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Hum. Reprod. Advance Access originally published online on December 1, 2008
Human Reproduction 2009 24(2):320-324; doi:10.1093/humrep/den425
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A randomized trial to compare two dosing intervals of misoprostol following mifepristone administration in second trimester medical abortion

J. Chai1, O.S. Tang1, Q.Q. Hong1, Q.F. Chen2, L.N. Cheng2, E. Ng1 and P.C. Ho1,3

1 Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong Special Administrative Region, China 2 Shanghai Institute of Family Planning, Technical Instruction, Shanghai, China

3 Correspondence address. E-mail: pcho{at}hkusua.hku.hk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 References
 
BACKGROUND: The conventional timing of misoprostol administration after mifepristone for second trimester medical abortion is 36–48 h, but simultaneous administration, which may make the regimen more convenient, has not been studied. The objective of this randomized comparison study is to compare two intervals of administration of misoprostol after pretreatment with mifepristone for second trimester medical abortion.

METHODS: Eligible women with gestational age between 12 and 20 weeks were randomized to receive mifepristone 200 mg orally followed by 600 µg misoprostol vaginally either immediately or 36–38 h later, followed by 400 µg vaginal misoprostol every 3 h for a maximum of four doses. The primary outcome measure was the success rate at 24 h after the start of misoprostol treatment and the secondary outcome measures were the induction-to-abortion interval and the frequency of side effects.

RESULTS: There was a significant difference in the success rate at 24 h (36–38 h: 100%; immediate: 91.5%). The median induction-to-abortion interval was significantly shorter in the 36–38 h regimen (4.9 h) compared with the immediate regimen (10 h). Side effects in terms of febrile episodes and chills/rigors were significantly higher in the immediate administration group.

CONCLUSIONS: Simultaneous use of mifepristone and misoprostol for second trimester medical abortion is not as effective as the regimen using a 36–38 h dosing interval.

Key words: mifepristone/misoprostol/second trimester medical abortion


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Funding
 References
 
Misoprostol with or without mifepristone is one of the commonly used regimens for medical termination of pregnancy in the second trimester. It has been demonstrated that pretreatment with mifepristone enhances the stimulatory effect of misoprostol on uterine muscle, resulting in increased amplitude and frequency of uterine contractions (Norman et al., 1991Go). Mifepristone can shorten the induction-to- abortion interval and reduce the amount of prostaglandins required if it is given 36–48 h before prostaglandin administration (Thong and Baird, 1992Go; Ho and Ma, 1995Go), and this interval has consequently been adopted as the regimen for medical abortion.

This 36–48 h dosing interval poses several problems in clinical setting including the increased duration of treatment, the requirement of repeat attendance to hospital for drug administration and the possibility that the woman may change her mind during the time interval between the administration of the two drugs. Some women may abort after the administration of mifepristone but before the administration of misoprostol, which will create inconvenience and anxiety to the patient. Research work continues in this field to establish the optimal dosages and dose intervals for maximal efficacy and minimal adverse effects. A prospective randomized trial (Schaff et al., 2000Go) compared the effectiveness of 800 µg vaginal misoprostol administered 24, 48 or 72 h after 200 mg mifepristone among 2295 women undergoing the first trimester medical abortion, and found that the complete abortion rates were 98, 98 and 96%, respectively. A more recent trial (Creinin et al., 2007Go) randomized 1128 women requesting first trimester termination of pregnancy into misoprostol 800 µg vaginally administered simultaneously with, or 24 h after, mifepristone 200 mg orally, and found that simultaneous use of mifepristone and misoprostol was as effective for abortion when compared with the regimen using a 24-h interval between mifepristone and misoprostol. However, the effectiveness of shortened interval remains controversial as another randomized trial (Guest et al., 2007Go) found that an oral mifepristone dose of 200 mg followed by vaginal misoprostol 800 µg after 6 h was not as effective at achieving a complete abortion when compared with the regimen with a 36–48 h interval between misoprostol and mifepristone in first trimester termination of pregnancy.

It is anticipated that a reduction in the number of hospital visits and in the treatment duration will increase patient satisfaction. A retrospective cohort study (Nilas et al., 2007Go) has been performed to assess whether shortening this mifepristone–misoprostol interval in second trimester termination of pregnancy will affect the efficacy of the regimen, and it found that the time to fetal expulsion was longer in the group with shortened interval. Another retrospective analysis (Heikinheimo et al., 2004Go) also showed that the time from the first dose of misoprostol to abortion was longer in the 1-day interval group than in the standard 2-day interval group. However, the time interval from ingestion of mifepristone to abortion was significantly shorter in the 1-day interval group. It was suggested that both 1-day and 2-day mifepristone–misoprostol intervals are useful in termination of second trimester pregnancy. There is as yet no randomized trial comparing different mifepristone–misoprostol intervals in second trimester medical abortion. We therefore conducted a randomized trial to compare the efficacy of two intervals of administration of misoprostol after pretreatment with mifepristone for second trimester medical termination of pregnancy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Funding
 References
 
The study was an open randomized trial conducted at two centres: Department of Obstetrics and Gynaecology, Queen Mary Hospital (Hong Kong), and the Shanghai Institute of Family Planning, Technical Instruction. It was approved by both the Institutional Review Board of the University of Hong Kong and the Shanghai Institute of Family Planning Technical Instruction. The trial was registered with HKClinicalTrials.com. Written consent was obtained from all participants before participation in the study.

Women presenting to the centres requesting termination of pregnancy were assessed by a gynaecologist. The medical history was reviewed, and a clinical examination including gynaecological and breast examination was performed by the gynaecologist. The research nurse recruited women at the outpatient clinic after they had been seen by the medical staff if the women were found to be suitable. We recruited healthy women aged 18 or older who requested termination of second trimester pregnancy at 12–20 weeks of gestation and were willing to comply with the schedule of follow-up visits. Exclusion criteria included (i) any contraindications to mifepristone, including adrenal disease or steroid-dependent cancer; (ii) any contraindications to misoprostol, including mitral stenosis, glaucoma, sickle cell anaemia, diastolic pressure over 100 mmHg, severe asthma or known allergy to prostaglandin; (iii) history or evidence of thrombo-embolism, severe or recurrent liver disease or pruritus of pregnancy; (iv) a known history of or active medical disease; (v) a history of regular use of prescription drugs; (vi) an intrauterine contraceptive device in utero; (vii) a haemoglobin level <100 g/l or abnormal liver or renal function tests; (viii) breastfeeding or (ix) heavy smoker of more than 20 cigarettes per day. Following recruitment at the outpatient clinic, blood was taken for haemoglobin and liver/renal function tests. An ultrasound examination was performed to verify the duration of pregnancy.

The randomization was done by computer-generated random numbers and the group assignments were put into sealed, opaque envelopes. The randomization envelope was opened by the research nurse after recruitment. The investigating team members and the research nurse responsible for recruitment were not aware of the randomization. The women were randomized into two groups. Women randomized to the conventional dosing group (Group 1) were asked to swallow 200 mg mifepristone (Hua Lian Pharmaceutical Co., Shanghai, China) and returned to hospital 36–38 h later for misoprostol administration, where 600 µg misoprostol (Cytotec; Pfizer, New York, USA) was given vaginally, followed by 400 µg vaginal misoprostol every 3 h for a maximum of four doses. Those women randomized to the immediate dosing group (Group 2) had the procedure started in the hospital, where 200 mg mifepristone was given orally and 600 µg misoprostol was given vaginally simultaneously, followed by 400 µg vaginal misoprostol every 3 h for a maximum of four doses. The side effects, uterine contractions, blood pressure, pulse rate and temperature were recorded every 3 h after misoprostol insertion. Pelvic examination was performed every 3 h before the next dose of misoprostol. The patient was reassessed if abortion had not occurred after 24 h. If there were no signs and symptoms suggestive of imminent abortion, a second course of vaginal misoprostol was given for a maximum of five doses (600 µg for the first dose followed by 400 µg every 3 h for a maximum of four doses). If abortion still did not occur, gemeprost was given to terminate the pregnancy. In the centre in Hong Kong, the products of gestation were examined for completeness of abortion after expulsion of the fetus. If the abortion was incomplete, evacuation of the uterus was performed under general anaesthesia. In the centre in Shanghai, evacuation of the uterus was done in all women after abortion to ensure that the abortion was complete. The woman was discharged 24 h after the abortion if there were no complications. Blood was taken for complete serum analysis before discharge.

The woman was scheduled to return for a follow-up assessment 8 weeks after the abortion, or earlier if medically indicated. At the follow-up clinic, she was asked about the return of menstruation, and development of any complications that required treatment after the abortion. Blood pressure and pulse rate were recorded and a gynaecological examination was performed.

The primary outcome measure was the success rate at 24 h. Success was defined as the expulsion of fetus, irrespective of whether evacuation was necessary because of incomplete abortion. Secondary outcome measures included the difference in the induction-to-abortion interval and the frequency of side effects between two groups. Differences in continuous variables were analysed with Student's t-test for normally distributed data and the Mann–Whitney U tests for skewed data. The analysis and comparison were performed on an intention-to-treat basis.

The difference in success rate at 24 h was used to calculate the sample size required. Pretreatment with mifepristone 36–48 h prior to misoprostol resulted in a success rate of 98% (Ashok et al., 2004Go). The simultaneous use of mifepristone and misoprostol would be considered to be an acceptable alternative if the difference in success rate of the two arms was <6%. Based on the above data, the total number of subjects required was 134 in order to give a power of 80% at a 5% significance level. Assuming a 5% default rate, the total sample required was 140.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Funding
 References
 
Between June 2006 and September 2007, 40 and 102 subjects were recruited from the Hong Kong center and Shanghai center, respectively, giving a total of 142 subjects. One subject from the Shanghai centre was excluded because the ultrasound showed a gestational age of <12 weeks. All 141 women consented to participate in this study, with 71 women allocated to the immediate dosing group, i.e. administration of misoprostol immediately after mifepristone and 70 women were allocated to the conventional dosing group, i.e. misoprostol given at 36–38 h after mifepristone. The final analysis was therefore performed on 71 women allocated to the immediate dosing group and 70 women allocated to the 36–38 h group. In the immediate dosing group, one participant had a protocol violation as she only received 25 mg of mifepristone instead of 200 mg before misoprostol administration by mistake. A participant flow chart is shown in Fig. 1.


Figure 1
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  		Figure 1 Trial profile.

 
The baseline demographics of the two study groups were similar as presented in Table I. The characteristics of the abortion process are shown in Table II. The median induction-to-abortion interval (defined as the interval between the administration of the first dose of prostaglandin and the abortion) was significantly shorter in the conventional dosing group when compared with that of the immediate dosing group (4.9 versus 10.0 h, respectively, P < 0.0001), and the amount of misoprostol required to achieve abortion was also significantly less (1000 versus 1800 µg, respectively, P < 0.0001). Of the 70 women in the conventional dosing group, 69 (98.6%) aborted within 12 h of misoprostol administration, whereas only 73.2% of women in the immediate dosing group aborted within the first 12 h (P < 0.0001). The difference in abortion rate between the conventional dosing group and the immediate dosing group remained statistically significant for up to 24 h after first dose of misoprostol administration (100 versus 91.5%, respectively, P = 0.028). All women except one in the immediate dosing group aborted within 48 h. The cumulative rate of abortions after misoprostol given on the same day and after misoprostol given at 36–38 h is shown in Fig. 2.


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  		Table I Baseline demographics of the study population

 

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  		Table II Abortion outcomes after misoprostol given immediately or after misoprostol given at 36–38 h after mifepristone

 

Figure 2
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  		Figure 2 Cumulative rate of abortions in the two groups of women with different mifepristone–misoprostol intervals (a) immediate (b) 36–38 h.

 
The incidence of complaints after the administration of prostaglandins is shown in Table III. The incidence of nausea, dizziness, fatigue, breast tenderness, headache, diarrhoea and need for analgesia was not significantly different between the two groups. However, the percentage of women with chills (59.2 versus 40.0%, respectively, P = 0.023) and documented febrile episodes (73.2 versus 34.3%, respectively, P ≤ 0.0001) were significantly higher in the immediate dosing group when compared with the conventional dosing group.


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  		Table III Incidence of side effects after prostaglandin administration

 
Six patients from Hong Kong centre (five from the immediate dosing group and one from the conventional dosing group) required suction evacuation of the uterus for retained placenta before discharge from the hospital. All patients from Shanghai centre had dilatation and curettage the day following abortion, as it was the routine practice in that hospital. None were re-admitted for retained products of gestation. There was no significant difference in the haemoglobin levels before and after termination of pregnancy between the two groups. No blood transfusion was required. The overall follow-up rate at 8 weeks post-procedure from the two centres was ~60%. Of those who attended follow-up, one woman from the immediate dosing group required antibiotics for presumed pelvic infection.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Funding
 References
 
A regimen that requires misoprostol to be given 36–48 h after mifepristone creates scheduling and additional cost barriers to women. A review article by Schaff (2006Go) identified five studies that evaluated shorter intervals between mifepristone and either misoprostol or gemeprost from 6 to 8 h to the usual 48 h in first trimester medical termination of pregnancy, and concluded that the interval between mifepristone and misoprostol can be decreased from 48 to 6–8 h without loss of efficacy. Creinin et al. (2007)Go demonstrated that simultaneous administration of mifepristone and vaginal misoprostol is at least as effective as administration of the medications 24 h apart.

This is the first randomized study comparing two intervals of administration of misoprostol after pretreatment with mifepristone for second trimester abortion. Our results showed that the success rate of medical termination of pregnancy at 24 h with 200 mg oral mifepristone followed by vaginal misoprostol was significantly lower with the simultaneous regimen compared with that of the 36–38 h regimen. The simultaneous use of mifepristone and misoprostol was associated with a longer induction-to-abortion interval and a higher requirement of misoprostol. It was also associated with more side effects in terms of febrile episodes and chill and rigors, which were typical side effects of misoprostol. The increase in incidence of these side effects was probably due to the increase in the total amount of misoprostol required to induce abortion in the simultaneous administration group.

The effectiveness of the 36–38 h regimen in our study was similar to those previously published for this regimen, inferring external validity. Ashok et al. (2004)Go reviewed 1002 women undergoing medical abortion using oral mifepristone 200 mg followed by 800 µg vaginal misoprostol at 36–48 h later, and then 400 mg oral misoprostol at 3-h intervals to a maximum of four doses. The result showed that 91.5 and 98.3% aborted within 12 and 24 h of prostaglandin administration, respectively. In our study, 98.6% aborted within 12 h and 100% within 24 h. Additionally, the median induction-to-abortion interval (4.9 h) was shorter in our study than in the one reported by Ashok et al. (6.25 h).

One limitation of this study is that a significant number of participants failed to attend the follow-up assessment visit at 8 weeks post procedure. This may potentially have an impact on the delayed complications rates; however, it would not affect the primary outcome of this study, which was defined as the success rate at 24 h. Determination of complete abortion rate without the need of suction evacuation was not feasible in our study due to the low follow-up rate and the fact that women in Shanghai centre routinely received dilatation and curettage following medical abortion.

A simultaneous regimen for the administration of mifepristone and misoprostol for second trimester termination of pregnancy has the potential to minimize hospital visits, shorten the duration of procedure and reduce women's anxiety. Unfortunately, our results suggested that this regimen was not as effective as the routine regimen of 36–38 h interval with the success rate at 24 h of 91.5% only as compared with 100%. A delay of 36–38 h before misoprostol is given may be clinically inconvenient for the woman, but it pays off by reducing the induction-to-abortion interval and the dosage of misoprostol required significantly. Abdominal cramps, fever and chills usually develop after administration of misoprostol. By requiring less misoprostol and shortening the induction-to-abortion interval, women will experience less adverse effects. Our findings do not support the simultaneous use of mifepristone and misoprostol for second trimester medical abortion, in contrast to the results reported by Creinin et al. (2007)Go for first trimester medical abortion. One possible explanation for the difference was that misoprostol alone was highly effective to induce abortion in early pregnancy with a success rate of 90% (Faundes et al., 2007Go) and hence the beneficial effect of increasing the mifepristone–misoprostol interval may not be so obvious. Moreover, the results of Guest et al. (2007Go) were different from these of Creinin et al. (2007)Go. The actions of mifepristone on the pregnant uterus were believed to take effect over 24 h after ingestion of the medication (Mahajan and London, 1997Go) and the effect was further pronounced after 36–48 h (Swahn and Bygdeman, 1988Go); whether gestational age has an impact on the actions of mifepristone remains uncertain.

Mifepristone is not available in many developing countries and it is expensive in some of the countries. The use of mifepristone will increase the cost of the medical abortion. If it is to be used, our study supports pretreatment with mifepristone 36–38 h before, instead of simultaneous use with misoprostol.


   Funding
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
References
 
This research was funded by the Committee on Research and Conference Grants of University of Hong Kong.

Trial registration: HKCTR-121


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 References
 
Ashok PW, Templetn A, Wagaarachchi PT, Flett GMM. Midtrimester medical termination of pregnancy: a review of 1002 consecutive cases. Contraception (2004) 69:51–58.[CrossRef][Web of Science][Medline]

Creinin MD, Schreiber CA, Bednarek P, Lintu H, Wagner MS, Meyn LA. Mifepristone and misoprostol administered simultaneously versus 24 hours apart for abortion. Obstet Gynaecol (2007) 109:885–894.[CrossRef][Web of Science][Medline]

Faundes A, Fiala C, Tang OS, Velasco A. Misoprostol for termination of pregnancy up to 12 completed weeks of pregnancy. Int J Gynecol Obstet (2007) 99:S172–S177.

Heikinheimo O, Suhonen S, Haukkamaa M. One- and 2-day mifepristone-misoprostol intervals are both effective in medical termination of second-trimester pregnancy. Reprod Biomed Online (2004) 8:236–239.[Web of Science][Medline]

Ho PC, Ma HK. Termination of second trimester pregnancy with sulprostone and mifepristone: a randomized double-blind placebo-controlled trial. Contraception (1993) 47:123–129.[Medline]

Guest J, Chien PFW, Thomson MAR, Kosseim ML. Randomised controlled trial comparing the efficacy of same-day administration of mifepristone and misoprostol for termination of pregnancy with the standard 36 to 48 hour protocol. BJOG (2007) 114:207–215.[Medline]

Mahajan DK, London SN. Mifepristone (RU486): a review. Fertil Steril (1997) 86:967–976.

Nilas L, Glavind-Kristensen M, Vejborg T, Knudsen UB. One or two day mifepristone-misoprostol interval for second trimester abortion. Acta Obstet Gynecol Scand (2007) 86:1117–1121.[Medline]

Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet (1991) 338:1233–1236.[CrossRef][Web of Science][Medline]

Schaff EA. Evidence for shortening the time interval of prostaglandin after mifepristone for medical abortion. Contraception (2006) 74:42–44.[Medline]

Schaff EA, Fielding SL, Westhof C, Ellertson C, Eisinger SH, Stadius LS, Fuller L. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion. JAMA (2000) 284:1948–1953.[Abstract/Free Full Text]

Swahn ML, Bygdeman M. The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin. BJOG (1988) 95:126–134.

Thong KJ, Baird DT. A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy. Contraception (1992) 46:11–17.[CrossRef][Web of Science][Medline]

Wong KS, Ngai CSW, Yeo ELK, Tang LCH. A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial. Hum Reprod (2000) 15:709–712.[Abstract/Free Full Text]

Submitted on September 26, 2008; resubmitted on October 30, 2008; accepted on November 4, 2008.


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This Article
Right arrow Abstract Freely available
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