Original Article
A Comparison of Intravaginal Misoprostol with Prostaglandin E2 for Termination of Second-Trimester Pregnancy
N Engl J Med 1994; 331:290-293August 4, 1994
- Abstract
Background
The most widely used medical method of terminating second-trimester pregnancy is the intravaginal administration of prostaglandin E2 (dinoprostone [PGE2]). This treatment is highly effective but is associated with severe gastrointestinal side effects and hyperpyrexia.
Methods
We conducted a prospective, randomized trial comparing the efficacy and safety of misoprostol, a prostaglandin E1 analogue (200 μg intravaginally every 12 hours), with the efficacy and safety of PGE2 (20 mg intravaginally every 3 hours). The study population included 55 pregnant women between 12 and 22 weeks' gestation who were undergoing termination of pregnancy for either intrauterine fetal death (37 women) or medical or genetic reasons (18 women).
Results
The rate of successful abortions within 24 hours was 81 percent (22 of 27 women) with PGE2 and 89 percent (25 of 28 women) with misoprostol (P = 0.47). All the women who received misoprostol had successful abortions within 38 hours. Among those who had an abortion within 24 hours, the mean interval from treatment to abortion was similar in both groups (10.6 hours with PGE2 and 12.0 hours with misoprostol, P = 0.33). The rate of complete abortion, defined as the passage of the fetus and the placenta simultaneously, was 32 percent for PGE2 and 43 percent for misoprostol (P = 0.56). Certain side effects were more frequent in the women receiving PGE2 than in those receiving misoprostol: pyrexia (63 percent vs. 11 percent; P<0.001), uterine pain (67 percent vs. 57 percent, P = 0.58), vomiting (33 percent vs. 4 percent, P = 0.005), and diarrhea (30 percent vs. 4 percent, P = 0.012). The average cost per treatment was $315.30 for PGE2, as compared with $0.97 for misoprostol.
Conclusions
Misoprostol is at least as effective as PGE2 for the termination of second-trimester pregnancy involving either a dead or a living fetus, but it is less costly, is easier to administer, and is associated with fewer adverse effects.
Media in This Article
Table 1
Characteristics of the Study Groups.Table 2
Interval from Treatment to Abortion.Article Activity
- Article
Misoprostol ((±)-methyl-11α, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate) is a synthetic prostaglandin structurally related to prostaglandin E1 1. It is principally used to prevent peptic ulcer disease induced by the ingestion of nonsteroidal antiinflammatory agents. In previous studies of misoprostol as an abortifacient, an oral route of administration has been used. When given in the first trimester of pregnancy in oral doses ranging from 400 to 800 μg, misoprostol was associated with a low rate of abortion and a high incidence of vaginal bleeding and abdominal pain2. When given 48 hours after an oral dose of 200 mg of mifepristone, oral doses of misoprostol ranging from 200 to 1000 μg resulted in a high rate of abortion3. Intravaginal administration of drugs provides a slower, more constant rate of absorption than does oral ingestion4. Therefore, we decided to administer misoprostol alone by the vaginal route to induce second-trimester abortion, as was previously reported by Bugalho et al.5,6 Unlike them, we gave misoprostol at a lower dose and gave it more frequently. Our goal was to compare the efficacy and side effects of 200 μg of misoprostol administered intravaginally every 12 hours with those of 20 mg of prostaglandin E2 (dinoprostone [PGE2]) administered intravaginally every 3 hours for the induction of abortion in the second trimester in women with living or dead fetuses.
Methods
The study population consisted of 55 pregnant women, between 12 and 22 weeks' gestation, with either intrauterine fetal death (37 women) or medical or genetic reasons for the termination of pregnancy (18 women). The latter included 1 patient with systemic lupus erythematosus, another with chronic myelogenous leukemia, and 16 with fetuses with various severe chromosomal or morphologic anomalies as determined by ultrasonographic examination or karyotyping of fetal cells obtained by amniocentesis. The mean age of the subjects was 26.7 years (range, 16 to 41). Seventeen of the 55 women were nulliparous, and the remaining subjects ranged in parity from 1 to 7 (mean, 2.7). The mean gestational age was 19.8 weeks (range, 16 to 22) for live fetuses and 15.7 weeks (range, 12 to 22) for dead fetuses, with an overall mean gestational age of 17.0 weeks (range, 12 to 22).
Ultrasound examination was performed with an Ultramark 4 Plus (Advanced Technology Laboratories). Gestational age was estimated by measuring the biparietal diameter and correlating this measurement with a standard table of gestational age. Criteria for exclusion from the study included previous uterine incision, maternal infection, or maternal pulmonary, hepatic, renal, or cardiovascular disease. No woman with any degree of cervical dilatation was included in this study.
We used a random-number table to assign the women to receive either 200 μg of misoprostol (Cytotec, Searle), administered as two 100-μg tablets placed in the posterior vaginal fornix every 12 hours, or 20 mg of PGE2 (Prostin E2, Upjohn), administered as one vaginal suppository placed in the posterior vaginal fornix every 3 hours. House-staff physicians placed the tablets and suppositories, and all patients remained at bed rest in the hospital for the duration of treatment. Patients who were randomly assigned to receive PGE2 were premedicated 30 minutes before receiving the initial suppository with an antidiarrheal medication (diphenoxylate plus atropine [Lomotil, Searle], 5.0 mg orally), an antipyretic medication (acetaminophen [Tylenol, McNeil], 650 mg orally), and an antiemetic medication (prochlorperazine [Compazine, SmithKline Beecham], 10 mg intramuscularly). Those who were randomly assigned to receive misoprostol received no premedication. Live fetuses received a lethal intracardiac injection of 1 to 4 ml of potassium chloride (2 mmol per milliliter) with a 20-gauge spinal needle under direct ultrasound guidance approximately four hours before the start of treatment, to avoid mandatory postnatal efforts to resuscitate fetuses with severe anomalies. The patients' vital signs were monitored every four hours, and the progression of labor was assessed by cervical examination at the time of each drug administration. The occurrence of adverse signs and symptoms, such as fever, pain, vomiting, and diarrhea, was recorded. Treatment failure was defined as the failure of abortion to take place within 24 hours after the initial medication or as the occurrence of systemic adverse signs and symptoms severe enough to preclude the use of additional drug. After the passage of the fetus, whether or not the placenta was passed, all patients received an intravenous infusion of oxytocin, administered as 30 units in 1 liter of dextrose-lactated Ringer's solution. Within six hours of the passage of the fetus, the uterus of each patient was curetted in the outpatient area, without further dilatation of the cervix. Immediately before this procedure, all the women received an intravenous bolus of 50 mg of meperidine and 20 mg of promethazine for sedation and an intracervical injection of 10 ml of a 0.5 percent solution of lidocaine for anesthesia.
The study was approved by the research committee of the Los Angeles County-University of Southern California Medical Center, and each patient gave written informed consent. Student's t-test was used to evaluate the interval from treatment to abortion, and Fisher's exact test was used to assess abortion rates, complete-abortion rates, and side effects7,8. The analyses were carried out with the SAS statistical software package (SAS Institute). All reported P values are two-sided.
Results
Twenty-seven women were randomly assigned to receive PGE2, and 28 women were assigned to receive misoprostol. Of the 27 women randomly assigned to receive PGE2, 18 had had intrauterine fetal deaths and 9 had live fetuses. Of the 28 women randomly assigned to receive misoprostol, 19 had had intrauterine fetal deaths and 9 had live fetuses. The two groups had similar mean ages, parities, and gestational ages (Table 1Table 1
Characteristics of the Study Groups.). The mean gestational age for the women receiving PGE2 was 17.0 weeks (range, 12 to 22). For the women receiving misoprostol, the mean gestational age was 17.1 weeks (range, 13 to 22). The overall mean gestational age for all the subjects was 17.0 weeks.Twenty-two of the 27 women receiving PGE2 (81 percent) had successful abortions within 24 hours. Among the five women in whom abortion was unsuccessful, one had severe hyperpyrexia (temperature, 41.3 °C) after using two suppositories, and one had tachycardia and shortness of breath necessitating the administration of nasal oxygen after using one suppository. The pregnancies were both terminated by cervical dilatation and curettage. The remaining three women did not have successful abortions within 24 hours. After that period had passed, they received a single injection of 250 mg of prostaglandin F2a (dinoprost [PGF2a]) (Hemabate, Upjohn) and had successful abortions within two hours. Of the 28 women receiving misoprostol, 25 (89 percent) had successful abortions within 24 hours, a rate similar to that in the group receiving PGE2 (P = 0.47). Of the remaining three women, two received an additional dose of 200 μg of misoprostol at 24 hours and had successful abortions 27 and 34 hours after the start of therapy; the third woman received additional doses of misoprostol at 24 and 36 hours and had a successful abortion 38 hours after the start of therapy (Table 2Table 2
Interval from Treatment to Abortion.).The rate of complete abortion, defined as the simultaneous passage of the fetus and the placenta, was 32 percent in the 22 patients treated only with PGE2 and 43 percent in the 28 patients treated only with misoprostol (P = 0.56). Subsequent curettage in these women revealed no grossly apparent placental tissue after the women received an infusion of oxytocin for two to six hours. In the remaining women, attempts were made to remove the placenta manually. If this was easily done, a rapid curettage (less than two minutes) was performed. When the placenta was adherent, a more thorough curettage (for 2 to 10 minutes) was performed. The complete-abortion rate did not differ significantly between women with earlier and those with later gestational ages or between nulliparous and parous women (Table 3Table 3
Rates of Complete Abortion in the Two Study Groups.).In both groups, women who had an intrauterine fetal death aborted earlier than those with a live fetus (mean interval from treatment to abortion, 9.1 and 13.2 hours, respectively, among women receiving PGE2, and 10.4 and 15.4 hours among women receiving misoprostol). Overall, the mean interval from treatment to abortion was similar in both groups (PGE2, 10.6 hours; misoprostol, 12.0 hours; P = 0.33) when the women who had abortions after 24 hours were excluded.
The mean number of doses of PGE2 was 3.7 (average cost per treatment, $315.30), significantly higher than the mean of 1.4 doses of misoprostol (average cost per treatment, $0.97). More than half the patients receiving misoprostol (16 of 28, or 57 percent) had successful abortions after a single administration of 200 μg of the drug.
Among the 27 women receiving PGE2, 17 (63 percent) had fever (temperature, ≥ 38 °C), as compared with 3 of the 28 women receiving misoprostol (11 percent) (P<0.001). Uterine pain necessitating analgesia with 50 mg of intramuscular meperidine occurred in 18 of the 27 women receiving PGE2 (67 percent) and in 16 of the 28 women receiving misoprostol (57 percent) (P = 0.58). Severe pain necessitating the use of analgesic medication more than once occurred in seven women receiving PGE2 (26 percent) and in one woman receiving misoprostol (4 percent) (P = 0.025). Vomiting was noted in nine women receiving PGE2 (33 percent) and in one woman receiving misoprostol (4 percent) (P = 0.005). Diarrhea was noted in eight women receiving PGE2 (30 percent) and in one woman receiving misoprostol (4 percent) (P = 0.012). The estimated blood loss associated with each treatment was less than 500 ml in all women. No woman required a blood transfusion.
Discussion
Currently, the most widely used methods of terminating pregnancy during the second trimester of gestation are the vaginal administration of PGE2 suppositories and the surgical dilatation and evacuation of the uterine cavity. The former is associated with a high frequency of gastrointestinal side effects, and the latter with serious complications of uterine rupture and intestinal injury. In addition, medical abortion is preferable to dilatation and evacuation when morphologic evaluation of the fetus for genetic abnormalities is indicated. The results of this study indicate that vaginal administration of 200 μg of misoprostol every 12 hours is an effective and convenient way to induce abortion during the second trimester of pregnancy in women with either an intrauterine fetal death or a live fetus. In this prospective, randomized study, treatment with misoprostol was compared with PGE2 therapy, and the success rates of the two drugs were similar. The abortion rate was 89 percent within 24 hours and 100 percent within 38 hours after the start of misoprostol therapy in a group of 28 women, 19 of whom had a dead fetus and 9 of whom initially had a live fetus.
At our institution, PGE2 has been the standard agent used in terminating second-trimester pregnancies for the past several years. If fetal expulsion has not occurred within 24 hours, pregnancies have usually been terminated successfully with a single injection of PGF2a, as was done in this study. If abortion has not occurred after the administration of eight PGE2 suppositories, a single injection of PGF2a is more effective than continued administration of PGE2. In the group receiving misoprostol in this study, however, if abortion did not occur within 24 hours, additional tablets of misoprostol were given to determine their effectiveness. Because of the high frequency of gastrointestinal side effects with PGE2, all the women receiving that medication at this institution are treated with antiemetic, antidiarrheal, and antipyretic analgesic medications 30 minutes before receiving the initial suppository. In this study such pretreatment was continued for the group receiving PGE2, but not for the group receiving misoprostol, since the incidence of side effects associated with intravaginal misoprostol is not known. It was determined that vomiting and diarrhea were very uncommon with this dosage of intravaginal misoprostol, in contrast to their high incidence in association with PGE2, as seen in this study despite premedication.
Pharmacodynamic and clinical data are available on misoprostol administered orally. The absorption of the drug is rapid, resulting in a peak plasma concentration of misoprostol acid, the biologically active metabolite, in less than 30 minutes, with a terminal half-life of 20 to 40 minutes9. Orally administered misoprostol is well tolerated, with few systemic side effects, mainly gastrointestinal9. No data on the pharmacodynamic properties of intravaginal misoprostol have been reported. Misoprostol has been administered vaginally to produce cervical ripening and induction of labor in late pregnancy, and no severe adverse effects have been noted10,11. In this study of 28 women as well as the studies by Bugalho et al.5,6 involving 169 women treated with a larger dose of misoprostol, no significant adverse effects were noted. Experience with larger numbers of women is needed to define the safety of intravaginal misoprostol more carefully.
In this study, complete abortion was defined as the expulsion of both the fetus and the placenta without operative assistance. The complete-abortion rates of 43 percent with misoprostol and 32 percent with PGE2 were not significantly different (P = 0.56). Surrago and Robins reported a series of 400 patients undergoing pregnancy termination in the second trimester, 232 of whom received PGE2 in the dose and frequency used in this study12. Although Surrago and Robins reported a complete-abortion rate of 79 percent, markedly higher than the rate we observed, they included among their complete abortions both cases in which the products of conception were completely expelled and instances in which the products could be removed manually or with forceps from the vagina or dilated cervical os. In our study, if the products of conception were not completely expelled or had to be evacuated with an instrument or manually, the woman was considered to have had an incomplete abortion. Thus, the difference between the results of the two studies can be explained by a difference in the definition of complete abortion. Retained products of conception are an important cause of morbidity, mainly infection and bleeding. In this institution a curettage is routinely performed after all second-trimester abortions. The decision to do so is based on the findings of Berger and Kerenyi,13 who evaluated the effect of a retained placenta in a large series of second-trimester abortions performed by saline infusion. They reported that the complication rate associated with operative removal of the placenta within two hours after the expulsion of the fetus was significantly lower than that associated with placental retention beyond that time.
Finally, because significantly fewer doses of misoprostol than of PGE2 are needed to induce abortion, it is easier as well as less expensive to administer misoprostol. The average dose of misoprostol used in this study cost $314 less than the average dose of PGE2. Medical abortion, however, may not be as cost effective as dilatation and evacuation, a procedure usually performed on an outpatient basis. The estimated cost of dilatation and evacuation in this community ranges from $800 to $2,000, whereas the estimated cost of a prostaglandin-induced abortion for an inpatient is $1,800.
In the study by Bugalho et al.,6 an abortion rate of 91 percent was noted with the administration of mostly higher doses of misoprostol vaginally every 24 hours. The optimal dosage and frequency of administration of this agent need to be determined in further studies. About 10 percent of elective abortions in the United States are performed when the gestational age is more than 12 weeks. The technique most commonly used to terminate these pregnancies is dilatation and evacuation. Although this procedure has been shown to have low rates of minor morbidity through the 20th week of gestation, the risk of major morbidity, including bowel injury and uterine injury requiring hysterectomy, increases with advancing gestational age, and serious injuries sometimes occur even when the procedure is performed by experienced operators14,15. Other techniques used to terminate pregnancies in the second trimester include the intrauterine infusion of saline or prostaglandin. These techniques are also associated with severe maternal complications, including coagulopathy, hemorrhage, and infection16. Misoprostol may thus prove to be a safe alternative means of achieving elective abortion in the second trimester. In conclusion, although there are only limited data on the efficacy of oral misoprostol, it does not appear to be an effective means of terminating second-trimester pregnancy. The vaginal administration of this agent is, however, very effective and is associated with a low frequency of side effects.
Source Information
From the Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles.
Address reprint requests to Dr. Jain at Women's and Children's Hospital, Los Angeles County-University of Southern California Medical Center, 1240 N. Mission Rd., Rm. L1009, Los Angeles, CA 90033.
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