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Towards more eff ective emergency contraception?In The Lancet today, Anna Glasier and colleagues1 report a randomised single-blind non-inferiority multicentre trial involving an analysis of nearly 2000 women who requested emergency contraception within 5 days of unprotected sexual intercourse. The investigators compared the effi cacy and side-eff ects of levonorgestrel, the widely marketed emergency contraceptive, and ulipristal acetate, a selective progesterone-receptor modulator, recently licensed for emergency contraception in Europe. Both treatments decreased the pregnancy rate: from an expected 5·5% to 1·8% in the ulipristal group and from 5·4% to 2·6% in the levonorgestrel group. High eff ectiveness is an important requirement for an ideal emergency contraceptive and research to improve its effi cacy is most welcome.

Along with previous research,2 today’s study shows that the use of emergency contraception decreases a woman’s risk of an unwanted pregnancy, although attempts to show that it also reduces abortion rates have so far failed.3 The problem is that there are too many factors infl uencing rates of pregnancy termination in a given setting, and availability of emergency contraception is just a small one among them. Indeed, the risk of pregnancy in women seeking emergency contraception is small (around 6–8%;4 in today’s study, the risk was even lower), and within this group, emergency contraception at best prevents 70–80% of expected pregnancies.2 Additionally, use of emergency contraception often refers to one act of intercourse in one cycle while abortion rates are calculated per year, a period during which there might be a hundred acts.

Glasier and colleagues provide further evidence that selective progesterone-receptor modulators are, in magnitude, slightly more eff ective for emergency contraception than are synthetic progestins (levo-norgestrel). Ulipristal has similar biological eff ects to mifepristone,5 the antiprogestin used in medical abortion and marketed for emergency contraception in China and Russia. When used correctly, mifepristone is also an eff ective emergency contraceptive and, in a WHO study, its use was associated with a delay in menses6 whereas levonorgestrel is associated with early rather than late post-treatment menses, which thereby relieves the woman from the anxiety of being pregnant. In women who did not have intercourse after treatment, failure

was lower (0·76%, 7/916) than that observed in two levonorgestrel groups (1·30%, 25/1920).2

The mechanism of action of mifepristone has been extensively studied and the striking similarity with ulipristal suggests a similar mechanism of action for both. Indeed, administration of ulipristal in mid-follicular phase suppresses lead follicle growth, causing a dose-dependent delay in folliculogenesis and suppression of plasma oestradiol with, at higher doses, a new lead follicle often recruited. A delay in endometrium maturation was seen after ulipristal at 10, 50, and 100 mg.7 Furthermore, menstruation is delayed by 1–2 weeks in 30% of the cases after 100 mg, 27% after 50 mg, and 9% after 10 mg doses.7 These results are similar to those described after mifepristone.8

What could be the advantages of ulipristal compared with levonorgestrel or mifepristone? According to Glasier and colleagues, they are two-fold: overall higher eff ectiveness and eff ectiveness between 73 h and 120 h after unprotected intercourse. In the meta-analysis they include in their report, the former is in magnitude only 0·9% and the latter is based on only 203 women. Had the authors done stratifi cation, instead of showing effi cacy for the whole range of 0–120 h, the diff erence between ulipristal and levonorgestrel for women with 73–120 h of spacing between intercourse and treatment would not have reached signifi cance.

Published OnlineJanuary 29, 2010DOI:10.1016/ S0140-6736(10)60146-8

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Should we dispense with preoperative breast MRI?The COMICE trial, presented in The Lancet today by Lindsay Turnbull and colleagues,1 has been eagerly awaited by the breast cancer community. COMICE is the fi rst randomised trial to assess whether preoperative breast MRI in early-stage breast cancer can decrease reoperation rates. Historically, MRI reveals extent of

disease much better than does conventional imaging,2 and therefore the hope was that MRI information could translate into better surgical outcomes.

In COMICE, just over 1600 women with early-stage breast cancer were randomly assigned to receive preoperative MRI or not. The primary endpoint,

Levonorgestrel and mifepristone, in an in-vitro model, have diff erent mechanisms of action, because levonorgestrel has no eff ect on implantation whereas mifepristone can prevent it,9,10 which might also apply to ulipristal. Additionally, in a study in which the date of ovulation was estimated in 625 menstrual cycles in women seeking pregnancy, probability of conception was 0·10 when intercourse occurred 5 days before ovulation and only 6% of the pregnancies could be fi rmly attributed to spermatozoa that were 3 or more days old.11 This fi nding suggests that in women receiving ulipristal 72–120 h after an unprotected intercourse, an anti-implantation eff ect cannot be excluded, as Glasier and colleagues acknowledge. This suggestion has important practical implications at a time when some pro-life physicians and experts begin to accept the fact that levonorgestrel-based emergency contraception does not have abortifacient eff ects.12,13

Treatment with antiprogestins often simply postpones ovulation and, when this happens, the woman con tinues to be fertile. In a meta-analysis of 10 mg mifepristone, the relative risk of pregnancy was almost 28 times higher for women reporting unprotected intercourse after treat-ment, relative to women abstaining from sexual inter-course.14 For this reason, counselling providers should high light that the risk of pregnancy persists after treat-ment, because women might falsely think they are pro-tected from pregnancy up to 72–120 h after inter course.

High effi cacy, easy access, and an aff ordable price are crucial for the success of emergency contraception. Today, levonorgestrel is available without prescription in many countries and is not associated with a delay of menses, whereas the availability of mifepristone is highly restricted. Only the future will show whether ulipristal will become easily accessible and aff ordable for women and whether the slightly higher eff ectiveness compensates the possible disadvantages involved in postponing ovulation.

*Giuseppe Benagiano, Helena von HertzenDepartment of Obstetrics and Gynaecology, Sapienza, University of Rome, 00161 Roma, Italy (GB); and Concept Foundation, Geneva, Switzerland (HvH) giuseppe.benagiano@uniroma1.it

GB declares that he has no confl icts of interest. HvH declares that one of the aims of the Concept Foundation is to increase access to medical abortion; the Foundation does no work in emergency contraception.

1 Glasier AF, Cameron ST, Fine PM, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet 2010; published online Jan 29. DOI:10.1016/S0140-6736(10)60101-8.

2 von Hertzen H, Piaggio G, Ding J, et al, for the WHO Research Group on Post-ovulatory Methods of Fertility Regulation. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet 2002; 360: 1803–10.

3 Raymond EG, Trussell J, Polis CB. Population eff ect of increased access to emergency contraceptive pills: a systematic review. Obstet Gynecol 2007; 109: 181–88.

4 Wilcox AJ, Weinberger CR, Baird DD. Timing of sexual intercourse in relation to ovulation: eff ects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med 1995; 333: 1517–21.

5 Poyser NL, Forcelledo ML. A comparison of the pregnancy-terminating potencies of three antiprogestins in guinea-pigs and the eff ects of sulprostone. Prostaglandins Leukot Essent Fatty Acids 1994; 50: 245–47.

6 Task Force on Postovulatory Methods of Fertility Regulation. Comparison of three single doses of mifepristone as emergency contraception: a randomised trial. Lancet 1999; 353: 697–702.

7 Stratton P, Hartog B, Hajizadeh N, et al. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial diff erentiation in normally cycling women. Hum Reprod 2000; 15: 1092–99.

8 Liu JH, Garzo G, Morris S, Stuenkel C, Ulmann A, Yen SS. Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486. J Clin Endocrinol Metab 1987; 65: 1135–40.

9 Lalitkumar PG, Lalitkumar S, Meng CX, et al. Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model. Hum Reprod 2007; 22: 3031–37.

10 Meng CX, Andersson KL, Bentin-Ley U, Gemzell-Danielsson K, Lalitkumar PG. Eff ect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model. Fertil Steril 2009; 91: 256–64.

11 Wilcox AJ, Baird DD, Dunson DB, McConnaughey DR, Kesner JS, Weinberg CR. On the frequency of intercourse around ovulation; evidence for biological infl uences. Hum Reprod 2004; 19: 1539–43.

12 Austriaco NPG. Is Plan B Abortifacient? A critical look at the scientifi c evidence. National Catholic Bioethics Q 2007; 7: 703–07.

13 Hamel R. Thinking ethically about emergency contraception critical judgments require adequate and accurate information. Health Progr 2010; 91: 62–67.

14 Piaggio G, von Hertzen H, Heng Z, Bilian X, Cheng L. Meta-analyses of randomized trials comparing diff erent doses of mifepristone in emergency contraception. Contraception 2003; 68: 447–52.

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