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A Comparison of Two Dosing Regimens of Intravaginal Misoprostol for Second-Trimester Pregnancy Termination

From the Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Women’s & Children’s Hospital, Los Angeles County Medical Center–University of Southern California, Los Angeles, California.

Address reprint requests to: John K. Jain, MD, Department of Obstetrics and Gynecology, Women’s & Children’s Hospital, 1240 North Mission Road, Room 8K6, Los Angeles, CA 90033, E-mail: sdavenpo{at}hsc.usc.edu

	Abstract

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Objective: To compare the effectiveness of misoprostol administered intravaginally every 6 versus every 12 hours for termination of second-trimester pregnancies.

Methods: One hundred pregnant women at 12–22 weeks’ gestation were randomized to receive 200 µg of misoprostol intravaginally either every 6 or every 12 hours for up to 48 hours.

Results: The incidences of abortion within 48 hours after initial drug administration were 87.2 and 89.2%, the complete abortion rates 43.9 and 33.3%, and the mean abortion intervals 13.8 and 14.0 hours in the 6- and 12-hour groups, respectively. Side effects were similar between groups.

Conclusion: Misoprostol administered vaginally is effective for terminating second-trimester pregnancies. Shortening the dosing interval from 12 to 6 hours produced no significant benefit.

Second-trimester abortions account for 10% of the approximately 1.5 million abortions done annually in the United States, but they are responsible for two-thirds of all abortion-related major complications and more than half of the maternal deaths associated with abortion.¹ In the United States, the technique most commonly used to terminate these pregnancies is dilation and evacuation (D&E). Although morbidity and mortality rates associated with D&E are lower than those associated with medical methods, D&E requires more technical skill than does administration of drugs. Serious complications such as cervical laceration, uterine perforation, and bowel injury occur even when the procedure is done by experienced personnel.^2–5 Of American obstetrics and gynecology residency programs that offer training in second-trimester abortion techniques, 43% provide training in D&E for gestations longer than 16 weeks and 9% for gestations longer than 20 weeks, whereas 96% provide training in medical abortion with prostaglandins (PGs).⁶ This trend of decreased abortion training is consistent with the survey finding that 43% of graduating residents enrolled in 184 obstetrics and gynecology residency programs had never done a D&E procedure.⁷

Medical abortion is preferable to D&E when morphologic evaluation of the fetus is important, such as when genetic abnormalities are present. A survey found that half of all women requesting abortions in the first trimester prefer medical to surgical therapy.⁸

Misoprostol, a synthetic analogue of PGE₁, initiates cervical dilation and stimulates an increase in frequency and intensity of uterine contractions.^9,10 Three randomized clinical trials were conducted at our institution to evaluate the efficacy and side effects of misoprostol when used as a second-trimester abortifacient. In the first trial, vaginal administration of 200 µg of misoprostol every 12 hours was compared with use of vaginal suppositories of PGE₂; in the second trial, 200 µg of misoprostol was administered vaginally every 12 hours with and without the use of laminaria tents; and in the third trial, misoprostol was administered vaginally at 6-or 12-hour intervals. The methods and results of the first two trials, involving 96 of the total 180 subjects, were reported.^11,12 The purpose of this study was to compare intravaginal administration of misoprostol at 6- versus 12-hour intervals for termination of second-trimester pregnancies. The composite results of this study and two published trials using misoprostol for second-trimester pregnancy termination are summarized to provide a more accurate abortifacient profile.

	Materials and Methods

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Our study population consisted of 100 women at 12–22 weeks’ gestation who were assigned, using a random number table, to receive 200 µg of misoprostol intra-vaginally every 6 or 12 hours. Four of 51 women in the 6-hour group and 12 of the 49 women in the 12-hour group were excluded from final analysis for reasons including gestational age outside the 12- to 22-week interval and incorrect administration of misoprostol. Of 16 women excluded from final analysis, one in the 6-hour group did not abort with misoprostol. The final study sample consisted of 84 women, 32 with living fetuses at the start of the procedure (herein referred to as live fetuses) and 52 with dead fetuses. Of the 32 with live fetuses, eight had terminations of pregnancy for maternal medical indications and 24 for fetal chromosomal or morphologic abnormalities determined by ultrasonography and/or fetal karyotyping of cells harvested by amniocentesis. Ultrasonography was performed with an Ultramark 4 Plus (Advanced Technology Laboratories, Bothell, WA). Gestational age was estimated by measuring the biparietal diameter of the fetal head and correlating it with a standard table of gestational age as described by Shepard et al.¹³ Exclusion criteria included previous uterine incisions; maternal infections; maternal pulmonary, hepatic, renal, or cardiovascular diseases; and cervical dilation or uterine bleeding. Prostaglandin tablets were placed in the vagina without being moistened and without cleansing of the vagina. The use of surgical lubricants that potentially could retard PG absorption was limited. All women were hospitalized and were prescribed bed rest for the duration of treatment. Vital signs were checked every 4 hours, and progression of labor was assessed by cervical examination during each drug administration. The occurrence of adverse signs or symptoms, including fever (temperature above 38C), vomiting, diarrhea, and pain, was recorded. None of the women received premedication. Women were treated for side effects when symptoms developed. Diphenoxylate plus atropine (Lomotil; G. D. Searle & Co., Chicago, IL) 5.0 mg orally was used to treat diarrhea, acetaminophen (Tylenol; McNeil Consumer Products Co., Raritan, NJ) 650 mg orally to treat fever (temperature above 38C), prochlorperazine 10 mg intramuscularly (IM) to treat vomiting, and meperidine 50 mg IM to treat pain.

To preclude mandatory postnatal resuscitation, live fetuses with chromosomal or morphologic anomalies were given a lethal intracardiac injection of 1–4 mL of potassium chloride (2 mmol/mL) with a 20-gauge spinal needle, under sonographic guidance, 4 hours before the start of PG administration. Treatment failure was defined as failure of abortion to occur within 48 hours after administration of the initial dose of misoprostol or severe systemic signs and symptoms that were unrelieved by medications. After expulsion of her fetus, each woman received intravenous (IV) oxytocin, 30 U in 1 L of dextrose-lactated Ringer’s solution. Within 6 hours after expulsion, whether or not the placenta also had been expelled, the uterine cavity of each patient was curetted in an outpatient area, without further dilation of the cervix. Before curettage, each women received an IV bolus of 50 mg of meperidine and 25 mg of promethazine for sedation. A paracervical injection of 10 mL of a 0.5% solution of lidocaine was used for local anesthesia. Women who did not abort within 48 hours after initial treatment with misoprostol received one or more IM injections of 250 µg of 15-methyl-prostaglandin F₂ (Hemabate; Upjohn Co., Kalamazoo, MI) every 2 hours or had D&E. Each women was discharged with nine tablets of 0.2 mg of methylergonovine maleate (Methergine; Sandoz Pharmaceuticals Corp., East Hanover, NJ) and instructions to ingest one tablet every 8 hours for 3 days.

Results from the 84 pregnancy terminations were combined with data from the first two trials, to establish a composite sample of 180 second-trimester pregnancy terminations with misoprostol. In the first trial, 28 women received 200 µg of misoprostol (Cytotec; G. D. Searle & Co), in two 100-µg tablets placed deep in the posterior vaginal fornix every 12 hours; these women were compared with 27 women who underwent vaginal administration of dinoprostone suppositories (Prostin E₂; Upjohn Co.). In the second trial, 35 women received 200 µg of misoprostol vaginally every 12 hours, with intracervical laminaria tents (Laminaria japonica [Dilateria; Milex Products, Inc., Chicago, IL]) used concurrently for the first 12 hours of treatment, and these women were compared with 33 women who received 200 µg of misoprostol vaginally every 12 hours, without laminaria tents. The three trials were conducted between 1993 and 1996. All women were at 12–22 weeks’ gestation and had pregnancy terminations for fetal death (109) or medical or genetic reasons (71). Of the 71 women with live fetuses, 12 had terminations for maternal medical indications and 59 for fetal chromosomal or morphologic abnormalities.

Each study was approved by the Institutional Review Board of the Los Angeles County–University of Southern California Medical Center, and each woman gave written informed consent. Student t-test was used to analyze the time from initial treatment to abortion and Fisher exact test to assess abortion rates, complete abortion rates, side effects, and characteristics of unsuccessful treatments.¹⁴ The analyses were done with the SAS (SAS Institute, Cary, NC) and Primer (McGraw-Hill, New York, NY) software packages. All tests of significance were two-sided.

	Results

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In the third trial, 38 (80.9%) of the 47 women who received misoprostol every 6 hours and 32 (86.5%) of the 37 women who received misoprostol every 12 hours aborted within 24 hours (P > .05). At 48 hours of treatment, the success rate was 87.2% (41 of 47) and 89.2% (33 of 37) in the 6- and 12-hour groups, respectively. The mean abortion intervals, defined as the intervals from the first dose of misoprostol to the expulsion of the fetus, were 13.8 and 14.0 hours in the 6-and 12-hour groups, respectively (P > .05). The rates of complete abortion, defined as the simultaneous passage of the fetus and the placenta, also were similar between groups, with complete abortion occurring in 18 (43.9%) of 41 successful abortions in the 6-hour group and 11 (33.3%) of 33 successful abortions in the 12-hour group (P > .05). Overall, 48 (92.3%) of the 52 women with dead fetuses and 26 (81.2%) of the 32 women with live fetuses successfully aborted their pregnancies (P > .05). Among the 47 women who received misoprostol every 6 hours, 12 (26%) had fever (temperature over 38C), compared with three of 37 (8%) who received misoprostol every 12 hours (P > .05). Vomiting occurred in four women in the 6-hour group (9%) and in no women in the 12-hour group (P > .05). Diarrhea occurred one woman in the 6-hour group (2%) and in no women in the 12-hour group (P > .05). Moderate uterine pain requiring analgesia with 50 mg of IM meperidine occurred once in 23 women in the 6-hour group (49%) and in 18 in the 12-hour group (49%). Severe pain requiring meperidine more than once occurred in eight women in the 6-hour group (17%) and three in the 12-hour group (8%) (P > .05). In all cases, estimated blood loss was less than 500 mL and no women needed blood transfusions.

The sample size when the data of all three trials were combined was 180 subjects. The mean age of the 180 subjects was 28.4 years (range 15–44); 56 (31.1%) were nulliparous and mean parity for the remaining 124 subjects (68.9%) was 2.8 (range 1–11). The mean gestational age was 18.7 weeks (range 12–22) for live fetuses and 15.5 weeks (range 12–22) for dead fetuses, and the overall mean gestational age was 16.8 weeks (range 12–22).

Abortion occurred within 24 hours after initial administration of misoprostol in 142 (78.9%) of the 180 women and within 48 hours in 162 women (90.0%). Of the 18 women who did not abort within 48 hours, two aborted spontaneously in the subsequent 2 hours without further intervention, ten were treated with PGE₂ vaginal suppositories or injections of 15-methyl-prostaglandin F₂ that successfully terminated their pregnancies, and six had D&E. The abortion rate for dead fetuses (89.0%) was significantly higher than the abortion rate for live fetuses (63.4%), within 24 hours of initial treatment (P < .05). By 48 hours after initial treatment, the rate of abortion for dead fetuses (93.6%) was still higher than that for live fetuses (84.5%), but the difference was not statistically significant (P > .05). Seven (12.5%) of the 56 nulliparous women did not abort within 48 hours, compared with 11 (8.9%) of the 124 parous women (P > .05). Among the 71 women with live fetuses, eight (13.6%) of 59 having abortions for genetic reasons and three (25.0%) of 12 having abortions for maternal reasons did not abort within 48 hours (P > .05). The abortion rates at different gestational ages were similar. Abortion did not occur within 48 hours in eight (8.8%) of 91 early pregnancies (12–16 weeks) and 10 (11.2%) of 89 later pregnancies (17–22 weeks) (P > .05).

The mean abortion interval for the 162 women who aborted was 14.8 hours (median 12.2, range 2.5–48.0). In all three studies, women who had dead fetuses aborted sooner after initial therapy than did those with live fetuses. The mean abortion intervals were 12.0 and 19.8 hours, respectively (P < .05).

The rate of complete abortion was 39.5% in the 162 women who aborted their pregnancies. Subsequent uterine curettage in these women, after an infusion of oxytocin for 2–6 hours, revealed no gross placental tissue. In the remaining women, attempts were made to remove the placenta manually. If removal was accomplished easily, rapid curettages (taking less than 2 minutes) were performed. When placentas were adherent, more thorough curettages (taking 2–10 minutes) were performed. Complete abortion rates did not differ significantly between women with earlier gestations (12–16 weeks) and those with later gestations (17–22 weeks), between those with live fetuses and those with dead fetuses, or between nulliparous and parous women (P > .05) (Table 1).

	Discussion

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Zieman et al¹⁵ found that when 400 µg of misoprostol is given vaginally, peak levels of the principal metabolite, misoprostol acid, are reached in a mean of 80 minutes and levels decrease slowly to an average of 61% of peak levels 240 minutes after administration. Theoretically, a dosing interval of 6 hours would be preferable to one of 12 hours to maintain high plasma levels of misoprostol. Higher concentrations of misoprostol (which would occur with more frequent dosing) for a longer duration could result in a shorter time to and a higher rate of abortion.

The 180 pregnancy terminations discussed here represent one of the largest series involving intravaginal misoprostol and the findings serve better to define the abortifacient properties of misoprostol, specifically in relation to second-trimester pregnancies. Those results show that misoprostol is less effective for terminating pregnancies involving live fetuses than those involving dead fetuses. The mean time from start of treatment to expulsion of the fetus is longer when the fetus is living than when the fetus is dead. The incidence of abortion is less with a live fetus. A low incidence of vomiting, diarrhea, and pyrexia was noted in all three trials. These side effects occurred in less than 15% of the women and did not lead to withholding of medication.

Although misoprostol is inexpensive compared with other agents used for medical abortion, the expense associated with inpatient treatment adds to the cost. The total cost of inpatient treatment with misoprostol is comparable to that of D&E, which can be performed in an ambulatory surgical center. Costs might be less if ambulatory outpatient sites were developed for medical termination of second-trimester pregnancies. Ancillary methods by which misoprostol can be used in ambulatory settings include pretreatment with laminaria or mifepristone. El-Refaey and Templeton¹⁶ reported that when mifepristone was ingested 36 hours before administration of vaginal misoprostol in the second trimester, the abortion rate was 97%, with a mean induction to abortion time of 6.4 hours and a complete abortion rate of 91%. It is also possible that administration of laminaria 12–24 hours before administration of misoprostol would shorten the time to abortion.

Misoprostol is an effective agent for terminating pregnancy in the second trimester, and it appears to be more effective for terminating pregnancies when fetal death has occurred. No additional benefit was produced by administering misoprostol every 6 hours compared with every 12 hours, but those results might have been influenced by the relatively small sample size. Further studies are needed to ascertain the optimal dosing interval for intravaginal misoprostol.

	Footnotes

 
PII S0029-7844(98)00485-2

Received June 2, 1998. Received in revised form September 29, 1998. Accepted October 15, 1998.

	References

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1. Toppozada M, Ismail AA. Intrauterine administration of drugs for termination of pregnancy in the second trimester. Baillieres Clin Obstet Gynaecol 1990;4:327–49.[Medline]

2. Mishell DR Jr. Induced abortion. In: Berkow R, ed. The Merck manual of diagnosis and therapy. 16th ed. Rahway, New Jersey: Merck Research Laboratories, 1992:1781–3.

3. Grimes DA, Cates W Jr. Complications from legally-induced abortion: A review. Obstet Gynecol Surv 1979;34:177–91.[Medline]

4. Peterson WF, Berry FN, Grace MR, Gulbranson CL. Second-trimester abortion by dilatation and evacuation: An analysis of 11,747 cases. Obstet Gynecol 1983;62:185–90.[Abstract/Free Full Text]

5. Wadhera S, Millar WJ. Second trimester abortions: Trends and medical complications. Health Rep 1994;6:441–54.[Medline]

6. MacKay HT, MacKay AP. Abortion training in obstetrics and gynecology residency programs in the United States, 1991–1992. Fam Plann Perspect 1995;27:112–5.[Medline]

7. Westhoff C, Marks F, Rosenfield A. Residency training in contraception, sterilization, and abortion. Obstet Gynecol 1993;81:311–4.[Abstract/Free Full Text]

8. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537–40.[Abstract/Free Full Text]

9. Herting RL, Nissen CH. Overview of misoprostol clinical experience. Dig Dis Sci 1986;31(suppl 2):47S–54S.[Medline]

10. el-Refaey H, Calder L, Wheatley DN, Templeton A. Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost. Lancet 1994;343:1207–9.[Medline]

11. Jain JK, Mishell DR Jr. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331:290–3.[Abstract/Free Full Text]

12. Jain JK, Mishell DR Jr. A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion. Am J Obstet Gynecol 1996;175:173–7.[Medline]

13. Shepard MJ, Richards VA, Berkowitz RL, Warsof SL, Hobbins JC. An evaluation of two equations for predicting fetal weight by ultrasound. Am J Obstet Gynecol 1982;142:47–54.[Medline]

14. Zar JH. Biostatistical analysis. 2nd ed. Englewood Cliffs, New Jersey: Prentice-Hall, 1984.

15. Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92.[Abstract]

16. el-Refaey H, Templeton A. Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: A randomized comparison between two misoprostol regimens. Hum Reprod 1995;10:475–8.[Abstract/Free Full Text]

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