Elsevier

The Lancet

Volume 360, Issue 9348, 7 December 2002, Pages 1803-1810
The Lancet

Articles
Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial

https://doi.org/10.1016/S0140-6736(02)11767-3Get rights and content

Summary

Background

A single 10 mg dose of mifepristone, and two 0·75 mg doses of levonorgestrel 12 h apart, are effective for emergency contraception. Because no studies had compared the efficacies of both compounds, or investigated a single dose of 1·5 mg levonorgestrel, we undertook this three-arm trial.

Methods

We did a randomised, double-blind trial in 15 family-planning clinics in 10 countries. We randomly assigned 4136 healthy women with regular menstrual cycles, who requested emergency contraception within 120 h of one unprotected coitus, to one of three regimens: 10 mg singledose mifepristone; 1·5 mg single-dose levonorgestrel; or two doses of 0·75 mg levonorgestrel given 12 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Analysis was by intention to treat, but we did exclude some patients from the final analyses.

Findings

Of 4071 women with known outcome, pregnancy rates were 1·5% (21/1359) in those given mifepristone, 1·5% (20/1356) in those assigned single-dose levonorgestrel, and 1·8% (24/1356) in women assigned two-dose levonorgestrel. These proportions did not differ significantly (p=0·83). The relative risk of pregnancy for single-dose levonorgestrel compared with two-dose levonorgestrel was 0·83 (95% Cl 0·46–1·50), and that for levonorgestrel (the two regimens combined) compared with mifepristone, 1·05 (0·63–1·76). Side-effects were mild and did not differ greatly between groups, and most women menstruated within 2 days of the expected date. Women who took levonorgestrel had earlier menses than did those who took mifepristone.

Interpretation

The three regimens studied are very efficacious for emergency contraception and prevent a high proportion of pregnancies if taken within 5 days of unprotected coitus. Mifepristone and levonorgestrel do not differ in efficacy. A 1·5 mg single levonorgestrel dose can substitute two 0·75 mg doses 12 h apart.

Introduction

Two 0·75 mg doses of levonorgestrel administered 12 h apart, taken up to 72 h after unprotected intercourse is better tolerated and more efficacious than the standard in hormonal emergency contraception—ie, the Yuzpe regimen (two doses of 0·1 mg ethinyloestradiol, 0·5 mg levonorgestrel, 12 h apart).1 Results from a systematic review2 that combined these data with those from another trial, in which treatment was administered up to 48 h after unprotected intercourse,3 confirmed these conclusions. The two-dose regimen of levonorgestrel has been approved in more than 80 countries and is progressively replacing the Yuzpe regimen.

A comparison of three single doses of mifepristone (600 mg, 50 mg, and 10 mg) administered up to 120 h after intercourse for emergency contraception showed that the proportions of pregnancies (1·3%, 1·1%, and 1·2%, respectively) did not differ between these three doses.4 The investigators concluded that a 60-fold reduction in the dose of mifepristone did not seem to decrease its effectiveness as an emergency contraceptive. No major side-effects occurred in any participants of that trial; however, the delay in the onset of next menstruation was significantly related to the mifepristone dose (p<0·01). A systematic review2 combined results of trials that compared high doses of mifepristone (>50 mg) with low doses (≤l10mg), or that compared mid-range doses (25–50 mg) with low doses (≤10 mg) and reported no evidence of a dose-related efficacy. However, the sideeffect profile was better with low doses than with mid or high doses. These results suggest that mifepristone could improve existing emergency contraception options, because it can be administered in a single low dose with few side-effects. If levonorgestrel could also be given as a single dose, treatment would be simplified and compliance and patients' acceptance of the drug could be increased.

Our aim in this randomised, double-blind, multinational trial was, therefore, to compare the efficacy and side-effects of three treatments, when administered up to 120 h (5 days) after unprotected coitus: a single dose of 10 mg mifepristone; a single dose of 1·5 mg levonorgestrel; and two separate doses of 0·75 mg levonorgestrel given 12 h apart. The main outcomes were pregnancy rates, proportions of pregnancies prevented, side-effects and timing of the first menstrual period after treatment. We also planned to analyse the effect of treatment delay on efficacy.

Section snippets

Patients

This trial was done in 15 family-planning clinics in China, Finland, Georgia, Hungary, India, Mongolia, Slovenia, Sweden, Switzerland, and the UK (table 1).

We asked women presenting for emergency contraception to participate, and included those who were healthy, had regular menstrual cycles (24–42 days' duration), and who requested emergency contraception within 120 h of a single act of unprotected coitus in the present menstrual cycle. Participants also had to be willing to abstain from

Results

4136 women were enrolled in the trial by 15 centres; each centre recruited between 122 and 447 women (table 1), 1380 were assigned mifepristone, 1379 single-dose levonorgestrel, and 1377 two-dose levonorgestrel (figure 1). We did not record the number of women who requested emergency contraception but were not enrolled.

All women received the first dose of treatment. We did not have information about the second dose intake for 62 women, most of whom (52) missed the first follow-up visit

Discussion

We started this trial with the objective of comparing the efficacy of three regimens in prevention of pregnancy, and we noted no difference between the treatments. However, because of our sample size, we cannot discard the possibility that the single-dose levonorgestrel regimen increases the risk of pregnancy up to 1·5-fold compared with the two-dose regimen, or that the two-dose regimen increases the risk of pregnancy up to more than two times that of the single dose regimen. To prove

References (11)

There are more references available in the full text version of this article.

Cited by (535)

  • Emergency contraception

    2023, Orvosi Hetilap
  • Is contragestion the future?

    2023, BMJ Sexual and Reproductive Health
View all citing articles on Scopus

Members listed at the end of the paper

View full text