Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 μg initially and 300 μg every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PGF_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PFG_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Termination of second trimester pregnancy with intra-amniotic 15 (S) 15 methyl prostaglandin F2α — A two dose schedule study

Termination of second trimester pregnancy with intra-amniotic administration of 15 (S) 15 methyl prostaglandin F_2α (15 me F_2α) was attempted in fifty patients. One group (25 patients) was given 1 mg of the analogue and the other group received 2.5 mg. The abortifacient efficacy of 15 me F_2α was similar in both groups; over 90% of the patients aborted with a single dose. There was a higher incidence of vomiting, diarrhoea and incomplete abortions in the group treated with 2.5 mg 15 me F_2α. Although the mean injection-abortion interval in the 2.5 mg group was shorter, it is concluded that intra-amniotic administration of 1 mg 15 me F_2α provides a better regime, giving high efficacy with a single dose, a low incidence of side effects and greater safety in case of inadvertent entry of the intra-amniotic dose into systemic circulation.     

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 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.     

15-methylation augments the cardiovascular effects of prostaglandin F2α

Intramuscular injection of the 15-methyl analogue of prostaglandin F_2α (15-me-PGF_2α) is being used to initiate second trimester abortion. The natural prostaglandin F_2α (PGF_2α) is a known pulmonary pressor agent but there is little information about the cardiovascular effects of the analogue. Consequently, we compared the hemodynamic responses to the two forms in twenty-three anesthetized dogs. Given I.M. or I.V. 15-me-PGF_2α produced a greater and more sustained rise in pulmonary arterial pressure than PG F_2α. Intramuscular 15-me-PGF_2α also elicited a more prolonged increase in pulmonary vascular resistance than prostaglandin F_2α given I.M. or I.V. The methyl analogue (I.M. or I.V.) causes a greater initial fall in systemic arterial oxygen tension and cardiac output, and a greater increase in systemic resistance than I.M. PG F_2α Breathlessness seen during abortion induced by prostaglandin F_2α or its methyl analogue may be caused by acute pulmonary hypertension in addition to bronchoconstriction.     

Administration of prostaglandins by various routes for induction of abortion merits and demerits

Prostaglandin F_2α and its methyl analogues were used for induction of abortion in 598 patients with gestational age from 9 to 20 weeks. Different routes of administration were studied and varous dosages given. The incidence of gastrointestinal side effects were within acceptable range for all methods. Both intra-amniotic injections of 50 mg PGF_2α and 2.5 mg 15-methyl PGF_2α as well as intramuscular and vaginal administration of 15-methyl PGF_2α or its methyl ester, respectively, were highly effective in termination of pregnancy. The intramuscular route was, however, associated with the highest frequency of gastrointestinal side effects. If both efficacy and side effects were taken into consideration, the intra-amniotic and vaginal routes were superior. The ease of administration as well as the applicability over a wider range of gestation in termination of pregnancy may, however, in many situations speak in favour of the repeated vaginal administration of 15-methyl PGF_2α methyl ester.     

Luteolytic action of 15-keto prostaglandin F2α in the rhesus monkey

The naturally-occurring metabolite of prostaglandin F_2α, 15-keto prostaglandin F_2α (15-keto PGF_2α), elicited rapid and sustained declines in serum progesterone concentrations when administered to rhesus monkeys beginning on day 22 of normal menstrual cycles. Evidence for luteolysis of a more convincing nature was obtained in studies where a single dose of 15-keto PGF_2α was given on day 20 of ovulatory menstrual cycles in which intramuscular injections of hCG were also given on days 18–20; serum progesterone concentrations fell precipitously in monkeys within 24 hours following intramuscular administration of 15-keto PGF_2α. However, corpus luteum function was impaired in only 4 of 11 early pregnant monkeys when 15-keto PGF_2α was administered on days 30 and 31 from the last menses, a time when the ovary is essential for the maintenance of pregnancy. Gestation failed in 2 additional monkeys 32 and 60 days after treatment with 15-keto PGF_2α, but progressed in an apparently normal manner in the remaining 5 animals. Two pregnant monkeys treated with 15-keto PGF_2α on day 42 from the last menstrual period, a time when the ovary is no longer required for gestation, continued their pregnancies uneventfully. Corpus luteum function was not impaired in 9 control monkeys which received injections of vehicle or hCG at appropriate times during the menstrual cycle or pregnancy.     

Serial intramuscular injections of 15(S)-15-methyl-prostaglandin F2α in the induction of abortion

Abortion was successfully induced in 62 of 68 patients in the 9th to the 26th week of pregnancy by serial intramuscular administration of 15(S)-15-methyl-prostaglandin F_2α (15-ME-PGF_2α). In 6 patients who failed to abort after 24 hours of prostaglandin administration, a concomitant infusion of oxytocin was initiated; 5 of these patients aborted within 12 hours of the combined therapy. A single patient failed to abort, even with the combined therapy, and underwent surgical evacuation. The mean abortion time in the 67 successful inductions was 14.56 hours. Parous patients aborted somewhat faster, mean 13.98 hours, as compared to nulliparous patients, mean 15.02 hours, but this difference was not statistically significant. In this study initial intramuscular injection of 100 μg 15-ME-PGF_2α was followed in 1 hour by 250 μg and then 250 μg every 2 hours with concomitant oxytocin therapy initiated after 24 hours. The results with this dose schedule were compared to the results obtained in a previous study with a higher dose schedule, an initial dose of 100 μg 15-ME-PGF_2α, followed in 1 hour by 250 μg then 500 μg every 2 hours. There was no significant difference in the mean abortion time and the incidence of side effects between the 2 dose schedules. The mean abortion time for patients with gestational ages of 16 weeks and less was the same with both dose schedules, however patients with gestational ages of 17 weeks and higher aborted somewhat faster with the higher dose schedule. It might therefore be advisable for patients with gestations of 17 weeks and higher to be treated with the higher dose schedule. In earlier gestations patients could be started on the lower schedule, and if abortion had not occurred within 15 hours the dose of 15-ME-PGF_2α could then be increased to 500 μg every 2 hours.     

Induction of second trimester abortion: Comparison between vaginal 15-methyl-PGF2α methyl ester and intra-amniotic PGF2α

The efficiency and acceptability of a single-dose, long-acting vaginal suppository containing 3.0 mg of 15-methyl PGF_2α methyl ester was compared with intra-amniotic administration of 50 mg of PGF_2α in 100 patients with a second trimester pregnancy termination. Within 24 hours, 78 per cent of the patients in the vaginal group and 92 per cent in the intra-amniotic group had aborted. The mean induction-abortion interval was 17.9 hours in the vaginal group and 15.8 hours in the intra-amniotic group.Gastrointestinal side-effects were more frequent, but the procedure was less painful, with vaginal 15-methyl PGF_2α methyl ester than with intra-amniotic PGF_2α.The vaginal route is technically simple for adaptation to large-scale use, but the high frequency of gastrointestinal side-effects still limits the acceptability of 15-methyl PGF_2α methyl ester in vaginal administration.     

Early mid trimester abortion — By intramuscular 15 methyl prostaglandin E2

Intramuscular administration of 15(s) 15 Methyl Prostaglandin E₂ was successful in terminating twelve of thirteen second trimester pregnancies. Two patients had an incomplete abortion and one case was classified a failure. Side effects were limited to nausea and vomiting in seven cases, diarrhea in eight cases, chills in twelve cases and and elevated temperatures in eight cases. The intramuscular route does offer an advantage in early second trimester abortions and in patients where the intra-amniotic route is not available.     

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.     

Termination of early pregnancy by a single-dose 3.0 mg 15-methyl PGF2α methyl ester vaginal suppository

The abortifacient effect of a single-dose, long-acting vaginal suppository containing 3.0 mg of 15-methyl PGF_2α methyl ester was investigated in 104 early pregnancies. The pregnancy was terminated in 91 per cent of the cases. The abortion was uncomplicated in 79 patients, while 12 patients experienced prolonged bleeding.In 21 uncomplicated cases, Vabra® curettage done 4 weeks after therapy revealed necrotic residual tissue in 16 patients and nonspecific endometritis in 20 patients. Residual tissue was found in about 50 per cent of the patients curettaged after 1st menstruation, but no residua was found after 2nd menstruation.In patients with prolonged bleeding, substantial amounts of necrotic residual tissue was found in all patients curettaged 4 weeks after therapy. The decline of serum hCG and plasma progesterone levels was significantly slower in these patients as compared with uneventful abortions.     

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.     

Induction of midtrimester abortion by serial intravaginal administration of 15(S)-15-methyl-prostaglandin F2α (THAM) suppositories

Midtrimester abortion was successfully induced in 13 of 22 patients by serial intravaginal administration of 15(S)-15-methyl-prostaglandin F_2α (THAM) suppositories. Nine patients, 4 nulliparas and 5 multiparas, failed to abort after 24 hours of prostaglandin administration and a concomitant infusion of oxytocin was initiated. Seven of the nine patients aborted within 7 hours of the combined therapy and one patient on methadone maintainence aborted after 17.5 hours of combined therapy, 41.5 hours after the first dose of prostaglandin. A single patient failed to abort, despite the concomitant prostaglandin-oxytocin administration and underwent surgical evacuation. The mean abortion time for the 21 successful abortions was 22.56 hours. Nulliparous patients aborted somewhat faster, mean 21.79 hours, than multiparous patients, mean 23.80 hours, but this difference was not statistically significant. In this study, one patient aborted in less than 12 hours, and 62% of the successful cases aborted within 24 hours. The plasma levels of 15-ME-PGF_2α were analyzed by radioimmunoassay in 10 patients. Plasma prostaglandin levels rose significantly 30 minutes after the insertion of the first suppository, but there was a wide variation in levels from patient to patient. It was observed that the 2 patients with the highest levels had the fastest abortion times and episodes of gastro-intestinal side effects appeared related to a rise in prostaglandin levels. Sixty-four percent of the patients in this study had no gastro-intestinal side effect related to prostaglandin administration.     

Termination of second trimester pregnancy with intra-amniotic 15 (S) 15 methyl prostaglandin F-2alpha - a two dose schedule study.

Termination of second trimester pregnancy with intra-amniotic administration of 15 (S) 15 methyl prostaglandin F-alpha (15 me F-alpha) was attempted in fifty patients. One group (26 patients) was given 1 mg of the analogue and the other group received 2.5 mg. The abortifacient efficacy of 15 me F-2alpha was similar in both groups; over 90% of the patients aborted with a single dose. There was a higher incidence of vomiting, diarrhoea and incomplete abortions in the group treated with 2.5 mg 15 me F-2alpha. Although the mean injection-abortion interval in the 2.5 mg group was shorter, it is concluded that intra-amniotic administration of 1 mg 15 me F-2alpha provides a better regime, giving high efficacy with a single dose, a low incidence of side effects and greater safety in case of inadvertent entry of the intra-amniotic dose into systemic circulation.     

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.     

Administration of 15-methyl-prostaglandin F2α as a pre-operative means of cervical dilatation

Pre-operative dilatation of the cervix prior to vacuum aspiration was accomplished in 67 volunteers by extra-amniotic or intra-muscular administration of 15(S)-15-methyl-PGF_2α (15-me-PGF_2α). Ninety-four per cent of the patients were in the 11th–13th week of gestation and 61% were nulliparae. A single extra-amniotic instillation (mean of 400 μg) or 3 intramuscular injections (300–800 μg per injection) of the compound induced a satisfactory outcome in terms of either abortion or sufficient dilatation of the cervix in 81% of the patients. In the remaining cases, the cervix was found at operation to be open for 7–9 mm which simplified the process of additional instrumental dilatation. In general the outcome of the trial turned the operation into an easy and safe procedure. Vacuum aspiration was performed in all cases after a mean time lag of 16 hours following the onset of the treatment. Extra-amniotic administration was associated with a low incidence of gastro-intestinal side-effects, but there was a transient and moderate degree of uterine pain reaction. The intramuscular route was technically more simple and caused less uterine pain but the high incidence of vomiting and diarrhoea constituted a clinical disadvantage. In late first trimester abortions, particularly cases where the uterus appears larger than expected, it is believed that dilatation of the cervix by PG prior to vacuum aspiration is a sound clinical indication. The method offers definite advantages that compensate for the price of some minor side-effects.     

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.