2.1 Mechanism of Action

The precise mechanism of action of emergency contraception in an individual case cannot be certain as it depends on the time in the menstrual cycle when the intercourse has occurred and when EC is taken.

The various postulated mechanisms depending on the phase of cycle are:

• inhibition or delay of ovulation when used prior to ovulation
  
• thickening of cervical mucus resulting in trapping of sperms.
  
• direct inhibition of fertilization
  
• histological and biochemical alterations in the endometrium leading to impaired inhibition or delay of ovulation when used prior to ovulation endometrial receptivity to implantation of a fertilized egg.
  
• alteration in the transport of egg, sperm, or embryo.
  
• interference with corpus luteum function and luteolysis

In summary, emergency contraception can interfere with ovulation, fertilization or implantation depending on the phase of menstrual cycle. EC is not effective once the process of implantation of a fertilized ovum has begun and this is the basis for the window-period of effective time frame.

2.2 Overview of methods

+ High dose estrogen

This was the first scientific method introduced in the 1960s. The method consisted of diethylstilbestrol (DES) being given in a dose of 50 mg per day for 5 days. Subsequently, the dose was reduced to 10 mg per day. Association of DES with potential effects on female offspring resulted in the discontinuation of use of DES. Other estrogens like conjugated equine estrogen; ethinyl estradiol and depot estrogens were also used. Though found effective in preventing pregnancy, high-dose estrogen use is associated with a high incidence of side-effects, especially nausea and vomiting. Thus, women sometimes fail to complete the prescribed course of treatment. Besides, menstrual pattern is disrupted following estrogen use and the next period can be earlier with heavier flow. After treatment failure, 10% of pregnancies are likely to be ectopic pregnancies; thus estrogens alone are no longer used as Emergency Contraception.

+ Estrogen-Progestin combination

In 1972 Yuzpe and his colleagues evaluated a combined ethinyl estradiol and norgestrel pill each containing 50µg ethinyl estradiol and 0.5 mg of norgestrel, 2 tablets being given twice, 12 hours apart, within 72 hours of unprotected intercourse. This is commonly known as Yuzpe Method. This has fewer side-effects compared to high dose estrogen but still about 50% have nausea and 10- 25% vomit. This is an easily available method. Regular dose oral contraceptive pill can be used as post-coital pill in prescribed dose. A 4 pill dedicated pack of combined ECP has been withdrawn from market in certain countries following reports of higher efficacy and fewer side effects with levonorgestrel.

+ Progestogens

Norgestrel as well as quingestanol have been tried and shown to be effective over a range of doses. The side-effects of progestogen-only pills are less than combination pills. In low doses, progestogen may change the menstrual pattern. Trials have shown progestogen-only pill containing 0.75mg levonorgestrel (LNG) given in 2 doses, 12 hours apart within 72 hours of unprotected intercourse, to be more effective with fewer side-effects compared to Yuzpe method 6 . LNG has also been tried as 2 doses of 0.75mg, 12 hours apart upto 120 hours after sexual exposure, as well as, as a single dose of 1.5mg again within 120 hours¹¹. Single dose has been reported to be as effective as two doses 12 hours apart without increasing the side effect and is more convenient to use. Currently LNG is the most accepted method for emergency contraception.

+ Antiprogestogens

These are anti-implantation agents when given post-coitally, menses inducers when given in luteal phase and abortifacients when given in early pregnancy. Several antiprogestogens have been tried. RU486 (mifepristone) has been found effective in a single dose of 600mg, 100mg and 10mg when used as emergency contraception. Current accepted dose for emergency contraception is 10mg. In a comparative trial of RU486 with Yuzpe regimen, side-effects were less common with mifepristone but menstrual disturbances occurred more often¹².

+ Antiestrogens

Danazol has a direct luteolytic effect. A 400mg dose repeated 12 hourly for 2 or 3 doses has been used with lesser side effects compared to Yuzpe regimen¹³.

+ Centchroman

This an antiestrogen with no progestational, androgenic or antiandrogenic effects. It has been used as two 50 mg tablets given 12 hours apart within 72 hours. Main side-effect is ovarian enlargement and delay in menstruation causing confusion and tension. Adequate trials of Centchroman as an effective emergency contraceptive are yet to be conducted.

+ Intra-uterine Device (IUD)

Insertion of copper-T and copper-7 within 7 days of unprotected intercourse have been reported as a highly successful method for post-coital contraception. Copper-T is effective following even multiple coital exposures during a short interval especially when the delay is beyond 120 hours, but less than 1 week, making hormonal methods ineffective. IUD is particularly suitable for women who would like to continue using it as a regular contraceptive. Contraindications to emergency IUD use are the same as regular use.

2.3 Effectiveness and probability of conception

Overall emergency contraception methods are less effective than regular contraceptive methods. As a woman is not capable of conceiving throughout cycle, EC effectiveness is better expressed in terms of ‘prevented fraction’ of pregnancies after calculating the probability of conception rather than the percentage failure.

The probability of conception after single act of intercourse is approximatly 8%. Conception rate has been calculated to be about 33% per cycle if intercourse occurs on average every other day;14 if it occurs only once a week, the risk of
pregnancy is about 15%. Most women who have unprotected intercourse on a single occasion, therefore, will not conceive. But the number of fertile days of a menstrual cycle is difficult to quantify. The sperms remain alive in the female genital tract and are capable of fertilization for up to 5 days after ejaculation; the egg appears to be capable of being fertilized for only about 24 hours. In a recent study of couples actively trying to conceive with hormone measurements to determine the timing of ovulation, the fertile period lasted about six days, ending on the day of
ovulation¹⁴ . Acknowledging the small sample size in their study, however, the authors concluded that a probability of conception of up to 12% was theoretically possible if intercourse occurred on the day after ovulation.

A normal fertile sexually active couple not using contraception has an average monthly chance of conception of 20-25% (counting only pregnancies that result in live births). After fertilization, 25% of zygotes do not implant and
those that implant, a proportion (17%) is lost before a pregnancy becomes clinically recognizable. Thus, in 42% cases no clinically recognizable pregnancy results. Eight per cent of pregnancies are lost spontaneously even after clinical confirmation¹³. Accordingly, prospect of EC within 120 hrs of intercourse, interrupting the natural development of a fertilized ovum appears very low, and more so after a single act of unprotected intercourse. Therefore, in a vast
majority of cases, EC addresses a theoretical or statistical, rather than an actual, chance of fertilization having occurred and relieves the woman’s apprehension of unwanted pregnancy considerably.

Efficacy

For calculating the prevented fraction the formula used is:

1 - Observed Pregnancies
----------------------------------
Expected Pregnancies

For calculating the expected pregnancies, conception risk in menstrual cycle is calculated by probability of conception on that day of cycle which has been calculated scientifically (Fig 1). The day of ovulation is calculated by subtracting
14 days from the expected date of next period and depending on the day of coitus in relation to this
day probability is estimated. Thus efficacy of EC in expressed in 2 ways

• Overall pregnancy rate and

• Prevented fraction of pregnancies

2.4 Levonorgestrel (LNG) - the dedicated method of choice

Levonorgestrel - two tablets of 0.75mg (single pack) is specifically developed for emergency contraception. Though a wide range of regular oral contraceptive pills can also be used, it is believed that a dedicated product that is ‘a product which is specifically packaged and labeled for use as emergency contraception’ would ensure correct dosage, along with trust of the client and service-providers towards emergency contraception. Levonorgestrel is the preferred method over Yuzpe regimen due to its higher efficacy and lesser side effects⁶.

2.4.1 Dosage schedule and time frame

LNG ECP is available as a two pill pack each tablet containing 0.75 mg of levonorgestrel. The pill can be prescribed in two ways –

• single dose – both tablets (total 1.5 mg LNG) to be taken together as a single dose within 120 hours of sexual exposure

• two dose regimen - one tablet to be taken as soon as possible after intercourse but not later than 120 hours, and second tablet 12 hours later.

2.5 Alternate methods for EC

2.5.1 Combined oral contraceptive pill

(Yuzpe Regimen)

Combined estrogen-progestin contraceptive pills (COC) used in dosage so as to deliver 100 µg of ethinyl estradiol plus 0.5 mg of levonorgestrel (or 1.0 mg norgestrel) as soon as possible but optimally within 72 hours after unprotected intercourse, twice at 12 hours interval.

As different COC formulations are available, the number of tablets to be used can be decided according to Table 4.

Advantages :

• universally available

• women familiar with pills thus find COC more acceptable

Disadvantages :

• confusion about doses in different formulations

• contraindications to estrogen use in some women

• higher probability of side-effects as compared to LNG

2.5.2 Intra–uterine device (IUD)

A trained healthcare provider can insert a Copper T IUD within 5-7 days of unprotected sex.

This is the most effective EC method but is not suitable for masses since infrastucture and training is required. CuT use is undesirable in young nulliparous women or in women with multiple sex partners. There is a risk of pelvic inflammatory disease and subsequent infertility following CuT use especially in high-risk women. Sometimes, irregular bleeding associated with IUD insertion may mask diagnosis of early pregnancy.

Advantages :

• higher efficacy rates (over 99%)⁴
  
• very few compliance issues
  
• no systemic effects
  
• can be used as ongoing long-term contraception
  
• suitable for clients with history of thrombo-embolic disease, stroke, heart attack and women who have difficulty ingesting ECP due to vomiting
  
• may be suitable for women who present later than 120 hours and before 7 days of unprotected intercourse 4 .
  
• can be used as a ‘third-chance’ when EC pill has been vomited or the woman is unable to take the full dose due to intractable nausea or other side effects.

Disadvantages :

• unsuitable for women with multiple sex partners and those with active reproductive tract infection
  
• relatively contraindicated in nulliparous women
  
• not suitable for women with previous ectopic pregnancy
  
• the infrastructure and trained personnel may not be available everywhere
  
• irregular bleeding or spotting associated with CuT insertion may be confused with bleeding due to abortion or ectopic pregnancy and vice versa, delaying the diagnosis.

2.5.3 Mifepristone (RU-486)

These anti-progestins act as :

• anti-implantation agents when given post-coitally

• menses-inducers when given in luteal phase

• abortifacients when given in early pregnancy

Mifepristone (RU486) has been found effective in single dose of 600 mg, 50 mg and 10 mg when used as emergency contraception^7,12. Current accepted dose is 10 mg as a single dose to be used within 120 hours of sexual exposure.

In comparative trial of RU 486 with Yuzpe regimen, side-effects were less common with mifepristone but menstrual disturbances were observed more often.

Advantages :

• single dose

• well tolerated with minimal side-effects

Disadvantages :

• menstrual delay adds to anxiety in women

• break-through ovulation may occur resulting in failure if further sexual exposure occurs

• higher risk of ectopic pregnancy

•10 mg formulation is not available in India

2.6 Special Consideration

2.6.1 Limitations

• the efficacy of emergency contraceptive pills is influenced by the time elapsed since unprotected intercourse and the time in a women’s cycle at which she had sex. The earlier the ECP are taken after unprotected intercourse, the more effective they are. The closer a woman is to ovulation at the time of unprotected intercourse lower is the efficacy.
• the failure of ECP to prevent pregnancy beyond the time-frame of efficacy window (120 hours) following unprotected intercourse may limit it’s use in clients who report later than this interval, as awareness is low.
• copper IUD (most effective method of EC) is unsuitable for nullipara and clients at risk of STIs.

2.6.2 Safety of ECP

In more than 30 years of ECP use no deaths or serious medical complications have been reported. The dose of
hormones is relatively small and the short exposure does not have any metabolic effects.

The use is not associated with fetal malformations or congenital defects.

ECP do not increase the risk of ectopic pregnancy, but there may be a higher percentage of ectopic pregnancies among failures, thus possibility of ectopic pregnancy is to be ruled out in all cases of ECP failure.

2.6.3 Side-effects

There are no major side-effects reported. A few temporary minor adverse events, which are not present usually beyond 48 hours are listed in Table 5.

Some women also experience inter-menstrual bleeding and altered menstrual cycles including heavier menstrual bleeding (13.8%) or lighter bleeding (12.5%). Majority of women (58%) will have their next menstrual period at the expected time or within a few days of the expected date⁶.

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