Vaginal misoprostol as medical treatment for first trimester spontaneous miscarriage

Suk Wai Ngai,1, Yik Ming Chan, Oi Shan Tang and Pak Chung Ho

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Misoprostol is effective for cervical priming prior to suction evacuation in first trimester pregnancy termination. This is the first randomized study to compare vaginal misoprostol versus expectant treatment in women presenting with spontaneous miscarriage. METHODS: Sixty women presenting with spontaneous miscarriage were recruited to the study at the Queen Mary Hospital between 1998 and 1999. They were randomized to group 1: misoprostol; and group 2: expectant management. Women in the misoprostol group received vaginal misoprostol 400 µg on days 1, 3 and 5. The expectant group was followed up according to the same schedule. Suction evacuation was performed if there was excessive bleeding or abdominal pain; or if a gestational sac was detected by transvaginal scan on day 15. RESULTS: Fifty-nine women completed the trial. Those who did not require suction evacuation up to the time of return of normal menstruation were considered to be successful. The incidence of side-effects was comparable between the two groups. Three women in the expectant group and one in the misoprostol group underwent emergency suction evacuation because of excessive bleeding. The mean duration of vaginal bleeding was similar for both groups (14.6 days in the misoprostol group versus 15.0 days in the expectant group). The successful rate in the misoprostol group was significantly higher than that of the expectant group (83.3 versus 48.3%, P < 0.05). CONCLUSION: We recommend repeated vaginal misoprostol 400 µg given on days 1, 3 and 5 as a treatment option for women with first trimester spontaneous miscarriage.

Key words: expectant management/misoprostol/randomized trial/spontaneous miscarriage


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Spontaneous miscarriage occurs in about 14–19% of clinical pregnancies (Laferia, 1986Go; Hammerslough, 1992Go). Over the past 50 years, suction evacuation has been the conventional method of treatment. The aim is to evacuate the uterus as soon as possible to decrease the risk of infection. Nowadays, diagnosis of early pregnancy failure is made possible by improvements in ultrasound imaging, which may have resulted in an increase in the number of suction evacuations performed. However, this procedure is not without risks. It may be associated with cervical injury, uterine perforation, pelvic infection and excessive bleeding. The overall complication rate varies between 4 and 10% (Farell et al., 1982Go; Heisterberg et al., 1986Go).

Recently, alternative treatment approaches have been suggested. There is evidence that a substantial proportion of spontaneous miscarriage will resolve spontaneously (Letterie et al., 1991Go). Furthermore, medical treatment using prostaglandin analogues and antiprogesterone have been shown to be effective in the management of spontaneous miscarriage (Henshaw et al., 1993Go; Chung et al., 1995Go; Nielsen and Hahlin, 1995Go). Medical management was also found to be effective and may be able to generate cost savings when compared with surgical management (Huges et al., 1996Go). The need for routine suction evacuation is thus being questioned.

Misoprostol, a synthetic prostaglandin oestrone analogue, has been shown to be effective for cervical priming prior to suction evacuation in first trimester pregnancy terminations (Ngai et al., 1999Go). However, data from randomized trials comparing expectant versus repeated vaginal misoprostol for spontaneous abortion are lacking. We therefore performed a randomized study to investigate its role in the management of first trimester spontaneous miscarriage.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Ethical approval for the study was granted by the Ethics Committee, Queen Mary Hospital, Hong Kong. A total of 60 women with a clinical diagnosis of spontaneous miscarriage were recruited. 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 subsequent medical care. All women satisfied the following criteria: (i) >16 years old; (ii) good past health; (iii) positive pregnancy test; (iv) gestation age <=;12 weeks; (v) ultrasound confirmed the diagnosis of missed miscarriage (Bernard and Cooperberg, 1985Go): (a) intrauterine gestational sac with a mean sac diameter of >=2 cm without fetal pole; (b) presence of fetal pole with no cardiac pulsation; (c) the gestational sac was <2 cm with no interval growth or persistent absence of fetal cardiac pulsation on rescanning 7–10 days later. Incomplete miscarriage was diagnosed with opened endocervical os and ultrasound findings of an endometrial echo showing mixed echogenicity. Exclusion criteria included: (i) severe blood loss; (ii) sepsis; (iii) known allergy to prostaglandins; (iv) transvaginal scan showing thin endometrial echo suggesting complete miscarriage or extrauterine pregnancy.

The randomization table was constructed as described by Meinert (Meinert, 1986Go). The grouping allocation number was put into an opaque envelope that was serially labelled. Each patient, with consent for randomization, was assigned to the latest numbered envelope. Women were randomized into two groups: group 1: misoprostol treatment; group 2: expectant treatment.

Medical treatment
In our previous study, we have shown that the vaginal route was more effective and the incidence of side-effects was lower when compared with the oral route in second trimester termination of pregnancy (Ho et al., 1997Go). Therefore the vaginal route was used in this study. As we were planning a protocol that could be managed in an out-patient setting, side-effects such as excessive vaginal bleeding and gastro-intestinal upset leading to emergency admission should be avoided. Chung et al. (1999) used the daily dose of 1200 µg misoprostol for the management of spontaneous miscarriage (Chung et al., 1999Go). In order to minimize the incidence of side-effects, we decided to use a lower daily dose (400 µg) and give it every other day. The day of diagnosis and recruitment was defined as day 0. On day 1, women were given 400 µg vaginal misoprostol followed by a 4 h clinical observation period (hourly recording of blood pressure, pulse rate and the amount of oral analgesia given) in the day care centre. Expulsion of gestational products, where present, was recorded on the data forms. Side-effects such as nausea, vomiting and abdominal pain were also recorded. Patients were discharged if there was no excessive vaginal bleeding. Emergency suction evacuation was arranged where excessive blood loss or abdominal pain occurred. The decision for emergency suction evacuation was made by the on-call medical officer based on clinical judgement. The amount of blood loss was assessed clinically by the on-call doctor. Objective measurement of blood loss was not done. All women were advised to record and bring the tissue mass back if it was passed at home. Oral analgesia was given and the dosage and frequency of medication taken were recorded. Sexual intercourse was avoided in the following 2 weeks. The same procedure was repeated on day 3 and day 5.

Expectant management
On day 1, women were discharged if there was no excessive vaginal bleeding. They were advised to come back if excessive bleeding was noted. They were then followed up on day 3 and day 5. If they had passed tissue masses, transvaginal ultrasonography was performed to check for retained gestational product.

Outcome assessment
The initial judgement about the outcome was made on day 15. If the ultrasound findings were compatible with a missed miscarriage (identifiable gestational sac without fetal heart activity), suction evacuation was performed and the aspirates were sent for histological examination. If the ultrasound findings were compatible with complete or incomplete miscarriage, no further action was taken. All women were followed up on day 43. If menstruation did not return, an additional follow-up visit was arranged. Those who did not require suction evacuation up to the time of normal menstruation were classified as successful cases. Failure was defined as the recourse to surgical treatment either due to method failure or change of patients' decision. The incidences of side-effects, duration of vaginal bleeding, dosage of analgesic requirement and infection rate between the two groups were also compared. Standardized questionnaires were given to patients during and after the abortion in order to assess patients' acceptability and the incidence of side-effects.

The calculation of the sample size was based on the following assumptions: (i) type 1 error of 0.05 and power of 0.85 were acceptable; (ii) the use of misoprostol would achieve a complete abortion rate of 60% (Chung et al., 1995Go) so that it could be clinically useful as an alternative when compared with surgical intervention. The chance of spontaneous resolution in the expectant group was about 20%. Assuming that 10% of the data were retrospectively excluded due to incomplete data, the number was 29 in each group. Thus, the total required sample size was 58. The differences of discrete variables were analysed by {chi}2 test or Fisher's exact test. The differences of continuous variables were analysed by the Student's t-test for normally distributed data and Mann–Whitney's U-test for skewed data.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 60 women were recruited to this study. One patient in the expectant group was excluded from analysis. This patient was recruited in error because an ultrasound scan showed that the fetal parameter was >13 weeks gestation. She subsequently passed the fetus spontaneously. Patients' characteristics are presented in Table IGo. The percentage of women who had a previous termination of pregnancy was significantly higher in the misoprostol group (46.7 versus 20.0%, P = 0.03). Other demographic characteristics were comparable between the two groups.


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Table I. Patient characteristics
 
The incidences of side-effects were comparable between both groups (Table IIGo). Nausea and vomiting were common but considered as tolerable and transient. The number of women who had no side-effects was similar between the two groups (eight in the misoprostol group versus nine in the expectant group). There was no significant difference between the two groups in the proportion of women having one or more side-effects (73.3% in misoprostol group versus 69.0% in expectant group). Three women in the expectant group and one in the misoprostol group underwent emergency suction evacuation because of excessive bleeding. None of them required blood transfusion.


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Table II. Side-effects during treatment
 
The outcome of treatment is shown in Table IIIGo. The complete abortion rate in the misoprostol group was significantly higher than in the expectant group (83.3 versus 48.3%, P < 0.05). The breakdown of failure cases according to the classification of Winikoff et al. (1996) was as follows: (i) method failure: seven women in the expectant group and two in the misoprostol group; (ii) woman's own decision: five in the expectant group and two in the misoprostol group; (iii) doctor's decision: three in the expectant group and one woman in the misoprostol group had an emergency operation because of excessive bleeding.


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Table III. Outcome of treatment
 
We recruited those presenting with missed miscarriage and incomplete miscarriage because both groups required suction evacuation according to our usual treatment protocol. The chance of the incomplete miscarriage group not requiring suction evacuation was higher than that of the missed miscarriage. The fact that more patients presenting with a missed miscarriage were included in the misoprostol group than the expectant group (83.3 versus 63.3%) suggested that the actual clinical benefit from the former was likely to be larger than that which has been demonstrated by this study.

The mean duration of vaginal bleeding was similar between the two groups (14.6 days in misoprostol group versus 15.0 days in expectant group). For those who required suction evacuation, prophylactic antibiotics were not given. No patient suffered from infection or operative complications. Four women in each group had not menstruated by day 42. Extra follow-up was arranged for these women until normal menstruation returned.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The use of misoprostol for treatment of spontaneous miscarriage is not new. Herabutya and Prasertwawat (1997) showed that 200 µg vaginal misoprostol caused a significant increase in the passage of tissue mass when compared with a placebo (83.3% in misoprostol versus 17.1% in placebo), when given 1 day prior to suction evacuation for missed miscarriage. However, transvaginal scans were not repeated prior to the procedure and therefore the percentage of complete miscarriages induced by misoprostol was not known.

This is the first randomized study comparing repeated doses of vaginal misoprostol with expectant management for first trimester spontaneous miscarriage. Our results showed that outpatient treatment using vaginal misoprostol was more effective when compared with expectant management.

Nielsen et al. (1999) showed that the combination of mifepristone and oral misoprostol was effective for first trimester miscarriage (Nielsen et al., 1999Go). They used 400 mg oral mifepristone followed by a single dose of 400 µg oral misoprostol. A total of 82% of women had an empty uterine cavity after 5 days. However, mifepristone is only available in a few countries. The addition of mifepristone also added to the drug costs of the regimen. We demonstrated that by using vaginal misoprostol alone, the successful rate was comparable with the combination of mifepristone and misoprostol. Patients can have an option of medical treatment where mifepristone is not available.

Chung et al. (1999) had compared oral misoprostol versus surgical treatment in a randomized trial (Chung et al., 1999Go). In their study, women who presented with the clinical diagnosis of spontaneous miscarriage were recruited. Those who presented with ultrasound scan findings showing a choriodecidual reaction measuring <5 cm2 in transverse and <6 cm2 in the sagittal plane were considered to have an empty uterus and were excluded from the trial. In their study, the successful rate of misoprostol treatment was 50.4%. Women treated with misoprostol had significantly more blood loss and required more analgesia when compared with the surgical group. Seven subjects in the misoprostol group failed to complete the protocol because of excessive side-effects. In our study, all women considered the side-effects tolerable and transient. Only one patient in the misoprostol group underwent emergency suction evacuation because of excessive bleeding. Our complete miscarriage rate (83.3%) is also higher. This is probably due to the difference in administration route and the dosage of treatment protocol. They used oral misoprostol 400 µg every 4 h up to a total dose of 1200 µg, whereas in our study, we were using a lower daily dosage (400 µg) vaginally and the repeated medication was given on alternate days.

Although effective, our regimen required additional follow-up visits for drug administration. Patients considered it inconvenient and it was the major reason for withdrawal from the study. The cost was also increased if repeated follow-up was required. An optimal regimen should be acceptable to both health care consumers and providers. We suggest further comparative studies for different dosages and schedule to shorten the treatment regimen and decrease the number of follow-up visits.

In view of the high success rate in the misoprostol group, we support the use of repeated vaginal misoprostol in the management of first-trimester spontaneous miscarriage. Further comparative studies on the dosage and drug treatment interval are needed.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was supported by the Committee on Research and Conference Grants, the University of Hong Kong.


    Notes
 
1 To whom correspondence should be addressed. E-mail: cora{at}hkucc.hku.hk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on August 25, 2000; accepted on March 14, 2001.