Double-blind randomized trial of mifepristone in combination with vaginal gemeprost or misoprostol for induction of abortion up to 63 days gestation

Julia Bartley, Audrey Brown, Rob Elton and David T. Baird,1

Centre for Reproductive Biology, University of Edinburgh, 37 Chalmers Street, Edinburgh EH3 9ET, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Gemeprost and misoprostol are two of the most widely used prostaglandins in combination with mifepristone for medical abortion in early pregnancy. However, the efficacy and side-effects of those two drugs given vaginally have not been assessed in a randomized trial. METHODS: Randomized double-blind controlled trial involving 999 women undergoing an abortion at gestational age <=63 days who received either 0.5 mg gemeprost (group I, n = 499) or 800 µg misoprostol (group II, n = 500) vaginally ~48 h after taking 200 mg mifepristone by mouth. The rate of complete abortion and the side-effects were compared between the groups. RESULTS: A total of 89 cases was excluded from full analysis of outcome because either they aborted after mifepristone alone (n = 2), had an ectopic pregnancy (n = 1), or because the outcome was uncertain as they failed to attend their follow-up appointment (n = 86). The rate of complete abortion was very high (>95%) in both groups but significantly higher after treatment with misoprostol than with gemeprost [436/453 (98.7%) versus 451/457 (96.2%), P = 0.019, difference 2.5%, confidence interval 0.4–4.7%] and there were fewer ongoing pregnancies (n = 1 versus n = 8, P < 0.018). Surgical intervention rose significantly with gestation in women who received gemeprost (P < 0.03) but not with misoprostol. The incidence of side-effects such as diarrhoea (13.7 versus 16.4%) and vomiting (27.8 versus 29.7%) was similar in women who received misoprostol or gemeprost respectively, as was the duration and amount of bleeding. CONCLUSIONS: (i) Both regimens using a reduced dose of mifepristone are highly effective methods of inducing abortion in early pregnancy; (ii) vaginal misoprostol is the preferred prostaglandin because it is it is associated with fewer failures than low-dose gemeprost, particularly at gestation 49 days.

Key words: gemeprost/medical abortion/mifepristone/misoprostol


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The combination of the antigestagen, mifepristone, with a suitable prostaglandin is a safe and effective alternative to vacuum aspiration for induction of abortion in early pregnancy up to 63 days of gestation (Ulmann et al., 1992Go). In several European countries it is now the method preferred by the majority of women when given the choice (Bachelot et al., 1992Go; Henshaw et al., 1993Go; Cameron et al., 1996Go). However, neither the optimum doses of the drugs, nor the best prostaglandin has yet been established and even the time between the administration of mifepristone and the prostaglandin is a matter for discussion (Schaff et al., 2000Go). The most widely recommended and registered regime is the combination of 600 mg mifepristone followed 48 h later by 1 mg of the prostaglandin E1 analogue, gemeprost (UK Multicentre Trial, 1990Go). However, several studies have confirmed that the dose of 200 mg mifepristone is equally effective as 600 mg in practice (World Health Organization Task Force, 1993Go; McKinley et al., 1993Go) and this has led several centres to reduce the dose of mifepristone in their regime (Ashok et al., 1998Go; Schaff et al., 1999Go; Bartley et al., 2000Go). Various prostaglandin E1 analogues, such as gemeprost and misoprostol, are used for medical termination in routine clinical practice (Ashok et al., 1998Go; Bartley et al., 2000Go). The administration of prostaglandins is associated with side-effects due to their effect on smooth muscles such as low abdominal pain, diarrhoea, nausea and vomiting and even cardiovascular collapse (Anon, 1991Go; Kruse et al., 2000Go). Therefore it is important to identify the type and dose of prostaglandin, that provides a high efficacy with the lowest possible incidence of side-effects. Previous studies have demonstrated that the incidence of side-effects is much reduced when the recommended dose of gemeprost of 1 mg is halved to 0.5 mg while still maintaining a high efficacy (Roger et al., 1989; Baird et al., 1995Go; Bartley et al., 2000Go). Misoprostol is an alternative prostaglandin E1 analogue widely used in practice with an equivalent efficacy compared with gemeprost (Norman et al., 1991Go; Peyron et al., 1993Go; Ashok et al., 1998Go). Misoprostol could be an attractive alternative to gemeprost, as it is considerably cheaper and unlike gemeprost does not require special transport and storage. Oral misoprostol (2x200 µg tablets) is licensed for use in combination with mifepristone in France and the USA but its use is restricted to pregnancies <49 days because, after that gestation the failure rate increases (Baird et al., 1995Go; Spitz et al., 1998Go). It has been reported that misoprostol is much more effective and is associated with fewer side-effects if the tablets are administered into the vagina rather than orally (El-Rafey et al., 1995).

However, to our knowledge, vaginal gemeprost and misoprostol have never been compared in a prospective randomized trial. This study was designed to compare the clinical efficacy and side-effects of the low-dose regimen of 200 mg mifepristone and 0.5 mg gemeprost with the combination of 200 mg mifepristone and 800 µg misoprostol.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 999 pregnant women (<63 days gestation) were recruited for this study. They were referred by their general practitioner or the local Family Planning Clinics to a gynaecologist in the Royal Infirmary of Edinburgh requesting a medical termination of pregnancy under the conditions of the 1967 Abortion Act (UK). Approval for the study was obtained from the local ethics committee. After a decision had been made to terminate the pregnancy the women were referred to the Medical Abortion Unit where they were given leaflets to read regarding the procedure. The women were subsequently counselled by a member of the nursing staff and informed consent was obtained.

A medical and gynaecological history was taken and careful assessment of gestation was made based on the date of the last menstrual period, date of conception (if known) and pelvic examination. If there was doubt about gestational age, a pelvic ultrasound was performed. Blood was taken for measurement of haemoglobin and the identification of blood group. To Rhesus-negative women, anti-D immunoglobulin was administered following the treatment prior to discharge from hospital. An endocervical swab was taken to screen for chlamydial infection which, if present, was treated with appropriate antibiotics on the day of termination and contact-tracing of partners was arranged.

Prospective subjects for the study had to meet the following criteria listed in a study checklist: aged >=16 years, available for follow-up within 2 weeks and being <=63 days of gestation. Women with a known or suspected ectopic pregnancy, active asthma, liver and renal disease, adrenal insufficiency, anaemia and haemolytic disease of treatment with anticoagulants and who smoked >20 cigarettes per day were excluded from the study.

All women were given 200 mg mifepristone (Mifegyne; Exelgyn, Henley-on-Thames, Oxon, UK) by mouth and were allowed home 10–15 min after swallowing the tablet. Approximately 48 h later they were admitted for the administration of the prostaglandin to the Medical Abortion Unit. The women were randomized to one of two treatment groups by a series of computer-generated random numbers. Group I was treated with 500 µg, i.e. a half pessary gemeprost (Cervagem; Farillon, Romford, Essex, UK), group II received 800 µg, i.e. four 200 µg tablets of misoprostol (Pharmacia Ltd., Milton Keynes, Bucks, UK). Both prostaglandin drugs were placed into the posterior fornix of the vagina; thus the women were unaware as to which treatment they received. Treatment was done by a member of the nursing staff assigned to this duty only and not involved in the care of patients before and after treatment. Thus the information of treatment was withheld from the remaining nursing and medical staff who cared for the women. The treatment codes were only available to the investigators after the completion of the study.

The women stayed in hospital for an observation period of 4–6 h. Analgesia was given as requested: paracetamol, codeine or diamorphine. The frequency of diarrhoea and vomiting was recorded by the nursing staff. All women had a vaginal examination before discharge to determine whether fetal tissue had been expelled. When fetal tissue was passed spontaneously it was identified by nursing staff. The women were discharged home when their clinical condition was satisfactory.

A menstrual calendar was given to the women to record the duration and amount of their bleeding. A follow-up visit was arranged for all women 12–16 days after administration of prostaglandin for review by medical staff. Blood was collected to assess the haemoglobin concentration after treatment. If the women had passed fetal tissue during their observation period in hospital, complete abortion was diagnosed on the basis of the duration and heaviness of bleeding and size of the uterus, determined by bimanual pelvic examination. If fetal tissue had not been identified previously or there was doubt about the outcome, an ultrasound scan of the uterus was carried out additionally. When there was clinical evidence of endometritis or pelvic infections, women were treated with appropriate antibiotics (doxycycline or azithromycin) and were given another appointment for follow-up. The outcome was then classified as `success' for women with complete abortion who did not require surgical evacuation of the uterus or as `failure' for women with incomplete abortion or ongoing pregnancy (fetal heart present at follow-up). The presence of tissue in the uterus as detected by ultrasound scan at follow-up was not regarded as an incomplete abortion requiring surgical evacuation of the uterus unless there was prolonged or heavy bleeding. For those women with incomplete abortion and ongoing pregnancies, evacuation of the uterus by vacuum aspiration was arranged. Women discharged from further follow-up were asked to complete their menstrual record card until the first menstrual period following the abortion and to return the card by post.

Women who failed to attend their follow-up appointment were sent a reminder on two occasions and were asked to return their menstrual record card. If no response was received from the women a questionnaire was sent to the referring doctor.

The data of women and outcome of treatment were summarized and entered into a sample standardized case record form. The data were then coded and transcribed to a database. The power of the study was designed to detect clinically significant differences in either efficacy or side-effects. It was calculated that with at least 360 women in each group the study should have 80% power (P < 0.05) of detecting a difference of 5% in the proportion of women who had a complete abortion, e.g. from 93 to 98%, or diarrhoea/vomiting. Allowing for loss to follow-up of <=20%, 999 women were recruited.

Statistical analysis
Continuous variables are presented as means and SD. Comparisons between groups were made by {chi}2 test or {chi}2 test for trend. 95% confidence interval (CI) was used to compare the failure rate between the two groups. Analysis of co-variance was used to assess changes in pre- and post-treatment haemoglobin.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 999 women were recruited for this study, 499 for group I (gemeprost) and 500 for group II (misoprostol). Three women were excluded from analysis because of the following reasons: two women (group II) aborted after mifepristone alone and were not treated with prostaglandin. One woman (group II) who was treated with misoprostol subsequently was discovered to have an ectopic pregnancy and should not have been entered. Of the remaining 996 women, 86 were excluded from analysis of the outcome as they failed to attend their follow-up appointment and no information was obtained from their referring doctor about their outcome.

Compared with women who did attend their follow-up appointment, these women were younger (26 versus 24 years of age) and more had one or more previous pregnancies (50.9 versus 65.1%, P = 0.012) or medical termination of pregnancy (8.4 versus 17.4%, P = 0.008). The gestational age was not different between those who did or did not attend their follow-up appointment and the number of women who passed products of conception while in hospital was not significantly different (69.9 and 65.1% respectively). We have no records that any of those women had been readmitted to the Royal Infirmary for treatment. An ongoing pregnancy is therefore unlikely to have occurred without our knowledge.

The records of the remaining 910 women were suitable for analysis, 453 of group I and 457 of group II. There was no significant difference between the groups in age, parity, gestation and previous termination of pregnancy (Table IGo). The clinical management of women in both groups was similar: the hours between the administration of mifepristone and the prostaglandin and the percentage of women who passed fetal tissue during their observation time in hospital were not significantly different. However, more women who had misoprostol had a pre-treatment ultrasound scan (41.7 versus 48.1%, P = 0.042) (Table IIGo).


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Table I. Characteristics of women undergoing termination of pregnancy with two treatments
 

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Table II. Clinical management of women undergoing medical abortion
 
Outcome of treatment
In both groups a similar number of women passed fetal tissue during their observation time of 4–6 h in hospital (69.3% group I, 69.6% group II). However, the rate of complete abortion was significantly higher after treatment with misoprostol than with gemeprost (98.7 versus 96.2% respectively, P = 0.019, difference 2.5%, CI 0.4–4.7%) (Table IIIGo). Both incomplete abortion and ongoing pregnancies were more frequent in the women who received gemeprost than in those who received misoprostol. However, the difference between the groups was only significant for ongoing pregnancies (eight versus one, P = 0.018) but not for incomplete abortions (nine versus five) (Table IIIGo).


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Table III. Outcome of medical abortion by treatment and gestation
 
The outcome was separately analysed by weeks of gestation. Gestational age was found to be related to the outcome in both groups. For gemeprost the surgical intervention rate (`failure') was higher at gestation >49 days compared with <=49 days (5.5 versus 2.4%, P = 0.086) but significantly higher only at gestation >56 days compared with <=56 days (10.0 versus 3.1%, not significant). A similar trend was seen in women treated with misoprostol, with a higher surgical intervention rate at gestation of >49 days compared with <=49 days (2.2 versus 0.4%, not significant) and at >56 days compared with <=56 days (3.5 versus 1.0%, P = 0.120). However, due to the overall low failure rate in this group, it did not reach statistical significance.

Parity was also related to the outcome with parous women having more incomplete/ongoing pregnancies than nulliparous women (3.2 versus 1.8%), although this was statistically insignificant for both groups (P = 0.164, not significant).

Side-effects and complications
During the observation period, a minority of women experienced gastrointestinal side-effects. There was no significant difference in the percentage of women who had at least one episode of diarrhoea (16.4% group I versus 13.7% group II, not significant) or vomiting (29.7% group I versus 27.8% group II, not significant) between the groups. However, significantly more women who received gemeprost had repeated episodes of diarrhoea (6.4 versus 2.4%, P = 0.002) and vomiting (15.6 versus 10.5%, P = 0.016) than those who received misprostol. The intensity of pain seemed to be similar in both groups, as painkillers requested were very similar for both treatment groups (Table IVGo).


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Table IV. Requests for analgesia in women during medical abortion with two treatments
 
Women bled for a median of 14 days after the abortion with a very large range (2–77 days). There was no significant difference in the duration or amount of bleeding between the treatment groups (Table VGo). The majority of women reported that the bleeding was more (42.3 and 41.8%) or much more (31.0 and 27.3%) than their normal menses. However, slightly more women were classified as having a `haemorrhage' (>500 ml) after treatment with gemeprost than with misoprostol (1.5 versus 0.4%). Consistent with this observation is the finding that there had been a small but statistically insignificant fall in the concentration of haemoglobin before and at 2 weeks after abortion (0.2 g/l group I versus 0.3 g/l group II; analysis of variance, not significant). One woman in each group required a blood transfusion.


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Table V. Bleeding after medical abortion with two treatmentsa
 
Chlamydia was isolated from 8.4 and 8.3% asymptomatic women in groups I and II respectively and they were treated with appropriate antibiotics. Endometritis was diagnosed clinically in a similar percentage of women in both groups (5.7% group I, 5.5% group II). Antibiotics were prescribed to a similar number of women in both groups for endometritis or for prophylaxis due to small retained products of conception (9.9% group I, 9.8% group II).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The overall efficacy in both groups (96.2 and 98.7% complete abortion for gemeprost and misoprostol respectively) was as high or higher than similar studies using larger doses of mifepristone, e.g. 600 mg in combination with gemeprost (Urquhart et al., 1997Go), sulprostone (Ulmann et al., 1992Go), or vaginal misoprostol (El-Refaey et al., 1995Go). This study confirms that the dose of mifepristone can safely be lowered from 600 to 200 mg without loss of efficacy (McKinlay et al., 1993; World Health Organization Task Force, 1993Go).

The efficacy of misoprostol was superior to that of gemeprost at all gestations. Of particular clinical significance is the fact that only a single woman (63 days gestation) had an ongoing pregnancy in group II. Although the overall incidence of complete abortion is acceptable in women receiving 500 µg gemeprost (96.2%), the number of failures at gestation >56 days (10%) is of particular concern because of the risk of fetal abnormalities in ongoing pregnancies in women who have received prostaglandin as well as mifepristone for attempted medical abortion (Sitruk-Ware et al., 1998Go). The number of ongoing pregnancies at gestation >56 days could probably be reduced to <1% by increasing the dose of gemeprost to the licenced dose of 1 mg but at the cost of an increase in side-effects (UK Multicentre Trial, 1990Go; World Health Organization Task Force, 1993Go).

This is the first randomized trial to compare vaginal prostaglandins for medical abortions. The execution of the trial was not totally `double blind' because it was not possible to `blind' all the clinical staff throughout the study. In many women, remnants of the misoprostol tablets were identifiable in the vagina at the time of pelvic examination prior to discharge from the Unit. However, we think it is unlikely that this knowledge would influence the recording of diarrhoea, vomiting and pain, which had occurred before this point. Moreover, the research staff responsible for making the decision as to whether the abortion was complete or not at the follow-up visit were unaware of the treatment group. The women themselves were ignorant of the group to which they had been assigned and hence we think it unlikely that the sub-optimal mechanism for obscuring the treatment from the staff would significantly bias the main endpoints.

Many of the side-effects associated with medical abortion relate to the effects of prostaglandins on smooth muscle throughout the body. The frequency of side-effects is related to the dose of prostaglandin as well as its route of administration. Oral misoprostol is associated with a relatively high incidence of nausea and vomiting when compared with the same dose administered vaginally (El Rafey et al., 1995). In this study, the incidence of recurrent diarrhoea and vomiting was lower in women who received misoprostol than in those who received gemeprost, despite the fact that the latter received half the licensed dose. The low incidence of diarrhoea with vaginal compared with oral or systemic routes probably relates to the pharmacokinetics of vaginal preparations which are characterized by a lower peak concentration than that found following injection or oral ingestion (Zieman et al., 1997Go; Gemzell-Danielson et al., 1999).

Misoprostol is formulated in 200 µg oral tablets and licensed for the prevention and treatment of peptic ulcer. Oral misoprostol induces contraction of the uterus in early pregnancy, an effect which is amplified by pre-treatment with mifepristone (Norman et al., 1991Go). Although Searle (the company responsible for its manufacture and marketing) are opposed to the use of misoprostol for induction of abortion (Downie, 1991Go), it is licensed in France and the USA for this purpose at a dose of 400 µg. However, its use orally is restricted to very early pregnancy (<=49 days) because beyond this gestation the incidence of failures is too high to be clinically acceptable (Baird et al., 1995Go; Spitz et al., 1998Go). This study has confirmed that 800 µg misoprostol vaginally in combination with 200 mg mifepristone is very effective up to 63 days gestation (Ashok et al., 1998Go). This may be due to a significantly higher bioavailability following the vaginal administration of misoprostol in comparison with oral administration (Zieman et al., 1997Go).

Both regimes were associated with a highly variable amount and duration of vaginal bleeding. Heavy loss in the hours following the prostaglandin was a rare event (<1%) and only two women required blood transfusion. Nevertheless these complications do emphasize the requirement for access to facilities for resuscitation and treatment of potentially serious complications.

Minor complications such as suspected endometritis occurred infrequently. A policy of prophylactic prescription of antibiotics for those women found to be carrying Chlamydia prior to abortion and relatively low threshold for treatment of women with clinical symptoms during follow-up resulted in a very low incidence of proven pelvic infection.

In conclusion, this double-blind randomized study has demonstrated that vaginal misoprostol (4x200 µg tablets) is superior to 500 µg gemeprost (half-pessary) for induction of abortion in early pregnancy. Misoprostol, unlike gemeprost, is stable at room temperature and is much cheaper. Although the tablets are not formulated for the vaginal route, clinical experience of their efficacy and safety is increasing due to widespread `off label' use. Because a high clinical efficacy is associated with a low incidence of gastrointestinal side-effects, vaginal misoprostol is the preferred prostaglandin used for inducing abortion up to 63 days amenorrhoea. At gestation <=49 days, oral misoprostol or vaginal gemeprost (0.5–1.0 mg) are useful alternatives but may have a higher incidence of side-effects.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We would like to thank the staff of the Medical Abortion Unit, Simpson Memorial Maternity Unit, Royal Infirmary, Edinburgh for their help in the recruitment and management of the patients.


    Notes
 
1 To whom correspondence should be addressed. E-mail: dtbaird{at}ed.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on February 22, 2001; accepted on July 9, 2001.