study, however, refute such an assumption. A non-competitive anti-oestrogenic action of anti-progestogen on the endometrium has been described in animal ...
Human Reproduction vol.14 no.3 pp.722–725, 1999
A randomized double-blind placebo-controlled study to assess the effect of oral contraceptive pills on the outcome of medical abortion with mifepristone and misoprostol Oi Shan Tang1,3, Pei Pei Gao2, Linan Cheng2, Sharon W.H.Lee1 and Pak Chung Ho1 1Department
of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, China and 2Shanghai Institute of Family Planning Technical Instruction, International Peace Maternity and Child Health Hospital, China Welfare Institute, Shanghai, People’s Republic of China
3To
whom correspondence should be addressed
This was a randomized double-blind placebo-controlled trial to determine the effect of oral contraceptive (OC) pills taken immediately after medical abortion on the duration of bleeding and complete abortion rate. Two hundred women in the first 49 days of pregnancy were given 200 mg mifepristone orally followed by 400 µg misoprostol vaginally 48 h later. One day later, they were randomized to receive either OC pills (30 µg of ethinyl oestradiol and 0.15 mg of levonorgestrel per tablet) or placebo for 21 days. The complete abortion rates were 98% in the OC group and 99% in the placebo group. The median duration of bleeding was similar: 17 (range: 5–57) days in the OC group and 16 (range: 6–55) days in the placebo group. In the OC group there was a small but significant fall in the haemoglobin concentration by 14 days (5.3 g/dl) after administration of mifepristone. The incidence of side-effects was similar in the two groups. We conclude that the use of OC pills does not decrease the duration of bleeding after medical abortion nor does it affect the abortion rate. Key words: mifepristone/misoprostol/oral contraceptive pills/ post-abortion bleeding
Introduction The combination of mifepristone and a prostaglandin analogue has been shown to be an effective and safe method of termination of early pregnancy (UK Multicentre Trial, 1990; Norman et al., 1991; WHO, 1993; Baird et al., 1995). However, the amount of bleeding in women undergoing medical abortion was significantly greater than that in women undergoing vacuum aspiration (Chan et al., 1993). The prolonged bleeding after medical abortion is one of the features that was of concern to the women (Tang et al., 1993). Combined oral contraceptive pills (OC) containing 30 µg of ethinyl oestradiol and 0.15 mg of levonorgestrel have been used for treatment of dysfunctional uterine bleeding for a long time. It is possible that the use of these combined OC pills may decrease the duration of bleeding in the post-abortion period following treatment with mifepri722
stone and misoprostol. The second possible benefit of the use of combined OC pills before the return of the menstrual periods is that the method offers effective protection against an unwanted pregnancy. Therefore, it was the aim of this project to study the effect of the early use of combined OC pills on vaginal bleeding after medical abortion with mifepristone and misoprostol.
Materials and methods A total of 200 pregnant women with a menstrual delay of ø21 days was recruited in Hong Kong and Shanghai (100 subjects in each centre) from among women requesting legal termination of pregnancy. If the size of the uterus on physical examination was not compatible with gestational age, an ultrasound examination was performed for confirmation. Women were given 200 mg of mifepristone as a tablet which they had to swallow in the presence of the medical or nursing staff. At 48 h after mifepristone (Mifegyne; Roussel UCLAF, Romainville, France) the women were admitted to the hospital and vaginal misoprostol (Cytotec; Searle Pharmaceutical, Skokie, IL, USA) 400 µg was given. Blood was taken for haemoglobin before the administration of vaginal misoprostol. They stayed in the hospital for 4 h, and blood pressure and pulse were recorded hourly. Vaginal examination was done at the end of the 4-hour observation. The women were randomized into two groups using a computer-generated random table. In group 1, the OC pills (containing 30 µg of ethinyl oestradiol and 0.15 mg of levonorgestrel per tablet) were started 1 day after the administration of misoprostol daily for 21 days. In group 2, the placebo tablets were started 1 day after the administration of misoprostol every day for 21 days. The study was a double blind placebo-controlled trial. The randomization schedule, the preparation and packaging of the OC pills and placebo were done by Gedeon Richter Ltd., (Budapest, Hungary) and they were not known to the investigators. The women were given a diary card to record days and amount of vaginal bleeding (in comparison to usual menstrual periods) and side-effects. The women then came back on day 15 (after mifepristone) and vaginal examination, measurement of blood pressure and pulse, ultrasound of pelvis and haemoglobin level were carried out. If pelvic ultrasound examination showed that there was a live fetus with cardiac activity, suction evacuation would be performed. If pelvic ultrasound examination showed that there was incomplete abortion or missed abortion, the women would be observed unless there was heavy bleeding. The women were followed up again on day 43. The examination and investigations on day 15 were repeated except ultrasound 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 by the investigator during the follow-up visits. The main outcome measures were the complete abortion rate, duration of bleeding, haemoglobin concentration and side-effects. 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 © European Society of Human Reproduction and Embryology
Medical abortion, post-abortion bleeding and oral contraceptives
Table I. Characteristics of the 200 women receiving medical termination of pregnancy (mean 6 SD)
Age (years) Weight (kg) Height (cm) Body mass index (kg/m2) Menstrual delay (days) Women with previous pregnancy (%)
Group 1 OC pills (n 5 100)
Group 2 Placebo (n 5 100)
28.0 6 5.9 52.1 6 7.2 159.8 6 5.4 20.4 6 2.6 12.9 6 4.0 63
28.8 6 5.6 51.9 6 5.5 160.1 6 9.1 20.5 6 4.2 12.6 6 3.8 66
during the interval up to the first menstruation, the outcome was classified as a complete abortion. The protocol was approved by the ethics committees of the participating institutions. Comparisons between the treatment groups were made by the Fisher’s exact test or χ2 test for categorical data and the Student’s t-test for continuous data. P values (two-tailed) of , 0.05 were considered as statistically significant.
Results The two groups of women were comparable in age, weight, height, body mass index, parity and duration of menstrual delay (Table I). In the OC group, 98 women (98%, 95% confidence interval: 92.96–99.76%) had complete abortions, one had an ongoing live pregnancy and one had a missed abortion. In the placebo group, 99 women (99%; 95% confidence interval: 94.55–99.97%) had complete abortions and one had an incomplete abortion. There was no statistically significant difference in the complete abortion rate between the two groups. Elective vacuum aspiration was performed for the two patients with missed abortion and ongoing live pregnancy. For the patient with incomplete abortion in the placebo group, vacuum aspiration was performed electively because she had persistent bleeding and ultrasound examination showed retained products of gestation. The median durations of bleeding in the two groups were similar: 17 days (range: 5–57) in the OC group and 16 days (range: 6–55) in the placebo group. The subjective amount of bleeding was similar in both groups. A total of 53% of women in the OC group described the bleeding as more or much more than their normal menses as compared with 59% in the placebo group. Haemoglobin concentrations were similar in the two groups before the study (122.1 6 9.8 g/l in the OC and 123.5 6 8.7 g/l in the placebo groups). However, there was a small but significant drop in haemoglobin concentration of 5.3 g/dl in the OC group on day 15 so that it was significantly lower than the placebo group (Table II). Thirty (31.3%) women in the OC group had a fall in haemoglobin of more than 10 g/l as compared to 13 (13.4%) women in the control group. The haemoglobin concentration returned to normal by day 43 so that there was no difference between the two groups. Figure 1 shows the symptoms reported by the women before and after termination of pregnancy in both groups. The y axis shows the percentage of women who had the symptoms within the specific time interval. Before termination of pregnancy, women in both groups had a high incidence of pregnancy-
related symptoms such as nausea, vomiting and fatigue. These symptoms disappeared in most women after termination of pregnancy. Lower abdominal pain was common on the day of misoprostol administration in both groups (86% in the OC and 79% in placebo group) probably related to the abortion itself. The number of women who complained of a fainting sensation was similar in both groups and there was no relationship between the fainting sensation and haemoglobin concentration. Overall, there was no statistically significant difference in the incidence of symptoms between the two groups. Discussion The use of a combination of mifepristone and misoprostol has been shown to be an effective method of termination of pregnancy (Norman et al., 1991; Baird et al., 1995) The main advantage is that surgical vacuum aspiration can be avoided. However, prolonged bleeding after medical abortion is one of the problems that is of concern to both the woman and the doctor. The acceptability of medical termination of first trimester pregnancy by mifepristone and prostaglandin was previously studied in our unit. The study showed that about 10% of women found that the prolonged bleeding was a nuisance for them and 8% of the women would not choose the same method next time because of the prolonged bleeding (Chan et al., 1993). Therefore measures to decrease the amount and duration of bleeding can improve the acceptability of medical termination of pregnancy using mifepristone and misoprostol. Combined OC pills containing 30 µg ethinyl oestradiol and 0.15 mg of levonorgestrel are usually started immediately after surgical termination of pregnancy to avoid unwanted pregnancy before the return of menses. Therefore it is important to study its effect on the amount and duration of bleeding in the post-abortion period as well as the complete abortion rate. The complete abortion rates (98–99%) in the current study were high and similar in both groups. This showed that the use of OC pills did not affect the efficacy of medical termination of pregnancy. The incidence of side-effects is the same. The use of OC pills immediately after medical termination did not decrease the duration of bleeding. The subjective amount of bleeding assessed by the women was also similar in both groups. Therefore combined OC pills containing 30 µg ethinyl oestradiol and 0.15 mg of levonorgestrel cannot help to decrease the duration and amount of bleeding after medical abortion. The mechanism of prolonged bleeding after medical abortion is not clear. It may be related to the abortion process itself which usually takes a longer time to complete as compared with surgical abortion. Another possible mechanism is that endometrial proliferation is impaired by mifepristone and misoprostol. There is some evidence in the literature that supports the latter mechanism. Endometrial proliferation is known to be oestradiol dependent and administration of OC pills that contain oestradiol should theoretically result in better endometrial repair after medical abortion. The findings in this study, however, refute such an assumption. A non-competitive anti-oestrogenic action of anti-progestogen on the endometrium has been described in animal models (Wolf et al., 1989; Neulen 723
O.Shan Tang et al.
Table II. The mean 6 SD haemoglobin concentration (g/l) of the women measured at various times before and after medical termination of pregnancy with or without OC pills Group 1 OC pills
On day of mifepristone (day 1) Day 15 Day 43 aSignificantly
Group 2 Placebo
Haemoglobin concentration (g/l)
No. of subjects
Haemoglobin concentration (g/l)
No. of subjects
122.1 6 9.8 116.8 6 10.4a 123.5 6 10.8
96 96 88
123.5 6 8.7 123.1 6 10.0 124.2 6 10.6
97 97 93
different from the level on day 1, P , 0.001.
Figure 1. The side-effects before and after medical termination of pregnancy of the 200 women given either OC pills or placebo for 21 days. j denotes the OC group and u denotes the placebo group. There was no statistically significant difference between the OC group and the control group in the incidence of side-effects (day 15 day of mifepristone administration).
et al., 1990, 1996; Slayden and Brenner, 1994). Mifepristone was found to inhibit the ability of oestradiol to stimulate endometrial regeneration in monkeys (Wolf et al., 1989; Neulen et al., 1996). Since mifepristone does not bind to oestrogen receptors its anti-oestrogenic action is termed non-competitive (Wolf et al., 1989). The oestrogen receptors were found to be increased after pretreatment with anti-progesterone (Neulen et al., 1996). It is postulated that the anti-proliferative activity 724
of the anti-progestogen is due to the over-expression of oestrogen receptors. In this situation, the post-receptor mechanism is not activated (Neulen et al., 1996). This may help to explain why the use of OC pills containing oestradiol is not effective in reducing the bleeding after medical abortion. The role of prostaglandin in this situation is unknown. Another interesting finding in the study is that when we compared the haemoglobin concentration before and 2 weeks
Medical abortion, post-abortion bleeding and oral contraceptives
after the medical termination of pregnancy, we found a small but statistically significant drop in the OC group. The haemoglobin concentration increased again afterwards and there was no difference between the two groups on day 43 showing that the drop might not be clinically significant. The reason for the difference in haemoglobin levels is not known but one possible reason is increased blood loss in the OC group. Drop in haemoglobin level is just an indirect evidence of blood loss. Further study to measure the actual blood loss is required. If blood loss is really found to increase, use of OC pills immediately after medical abortion may affect the action of mifepristone and misoprostol. The findings in this study may affect the choice of contraception after medical abortion. In order to provide immediate and effective contraception, OC pills should be given immediately after misoprostol administration. Nevertheless, if the amount of bleeding is actually more in the OC group, we may need to advise the women not to use OC pills until the bleeding decreases, usually 1–2 weeks after the medical termination of pregnancy. This is especially true in anaemic women. Acknowledgements The study was supported by the Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland. The investigators also acknowledge the support of the Family Planning Association of Hong Kong in the recruitment of subjects in Hong Kong.
References Baird, D.T., 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. Chan, Y.F., Ho, P.C. and Ma, H.K. (1993) Blood loss in termination of early pregnancy by vacuum aspiration and by combination of mifepristone and gemeprost. Contraception, 47, 85–95. Neulen, J., William, R. and Hodgen, G.D. (1990) RU 486 (Mifepristone): induction of dose dependent elevations of estradiol receptor in endometrium from ovariectomized monkeys. J. Clin. Endocrinol. Metab., 71, 1074–1075. Neulen, J., Williams, R.F., Breckwoldt, M. et al. (1996) Non-competitive antioestrogenic actions of progesterone antagonists in primate endometrium: enhancement of oestrogen and proliferative mechanisms. Hum. Reprod., 11, 1533–1537. Norman, J.E., Thong, K.J. and Baird, B.T. (1991) Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet, 338, 1233–1236. Slayden, O.D. and Brenner, R.M. (1994) RU 486 action after estrogen priming in the endometrium and oviducts of rhesus monkeys (Macaca mulatta). J. Clin. Endocrinol. Metab., 78, 440–448. Tang, G.W.K., Lau, O.W.K. and Yip, P. (1993) Further acceptability evaluation of RU486 and ONO802 as abortifacient agents in a Chinese population. Contraception, 48, 267–276. UK Multicentre Trial (1990) The efficacy and tolerance of mifepristone and prostaglandin in first trimester termination of pregnancy. Br. J. Obstet. Gynaecol., 97, 480–486. Wolf, J.P., Ulmann, A., Hsiu, J.G. et al. (1989) Noncompetitive antiestrogenic effect of RU 486 in blocking the estrogen-stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys. Fertil. Steril., 52, 1055–1060. World Health Organization (1993) Termination of pregnancy with reduced doses of mifepristone. Br. Med. J., 307, 532–537. Received on July 27, 1998; accepted on December 9, 1998
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