Wu, Shangchun MD; Dong, Jing; Cong, Jie; Wang, Cuiping MD; VonHertzen, Helena DDS, MD; Godfrey, Emily M. MD, MPH
From the National Research Institute For Family Planning, Beijing, People's Republic of China; the Qingdao Family Planning Research Institute, Qingdao, People's Republic of China; the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Geneva, Switzerland; and the Department of Family Medicine, University of Illinois College of Medicine, Chicago, Illinois.
Supported by the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.
The authors thank their colleagues, Cheng Linan, Ren Fangming, Shao Wenqi, Cheng Weiyu and Cao Xiaoming, for their assistance in design and performance of the trial.
Corresponding author: Emily M. Godfrey, MD, MPH, Department of Family Medicine, University of Illinois College of Medicine, 1919 W. Taylor St., Rm 145 (M/C 663), Chicago, IL; e-mail: email@example.com.
Financial Disclosure Shangchun Wu has received the following from the World Health Organization: support in kind such as writing, provision of medicines or equipment, or administrative support; travel/accommodations expenses covered or reimbursed; and is a member of the Steering Committee on IUD Research, Human Reproduction Program, for the World Health Organization. Emily M. Godfrey is a consultant to the World Health Organization in Switzerland, has received honoraria from Schering-Plough USA, is a board member of the Association of Reproductive Health Professionals, and received payment from Midwest Professional Research and Educational Services in 2007 for development of educational presentations. The other authors did not report any potential conflicts of interest.
Mifepristone (also known as RU-486) is a progesterone and glucocorticoid receptor antagonist that has been shown to be effective as postcoital emergency contraception. In two randomized trials, it had fewer side effects than the standard Yuzpe regimen and equal efficacy to the levonorgestrel regimen.1,2 In an earlier dose-finding randomized trial, the World Health Organization (WHO) showed that mifepristone at 600 mg, 50 mg, or 10 mg equally prevented pregnancy postcoitally when taken within 5 days after intercourse.3 The women in the group using mifepristone 10 mg had significantly less menstrual irregularity than did those in the higher-dose groups (P<.01). Although women with repeated acts of intercourse after taking the emergency contraception dose had a higher risk of pregnancy than did those who did not (relative risk 3.6; 95% confidence interval [CI] 1.3–10.0), the overall pregnancy rate was still low at 1.9%.
Gestrinone (also known as R2323) is a 19-nortestosterone derivative with antiprogestagenic, antiestrogenic, and antigonadotropic properties.4,5 It is used most commonly for the treatment of endometriosis.6,7 It is also an effective contraceptive agent.8 Weekly administration of 2.5 mg gestrinone as a contraceptive to 181 women for 2 to 44 months (2,971 total women-months of use) demonstrated a typical-use failure rate of 7.3%.9 When given within 72 hours of unprotected coitus, 5 mg gestrinone was 88.9% effective against unwanted pregnancy.10 When administered as an emergency contraceptive, gestrinone is thought to inhibit blastocyst implantation.11 The objective of our study was to compare the efficacy of gestrinone with that of mifepristone for emergency contraception.
MATERIALS AND METHODS
We conducted a prospective multicenter trial in five family-planning clinics in China. Institutional review boards at each of the participating clinics and the WHO Secretariat Committee on Research Involving Human Subjects gave ethics and academic approval. Participants were eligible if they were healthy, had regular menstrual cycles (24–42 days' duration with variation of no more than 5 days), desired emergency contraception within 72 hours of a single act of unprotected intercourse during the present menstrual cycle, agreed to no further acts of intercourse after treatment during that cycle, and were available for follow-up over the subsequent 6 weeks. Women who had a recent induced or spontaneous abortion or were postpartum were eligible to enroll only if they had had at least one complete and normal menstrual cycle before the current cycle. Exclusion criteria included 1) pregnancy, 2) contraindication to mifepristone (chronic adrenal failure, long-term corticosteroid use, known allergy to mifepristone, hemorrhagic disorder or taking anticoagulants, or an inherited porphyria), 3) presence of a chronic medical condition 4), subfertility (ie, hormonal contraceptive method discontinuation or rhythm method use in same menstrual cycle, gonadotropin-releasing hormone analog or danazol users, or depo-medroxyprogesterone acetate use within the past 6 months), and 5) desire to continue a pregnancy should one occur during the study because of the theoretical teratogenic effects of mifepristone.
The randomization sequence was computer-generated by WHO and stratified by clinic. Randomization was performed using randomized blocks so that the chance of being assigned to either treatment group was equal in each block. All clinics received sets of opaque, sealed envelopes containing the randomly allocated emergency contraception treatment packs assigned to a given participant number. When a woman was assigned to a participant number, the envelope containing the emergency contraception tablets with the corresponding participant number was given to her. Each envelope contained one tablet and four capsules. Participants assigned to the gestrinone group received four 2.5-mg gestrinone capsules and one placebo tablet identical in appearance to mifepristone. Participants assigned to the mifepristone group received one 10 mg mifepristone tablet and four placebo capsules identical in appearance to gestrinone. The gestrinone capsules and gestrinone placebo capsules were provided by Roussel-Uclaf (Romainville, France), and the mifepristone tablets and the mifepristone placebo tablets were provided by Hualian (Shanghai, China). The clinicians, participants, and investigators were blinded to the drug assignments. Double-blinding was maintained until after the final analysis.
The primary outcome was unintended pregnancy, confirmed by positive high-sensitivity urine pregnancy test, and the estimated reduction in expected pregnancy or prevented fraction of pregnancies using the equation based on Dixon (ie, 1-[observed pregnancy/ expected pregnancies]).12 Effectiveness analysis also included effect of treatment administration time and repeat coitus after emergency contraception treatment during the current treatment cycle. Additional outcome measures included side effects and timing of next menstruation.
After providing informed written consent, all participants underwent relevant medical, gynecologic, and obstetric histories, including date of last normal menstrual period, expected date of start of next menses, and the interval between unprotected intercourse and emergency contraception treatment. Women then were assigned randomly to either gestrinone or mifepristone according to the randomization procedure described above. Participants ingested each of the tablets and capsules in the medical clinic and were given a menstrual diary for daily recording until the next menses or follow-up visit, whichever came first. Researchers instructed the participants on menstrual-diary recording, including side effects, spotting or bleeding episodes, acts of subsequent intercourse, and condom use.
A follow-up visit was arranged about 1 week after the estimated first day of the next menstrual period based on the participant's reported prior menstrual period and reported usual cycle length. A high-sensitivity urine pregnancy test was performed at this follow-up visit. If a woman had a normal menstrual period and a negative urine pregnancy test, she had completed the trial. If a woman did not have a normal menstrual period or if her period had not started by the time of her assigned follow-up visit and her urine pregnancy test was negative, a subsequent 1-week follow-up visit was scheduled. If the urine pregnancy test was positive, an ultrasound examination was performed to approximate the gestational age of the pregnancy. If a normal menstrual period had not occurred by the subsequent follow-up visit and the urine pregnancy test was again negative, treatment was regarded as successful.
The initial trial sample size of 489 participants per treatment group was based on two-sided 5% level significance testing with 80% power and the assumption that the failure rate of gestrinone is 5% and that of mifepristone is 1.6%. We increased our final trial sample size to 499 participants per treatment group because we assumed a 2% loss to follow-up rate in each group.
Statistical analysis was completed with SPSS 10.0 (SPSS, Inc., Chicago, IL) and SAS 6.12 (SAS Institute, Inc., Cary, NC) software. We calculated relative risks and their 95% CIs. We also calculated the ratio of observed to expected pregnancies, the prevented fraction, and their 95% CIs based on the conception probability estimates by Trussell.13 Women who were lost to follow-up were excluded from the analysis because their outcomes were unknown. Logistic regression was used to adjust for some variables such as treatment administration time after intercourse, additional acts of intercourse, and age. Treatment administration time after intercourse was divided into three subgroups: treatment within 24 hours, 25–48 hours, and 49–72 hours. We used the χ2 test to compare categorical data and the Student's t test to compare continuous data. The Mann-Whitney rank sum test was used for nonparametric data. A two-tailed P<.05 was considered statistically significant.
A total of 998 women were enrolled and randomly assigned to groups, 499 to gestrinone and 499 to mifepristone, between October 2001 and March 2003. Each clinic recruited 199 to 200 women. The final analysis excluded two women (one gestrinone group, one mifepristone group) who were lost to follow-up; thus, 498 participants in each group were included in the final analysis. Although three women vomited the pills shortly after ingestion (one gestrinone group, two mifepristone group), their outcomes were included in the final analysis. The baseline characteristics of the participants, including age, body mass index, timing of intercourse in relation to expected ovulation, pregnancy history, and reasons for requesting emergency contraception, are shown in Table 1. There were no notable differences between the treatment groups.
In the final analysis of 996 women (498 in each group), 21 pregnancies occurred. None of the pregnancies were considered pretreatment pregnancies based on gestational age assessed by ultrasonography. Twelve pregnancies occurred in the gestrinone group (2.4%, 95% CI 1.2–4.2), and nine occurred in the mifepristone group (1.8%, 95% CI 0.8–3.4). There were no significant differences in pregnancy rates between the two treatment groups (P=.51). Using the expected pregnancies based on the day of exposure relative to estimated day of ovulation, the gestrinone users experienced a 68% reduction in the number of pregnancies compared with what would be expected with no treatment, whereas mifepristone users experienced a 76% reduction (Table 2). Pregnancy rates appeared to be higher in participants who had further acts of intercourse after treatment (2.9% for each treatment group), but they did not differ significantly compared with rates in those without additional acts of intercourse (P=.99). Additionally, effectiveness rates for delay in treatment for each 24-hour period up to 72 hours did not differ significantly, although results are inconclusive owing to low pregnancy rates in each treatment group.
The majority of participants did not experience a change in cycle length during the cycle in which treatment was administered (Fig. 1). About 56% in the gestrinone group and 58% in the mifepristone group menstruated within 2 days of estimated onset of the next menstrual period. Gestrinone appeared to shorten the menstrual cycle; 7.1% of gestrinone users compared with 2.6% of mifepristone users reported menstruation 7 days before the estimated first day of the next menstrual period (P<.001). Mifepristone appeared to lengthen the menstrual cycle; 19.5% of mifepristone users compared with 14.3% gestrinone users reported menstruation 3 to 7 days later than the estimated first day of the next menstrual period (P=.03). Complaints of side effects were uncommon and did not differ significantly between the treatment groups. Bleeding or spotting was the most common complaint in both groups (Table 3).
As emergency contraception, gestrinone (R2323) 10 mg did not differ significantly from mifepristone 10 mg. Pregnancy rates were similar between the groups and were not statistically significant even when treatment was delayed for more than 24 hours or when participants had additional acts of intercourse after treatment during the same cycle. Additionally, side effects were rare and did not differ significantly between the groups.
The majority of participants experienced no change in cycle length; however, some reported changes in their expected first day of menstruation. Gestrinone appeared to shorten the expected cycle length somewhat, whereas mifepristone appeared to lengthen it somewhat. These findings are consistent with other mifepristone emergency contraception studies demonstrating that onset of menstruation is often delayed,1,3 but they are in contrast to Gao et al,11 who found that 5 mg gestrinone did not have any significant effect on menstrual-cycle length. The present study used 10 mg gestrinone, and the increased dosage may explain our findings. Nonetheless, an earlier menstruation noted by some gestrinone users may be more desirable for women who are concerned about unintended pregnancy after taking emergency contraception.
This study's strength is its large sample size. Another strength is the small number of women lost to follow-up, making it unlikely that having excluded them in the final analysis biases the effectiveness results. One limitation, however, is that this study was conducted within one country and may not be generalizable to women living in other countries. One emergency contraception trial noted slightly higher pregnancy rates in Chinese women compared with non-Chinese women.1 Although this reported finding was not significant, a multinational trial is necessary to assess fully the generalizability of gestrinone as emergency contraception.
Levonorgestrel is a contraceptive hormone that has shown similar efficacy to mifepristone as emergency contraception.1 Additionally, its postcoital regimen has been simplified into a single 1.5-mg dose and is approved and registered in more than 100 countries.14 However, some evidence suggests that levonorgestrel may be less effective after a 48-hour delay in treatment.1,15 Sustained effectiveness would be important, particularly in low-resource areas where transportation to medical facilities that may administer emergency contraception is often limited. A head-to-head trial is necessary to determine whether gestrinone has benefits over levonorgestrel regarding treatment delay.
In conclusion, 10 mg gestrinone does not differ significantly from 10 mg mifepristone as emergency contraception. The findings of the present study suggest that gestrinone is safe to use for emergency contraception; however, larger studies are needed to assess further the extent to which gestrinone can protect postcoitally against unwanted pregnancy and how it may compare with the more widely available levonorgestrel regimen.
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