Contraception 75 (2007) 112 – 118

Original research article

Effectiveness of levonorgestrel emergency contraception given before or after ovulation — a pilot studyB Natalia Novikovaa, Edith Weisberga,b, Frank Z. Stanczykc, Horacio B. Croxattod, Ian S. Frasera,b,4 a Department of Obstetrics and Gynaecology, University of Sydney, NSW, 2006, Australia Sydney Centre for Reproductive Health Research, Division of Research, FPA Health, Sydney, NSE, 2006, Australia c Reproductive Endocrine Research Laboratory, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA d Instituto Chileno de Medicina Reproductiva, Correo 22, Casilla 96, Santiago, Chile Received 3 July 2006; revised 28 August 2006; accepted 29 August 2006 b

Abstract 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 F24-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. D 2007 Elsevier Inc. All rights reserved. Keywords: Emergency contraception; Pregnancies; Ovulation; Timing of intercourse; Timing of emergency contraception

1. Introduction Oral levonorgestrel (LNG) has been widely used as an emergency contraceptive pill (ECP) for many years [1]. Large studies have confirmed its high efficacy [2] if taken within 72 h of unprotected intercourse but show that it can still have some effect if taken as late as 120 h after unprotected intercourse. A single dose of 1.5 mg of LNG has the same efficacy as two 0.75-mg doses taken 12 h apart [2].

B Funding for this study came from The Family Planning Foundation, FPA Health, Sydney. 4 Corresponding author. Tel.: +61 2 9351 2478; fax: +61 2 9351 4560. E-mail address: [email protected] (I.S. Fraser).

0010-7824/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2006.08.015

Although widely used, the mechanisms of action of the LNG ECP are still unclear [3]. It has been postulated that it may interfere with follicular growth and function, ovulation, migration and function of spermatozoa, fertilization, implantation and endometrial function [4]. There are increasing data to indicate that LNG is particularly effective as an ECP by interrupting follicular development and ovulation [5–7]. An important outstanding question is whether it has any effect on fertilization or implantation. Recent studies in rats and cebus monkeys have convincingly demonstrated the absence of effect of high-dose LNG on postfertilization events [8,9]. Calculating the efficacy of emergency contraception (EC) is problematic as it is impossible to carry out a

N. Novikova et al. / Contraception 75 (2007) 112–118

randomized placebo-controlled study. Efficacy is generally estimated by calculating the ratio of the number of observed pregnancies to the number of pregnancies expected [10]. The expected number of pregnancies is estimated by multiplying the number of treated women who had unprotected sexual intercourse on each day of the menstrual cycle by external estimates of the probability of conception resulting from unprotected sexual intercourse on that day of the cycle. The expected day of ovulation is presumed to be the 14th day before the next menses, although it has been shown that only a small percentage of women ovulate exactly 14 days before the onset of menses [11]. Hence, there are a number of assumptions that are required, which introduce considerable uncertainty into the calculations. Reliance on women’s self-report of the day of the menstrual cycle on which unprotected sexual intercourse occurred and assurance that this is the only episode of unprotected intercourse to have occurred during that cycle also make calculations of ECP efficacy unreliable [12–14]. Other unknown factors are the fertility of the couple and whether the cycle was ovulatory [15]. Most previous studies have related efficacy to the length of time between unprotected intercourse and intake of the ECP and have not taken into account the time relationship between intake of the ECP and ovulation. Based on animal studies, it seems likely that the timing of ECP intake in relation to ovulation may be important in both estimating efficacy and determining mode of action. In this study, the serum levels of progesterone (P4), estradiol (E2) and LH were measured at the time of ECP ingestion in order to provide a more reliable estimate of the time at which unprotected intercourse occurred in relation to ovulation. This has also allowed more accurate estimations of the timing of unprotected intercourse and the pregnancy risk in relation to the timing of ECP intake.

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The Ethics Committee of FPA Health gave approval of the study for all centers. All participants received a detailed information sheet and a thorough discussion of the information and signed an informed consent form. 2.2. Study design The primary outcome of the study was the number of pregnancies that occurred when the ECP was taken before or after ovulation. Women who agreed to participate in this study were asked to complete a questionnaire that records their reproductive and social histories as well as their knowledge about EC. All women took LNG 1.5 mg in a single dose during the course of the clinic consultation. A blood sample (8 mL of venous blood from the cubital fossa) was taken prior to ingestion of the ECP for measurement of serum LH, E2 and P4 levels to assist in estimating the day of ovulation. Blood samples were centrifuged, and serum was separated and frozen at 208C until the specimens were sent to the Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia, to be analyzed in a single batch. Women were followed up via telephone 4–6 weeks later to ascertain their menstrual and pregnancy status. All women who conceived had an ultrasound to confirm the pregnancy. We recruited 70% of eligible women who presented for EC at the clinics. The most common reason for refusal to participate in the study was a requirement to have a venipuncture. 2.3. Hormone assays The levels of E2 and P4 were measured by chemiluminescent immunoassay using the ImmuliteR 2000 analyzer [Diagnostic Products Corporation (DPC), Los Angeles, CA] [16]. Reference ranges for E2 were provided by DPC. They used E2 values obtained in a multinational study involving

2. Materials and methods 2.1. Participants One hundred ten women were recruited in six family planning clinics in NSW (61 in Newcastle and 16 in Chatswood, Hurstville and Penrith) and in Queensland (21 in Brisbane and 12 in Toowoomba) at the time they presented with a request for EC. Women who agreed to participate in the study were in good health, were of reproductive age (15–43 years old; mean, 23.4 years), had regular periods (menstrual cycle lengths between 21 and 35 days) and reported a single act of unprotected sexual intercourse within the previous 120 h. Women who had used hormonal contraceptives or an intrauterine device during the 4 weeks prior to presentation and those who were pregnant, breastfeeding or were unable to abstain from further unprotected intercourse for the remainder of their current menstrual cycle were excluded from the study.

Fig. 1. Menstrual cycle plot for serum P4 levels in 27 women with regular menstrual cycles sampled on a daily basis throughout the menstrual cycle. Serum P4 was assayed in a single batch using the DPC Immulite technique [16].

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women in apparent good health (age, 16 –44 years), who volunteered to have daily blood samples throughout one complete ovulatory cycle. The range of intervals for E2 was b308 pmol/L in the early to midfollicular phase, 124– 1468 pmol/L in the periovulatory phase and 101–905 pmol/L in the luteal phase. The analytical sensitivity was 55 pmol/L for the E2 assay and 0.6 nmol/L for the P4 assay. Reference ranges for P4 during the normal menstrual cycle obtained from a study using this assay [15] were b 3.6 nmol/L in the follicular phase, 1.5–5.5 nmol/L in bmidcycle,Q 3.0– 68 nmol/L for the early luteal phase and 19–76 nmol/L in the midluteal phase. The normal cycle serum levels for P4 are shown in Fig. 1, which demonstrates the sharp rise in serum progesterone levels beginning around the day of the LH peak (Day 1). The data for each hormone were orientated around the LH peak, and the timing of ovulation (Day 0) was estimated at 18–24 h after the peak. LH was measured by means of a microparticle enzyme immunoassay using the Abbot AxsymR system (Abbott, Chicago, IL). The LH reference range was obtained from the manufacturer and was based on specimens obtained daily from 26 women with regular menstrual cycles. Normal ranges were determined for the following: 1–18 IU/L in the follicular phase, 24–35 IU/L at the midcycle peak and 0.4–20 IU/L in the luteal phase. 2.4. Determination of the interval between unprotected intercourse and ovulation and timing of ECP administration The key requirement was determining when intercourse occurred in relation to the day of ovulation and whether the ECP was taken before or on the day of or after ovulation. We divided the bidealizedQ menstrual cycle as follows: with ovulation, Day 0; early follicular, Days 13 to 9; midfollicular, Days 8 to 5; late follicular, Days 4 to 2; periovulatory, Days 1 to 0; early luteal, Days +1 to +4; midluteal, Days +5 to +11; late luteal, Days +12 to +14. The E2 peak was on Day 2, and the LH peak occurred on Day 1. Based on these calculations, the treated women were divided into two groups: those who took the ECP prior to ovulation (Days 13 to 1) and those

who took it on the day of ovulation or postovulation (Days 0 to +14). The timing of unprotected intercourse in relation to ovulation was calculated based on women’s report of the time of the intercourse. We initially determined the day of the cycle on which ECP was taken according to serum P4 levels (Fig. 1) and subsequently adjusted it according to LH and E2 levels. The time of probable ovulation was calculated primarily on the absolute level of P4, with the day of ovulation being designated as Day 0. This calculation allowed us to pinpoint the day of ovulation within F24 h with an 80% level of accuracy. We first calculated the medians and ranges (in nanomoles per liter) of the serum P4 levels from the control group of women from the LH peak (Day 1; median, 2.0 nmol/L; range, 1–5 nmol/L), ovulation (Day 0; median, 4.0; range, 2–8), Day +1 (median, 10.0; range, 3–25) through Day +2 (median, 15.0; range, 8–35). Day 1 also coincided with a high LH level (N 24 IU/L) and a serum E2 level N 400 pmol/ L. Serum E2 dropped to a low level (b 250 pmol/L) by Day +2. LH levels between 15 and 24 IU/L indicated the day before or the day after the LH peak depending on the serum P4 and E2 levels. A serum E2 level N 450 pmol/L indicated the E2 peak on Day 2. A level of E2 between 300 and 450 pmol/L indicated Day 3 or Day 1 (or later in the luteal phase) depending on the LH and P4 levels. LH levels below 15 IU/L were seen on Days 3 and +2. Intermediate levels of these two hormones were used to attempt to pinpoint the other days in and around the periovulatory phase. The accuracy of prediction of the day of ovulation from endocrine data was tested by setting up a model based on daily serum P4 ranges and then testing by logistic regression, using serum P4 alone as the predictor of Day 0 or not Day 0. This was achieved with an 87% accuracy. The level of accuracy of prediction varied somewhat with each day on either side of Day 0, and although the accuracy increased with inclusion of E2 and LH, the model became much more complex. For the purposes of this pilot trial, where data were limited, we felt that it was important to be

Table 1 Distribution of women having unprotected intercourse in the fertile period of the menstrual cycle based on endocrine data and probability of clinical pregnancy using Wilcox calculations [17,18] Cycle day of intercourse (Day 0 = day of ovulation)

5 4 3 2 1 0 Total

Probability of clinical pregnancy (%) — based on data from Wilcox calculations (see Table 1 of Ref. [18])

Number of women who had sexual intercourse on each cycle day (based on endocrine data)

Expected number of clinical pregnancies based on endocrine data and Wilcox calculations

Observed pregnancies

4 13 8 29 27 8

7 9 12 6 11 6 51

0.28 1.17 0.96 1.74 2.97 0.48 7.60

0 0 0 0 1 2 3

4.15

3.45

N. Novikova et al. / Contraception 75 (2007) 112–118

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able to confirm that the prediction gave an accuracy of at least 80% in determining that a serum sample was obtained on a specific day in relation to ovulation. 2.5. Calculating the efficacy of the LNG ECP To determine the efficacy of the ECP, we compared the number of observed pregnancies with the number of expected pregnancies [17–19]. Prevented pregnancies were calculated by subtracting the ratio of expected pregnancies to observed pregnancies from 1. Expected pregnancies were calculated by multiplying the number of women having unprotected intercourse on each day of the fertile period by the probability of clinical pregnancy described by Wilcox et al. [17,18] (Table 1). The fertile period of the cycle was taken to extend from 5 days before ovulation to the day of ovulation.

Fig. 2. Comparison between stages of cycle at the time the ECP was taken based on endocrine data or women’s self-report. For the purposes of this figure, cycle phases were defined as follicular (Day 3 and earlier), periovulatory (Days 2 to +1) and luteal (Day +2 and later).

2.6. Statistical analysis Data were analyzed using Excel 2003 and SPSS 11.5 (SPSS Inc., Chicago, IL). Variables that were normally distributed are presented as means and standard deviations and were analyzed using the independent and paired t test. Confidence intervals were used where appropriate, and statistical significance was defined as p b .05. 3. Results One hundred ten women aged 15 to 43 years (mean, 21; SD, 7.6) were enrolled in this study, but 11 women were excluded due to insufficient blood samples for complete hormonal analysis. Therefore, 99 women were investigated. Sixty women had not been pregnant previously, 14 had one pregnancy, 6 had two pregnancies, 6 had more than three pregnancies and 2 women did not report their reproductive history. Forty-nine women had used ECP previously. Twenty women had used the ECP once, 11 had used it twice, 7 had used it three times, 4 had used it four times and 8 women had used it five or more times. One woman reported becoming pregnant after previous use of the Yuzpe method of EC. Table 1 shows the distribution of women having unprotected intercourse on different days of the fertile period (between Days 5 and 0) compared with the number

Table 2 Timing of sexual intercourse and taking the ECP for three women who became pregnant, based on serum hormone levels at the time of ECP administration E2 (pmol/L) 1 2 3

214 154 181

P4 (nmol/L)

LH (IU/L)

11.5 13.1 13.2

10.6 12.7 8.4

No. of hours between IC and ECP 33 66 20

Day of sexual intercourse 0F1 1F1 0F1

Day of ECP +2F1 +2F1 +2F1

IC, unprotected intercourse; ECP, levonorgestrel emergency contraceptive pill.

of clinical pregnancies. Fifty-one women had the index episode of unprotected intercourse on Days 5 to 0. According to the data of Wilcox et al. [17,18], we should have expected seven to eight clinical pregnancies in our study, and we observed three pregnancies. Thus, the failure rate of the ECP was 3.0%, and its efficacy in this study was found to be 60.5% based on Wilcox’s calculations of pregnancy probability [17,18]. Twenty-three women had their index episode of unprotected intercourse in the early to midfollicular phase prior to Day 5, and 25 had intercourse in the luteal phase. From the data in Table 1, it is clear that pregnancies did not occur when unprotected intercourse occurred on Day 2 or earlier and when the ECP was taken before Day 0, whereas all three pregnancies occurred when intercourse took place around Days 1 to 0 and when the ECP was taken on Day +2. Data from Wilcox et al. [17,18] suggest that four or five clinical pregnancies would have been expected among the group of 34 women who had intercourse on Days 5 to 2 (and took the ECP before or around ovulation), but none occurred. Among the 17 women who had intercourse around Days 1 to 0 (and took the ECP on Day +2), three or four pregnancies would have been expected, and three were observed. Hormonal levels, time of sexual intercourse and day of taking the ECP in these three cases are presented in Table 2. For the third participant who became pregnant, endocrine data suggested that unprotected intercourse may have occurred 12 to 24 h after ovulation. We have taken this to be Day 0. There was substantial discord between the determination of stages of cycle from endocrine data compared with data from the woman’s self-report (Fig. 2). Of the 41 women, who, on endocrine data, were in the follicular phase of the menstrual cycle, only 16 (39%) were correct in their personal estimation, 7 of these (17%) thought that they were in the periovulatory phase and 16 (39%) thought that they were already in the luteal phase. Two of these women were unable to identify the stage of their cycle at the time of

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consultation. Only 7 out of 30 women (23.3%), who were in the periovulatory phase of the menstrual cycle according to endocrine data, were correct in their own estimation of this phase. Four (13%) thought that they were in the follicular phase, 16 (53%) thought that they were in the luteal phase and 3 could not remember when their last menstrual period was (Fig. 2). Twenty-eight women were in the luteal phase of the cycle at the time the ECP was taken, and the majority of them [19 (68%)] reported correctly that they thought they were in this phase of the cycle: 5 (18%) thought that they were in the periovulatory phase, 2 (7%) thought that they were in the follicular phase and 2 were unable to remember the day of their cycle. Overall, 21 out of the 99 women (21%) were unsure of the actual date of their last menstrual period. 4. Discussion A most important question today is whether the LNG ECP has an effect on postfertilization events. If the LNG ECP is ineffective once fertilization has occurred, it would become an acceptable contraceptive option for many people who consider that human life begins at fertilization. A problem with efficacy studies of EC is pinpointing the exact time relationship of unprotected intercourse and ECP ingestion to the occurrence of ovulation. Timing is usually based on data reported by the women and calculations done by the investigator using uncertain assumptions, which have been shown in this study as well as in other studies to be quite unreliable [14]. In this study, we were able to pinpoint the day within or after the fertile period in which the ECP was taken to within 24 h with an estimated 80% accuracy, based on individual endocrine data. Accuracy could have been improved had we been able to take repeated blood samples over several days and perform ultrasound examinations of the ovary at the time that blood was taken. Unfortunately, this was logistically impossible. Both endocrine and ultrasound examinations are costly, which would make it very expensive and difficult to conduct such a study with sufficient numbers to provide adequate power, as the overall pregnancy rate in women who use EC is low. There have been several attempts to design external estimates for the probability of conception in natural cycles [17–23], but most of these reports have relied on women’s self-report of cycle day and day of intercourse, which is sometimes supplemented by basal body temperature or urinary hormone data. Wilcox et al. [17] determined the probability of conception based on endocrine data to estimate the day of ovulation for 221 North Carolina women who provided daily urine samples for measurement of urinary estrogen and P4 metabolites from the time they stopped contraception until they became pregnant or had provided 6 months data. As the urinary ratio of estrogen to P4 metabolites decreases abruptly with luteinization of the ovarian follicle, this measure of ovulation corresponds approximately with the LH peak [22].

We used endocrine data from the measurement of three hormones that change markedly in serum in the periovulatory period to predict the day on which women ovulated and took the ECP. This appears to be a more precise method (to at least an 80% accuracy) of estimating the day within or after the fertile period than methods used in some studies such as basal body temperature or urinary LH. A recent study has shown that urinary LH on its own may be unreliable for determining the day of ovulation [6]. The serum level of P4 (Fig. 1) was used as the initial determinant and serum LH and E2 levels were used as additional determinants of the more precise time in the cycle when women took the ECP. We initially used Fig. 1 to determine the day before, the day of or the day after ovulation for individual participants according to the P4 level. The data in this graph were generated in a multinational study involving women in apparent good health [16], but these data have not been specifically validated for Australian women. The participants in our study had similar characteristics to those enrolled in the abovementioned study, although it is unknown if other important factors such as weight, smoking habits and parity were also similar. The patterns of Immulite data are similar but not identical to data obtained by other authors on P4, LH and E2 profiles during the normal menstrual cycle [24,25]. We found substantial discrepancies between hormonal findings and the stage of the menstrual cycle reported by women. Self-report of cycle phase coincided with hormonal parameters in only 43.4% of women. Stirling and Glasier [14] found that hormonal results in 30% of women in their study were incompatible with the cycle day estimated by calendar and were most likely to be inconsistent in those women presenting in the luteal phase (when their last menstrual period was more distant in their memory). In contrast, we found that endocrine data were more consistent with self-report by women in the luteal phase (67.9%) and least consistent in the periovulatory phase (23.3%). Our findings confirm that it is unreliable to base the estimation of cycle phase on women’s self-report. Hormonal confirmation is required. The bpregnancy rateQ in this study was 3.0%, which is similar to other studies on the efficacy of ECP [2,15]. All three women who became pregnant had very similar endocrine data and took the ECP around 2 days after ovulation and had unprotected intercourse between Days 1 and 0. The expected number of clinical pregnancies in our study was seven to eight, based on Wilcox probability of clinical pregnancy [17,18]. From the data in Table 2, it is clear that pregnancies did not occur when unprotected intercourse occurred on Day 2 or earlier and when ECP was then taken around or before ovulation. Four or five clinical pregnancies could have been expected in this group of women, but none occurred. These data are supportive of the concept that the LNG ECP has little or no effect on postovulation events. This is in agreement with animal studies showing that LNG does not

N. Novikova et al. / Contraception 75 (2007) 112–118

interfere with postfertilization events [8,9]. Durand et al. [6] showed that LNG, given postcoitally, has an antiovulatory effect if administered prior to the LH surge but not after it. Other studies of the Yuzpe regimen for ECP also found that this method of contraception is unlikely to prevent pregnancy if given postfertilization [26]. The failure rate reported in randomized controlled trials of the LNG ECP has varied from 1.1% to 2.9%, with efficacy rates between 60% and 85% [2,7,27,28] depending on whether they were based on Wilcox or Trussell or other calculations of pregnancy probability. The efficacy rate of the ECP in our study, based on Wilcox calculations, was 60.5% (4.6 of the expected 7.6 pregnancies were prevented) when timing of ovulation was based on endocrine data. This efficacy rate is lower than what was reported in other studies where cycle day was based on the woman’s self-report. 5. Conclusion It is clear from this study that ovulation dating based on retrospective menstrual data is unreliable and does not correlate well with the endocrine data. Studies of EC efficacy based on endocrine data are expensive and, therefore, potentially limit the number of participants. However, to obtain more accurate data on both efficacy and mode of action of EC, more extensive studies of this nature using transvaginal ultrasound in conjunction with endocrine data are required in much larger numbers of women. The small number of participants in our study does not enable us to make a definitive statement on the hypothetical postfertilization effect of the ECP. However, our interpretation of the data in terms of timing of treatment relative to ovulation may explain why EC with LNG works sometimes and fails at other times. The fact that all three pregnancies in this study occurred when women took the ECP around 2 days after ovulation suggests that the ECP may be less effective or ineffective if taken postfertilization. A larger study is needed to prove our hypothesis that the LNG ECP has a major contraceptive effect when taken prior to but not after ovulation and that it does not interfere with postfertilization events.

Acknowledgments The authors are grateful to the administrators and staff of the six clinics in NSW and Queensland and to Dr. Georgina Luscombe for expert statistical advice.

References [1] Seregely G, Vero T. Postcoital contraception with 0.75 mg d-norgestrel (Postinor). Ther Hung 1981;29:31 – 4. [2] 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.

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[3] Trussell J, Jordan B. Mechanism of action of emergency contraceptive pills. Contraception 2006;74:87 – 9. [4] Croxatto HB, Devoto L, Durand M, et al. Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature. Contraception 2001;63:111 – 21. [5] Croxatto HB, Ortiz ME, Muller AL. Mechanisms of action of emergency contraception. Steroids 2003;68:1095 – 8. [6] Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception 2001;64:227 – 34. [7] Marions L, Hultenby K, Lindell I, et al. Emergency contraception with mifepristone and levonorgestrel: mechanism of action. Obstet Gynecol 2002;100:65 – 71. [8] Muller AL, Llados CM, Croxatto HB. Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat. Contraception 2003;67:415 – 9. [9] Ortiz ME, Ortiz RE, Fuentes MA, et al. Post-coital administration of levonorgestrel does not interfere with post-fertilization events in the New-World monkey Cebus apella. Hum Reprod 2004;19: 1352 – 6. [10] Dixon GW, Schlesselman JJ, Ory HW, Blye RP. Ethinyl estradiol and conjugated estrogens as postcoital contraceptives. JAMA 1980;244: 1336 – 9. [11] Lenton EA, Landgren BM, Sexton L. Normal variation in the length of the luteal phase of the menstrual cycle: identification of the short luteal phase. Br J Obstet Gynaecol 1984;91:685 – 9. [12] Glasier A, Thong KJ, Dewar M, et al. Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency postcoital contraception. N Engl J Med 1992;327:1041 – 4. [13] Espinos JJ, Senosiain R, Aura M, et al. Safety and effectiveness of hormonal postcoital contraception: a prospective study. Eur J Contracept Reprod Health Care 1999;4:27 – 33. [14] Stirling A, Glasier A. Estimating the efficacy of emergency contraception — how reliable are the data? Contraception 2002;66: 19 – 22. [15] Task Force on Postovulatory Methods of Fertility Regulation, World Health Organization. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998;352:428 – 33. [16] Vankrieken L. Immulite reproductive hormone assays: multicenter reference range data. Los Angeles7 Diagnostic Products Corp; 2000 Document; No. ZB157-D. [17] Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med 1995; 333:1517 – 21. [18] Wilcox AJ, Weinberg CR, Baird DD. Postovulatory ageing of the human oocyte and embryo failure. Hum Reprod 1998;13: 394 – 7. [19] Trussell J, Rodriguez G, Ellertson C. New estimates of the effectiveness of the Yuzpe regimen of emergency contraception. Contraception 1998;57:363 – 9. [20] Barrett JC, Marshall J. The risk of conception on different days of the menstrual cycle. Popul Stud 1969;23:455 – 61. [21] Schwartz D, Macdonald PDM, Heuchel V. Fecundability, coital frequency and the viability of ova. Popul Stud 1980;34: 397 – 400. [22] Baird DD, Weinberg CR, Wilcox AJ, McConnaughey DR, Musey PI. Using the ratio of urinary oestrogen and progesterone metabolites to estimate day of ovulation. Stat Med 1991;10:255 – 66. [23] Wilcox AJ, Dunson DB, Weinberg CR, et al. Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives. Contraception 2001;63: 211 – 5. [24] Lenton EA, Adams M, Cooke ID. Plasma steroid and gonadotrophin profiles in ovulatory but infertile women. Clin Endocrinol 1978;8: 241 – 55.

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[25] Landgren BM, Unden AL, Diczfalusy E. Hormonal profile of the cycle in 68 normally menstruating women. Acta Endocrinol 1980;94: 89 – 98. [26] Trussell J, Ellertson C, Dorflinger L. Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action. Contraception 2003;67:167 – 71.

[27] Ho PC, Kwan MS. A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception. Hum Reprod 1993;8:389 – 92. [28] Hamoda H, Ashok PW, Stalder C, et al. A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol 2004;104:1307 – 13.

Effectiveness of levonorgestrel emergency ...

E-mail address: [email protected] (I.S. Fraser). Contraception 75 ... Serum P4 was assayed in a single batch using the DPC Immulite technique [16].

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89 THE EFFECTIVENESS OF CONTINGENCY ...
pi, Hattiesburg, Mississippi 39406-5025 (E-mail: [email protected]). pletely eliminated graffiti in men's bath- rooms. Watson (1996) used a sign with an ...

Board Effectiveness Indicators
Are directors offered continuing education in governance or a program of director certification? ❑Yes ❑ No. Does each director display a keen interest or passion ...

Evaluation of the Effectiveness of a Silver-Impregnated Medical Cap ...
Page 3 of 7. Evaluation of the Effectiveness of a Silver-Impregnate ... eatment of Nipple Fissure of Breastfeeding Mothers.pdf. Evaluation of the Effectiveness of a ...

Experimental Demonstration of the Effectiveness of ...
Apr 28, 2016 - This cycle is repeated and every data point presented below corresponds ... mated by a decaying exponential with decay constant τ. The result ...

Effectiveness of Treatment Strategies of Some Women ...
Human subject use approval was obtained at each ... There were 1,515 women eligible. Of these, 651 refused participation, and of 864 women enrolled,. 831 (54.9% of those eligible) were contacted at least ... Neither patients nor providers were blinde

Evaluation of the Effectiveness of a Silver-Impregnated Medical Cap ...
Page 1 of 7. Clinical Research. Evaluation of the Effectiveness of a Silver-Impregnated. Medical Cap for Topical Treatment of Nipple. Fissure of Breastfeeding Mothers. Adriano Marrazzu,1 Maria Grazia Sanna,2 Francesco Dessole,1 Giampiero Capobianco,1

Effectiveness of Opcode ngrams for Detection of Multi ...
to the web and cloud resources. The growth rate in ... result, static scanning of host applications to capture the malicious ...... Another free app: Does it have the ...

Safety Emergency Drills Reporting and Cardiac Emergency ...
Retrying... Safety Emergency Drills Reporting and Cardiac Emergency Response Plan.pdf. Safety Emergency Drills Reporting and Cardiac Emergency Response Plan.pdf. Open. Extract. Open with. Sign In. Main menu. Displaying Safety Emergency Drills Reporti

The Astounding Effectiveness of Dual Language ...
We define one-way programs as demographic contexts where only one .... system includes data stored on magnetic media in machine-readable files from their ...