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° 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.     

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: 0.4mg PGE₂ gel placed retroamnially by means of a balloon catheter, 0.4 and 0.5mg PGE₂ applied endocervically and 3mg PGE₂ placed intravaginally in form of a single vaginal tablet; also induced 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.     

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.     

On the mechanism of action of 15-methyl-PGF2α as an abortifacient

Several hours following administration of long acting vaginal suppositories containing 3.0 mg of 15-methyl-PGF_2α for interruption of second trimester pregnancies there is an up to 10-fold increase in endogenous production of PGE₂ and PGF_2α before abortion as reflected by gas chromatographic-mass spectrometric determination of the major plasma metabolites of PGE₂ and PGF_2α. The data suggest that this increased formation of endogenous prostaglandins contributes to the induced uterine activity during the latter part of the abortion process.     

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 (3g), 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. Od 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 0/7 (0 %) for placebo. In as much as a very low incidence of side effects accompanied this treatment scheme, expanded multi-center testing is recommended.     

Termination of second trimester pregnancy with laminaria and intramuscular 16 phenoxy-ω-17,18,19,20 tetranor PGE2 methylsuldonylamide (sulprostone) — A randomised study

16 phenoxy-ω-17,18,19,20 tetranor PGE₂ methylsulfonylamide (Sulprostone) was used for termination of second trimester pregnancy in four groups of 30 patients. The drug was administered in intramuscular doses of either 0.5 mg four hourly or 1.0 mg 8 hourly. In two groups of 30 patients a medium size sterile laminaria was inserted into the cervical canal eight hours before the start of prostaglandin treatment. In the group treated with 1.0 mg sulprostone eight hourly, 96.7% of those with laminaria and 86.7% without laminaria aborted in respective mean times of 11.2 hrs and 17.5 hrs. All 30 patients (100%) in the laminaria group treated with 0.5 mg sulprostone four hourly aborted within 30 hours in a mean time of 10.4 hours compared with 26 patients (86.7%) in a mean time of 16.7 hours in the group without laminaria.One patient receiving 0.5 mg sulprostone four hourly (no laminaria) sustained a cervical tear requiring repair. The incidence of nausea, vomiting, diarrhoea, cold and shivering was low and similar in the four groups.     

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 μg 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.     

Management of missed abortion and fetal death in utero

Termination of pregnancy in missed abortion and intra-uterine fetal death was accomplished using vaginal suppositories of 20 mg PGE₂ in 31 cases and the results were compared with oxytocin induction (with or without estrogen pre-treatment) in 17 cases at the doses routinely used in our hospital. The PG suppositories proved much more superior (96.7%) than oxytocin (47.7%), but induced a higher rate of side effects. The latter were not serious and were generally tolerated by the patients. There was a positive correlation between duration of fetal retention in utero and the induction expulsion time. The over all patient acceptance of the method was quite favourable and the approach appears to be a definite advance towards management of these cases.     

Essential fatty acid deficiency and platelet fatty acids of normotensive and genetically hypertensive rats

Termination of pregnancy in missed abortion and intra-uterine fetal death was accomplished using vaginal suppositories of 20 mg PGE₂ in 31 cases and the results were compared with oxytocin induction (with or without estrogen pre-treatment) in 17 cases at the doses routinely used in our hospital. The PG suppositories proved much more superior (96.7%) than oxytocin (47.7%), but induced a higher rate of side effects. The latter were not serious and were generally tolerated by the patients. There was a positive correlation between duration of fetal retention in utero and the induction expulsion time. The over all patient acceptance of the method was quite favourable and the approach appears to be a definite advance towards management of these cases.     

Clinical experiences with a new gel for intracervical application of prostaglandin E2 before therapeutic abortion or induction of term labor

A new gel for intracervical application of prostaglandin E₂ (PGE₂) has been elaborated and evaluated. The main component of the gel is a cross-linked starch polymer to which prostaglandins can be added and preserved for long-term storage (> 12 months).In a double blind study, 20 patients requiring legal abortion in late first trimester were given gel containing 0.25 mg PGE₂ or gel without PGE₂. The gel was applied within the cervical canal. In all patients receiving PGE₂-gel, a rapid ripening of the cervix occurred which facilitated the subsequent dilatation and evacuation. In patients receiving gel without PGE₂ cervix did not ripen. In a subsequent open study, 30 patients were treated with PGE₂-gel before therapeutic abortion. The same degree of cervical ripening was registered as for the patients receiving PGE₂-gel in the double blind study.In 50 patients at term, intracervical application of 3 ml gel containing 0.50 mg PGE₂ induced labor in 27 cases, i.e. 54 per cent of the patients. In the remaining undelivered women, a prominent cervical ripening occurred within 24 hours. No side effects of the treatment were observed.We conclude the new PGE₂-gel to be a promising future alternative in the treatment of patients with an unfavorable cervix, prior to surgical evacuation of the uterus in late first trimester abortion, as well as before induction of labor at term.     

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.     

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.     

The concurrent in vitro and in vivo release of PGE2 from 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 pressary containing 10mg prostaglandin E₂(PGE₂), designed to release 0.6mg 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 0.63mg/hr. to 1.23 mg/hr. This compared with a concomitatnt 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.     

Prostaglandin E1 or E2 inhibits an oxytocin-induced premature luteolysis in ewes when oxytocin is given early in the estrous cycle

The objective of this study was to determine whether PGE₁ or PGE₂ prevents a premature luteolysis when oxytocin is given on Days 1 to 6 of the ovine estrous cycle. Oxytocin given into the jugular vein every 8 hours on Days 1 to 6 postestrus in ewes decreased (P ≤ 0.05) luteal weights on Day 8 postestrus. Plasma progesterone differed (P ≤ 0.05) among the treatment groups; toward the end of the experimental period, concentrations of circulating progesterone in the oxytocin-only treatment group decreased (P ≤ 0.05) when compared with the other treatment groups. Plasma progesterone concentrations in ewes receiving PGE₁ or PGE₁ + oxytocin were greater (P ≤ 0.05) than in vehicle controls or in ewes receiving PGE₂ or PGE₂ + oxytocin and was greater (P ≤ 0.05) in all treatment groups receiving PGE₁ or PGE₂ than in ewes treated only with oxytocin. Chronic intrauterine treatment with PGE₁ or PGE₂ also prevented (P ≤ 0.05) oxytocin decreases in luteal unoccupied and occupied LH receptors on Day 8 postestrus. Oxytocin given alone on Days 1 to 6 postestrus in ewes advanced (P ≤ 0.05) increases in PGF_2α in inferior vena cava or uterine venous blood. PGE₁ or PGE₂ given alone did not affect (P ≥ 0.05) concentrations of PGF_2α in inferior vena cava and uterine venous blood when compared with vehicle controls or oxytocin-induced PGF_2α increases (P ≤ 0.05) in inferior vena cava or uterine venous blood. We concluded that PGE₁ or PGE₂ prevented oxytocin-induced premature luteolysis by preventing a loss of luteal unoccupied and occupied LH receptors.     

Dissociation between renal medullary PGE2-synthesis and urine PGE2-excretion. Antagonism by bumetanide of chlorazanil induced urine PGE2-excretion in rats

Normal conscious female Sprague-Dawley rats were treated with chlorazanil (3 mg/kg i.p.), and urine was collected for 3 hours. Urine prostaglandin E₂-excretion increased from 25±3 to 271±32 ng/kg/3 h. The enhancement of urine PGE₂-excretion was inhibited by pretreatment with bumetanide (75 mg/kg p.o.). In separate experiments the papillary quantity of PGE₂ was determined in freshly homogenized tissue. The basal level (14±2 ng PGE₂/papilla) was increased by chlorazanil to 51±11 ng PGE₂/papilla and 24±7 ng PGE₂/papilla at one and two hours respectively after drug administration. The capacity of chlorazanil to increase medullary PGE₂ accumulation was unaffected by bumetanide dissociated the medullary PGE₂ level from the excretion of PGE₂ in urine, when the former was elevated by chlorazanil.     

Plasma levels of 13,14-dihydro-15-keto PGE2 after vaginal application of a new PGE2 film

To determine the release and absorption profile of prostaglandin E₂ from a new vaginal film formulation containing 850 μg PGE₂, serial plasma levels of 13,14-dihydro-15-keto PGE₂ were measured by radioimmunoassay in pregnant women between 16 and 18 weeks gestation. A control group, using placebo vaginal film was included in the study. There was a somewhat uniform increase in the plasma levels of the PGE₂ metabolite, reaching peak levels between 4 and 6 hours after application of the film. The findings suggest that this drug formulation could be used clinically when slow constant release of the prostaglandin is required over a period of hours such as in pre-induction cervical ripening of term pregnancy.     

15(S)15-Methyl protaglandin F2α for termination of very early human pregnancy. A comparative study of a single intramuscular injection and vaginal suppositories

The results of a comparative study of the efficacy and acceptability of 15(S)15-methyl prostaglandin F_2α (15-Me-PGF_2α) administered as a single i.m. injection or vaginal suppositories (15-Me-PGF_2α methyl ester) every 3rd hr for termination of very early human pregnancy is reported. The amenorrhoic period varied from 37 to 60 days. (30 cases) received 0.6 mg as a single i.m. injection without any pretreatment. Restrospectively 24 of the 30 women were in fat pregnant and 22 of them aborted. received suppositories (1.0 or 1.5 mg per suppository). In this group all women were pregnant and they all aborted.Symptoms such as pain, bleeding, vomiting and diarrhea started in general earlier in the i.m. group and they were more marked. In the present series the efficacy and acceptability were highest for the vaginal route of administration.     

Plasma levels of the methyl ester of 15-methyl PGF2α in connection with intravenous and vaginal administration to the human

After intravenous injection of the methyl ester of 15-methyl-PGF_2α the drug initially disappeared faster than the corresponding free acid, but still after one hour, about 1% of the active drug is circulating in plasma. Vaginal administration of single suppositories containing 1 mg of 15-methyl-PGF_2α methyl ester and determination of plasma levels using gas chromatography - mass spectrometry demonstrated that the highest plasma levels were reached after 1.5 - 3 hours.Vaginal suppositories were administered according to different dose schedules for induction of abortion and plasma levels of 15-methyl-PGF_2α and it's ester were determined. There seemed to be a gross correlation between given doses and obtained plasma level. The data will serve as basis for further development of vaginal delivery devices.