Vaginal misoprostol alone for medical abortion up to 9 weeks of gestation: efficacy and acceptability

S.W. Ngai1, O.S. Tang, Y.M. Chan and P.C. Ho

Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Misoprostol and mifepristone have been shown to be effective for medical abortion up to 9 weeks of gestation. When used alone, the successful complete abortion rate dropped to ~60%. It has been demonstrated that by adding water to misoprostol, the success rate rose to 92%. This is the first randomized study to investigate the efficacy of misoprostol and water versus misoprostol alone for first trimester medical abortion in women at <= 9 weeks of gestation. Eighty women were randomly assigned to group 1 (water added to misoprostol) and group 2 (misoprostol alone). Vaginal misoprostol 800 µg was given on days 1, 3 and 5. If the woman did not require vacuum aspiration during the period up to the return of first menstruation after medical abortion, the outcome was classified as complete abortion. The incidence of side-effects and the acceptability were assessed through a standardized questionnaire during and after the abortion. The complete abortion rate appeared higher when water was added but the difference did not reach statistical significance. Gastro-intestinal side-effects were common but well tolerated in both groups. Overall, 40% of the women preferred a surgical method in the future because of the high failure rate. With an overall complete abortion rate of 85%, it is probably not a clinically acceptable method even if the addition of water can improve the results. We conclude that the addition of water onto misoprostol tablets does not improve its efficacy in first trimester medical abortion. Misoprostol alone is not recommended for medical abortion (up to 9 weeks of pregnancy) because of the high failure rate and low acceptability.

Key words: abortion/medical/misoprostol


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Termination of pregnancy is one of the most common procedures in gynaecological practice. Vacuum aspiration has been used for first trimester termination of pregnancy. With the introduction of a cervical priming agent, the complications were significantly reduced. Although complications are uncommon, vacuum aspiration has been shown to be associated with uterine perforation, cervical injuries and excessive haemorrhage (Heisterberg et al., 1986Go). The overall complication rate varies between 4 and 10% (Farell et al., 1982Go). In the absence of complications, there is little evidence to suggest that surgical abortion has an adverse effect on future fertility.

Medical abortion had been available in Europe since 1990. Women can avoid the risks of surgery and anaesthesia. Mifepristone in combination with misoprostol is highly effective for first trimester medical abortion (Norman et al., 1991Go). Alternative regimens had been explored because mifepristone was not readily available in many countries. Methotrexate followed by misoprostol has also been shown to be effective (Creinin et al., 1995Go). However, side-effects related to methotrexate and the possibility of teratogenicity limit its popularity.

Misoprostol is a synthetic prostaglandin E1 analogue that was initially used for the treatment of gastric ulcer. We have shown that it is a safe and effective cervical priming agent prior to vacuum aspirations in first trimester abortion (Ngai et al., 1995Go, 1996Go). It is also an effective abortifacient when given in repeated doses in second trimester abortion (Ho et al., 1997Go). The results of misoprostol alone in first trimester medical abortion were disappointing. The complete abortion rates were only 61–66% (Bugalho et al., 1996Go; Koopersmith and Mishel, 1996Go). A 92% complete abortion rate in first trimester medical abortion (amenorrhoea <70 days) has been achieved simply by adding water to the misoprostol tablets prior to vaginal insertion (Carbonell et al., 1997Go). This was, however, the only published series that showed a satisfactory result. We decided to perform this prospective study to find out whether addition of water onto misoprostol tablets before insertion can improve the efficacy of misoprostol alone on first trimester medical abortion.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ethical approval for the study was granted by the Ethics Committee, Queen Mary Hospital. A total of 80 women requesting termination of pregnancy up to 9 weeks of gestation was recruited in our outpatient clinic and Family Planning Association of Hong Kong. All gave informed consent after the study had been explained, including their right to withdraw from the trial at any time without prejudice to their further medical care.

The subjects were between 16 and 42 years of age. All women satisfied the following criteria: (i) normal general and gynaecological examination; (ii) <=9 weeks of gestation (as calculated from the date when the missed menstrual period should have started) on day 1 of the study; (iii) the size of the uterus on pelvic examination was compatible with the estimated duration of pregnancy. Exclusion criteria included: (i) history or evidence of disorders that represent a contraindication to the use of misoprostol (mitral stenosis, glaucoma, sickle cell anaemia, diastolic pressure >100 mm Hg, bronchial asthma); (ii) history or evidence of thrombo-embolism, severe or recurrent liver disease or pruritus of pregnancy; (iii) presence of intrauterine contraceptive device (IUCD) in utero; (iv) suspect or proven ectopic pregnancy; (v) heavy smoker (smoking >10 cigarettes daily in the past 2 years) or had another risk factor for cardiovascular disease.

Women were randomized into two groups: group 1, misoprostol with 3 drops of water per tablet (water group) and group 2, misoprostol only (no water group). On day 1, women in group 1 received vaginal misoprostol 800 µg with 3 drops of water added onto each tablet; women in group 2 received vaginal misoprostol 800 µg without water. They stayed in the day ward for a 4 h clinical observation period (hourly recordings of blood pressure and pulse rate). The time of misoprostol administration and expulsion of gestational products, if it occurred, were recorded on the data forms. They were assessed by one of the investigators at the end of the 4 h period. Women were asked to bring back the tissue mass if it was passed at home. They were advised to come back if excessive bleeding or abdominal pain was noted. On days 3 and 5, vaginal misoprostol (same treatment as that on day 1) was inserted and the observations were repeated. They were followed up again on days 15 and 43. Transvaginal ultrasound scan was performed in all women on day 15. Patients were examined and the bleeding patterns were checked on day 43. For those presenting with persistent bleeding or when menstruation had not returned, a further follow-up appointment was made.

The outcome of treatment was classified as: (i) complete abortion; (ii) incomplete abortion; (iii) missed abortion; and (iv) live pregnancy. The initial judgement about the outcome of therapy was made at the follow-up visit on day 15. If the ultrasound findings showed a live pregnancy (i.e. fetal heart activity present) on day 15, vacuum aspiration would be performed and the aspirates were sent for histological examination. If the ultrasound findings on day 15 were compatible with missed abortion (identifiable gestational sac without fetal heart activity), the investigator had the option of either termination of the pregnancy by vacuum aspiration or awaiting spontaneous expulsion of the products of conception. The choice between these two alternatives was left to the principal investigator after discussion with the subject. If the ultrasound findings were compatible with complete or incomplete abortion, no further action would be taken unless there was heavy bleeding or signs of pelvic infection. In these women the final judgement would be made on day 43. If no emergency or elective vacuum aspiration was necessary during the period up to the first menstruation, the outcome was classified as complete abortion. Tissues removed by vacuum aspiration were sent for histological confirmation.

Those who did not require vacuum aspiration were defined as successful cases. Failure was defined as the recourse to surgical abortion either due to method failure or change of patients' decision. The incidence of side-effects, duration of vaginal bleeding, dosage of analgesic requirement and infection rate between the two groups were also compared. A standardized questionnaire was given to patients during and after the abortion in order to assess acceptability to the patients. The differences in the discontinuous variables were analysed by {chi}2 test or Fisher's exact test. The differences of continuous variables were analysed by Student's t-test for normally distributed data and the Mann–Whitney test for skewed data.

The calculation of sample error was based on the following assumptions: (i) type 1 error of 0.05 and power of 0.8 were acceptable; (ii) the `water group' and `no water group' would lead to complete abortion rates of 90 and 60% respectively. The sample size in each group should have been 38. Allowing for ~5% of the data not being available for use, the number in each group was 40. Therefore, the total sample size was 80.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients' characteristics are presented in Table IGo. A total of 73 women out of 80 completed the medical treatment. In all, seven women in group 2 dropped out of the study and underwent surgical treatment after two doses of misoprostol. No statistically significant differences were obtained when the demographic characteristics were compared between the two groups.


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Table I. Patient characteristics
 
The incidence of side-effects is shown in Table IIGo. No statistically significant differences were obtained for the frequency of any side-effects between the groups. All patients considered that the side-effects were tolerable, transient and decreased gradually after the first day of treatment. Nausea and vomiting were common but were well tolerated. About one-fifth of patients in both groups complained of breast tenderness and half of them complained of fatigue which was probably related to the pregnancy itself. Uterine cramps were the most common problem (75 and 57% in groups 1 and 2 respectively). The analgesia requirement was similar between the two groups (55.8 and 55.3% in groups 1 and 2 respectively). The majority of these patients needed a single dose of oral doloxene. The incidence and intensity of pain did not vary in relation to the treatment group or gestational age. The duration of bleeding was well accepted in all women. The pre- and post-treatment haemoglobin values were comparable between the two groups and there was no significant drop of haemoglobin after treatment. No patient suffered from excessive bleeding or required blood transfusion. The mean time for onset of bleeding was at 6.9 h in group 1 and 4.4 h in group 2.


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Table II. Side-effects during treatment (percentage)
 
The outcome of termination of pregnancy was shown in Table IIIGo. The rates of success were similar in the two groups. In group 1, treatment was successful for 34 of the 40 patients in group 1 who had water added [85%; 95% confidence interval (CI), 70–94%] and for 26 of the 40 patients in group 2 who had no water added (65%; 95% CI, 48–79%; not significant). In early pregnancy (<=7 weeks of gestation), the success rate in group 1 was 94.4% (95% CI, 72–99%) compared with 68.4% (95% CI, 43–87%; not significant) in group 2.


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Table III. Outcome of abortion. Values in parentheses are percentages
 
The cases in which failure occurred were classified (Winikoff, 1996) as follows: (i) method failure: group 1 (n = 6) and group 2 (n = 7) either live pregnancy or missed abortion on day 15 requiring vacuum aspiration, (ii) women's own decision: group 2 (n = 7), changed their decision and opted for vacuum aspiration before completion of medical treatment, (iii) doctor's decision. No women required transfusion or i.v. therapy and none of them had emergency surgery because of excessive pain or bleeding.

Seven women withdrew from the study. They all belonged to group 2, the no water group. Three of them withdrew on day 3 and four of them withdrew on day 5. All of them had suction evacuation with no complication.

The reasons for choosing medical abortion are listed in Table IVGo. It was noticed that worry about risks and complications of surgery was the major reason. Other factors that contributed to the decision making included the possible adverse effect on future pregnancy and the confidence about new medical technology.


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Table IV. Reasons for choosing medical abortion
 
Overall, 40% of the patients would prefer surgical treatment in the future; 60% in this group had experienced treatment failure. The reasons for choosing surgery if necessary, included inconvenience due to repeated visits (n = 15); high failure rate (n = 8); prolonged bleeding (n = 3); uncertainty about the success of medical treatment (n = 1) and pain (n = 1).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A combination of the antiprogestin (mifepristone) and an exogenous prostaglandin given by i.m. injection or intravaginal pessary is a highly effective means of inducing abortion in early pregnancy (Rodger and Baird, 1987; World Health Organization, 1989Go). However, the search for a stable oral prostaglandin preparation has been largely unsuccessful. Misoprostol has greater advantages over other synthetic prostaglandin analogues. It is cheap and stable at room temperature. The drug is readily available. When 200–1000 µg of misoprostol was given 48 h after 200 µg oral mifepristone, complete abortion occurred in 95% of the women (Norman et al., 1991Go) with pregnancy <56 days. However, mifepristone is only available in four countries (France, UK, Sweden and China). This limits the widespread use of this regimen for first trimester medical abortion. Intramuscular or oral methotrexate, followed by misoprostol, has also been shown to be effective in first trimester medical abortion. The success rates range from 83 to 98% (Creinin et al., 1995Go, 1996Go; Hausknecht, 1995Go). However, the methotrexate-related side-effects and the potential teratogenicity in future pregnancy limit its popularity.

The efficacy of vaginal misoprostol alone for first trimester medical abortion varies widely, from 47 to 94% (Creinin et al., 1994; Carbonell et al., 1997Go). The latter group (Carbonell et al., 1997Go) used three doses of 800 µg every 48 h in women with pregnancy length <70 days. He modified the administrative procedure by adding 3 drops of water with misoprostol. The complete abortion rate in his study was 92%, which was comparable to that obtained from using mifepristone together with misoprostol (Normal et al., 1991). However, the size of the study was small and no control group was included. We therefore conducted a randomized trial to evaluate the use of misoprostol (with and without water) in medical abortion up to 9 weeks of gestation.

We showed that there was an apparent but not significant trend towards achieving higher complete abortion rate when water was added to misoprostol in medical abortion up to 9 weeks of pregnancy. However, this did not reach statistical significance and the difference was less than that estimated from previous results (Carbonell et al., 1997Go). With the overall complete abortion rate of 85%, it is probably not a clinically acceptable method even if the addition of water can improve the results. Moreover, the inconvenience of repeated administration of vaginal misoprostol compares unfavourably with the mifepristone–misoprostol regimen. However, the complete abortion rate with addition of water appears reasonable (94%) in pregnancies with menstrual delay of <=7 weeks. Further studies may be worthwhile in this group of women.

All the women who withdrew from the study did so after the second dose of misoprostol. This was probably related to the relatively long treatment protocol. Patients became more anxious and the worry of treatment failure grew if they were not responding after `repeated medication'. From our results, we noted that ~70% in both groups passed the tissue mass after the second dose and a further 10% passed the tissue mass after the third dose. This information is useful in counselling in the future.

There is an increasing awareness among both the general public and the medical profession of the need to incorporate patients' preferences into medical decision making. The acceptability of any method of treatment will influence the degree to which it is used by consumers, with important implications for health care planners (McNeil et al., 1982Go). Therefore, we included the patients' views on acceptability in this study. A similar study had been performed in our department using RU486 and ONO802 in first trimester abortion (Tang et al., 1992). The reasons for patients choosing medical abortion in this study were very similar to those of the previous study. The worry about surgical complications remained the major concern prompting patients to choose a medical rather than a surgical method of abortion. The side-effects produced by misoprostol were minimal, transitory and comparable between the treatment groups. Pain was the most common physical symptom and was well tolerated. There was no difference in the incidence and intensity of pain between treatment groups. In the previous study (Tang et al., 1993Go), 80% of women would have chosen the same medical regimen again in future. In our study, we considered that the acceptability of the misoprostol regimen with or without water was low because 40% of women would not choose this regimen again. This was largely due to the high failure rate and inconvenience related to frequent visits. Overall, about one-fifth of the patients commented that the frequency of visits was higher than expected. Unacceptable side-effects, including prolonged bleeding and pain, also contributed to the preference for a surgical method in the future, if necessary.

We conclude that the use of misoprostol alone (either with or without water added) is not recommended for medical abortion up to 9 weeks of pregnancy because of the high failure rate and low acceptability by patients. Further study focusing on the medical abortion up to 7 weeks may be worthwhile.


    Notes
 
1 To whom correspondence should be addressed Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bugalho, A., Faundes, A., Jamisse, L. et al. (1996) Evaluation of the effectiveness of vaginal misoprostol to induce first trimester abortion. Contraception, 53, 243–246.[ISI]

Carbonell, J.L.L., Varela, L., Velazco, T. and Fernandez, T. (1997) The use of misoprostol for termination of early pregnancy. Contraception, 55, 165–168.[ISI][Medline]

Creinin, M.D. and Vittighoff, E. (1994) Methotrexate and misoprostol vs misoprostol alone for early abortion. JAMA, 272, 1190–1195.[Abstract]

Creinin, M.D., Vittinghoff, E., Galbraith, S. and Klaisle, C. (1995) A randomized trial comparing misoprostol three and seven days after methotrexate for early abortion. Am. J. Obstet. Gynecol., 173, 1578–1584.[ISI][Medline]

Creinin, M.D., Vittinghoff, E., Keder, L. et al. (1996) Methotrexate and misoprostol for early abortion: a multicenter trial. Safety and efficacy.Contraception, 53, 321–327.[ISI][Medline]

Farell, R.G., Stonington, D.T. and Ridgeway, R.A. (1982) Incomplete and inevitable abortion: treatment by suction curettage in the emergency department. Ann. Emerg. Med., 11, 652–658.[ISI][Medline]

Heisterberg, L., Hebjoin, S., Andersen, L.F. and Petersen, H. (1986) Sequelae of induced first trimester abortion. A prospective study assessing the role of postabortal pelvic inflammatory disease and prophylactic antibiotics. Am. J. Obstet. Gynecol., 155, 76–80.[ISI][Medline]

Hausknecht, R.U. (1995) Methotrexate and misoprostol to terminate early pregnancy. N. Engl. J. Med., 333, 537–540.[Abstract/Free Full Text]

Ho, P.C., Ngai, S.W., Liu, K.L. et al. (1997) Vaginal misoprostol compared with oral misoprostol in termination of second trimester pregnancy. Obstet. Gynecol., 90, 735–738.[Abstract/Free Full Text]

Koopersmith, T.B. and Mishel Jr, D.R. (1996) The use of misoprostol for termination of early pregnancy.Contraception, 53, 237–242.[ISI]

McNeil, B.J., Pauker, S.G., Sox, H.C. and Tversky, A. (1982) On the elicitatation of preferences for alternative therapies. N. Engl. J. Med., 306, 1259–1262.[Abstract]

Ngai, S.W., Tang, O.S. and Lao, T. (1995) Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy. Hum. Reprod., 5, 1220–1222.

Ngai, S.W., Au Yeung, K.C., Lao, T. and Ho, P.C. (1996) Oral misoprostol versus mifepristone for cervical dilatation before vacuum aspiration in first trimester nulliparous pregnancy: a double blind prospective randomized study. Br. J. Obstet. Gynecol., 103, 1120–1123.[ISI][Medline]

Norman, J.E., Thong, K.F. and Baird, D.T. (1991) Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet, 338, 1233–1236.[ISI][Medline]

Roger, M.W. and Baird, D.T. (1987) Induction of therapeutic abortion in early pregnancy with mifepristone in combination with prostaglandin pessary. Lancet, ii, 1415–1418.

Tang, G.W.K., Lau, K.W.O. and Yip, P. (1993) Further acceptability evaluation of RU486 and ONO 802 as abortifacient agents in Chinese population.Contraception, 48, 267–276.[ISI][Medline]

Winikoff, B., Ellertson, C. and Clark, S. (1996) Analysis of failure in medical abortion.Contraception, 54, 323–327.[ISI][Medline]

World Health Organization (1989) Termination of early human pregnancy with RU486 (mifepristone) and the prostaglandin analogue sulprostone: a multicentre, randomized comparison between two treatment regimens. Hum. Reprod., 4, 718–725.[Abstract]

Submitted on September 16, 1999; accepted on February 8, 2000.