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.     

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

Midtrimester abortion was successfully induced in a series of 20 patient by intra-amniotic instillation of 15(S)-15-methyl-prostaglandin F_2α with a mean abortion time of 17.78 hours. The patients in this study were divided into two groups, Groups I received on initial dose of 2.5 mg 15-ME-PGF_2α and aborted in a mean time of 16.26 hours. The patients in Group II received 3.0 mg 15-ME-PGF_2α and aborted in a mean time of 18.94 hours. There was no significant difference in the abortion time, occurrence of side effects or the initiation of uterine activity between Group I and Group II. Parous patients aborted somewhat faster than nulliparous patients but this difference was not significant. In this study 80% of the patients aborted in 24 hours or less, and the intra-amniotic instillation of 15-ME-PGF_2α was an effective abortifacient technique from the 15th to the 23rd week of gestation. The uterine response to intra-amniotic instillation of 15-ME-PGF_2α was characterized by the gradual appearance of low amplitude, high frequency contractions accompanied by a rise in baseline intrauterine tonus. Uterine activity developed gradually and peaked at 1:50 hours after intra-amniotic instillation of 15-ME-PGF_2α. In this small series 15-ME-PGF_2α administered via intra-amniotic instillation did not appear to have a distinct advantage over the naturally occurring PGF_2α administered by the same method for the induction of midtrimester abortion; a larger series is indicated to define the advantages of either technique.     

Midtrimester abortion induced by a single intra-amniotic instillation of two dose schedules of 15(S)-15-methyl-prostaglandin F2α

Midtrimester abortion was successfully induced in a series of 20 patient by intra-amniotic instillation of 15(S)-15-methyl-prostaglandin F_2α with a mean abortion time of 17.78 hours. The patients in this study were divided into two groups, Groups I received on initial dose of 2.5 mg 15-ME-PGF_2α and aborted in a mean time of 16.26 hours. The patients in Group II received 3.0 mg 15-ME-PGF_2α and aborted in a mean time of 18.94 hours. There was no significant difference in the abortion time, occurrence of side effects or the initiation of uterine activity between Group I and Group II. Parous patients aborted somewhat faster than nulliparous patients but this difference was not significant. In this study 80% of the patients aborted in 24 hours or less, and the intra-amniotic instillation of 15-ME-PGF_2α was an effective abortifacient technique from the 15th to the 23rd week of gestation. The uterine response to intra-amniotic instillation of 15-ME-PGF_2α was characterized by the gradual appearance of low amplitude, high frequency contractions accompanied by a rise in baseline intrauterine tonus. Uterine activity developed gradually and peaked at 1:50 hours after intra-amniotic instillation of 15-ME-PGF_2α. In this small series 15-ME-PGF_2α administered via intra-amniotic instillation did not appear to have a distinct advantage over the naturally occurring PGF_2α administered by the same method for the induction of midtrimester abortion; a larger series is indicated to define the advantages of either technique.     

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.     

Induction of Abortion by Extra-amniotic Administration of Prostaglandins E2 and F2 α

The use of prostaglandins E₂ and F₂α, administered by extra-amniotic instillation, for the induction of abortion was studied in 94 patients in the first and second trimesters of pregnancy. Abortion was successfully induced in 87% of patients within 36 hours and in 94% within 48 hours. The mean abortion time was 22·4 hours. In 60% of patients abortion was complete.Though the differences were not statistically significant, on average multigravid patients aborted more quickly than primigravidae, while the mean abortion time in PGE₂-treated patients was less than in those receiving PGF₂α.No serious complications occurred. Some side effects were observed. Occasional vomiting was the commonest symptom but the incidence of side effects was lower than with alternative routes of administration. A leucocytosis was often noted but there were no significant instances of infection.The method has proved a safe and effective means of terminating pregnancies in the second trimester.     

Midtrimester abortion induced by single intra-amniotic instillation of two dose schedules of 15(S)-15-methyl-prostaglandin F2alpha.

Midtrimester abortion was successfully induced in a series of 20 patient by intraamniotic instillation of 15(S)-15-methyl-prostaglandin F2alpha with a mean abortion time of 17.78 hours. The patients in this study was divided into two groups, Groups 1 received an initial dose of 2.5 mg 15-ME-PGF2alpha and aborted in a mean time of 16.26 hours. The patients in Group II received 3.0 mg 15-ME-PGF2alpha and aborted in a mean time of 18.94 hours. There was no significant difference in the abortion time, occurrence of side effects or the initiation of uterine activity between Group I and Group II. Parous patients aborted somewhat faster than nulliparous patients but this difference was not significant. In this study 80% of the patients aborted in 24 hours or less, and the intra-amniotic instillation of 15-ME-PGF2alpha was an effective abortifacient technique from the 15th to the 23rd week of gestation. The uterine response to intra-amniotic instillation of 15-ME-PGF2alpha was characterized by the gradual appearance of low amplitude, high frequency contractions accompanied by a rise in baseline intrauterine tonus. Uterine activity developed gradually and peaked at 1:50 hours after intraamniotic instillation of 15-ME-PGF2alpha. In this small series 15-ME-PGF2alpha administered via intra-amniotic instillation did not appear to have a distinct advantage over the naturally occuring PGF2alpha administered by the same method for the induction of midtrimester abortion; a large series in indicated to define the advantage of either technique.     

Uterine activity and prostaglandin production following intraamniotic hyperosmolar urea

The relationship between endogenous prostaglandin (PG) production and uterine activity was studied in hyperosmolar urea induced abortion patients. Polygraphic recordings of intraamniotic pressure were obtained at periodic intervals following intraamniotic injection of 80 gm urea. At 0, 0.25, 1, 4 and 8 hours amniotic fluid and blood samples were obtained for PGE, PGF and 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) analysis by radioimmunoassay. Blood was also sampled at time of absorption. In eight patients studies, uterine tone was elevated by 0.25 hour although no rhythmic contractions were observed by 1 hour. At 4 hours, amniotic fluid PGF concentration increased significantly (P < .01) over the pre-injection value and continued to increase at 8 hours. Amniotic fluid PGE, PGFM and all plasma PG's showed no change during the 8 hour period following urea administration. At time of abortion the plasma PGFM concentration was significantly greater than at the time of injection (238 ± 54.4 vs. 86.7 ± 7.3 pg/ml). There was no significant differences between pre-injection and absorption plasma PGF or PGE concentrations. In the present study, there is no evidence that increased prostaglandin production precedes urea induced contractions. The possible role of PG's in uterine contractions is discussed.     

Effect of bisenoic prostaglandins on the uterine vasculature of the nonpregnant sheep

The effects of the bisenoic prostaglandins on the uterine vasculature and uterine contractile activity have been evaluated in an unanesthetized chronically catheterized nonpregnant sheep preparation. Changes in uterine blood flow were monitored with electromagnetic flow probes while uterine contractile activity and tone were determined via an intra-uterine balloon connected to a pressure transducer. Prostaglandins A₂, D₂, E₂, and prostacyclin (PGI₂) were all found to be vasodilators. PGD₂ and PGI₂ were much more potent than PGA₂ and PGE₂ in dilating the uterine vasculature. The prostacyclin breakdown product 6-keto PGF_1α, PGF_2α, thromboxane B₂, and the endoperoxide analogues U44069 and U46619 produced vasoconstriction of the uterine vasculature. Prostaglandins A₂, D₂ and F_2α increased while PGI₂ decreased uterine contractile activity. PGF_2α also increased uterine tone suggesting that a portion of its vasoconstrictor activity may be due to mechanical compression of the uterine vasculature.     

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.     

Laminaria augmentation of intra-amniotic PGF2 for midtrimester pregnancy termination

In our hands, intra-amniotic PGF_2^α 40 mg for midtrimester pregnancy termination had a mean infusion to abortion interval of 29.4 hr. However, pretreatment of 230 patients with laminaria tents inserted 14–18 hr before PGF_2^α infusion resulted in a dramatically reduced time to abortion (14.3 hr mean) with a low incidence of gastrointestinal and other side effects. Laminaria tents inserted at the same time as PGF_2^α infusion in 26 patients also resulted in reduced time to abortion (18.6 hr mean). In the laminaria pretreated group, the infusion to abortion interval was indirectly related to the number of laminaria inserted and not to the nulliparous or parous state. Although we have made significant strides in shortening the abortion interval in the hospital, retained placentae and blood loss persist as problems related to the use of prostaglandin for abortion.     

Laminaria augmentation of intra-amniotic PGF2α for midtrimester pregnancy termination

In our hands, intra-amniotic PGF₂α 40 mg for midtrimester pregnancy termination had a mean infusion to abortion interval of 29.4 hr. However, pretreatment of 230 patients with laminaria tents inserted 14–18 hr before PGF₂α infusion resulted in a dramatically reduced time to abortion (14.3 hr mean) with a low incidence of gastrointestinal and other side effects. Laminaria tents inserted at the same time as PGF₂α infusion in 26 patients also resulted in reduced time to abortion (18.6 hr mean). In the laminaria pretreated group, the infusion to abortion interval was indirectly related to the number of laminaria inserted and not to the nulliparous or parous state. Although we have made significant strides in shortening the abortion interval in the hospital, retained placentae and blood loss persist as problems related to the use of prostaglandin for abortion.     

Decreased smooth muscle side effects with 16, 16-dimethyl-trans-Δ2-PGE1 methyl ester in Japanese monkey (Macaca fuscata fuscata)

The smooth muscle stimulating activity of a new PGE₁ analog, 16, 16-dimethyl-trans-Δ²-PGE₁ methyl ester (ONO-802) was evaluated by simulataneous;y recording the EMG of the uterus and intestines, along with urinary bladder pressure, and blood pressure in pregnant and non-pregnant Japanese monkeys ($\text{Macaca fuscata fuscata}$). Single intravenous injections of ONO-802 in increasing dosages (0.2–5 μg/kg) were found to be 50–100 times or more effective in inducing uterine contraction than PGF₂α and PGE₁. A mild, transient gastrointestinal muscle stimulating activity was observed, but change in urinary bladder pressure and blood pressure was not evident. ONO-802 induced uterine contractions in the pregnant animals were 10 times greater than in the non-pregnant animals. These results suggest that ONO-802 may be a suitable clinical prostaglandin for use in therapeutic abortion.     

In vivo inhibition of the human non-pregnant uterus by prostaglandin E2

The discrepancy between the effect of PGE₂ on the non-pregnant myometrium (relaxation) as compared to (stimulation) has not yet been solved. Nine women in the early post-menopause volunteered for the investigation. Prostaglandin (PG) F_2α or E₂ was administered either by single intravenous (i.v.) injection or by intra-uterine instillation and the uterine contractility was recorded by the microballoon technique. The response of the menopausal uterus to i.v. injections of PGF_2α or PGE₂ was characterized by rapid stimulation while intra-uterine instillation of PGF_2α induced gradual but sustained elevation of uterine tonus. However, the intra-uterine injection of PGE₂ caused inhibition of different components of uterine contractility. The fact that PGE₂ can also inhibit the motility of the menopausal non-pregnant uterus coincides with earlier results i.e. the discrepancy may not exist. Moreover, in one cycling patient (13–18th days of the menstrual cycle) similar results were also obtained. Two theories were offered to explain why PGE₂ stimulated the uterus when given as a single i.v. injection but inhibited the same organ when instilled locally into the uterine cavity.     

Early pregnancy-abortion model using sulprostone

Sulprostone has been demonstrated to be effective as a parenteral abortifacient, but not as a vaginal suppository. A vaginal preparation was given to 19 women to determine its mechanism of action, and to confirm the principle of uterine conversion as a biological model for the induction of an early abortion.The drug was administered to women with confirmed pregnancies and amenorrhea and not exceeding 49 days. A 95% success rate was obtained with an incidence of drug related side effects of 20% as opposed to the general 80–90% figure of PGE₂ and F₂a. The hormone profile obtained revealed a parallel fall in hCG and estradiol, and progesterone.This study confirms the value of uterine conversion, a concept that describes the change in uterine reactivity following PG administration and determines the phase when uterine activity is no longer dependent on exogenous oxytocic medication.     

Intrauterine instillation of prostaglandin F2α in early pregnancy

Intrauterine PGF_2α (5mg) was administered for termination of early pregnancy in 14 healthy volunteers. With 11 complete abortions, the efficiency rate of this technique is below conventional methods. In addition, the incidence of infection was high occurring in 12 out of 14 subjects. Because of persistent bleeding, six patients underwent a dilatation and curettage. Other significant side effects included transient hypertension, pain, nausea and restlessness. In the patients with a complete abortion, the mean plasma progesterone concentration fell 37% after 8 hours post PGF_2α instillation and 90% 14 days later. The mean plasma estradiol-17β fell 26% over the initial eight hour period and 75% over the next 14 days.     

Uterine trauma associated with midtrimester abortion induced by intra-amniotic prostaglandin F2α with and without concomitant use of oxytocin

Five of 80 (6.2%) nulliparous women sustained uterine trauma in association with midtrimester abortion induced by intra-amniotic prostaglandin F_2α and intravenous oxytocin. All five women suffered cervical lacerations, one extending to the lower uterine segment of the corpus and another associated with myometrial necrosis caused by cornual sacculation and ischemia. No uterine trauma was observed among 95 parous women aborted in the same fashion during this study. The different mechanisms of cervical dilatation in the parous woman and the nullipara are offered as an explanation for this difference. Thirty-nine other cases of uterine injury associated with the use of intra-amniotic prostaglandin F_2α from the literature were reviewed, and found to indicate that midtrimester abortion induced by intra-amniotic prostaglandin F_2α is associated with a significant risk of uterine trauma in the nullipara. The risk seems to increase with the use of oxytocin and with increasing gestational age.     

Prostaglandin E2: Midterm abortion in rats using Silastic-PVP tubes

The results of the present study establish that 1.5 mg PGE₂ (lyophilized sodium salt) incorporated in one cm long open-ended Silastic-polyvinylpyrrolidone (PVP) tube when inserted into 10 day pregnant rats induced abortion within 70–72 hours in all the treated rats. A combined treatment of PGE₂ and 17β-estradiol failed to increase the abortion inducing effect of a Silastic-PVP-PGE₂ tube. It is observed that PGE₂ is about 4 times less potent than PGF_2α in inducing midterm abortion in rats. It is suggested that either PGE₂ exerts luteolytic effect after being converted to PGF_2α, although how it occurs is not clear; or PGE₂ causes expulsion of the fetuses by its uterine stimulating property. 17β- estradiol increases the uterine synthesis of PGF_2α as described earlier but seems not affecting the production of PGE₂ by the uterus. The release rate of ³H-PGE₂ from Silastic-PVP tube and is also described.     

Effects of suprofen and other prostaglandin synthstase inhibitors in a new animal model for myometrial hyperactivity

An model for studying factors related to dysmenorrhea and for evaluating drugs for their inhibitory effects on uterine contractility induced by arachidonic acid and prostaglandins has been developed. Intravenous administration of arachidonic acid and PGF₂α to guinea pigs during the late stage of the estrous cycle, induced dose related uterine contractions and an elevation in uterine basal pressure similar that seen in patients with dysmenorrhea. Pretreatment with prostaglandin synthetase inhibitors inhibited the response to arachidonic acid. The order of relative potency was suprofen (1) > indomethacin (0.65) > naproxen (0.52) > ibuprofen (0.43) > aspirin (0.31). The effectiveness of maximal response for suprofen was significantly greater than that of the other compounds tested. Simultaneous administration of suprofen with PGF₂α also blocked induction of uterine contractions, suggesting the possibility that suprofen also antagonizes PGF₂α receptor binding. Bradykinin also induced uterine constractions, an effect blocked by pretretment with suprofen. Finally, histochemical studies demonstrated stimulation of uterine catecholamine levels (norepinephrine) by arachidonic acid, PGF₂α and bradykinin. These effects were blocked by suprofen.These data suggest that suprofen, an analgesic prostaglandin synthetase inhibitor, may be of use in the clinical tretment of the uterine contractions associated with primary dysmenorrhea.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

The present investigation was undertaken to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F_2α.1. . Both 15-methyl-PGF_2α and 15-methyl-PGF_2α methyl ester can be absorbed from the vagina in sufficient amounts to induce abortion. The potency of the methyl ester was approximately twice that of the free acid. The most successful treatment schedule consisted of an initial dose of 0.5 mg of the methyl ester followed by 1.0 or 2.0 mg every third hour. On this treatment all patients aborted within 24 hours.2. . Initially 200 μg of 15-methyl-PGF_2α was given. The dose was increased to 400 μg or occasionally to 500 μg depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100 per cent abortion rate and the mean induction-abortion interval was 16.1 hours.Both routes were associated with a higher frequency of side effects than that reported for intra-amniotic administration of 15-methyl-PGF_2α. It seems justified to conclude that the intra-amniotic route is preferable after the 14th week when the uterine cavity is easy to puncture but that vaginal or intramuscular injections of the compounds could be an alternative in late first trimester and early second trimester cases.     

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.