Interruption of Pregnancy by Prostaglandin 15-Methyl F2α*

Vol. 26, No.7, July 1975 Printed in U.S.A.

FERTILITY AND STERILITY Copyright c 1975 The American Fertility Society

INTERRUPTION OF PREGNANCY BY PROSTAGLANDIN 15-METHYL F 2..* RONALD J. BOLOGNESE, M.D.,

AND

STEPHEN L. CORSON, M.D.

Department of Obstetrics and Gynecology, Pennsylvania Hospital, and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19107

In previous reports, 1• 2 we demonstrated that prostaglandin (PG) E 2 vaginal suppositories successfully induce abortion in 13- to 20-week gestations. Gastrointestinal side effects, however, were noted in 81% of the patients, and a temperature elevation to more than 100° F developed in 61% of the subjects. It was hoped that PG analogs would reduce the incidence of side effects while proving to be equally effective abortive agents. Natural PGE2 and PGF2a compounds are rapidly metabolized and inactivated by dehydrogenation at carbon 15 (C-15) by the enzyme prostaglandin 15-dehydrogenase. In 1971, Bundy et al,3 reported the synthesis of prostaglandin modified at C-15 with retarded enzymic degradation. Confirmation of the uterine-stimulating activity of the 15-methyl analogs of PGE 2 and PGF 2 .. in the rhesus monkey was provided by Kirton and Forbes. 4 Karim and Sharma5 demonstrated that a methyl group in position 15 markedly increased the uterine smooth musclestimulating potency of these compounds in humans. Wiqvist and co-workers6 reported that intra-amniotic administration of 15-methyl PGF 2 .. for abortion resulted in a high level of uterine contractility, a high rate of success, and a low incidence of side effects.

The current study was formulated to investigate the abortifacient activity of 15-methyl PGF 2 .. administered intramuscularly in 8- to 22-week gestations. Goals were the establishment of an effective dosage schedule and the assessment of the incidence and severity of side effects. The results in the intramuscular 15-methyl PGF2a group were compared with those for patients matched for parity and gestational age who were aborted with PGE 2 vaginal suppositories (20 mg given at 4-hour intervals). MATERIALS AND METHODS

The study population consisted of 80 healthy women, ages 14 to 40, with gestations between 8 and 22 weeks. Fifty-six patients were nulliparous. Transabdominal intra-amniotic pressure monitoring was utilized to evaluate uterine contractility and to establish an effective dosage schedule. On the basis of these measurements, 350 to 500 /J-g of drug were administered intramuscularly at 2-hour intervals until abortion was achieved. In six cases, an intravenous infusion of 20 units of oxytocin in 1000 ml of 5% dextrose in water was used to facilitate passage of retained placental tissue. All patients received prophylactic Lomotil (Searle & Co., San Juan, P. R.) Received November 1, 1974. in an effort to reduce diarrhea. Pro*Presented at the Annual Meeting of The Pacific chlorperazine was utilized for severe and Coast Fertility Society, October 1974, Scottsdale, protracted bouts of vomiting. IntraAriz. 695

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July 1975

BOLOGNESE AND COMoN

muscular pentazocine was administered for analgesia at patient request. Complete abortion was defined as the entire passage of fetal and placental tissue with no surgical intervention required. Partial expulsion of the products of conception necessitating a dilatation and suction evacuation for retained tissue was defined as an incomplete abortion. The time of incomplete abortion was computed as the interval from first drug administration to surgical intervention. Most placental evacuation procedures were performed within a 2-hour interval following fetal expulsion. An absence of passage of the products of conception within 36 hours was considered a method failure. In addition to routine urinalysis, blood specimens were obtained from all patients for complete blood count, platelet count, bilirubin, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, creatinine, blood urea nitrogen, serum electrolytes, glucose, and cortisol determinations. These specimens were obtained before treatment, 6 hours after the initial dose, and after the last dose of drug.

in 71 gravidas (89%) with a 4.3 (SD, 3.0) mean number of episodes. Temperature elevations to ;:3 100.6° F were noted in 14 cases (18% ). No other significant complications were encountered during the study. Blood studies for hemotopoietic, hepatic, and renal toxicity demonstrated no significant alterations. Transabdominal intra-amniotic pressure monitoring was accomplished in 10 patients. Twenty to thirty minutes after intramuscular administration of 15methyl PGF 2 a, a sustained hypertonic (40 mm Hg) uterine response was observed. Frequent low-amplitude (5 mm Hg) contractions developed above this resting pressure. Gradually, the contractions became more organized, with greater amplitude and reduced frequency. By 1.5 to 2 hours, the contraction amplitude and the sustained 40 mm Hg resting pressure had begun to diminish.

DISCUSSION

The 15-methyl PGF 2 a patients were matched for parity and gestational length with 80 gravidas aborted with PGE 2 RESULTS (20 mg) vaginal suppositories given at All 80 gravidas were aborted with 4-hour intervals. The difference in interintramuscular 15-methyl PGF 2 a. The val to abortion was not statistically sigtotal drug dose ranged from 900 to 8400 nificant (Fig. 1). Thirty-nine gravidas aborted comJLg, with a mean dose of 3254.32 J.tg (SD, 1482.57). The duration of treatment pletely with PGE 2 suppositories alone, while an oxytocin infusion was used to ranged from 4 to 34 hours. The time to abortion ranged from 5.5 facilitate fetal and placental passage in to 35 hours, with a mean interval of fourteen cases and for placental expulsion 15.70 hours (SD, 6.52). Complete abortion in four instances. The remaining 22 with drug alone occurred in 51 patients, women required dilatation and suction while an oxytocin infusion induced pla- evacuation for retained placental tissue. cental passage in 1 case. Surgical evacua- Complete abortion with 15-methyl PGF2a tion for retained tissue was necessary in alone occurred in 51 patients, while pla28 subjects. cental expulsion was accomplished with Gastrointestinal side effects were fre- intravenous oxytocin in 1 case. Dilatation quent. Vomiting occurred in 71 women and suction evacuation for incomplete (89%) with a 4.9 (SD, 2.8) mean number abortion was necessary in 28 gravidas. of episodes. Similarly, diarrhea developed (Table 1).

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INTERRUPTION OF PREGNANCY BY 15-METHYL PGFza

Vol. 26, No.7

Cumulative Abortion Rate 100"

90 80 70 60

50

40 30

20 10

10

15

20

25

30hrs.

FIG. 1. Cumulative abortion rate for 80 PGE 2 vaginal suppository patients (Suppos.) and 80 15-methyl PGFoa patients.

The frequency of vomiting, diarrhea, 2.7). Again, frequent gastrointestinal and temperature elevation for the two side effects were reported. The current study demonstrates in a groups is presented in Table 2. The differences are statistically significant larger series of patients the effectiveness at P < 0.05, P < 0.01, and P < 0.01, re- of intramuscular 15-methyl PGF2a as an abortifacient. Both the rate of success spectively. 5 Karim and Sharma successfully and abortion interval are comparable aborted three patients with 250 JLg of 15- to our experience with PGE 2 vaginal methyl PGF2a, administered intramus- suppositories. Intra-amniotic drug administration is cularly at 8-hour intervals. The times the predominant method for induction to abortion were 10, 14, and 24 hours; in gestations greater than 12 of abortion frequent episodes of diarrhea and vomweeks. This approach is limited by the iting were noted. Liebman et al.7 foltechnical restrictions of amniocentesis lowed a similar dosage schedule and prior to 16 weeks. Unless strict aseptic aborted 9 of 16 patients; the mean are maintained, intrauterine procedures interval to abortion was 20.2 hours (SD, infection may be initiated by amnioTABLE 1. Comparison of 15-Methyl PGF2a and centesis. Systemic high vascular levels of PGE.,· 80 Terminations Matched for Parity and Gestational Length Parameter

Interval to abortion (hr ± SD) Abortion Complete Incomplete Failure

15-Methyl PGF,a

PGE,

15.7 ± 6.5

14.2 ± 6.3

52 28 0

57 22 1

TABLE 2. Comparison of Side Effects of 15-Methyl PGFza and PGE 2 : 80 Terminations Matched for Parity and Gestational Length Side effect

15-Methyl PGF,a

Vomiting Diarrhea Temperature ;;.100.6" F

89 89 18

PGE,

%

74 23 59

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July 1975

BOLOGNESE AND CORSON

drug from inadvertent injection during bloody taps is possible. Intramuscular drug administration along with vaginal suppositories offer approaches which avoid these problems. The abortion interval with PGE 2 suppositories or intramuscular 15-methyl PGF2a is shorter than with either intra-amniotic PGF 2 a or hypertonic saline alone or supplemented with intravenous oxytocin. A lower mean time to abortion (9 .25 hours) has been reported by Engel and coworkers8 with only the use of laminaria inserted 12 to 24 hours prior to intraamniotic PGF 2a and subsequent intravenous oxytocin augmentation. The intramuscular route eliminates the problem associated with rupture of the membranes during vaginal suppository therapy. Continued leakage of amniotic fluid may dilute or wash out the drug. Similarly, early rupture of the membranes after intra-amniotic drug administration may be associated with reduced or total cessation of uterine activity. Augmentation with high concentrations of oxytocin may then be required, with the inherent risks of water intoxication. Unfortunately, gastrointestinal side effects induced by intramuscular 15-methyl PGF2a occur very frequently. The incidence of diarrhea and vomiting was significantly greater than that with PGE 2 vaginal suppositories. The prophylactic use of 2.5 mg of diphenoxylate hydrochloride with 0.025 mg of atropine sulfate did not appear to be very helpful. Early administration of intravenous fluids is important to avoid dehydration in cases associated with protracted vomiting and/ or diarrhea. More encouraging was the significant reduction in temperature elevation frequently (59%) noted during PGE 2 vaginal suppository therapy. Headache, a less common side effect of PGE 2 vaginal suppositories, was not encountered with intramuscular 15-methyl PGF2a.

The introduction of a methyl group in position 15 of PGF 2 a has substantially increased the drug potency, as judged by dosage necessary to stimulate uterine contractility. However, in our experience, the altered compound failed to sustain effective uterine contractions beyond 2 hours. It is hoped that prolongation of activity can be achieved by retarding absorption from the injection site with use .;. of a different drug vehicle.

SUMMARY

The current study was formulated to investigate the abortifacient activity of prostaglandin 15-methyl F 2a (15-methyl PGF 2 a) administered intramuscularly to 80 healthy women with gestations between 8 and 22 weeks. Goals were the establishment of an effective dosage schedule and assessment of the incidence and severity of side effects. All 80 gravidas were aborted, with a mean time to abortion of 15.70 hours (SD, 6.52). Gastrointestinal side effects occurred in 89% of the patients; temperature elevations to ;;.100.6° F were noted in 14 cases. No other significant complications were encountered. Transabdominal intra-amniotic pressure monitoring indicated the need to administer the drug at 2-hour intervals. The 15-methyl PGF2a patients were matched for parity and gestational length with 80 gravidas aborted with PGE 2 20-mg vaginal suppositories. The difference in interval to abortion in the two groups was not statistically significant. While gastrointestinal side effects were more common with 15-methyl PGF 2 a, the frequency of drug-induced temperature elevations was reduced. Acknowledgments. We acknowledge the financial sup}lort and supplies of drug provided by The Upjohn Company, and the efforts of our research associate, MiBB Claire Connor, R.N.

Vol. 26, No.7

INTERRUPTION OF PREGNANCY BY 15-METHYL PGF.a

REFERENCES 1. Bolognese RJ, Corson SL: Prostaglandin Ez vaginal suppository as an early second trimester abortifacient. Obstet Gynecol43:104, 1974 2. Bolognese RJ, Corson SL: Prostaglandin Ez vaginal suppository as a midtrimester abortifacient. Am J Obstet Gynecol 120:281, 1974 3. Bundy G, Lincoln F, Nelson N, Pike J, Schneider W: Novel prostaglandin syntheses. Ann NY Acad Sci 180:76, 1971 4. Kirton KT, Forbes AD: Activity of 15(S) 15methyl prostaglandin E 2 and F,a as stimulants of uterine contractility. Prostaglandins 1:319, 1972

699

5. Karim SMM, Sharma SD: Termination of second trimester pregnancy with 15 methyl analogues of prostaglandin E2 and Fza. J Obstet Gynaecol Br Commonw 79:737, 1972 6. Wiqvist N, Bygdeman M, Toppozada M: Intraamniotic prostaglandin administration-a challenge to the currently used methods for induction ofmidtrimester abortion. Contraception 8:113, 1973 7. Leibman T, Saldana L, Schulman H, Cunningham MA, Randolph G: Mid-trimester abor· tion with 15(S) methyl prostaglandin F.a. Prostaglandins 7:443, 1974 8. Engel T, Greer B, Kochenour N, Droegemueller W: Midtrimester abortion using oxytocin, prostaglandin F 2a, and laminaria. Fertil Steril 24:565, 1973