following tablet insertion and a 3-hour observation time, a second 60-minute ultrasound recording of fetal movements was taped. The videotape recordings were interpreted according to the total amount of time occupied by fetal body movements and fetal breathing movements. RESULTS: There was a total of 2180 minutes of ultrasound tape recordings, with 136.2 minutes of fetal body movements (6.2%) and 207.8 minutes of fetal breathing movements (9.5%). Mean (+/- standard deviation) observation times per patient before and after tablet insertion were 60.3 +/- 1.2 and 56.4 +/- 1.2 minutes for the PGE2 group and 60.1 +/- 1.3 and 60.4 +/- 1.1 minutes for the control group. Three hours after PGE2 insertion, there were significant decreases in the percentage of time occupied by body movements (7.8 +/- 3.1 versus 3.4 +/- 2.0%; P < .003) and breathing movements (10.6 +/- 8.6 versus 3.9 +/- 2.3%; P < .007). Three hours after tablet insertion, there were statistically significant decreases in the percentage of time occupied by body movements (P < .025) and breathing movements (P < .01) between the control and study groups. CONCLUSION: Induction of labor with intravaginal PGE2 tablets inhibits fetal body and breathing movements. The effects could be due to direct action on the fetus or indirect effects of PGE2 (through uterine contraction and/or endogenous PG).     

Prostaglandins, chorioamnionitis and preterm labour

The production of prostaglandin E (PGE) and leukotriene B4 (LTB4) by amnion was measured in vitro in 12 women delivered after spontaneous preterm labour and in 15 women delivered after spontaneous labour at term. The placenta and fetal membranes were examined histologically in all cases. PGE output (fmol/mg dry weight/2 h) in the amnions from uncomplicated preterm deliveries was low (median 486, range 232-3203, n = 7) compared with the values obtained after spontaneous labour at term (5529, 1722-14,226, n = 15). In amnions from preterm deliveries complicated by acute chorioamnionitis or round cell infiltration there was massive release of PGE (15,262, 10,905-27,640, n = 5) which was accompanied by an increase in LTB4 production. Inflammatory infiltration of the fetal membranes results in a huge increase in PG production which could cause preterm labour.     

Effects of maternally administered dexamethasone and acute hypoxemia at 0.7 gestation on blood pressure and placental perfusion in sheep.

Glucocorticoid administration to women in premature labor significantly decreases preterm infant morbidity and mortality. Fetal exposure to maternally administered glucocorticoids in late gestation causes fetal hypertension. We determined the effects of a single course (4 injections at 12-hr intervals) of dexamethasone (DM; 2 mg, a weight-adjusted dose equivalent to one-third the dose administered to pregnant women) or saline (S) in sheep at 103-104 days of gestation (dGA; term 149 dGA) on maternal and fetal blood pressure (BP). We also determined the BP and placental perfusion effects of acute maternal hypoxemia. Venous and arterial catheters were placed in 10 ewes and fetuses (DM = 6, S = 4) at 96 +/- 1 dGA. Maternal and fetal placental perfusion was determined with fluorescent microspheres. Dexamethasone increased fetal but not maternal BP; maternal and fetal placental blood flow and vascular resistance (VR) were unchanged. At 105 dGA, hypoxemia was induced for 1 hr by maternal nitrogen gas inhalation to decrease fetal PaO2 by 40%. Hypoxemia increased BP in DM but not S fetuses or mothers in either group. Hypoxemia decreased maternal placental blood flow by 39 +/- 7% and 51 +/- 9% and increased maternal placental VR by 65 +/- 7% and 69 +/- 6% in S and DM mothers, respectively. Hypoxemia did not alter fetal placental blood flow or VR in either treatment group. In summary, at 0.7 gestation, DM induces a hypertensive response to fetal hypoxemia that is characteristic of older fetuses but does not alter hypoxemia-induced reductions in maternal placental blood flow.     

The physiological and clinical effects of progesterone inhibition with mifepristone (RU 486) in the second trimester

A double-blind placebo-controlled trial was performed in 20 primigravidae to assess the physiological and clinical effects of oral mifepristone on myometrial contractility and sensitivity in the second trimester. Ten women received 600 mg of oral mifepristone and 10 women a placebo 24 h before abortion was induced in both groups, with extra-amniotic PGE2 instillation. Intrauterine pressure recordings demonstrated increased spontaneous uterine activity and increased sensitivity to PGE2 and ergometrine, but no change in oxytocin sensitivity after mifepristone treatment. There were no significant differences in PGE or PGF metabolite concentrations in peripheral maternal plasma over the 24-h study period after treatment between the mifepristone and placebo groups. The mean induction abortion interval in the mifepristone group was 512 (SD 321) min compared with 1128 (SD 606) min in the placebo group (P less than or equal to 0.02). The mechanism whereby mifepristone provokes enhanced uterine contractility and sensitivity to prostaglandins, with a reduction in abortion times, does not appear to be through endogenous production of PGE or PGF.     

Vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening at term: a randomized controlled study

OBJECTIVE: Our aim was to examine the effect of the nitric oxide donor isosorbide mononitrate on the uterine cervix at term and to evaluate possible adverse effects of this treatment. STUDY DESIGN: Term pregnant women were randomly selected to receive either 40 mg vaginally administered isosorbide mononitrate or placebo 4 hours before elective cesarean section. Cervical status, maternal blood pressure, maternal pulse rate, fetal heart rate, umbilical arterial Doppler indices, and various side effects were examined. RESULTS: Isosorbide mononitrate induced a significant increase in cervical distensibility. It also caused a significant change in maternal blood pressure and maternal pulse rate. In addition, the frequency of maternal headache and palpitations was significantly higher in the isosorbide mononitrate group versus the placebo group. However, the intensity of these symptoms was moderate. CONCLUSION: Vaginal administration of 40 mg of isosorbide mononitrate induces cervical ripening at term. Although the majority of women experienced side effects, no serious clinical maternal or fetal adverse effects, resulting in specific medication or emergency cesarean section, were diagnosed.     

Prostaglandins, chorioamnionitis and preterm labour

Summary. The production of prostaglandin E (PGE) and leukotriene B₄ (LTB₄) by amnion was measured in vitro in 12 women delivered after spontaneous preterm labour and in 15 women delivered after spontaneous labour at term. The placenta and fetal membranes were examined histologically in all cases. PGE output (fmol/mg dry weight/2 h) in the amnions from uncomplicated preterm deliveries was low (median 486, range 232–3203, n = 7) compared with the values obtained after spontaneous labour at term (5529, 1722–14226, n = 15). In amnions from preterm deliveries complicated by acute chorioamnionitis or round cell infiltration there was massive release of PGE (15 262,10 905–27 640, n = 5) which was accompanied by an increase in LTB₄ production. Inflammatory infiltration of the fetal membranes results in a huge increase in PG production which could cause preterm labour.     

Oxytocin-induced labor characteristics and uterine activity after preinduction cervical priming with prostaglandin E2 intracervical gel

Labor characteristics and quantitation of uterine activity resulting from oxytocin induction of labor after intracervical prostaglandin E2 (PGE2) gel priming have not been previously reported. Forty-seven women with modified Bishop scores of 5 or less received preinduction priming with 0.5 mg of intracervical PGE2 gel. Oxytocin was used to induce labor after priming, and uterine activity was quantitated. A matched group of control patients was managed identically but did not receive PGE2 gel. In the gel group, modified Bishop scores improved significantly and in two patients (4%), priming alone induced labor. No uterine hyperstimulation or fetal heart rate abnormalities occurred during priming. Cesarean sections for all indications and those for failed induction were less common in the gel group. The length of the active phase and the second stage of labor were significantly shorter in the gel group. Uterine activity was similar in both groups. The data suggest a primary cervical action of the gel.