CONTRACEPTION

Understanding emergency contraception

J Guillebaud

Is it ethical and legal to use EC contraception?

Yes. Legally in the UK a pregnancy is not recognized to exist until implantation is completed (Judicial Review of Emergency Contraception, Department of Health 2002; quoted in FFP Guidance). Although the methods usually work by preventing fertilization, it is undeniable that the mechanism might often be through blocking implantation. The question is whether the prescriber and the woman concerned are happy to accept the view of most modern biologists and ethicists, that conception is a process, which certainly begins with the fusion of sperm and ovum, but is not complete until implantation. The situation is clarified by considering the status of the unimplanted blastocyst (Table.1). If it stays where it is in the cavity of the uterus it is in a 100% no-go situation unless and until it can stop itself being washed away in the next menstrual flow by secreting enough hCG into the womans circulation to maintain the corpus luteum. The all-destroying menses cannot be prevented without successful implantation. A second feature of the unimplanted situation is that the womans physiology does not know the blastocyst is present, yet. Only after implantation is there a two-way relationship, and for the rst time 100% no-go for the blastocyst becomes go; now there is carriage. As has been well said, at the earlier stage, when there is not yet carriage, how could application of any method of birth control be procuring a miscarriage? Finally, with at least 40% of blastocysts regularly failing to implant there seems little logic in putting a high value on something with which Nature itself is so prodigal. Prescribers must, of course, respect the views of their patients, and EC methods should not be used for any who are unhappy with the above interpretation. They should then, however, also understand the implications in relation to other methods.

What is the definition of postcoital contraception, or emergency contraception (EC)?

In current usage, this is any female method that is administered after intercourse but has its effects prior to the stage of implantation. The latter is believed to occur no earlier than 5 days after ovulation. Any method applied after intercourse that acts after implantation, even if this is before the next menses, should properly be called a postconceptional or contragestive agent. The term morning-after pill is not ideal because it could actually result in pregnancies by preventing women from presenting many hours later than the morning after. Yet efficacy does appear to be greater the earlier hormone regimens are commenced.

Given all the new data and their implications, is there up-todate guidance for clinicians about EC?
Yes, Guidance, emergency contraception was issued in April 2006 by the Clinical Effectiveness Unit of the Faculty of Family Planning and Reproductive Health Care (FFPRHC; Journal of Family Planning and Reproductive Healthcare 32: 1217). In the rest of this article this will be referred to as FFP Guidance. As it includes all the most important references, these will not be referenced individually here, aside from the two seminal WHO studies: Multicentre, double-blind randomized controlled trial of 1998 women randomized to Levonorgestrel (LNG) 0.75 mg stat versus two tablets of a contraceptive containing 250 mg of LNG with 50 mg of EE, each repeated in 12 h. This will be referred to as WHO 1998 study (Lancet 1998; 352: 428433) Multicentre, double-blind randomised controlled trial of 4136 women randomized to 10 mg mifepristone as a single dose or two LNG regimens, which were for 1356 subjects standard progestogenonly emergency contraception (POEC) two doses of 0.75 mg LNG 12 h apart and for another 1356 the whole 1.5 mg was taken as a single LNG dose. This will be called WHO 2002 study (Lancet 2002; 360: 18031810).

What are the implications of rejection of EC methods on ethical grounds?

In the main, this means that the woman concerned should also not use either intrauterine devices (IUDs) or intrauterine systems (IUSs), or the old-type progestogen-only pill. All these methods although primarily working before fertilization, can operate in a small minority of cycles by blocking implantation.

What is the history of EC?

This is probably almost as old as the rst recognition that semen is in some way responsible for pregnancy. Douching has been used since ancient times and remains in use today; 25% of women presenting for EC treatment in one UK study had rst used a shower attachment, flannel or paper tissues, with or without a spermicide or household germicide. These methods are doomed to frequent failure; because sperm have been found in cervical mucus within 90 s of ejaculation. The Persian physician Al-Razi suggested: First immediately after ejaculation let the two come apart and let the woman arise roughly, sneeze and blow her nose several times and call out in a loud voice. She should jump violently backwards

J Guillebaud MA FRCSE FRCOG is Emeritus Professor of Family Planning and Reproductive Health at University College London. This article has been reproduced from: John Guillebaud. Contraception: Your Questions Answered (4th ed.). Edinburgh: Churchill Livingstone, 2004.

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Choice of methods for post coital contraception a brief summary

Copper IUD Levonorgestrel (LNG) method (Levonelle 1500TM or over-the-counter, Levonelle One StepTM) Levonorgestrel 1.5 mg stat Combined hormone method

Normal timing Up to 5 days after earliest calculated day of ovulation or 5 days after earliest exposure in that cycle Efcacy Almost 100% (timing as above) Side-effects Pain, bleeding, risk of infection through insertion Contraindications Pregnancy and as for IUDs generally

(Yuzpe: NB used only when LNG method not available) Microgynon-30 4 pills stat, 4 pills 12 hours later Up to 72 h

Up to 72 h but usable to 120 h after earliest act of intercourse

98.5%* (within 72 h)

97% (within 72 h)

Nausea 23% (15%)* and vomiting 6% (14%)* Pregnancy Active acute porphyria Severe allergy to a constituent

Nausea 51% and vomiting 19% Pregnancy Current focal migraine, jaundice, active acute porphyria, sickle-cell crisis, severe liver disease or serious past thrombosis Severe allergy to a constituent

References: WHO (1998) Lancet 352: 42833 and *WHO (2002) Lancet 360: 180310. Numbers rounded to one decimal place.

Table 1

seven to nine times. Jumping backwards supposedly dislodged the semen; jumping forwards would assure pregnancy. A range of EC pessaries and douches have been described over the years, including wine and garlic with fennel, used in Egypt as early as 1500 BC; ground cabbage blossoms in the fourth century; and culminating in Coca-Cola in some developing countries even today. Diet Coke may actually have had some spermicidal action but then they removed the quinine! The history of more effective methods begins in 1963 with trials of diethylstilboestrol (DES) at Yale University. Because of the risks to any pregnancy should the method fail, DES should now never be used. After the mid-1970s the Yuzpe method (devised by a Canadian gynaecologist) became the first-choice method, using much less ethinylestradiol (EE) in combination with LNG. Immediate insertion of a copper IUD is an alternative method rst reported in 1972 and appropriate in some cases.

What are the currently accepted regimens of EC treatment?

See Tables 1 and 2. Immediate insertion of a copper-bearing IUD (not the LNG-IUS), not more than 5 days after the most probable calculated date of ovulation, even if there have been multiple acts of unprotected intercourse; or 5 days after any single (earliest) exposure. The Yuzpe method: this is started within 72 h of the earliest

act of unprotected intercourse, its efficacy being greatest in the rst 24 h and declining thereafter (although not to nil after 72 h). Two tablets of a contraceptive containing 250 mg of LNG with 50 mg of EE (or Ovran) are given at once, followed by a further two tablets 12 h later. Although in the UK this has been supplanted by POEC and will be little discussed below, practitioners in some countries are forced where there is no source of oral LNG (i.e. no appropriate POPs on the market) to continue to recommend the Yuzpe method. This commonly entails using four tablets of Microgynon-30 or local equivalent brand stat, repeated in 12 h. Use of LNG alone: this is referred to here and in the FFP Guidance as POEC. If started within 72 h of the earliest exposure it again has its greatest efficacy in the rst 24 h, declining thereafter but, not to nil, at 72 h (Table 2). It requires 1500 mcg LNG stat. In the WHO 1998 study it proved to be more effective, with fewer side-effects (especially vomiting) and there are also fewer contraindications. In the UK this is now marketed to clinicians as Levonelle 1500 and to the public over the counter as Levonelle One Step. In the US, a version of POEC EC has the excellent brand name Plan B! Outside Europe and the US practitioners are usually forced to construct the dose from marketed POPs (e.g. by giving 50 tablets of the local equivalent of Norgeston stat). If this can be done it is still preferable (with much reassurance of the woman that 50 tablets is not an overdose!) to constructing the less effective Yuzpe regimen in (2), above. Other methods previously in use are now of historical interest

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Efcacy of Yuzpe (combined oestrogen-progestogen) compared with POEC (progestogen-only emergency contraception) WHO ndings (1998 and 2002)
Coitus-to-treatment 72 h or less Combined oestrogen-progestogen POEC 24 h or less Combined oestrogen-progestogen POEC 2548 h 2.0% 0.4% 95% Pregnancy rate WHO 1998 Study 3.2% 1.1% 1.5% (to 120 h if abstained after treatment) 80% WHO 2002 Study Of those truly at risk, % of conceptions prevented

Combined oestrogen- progestogen POEC 4972 h Combined oestrogen- progestogen POEC 72120 h LNG-only (both regimens)

4.1% 1.2% 4.7% 2.7% 2.5% (? as small nos in 2002 study)

85%

58%

In the WHO trial, it is calculated that with just the single sexual exposure, only about 8% of all those treated would have conceived without treatment. Percentages in the last column use these as the denominator.

Table 2

only.

What is the mechanism of action of EC contraceptive methods?

The IUD operates by blocking implantation when, as commonly it is, inserted after ovulation, although if applied earlier in the cycle it will use its primary action (as in more usual long-term use) to block fertilization. The mode of action of POEC is incompletely understood. If taken before the LH surge it will usually inhibit ovulation, and it is probable that the uterine fluid/genital tract mucus can also be rendered hostile to the sperm. After ovulation, other effects on LH levels and the length of the luteal phase might be important but there is little evidence to support a direct antiimplantation effect (FFP Guidance). Most authorities now believe that if POEC is not administered in time to block ovulation or fertilization, the method is much more likely to fail. It is important to remember that fertile ovulation might simply be postponed in that cycle, hence the requirement to use a method such as the condom until the next period.

Will POEC work if given later than 72 h?

Yes, but less well. Although many prescribers have treated it as such, the 72-h time limit as licensed has never implied an absolute contraindication. From the data of the rst WHO trial (1998), it
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appeared (although not well confirmed in the later 2002 trial) that POEC worked best if started in the rst 24 h, and the failure rate increased with time thereafter. In the second WHO (2002) trial, the two-dose POEC regimen had a 1.7% failure rate for treatment in the rst 72 h, rising to 2.4% for treatment between 72 and 120 h. Given that so many would not have conceived anyway, calculations based on the best available data for conception risk by cycle day before or after ovulation showed that this corresponds to a fall from preventing 79% of actual conceptions to 60%. The results for the single dose were very similar at both time periods of the intervention, and if the two LNG regimens were pooled, treatment from 72 to 120h had an overall failure rate of 8/314 cases or 2.5% (equating to prevention of about 60% of actual conceptions expected). Most clients, if they have rejected the alternative of having a copper IUD inserted, will see those numbers as considerably better than doing nothing. Moreover, the WHO researchers concluded: Even if a declining trend in efficacy with time were verified, the regimens studied still prevent a high proportion of pregnancies even up to 5 days after coitus. Only 12% of the WHO subjects were treated on days 4 and 5, confidence intervals were wide including zero effect. So the FFP Guidance is cautious saying only LNG EC (=POEC) may be considered between 73 and 120 hours after UPSI, but women should be informed of the limited evidence of efficacy, that such use is

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outside product licence and of the alternative of an IUD.

This late treatment ought certainly to be better than nothing,

stopping at best 6 out of 10 actual pregnancies to be expected with no treatment (contrast about 8 out of 10 if she had been treated earlier) and: The treatment must be on a named patient basis until the SPC changes, as it probably will in due course.

Do you consider it is now adequately evidence-based (although unlicensed) to use POEC between 72 and 120 h after UPSI in selected cases?
Yes, I do! In the WHO 2002 study for the POEC and single-dose LNG groups combined, the conception rate was only 1.5% in all those who claimed abstinence after treatment when it was up to 5 days after the unprotected sexual intercourse (UPSI, although only about 12% were treated on days 4 or 5). However, it should be recorded that the woman understands that: She needs to be completely transparent about any possible earlier exposure, so that you can then proceed in good faith, in the belief that you will not be disturbing an already implanted pregnancy Insertion of a copper IUD would be more effective (indeed, I agree with the Faculty that should always be said, even to women presenting within 72 h of exposure)

Can POEC be given more than once in a cycle?

Yes. The FFP Guidance is in full agreement about this one!

Might other progestogens be effective?

Other progestogens such as desogestrel or gestodene, or even DMPA by injection, might well be effective but neither their efficacy nor the best doses have so far been evaluated in proper trials. The antiprogestogen, mifepristone, in a single 10-mg dose was shown definitively, in the third arm of the WHOs 2002 trial, to work as well as either LNG regimen.

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