Updated estimates of the effectiveness of the Yuzpe regimen of emergency contraception.

The purpose of this study was to provide revised estimates of the effectiveness of the Yuzpe method of emergency contraception. 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 the effectiveness of the Yuzpe regimen. The 45 estimates of effectiveness, based on eight separate studies and the eight studies combined and five different sets of conception probabilities by cycle day, ranged from a low of 56.4% to a high of 89.3%. Our preferred point estimate is that the Yuzpe regimen reduces the risk of pregnancy by 74.1%, with a 95% confidence interval extending from 62.9% to 79.2%. True effectiveness is likely to be > 74% because treatment failures (observed pregnancies) include women who were already pregnant when treated and women who became pregnant after being treated.     

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.     

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.     

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.     

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.     

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.     

Effect of single administration of levonorgestrel on the menstrual cycle

BACKGROUND: Levonorgestrel (LNG) 1.5 mg administered within 72 h of unprotected coitus is an established method of emergency contraception. Currently, there is some, although incomplete, knowledge about the mechanism of action. METHODS: We administered 1.5 mg LNG peri-ovulatory to determine the effects on serum gonadotrophins, estradiol and progesterone levels. Fourteen women were studied in a pretreatment and treatment cycle; eight women (Group A) took LNG 3 days before the expected day of ovulation, while 6 (Group B) took LNG a day before the expected day of ovulation. RESULTS: The women in Group A had a significant delay in their LH peak and onset of the next menses compared with their pretreatment cycles (26.4 vs. 39.1 days, p<.05). Those in Group B had no significant changes in the endocrine parameters but there was a significant shortening of the mean cycle length in comparison with their pretreatment cycles (25.1 vs. 20.2 days). CONCLUSION: Levonorgestrel 1.5 mg acts as an emergency contraception by delaying the LH surge and interfering with ovulation. It may also disrupt corpus luteum formation causing premature luteinization of unruptured follicles.     

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.     

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。     

The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle

Levonorgestrel (LNG) 0.75 mg administered 12 h apart within 72 h of unprotected coitus, is an established method of emergency contraception (EC). The mechanism of action of LNG used in this manner is unknown. We administered LNG 0.75 mg twice immediately before ovulation, to test the hypothesis that LNG acts as an emergency contraceptive by abolishing the pre-ovulatory lutenizing hormone (LH) surge and thereby delaying ovulation. Twelve women took LNG on or before the day of the first significant rise in urinary LH in 12 cycles. In four women, the LH peak and the onset of next menses were significantly delayed (delay of 16.8 days (SD +/- 8.7) from the day of mean LH peak in placebo cycles). One woman did not ovulate at all, despite a normal LH peak and cycle length. In the remaining eight women, LNG did not affect ovulation or the cycle length, but the length of the luteal phase and the total luteal phase LH concentrations were significantly reduced. We suggest that LNG acts as an emergency contraceptive by other mechanisms as well as delaying the LH surge and interfering with ovulation.     

Estimating the efficacy of emergency contraception--how reliable are the data?

Ninety-four women attending a family planning clinic for emergency contraception (EC) were asked how certain they were of the date of their last menstrual period (LMP), of the timing of intercourse, and how many times in the cycle they had had sex. Urinary pregnanediol concentrations were analyzed in 64 women to assess whether they had ovulated before they used EC. Forty-five women were certain of the date of the LMP, the rest were not. Only four women could not accurately recall the timing of intercourse, and 60% had had intercourse more than once in the cycle. Twenty-one women had urinary pregnanediol concentrations that were inconsistent with their cycle day. Calculations of the efficacy of EC depend on knowing the timing of intercourse in relation to the estimated day of ovulation. The results of this study suggest that these calculations are likely to be inaccurate for a significant minority of women.     

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。     

Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat

Levonorgestrel (LNG), a progestin widely used for regular hormonal contraception, is also used for emergency contraception (EC) to prevent pregnancy after unprotected intercourse. However, its mode of action in EC is only partially understood. One unresolved question is whether or not EC prevents pregnancy by interfering with postfertilization events. Here, we report the effects of acute treatment with LNG upon ovulation, fertilization and implantation in the rat. LNG inhibited ovulation totally or partially, depending on the timing of treatment and/or total dose administered, whereas it had no effect on fertilization or implantation when it was administered shortly before or after mating, or before implantation. It is concluded that acute postcoital administration of LNG at doses several-fold higher than those used for EC in women, which are able to inhibit ovulation, had no postfertilization effect that impairs fertility in the rat.     

Accounting for unreported and missing intercourse in human fertility studies

In prospective studies of human fertility that attempt to identify days of ovulation, couples record each day whether they had intercourse. Depending on the design of the study, couples either (I) mark the dates of intercourse on a chart or (II) mark 'yes' or 'no' for each day of the menstrual cycle. If protocol I is used, intercourse dates that couples fail to record are indistinguishable from dates of no intercourse. Consequently, estimates of day-specific fecundability are biased upwards. If protocol II is used, data from menstrual cycles with missing intercourse information must be discarded in order to fit current fertility models. We propose methods to account for unreported and missing intercourse under the assumption that the missingness mechanism is independent of time conditional on the unobservable true intercourse status. We use probit mixture models to allow for heterogeneity among couples, both in fecundability and in the missingness and non-reporting mechanisms. Markov chain Monte Carlo (MCMC) techniques are used for Bayesian estimation. The methods are generally applicable to the analysis of aggregated Bernoulli outcomes when there is uncertainty in whether a given trial, out of a series of trials, was completed. We illustrate the methods by application to two prospective fertility studies. Published in 2000 by John Wiley & Sons, Ltd.     

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.     

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation

Background

The contraceptive efficacy of emergency contraceptive pills containing levonorgestrel (LNG-EC) has been estimated in most previous studies by judging the day of ovulation from presumptive menstrual cycle data, thus providing poorly reliable estimates.

Methods

In the present study, the efficacy of LNG-EC was determined in 393 cycles by dating ovulation on the basis of reliable hormonal and ovarian parameters validated by a database constructed in a separate study. In addition, the efficacy was determined separately for cycles in which LNG-EC was given before or after ovulation.

Results

For the 148 women who had sexual intercourse during the fertile days, the overall accumulated probability of pregnancy was 24.7, while altogether 8 pregnancies were observed. Thus, the overall contraceptive efficacy of LNG-EC was 68%. Among the 103 women who took LNG-EC before ovulation (days −5 to −1), 16 pregnancies were expected and no pregnancy occurred (p<.0001). Among the 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p=1.00). These findings are incompatible with the inhibition of implantation by LNG-EC in women. The same cases were also analyzed using the presumptive menstrual cycle data, and important discrepancies were detected between the two methods.

Conclusion

The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.     

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation

Background

We aimed to evaluate whether emergency contraception with levonorgestrel (LNG-EC) administered after ovulation is equally effective to LNG-EC administered before ovulation.

Study design

We studied a cohort of women attending a family planning clinic for EC. From interview, we recorded menstrual history, time of intercourse and of intake of LNG-EC. On the day of intake of LNG-EC and during 5 days' follow-up, blood samples were taken for examination of luteinizing hormone, estradiol and progesterone concentrations, and vaginal ultrasound examinations were done for size of the leading follicle and/or corpus luteum. Thereafter women were not contacted until next menses or pregnancy occurred.

Results

Of 388 women attending for LNG-EC, 122 women had intercourse on fertile cycle days according to ultrasound and endocrine findings. At the time of LNG-EC intake, 87 women were in Days −5 to −1 and 35 women were in Day 0 (day of ovulation) or beyond. With the use of the probability of clinical pregnancy reported by Wilcox et al. [N Engl J Med 333 (1995) 1517-1521], expected numbers of pregnancies among the 87 and 35 women were 13 and 7, respectively, while 0 and 6 pregnancies, respectively, occurred.

Conclusion

We conclude that LNG-EC prevents pregnancy only when taken before fertilization of the ovum has occurred.     

Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives

Emergency post-coital contraceptives effectively reduce the risk of pregnancy, but their degree of efficacy remains uncertain. Measurement of efficacy depends on the pregnancy rate without treatment, which cannot be measured directly. We provide indirect estimates of such pregnancy rates, using data from a prospective study of 221 women who were attempting to conceive. We previously estimated the probability of pregnancy with an act of intercourse relative to ovulation. In this article, we extend these data to estimate the probability of pregnancy relative to intercourse on a given cycle day (counting from onset of previous menses). In assessing the efficacy of post-coital contraceptives, other approaches have not incorporated accurate information on the variability of ovulation. We find that the possibility of late ovulation produces a persistent risk of pregnancy even into the sixth week of the cycle. Post-coital contraceptives may be indicated even when intercourse has occurred late in the cycle.     

Emergency contraception

Emergency contraception is used after unprotected intercourse or a contraceptive accident to prevent unwanted pregnancy. It is thought to work by stopping or delaying ovulation or preventing implantation if fertilization has already taken place. Hormonal methods, mifepristone, and intrauterine device insertion are among the methods used worldwide. Combination estrogen-progestin birth control pills are the most commonly used form of emergency contraception in the United States. According to the Yuzpe method, combination pills are taken within 72 hours after intercourse, followed by a second identical dose 12 hours later. With this method, the number of unintended pregnancies is reduced by about 75%. Nausea and vomiting are the most troublesome adverse effects, but these can be controlled with antiemetic medication taken prior to the first dose. The Food and Drug Administration, Washington, DC, has approved an emergency contraception kit consisting of 4 combination pills, a urine pregnancy test, and a patient information book. Most recently, the Food and Drug Administration has approved a progestin-only formulation, which has fewer adverse effects and equal or improved efficacy compared with the combination formula. An intrauterine device can be inserted up to 5 days after unprotected intercourse and is a cost-effective option if it is used as ongoing contraceptive protection. The most readily available form of emergency contraception consists of 2 doses of estrogen-progestin combination birth control pills or 2 levonorgestrel pills taken 12 hours apart. Emergency contraception should not be considered as an alternative to ongoing contraceptive methods, but can prevent unwanted pregnancy.     

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.