Controlled trial of induction of labor by vaginal suppositories containing prostaglandin E2

A group of 84 women at 39 – 43 weeks of pregnancy were randomly allocated to a blind trial of induction of labor with vaginal suppositories containing inert material or either 0.2 mg or 0.4 mg of prostaglandin E₂. The suppositories were self-administered every two hours during waking hours on two successive days until labor started or 15 had been used. Side-effects were absent. Labor was established within 48 hr of insertion of the first suppository in 9.3% of control patients, 65.4% of those treated with 0.2 mg PGE₂ and 85.7% of those treated with 0.4 mg PGE₂. The mean Apgar scores in the three groups were the same. The mean total dose of PGE₂ were 2.0 mg (0.2 mg group) and 2.3 mg (0.4 mg group). It is concluded that vaginal PGE₂ is an effective and acceptable method of inducing labor at term.     

Midtrimester abortion induced by serial intravaginal administration of prostaglandin E2 suppositories in conjunction with a contraceptive diaphragm.

Midtrimester abortion was successfully induced in 68 of 69 patients with serial intravaginal administration of prostaglandin E2 suppositories behind a contraceptive diaphragm. The mean abortion time for the successful inductions was 13.07 hours; multiparous patients aborted somewhat faster, mean 12.72 hours, as compared to nulliparous patients, mean 14.22 hours. In 36 patients the PGE2 suppositories were placed behind an intact diaphragm and the mean abortion time was 14.89 hours. In 33 patients the PGE2 suppositories were placed behind a diaphragm modified by having an opening incised in the center, the mean time in these patients was 11.96 hours. Of the 68 successful abortions 59% of the patients aborted in 12 hours or less and 88% aborted within 24 hours. The most frequently encountered side effect was temperature elevation of 2 degrees F or higher which occurred in 68% of the patients. Temperatures returned to normal levels within 4 to 6 hours after the last adminstration of PGE2. Gastrointestinal side effects occurred in 45% of patients, but these side effects were well tolerated and did not require termination of drug administration in any of the patients. Intravaginal administration of PGE2 suppositories is a very effective abortifacient technque during the midtrimester, however the use of PGE2 in conjunction with a diaphragm did not appreciabley improve the technique although the amount of drug administered and the incidence of side effects was somewhat lower than when the PGE2 suppositories are used alone. If a diaphragm is to be used, a modified diaphragm is indicated since it simplifies the clinical management of the abortion, eases administration of the suppositories and permits a more accurate estimation of cervical changes, vaginal bleeding and abortion.     

Plasma concentration of 13,14-dihydro-15-keto-PGE2 (PGEM) after various ways of cervix ripening with PGE2

PGEM concentration was determined radioimmunologically in a non-pregnant woman, in whom PGE2 was infused intravenously at increasing rates and in women, in whom labor was induced by various methods for local application of PGE2. There was excellent correlation between the amount of PGE2 infused intravenously and the levels of PGEM determined in the peripheral plasma. The following methods of local application of PGE2 were included in the study: 0.4 mg PGE2 gel placed retroamnially by means of a balloon catheter, 0.4 and 0.5 mg PGE2 applied endocervically and 3 mg PGE2 placed intravaginally in form of a single vaginal tablet; also included was a control-group, where only vaginal examination was performed. Bloods were drawn before, 30 minutes, 1, 2 and 3 hours after PGE2 administration. Mean levels of PGEM in the maternal peripheral plasma did not change neither within nor between the various groups. It is concluded from the present study, that local application of doses currently used to soften the cervix and/or induce labor at term do not lead to the same PGEM-concentration in the maternal blood as after intravenous infusion of PGE2 in doses normally used to induce labor.     

Letter: PGE2 as a vaginal abortifacient - diaphragm effect.

Schulman et al reported reduction in interval-abortion time and decreased side effects when prostaglandin (PG) E2 vaginal suppositories were administered within a contraceptive diaphragm. The authors conducted a study to confirm Schulman et al' finding. 2 groups of 20 patients with gestational ages ranging from 13 to 20 weeks were matched. 1 group (non-diaphragm) had a 20 mg. suppository inserted every 4 hours high in the vaginal fornix. The other group (diaphragm) had a contraceptive diaphragm containing the suppository inserted at 4-hour intervals. The authors' protocol differed from that of Schulman's in that oxytocin sensitivity was not sought and PGE2 alone was used. Oxytocin, however, was used to promote placental expulsion following fetal delivery in 4 cases. There were no statistically significant differences observed between the groups with respect to total drug dose (84 mg. for diaphragm group and 80 mg. for non-diaphragm), abortion-interval time (15.2 hours vs. 14.3 respectively), or frequency of side effects (vomiting, diarrhea). Schulman's reduced side effects may have followed the decreased absorption rate of PGE2 and avoidance of plasma peaks secondary to reduction in drug-mucosal interface. Schulman also reported onset of uterine activity in the diaphragm group (mean, 41 minutes) versus the control group's mean of 79.4 minutes. There is no known physiologic explanation for such findings.     

Clinical evaluation of endocervical prostaglandin E2-triacetin-gel for preinduction cervical softening in pregnant women at term

In an open randomized clinical trial 100 pregnant women with low Bishop Scores at term were treated either with intracervical Prostaglandin (PG) E2 (0.5 mg in 2.5 ml triacetin-gel) 12 hours before labor induction with intravenous oxytocin or with oxytocin infusion alone. In 46 of the 50 pretreated patients (92%) the Bishop Score progressed at least 3 points, in four cases only 2 points. The mean Bishop score in the untreated patients increased insignificantly. After PGE2-gel administration 16 patients delivered during the 12 hour interval compared to 3 in the group without pretreatment. The first induction attempt was successful in 14 (64%) of the 22 patients that were left to be induced after cervical softening and in 26 (57%) of the 47 women without cervical priming. The Cesarean section rate was 10% (n = 5) in the PGE2-gel group and 12% (n = 6) in the control group. Dosage of oxytocin required for labor induction was significantly lower after cervical softening. No serious fetal or maternal side effects were observed after PGE2 pretreatment.     

Development of a vaginal gel containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 for cervical dilatation and pregnancy termination

A stable hydrophilic gel for vaginal administration containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) was developed and its clinical usefulness for preoperative cervical dilatation and for termination of first and second trimester pregnancy evaluated in 521 pregnant patients admitted to the hospital for therapeutic abortion. Following vaginal administration of 3 mg of 9-methylene PGE2 gel a peak plasma level of between 3.5 and 10 ng/ml was found 3 to 6 hours following treatment. The "bioavailability" of the drug was in the order of 25-30%. 9-methylene PGE2 was found to be equally effective as 1 mg Cervagem for preoperative cervical dilatation. With a pretreatment period of 3 hours side effects were rare with both compounds. If the pretreatment period was extended to 12 hours the degree of cervical dilatation, but also the frequency of side effects increased significantly. Repeated administration of 9-methylene PGE2 was found to be effective (96% complete abortion) in terminating very early pregnancy provided the total dose was 10 mg or more. During second trimester the minimum effective dose was 4.5 mg of the compound repeated every fourth hour. The results of the present study have shown that with the new gel formulation the amount of 9-methylene PGE2 needed to terminate first and second trimester pregnancy was approximately ten times less in comparison with the previously used lipid base suppositories. The treatment was also associated with a low frequency of side effects.     

Prostaglandin E2 induced abortion with vaginal suppositories in a contraceptive diaphragm

PGE2 (prostaglandin E2), 20 mgm vaginal suppositories were administered to 2 groups of women seeking termination of pregnancy. 1 group had the suppository inserted inside a contraceptive diaphragm. Statistical comparisons were carried out for instillation to abortion time, side effects, and intrauterine pressure parameters. The usage of the diaphragm significantly reduced side effects, and resulted in an instillation to abortion time of 12.8 + or - 2.3 hours with no failures. The quantitative analysis of the uterine pressure recordings revealed activity significantly different than that seen with intraamniotic or extraovular PGF2alpha. The development of uterine activity simulates that of normal labor in that elevation of resting pressure does not occur and maximum active pressure evolves slowly.     

Endocervical prostaglandin E2 gel for preinduction cervical softening

A single, endocervical application of a new commercial preparation of prostaglandin E2 (PGE2) gel, 0.5 mg of PGE2 in 2.5 ml (3 g), was evaluated for preinduction cervical softening. Safety and efficacy were assessed in a comparison with a 2.0 mg PGE2 vaginal tablet and placebo in normal nulliparous women at term, with low Bishop scores. Treatment was administered in randomized, double blind fashion. Overall success, defined as a progression in Bishop score of at least 3 points within 12 hours, was achieved in 22/40 (55%) of the gel group, 15/41 (37%) in the tablet treated women, and 8/40 (20%) in those receiving placebo. Of interest was the observation that of women with very unfavorable induction features (Bishop score 0-2), the cervical gel treatment resulted in a 6/8 (75%) success rate compared with 2/13 (15%) success for the vaginal tablet and 0/17 (0%) for placebo. In as much as a very low incidence of side effects accompanied this treatment scheme, expanded multi-center testing is recommended.     

On the mechanism of action of 15-methyl-PGF2 alpha as an abortifacient.

Several hours following administration of long acting vaginal suppositories containing 3.0 mg of 15-methyl-PGF2 alpha for interruption of second trimester pregnancies there is an up to 10-fold increase in endogenous production of PGE2 and PGF2 alpha before abortion as reflected by gas chromatographic-mass spectrometric determination of the major plasma metabolites of PGE2 and PGF2 alpha. The data suggest that this increased formation of endogenous prostaglandins contributes to the induced uterine activity during the latter part of the abortion process.     

Preoperative dilatation of the cervix by single vaginal administration of 15-methyl-PGF2alpha-methyl ester.

Two different vaginal suppositories have been developed suitable for one single treatment for preoperative dilatation of the cervix prior to vacuum aspiration in late first trimester abortion. The study included 60 patients equally distributed in one control group (Group I) where vacuum aspiration was performed without pretreatment; one group (Group II) where the patients obtained 2.0 mg 15-methyl-PGF2alpha-methyl ester in a rapid releasing base six hours prior to operation and one group (Group III) where the prostaglandin dose was increased to 2.5 mg 15-methyl-PGF2alpha-methyl ester and a more slow releasing base was used and the operation performed after 12 hours. The mean cervical dilatation at operation was in Group II 9 mm and in Group III 11 mm in comparison with 4.8 mm in the control group. The bleeding at the operation was also significantly reduced.     

Preinduction cervical priming with PGE2 vaginal film in primigravidae--a randomised, double blind, placebo controlled study

Previous reports with an 850 micrograms prostaglandin E2 film for cervical ripening before induction of labour in term pregnancy have been favourable. These studies however had no controls. The present study compares this PGE2 vaginal film with a nonmedicated similar vaginal film (placebo) for preinduction cervical ripening in primigravid women at term. A total of 69 women with modified Bishop's cervical scores 1-5 were assigned randomly to either the PGE2 group (33 women) or placebo group (36 women). Cervical score assessments were made at 12 and 24 hours after which labour was induced by amniotomy and oxytocin infusion. Although the cervical scores between placebo and PGE2 groups at 12 and 24 hours were not significantly different, the scores were marginally better with the prostaglandin film. Pregnancy outcome was satisfactory in both groups with no perinatal or maternal mortality and morbidity. The caesarean rate was 30.6% in the placebo group and 24.2% in the PGE2 group. This study emphasizes the need for a control group when studying the success of agents used for ripening the pregnant cervix at term.     

Midtrimester abortion induced by serial intravaginal administration of prostaglandin E2 suppositories in conjunction with a contraceptive diaphragm

Midtrimester abortion was successfully induced in 68 of 69 patients with serial intravaginal administration of prostaglandin E₂ suppositories behind a contraceptive diaphragm. The mean abortion time for the successful inductions was 13.07 hours; multiparous patients aborted somewhat faster, mean 12.72 hours, as compared to nulliparous patients, mean 14.22 hours. In 36 patients the PGE₂ suppositories were placed behind an intact diaphragm and the mean abortion time was 14.89 hours. In 33 patients the PGE₂ suppositories were placed behind a diaphragm modified by having an opening incised in the center, the mean time in these patients was 11.96 hours. Of the 68 successful abortions 59% of the patients aborted in 12 hours or less and 88% aborted within 24 hours. The most frequently encountered side effect was temperature elevation of 2° F or higher which occurred in 68% of the patients. Temperatures returned to normal levels within 4 to 6 hours after the last administration of PGE₂. Gastrointestinal side effects occurred in 45% of patients, but these side effects were well tolerated and did not require termination of drug administration in any of the patients. Intravaginal administration of PGE₂ suppositories is a very effective abortifacient technique during the midtrimester, however the use of PGE₂ in conjunction with a diaphrgam did not appreciabley improve the technique although the amount of drug administered and the incidence of side effects was somewhat lower than when the PGE₂ suppositories are used alone. If a diaphragm is to be used, a modified diaphragm is indicated since it simplifies the clinical management of the abortion, eases administration of the suppositories and permits a more accurate estimation of cervical changes, vaginal bleeding and abortion.     

Preoperative dilatation of the cervix by single vaginal administration of 15-methyl-PGF2α-methyl ester

Two different vaginal suppositories have been developed suitable for one single treatment for preoperative dilatation of the cervix prior to vacuum aspiration in late first trimester abortion. The study included 60 patients equally distributed in one control group (Group I) where vacuum aspiration was performed without pretreatment; one group (Group II) where the patients obtained 2.0 mg 15-methyl-PGF_2α-methyl ester in a rapid releasing base six hours prior to operation and one group (Group III) where the prostaglandin dose was increased to 2.5 mg 15-methyl-PGF_2α-methyl ester and a more slow releasing base was used and the operation performed after 12 hours. The mean cervical dilatation at operation was in Group II 9 mm and in Group III 11 mm in comparison with 4.8 mm in the control group. The bleeding at the operation was also significantly reduced.     

Vaginally administered 16,16-dimethyl-PGE2 for the induction of midtrimester abortion

Thirty patients in the 13th–20th week of gestation underwent therapeutic abortion utilizing vaginally administered 16,16-dimethyl-PGE₂ (free acid) suppositories. The first 15 patients obtained individual doses in the range of 400–1200 μg given every three hours (mean total dose 4.2 mg). In the following 15 patients a fixed dose schedule was used (800 μg followed by 1000 μg every three hours; mean total dose 5.3 mg). All but one of the 30 patients aborted. The mean induction-abortion interval for all patients was 16.8±6.9 hours (mean ± S.D.) With the fixed dose regime the success rate was 100% and the induction-abortion interval 16.0±5.9 hours. Because gastro-intestinal side effects were minimal, neither anti-emetic nor anti-diarrheic medication was required. A slight elevation of temperature was noted in five patients. The uterine response to the vaginal administration of this compound was characterized by a gradual increase in uterine tonus followed by sustained stimulation. The results are interpreted to suggest that the vaginal administration of 16,16-dimethyl-PGE₂ is a useful alternate method for the induction of second trimester abortion. Moreover, this compound seems to cause fewer gastro-intestinal side effects than other prostaglandins administered by the vaginal route at our department.     

Prospective study of different methods and routes of administration of prostaglandin E2 to improve the unripe cervix.

Methods of vaginal and extra-amniotic prostaglandin administration to achieve ripening of the cervix as a preliminary to induction of labour are described. Three groups of twenty patients with unfavourable induction features were studied, each receiving prostaglandin E2 the evening prior to planned induction. One group received PGE2 500 micrograms suspended in a viscous medium extra-amniotically. One group received PGE2 3 mg suspended in a viscous medium into the vaginal vault. A third group received a 3 mg PGE2 vaginal pessary to the posterior fornix. Improvement in cervical status at time of induction occurred in all groups but no single group had a significant advantage when regarding mean improvement, the induction-delivery interval or the number of patients in whom labour began before formal induction. However, with regard to relative cost, ease of preparation and storage, as well as patient and medical staff convenience, Prostaglandin E2 in pessary form is a superior form of administration.     

A comparison of buccal (oromucosal) and oral prostaglandin E2 for the elective induction of labor.

In 100 clinically-normal women, labor was induced at term by low amniotomy and PGE2. The drug was administered by either the oral or the oromucosal route, the same incremental dose scheme (initial dose of 0.5 mg; hourly increment of 0.5 mg until adequate uterine stimulation or a maximum single dose of 3.0 mg) being applied. Both routes of administration had comparable efficacy and were equally safe. The incidence of abnormal monitoring findings (uterine hypertonus, transient bradycardia and dips II during the first stage; late decelerations, progressive and transient bradycardia during the second stage of labor) and of low Apgar scores were similar. Acid-base and lactate-pyruvate equilibria in mother and fetus were not influenced by the route of drug administration in parous women. In nulliparae treated with PGE2 by the oromucosal route, higher values were found for the fetal-maternal difference in excess lactate than in those given oral PGE2; however, this is probably of little clinical importance.     

A comparison of buccal (oromucosal) and oral prostaglandin E2 for the elective induction of labor

In 100 clinically-normal women, labor was induced at term by low amniotomy and PGE2. The drug was administered by either the oral or the oromucosal route, the same incremental dose scheme (initial dose of 0.5 mg; hourly increment of 0.5 mg until adequate uterine stimulation or a maximum single dose of 3.0 mg) being applied.Both routes of administration had comparable efficacy and were equally safe. The incidence of abnormal monitoring findings (uterine hypertonus, transient bradycardia and dips II during the first stage; late decelerations, progressive and transient bradycardia during the second stage of labor) and of low Apgar scores was similar. Acid-base and lactate-pyruvate equilibria in mother and fetus were not influenced by the route of drug administration in parous women. In nulliparae treated with PGE2 by the oromucosal route, higher values were found for the fetal-maternal difference in excess lactate than in those given oral PGE2; however, this is probably of little clinical importance.     

Prostaglandin E2 induced abortion with vaginal suppositories in a contraceptive diaphragm

Prostaglandin E₂, 20 mgm vaginal suppositories were administered to two groups of women seeking termination of pregnancy. One group had the suppository inserted inside a contraceptive diaphragm. Statistical comparisons were carried out for instillation to abortion time, side effects, and intra-uterine pressure parameters. The usage of the diaphragm significantly reduced side effects, and resulted in an instillation to abortion time of 12.8 ± 2.3 hours with no failures. The quantitative analysis of the uterine pressure recordings revealed activity significantly different than that seen with intra-amniotic or extra-ovular PG F_2α. The development of uterine activity simulates that of normal labor in that elevation of resting pressure does not occur and maximum active pressure evolves slowly.     

Effect of vaginally administered 15(S)15-methyl-PGF2alpha on egg transport and fertility in rabbits.

The effects of vaginal suppositories containing 1.0 mg of 15[S]15-methy-PGF2alpha on oviductal motility, egg transport, and fertility were determined in rabbits. Suppository treatment caused a significant increase (P less than 0.02) in the amplitude of oviductal contractions, and a decrease in the frequency of contractractions (P less than 0.04). Altered oviductal motility persisted for an average of 2 hr after treatment. Treatment with 1, 2, or 3 suppositories at various times after ovulation caused a significant reduction in the number of eggs located in the oviducts (P less than 0.025). There was, however, a great deal of variation in egg recovery in treated animals (range 0 to 100%). Treatment of mated rabbits during the time of tubal egg transport caused a significant reduction in the number of Day-12 implants (P less than 0.05). The percentage of corpora lutea represented by Day-12 implants was similar to egg recovery rates in animals similarly treated. The treatment had no effect on fetal survival from Day 12 to 28 of pregnancy. The decrease in fertility caused by these vaginal suppositories is presumably due to the stimulatory effect on oviductal motility which accelerates tubal transport of the embryos into the uterus. Embryos that arrive in the uterus prematurely probably do not implant and degenerate or are expelled.     

The concurrent in vitro and in vivo release of PGE2 from a controlled-release hydrogel polymer pessary for cervical ripening

Twenty five patients booked for induction of labour, at 38 weeks or more gestation, were administered a controlled release vaginal polymer pessary containing 10 mg prostaglandin E2 (PGE2), designed to release 0.6 mg per hour in vivo. The release profile from the polymer was linear throughout the eight hour observation period with a correlation coefficient of 0.81, and regression slope of 0.93 mg/hr. with 95% confidence intervals of 0.63 mg/hr. to 1.23 mg/hr. This compared with a concomitant release profile in vitro which was uniform with time for the first five hours, but then continued at a decreasing rate with a correlation coefficient of 0.98. The relationship between PGE2 release and cervical score change was linear, with a correlation coefficient of 0.65. The results show that PGE2 release from the pessary in vivo is predictable, and suggest that the controlled release pessary offers the advantages of greater control of cervical ripening than alternative vehicles currently available.