New estimates of the effectiveness of the Yuzpe regimen of emergency contraception

The purpose of this study was to provide new estimates of the effectiveness of the Yuzpe method of emergency contraception and to offer correctly computed estimates of the confidence intervals for estimated effectiveness rates.

Through a literature search, seven studies that present the number of women treated and outcome of treatment by cycle day of unprotected intercourse relative to expected day of ovulation were identified. Probabilities of conception by cycle day of intercourse among women not using contraception and the associated variance-covariance matrix from five other datasets were estimated, and these external estimates were used to assess the effectiveness of the Yuzpe regimen.

The 40 estimates of effectiveness, based on seven separate studies and the seven studies combined and five different sets of conception probabilities by cycle day, ranged from a low of 44.2% to a high of 88.7%. The preferred point estimate is that emergency contraceptive pills reduce the risk of pregnancy by 75.4%, with a 95% confidence interval extending from 65.6% to 82.4%.

True effectiveness is likely to be at least 75% because treatment failures (observed pregnancies) include women who were already pregnant when treated and women who became pregnant after being treated.     

Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action

OBJECTIVE: The purpose of this study was to provide evidence about the mechanism of action of the Yuzpe method of emergency contraception by examining effectiveness by cycle day of intercourse relative to ovulation. METHODS: Through a literature search, we identified eight studies that present the number of women treated and outcome of treatment by cycle day of unprotected intercourse relative to expected day of ovulation. Using five sets of external estimates of conception probabilities by cycle day of intercourse among women not using contraception, we assessed and compared the effectiveness of the Yuzpe regimen by whether intercourse occurred on or before the second day before ovulation or afterward, and whether intercourse occurred on or before the first day before ovulation or afterward. RESULTS: In 36 of the 45 pairs of estimates of effectiveness, based on eight separate studies and the eight studies combined and five different sets of conception probabilities by cycle day, effectiveness was higher-and in most cases substantially higher-when intercourse occurred on or before the second day before ovulation (day -2) than when it occurred later. When data were stratified by whether intercourse occurred on or before the day before ovulation (day -1), effectiveness was greater when intercourse occurred early in 43 of 45 pairs. CONCLUSIONS: These results suggest that one hypothesized mechanism of action of the Yuzpe method, inhibiting implantation of a fertilized egg, is unlikely to be the primary mechanism of action.     

Estimating the effectiveness of emergency contraceptive pills

OBJECTIVE: We use new estimates of conception probabilities by cycle day of intercourse, where cycle day is measured with day 1 being the first day of bleeding in a cycle, to propose a new approach for estimating the effectiveness of emergency contraceptive pills (ECPs). We use this new approach to examine the absolute effectiveness and the cost-effectiveness of ECPs and whether ECPs are more effective the sooner after unprotected intercourse they are initiated. METHODS: Using the new set of conception probabilities, we employ data from two recent clinical trials of ECPs, one from the Population Council and the other from the World Health Organization (WHO), to examine the effectiveness of the combined ECP regimen. RESULTS: The expected pregnancy rate among typical users was 6.2% in the Population Council trial and 7.4% in the WHO trial based on conception probabilities by cycle day relative to the day of ovulation. Based on conception probabilities by cycle day relative to the first day of bleeding, the expected pregnancy rates dropped to 5.4% and 5.2%, respectively. The two trials yield conflicting evidence regarding whether effectiveness declines with treatment delay. CONCLUSIONS: Our results suggest that the absolute levels of effectiveness for the Yuzpe regimen of emergency contraception and the cost-effectiveness of this regimen have probably been overstated when based on conception probabilities by cycle day relative to day of ovulation.     

How well do male latex condoms work? Pregnancy outcome during one menstrual cycle of use

To evaluate the contraceptive effectiveness of male latex condoms, we assembled a cohort of 300 women relying on male latex condoms for contraception and followed them prospectively for one menstrual cycle. None of the 234 women who completed the study and reported at least one act of intercourse conceived (one cycle pregnancy rate 0%; 95% CI 0%–2%). Given the pattern of intercourse during the cycle and 3 different sets of conception probabilities for different days of the cycle, we would have expected between 32 and 36 pregnancies if no condoms had been used. Thus, the prevented fraction due to condom use (effectiveness) is 100% and the lower bounds of the 95% CI are between 89% and 90%. For this cohort, male latex condoms were an effective method of contraception. This cost-efficient approach of evaluating contraceptive effectiveness shows promise for post-marketing studies.     

左旋18-甲基炔诺酮用于紧急避孕的效果与不良反应评价

目的和方法:对100例月经规律,未避孕或避孕措施失败性交后72小时内的妇女,口服左旋18-甲基炔诺酮(LNG),观察避孕效果与不良反应,并以50例妇女应用紧急避孕的经典方法Yuzpe法作对照。结果:LNG组2例妊娠,Yuzpe组1例妊娠,按Wilcox方法推算,避孕有效率分别为83％和82％,但LNG组的不良反应明显降低,P<0.001,优于经典的Yuzpe法。结论:推广使用LNG法将有利于减少非意愿妊娠,保障妇女身心健康。     

Release of progestin-only emergency contraception

Progestin-only emergency contraception has been available in a prepackaged product since 1999. In a multicenter randomized trial, the levonorgestrel-only regimen was better tolerated and significantly more effective than the previous standard of care, the Yuzpe regimen. The levonorgestrel-only regimen prevented 85% of unintended pregnancies compared with 57% in the Yuzpe regimen. Emergency contraception is more effective the earlier the treatment begins. With the emergence of specifically prepackaged kits, emergency contraception appears to be more accessible and convenient to providers and to women. However, substantial barriers still exist to women who wish to obtain emergency contraceptive within the recommended initiation of 72 hours after unprotected intercourse. More recent information that emergency contraception is more effective the sooner it is initiated underscores the need for effective educational and distribution strategies.     

Risk of pregnancy and external validity in clinical trials of emergency contraception

OBJECTIVES: To compare women who enroll in emergency contraception (EC) trials to those who decline and to understand why eligible women decline to participate. METHODS: Data were collected from all women seeking EC (n = 5,787) at three clinics in the USA and UK during a period of nearly 1 year (from September 1997 to August 1998). The main outcome measures were pregnancy risk calculated by adjusted cycle day of ovulation. RESULTS: Enrolled and non-enrolled women had similar mean ages and similar mean cycle lengths. However, the enrolled and non-enrolled groups were different with respect to adjusted cycle day of unprotected sexual intercourse (UPSI), the regularity of their cycles, recent hormone use, breastfeeding, the number of other acts of UPSI they had engaged in during the same cycle, and their willingness to participate in the study. Expected pregnancy risk among enrolled patients was higher than among non-enrolled EC seekers (6.5% vs 5.0%, p<0.001, calculated using Dixon conception probabilities, and 5.4% vs 4.6%, p = 0.086, calculated using Trussell conception probabilities). Unwillingness to take part in the study was the most common reason women did not enrol in the trial. Otherwise-eligible women most often declined to enrol because they were concerned about the effectiveness of the trial regimen. CONCLUSIONS: Women in EC trials are likely to face higher pregnancy risk than the general population. Clinical trials might overestimate the number of pregnancies averted by treatment because the number of expected pregnancies in trial populations is not representative of the population of all EC seekers. This information could be useful in projecting the public health impact of expanded EC access.     

The effectiveness of postcoital hormonal contraception.

The authors of a literature review of 10 studies on the efficacy of postcoital hormonal contraception (PCHC) contend that the studies' failure rates were too low because they divided the number of observed pregnancies by total number of women treated with PCHC. They claim that the only significant measure of efficacy is proportionate reduction in pregnancies caused by PCHC. Further, they examined the number of observed pregnancies and expected pregnancies if the women had not used PCHC. 2 different methods to estimate expected number of pregnancies resulted in 2 sets of failure rates for combined estrogen preparations (CEP): 4.2-100% and 5.9-44.4%. 2 other professionals find their use of Tietze's pregnancy risk estimates inapplicable, because women who use PCHC do not experience uniform distribution of unprotected intercourse across the cycle but rather near midcycle. Thus, their assumption of 2-4% risk of pregnancy per single unprotected act of intercourse biases the results. These professionals consider that the way to compare results from different studies is to use expected number of pregnancies estimated by corresponding the cycle day of intercourse with cycle day specific conception rates to obtain the only significant estimates of PCHC efficacy. Yet this methodology was applied in only 4 of the 10 studies examined by the authors of the literature review. Further, 1 study used a high-dose estrogen and 3 used a CEP preparation. Effectiveness rates were 84% for the high-dose estrogen and a mean of 76% for the 3 CEP studies. Further, there were 3 other CEP studies published after the literature review which had used the appropriate methodology. The weighted average of the 5 literature review CEP studies and these 3 studies is 74.%. Even though PCHC is not perfectly effective, it does adequately protect against unintended pregnancy. RU-486 is more effective than CEPs, but until it is available in the US, the best means of preventing unplanned pregnancies after intercourse is PCHC.     

The probability of conception on different days of the cycle with respect to ovulation: an overview

Several mathematical models have been developed over the past thirty years to investigate how the probability of conception changes on the different days of the cycle with respect to ovulation. A problem general to all models is to estimate the day of ovulation. Since the most fertile days are those close to ovulation, less precise estimates of this event will lead to less accurate estimates of the probability of conception on a given day of the cycle.Given that a reference point for ovulation is available, the first model considered conception as dependent only on the timing of intercourse. Conception was found to be most likely to occur on only six days in each cycle. However, the model is biologically unrealistic because it assumes that all ova can be fertilized and lead to a viable pregnancy. There are other factors that affect the probability of conception, including whether the ovum is viable or not. Recent models have extended the idea of cycle viability to allow for differences between cycles within couples and for the introduction of couple specific covariates. In a second group of models the probability of conception depends mainly on the time of intercourse and the survival times of sperm and ovum.A graphical summary of the results available in the literature is presented. Conception probabilities have been found to be significantly different from zero from five days before ovulation to the day of ovulation itself. On average, less than half of the cycles are viable in women, although recent studies suggest that different cycle viability between women should also be taken into account. Survival times for sperm and the ovum have been estimated to be 1.4 days and 0.7 days, respectively. Sperm would have a 5% probability of surviving more than 4.4 days and a 1% probability of surviving more than 6.8 days.     

Teenagers' use of emergency contraception in a general practice.

British teenagers who become pregnant commonly express ignorance about emergency contraception. A case-note survey was conducted in a general practice serving about 14,200 people in a Devon market town. Of the 373 registered girls aged 15-19 years, 59 (16%) had consulted for emergency contraception, 19 of them more than once. The oral method (Yuzpe regimen) was prescribed eighty times and 2 girls became pregnant. 4 of the 59 girls who used emergency contraception had subsequent unwanted pregnancies. A consultation for emergency contraception presents an opportunity to discuss more reliable and acceptable methods of contraception.     

紧急避孕效果评价的可信性研究

目的:探索以月经周期和末次月经推算受孕期与生化诊断间出现差异的原因,进而评价紧急避孕效果判断的可信性。方法:对100例要求紧急避孕服务的妇女末次月经日期、月经周期和未保护性生活时间的确信程度进行回忆问卷调查,同时以B超作为月经周期、排卵监测手段进行对比性研究。结果:51例(52.04%)妇女确信知道末次月经的日期;9例(9.18%)妇女不能准确回忆无保护性生活时间;58.16%的妇女在该研究周期中有过1次以上的性生活;32例(32.65%)妇女B超证实与她们的周期不符合;2例妊娠,其中1例根据wilcox方法评估其妊娠危险概率为0%。结论:对于一部分妇女依赖于对末次月经、性生活时间的回忆和排卵日的推算来评价紧急避孕效果的方法显然是不准确的,应采用更合理的评价方法。     

Contraception--the morning after

Although no postcoital method has been developed for safe and effective regular use, postcoital contraception is being offered in Canada and Western Europe on an emergency basis to people who experience such problems as a burst condom. It is little known in the US, however. The 1st commercial version of a postcoital method recently became available to women in England. A former postcoital contraceptive was diethylstilbestrol (DES) which has been linked to cancer in the daughters of women who had taken the drug to prevent miscarriage. A new postcoital contraceptive regime was developed by Albert Yuzpe and consists of 4 ordinary contraceptive pills combining estrogen and progestin to be taken over a 12-hour period. In the US, this is the formulaion of birth control pill marketed under the trade name Ovral by Wyeth Laboratories. England and Germany are the only countries in which the Yuzpe method is officially approved for use as an emergency postocital contraceptive, but the method is used to some degree in most European countries, being well-known in France and Denmark. The most frequent side-effect reported by Yuzpe is vomiting experienced by 29% of women; another 22% felt nauseated. Other side effects, e.g. headache, were infrequent. The findings of the Pregnancy Advisory Service and the Brook Advisory Centre in Britain are reported. Overall very few side effects were found. Postcoital contraceptive treatment may cause the length of the cycle in which it occurs to be irregular. Treatment before day 15 has been found to shorten the cycle, whereas treatment after day 15 lengthens it. The majority of women who become pregnant due to treatment failure tend to seek an abortion. Ectopic pregnancy incidence may also be a result of treatment failure. In 1981, the International Planned Parenthood Federation (IPPF) issued a statement endorsing the use of postcoital contraceptives. Reasons for using them include rape, problems with barrier methods, ineffective use of the pill and IUD expulsion. No drug company in the US has expressed interest in getting FDA approval to market a postcoital contraceptive, partly because its usage might not be widespread. Opposition to approval from groups who believe life begins at conception and consequently that postcoital contraceptives are an abortifacient is expected.     

The resolution of teenage first pregnancies

First conceptions occuring in tennage women in the U.S., the outcomes of the pregnancies, the marital status of the teenage women at conception and at the outcome, whether the pregnancy was intended or not, and whether contraception was used to prevent the pregnancy are discussed. It was determined that 30% of a cross section of teenage women have had premarital intercourse and 58% of those married had premarital intercourse. Of those experiencing premarital intercourse, 30% were pregnant before marriage, i.e., fewer than 10% of all females 15-19. Twice as many blacks have premarital intercourse than whites, and twice as many of these become pregnant. 35% of those who have a premarital first pregnancy marry before the baby is born. 64% of premarital first pregnancies are unintended. Of those who did not want to become pregnant, 13-16% used contraception to prevent the premarital pregnancy. 86% of births to blacks from first pregnancies are illegitimate compared with 23% for whites. More than 1/5 of the women who do not marry end the pregnancy by induced abortion. White teenagers who do not marry prior to the outcome of the pregnancy are 7 times more likely to have an induced abortion than blacks. 18% of the whites who have illegitimate births from first pregnancies give up their children for adoption compared with 2% blacks. Fewer than 30% of postmarital first pregnancies of teenage women are unintended. Blacks appear to display less anxiety than whites over illegitimate births. It may be that escape via abortion and marriage is less accessible to blacks than to whites both economically and psychologically.     

Young women under 16 years with experience of sexual intercourse: who becomes pregnant?

BACKGROUND: The UK has the highest rate of teenage pregnancies in western Europe. Although there is a large body of literature focusing on predictors of conception among this age group, almost all the work compares those young women who have become pregnant with their peers, regardless of whether or not their peers have experienced sexual intercourse. OBJECTIVE: To compare 16-year-old young women who have become pregnant with their peers who also have experience of sexual intercourse, but who have not conceived. DESIGN: Analysis of data from the baseline and follow-up surveys conducted as part of a trial of sex education. SETTING AND PARTICIPANTS: Female school students aged 14-16 years from the East of Scotland. MAIN RESULTS: Young age of self and partner, and non-use of contraception, all at first intercourse, are most strongly associated with pregnancy. CONCLUSIONS: Those who engage in sexual intercourse at a relatively young age will often have had more opportunity to become pregnant than those whose sexual debut comes later. Similarly, the fact that those who use contraception at first intercourse have been less likely to conceive than those who do not could reflect the overall patterns of contraceptive use: young women who have used contraception at each occasion of intercourse will have had less chance to conceive than those who have not. Having a young partner at first intercourse suggests that, if this pattern continues, the couple may lack the resources needed to prevent a pregnancy due to the immaturity of both partners.     

Bayesian methods for searching for optimal rules for timing intercourse to achieve pregnancy

With societal trends towards increasing age at starting a pregnancy attempt, many women are concerned about achieving conception before the onset of infertility, which precedes menopause. Couples failing to conceive a pregnancy within 12 months are classified as clinically infertile, and may be recommended for assisted reproductive therapy (ART). Because many ART procedures are expensive and may convey an increased risk of adverse outcomes for the offspring, it is advantageous to decrease time to pregnancy by natural methods. One possibility is to intentionally time intercourse during the days of the menstrual cycle having the highest conception probabilities. This article proposes a Bayesian decision theoretic approach for searching for optimal rules for timing intercourse based on cycle day, secretions and other information. Good rules result in high conception probabilities while requiring minimal targeted intercourse. A biologically based statistical model is used to relate cycle day and biomarkers to the conception probability. A stochastic search procedure is then developed to search for rules with high expected utility, and the methods are applied to data from a recent Italian study.     

Reasons for unprotected intercourse: analysis of the PRAMS survey

OBJECTIVES: This study was conducted to identify reasons why women had unprotected intercourse that led to an unintended pregnancy. METHODS: As part of the Pregnancy Risk Assessment Monitoring System (PRAMS) survey, women with a recent unintended viable pregnancy were asked after the birth why they had not used birth control. RESULTS: Of 7856 respondents, 33% felt they could not get pregnant at the time of conception, 30% did not really mind if they got pregnant, 22% stated their partner did not want to use contraception, 16% cited side effects, 10% felt they or their partner were sterile, 10% cited access problems and 18% selected "other." Latent class analysis showed seven patterns of response, each identifying strongly with a single reason. CONCLUSIONS: Almost half of women with viable unintended pregnancies ending in a birth felt they could not/would not get pregnant at the time of conception. Most women identified with a single reason for having unprotected intercourse.     

Results from pooled Phase III studies of ulipristal acetate for emergency contraception

BackgroundUlipristal acetate (UPA) is a new effective option to prevent unintended pregnancies up to 5 days after unprotected intercourse. We used pooled data from two Phase III studies to refine our understanding of the efficacy of UPA by time from unprotected intercourse and the effects of other factors on pregnancy rates.Study DesignData from two Phase III studies were pooled to create a larger analysis population. Analyses were performed on the first participation of 2183 women.ResultsA total of 41 women became pregnant despite the use of UPA, yielding an overall proportion pregnant of 1.9% (1.3%–2.5%). Proportions of pregnant women were higher among those with further acts of unprotected intercourse in the same cycle and among obese women. These varied from 1.3% (0.9%–2.0%) among nonobese women who had no further acts of unprotected intercourse (n= 1704) to 8.3% (0.2%–38.5%) among obese women who had subsequent unprotected intercourse (n= 12).ConclusionsUPA is effective and safe in preventing pregnancy after unprotected intercourse. Its effectiveness is lower among women who have subsequent unprotected intercourse and among obese women.     

Effectiveness of levonorgestrel emergency contraception given before or after ovulation--a pilot study

BACKGROUND: Although widely used, the mechanisms of action of the levonorgestrel emergency contraceptive pill (LNG ECP) are still unclear. There are increasing data to indicate that LNG is particularly effective as an ECP by interrupting follicular development and ovulation. An important outstanding question is whether it has any effect on fertilization or implantation. METHOD: Ninety-nine women participated; they were recruited at the time they presented with a request for emergency contraception. All women took LNG 1.5 mg in a single dose during the clinic consultation. A blood sample was taken immediately prior to ingestion of the ECP for estimation of serum LH, estradiol and progesterone levels to calculate the day of ovulation. The specimens were analyzed in a single batch. Based on these endocrine data, we estimated the timing of ovulation to be within a +/-24-h period with an accuracy of around 80%. Women were followed up 4-6 weeks later to ascertain pregnancy status. The effectiveness of ECP when taken before and after ovulation was determined. RESULTS: Three women became pregnant despite taking the ECP (pregnancy rate, 3.0%). All three women who became pregnant had unprotected intercourse between Days -1 and 0 and took the ECP on Day +2, based on endocrine data. Day 0 was taken as ovulation day. Among 17 women who had intercourse in the fertile period of the cycle and took the ECP after ovulation occurred (on Days +1 to +2), we could have expected three or four pregnancies; three were observed. Among 34 women who had intercourse on Days -5 to -2 of the fertile period and took ECP before or on the day of ovulation, four pregnancies could have been expected, but none were observed. We found major discrepancies between women's self-report of stage of the cycle and the dating calculation based on endocrine data. CONCLUSION: These data are supportive of the concept that the LNG ECP has little or no effect on postovulation events but is highly effective when taken before ovulation.     

The effect of occupational exposure to mercury vapour on the fertility of female dental assistants.

Exposure to mercury vapour or inorganic mercury compounds can impair fertility in laboratory animals. To study the effects of mercury vapour on fertility in women, eligibility questionnaires were sent to 7000 registered dental assistants in California. The final eligible sample of 418 women, who had become pregnant during the previous four years, were interviewed by telephone. Detailed information was collected on mercury handling practices and the number of menstrual cycles without contraception it had taken them to become pregnant. Dental assistants not working with amalgam served as unexposed controls. Women with high occupational exposure to mercury were less fertile than unexposed controls. The fecundability (probability of conception each menstrual cycle) of women who prepared 30 or more amalgams per week and who had five or more poor mercury hygiene factors was only 63% of that for unexposed women (95% CI 42%-96%) after controlling for covariates. Women with low exposure were more fertile, however, than unexposed controls. Possible explanations for the U shaped dose response and limitations of the exposure measure are discussed. Further investigation is needed that uses biological measures of mercury exposure.     

Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel

Background

Emergency contraception (EC) does not always work. Clinicians should be aware of potential risk factors for EC failure.

Study Design

Data from a meta-analysis of two randomized controlled trials comparing the efficacy of ulipristal acetate (UPA) with levonorgestrel were analyzed to identify factors associated with EC failure.

Results

The risk of pregnancy was more than threefold greater for obese women compared with women with normal body mass index (odds ratio (OR), 3.60; 95% confidence interval (CI), 1.96–6.53; p<.0001), whichever EC was taken. However, for obese women, the risk was greater for those taking levonorgestrel (OR, 4.41; 95% CI, 2.05–9.44, p=.0002) than for UPA users (OR, 2.62; 95% CI, 0.89–7.00; ns). For both ECs, pregnancy risk was related to the cycle day of intercourse. Women who had intercourse the day before estimated day of ovulation had a fourfold increased risk of pregnancy (OR, 4.42; 95% CI, 2.33–8.20; p<.0001) compared with women having sex outside the fertile window. For both methods, women who had unprotected intercourse after using EC were more likely to get pregnant than those who did not (OR, 4.64; 95% CI, 2.22–8.96; p=.0002).

Conclusions

Women who have intercourse around ovulation should ideally be offered a copper intrauterine device. Women with body mass index >25 kg/m² should be offered an intrauterine device or UPA. All women should be advised to start effective contraception immediately after EC.