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Advances in Methods of Emergency Contraception

Levonorgestrel – A new and effective Emergency Contraceptive
- Dr P C Ho, Hongkong

For many years, the standard method of Emergency Contraception was the Yuzpe regimen1. While it is a reasonably effective regimen, it is associated with a high incidence of nausea and vomiting, mainly due to the oestrogen component of the pills. To avoid these side-effects, a number of studies have been conducted to assess the value of levonorgestrel alone for Emergency Contraception.

Levonorgestrel is a potent progestogen which is orally active. When 0.75mg of levonorgestrel is administered by mouth, the peak plasma level is achieved within 1.9 hours, with a peak plasma concentration of 9 to 11.5g/ml. The plasma half-life is 8.9 to 14.5 hours. The use of levonorgestrel for Emergency Contraception was first reported by Hoffman2. In this study, a single dose of 0.6mg of levonorgestrel was administered within 12hours of an unprotected intercourse. The pregnancy rate was 2.9%.

The first randomised comparison of the levonorgestrel with the Yuzpe regimen was carried out in WHO supported study3. In this study, women requesting emergency contraception within 48 hours of an unprotected intercourse were randomised to receive either the Yuzpe regimen or levonorgestrel (0.75mg at the time of presentation and repeated 12 hours later). Because the results were very encouraging, WHO conducted a multicentre study comparing the Yuzpe regimen with levonorgestrel4. In this study, women requesting Emergency Contraception within 72 hours of unprotected intercourse were recruited.

In these two studies, 2878 women were recruited; 1437 were randomised to the Yuzpe regimen and 1441 were randomised to the levonorgestrel group. The outcome was available in 1403 in the Yuzpe group and in 1386 in the levonorgestrel group. 1400 women in the Yuzpe group and 1384 women in the levonorgestrel group fully complied with the regimens. The characteristics of the women are shown in Table 1. It can be seen that they are similar in the two groups of women.

Table 1 : Characteristics of women in the Yuzpe and levonorgestrel groups 

 GROUPS
YuzpeLevonorgestrel
Mean age (yr) 27.027.2
Mean cycle length (days)29.329.5
Mean body mass index (Kg/m2) 21.621.6

Percentage of women with previous pregnancies

56.8% 58.5%

Interval between coitus & treatment

  
24h 51.8% 51.9%
25 - 48 h37.5% 34.5%
49 - 72 h 10.7% 13.5%

Interval between coitus and estimated day of ovulation

  
> 1 day before42.9%45.9%
1 day22.1%23.0%
> 1 day after29.1% 31.1%
   

The pregnancy rates and efficacy of the two groups are shown in Table 2. The pregnancy rate in the Yuzpe group was significantly higher than that in the levonorgestrel group. Using the pooled estimates of the fecundity of women at various parts of the menstrual cycle5, we estimated the number of expected pregnancies in the two groups of women if no treatment was given. This was compared to the number of observed pregnancies in the two groups of women and the percentage of pregnancies prevented was calculated as the efficacy of the two methods. It can be seen that the efficacy of the levonorgestrel regimen was significantly higher than that of the Yuzpe regimen.

Table 2 : The pregnancy rates and estimated efficacy in the Yuzpe and levonorgestrel groups

 GROUPSRelative risk
(95% confidence intervals)
Yuzpe
n = 1403
Levonorgestrel
n = 1386
Pregnancy rate3.28%a1.66%a0.51
(0.29 - 0.85)
Estimated efficacy 66.6%b83.9%b0.79
(0.68 - 0.93)
a = p < 0.01; b = p < 0.005

The incidence of side-effects of the two regimens are shown in Table 3. It can be seen that the incidence of nausea, vomiting, dizziness and fatigue in the Yuzpe group was significantly higher than that in the levonorgestrel group.

Table 3 : Incidence of side-effects

 GROUPS
Yuzpe
n = 1403
Levonorgestrel
n = 1386
Nausea*49.2%26.6%
Vomiting* 19.9% 4.8%
Dizziness*18.6% 13.3%

Fatigue*

31.0% 19.0%
Breast tenderness 14.7%12.3%

 

  
* p<0.05  

 

An important finding from these two studies is the reduction in efficacy of the method with increase in the coitus-treatment interval. The implication is that the drugs must be given as early as possible after an unprotected intercourse in order to achieve maximal efficacy. Barriers to the easy access to Emergency Contraception must be removed so that the methods can be used effectively. Another important factor affecting the pregnancy rate is the occurrence of further acts of intercourse. The results showed that in women who had further acts of intercourse after the administration of Emergency Contraception, the pregnancy rates were higher. Therefore the women should be counselled that the emergency contraception cannot protect the women against pregnancy if they had further acts of intercourse subsequent to the use of Emergency Contraception.

The mechanism of action of levonorgestrel in emergency contraception is not yet known. In a study by landgren et al6 volunteers were given four to five doses of 0.75 mg of levonorgestrel every 48 hours in different parts of the menstrual cycle. The results showed that if the levonorgestrel was given on day 2, 4, 6 and 8, there was an increase in the duration of the follicular phase. When the levonorgestrel was given from day 9 onwards, there were varying effects on the menstrual cycle including anovulation, deficient luteal function and no effect. There were also variable effects on the endometrium. In another study7 it was found that 0.4 mg of levonorgestrel given 3 to 10 hours post-coital could lead to a reduction in the number of sperms in the uterine cavity beginning from 3 hours after treatment. There was pronounced alkalinization of the intra-uterine fluid beginning at 5 hours after treatment. There was also an increase in viscosity of cervical mucus. However, since the regimens used in these studies were different from that used in the two clinical studies, it is not certain whether these results can be extrapolated to the regimen used in the clinical studies. We have recently studied the effects of levonorgestrel on the in-vitro sperm function and found that levonorgestrel has only minimal effects on the sperm function.

Despite its efficacy, it must be emphasized that levonorgestrel should not be used as a regular post-coital contraceptive. In a multicentre study conducted by WHO8, levonorgestrel was tested for its efficacy as a regular post-coital contraceptive. In this study, the women were given 0.75 mg of levonorgestrel within 8 hours of intercourse followed by another dose 24 hours later. Further doses were given after each further act. There were two pregnancies from 259 cycles. Although the pregnancy rate was only 0.8% per cycle, the pearl index was 10. Moreover, over 20% of the women had some form of menstrual disturbance. Therefore, women who are expected to have regular sexual intercourse should be advised not to rely solely on post-coital levonorgestrel as the method of contraception. Other more reliable methods of regular contraception should be discussed.

Levonorgestrel was more effective and better tolerated than the Yuzpe regimen in emergency contraception. The efficacy decreases with increase in coitus-treatment interval.


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