A randomised study comparing a low dose of mifepristone and the Yuzpe regimen for emergency contraception

Authors


*Dr P. W. Ashok, Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen Maternity Hospital, Foresterhill, Cornhill Road, Aberdeen AB25 2ZD, UK.

Abstract

Objective To compare 100 mg mifepristone with the standard Yuzpe regimen for emergency contraception.

Design Randomised controlled trial.

Setting Family Planning Clinic, Aberdeen.

Sample One thousand women seeking emergency contraception within 72 hours after an episode of unprotected sexual intercourse.

Methods Women were randomised to receive either 100 mg (half tablet) of mifepristone as a single dose or the Yuzpe regimen (two tablets each with 50 μg ethinyloestradiol and 0.25 mg levonorgestrel, to be repeated 12 hours later).

Outcome measures Crude pregnancy rates, proportion of pregnancies prevented, side effects and patient acceptability.

Results The crude pregnancy rates (95% CI) for the Yuzpe regimen and mifepristone were 3.6% (2.3–5.7) and 0.6% (0.2–1.8), respectively, with a significant difference between the two groups (RR 6.04; 95% CI 1.75–20.75). Mifepristone prevented 92% of pregnancies and the Yuzpe regimen preventing 56%. An increasing coitus to treatment interval was associated with contraceptive failure in the Yuzpe group (P= 0.03) with no association seen with mifepristone. Following administration of mifepristone 24.5% and 13.1% given the Yuzpe regimen had a delayed period (RR 2.14; 95% CI 1.46–3.15). Overall, mifepristone was better tolerated than the Yuzpe regimen with significantly fewer side effects. More women were satisfied (P < 0.0001) with mifepristone as an emergency contraceptive and would recommend it to a friend (P= 0.02).

Conclusion Mifepristone administered in a 100 mg dose is a highly effective post-coital contraceptive with high patient acceptability and fewer side effects compared with the standard Yuzpe regimen. Delay in the onset of menstruation did not decrease patient acceptability.

Introduction

Two randomised controlled studies conducted in the United Kingdom compared a 600 mg dose of mifepristone with the Yuzpe regimen as an emergency contraceptive within 72 hours of coitus1,2. Results combined from these two studies showed that there were three pregnancies among 597 women who received mifepristone and nine pregnancies among 589 women who received the Yuzpe regimen, with no statistically significant difference in crude pregnancy rates between the two groups.

A recent study by WHO has shown that lower doses (10 mg and 50 mg) of mifepristone is as effective as a dose of 600 mg in the context of emergency contraception3. The major side effect with mifepristone was delay in the onset of the next menstrual period which was dose related. Hence WHO recommended a low dose for emergency contraception. However, mifepristone is currently available only as a 200 mg tablet.

The Cochrane Database of Systematic Reviews4 has included nine trials in which mifepristone was used in a 5–600 mg dose for emergency contraception. Due to the large variation in the dose of mifepristone used, the doses were categorised into high (>50 mg) mid (25–50 mg) and low (<25 mg). Six of the nine studies included in the review have been conducted in China using locally manufactured mifepristone, of which four were dose comparison studies. Although a low dose of mifepristone seems to have less side effects, a clear dose-related efficacy was not evident following the systematic review. The only two studies that compared the Yuzpe regimen with mifepristone, used a 600 mg dose if mifepristone and both studies were conducted in the UK1,2.

Mifepristone is an orally active synthetic 19 norsteroid with potent antiprogestional and antiglucocorticoid activity. The effect of mifepristone depends on the timing of administration in relation to the menstrual cycle. Administration in the follicular phase can inhibit or delay ovulation5,6. Given in the early luteal phase it is thought to block the effect of progesterone, preventing the development of secretory endometrium, and inhibiting implantation7–9.

In the United Kingdom until recently the Yuzpe regimen was the only method of oral emergency contraceptive approved by the Committee of Safety of Medicines. However, a study published by WHO showed that the levonorgestrel regimen was more effective and better tolerated than the Yuzpe regimen although efficacy decreased with both regimens if treatment was commenced after 24 hours of unprotected intercourse10.

We undertook a randomised study to assess the efficacy, side effects and patient acceptability of 100 mg mifepristone and the Yuzpe regimen up to 72 hours after intercourse as emergency contraception. Outcome measures included crude pregnancy rates and proportion of pregnancies prevented, side effects and patient acceptability.

Methods

The study was approved by the Grampian Research Ethics Committee and was conducted in a single centre (family planning clinic), in Aberdeen, Scotland between 1998 and 2000. A total of 1000 women were randomised with 500 women in each group. Women were assigned to receive either 100 mg (half tablet) of mifepristone as a single dose or the Yuzpe regimen (two tablets each with 50 μg ethinyloestradiol and 0.25 mg levonorgestrel, to be repeated 12 hours later). Women were randomised into two groups by opening sequentially numbered, sealed opaque envelopes which were prepared using random number tables. The study was not blinded and the clinician and patient were both aware of the treatment allocated since patient acceptability was an outcome measure.

On the basis of menstrual cycle data, women were considered to be treated at mid-cycle (a day before or after ovulation), in the follicular phase (two or more days before ovulation) or in the luteal phase (two or more days after ovulation) of the cycle. Blood was taken at the time of consultation for the measurement of plasma progesterone concentration. Where the possibility of an established pregnancy existed a pregnancy test was performed. A questionnaire was given to each woman to assess side effects in the first two weeks following drug administration as well as women's satisfaction with the method.

Women requesting emergency contraceptives up to 72 hours after a single act of unprotected intercourse were eligible for recruitment if they met the following criteria: 1. women aged 16–45 years; 2. regular menstrual cycles (21–35 days); 3. certain about dates of last menstrual period; 4. those willing to abstain from further acts of unprotected intercourse during the cycle. The exclusion criteria were as follows: 1. women taking oral contraceptives; 2. chronic adrenal failure; 2. long term corticosteroid treatment; 3. those breastfeeding; 4. known allergy or contraindications to mifepristone or oestrogen–progestogen; 5. women certain to continue with the pregnancy should emergency contraception fail; 6. those on hepatic enzyme inducing drugs.

A follow up appointment was made to return to the clinic within a week of the expected next menstrual period. Those unable to attend this visit were given a stamped addressed envelope to return the questionnaire and advised to inform the clinic of their last menstrual period. At the follow up visit the questionnaire was collected and period details noted. If menstrual bleeding had not occurred a pregnancy test was done and a further follow up appointment made a week later with additional follow up visits weekly until the woman had a period. If the pregnancy test was positive a dating scan was performed and various options including termination of pregnancy were discussed.

Attempts were made to contact women who failed to attend follow up or return the questionnaire. Hospital records (gynaecology, antenatal and general) of those who could not be contacted and lost to follow up were searched to exclude pregnancy. Grampian University Hospital is the only referral hospital for a 50-mile radius within both gynaecology and maternity referrals.

Figure 1 shows the number of women in each group with known outcome. Outcome was known in 487 (97.4%) and 471 (94.2%) in the mifepristone and Yuzpe groups, respectively. Of those in the mifepristone group, 461 women (92.2%) and 432 (86.4%) in the Yuzpe group attended follow up, were contacted by telephone or subsequently re-attended the family planning clinic. Hospital notes were found in a further 26 women (5.2%) in the mifepristone group and 39 (7.8%) who were given the Yuzpe regimen of whom 50% and 64% women in each group had subsequently attended hospital. One pregnancy was recorded in relation to the use of emergency contraception in the mifepristone group, which had already been included in the analysis. A total of 620 (62%) questionnaires were returned: 321 (64.2%) in the mifepristone group and 299 (59.8%) in the Yuzpe group.

Figure 1.

Trial design. FPC = Family planning clinic.

The primary outcome measure was unintended pregnancy. Secondary outcome measures included side effects, patient satisfaction and future preferred method. Both crude pregnancy rates and the expected and prevented pregnancies were calculated. Pregnancy rates, crude relative risks and their 95% confidence intervals were calculated from the binomial distribution (rates) and Taylor series (relative risks). The estimated date of ovulation was calculated by subtracting 14 days from the expected date of the next menstrual period. The expected pregnancies were calculated by multiplying the number of women having sexual intercourse on each day of the menstrual cycle by probability of conception on cycle day using Wilcox estimates11. Prevented pregnancies were calculated as follows: 1—observed/expected pregnancies.

Assay methods

Plasma progesterone was measured using a solid-phase, chemiluminescent enzyme immunoassay designed for the quantitative measurement of serum progesterone. The intra-assay and inter-assay coefficients of variation were 8% and 10%, respectively, and the sensitivity of the assay was approximately 0.64 nmol/L. Plasma progesterone concentrations of >9 nmol/L was considered to be compatible with ovulation, 5–9 nmol/L periovulatory and <4 nmol/L compatible with absence of ovulation.

Our sample-size estimate was based on a failure rate of 3.5% with the Yuzpe regimen. Using the equivalence criterion12 with a 3.5% incidence in each group, α= 0.05, and power of 80%, we estimated that 482 participants in each group were needed to demonstrate equivalence. To compensate for an estimated loss to follow up of 15 in each group we recruited 1000 women.

Data were analysed using the SPSS for Windows Statistical Package13. In presenting the results, categorical data are expressed as percentages, and comparisons are made by the χ2 test, χ2 test for trend and Fisher's exact test, where appropriate. Continuous variables are expressed as mean and standard deviation if normally distributed and compared by Student's t test, and Mann–Whitney U test for non-parametric variables. All tests were two tailored. Multiple logistic regression analysis was performed to assess the association of a variety of factors with failures of emergency contraception. Confidence intervals (95%) are applied where appropriate. Differences were regarded as statistically significant if P < 0.05. Analysis was by intention-to-treat, women allocated to a method of treatment were attributed to that method for the purpose of analysis, whether or not they had the particular method of treatment.

Results

Outcome was unknown in 42 women, (29 in the Yuzpe and 13 in the mifepristone group) who were excluded from analysis (Fig. 1). There were no significant differences between the groups in any baseline physical or sociodemographic characteristics apart from body mass index (Table 1).

Table 1.  Patient characteristics. Only women with known outcome included. EC = emergency contraception. Values are presented as n (%) or mean [SD].
CharacteristicsMifepristone group n= 487Yuzpe regimen n= 471(95% CI)
Mean [SD] age (years)22.43 [5.41]22.56 [5.76](−0.58 to 0.83)
Mean [SD] BMI23.13 [3.80]22.50 [3.40](−1.09 to −0.17)
Mean [SD] cycle length (days)29.68 [2.86]29.69 [2.93](−0.36 to 0.38)
Previous pregnancy112 (23.0)127 (27.0)(−0.01 to 0.09)
Previous live birth52 (10.7)54 (11.5)(−0.03 to 0.04)
Previous induced abortion71 (14.6)77 (16.3)(−0.02 to 0.06)
Previous use of EC320 (65.7)286 (60.9)(−0.01 to 0.11)
Circumstances for consultation
Unprotected intercourse148 (30.4)130 (27.6)(−0.02 to 0.08)
Failed barrier method339 (69.6)340 (72.2)(−0.03 to 0.08)
Others0 (0)1 (0.2) 
Mean [SD] time from coitus to treatment (h)35.4 [17.9]34.8 [16.9](−2.84 to 1.57)

Efficacy

Efficacy was significantly higher in the mifepristone group compared with the Yuzpe regimen. A total of 20 women were found to be pregnant after treatment, 17 who took the Yuzpe regimen and three in the mifepristone group. Dating scans done to establish gestation on women found to be pregnant correlated in all but two women. Both these women were in the mifepristone group and were designated user failures since there was more than a two-week discrepancy between the scan and the possibility of a pregnancy due to failed emergency contraception. One woman continued with the pregnancy and the second had the pregnancy terminated. The third pregnancy in the mifepristone group was a true failure, and the woman had a midtrimester medical abortion for social reasons; the fetus was noted incidentally to have isolated gastrochisis. All 17 women who were found to be pregnant following treatment with the Yuzpe regimen had the pregnancy terminated. All 17 pregnancies resulted from method failure, and there were no user failures. There were no ectopic pregnancies documented in either group. The pregnancy rate was 0.6% (CI 0.2–1.8) in the mifepristone group and 3.6% (CI 2.3–5.7) with the Yuzpe regimen. The crude relative risk of pregnancy for mifepristone compared with the Yuzpe regimen was 6.04 (CI 1.75 to 20.75).

Table 2 shows the overall efficacy of both regimens and the efficacy in relation to the time interval from coitus to treatment. The coitus to treatment interval was within 24 hours in 27% of the women in both groups and within 48 hours in over 71% of women. With the Yuzpe regimen earlier treatment resulted in greater efficacy with a pregnancy rate of 2.2% for treatment up to 24 hours rising to 5.2% for 49–72 hours. With mifepristone the pregnancy rate increased from 0% for up to 24 hours to 1.4% for 49–72 hours. We examined univariately the effect of age, parity, body mass index, circumstances for consultation, previous use of emergency contraceptives and coitus to treatment interval on failures of Yuzpe regimen. The coitus to treatment interval was the only variable significantly associated with failures P= 0.03. Multiple logistic regression was used to adjust for the effect of age, parity, body mass index, circumstances for consultation and previous use of emergency contraceptives and it was found to be still significant. No such association was found with mifepristone failures (goodness-of-fit test R2= 0.002).

Table 2.  Pregnancy rates by groups and time interval from coitus to treatment.
Coitus to treatment intervalPregnancies n (%)RR (95% CI)
  1. *User failures.

All women
Mifepristone (n= 487)3 (0.6)6.04 (1.75 to 20.75)
Yuzpe regimen (n= 471)17 (3.6)
<24 hours
Mifepristone (n= 135)0 (0)2.03 (1.79 to 2.29)
Yuzpe regimen (n= 134)3 (2.2)
25–48 hours
Mifepristone (n= 212)1 (0.5)7.03 (0.85 to 57.66)
Yuzpe regimen (n= 217)7 (3.2)
49–72 hours
Mifepristone (n= 140)2 (1.4)*4.27 (0.87 to 20.98)
Yuzpe regimen (n= 120)7 (5.2)

The observed and expected number of pregnancies in relation to coitus and predicted ovulation is shown in Figs 2a and 2b. The probability of conception based on Wilcox estimates showed that with the Yuzpe regimen 39 pregnancies were expected (17 observed) with 56% prevented. With the Yuzpe regimen 72% pregnancies were prevented if administered within the first 24 hours following coitus, falling to 63% and 24% for 25–48 hours and 49–72 hours, respectively. With mifepristone, 39 pregnancies were expected, three observed and 92% prevented overall. The prevented fraction with mifepristone for up to 24 hours, 25–48 hours and 49–72 hours following coitus was 100%, 94% and 84%, respectively. Should the two women who were user failures in the mifepristone group be excluded the crude pregnancy rate with mifepristone was 0.2% with 97% of pregnancies prevented.

Figure 2.

(A) Yuzpe regimen; (B) mifepristone group.

Table 3 shows the side effects experienced by women in relation to the type of emergency contraception used. Mifepristone was better tolerated than the Yuzpe regimen. Of those with known outcome, 17 women who were treated with the Yuzpe regimen and two who were given mifepristone required repeat treatment for vomiting (RR = 9.4, CI 2.2–41.0). Menstrual period details, following exclusion of women who became pregnant, are shown in Table 4.

Table 3.  Side effects. Values are n (%).
Side effectsMifepristone n= 321 (64.2%)Yuzpe Regimen n= 299 (59.8%)RR(95% CI)
Vomiting3 (9.25)46 (15.38)19.273(5.923–62.709)
Nausea91 (28.3)122 (40.8)4.665(3.324–6.547)
Breast tenderness79 (24.6)68 (22.7)0.902(0.622–1.307)
Abdominal pain105 (32.7)138 (46.2)1.763(1.273–2.442)
Tiredness157 (48.9)195 (65.2)1.959(1.417–2.706)
Lethargy91 (28.3)122 (40.8)1.742(1.246–2.435)
Headache83 (25.9)97 (32.4)1.337(0.972–1.950)
Hot flushes41 (12.8)71 (23.7)2.127(1.394–3.245)
Dizziness52 (16.2)89 (29.8)2.192(1.489–3.228)
Table 4.  Detail of next menstrual period. Values are n (%).
 Mifepristone group n= 380 (76%)Yuzpe regimen n= 358 (71.6%)RR(95% CI)
On time226 (59.4)200 (55.9)1.0(0.94–1.21)
Early (5 days before expected period)61 (16.1)111 (31.0)0.42(0.30–0.61)
Delayed period (over 7 days)93 (24.5)47 (13.1)2.14(1.46–3.14)
Early bleed (within 5 days of treatment)60 (15.8)61 (17.0)0.91(0.62–1.35)
2nd bleed following early bleed17 (4.5)16 (4.5)1.0(0.51–1.95)

Table 5 shows patient acceptability following treatment. Significantly more women were satisfied following treatment with mifepristone (P < 0.0001) and would recommend the method to a friend (P= 0.02). Of those given mifepristone and who returned questionnaires, 53% (170/321) of women had had the Yuzpe regimen of emergency contraception in the past. Of these 94.1% (160/170) would prefer mifepristone should they require emergency contraception in the future, with only 4.1% (7/170) wishing to use the Yuzpe regimen and 1.8% (3/170) finding either method acceptable for the future.

Table 5.  Patient acceptability. Values are n (%).
 Mifepristone groupYuzpe regimenP
Satisfactionn= 316n= 299 
Satisfied297 (94.0)240 (80.3)< 0.0001
No Strong Feelings17 (5.4)38 (12.7)
Dissatisfied2 (0.4)21 (7.0)
Recommend to a friendn= 314n= 296 
Yes295 (93.95)259 (87.5)= 0.02
No3 (0.95)4 (1.4)
Don't Know16 (5.1)33 (11.1)

Serum progesterone measured in 88% (841/958) of women in whom outcome was known. Of the 408 women who were considered to be in the follicular phase of the menstrual cycle on the basis of cycle data, 150 (32%) had biochemical evidence of presumed ovulation and a further 51 (11%) were periovulatory. Similarly, of the 304 women thought to be in the luteal phase, 170 (51%) had no evidence of ovulation, 30 (9%) were periovulatory and only 104 (31%) had biochemical evidence of ovulation. Of the 129 women believed to be midcycle based on cycle data, 41 (32%) had ovulated, 14 (11%) were periovulatory and 74 (57%) had no evidence of ovulation.

Discussion

To our knowledge this is the first randomised study comparing this dose (100 mg) of mifepristone with the Yuzpe regimen for emergency contraception. The study was conducted in a single centre with the outcome known in a large number of women (95.8%). Mifepristone administered in the pre-ovulatory phase of the menstrual cycle can delay or block ovulation and cause a delay in the onset of the next menstrual period5,6. Most published studies have assumed that such a delay can cause anxiety in women3 but to date there are no published data to assess the acceptability of mifepristone as an emergency contraceptive.

Although only 62% of women returned the acceptability questionnaire, significantly more women were satisfied and would recommend mifepristone as an emergency contraceptive to a friend. Of those women who were allocated to mifepristone and who had the Yuzpe method in the past, 94% would prefer mifepristone should they require further emergency contraception.

The WHO trial recommended a lower dose of 10 mg of mifepristone as an emergency contraceptive since it is cheaper and would be less likely to delay the onset of the next menstrual period3. The concern was that menstrual delay would both cause anxiety and expose the woman to the risk of pregnancy should she have further acts of coitus. In the WHO study 18% of women given the 10 mg dose of mifepristone had delayed menstruation and 85% of pregnancies were prevented (one user failure). In our study using a 100 mg dose of mifepristone, 24.5% women had a delayed period and 92% of pregnancies were prevented. Currently mifepristone is only available as a 200 mg single tablet and a 100 mg dose has a NHS drug cost of nearly £7.00, with Schering PC4 costing £1.6014.

There were only two trials included in the Cochrane systematic review4, which compared the Yuzpe regimen with mifepristone. Both the above studies were conducted in the UK and used a 600 mg dose of mifepristone. The Cochrane review has identified five mifepristone dose comparison studies, of which four were conducted in China using locally manufactured mifepristone whose potency and safety compared with the preparation on the European market has not been established. Additionally a clear dose-related efficacy is not evident although side effects seem to be dose related. Although in ‘an ideal world’ the lowest possible dose of mifepristone should be used, we chose a 100 mg dose in view of mifepristone being available only as a 200 mg tablet.

Two women in the mifepristone group conceived more than two weeks after the act of intercourse for which treatment was sought. The overall efficacy of mifepristone in our study was 0.6% including these women. However, if the two user failures were excluded, the crude pregnancy rate with mifepristone was 0.2% with over 97% of pregnancies prevented. With the Yuzpe regimen the crude pregnancy rate (3.6%) was similar (3.2%) to the recent WHO study comparing levonorgestrel and the Yuzpe regimen10. Our study also found a decreased efficacy with the Yuzpe regimen with increasing time from coitus to treatment, with no significant relationship between efficacy and timing of treatment with mifepristone although the failure rates were very small. Published results from our group have shown mifepristone to be effective up to 120 hours after unprotected intercourse in a 200 mg dose15.

One may argue that the study might be biased as no blinding of patients and clinicians was provided. Our primary outcome measure was unintended pregnancy, and it may be argued that pregnancy is a ‘hard’ outcome, which is less liable to bias. Additionally one of our secondary outcome measures was patient acceptability and it would have been difficult to assess ‘true’ acceptability should we have administered a second placebo tablet in the mifepristone group.

It would have been ‘ideal’ to use a very low dose of mifepristone (10 mg) as recommended by WHO3 but due to the unavailability of mifepristone in a smaller dose in the UK we used a 100 mg dose. However this is, to date, the only published study comparing a low dose of mifepristone (although considered as a high dose in the Cochrane Systematic review) to the Yuzpe regimen since previous studies have compared a 600 mg dose of mifepristone.

Only women who agreed to abstain from further acts of intercourse during the current treatment cycle were included in the study since otherwise it would not have been possible to calculate the probability of contraception based on the cycle day. There were no women excluded from the study at recruitment due to refusal to being compliant with the protocol. However compliance could not be ensured in all women, and we did not keep a record of the number of women who were non-compliant with the protocol. However, women who became pregnant following treatment were specifically asked whether they were compliant with the protocol.

Most published data on the efficacy of emergency contraception have reported failure rates as number of pregnancies of the total number treated. Not all women are at risk of a pregnancy depending on the phase of the menstrual cycle and more recently the effectiveness of emergency contraceptives has been estimated by the prevented pregnancies3,10. In our study discrepancy was noted in both the follicular and luteal phase of the cycle when cycle data and biochemical data were compared, indicating that most women do not keep an accurate record of their last menstrual period. Most studies of estimates of conception probabilities by cycle day are based on women who were planning to become pregnant16, a different group of women compared with those trying to prevent a pregnancy. Hence, extrapolating data from women who are trying to conceive and applying such data to women who are trying to prevent a pregnancy may not give a true reflection of the risk of conception in these women.

Emergency contraception is an important option for women both in developing and developed countries. Globally, nearly four in ten pregnancies are unplanned17. The World Health Organization estimates that between eight and 30 million unplanned pregnancies are the result of inconsistent or incorrect use of contraceptive methods, or from method-related failure18. Every year, worldwide nearly 50 million pregnancies are terminated, of which approximately 20 million abortions are unsafe, resulting in 80,000 maternal deaths. About 95% of unsafe abortions take place in developing countries, causing the death of at least 200 women each day19. Mifepristone seems promising as an emergency contraceptive, which would have good patient acceptability and compliance with minimal side effects compared with currently available methods of emergency contraception.

In conclusion mifepristone administered in a 100 mg dose is a highly effective emergency contraceptive with no decline in efficacy in relation to the time interval from coitus to treatment. Mifepristone has a high patient acceptability and few side effects compared with the standard Yuzpe regimen of emergency contraception. Delay in the onset of menstruation did not decrease patient acceptability, at least compared with the Yuzpe regimen.

Acknowledgements

We would like to thank the doctors and nurses in the family planning clinic who helped us conduct the study and Mrs H. Fraser for doing the serum progesterone assays.

Ancillary