The effect of contraceptive pills on the measured blood loss in medical termination of pregnancy by mifepristone and misoprostol: a randomized placebo controlled trial
Oi Shan Tang1,3,
Jieshuang Xu2,
Linan Cheng2,
Sharon W.H. Lee1 and
Pak Chung Ho1
1 Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR and
2 Shanghai Institute of Family Planning Technical Instruction, International Peace Maternity and Child Health Hospital, China Welfare Institute, Shanghai, People's Republic of China
 |
Abstract
|
---|
BACKGROUND: A prospective randomized placebo controlled trial was performed to assess the immediate use of oral contraceptive (OC) on the amount of blood loss in the post-abortion period in women undergoing medical abortion by mifepristone and misoprostol. METHODS: One hundred women were randomized by computer to receive either OC pills or placebo, immediately after medical abortion. RESULTS: There was no difference in the complete abortion rate between the two groups. The complete abortion rate was 98 and 92% in the OC and placebo groups respectively. The side-effects and duration of bleeding were also similar. The median days of vaginal bleeding were 17 (range: 341) and 15 (range: 548) in the OC and placebo groups respectively. There was a statistically significant decrease in the mean haemoglobin level on day 15 in the OC group (from 12.0 to 11.5 g/dl) whereas the mean haemoglobin level in the placebo group remained stable. The median measured blood loss was 69.9 ml in the OC group and 72.8 ml in the placebo group and there was no statistically significant difference between the two groups. CONCLUSION: We conclude that it is safe to offer women combined OC pills immediately after medical abortion as an option of contraception, as it does not affect the duration or amount of vaginal bleeding or the complete abortion rate.
Key words:
measured blood loss/mifepristone/misoprostol/OC pills
 |
Introduction
|
---|
The combination of mifepristone and a prostaglandin analogue has been shown to be an effective and safe method of termination of early pregnancy (El-Refaey et al., 1995
). The use of a reliable contraception in this group of women is obviously important in preventing further unwanted pregnancy. The combined OC (OC) pills are certainly one of the most frequently prescribed forms of contraception in this group of women. OC pills are usually started the day after termination of pregnancy so that contraception is immediately effective. Our previous study on the use of OC pills immediately after termination of pregnancy by mifepristone and misoprostol showed that the complete abortion rate and the duration of vaginal bleeding in the post-abortion period were not affected. However, there was a significant decrease in haemoglobin level of 0.5 g/dl in the women who used OC pills immediately after medical termination of pregnancy (Tang et al., 1999
). The reason for the decrease in haemoglobin level was unknown but it might be related to heavier vaginal bleeding in the group of women using OC pills immediately after medical abortion. It is therefore important to gather information on the amount of bleeding in women using OC pills immediately after medical abortion. If OC pills increase the amount of bleeding, we may have to consider starting their use later or using another form of contraception in this group of women. Therefore, the objective of this study is to find out what effect the immediate use of combined OC pills has on the measured blood loss in medical abortion by mifepristone and misoprostol.
 |
Materials and methods
|
---|
A total of 100 pregnant women with a menstrual delay of up to and including 35 days was recruited in Hong Kong (HK) (n = 50) and Shanghai (SH) (n = 50) from women requesting legal termination of pregnancy. The study was approved by the ethics committees of the participating institutions. The gestational age was confirmed in all women by ultrasound examination. The subjects were randomized into two groups using a computer-generated random table. OC pills were administered after medical abortion for the subjects in group 1 and placebo tablets were used in group 2. All women were given 200 mg of mifepristone (Mifegyne®; Roussel UCLAF, Romainville, France) in the presence of the medical or nursing staff. Forty-eight hours after mifepristone administration, the women were admitted to the hospital and vaginal misoprostol (Cytotec®; Searle Pharmaceutical, Skokie, IL, USA) 400 µg was given. They stayed in the hospital for 4 h, and blood pressure and pulse rates were recorded hourly. Vaginal examination was done at the end of the 4 h observation. 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 administered. The study was a double-blind placebo-controlled trial. All women were asked to save all the sanitary towels used from day 1 till 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 the amount of vaginal bleeding (in comparison to their 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. An extra sample of venous blood was taken at each visit, to be used as the standard for the laboratory determination of blood loss volume (see below). If pelvic ultrasound showed the presence of an ongoing pregnancy, vacuum aspiration would be arranged. 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 the ultrasound examination of the 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. All women were asked to use the barrier method of contraception.
The volume of blood loss on the sanitary towels was determined by the method described by Newton et al. (1977). 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.
According to our previous similar study, the women using OC pills in the post-abortion period had a decrease in haemoglobin of 0.53 g/dl from 12.2 g/dl. Therefore, the blood loss would be estimated to be 195 ml assuming an average blood volume of 4.5 l. In the literature, the mean measured blood loss in medical abortion was about 130 ml with a standard deviation of 100 ml (Chan et al., 1993
; Prasad et al., 1995
). Therefore a total sample size of 90 will have 80% power to detect a difference of 65 ml blood loss between the two groups at a significant level of 5%. Assuming a 10% default rate, 100 women were required.
Statistical analysis
SPSS 7.5 for Windows Statistical Package was used for statistical analysis. Comparison between treatment groups and between outcome categories were made by
2 test, Student's t-test and MannWhitney test as appropriate. Repeated measurements in haemoglobin levels were compared by paired t-test. P values (two-tailed) of < 0.05 were considered as statistically significant.
 |
Results
|
---|
Table I
showed the demographic characteristics of the 100 women. There was no difference between the two groups in age, weight, height and gestational age. The percentages of parous women and those with a history of induced abortion were also similar in the two groups. There was no difference in these demographic characteristics between the two centres. The clinical outcomes were essentially similar to our previous study (Tang et al., 1999
). There was no difference in the complete abortion rate between the two groups. The complete abortion rate was 98 and 92% in the OC and placebo groups respectively (Table II
). The side-effects (Table III
) and duration of bleeding were also similar in the two groups. The median days of vaginal bleeding were 17 and 15 respectively in the OC and placebo groups. No difference was found between the two centres in the amount and duration of blood loss. There was a statistically significant decrease in mean haemoglobin level of 0.5 g/dl on day 15 in the OC group whereas the mean haemoglobin level remained stable in the placebo group. The mean haemoglobin returned to their original levels on day 43 in both groups. The median measured blood loss was 69.9 ml in the OC group and 72.8 ml in the placebo group and there was no statistically significant difference between the two groups. Over 70% of the women had total blood loss less than 100 ml (Table IV
). Two women, one in each group, had blood loss more than 400 ml. The greatest blood loss was found in a subject in the placebo group whose total blood loss was 855 ml. Her haemoglobin level decreased by 2.3 g/dl after 43 days. No transfusion was required in any subject. A total of 76 and 87% of the subjects in the OC and placebo group respectively had a decrease in haemoglobin level of <1 g/dl.
View this table:
[in this window]
[in a new window]
|
Table IV. Distribution of total blood loss and decrease in haemoglobin level in the 100 women undergoing medical abortion
|
|
 |
Discussion
|
---|
The combination of mifepristone and a prostaglandin analogue has been shown to be an effective and safe method of termination of pregnancy (UK Multicentre Trial, 1990
; Norman et al., 1991
; WHO, 1993; Baird et al., 1995
; El-Refaey et al., 1995
). Most studies reported a success rate of over 95%. However, the amount of vaginal bleeding in women undergoing medical abortion was significantly greater than that in women undergoing surgical abortion (Chan et al., 1993
). The prolonged bleeding after medical abortion is a nuisance to many women. It is a concern to many women and may be a factor of not choosing the same method again next time (Tang et al., 1993
). It is also a concern for the attending doctor as prolonged bleeding can be a sign of incomplete abortion and it may lead to unnecessary surgical evacuation. While incomplete abortion is probably the most important factor leading to prolonged bleeding, other factors may also contribute to the increase in blood loss after medical abortion. Very few studies have addressed the problem of post-abortion blood loss in the literature. Our previous study had shown that use of OC pills in the immediate post-abortion period was associated with a significant reduction in haemoglobin level of 0.5 g/dl by 2 weeks after medical abortion. This raised the concern of whether the use of OC pills would increase the amount of vaginal blood loss after medical abortion. The combined OC pill is a convenient and reliable contraceptive method for women after abortion. It is perhaps the commonest contraceptive method prescribed to this group of women to prevent another unwanted pregnancy. Therefore, knowledge of the effect of OC pills on the amount of blood loss in the immediate post-abortion period is very important.
The present study confirmed the findings of the previous study on the effect of immediate use of OC pills in women undergoing medical abortion with mifepristone and misoprostol (Tang et al., 1999
). The use of OC pills does not affect the complete abortion rate and there is no effect on the incidence of side-effects. The finding of a decrease in haemoglobin level of 0.5 g/dl is congruent with the observation made in our previous study. It was hypothesized that this decrease in haemoglobin level was related to an increase in blood loss in women using OC pills in the immediate post-abortion period. This is refuted in the present study. No difference in the median vaginal blood loss was found between women using OC pills or placebo after medical abortion. The amount of measured blood loss agrees with two previous 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 84.1ml (Chan et al., 1993
) and 91.5ml (Prasad et al., 1995
) respectively. The median blood loss was about 70 ml in this study irrespective of whether the subjects used OC pills or not. The mean blood loss was 90.3 ml in the OC and 105.5 ml in the placebo group. This study did not have enough power to detect a difference in 15 ml blood loss in the two groups. However, a difference of 15 ml in blood loss would not be considered as clinically significant and could not explain the change in haemoglobin level.
The decrease in haemoglobin level may be explained by the direct effect of OC on plasma volume. A study in Norway found that the haemoglobin level was reduced by 0.7 g/dl after 3 months and by 0.5 g/dl after 6 months of monophasic OC (desogestrel 0.15 mg and ethinyl estradiol 30 µg) (Tollan et al., 1992
). There was no further decrease in haemoglobin after 6 months. It was suggested that the estrogen component of the OC causes a slight increase in plasma volume due to renal fluid retention. Our findings were slightly different. The haemoglobin level decreased by 0.5 g/dl after 2 weeks and returned to its original level after 6 weeks. This may be due to the racial difference in response to OC pills. The difference may also be due to difference in pregnancy status: in our study, the OC pills were started immediately after abortion whereas in the study by Tollan (Tollan et al., 1992
), the OC pills were given to non-pregnant women.
In conclusion, it is safe to offer women combined OC pills immediately after medical abortion as an option of contraception. The complete abortion rate and incidence of side-effects are not affected. It does not prolong the vaginal bleeding or increase the blood loss.
 |
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.
 |
Notes
|
---|
3 To whom correspondence should be addressed at: 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 
 |
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, 15211527.[Abstract]
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, 8595.[ISI][Medline]
El-Refaey, H., Rajasekar, D., Abdalia, M., Calder, L. and Templeton, A. (1995) Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N. Engl. J. Med., 332, 983987.[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, 269282.[ISI]
Norman, J.E., Thong, K.J. and Baird, D.T. (1991) Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet, 338, 12331236.[ISI][Medline]
Prasad, R.N.V., Choolani, M. and Ratnam, S.S. (1995) Blood loss in termination of early pregnancy with mifepristone and gemeprost. Aust. N.Z. J. Obstet. Gynaecol., 35, 329331.[ISI][Medline]
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, 267276.[ISI][Medline]
Tang, O.S., Gao, P.P., Cheng, L., Lee, S. and Ho, P.C. (1999) A randomized double-blind placebo-controlled study to assess the effect of OC pills on the outcome of medical abortion with mifepristone and misoprostol. Hum. Reprod., 14, 722725.[Abstract/Free Full Text]
Tollan, A., Kvenild, K., Strand, H. et al. (1992) Increased capillary permeability for plasma proteins in OC users. Contraception, 45, 473481.[ISI][Medline]
UK Multicentre Trial (1990) The efficacy and tolerance of mifepristone and prostaglandin in first trimester termination of pregnancy. Br. J. Obstet. Gynaecol., 97, 480486.[ISI][Medline]
World Health Organization (1993) Termination of pregnancy with reduced doses of mifepristone. Br. Med. J., 307, 532537.[ISI][Medline]
Submitted on July 25, 2001;
accepted on September 27, 2001.