A prospective randomized study on the measured blood loss in medical termination of early pregnancy by three different misoprostol regimens after pretreatment with mifepristone

Oi Shan Tang1, Sharon W.H. Lee and Pak Chung Ho

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Prolonged vaginal bleeding is a common complaint after medical abortion. The effect of a 1 week course of daily oral misoprostol after medical abortion with mifepristone and misoprostol on the amount of post-abortal blood loss was studied. METHODS: A total of 150 women (gestation <=63 days) were randomized to three groups using computer-generated tables. They received 200 mg oral mifepristone, followed 48 h later by 0.8 mg oral misoprostol and vaginal placebo in group A, and 0.8 mg vaginal misoprostol and oral placebo in groups B and C. In groups A and B, the women continued with oral misoprostol 0.4 mg twice daily on days 4–10, while the women in group C took placebo. The actual blood loss was measured by the alkaline haematin method. RESULTS: No significant difference in the median amount (82.8, 94.7 and 88.5 ml for A, B and C respectively) and duration (16, 15 and 16 days respectively) of vaginal bleeding was observed. The incidence of diarrhoea was significantly higher (66, 55.1 and 12.5% respectively) in the groups with oral misoprostol after abortion. CONCLUSION: A 1 week course of oral misoprostol (0.4 mg twice daily) could not decrease the duration and amount of vaginal bleeding. Further studies with a larger sample size are needed to assess whether the complete abortion rate can be improved with this regimen.

Key words: measured blood loss/mifepristone/misoprostol


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The combination of mifepristone and misoprostol is commonly used for medical termination of pregnancy in early first trimester. Different regimens have been investigated. Mifepristone is usually given 36–48 h before misoprostol, which is given either orally or vaginally. Vaginal misoprostol has been shown to be more effective than oral misoprostol for this purpose (El-Refaey et al., 1995Go). Therefore, 200 mg of oral mifepristone followed 36–48 h later by 800 µg vaginal misoprostol is the recommended regimen with a complete abortion rate of >90% (Baird et al., 1995Go; Ashok et al., 1998Go; Bartley et al., 2001Go). However, there are problems with this regimen. Firstly, misoprostol is licensed for oral use and there has been a study showing that women accept oral better than vaginal misoprostol (Ho et al., 1997Go). Secondly, the abortion process takes a long time to complete when compared with the surgical method and prolonged vaginal bleeding is one of the factors affecting the acceptability of this method of medical abortion (Tang et al., 1993Go). Incomplete abortion is often the reason for the prolonged vaginal bleeding. Misoprostol has been used for management of incomplete abortion (Pang et al., 2001Go). Also, repeated doses of misoprostol seem to increase the efficacy (Weeks and Steward, 1995). It is postulated that the use of additional doses of misoprostol may decrease the incidence of incomplete abortion, and could therefore decrease the amount and duration of vaginal bleeding after medical abortion. A 2 week course of oral misoprostol following mifepristone and vaginal misoprostol has been shown in a pilot study to be well tolerated by women undergoing first trimester medical abortion (Tang et al., 1998Go). The objective of this study was to assess whether the use of oral misoprostol for 1 week after medical abortion can reduce the amount and duration of blood loss. The complete abortion rate and incidence of side-effects were also examined.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 150 pregnant women up to 63 days gestation were recruited from among women requesting legal termination of pregnancy. The study was approved by the ethics committees of the Faculty of Medicine, University of Hong Kong. The inclusion criteria were good general health, intrauterine pregnancy, willing to use the barrier method of contraception until the first menses after termination of pregnancy and haemoglobin level >110 g/l. The exclusion criteria were a significant past or present illness, allergy towards mifepristone or misoprostol, presence of an intrauterine device, a heavy smoker, breast-feeding and contraindication to mifepristone or prostaglandins.

All women had a transvaginal ultrasound examination to confirm the gestational age. Women who were eligible for the study were allocated randomly to one of three treatment groups using a computer-generated random table. The study was a double-blind, placebo-controlled trial. All women received a single dose of 200 mg mifepristone (Mifegyne; Roussel UCLAF, Romainville, France) on day 1 of the study. On day 3, 48 h after the administration of mifepristone, women in group A were administered 0.8 mg misoprostol (Cytotec; Searle Pharmaceutical, Skokie, IL, USA) orally, and placebo tablets vaginally; women in groups B and C were given 0.8 mg of misoprostol vaginally and placebo tablets orally. They stayed in the hospital for 4 h, and blood pressure and pulse rates were recorded hourly. Vaginal examination was performed at the end of the 4 h observation period.

In groups A and B, the women continued with oral misoprostol 0.4 mg twice daily on days 4–10 and the women in group C took placebo tablets (Table IGo). All women were asked to return to the hospital on days 14 and 43 for follow-up. All women were asked to save all the sanitary towels used from day 1 until vaginal bleeding had stopped and to bring them at each follow-up visit. They were given the same brand of sanitary towels so that the results could be standardized. The women were given a diary card to record the days and amount of vaginal bleeding (in comparison with their usual menstrual periods) and any side-effects. The women then returned to the hospital on day 14 (after mifepristone) and vaginal examination, measurement of blood pressure and pulse, ultrasound of pelvis and measurement of haemoglobin level were carried out. An extra sample of venous blood was taken at each visit as the standard for the laboratory to determine the volume of blood loss. If pelvic ultrasound showed the presence of an ongoing pregnancy, vacuum aspiration was arranged. If pelvic ultrasound examination showed that there was an incomplete or missed abortion, the women were observed unless there was heavy bleeding.


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Table I. Regimens received by 150 women for medical abortion
 
The women were followed-up again on day 43. The examination and investigations on day 14 were repeated, except for the ultrasound examination of pelvis which was only performed when it was clinically indicated. The side-effects and duration of bleeding as recorded in the diary card were checked during the follow-up visits. An extra follow-up visit was arranged if the bleeding persisted or menstruation had not yet returned by 67 days after mifepristone. If no emergency or elective curettage was required during the interval up to the first menstruation, the outcome was classified as a complete abortion. The volume of blood loss on the sanitary towels was determined by a previously described method (Newton et al., 1977Go). This procedure is based upon the formation of alkaline haematin after the blood has been extracted from the sanitary pads or plain gauze by an automatic stomacher Lab Blender (Seward Laboratory) for 15 min in 2 l of 5% sodium hydroxide. The optical density at 550 nm of the alkaline haematin was measured by spectrophotometry and compared with that of a known concentration of a sample of the patient’s venous blood.

The primary outcome measure was the total amount of blood loss. The complete abortion rate, haemoglobin level, duration of vaginal bleeding and side-effects of treatment were also studied. The total amount of blood loss was used for calculation of the sample size required. In the literature, the mean measured blood loss in medical abortion was ~130 ml with a SD of 100 ml (Chan et al., 1993Go; Prasad et al., 1995Go). It would be of clinical significance if the use of an additional 1 week course of misoprostol could reduce the amount of blood loss by 50%. Therefore, a sample size of 38 in each group was required to detect such a difference in blood loss. Assuming a 10% default rate, a total of 150 women were required.

SPSS 10.0 for Windows statistical package was used for data analysis. Continuous variables were compared by one-way analysis of variance and post-hoc (Tukey) test for multiple comparison if the data were normally distributed. Kruskal–Wallis test was used if the data were skewed. Kolgoromov–Smirnov test was used to determine the distribution of samples. Paired data were compared by paired t-test. Categorical data were compared by {chi}2-test. A P-value (two-tailed) of < 0.05 was taken as statistically significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Table IIGo shows the demographic characteristics of the 150 women included in this study. There was no difference in the age, gestational age, gravity and parity among the three groups of women. Table IIIGo shows the outcomes of treatment. The complete abortion rate was high and there was no difference among the three groups. There were two on-going pregnancies in group 2 and they were at 56 and 59 days gestation on the day of mifepristone administration. Vacuum aspiration was performed on day 14 for both subjects.


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Table II. Demographic characteristics of the 150 women undergoing first trimester medical abortion (mean ± SD)
 

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Table III. Outcome of the medical abortion in 150 women
 
Blood loss was accurately determined in 116 women (37, 39 and 40 in groups A, B and C respectively). The remaining 34 women were excluded either because they had surgical evacuation before day 43 or they failed to collect all the sanitary towels for analysis. There was no significant difference among the three groups in terms of the amount of blood loss. The duration of vaginal bleeding after medical abortion was also similar in all three groups. There was no significant change in haemoglobin level on day 14 and 43 when compared with the baseline on day 1 in any of the three groups of subjects. The side-effects were compared as shown in Table IVGo. There was a significant increase in the incidence of diarrhoea on day 14 in groups A (66%) and B (55.1%) when compared with group C (12.5%). The other side-effects were comparable in the three groups of subjects. Most subjects (94.5, 92.3 and 95% in groups A, B and C respectively) had a total amount of blood loss <=250 ml (Table VGo).


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Table IV. Side-effects of 150 women undergoing medical abortion. Values are n (%)
 

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Table V. Distribution of the total amount of blood loss in 150 women undergoing medical abortion. All values are n (%)
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Prolonged vaginal bleeding has been a nuisance to both the attending doctor and the woman after medical abortion. It may be mistaken as a sign of method failure leading to unnecessary surgical evacuation. The acceptability of medical abortion may be improved if the duration of bleeding is decreased. Administration of low dose oral contraceptives pills has been tried immediately after medical abortion to decrease the duration and amount of vaginal bleeding. A randomized trial showed that it was not useful in reducing the amount or duration of post-abortal vaginal bleeding (Tang et al., 1999Go). It was postulated that the prolonged vaginal bleeding in medical abortion was very often due to incomplete abortion. Misoprostol has been shown to be effective in medical evacuation for women with incomplete abortion (Pang et al., 2001Go). Repeated doses were usually required in most of the studies reported (Chung et al., 1995Go; Ngai et al., 2001Go; Pang et al., 2001Go). Misoprostol is licensed for oral use and oral misoprostol taken for 2 weeks has been shown to be well tolerated by women after medical abortion (Tang et al., 1998Go). Oral misoprostol is more convenient than vaginal misoprostol, especially if it has to be taken for 1 week after medical abortion. Therefore, we chose to investigate the effects of oral misoprostal in reducing blood loss after medical abortion.

In this study, the incomplete abortion rate was not decreased by an additional 1 week course of misoprostol. There was also no significant difference in the bleeding pattern among the three groups of women. The duration of bleeding was the same for the three groups and was comparable with previous studies in the same population of women (Tang et al., 1999Go). The median amount of blood loss ranged from 83 to 95 ml in the three groups and the findings were comparable with two previous similar studies. Both of these studies used the same alkaline haematin method to measure blood loss as in this study. They reported a median blood loss of 84.1 (Chan et al., 1993Go) and 91.5 ml (Prasad et al., 1995Go). There was no significance difference among the three groups in the amount of blood loss, indicating that an additional 1 week course of oral misoprostol is not effective in reducing the amount of blood loss.

It has been postulated that incomplete abortion accounts for some of the failures of medical abortion and that it also causes the prolonged vaginal bleeding after treatment. Oral misoprostol has been shown to be less effective than vaginal misoprostol when combined with mifepristone in medical termination of pregnancy of <9 weeks gestation (El-Refaey et al., 1995Go). In the present study, the complete abortion rate in group A (oral misoprostol) was comparable with group C (vaginal misoprostol), indicating that the use of an additional 1 week course of misoprostol might have improved the complete abortion rate. However, the use of an additional 1 week course of oral misoprostol could not further improve the complete abortion rate of vaginal misoprostol (group B). The present study did not have enough power to confirm the above findings and a larger sample size is required to assess the difference in complete abortion rate among the three regimens.

In our previous pilot study, 50% of women complained of mild diarrhoea during treatment with misoprostol (Tang et al., 1998Go). This was confirmed in this randomized trial; the incidence of diarrhoea in the two groups taking an additional course of misoprostol was significantly higher than the group without an additional course. The incidence of diarrhoea was also similar to the previous pilot study (55–66%). The other side-effects were similar among the three groups.

In conclusion, an additional 1 week course of oral misoprostol (0.4 mg twice daily) did not decrease the duration and amount of vaginal bleeding after medical abortion. It also increased the side-effects of treatment and therefore is not recommended for the purpose of decreasing the amount of blood loss. A larger sample size is required to assess its effect on the complete abortion rate.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The investigators acknowledge the support of the Family Planning Association of Hong Kong in the recruitment of subjects. This study was supported by the Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland.


    Notes
 
1 To whom correspondence should be addressed: 6/F, Professorial Block, Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Road, Hong Kong SAR, China. E-mail: ostang{at}graduate.hku.hk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Ashok, P.W., Penney, G.C., Flett, G.M.M. and Templeton, A. (1998) An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum. Reprod., 13, 2962–2965.[Abstract/Free Full Text]

Baird, D., Sukcharoen, N. and Thong, K.J. (1995) Randomized trial of misoprostol and cervagem in combination with a reduced dose of mifepristone for induction of abortion. Hum. Reprod., 10, 1521–1527.[Abstract]

Bartley, J., Brown, A., Elton, R. and Baird, D. (2001) Double-blind randomized trial of mifepristone in combination with vaginal gemeprost or misoprostol for induction of abortion up to 63 days gestation. Hum. Reprod., 16, 2098–2102.[Abstract/Free Full Text]

Chan, Y.F., Ho, P.C. and Ma, H.K. (1993) Blood loss in the early pregnancy by vacuum aspiration and by combination of mifepristone and gemeprost. Contraception, 47, 85–95.[ISI][Medline]

Chung, T.K.H., Cheung, L.P., Leung, T.Y., Haines, C.J. and Chang, A.M.Z. (1995) Misoprostol in the management of spontaneous abortion. Br. J. Obstet. Gynaecol., 102, 832–835.[ISI][Medline]

El-Refaey, H., Rajasekar, D., Abdalia, M., Calder, L. and Templeton, A. (1995) Induction of abortion with mifepristone and oral or vaginal misoprostol. N. Eng. J. Med., 332, 983–987.[Abstract/Free Full Text]

Ho, P.C., Ngai, S.W., Liu, K.L., Wong, G.C.Y. and Lee, S.W.H. (1997) Vaginal misoprostol compared with oral misoprostol in termination of second trimester pregnancy. Obstet. Gynaecol., 90, 735–738.[Abstract/Free Full Text]

Newton, J., Barnard, G. and Collins, W. (1977) A rapid method for measuring menstrual blood loss using automatic extraction. Contraception, 16, 269–282.[ISI]

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Submitted on April 15, 2002; accepted on July 1, 2002.