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Emergency contraception
Reviews in Gynaecological Practice 3 (2003) 98–102
Review
Emergency contraception P.C. Ho∗ , O.S. Tang1 , E.H.Y. Ng2 Department of Obstetrics and Gynaecology, Queen Mary Hospital, University of Hong Kong, 6/F, Professorial Block, Pokfulam Road, Hong Kong, China Received 1 April 2003; accepted 14 April 2003
Abstract The standard method for emergency contraception used to be the Yuzpe regimen, which consists of two doses of combined oral contraceptive pills at 12 h interval. It can prevent 74% of the expected pregnancies but the incidence of side effects like nausea and vomiting is high. Recent studies have shown that both mifepristone and levonorgestrel are more effective and better tolerated than the Yuzpe regimen. The dose of mifepristone can be reduced to 10 mg without affecting its efficacy. However, 10 mg tablets of mifepristone are not commercially available except in China. A single dose of 1.5 mg of levonorgestrel is as effective as two doses of 0.75 mg levonorgestrel given at 12 h interval or 10 mg of mifepristone. This is likely to become the hormonal method of choice in many countries. The insertion of a copper intrauterine contraceptive device is probably the most effective method of emergency contraception, preventing over 90% of the pregnancies. However, it may not be suitable for women with high risk factors for pelvic inflammatory disease. There has been an increase in the awareness of emergency contraception in the recent decade but the knowledge is still poor in some countries. There is also a need to improve the access to emergency contraception. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Emergency contraception; Postcoital contraception; Levonorgestrel; Mifepristone
1. Introduction
2. Estimation of efficacy
Emergency contraception is contraception administered to a woman after an unprotected intercourse. In the past, it has also been named as postcoital contraception or morning after pills. Emergency contraception is needed when intercourse is unexpected and therefore contraception has not been used. Other indications include failure of barrier methods like the slipping or breakage of condom, and after rape. Emergency contraception may be an effective way to reduce the number of unwanted pregnancies. It has been estimated that the widespread use of emergency contraception may reduce the number of abortions in USA by more than 1 million [1]. In the last decade, a number of new and effective methods of emergency contraception have been introduced. There was also an increase in the awareness of emergency contraception. In this article, the various methods of emergency contraception are reviewed.
As not all women who have an unprotected intercourse will conceive, the proportion of women who did not conceive after the use of emergency contraception is not a good indicator of the percentage of pregnancies prevented. In many recent studies on the use of emergency contraception, the efficacy of the method is estimated by comparing the number of pregnancies expected without treatment with the number of observed pregnancies after treatment. The number of pregnancies expected is calculated from the probabilities of pregnancy on each cycle day derived from previous prospective studies involving women who are trying to conceive [2]. However, these estimates are based on a number of assumptions: (a) the woman is ovulating regularly, (b) the woman’s history of the last menstrual period is accurate, and (c) the fertility of women using emergency contraception is the same as that of women who are trying to conceive. Recent studies have cast doubt on the accuracy of these estimates [3,4]. Therefore, while there is as yet no better method of estimating the efficacy of emergency contraception, the current methods of estimation are probably not very reliable.
∗ Corresponding
author. Tel.: +852-28554260; fax: +852-28550947. E-mail addresses: [email protected] (P.C. Ho), [email protected] (O.S. Tang), [email protected] (E.H.Y. Ng). 1 Tel.: +852-28553360; fax: +852-28175374. 2 Tel.: +852-28553400; fax: +852-28175374.
1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00044-3
P.C. Ho et al. / Reviews in Gynaecological Practice 3 (2003) 98–102
3. Methods 3.1. High doses of oestrogens The first hormonal method used for emergency contraception is oestrogen in high doses for 5 days [5,6]. Ethinyl oestradiol, conjugated oestrogens or diethylstilboestrol have been used for this purpose. However, this method is associated with a high incidence of side effects like nausea and vomiting, and it is seldom used nowadays. 3.2. Yuzpe regimen This regimen consists of the administration of two doses of combined oral contraceptive pills (each dose containing 100 g of ethinyl oestradiol and 1 mg norgestrel) at 12 h interval within 72 h of the intercourse [7]. The reported failure rate in the literature ranged from 0.2 to 7.4%. It is estimated that the Yuzpe regimen can prevent over 74% of the pregnancies [2]. The pregnancy rate increases with the interval between intercourse and administration of the drugs [8]. Therefore, it is important that the drugs are given as early as possible after intercourse. The most common side effects of the regimen are nausea and vomiting with an incidence of 50 and 15%, respectively. Serious side effects or complications have not been reported with this regimen. Therefore, according to the eligibility criteria of the World Health Organization (WHO) [9], confirmed pregnancy is the only contraindication to the use of emergency contraception because once a pregnancy is established, this regimen is not effective. There is no evidence that there is an increased risk of fetal anomalies among women who conceived while taking combined oral contraceptive pills [10]. The Yuzpe regimen probably acts by suppressing or postponing ovulation. When the Yuzpe regimen is administered before the luteinizng hormone (LH) surge, it may blunt or delay the LH peak [11]. A more recent study [12] showed that if the Yuzpe regimen was administered when the follicle was 12–17 mm, ovulation was absent in the following 5 days in 65% of the women. However, if the Yuzpe regimen was given when the follicle was 18–20 mm in diameter, ovulation was not suppressed. As the Yuzpe regimen has only minimal effects on the endometrium [11], it is likely that if the Yuzpe regimen is given at this time of the cycle, it may not be effective in preventing pregnancy. 3.3. Mifepristone Mifepristone is a progesterone antagonist at the receptor level. Two early studies [13,14] in United Kingdom compared the use of 600 mg of mifepristone with the Yuzpe regimen in emergency contraception within 72 h of coitus. The pregnancy rate in the mifepristone group was lower than that in the Yuzpe regimen group. The incidence of nausea and vomiting in the mifepristone group was significantly
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lower than that in the Yuzpe regimen group but significantly more women in the mifepristone group had a delay in the return of menstruation of more than 3 days. This may cause undue anxiety about the possibility of pregnancy. A subsequent multicentre study conducted by WHO [15] compared the efficacy and side effects of three doses of mifepristone in women requesting emergency contraception within 120 h of an unprotected intercourse. The results showed that the pregnancy rates in the three groups were comparable (1.2, 1.1 and 1.3% in the 10, 50 and 600 mg groups, respectively). However, the incidence of delay in onset of next menses and bleeding within 5 days of drug administration was inversely related to the dose and lowest in the 10 mg group. Since 10 mg tablets of mifepristone are not commercially available except in China, Ashok et al. [16] compared the efficacy and acceptability of 100 mg of mifepristone with those of the Yuzpe regimen. The results showed that 100 mg of mifepristone was significantly more effective and better tolerated than the Yuzpe regimen. Despite the delay in the return of menstruation, significantly more women were satisfied with mifepristone as an emergency contraceptive. It was estimated that these regimens could prevent 84–92% [15,16] of pregnancies. The effects of mifepristone on the ovulation and endometrium depend on the dose and the time when it is given. If a single dose of 10 mg of mifepristone is given when the follicle is greater than 12 mm, the LH peak is either inhibited or depressed [17]. When 200 mg of mifepristone is given 2 days after the LH surge, endometrial development is inhibited and endometrial function is impaired [18]. A single dose of 10 mg given around the same time has a similar but less marked effect [19]. It is uncertain whether these effects are sufficient to inhibit implantation. Therefore, mifepristone at a dose of 10 mg may act mainly through its effects on the ovulation process. 3.4. Levonorgestrel Levonorgestrel is an orally active progestogen. The efficacy of levonorgestrel in emergency contraception was first demonstrated by Ho and Kwan [19] in a comparison of the Yuzpe regimen with levonorgestrel (two doses of 0.75 mg given at 12 h interval) within 48 h of an unprotected act of intercourse. The failure rate of levonorgestrel was slightly lower than that of the Yuzpe regimen and the incidence of nausea and vomiting in the levonorgestrel group was significantly lower than that in the Yuzpe regimen group. Because of these encouraging results, the WHO conducted a multicentre study comparing the efficacy and side effects of the levonorgestrel regimen with those of the Yuzpe regimen in emergency contraception within 72 h of coitus [8]. The pregnancy rate in the levonorgestrel group (1.1%) was significantly lower than that in the Yuzpe regimen group (3.2%). It was estimated that levonorgestrel could prevent 85% of the pregnancies while the Yuzpe regimen could prevent 57% of the pregnancies. The efficacy of both
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levonorgestrel and the Yuzpe regimen decreased with increase in the coitus-treatment interval. This study also confirmed that the incidence of side effects of levonorgestrel was significantly lower than that of the Yuzpe regimen. A more recent multicentre study by WHO [20] compared three regimens of emergency contraception: (1) 10 mg of mifepristone, (2) two doses of 0.75 mg of levonorgestrel at an interval of 12 h, (3) a single dose of 1.5 mg of levonorgestrel, within 120 h of coitus. The results of this study showed that the efficacy of the three regimens were similar and the pregnancy rates in the mifepristone group, the two-dose levonorgestrel group and the single-dose levonorgestrel group were 1.5, 1.8 and 1.5%, respectively. The incidence of side effects was similar in the three groups of women. Significantly more women in the mifepristone group had a delay of menses of more than 7 days (9% versus 5% in the other two groups). Even though the pregnancy rates were higher when the drugs were given between 72 and 120 h when compared to those when the drugs were given earlier, the administration of these drugs could still prevent 58–63% of the pregnancies. This study also showed that women who had further acts of intercourse had higher rates of pregnancy. Since a single dose of 1.5 mg levonorgestrel is more convenient for the women and the efficacy is similar to a double dose regimen, it should be the preferred regimen. Various groups have studied the mechanisms of action of levonorgestrel. Current evidence suggests that two doses of 0.75 mg of levonorgestrel probably act by inhibiting or interfering with the LH peak [17,21]. Although levonorgestrel does not affect in vitro sperm functions [22], it may affect the viscosity of the cervical mucus and migration of sperms in vivo [23]. Levonorgestrel did not appear to have any significant effects on the endometrium [17]. 3.5. Danazol Zuliani et al. [24] reported favorable results with the use of Danazol for emergency contraception with pregnancy rats of 1.7 and 0.8% for doses of 800 and 1200 mg, respectively. However, another study showed that the pregnancy rate with Danazol was 4.7%, which was higher than those of the Yuzpe regimen and mifepristone and the number of observed pregnancies was in fact not significantly different from that of expected pregnancies [13]. Therefore, it is now seldom used for emergency contraception. 3.6. Insertion of copper intrauterine contraceptive device The insertion of a copper intrauterine device (IUCD) is probably the most effective method of emergency contraception. It is effective up to 120 h after the unprotected intercourse. In a review of papers published up to 1995, the pregnancy rate was less than 0.1% in 8400 insertions of IUCD for emergency contraception [25]. A recent multicentre study in China showed that the pregnancy rate was only
0.2% after the postcoital insertion of IUCD within 120 h of an unprotected intercourse [26]. It was estimated that the percentage of pregnancies prevented was 98.1% in parous women and 92.4% in nulliparous women. The insertion of IUCD may be associated with the complications of pain, bleeding and pelvic inflammatory disease (PID) and it may not be the ideal method for women with high risk factors for PID. However, in carefully selected women, these complications are not common [26].
4. Barriers to the use of emergency contraception Despite an increase in interest and publicity on emergency contraception in the last decade, the knowledge of emergency contraception is still variable and remains poor in some countries [27]. Moreover, even when the women know about emergency contraception, they may not use it, probably because of an underestimation of the risk of pregnancy [28]. There is a need to educate the women on the risk of pregnancy and the need for emergency contraception if there is an unprotected intercourse. Since the efficacy of emergency contraception decreases with increase in the time interval between the act of intercourse and the treatment, it is essential that women should have easy access to emergency contraception. In many countries, drugs for emergency contraception need the prescription of a doctor. This makes it difficult for the women to obtain the drugs especially during weekends and holidays. The option of advanced provision of emergency contraception in women using the less reliable methods like the barrier method has been investigated [29,30]. Women tended to use emergency contraception more often if they were given a supply of emergency contraceptive drugs to be kept at home. On the other hand, the advanced provision of emergency contraception at home neither affects the regular use of contraception nor increases the incidence of unprotected intercourse. While these results are encouraging, many women especially teenagers may not have the opportunity of visiting a health care facility before the unprotected intercourse and other methods to improve access are necessary. Allowing pharmacy sales is one of the options that may help to improve access to emergency contraception [31]. The other option is to allow sales over the counter. It has been argued that emergency contraceptive pills meet all the requirements for over-the-counter use: low toxicity, no potential for overdose or addiction, no teratogenicity, no need for medical screening, self-identification of the need, uniform dosage and no important drug interaction [32].
5. Conclusion Mifepristone and levonorgestrel are equally effective for emergency contraception and both are more effective and better tolerated than the Yuzpe regimen. As levonorgestrel
P.C. Ho et al. / Reviews in Gynaecological Practice 3 (2003) 98–102
is more readily available than mifepristone, it is the drug of choice in many countries. Since the efficacy of a single dose of 1.5 mg of levonorgestrel is similar to that of two doses of 0.75 mg and the incidence of side effects is similar, it is the regimen of choice. Although there is an increase in awareness of emergency contraception, there is still a need to educate the women and to improve the access to emergency contraception so as to reduce the number of unwanted pregnancies. 6. Practice points • Both mifepristone and levonorgestrel are more effective and better tolerated than the Yuzpe regimen. • As mifepristone is still not widely available and not yet marketed for emergency contraception except in China, levonorgestrel is the drug of choice in many countries. • A single dose of 1.5 mg of levonorgestrel is as effective as the regimen of two doses of 0.75 mg of levonorgestrel given at 12 h interval. • The efficacy of the hormonal methods of emergency contraception declines with increase in coitus-treatment interval and therefore these drugs should be given as early as possible after an unprotected intercourse. • Hormonal methods of emergency contraception are less effective if there are further acts of unprotected intercourse in the same cycle and women should be counselled on this. • The insertion of a copper IUCD is probably the most effective method of emergency contraception but it may not be suitable for women with high risk factors for PID. • There is a need to improve the access to emergency contraception. 7. Research agenda • Studies on other drugs such as other antiprogestins to develop more effective hormonal methods of emergency contraception. • Studies to assess whether the advanced provision of emergency contraception can reduce the number of unwanted pregnancies. • Studies to assess the safety and impact of over-the-counter sales of emergency contraception. References [1] Trussell J, Stewart F. The effectiveness of the Yuzpe regimen of emergency contraception. Fam Plann Perspect 1996;28:58–64. [2] Trussell J, Rodriguez G, Ellertson C. New estimates of the effectiveness of the Yuzpe regimen of emergency contraception. Contraception 1998;57:363–9. [3] Stirling A, Glasier A. Estimating the efficacy of emergency contraception—how reliable are the data? Contraception 2002;66:19– 22.
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[4] Wilcox AJ, Dunson DB, Weinberg CR, Trussell J, Baird DD. Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives. Contraception 2001;63:211–5. [5] Dixon GW, Schlesselman JJ, Ory HW, Blye RP. Ethinyl estradiol and conjugated estrogens as postcoital contraceptives. JAMA 1980;244:1336–9. [6] Haspels AA. Interception: post-coital estrogens in 3016 women. Contraception 1976;14:375–81. [7] Yuzpe AA, Lancee WJ. Ethinylestradiol and dl-norgestrel as a postcoital contraceptive. Fertil Steril 1977;28:932–6. [8] World Health Organization Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998;352:428–33. [9] World Health Organization. Improving access to quality care in family planning: medical eligibility criteria for contraceptive use. Geneva: WHO; 1996. p. 31–3 [WHO/FRH/FPP/96.9]. [10] Bracken MB. Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studies. Obstet Gynecol 1990;76:552–7. [11] Swahn ML, Westlund P, Johannisson E, Bygdeman M. Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle. Acta Obstet Gynecol Scand 1996;75:738–44. [12] Croxatto HB, Fuentealba B, Brache V, Salvatierra AM, Alvarez F, Massai R, et al. Effects of Yuzpe regimen, given during the follicular phase, on ovarian function. Contraception 2002;65:121–8. [13] Webb AMC, Russell J, Elstein M. Comparison of Yuzpe regimen, danazol, and mifepristone (RU486) in oral postcoital contraception. BMJ 1992;305:927–31. [14] Glasier A, Thong KJ, Dewar M, Mackie M, Baird DT. Mifepristone (RU486) compared with high-dose estrogen and progestogen for emergency postcoital contraception. N Engl J Med 1992;327:1041–4. [15] 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. [16] Ashok PW, Stalder C, Wagaarachchi PT, Flett GM, Melvin L, Templeton A. A randomised study comparing a low dose of mifepristone and the Yuzpe regimen for emergency contraception. Br J Obstet Gynaecol 2002;109:553–60. [17] Marions L, Hultenby K, Lindell I, Sun X, Stabi B, Gemzell Danielsson K. Emergency contraception with mifepristone and levonorgestrel: mechanism of action. Obstet Gynceol 2002;100:65–71. [18] Gemzell Danielsson K, Svalander P, Swahn ML, Johannisson E, Bygdeman M. Effects of a single post-ovulatory dose of RU486 on endometrial maturation in the implantation phase. Hum Reprod 1994;9:2398–404. [19] Ho PC, Kwan MSW. A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception. Hum Reprod 1993;8:389–92. [20] von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet 2002;360:1803–10. [21] Hapangama D, Glasier AF, Baird DT. The effects of preovulatory administration of levonorgestrel on the menstrual cycle. Contraception 2001;63:123–9. [22] Yeung WSB, Chiu PCN, Wang CH, Yao YQ, Ho PC. The effects of levonorgestrel on various sperm functions. Contraception 2002;66:453–7. [23] Kesseru E, Garmendia F, Westphal N, Parada J. The hormonal and peripheral effects of dl-norgestrel in postcoital contraception. Contraception 1974;10:411–24. [24] Zuliani G, Colombo UF, Molla R. Hormonal postcoital contraception with an ethinylestradiol–norgestrel combination and two danazol regimens. Eur J Obstet Gynecol Reprod Biol 1990;37:253–60. [25] Trussell J, Ellertson C. Efficacy of emergency contraception. Fertil Cont Rev 1995;4:8–11.
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[26] Zhou L, Xiao B. Emergency contraception with multiload Cu-375 SL IUD: a multicentre clinical trial. Contraception 2001;64:107– 12. [27] Baiden F, Awini E, Clerk C. Perception of university students in Ghana about emergency contraception. Contraception 2002;66: 23–6. [28] Aneblom G, Larsson M, Odlind V, Tyden T. Knowledge, use and attitudes towards emergency contraceptive pills among Swedish women presenting for induced abortion. Br J Obstet Gynaecol 2002;109:155– 60.
[29] Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med 1998;339:1–4. [30] Ellertson C, Ambardekar S, Hedley A, Coyaji K, Trussell J, Blanchard K. Emergency contraception: randomized comparison of advance provision and information only. Obstet Gynecol 2001;98:570– 5. [31] Harrison-Woolrych M, Duncan A, Howe J, Smith C. Improving access to emergency contraception. Br Med J 2001;322:186–7. [32] Grimes DA. Switching emergency contraception to over-the-counter status. N Engl J Med 2002;347:846–9.
Review
Emergency contraception P.C. Ho∗ , O.S. Tang1 , E.H.Y. Ng2 Department of Obstetrics and Gynaecology, Queen Mary Hospital, University of Hong Kong, 6/F, Professorial Block, Pokfulam Road, Hong Kong, China Received 1 April 2003; accepted 14 April 2003
Abstract The standard method for emergency contraception used to be the Yuzpe regimen, which consists of two doses of combined oral contraceptive pills at 12 h interval. It can prevent 74% of the expected pregnancies but the incidence of side effects like nausea and vomiting is high. Recent studies have shown that both mifepristone and levonorgestrel are more effective and better tolerated than the Yuzpe regimen. The dose of mifepristone can be reduced to 10 mg without affecting its efficacy. However, 10 mg tablets of mifepristone are not commercially available except in China. A single dose of 1.5 mg of levonorgestrel is as effective as two doses of 0.75 mg levonorgestrel given at 12 h interval or 10 mg of mifepristone. This is likely to become the hormonal method of choice in many countries. The insertion of a copper intrauterine contraceptive device is probably the most effective method of emergency contraception, preventing over 90% of the pregnancies. However, it may not be suitable for women with high risk factors for pelvic inflammatory disease. There has been an increase in the awareness of emergency contraception in the recent decade but the knowledge is still poor in some countries. There is also a need to improve the access to emergency contraception. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Emergency contraception; Postcoital contraception; Levonorgestrel; Mifepristone
1. Introduction
2. Estimation of efficacy
Emergency contraception is contraception administered to a woman after an unprotected intercourse. In the past, it has also been named as postcoital contraception or morning after pills. Emergency contraception is needed when intercourse is unexpected and therefore contraception has not been used. Other indications include failure of barrier methods like the slipping or breakage of condom, and after rape. Emergency contraception may be an effective way to reduce the number of unwanted pregnancies. It has been estimated that the widespread use of emergency contraception may reduce the number of abortions in USA by more than 1 million [1]. In the last decade, a number of new and effective methods of emergency contraception have been introduced. There was also an increase in the awareness of emergency contraception. In this article, the various methods of emergency contraception are reviewed.
As not all women who have an unprotected intercourse will conceive, the proportion of women who did not conceive after the use of emergency contraception is not a good indicator of the percentage of pregnancies prevented. In many recent studies on the use of emergency contraception, the efficacy of the method is estimated by comparing the number of pregnancies expected without treatment with the number of observed pregnancies after treatment. The number of pregnancies expected is calculated from the probabilities of pregnancy on each cycle day derived from previous prospective studies involving women who are trying to conceive [2]. However, these estimates are based on a number of assumptions: (a) the woman is ovulating regularly, (b) the woman’s history of the last menstrual period is accurate, and (c) the fertility of women using emergency contraception is the same as that of women who are trying to conceive. Recent studies have cast doubt on the accuracy of these estimates [3,4]. Therefore, while there is as yet no better method of estimating the efficacy of emergency contraception, the current methods of estimation are probably not very reliable.
∗ Corresponding
author. Tel.: +852-28554260; fax: +852-28550947. E-mail addresses: [email protected] (P.C. Ho), [email protected] (O.S. Tang), [email protected] (E.H.Y. Ng). 1 Tel.: +852-28553360; fax: +852-28175374. 2 Tel.: +852-28553400; fax: +852-28175374.
1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00044-3
P.C. Ho et al. / Reviews in Gynaecological Practice 3 (2003) 98–102
3. Methods 3.1. High doses of oestrogens The first hormonal method used for emergency contraception is oestrogen in high doses for 5 days [5,6]. Ethinyl oestradiol, conjugated oestrogens or diethylstilboestrol have been used for this purpose. However, this method is associated with a high incidence of side effects like nausea and vomiting, and it is seldom used nowadays. 3.2. Yuzpe regimen This regimen consists of the administration of two doses of combined oral contraceptive pills (each dose containing 100 g of ethinyl oestradiol and 1 mg norgestrel) at 12 h interval within 72 h of the intercourse [7]. The reported failure rate in the literature ranged from 0.2 to 7.4%. It is estimated that the Yuzpe regimen can prevent over 74% of the pregnancies [2]. The pregnancy rate increases with the interval between intercourse and administration of the drugs [8]. Therefore, it is important that the drugs are given as early as possible after intercourse. The most common side effects of the regimen are nausea and vomiting with an incidence of 50 and 15%, respectively. Serious side effects or complications have not been reported with this regimen. Therefore, according to the eligibility criteria of the World Health Organization (WHO) [9], confirmed pregnancy is the only contraindication to the use of emergency contraception because once a pregnancy is established, this regimen is not effective. There is no evidence that there is an increased risk of fetal anomalies among women who conceived while taking combined oral contraceptive pills [10]. The Yuzpe regimen probably acts by suppressing or postponing ovulation. When the Yuzpe regimen is administered before the luteinizng hormone (LH) surge, it may blunt or delay the LH peak [11]. A more recent study [12] showed that if the Yuzpe regimen was administered when the follicle was 12–17 mm, ovulation was absent in the following 5 days in 65% of the women. However, if the Yuzpe regimen was given when the follicle was 18–20 mm in diameter, ovulation was not suppressed. As the Yuzpe regimen has only minimal effects on the endometrium [11], it is likely that if the Yuzpe regimen is given at this time of the cycle, it may not be effective in preventing pregnancy. 3.3. Mifepristone Mifepristone is a progesterone antagonist at the receptor level. Two early studies [13,14] in United Kingdom compared the use of 600 mg of mifepristone with the Yuzpe regimen in emergency contraception within 72 h of coitus. The pregnancy rate in the mifepristone group was lower than that in the Yuzpe regimen group. The incidence of nausea and vomiting in the mifepristone group was significantly
99
lower than that in the Yuzpe regimen group but significantly more women in the mifepristone group had a delay in the return of menstruation of more than 3 days. This may cause undue anxiety about the possibility of pregnancy. A subsequent multicentre study conducted by WHO [15] compared the efficacy and side effects of three doses of mifepristone in women requesting emergency contraception within 120 h of an unprotected intercourse. The results showed that the pregnancy rates in the three groups were comparable (1.2, 1.1 and 1.3% in the 10, 50 and 600 mg groups, respectively). However, the incidence of delay in onset of next menses and bleeding within 5 days of drug administration was inversely related to the dose and lowest in the 10 mg group. Since 10 mg tablets of mifepristone are not commercially available except in China, Ashok et al. [16] compared the efficacy and acceptability of 100 mg of mifepristone with those of the Yuzpe regimen. The results showed that 100 mg of mifepristone was significantly more effective and better tolerated than the Yuzpe regimen. Despite the delay in the return of menstruation, significantly more women were satisfied with mifepristone as an emergency contraceptive. It was estimated that these regimens could prevent 84–92% [15,16] of pregnancies. The effects of mifepristone on the ovulation and endometrium depend on the dose and the time when it is given. If a single dose of 10 mg of mifepristone is given when the follicle is greater than 12 mm, the LH peak is either inhibited or depressed [17]. When 200 mg of mifepristone is given 2 days after the LH surge, endometrial development is inhibited and endometrial function is impaired [18]. A single dose of 10 mg given around the same time has a similar but less marked effect [19]. It is uncertain whether these effects are sufficient to inhibit implantation. Therefore, mifepristone at a dose of 10 mg may act mainly through its effects on the ovulation process. 3.4. Levonorgestrel Levonorgestrel is an orally active progestogen. The efficacy of levonorgestrel in emergency contraception was first demonstrated by Ho and Kwan [19] in a comparison of the Yuzpe regimen with levonorgestrel (two doses of 0.75 mg given at 12 h interval) within 48 h of an unprotected act of intercourse. The failure rate of levonorgestrel was slightly lower than that of the Yuzpe regimen and the incidence of nausea and vomiting in the levonorgestrel group was significantly lower than that in the Yuzpe regimen group. Because of these encouraging results, the WHO conducted a multicentre study comparing the efficacy and side effects of the levonorgestrel regimen with those of the Yuzpe regimen in emergency contraception within 72 h of coitus [8]. The pregnancy rate in the levonorgestrel group (1.1%) was significantly lower than that in the Yuzpe regimen group (3.2%). It was estimated that levonorgestrel could prevent 85% of the pregnancies while the Yuzpe regimen could prevent 57% of the pregnancies. The efficacy of both
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levonorgestrel and the Yuzpe regimen decreased with increase in the coitus-treatment interval. This study also confirmed that the incidence of side effects of levonorgestrel was significantly lower than that of the Yuzpe regimen. A more recent multicentre study by WHO [20] compared three regimens of emergency contraception: (1) 10 mg of mifepristone, (2) two doses of 0.75 mg of levonorgestrel at an interval of 12 h, (3) a single dose of 1.5 mg of levonorgestrel, within 120 h of coitus. The results of this study showed that the efficacy of the three regimens were similar and the pregnancy rates in the mifepristone group, the two-dose levonorgestrel group and the single-dose levonorgestrel group were 1.5, 1.8 and 1.5%, respectively. The incidence of side effects was similar in the three groups of women. Significantly more women in the mifepristone group had a delay of menses of more than 7 days (9% versus 5% in the other two groups). Even though the pregnancy rates were higher when the drugs were given between 72 and 120 h when compared to those when the drugs were given earlier, the administration of these drugs could still prevent 58–63% of the pregnancies. This study also showed that women who had further acts of intercourse had higher rates of pregnancy. Since a single dose of 1.5 mg levonorgestrel is more convenient for the women and the efficacy is similar to a double dose regimen, it should be the preferred regimen. Various groups have studied the mechanisms of action of levonorgestrel. Current evidence suggests that two doses of 0.75 mg of levonorgestrel probably act by inhibiting or interfering with the LH peak [17,21]. Although levonorgestrel does not affect in vitro sperm functions [22], it may affect the viscosity of the cervical mucus and migration of sperms in vivo [23]. Levonorgestrel did not appear to have any significant effects on the endometrium [17]. 3.5. Danazol Zuliani et al. [24] reported favorable results with the use of Danazol for emergency contraception with pregnancy rats of 1.7 and 0.8% for doses of 800 and 1200 mg, respectively. However, another study showed that the pregnancy rate with Danazol was 4.7%, which was higher than those of the Yuzpe regimen and mifepristone and the number of observed pregnancies was in fact not significantly different from that of expected pregnancies [13]. Therefore, it is now seldom used for emergency contraception. 3.6. Insertion of copper intrauterine contraceptive device The insertion of a copper intrauterine device (IUCD) is probably the most effective method of emergency contraception. It is effective up to 120 h after the unprotected intercourse. In a review of papers published up to 1995, the pregnancy rate was less than 0.1% in 8400 insertions of IUCD for emergency contraception [25]. A recent multicentre study in China showed that the pregnancy rate was only
0.2% after the postcoital insertion of IUCD within 120 h of an unprotected intercourse [26]. It was estimated that the percentage of pregnancies prevented was 98.1% in parous women and 92.4% in nulliparous women. The insertion of IUCD may be associated with the complications of pain, bleeding and pelvic inflammatory disease (PID) and it may not be the ideal method for women with high risk factors for PID. However, in carefully selected women, these complications are not common [26].
4. Barriers to the use of emergency contraception Despite an increase in interest and publicity on emergency contraception in the last decade, the knowledge of emergency contraception is still variable and remains poor in some countries [27]. Moreover, even when the women know about emergency contraception, they may not use it, probably because of an underestimation of the risk of pregnancy [28]. There is a need to educate the women on the risk of pregnancy and the need for emergency contraception if there is an unprotected intercourse. Since the efficacy of emergency contraception decreases with increase in the time interval between the act of intercourse and the treatment, it is essential that women should have easy access to emergency contraception. In many countries, drugs for emergency contraception need the prescription of a doctor. This makes it difficult for the women to obtain the drugs especially during weekends and holidays. The option of advanced provision of emergency contraception in women using the less reliable methods like the barrier method has been investigated [29,30]. Women tended to use emergency contraception more often if they were given a supply of emergency contraceptive drugs to be kept at home. On the other hand, the advanced provision of emergency contraception at home neither affects the regular use of contraception nor increases the incidence of unprotected intercourse. While these results are encouraging, many women especially teenagers may not have the opportunity of visiting a health care facility before the unprotected intercourse and other methods to improve access are necessary. Allowing pharmacy sales is one of the options that may help to improve access to emergency contraception [31]. The other option is to allow sales over the counter. It has been argued that emergency contraceptive pills meet all the requirements for over-the-counter use: low toxicity, no potential for overdose or addiction, no teratogenicity, no need for medical screening, self-identification of the need, uniform dosage and no important drug interaction [32].
5. Conclusion Mifepristone and levonorgestrel are equally effective for emergency contraception and both are more effective and better tolerated than the Yuzpe regimen. As levonorgestrel
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is more readily available than mifepristone, it is the drug of choice in many countries. Since the efficacy of a single dose of 1.5 mg of levonorgestrel is similar to that of two doses of 0.75 mg and the incidence of side effects is similar, it is the regimen of choice. Although there is an increase in awareness of emergency contraception, there is still a need to educate the women and to improve the access to emergency contraception so as to reduce the number of unwanted pregnancies. 6. Practice points • Both mifepristone and levonorgestrel are more effective and better tolerated than the Yuzpe regimen. • As mifepristone is still not widely available and not yet marketed for emergency contraception except in China, levonorgestrel is the drug of choice in many countries. • A single dose of 1.5 mg of levonorgestrel is as effective as the regimen of two doses of 0.75 mg of levonorgestrel given at 12 h interval. • The efficacy of the hormonal methods of emergency contraception declines with increase in coitus-treatment interval and therefore these drugs should be given as early as possible after an unprotected intercourse. • Hormonal methods of emergency contraception are less effective if there are further acts of unprotected intercourse in the same cycle and women should be counselled on this. • The insertion of a copper IUCD is probably the most effective method of emergency contraception but it may not be suitable for women with high risk factors for PID. • There is a need to improve the access to emergency contraception. 7. Research agenda • Studies on other drugs such as other antiprogestins to develop more effective hormonal methods of emergency contraception. • Studies to assess whether the advanced provision of emergency contraception can reduce the number of unwanted pregnancies. • Studies to assess the safety and impact of over-the-counter sales of emergency contraception. References [1] Trussell J, Stewart F. The effectiveness of the Yuzpe regimen of emergency contraception. Fam Plann Perspect 1996;28:58–64. [2] Trussell J, Rodriguez G, Ellertson C. New estimates of the effectiveness of the Yuzpe regimen of emergency contraception. Contraception 1998;57:363–9. [3] Stirling A, Glasier A. Estimating the efficacy of emergency contraception—how reliable are the data? Contraception 2002;66:19– 22.
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