Experts' view on the role of oestrogens in combined oral contraceptives: emphasis on oestetrol (E4).

Introduction: The evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety. Methods: Seven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views. Results: Ethinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health. Conclusion: Oestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia.

OBJECTIVES: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. DESIGN: Multicenter, open-label, phase 3 trial. SETTING: Sixty-nine sites in Europe and Russia. POPULATION: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m2 . METHODS: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. MAIN OUTCOME MEASURES: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs. RESULTS: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. CONCLUSION: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. TWEETABLE ABSTRACT: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Ulipristal acetate for emergency contraception.

Ulipristal acetate is a progesterone receptor modulator. As an emergency contraceptive, a 30-mg micronized formulation is effective for use up to 120 h from unprotected sexual intercourse. Ulipristal acetate acts as an antagonist of the progesterone receptor at the transcriptional level and a competitive antagonist of glucocorticoid receptor function. In contrast to other contraceptives, it has little effect on sex hormone-binding globulin. Although a single small study demonstrated some potential endometrial effects after ulipristal acetate administration, the clinical relevance of these findings is unclear. The incidence of adverse events in clinical trials for emergency contraception has typically been minimal, with one study showing a higher than expected incidence of nausea upon ulipristal acetate use. Ulipristal acetate, like other emergency contraceptive products, can lengthen the time to the next expected menstruation. Ulipristal acetate may have several advantages over currently approved emergency contraceptives. When compared to levonorgestrel, ulipristal acetate maintains its efficacy for a full 120 h, whereas levonorgestrel formulations have declining efficacy over that time frame. Moreover, although the copper intrauterine device (IUD) is highly effective as an emergency contraceptive, accessibility is an issue since the IUD requires a skilled provider for insertion.

Endometrial thickness following medical abortion is not predictive of subsequent surgical intervention.

OBJECTIVES: To evaluate the ability of endometrial thickness after medical abortion to predict the need for subsequent dilatation and curettage (D&C). METHODS: We pooled data from two multicenter medical abortion trials involving 2208 women who received mifepristone orally followed by misoprostol vaginally. Women returned for transvaginal ultrasonography approximately 7 days later. The endometrial thickness was measured if no gestational sac was present. Final status was confirmed by a phone interview at 5 weeks. The area under the receiver-operating characteristics (ROC) curve was calculated to assess the overall ability of endometrial thickness to predict the need for subsequent D&C. Endometrial thickness was dichotomized using threshold values at 5-mm increments from 10 to 30 mm. The sensitivity, specificity, negative predictive value and positive predictive value were calculated to evaluate the ability of each endometrial thickness threshold value to predict subsequent D&C. Multivariable regression analysis was performed to adjust endometrial thickness values for study, treatment group, and study site. RESULTS: At 7 days after misoprostol treatment, 1870 women (84.7%) had endometrial thickness assessed. Thirty of these women (1.6%) subsequently underwent D&C. The mean endometrial thickness was 14.5 mm for women who underwent D&C and 10.9 mm for those who did not (difference 3.5 mm (95% CI, 1.8-5.3 mm)). Endometrial thickness was poorly predictive of the need for D&C, with an area under the ROC curve of 0.65. All endometrial thickness thresholds had positive predictive values of 25% or less. The results were unchanged by adjustment of endometrial thickness values by multivariable modeling. CONCLUSIONS: Although endometrial thickness following successful expulsion of the gestational sac is thicker in women who will eventually require surgical intervention after medical abortion, endometrial thickness is not a clinically useful predictor of the subsequent need for D&C.

Clinical indicators for success of misoprostol treatment after early pregnancy failure.

OBJECTIVE: To identify clinical indicators for success of misoprostol treatment after early pregnancy failure. METHODS: A total of 473 women with early pregnancy failure received 800 microg of vaginal misoprostol on treatment day 1. At the follow-up visit on day 3, a second dose was given if expulsion was incomplete. On day 8, vacuum aspiration was offered if expulsion had not occurred. Ultrasonography was used as gold standard for success. A Classification and Regression Tree analysis was undertaken to derive two decision trees for the success of misoprostol treatment on study days 3 and 8. RESULTS: Heavy bleeding after the first dose and an open cervical os were identified as clinical indicators of treatment success on day 3. Treatment success occurred in 84% of women with either or both indicators. Reporting passage of tissue after a second misoprostol dose and old blood in the vagina were potential indicators of treatment success or failure on day 8. A woman with either of these indicators has a 65% chance of treatment success after the second dose. Conversely, a woman with neither indicator on day 8 has a 94% chance of treatment failure. CONCLUSION: Standard clinical findings may be useful as indicators for success or failure of medical management of early pregnancy failure in settings with limited or no access to ultrasonography. More research to identify even better indicators is warranted.

Endometrial thickness after misoprostol use for early pregnancy failure.

OBJECTIVES: To assess if there was any potential relationship between endometrial thickness and final treatment outcome in women successfully treated with misoprostol for a first trimester anembryonic gestation, embryonic demise or fetal demise. METHODS: Eighty women were treated with up to two doses of misoprostol 800 microg vaginally for early pregnancy failure. Subjects were scheduled to return 2 (range 1-4), 7 (range 5-9) and 14 (range 12-17) days after treatment. Transvaginal ultrasonography was performed at each follow-up visit. RESULTS: The median endometrial thickness at each of the follow-up visits for women who had expelled the gestational sac was 14 mm, 10 mm, and 7 mm, respectively. The endometrial thickness at the first follow-up visit exceeded 15 mm in 20 subjects (36%) and 30 mm in four subjects (7%). Only three women had a suction aspiration for bleeding after documented expulsion. The endometrial thickness for these women was 11, 13, and 14 mm at the first follow-up visit. CONCLUSIONS: There is no obvious relationship between increasing endometrial thickness and the need for surgical intervention in women treated with misoprostol for early pregnancy failure.

The risks of oral contraceptive pills.

Oral contraceptive pills have been associated with increased risk for myocardial infarction, stroke, and venous thromboembolism. Studies have been published recently that suggest that these risks are minimal in appropriately chosen low-risk women. Stroke is a very uncommon event in childbearing women, occurring in approximately 11 per 100,000 women over 1 year. Thus, even a doubling of this risk with oral contraceptive pills would have minimal effect on attributable risk. The estimated risk of myocardial infarction associated with oral contraceptive pill use in nonsmokers is 3 per million women over 1 year. The estimated risk of venous thromboembolism attributable to oral contraceptive pills is less than 3 per 10,000 women per year. Additionally, the literature suggests that there may be an increased risk of breast cancer associated with long-term oral contraceptive pill use in women under the age of 35. However, because the incidence of breast cancer is so low in this population, the attributable risk of breast cancer from birth control pill use is small.

Mifepristone followed on the same day by vaginal misoprostol for early abortion.

We performed a pilot study to examine the clinical efficacy of mifepristone 200 mg followed on the same day by misoprostol 800 microg vaginally in women with pregnancies up to 49 days gestation. Forty women received mifepristone 200 mg after which they self-inserted misoprostol intravaginally 6 to 8 h later at home. Participants returned for an evaluation, including transvaginal ultrasonography, 24 +/- 1 h after using the misoprostol. Participants who had not aborted received a second dose of misoprostol to administer 48 h after the mifepristone. All participants returned approximately 2 weeks after receiving mifepristone. At 24 h after receiving misoprostol, 37/40 (92%, 95% CI 81-98%) had ultrasonographic evidence of complete abortion. By follow-up 2 weeks after the mifepristone, 40/40 (100%, 95% CI 92-100%) women were felt to have complete abortions. One subject subsequently had a suction aspiration for an incomplete abortion on study Day 44. Nausea, vomiting, diarrhea, and warmth/chills occurred in 38%, 13%, 13%, and 60%, respectively. This pilot study suggests that mifepristone 200 mg, followed on the same day by misoprostol 800 microg vaginally, effects abortion at rates comparable to regimens using the standard time interval of 48 h between medications.

Toxic shock syndrome after laminaria insertion.

BACKGROUND: Laminaria tents used to facilitate surgical abortion are rarely associated with significant infectious morbidity. CASE: A parous woman in midpregnancy had laminaria placed in her cervix followed by a second set after 24 hours. Eight hours later, she presented with dyspnea, hives, fever, tachycardia, and hypotension. Antibiotic treatment was initiated and a dilation and evacuation procedure was performed. Amniotic membrane cultures showed a heavy growth of Staphylococcus aureus with staphylococcal enterotoxin C expression, compatible with toxic shock syndrome. CONCLUSION: Laminaria cervical dilation might be associated with toxic shock syndrome.

Accuracy of serum beta-human chorionic gonadotropin cutoff values at 42 and 49 days' gestation.

OBJECTIVE: The accuracy of serum beta-human chorionic gonadotropin levels as cutoff values for estimating gestational age was studied. MATERIAL AND METHODS: A database was created using information from previously performed research studies, which allowed entry of women both less than and greater than 49 days' gestation, involving medical abortion. Serum beta-human chorionic gonadotropin determinations and vaginal ultrasonography were performed in all studies before treatment. A total of 574 women had data available for analysis. A receiver operating characteristic curve was created to evaluate the predictive value of potential beta-human chorionic gonadotropin cutoff values for 42 and 49 days' gestation. RESULTS: Appropriate serum beta-human chorionic gonadotropin cutoff values for 42 and 49 days' gestation were 23,745 mIU/mL (sensitivity, 96%; specificity, 91%; positive predictive value, 68%; negative predictive value, 99%) and 71,160 mIU/mL (sensitivity, 95%; specificity, 62%; positive predictive value, 76%; negative predictive value, 91%), respectively. Under 42 days' gestation, the serum beta-human chorionic gonadotropin-time relationship appears to be linear, with a greater diversity of individual values after 42 days. CONCLUSION: Serum beta-human chorionic gonadotropin values can be used with reasonable accuracy to screen for a gestational age up to 49 days' gestation.

Mifepristone 100 mg in abortion regimens.

OBJECTIVE: To examine the clinical efficacy of mifepristone 100 mg followed 2 days later by misoprostol 400 microg orally or 800 microg vaginally in women at up to 49 days' gestation. METHODS: Eighty participants received mifepristone 100 mg and then were randomized to misoprostol, administered 48 hours later, at a dose of 400 microg orally (group 1) or 800 microg vaginally (group 2). Women returned for follow-up evaluations 24 +/- 1 hour after using the misoprostol and then 2-3 weeks later. If abortion still had not occurred and the pregnancy was nonviable, the subject returned again after an additional 3 weeks. RESULTS: Twenty-four hours after receiving misoprostol, 34 (85%; 95% confidence interval [CI] 71%, 94%) of the 40 women in group 1 and 38 (95%; 95% CI 85%, 99%) of the 40 women in group 2 had complete abortions. Overall, complete abortion without surgical intervention occurred in 34 women in group 1 (85%; 95% CI 71%, 94%) and 40 women in group 2 (100%; 95% CI 91%, 100%; P =.03). Four women in group 1 required suction aspiration for continuing pregnancy at the second follow-up, compared with none in group 2 (P =.12). Side effects occurred with similar frequency in both treatment groups. CONCLUSION: Low-dose mifepristone (100 mg) combined with vaginal misoprostol 800 microg may be an effective alternative to regimens using 200 or 600 mg of mifepristone with misoprostol.

Efficacy of mifepristone followed on the same day by misoprostol for early termination of pregnancy: report of a randomised trial.

OBJECTIVE: To examine the clinical efficacy of mifepristone 600 mg followed on the same day or two days later by misoprostol 400 microg orally in women undergoing medical termination of pregnancy whose pregnancies have a gestational age up to 49 days. DESIGN: Prospective, randomised trial. SETTING: Clinical research office. PARTICIPANTS: Eighty-six women, requesting elective termination of a pregnancy which has a gestational age of < or = 49 days. METHODS: After administration of mifepristone 600 mg, participants were randomised to take misoprostol six to eight hours later (Group 1) or 48 hours later (Group 2). Women returned for a follow up evaluation 24 +/- 1 hours after taking the misoprostol. Participants in Group 1 who had not aborted received a second dose of misoprostol to take 48 hours after the mifepristone. All women returned approximately two weeks after receiving mifepristone. If termination of pregnancy had still not occurred and the pregnancy was non-viable, the woman returned again in three weeks. MAIN OUTCOME MEASURES: Rate of complete abortion 24 hours after administration of misoprostol. RESULTS: At 24 hours after receiving misoprostol, 21/42 (50%, 95% CI 35%, 65%) women in Group I and 40/44 (91%, 95% CI 82%, 99%) women in Group 2 had complete abortions. By follow up two weeks later after the administration of mifepristone, 40/42 (95%, 95% CI 89%, 100%) women in Group 1 and 43/44 (98%, 95% CI 93%, 99%) women in Group 2 were known to have complete abortions. Nausea, vomiting or diarrhoea in women using the standard regimen (Group 2) occurred in 68%, 36%, and 20%, respectively. CONCLUSIONS: After treatment with mifepristone 600 mg, administration of misoprostol 400 microg orally on the same day is not as effective at causing abortion within the first 24 hours compared with the standard time interval of 48 hours between medications.

Early pregnancy failure--current management concepts.

Approximately one in four women will experience a miscarriage during her lifetime. For more than 50 years, the standard management of early pregnancy failure has been a dilatation and curettage (D & C). Typically, the procedure is performed in an operating room, which significantly increases cost. There is little objective information in the modem literature to prove that a D & C for all patients will lower morbidity or improve emotional well being. Treatment options include expectant management, D & C in an outpatient setting, and medical management with misoprostol (not approved by the U.S. Food and Drug Administration for treatment of early pregnancy failure). The medical literature supports that expectant management may result in more complications, including the need for "emergent" curettage, if clinicians do not understand the true normal course of expectant management. In general, women prefer some form of active management. Dilatation and curettage can be performed safely in the office or other outpatient setting using manual vacuum aspiration. Vaginal misoprostol will cause expulsion in 80% to 90% of women up to 13 weeks' uterine size or gestation, including patients who have a gestational sac present. However, these data come from only three trials involving a total of 42 subjects treated with vaginal misoprostol, and another study of 42 women who received vaginal misoprostol for "missed abortion" before a scheduled D & C. There is a significant lack of information from large-scale studies about when treatment is necessary and the relative efficacy, rates of side effects, and acceptability of these various treatment options for early pregnancy failure.

Randomized comparison of efficacy, acceptability and cost of medical versus surgical abortion.

This randomized trial was performed to examine the clinical efficacy of, patient acceptance of, and provider resources needed for medical and surgical abortion in women with pregnancies up to 49 days' gestation. Women with no pre-treatment preference for method of abortion were randomized to medical abortion with methotrexate and misoprostol (group 1) or surgical abortion under local anesthesia using manual vacuum aspiration (group 2). Women in group 1 received methotrexate 50 mg orally followed 5 to 6 days later by misoprostol 800 microg vaginally; the misoprostol dose was repeated if the abortion did not occur. All subjects returned for a follow-up evaluation 7 and 14 days after the methotrexate or 14 days after the vacuum aspiration. The time spent by clinical staff for all interactions with participants was prospectively recorded. Enrollment of 50 subjects took 24 months; 25 women were randomized to each group. The complete abortion rates by study day 15 were 83% (95% CI 68, 98%) and 96% (95% CI 88, 100%) for groups 1 and 2, respectively. Of the women randomized to a surgical abortion, 92% (95% CI 81, 100%) stated they would choose a surgical for a next abortion, whereas only 63% (95% CI 43, 82%) of women randomized to a medical abortion would choose that option in the future. Overall, surgical abortion requires 0 to 10% more personnel cost than medical abortion using methotrexate and misoprostol. In women who did not have a strong preference between medical and surgical abortion, the side effect profile and patient acceptability was significantly better for surgical abortion compared to medical abortion.

Medical abortion regimens: historical context and overview.

Medical abortion offers an important alternative to surgical abortion for women with early pregnancies who wish to avoid a surgical procedure. More than 3 million women worldwide have had medical abortions in the past decade alone. The best-studied regimens include mifepristone orally followed 36 to 48 hours later by a prostaglandin analog administered either orally or intravaginally. Because of political and social restrictions related to mifepristone, however, researchers have investigated alternative regimens, most notably methotrexate and misoprostol. Mifepristone regimens are approximately 95% effective for abortion at

Alternatives to mifepristone regimens for medical abortion.

Alternatives to regimens with mifepristone and a prostaglandin analog for medical abortion emerged because of the need for accessible, effective, and safe options in areas of the world where mifepristone was unavailable. Studies of oral or intramuscular methotrexate combined with misoprostol have demonstrated complete abortion rates in the same range as mifepristone regimens at

Management of side effects and complications in medical abortion.

Side effects are an expected part of medical abortion; some, such as pain and bleeding, result from the abortion process itself and are generally managed with orally administered analgesics and counseling. True medication side effects most commonly include nausea, vomiting, diarrhea, and warmth or chills. Complications of medical abortion usually represent an extreme or severe side effect. Large series have reported transfusion rates of <1%. Because of the infrequency of uterine instrumentation, postabortal endometritis appears to be rare with medical abortion. As with early surgical abortion, the clinician must remain aware of the possibility for ectopic pregnancy. Overall approximately 2% to 10% of patients will require surgical intervention for control of bleeding, resolution of incomplete expulsion, or termination of a continuing pregnancy. Understanding the types of side effects and complications that can occur will enable the clinician to counsel patients properly as well as to understand when medical intervention is necessary during the medical abortion process.

Medical abortion alternatives to mifepristone.

Social and political constraints have prohibited the use of mifepristone in most countries. As a result, researchers, clinicians, and women throughout the world have pushed for the development of alternative medical abortion regimens. Methotrexate (both oral and intramuscular) combined with misoprostol has been under investigation since 1993, with complete abortion rates similar to mifepristone regimens for pregnancies up to 49 days' gestation. Thousands of women have had safe medical abortions in their own homes using these medications. The overall abortion process using methotrexate and misoprostol takes longer, however, with 20% to 30% of women waiting up to five weeks for the abortion to occur. More recently, misoprostol-only regimens have been proposed for medical termination of pregnancy. The efficacy of these misoprostol regimens has been reported in the same range as those combining mifepristone or methotrexate with misoprostol, although other investigators have been unable to confirm these results. Additionally, a few small studies have tested tamoxifen combined with misoprostol, with mixed results. Continued research is necessary to ensure that reported efficacy rates for all proven medical abortion regimens are true for various populations of women.

The efficacy of medical abortion: a meta-analysis.

Multiple clinical studies demonstrate the efficacy of medical abortion with mifepristone or methotrexate followed by a prostaglandin analogue. However, assessing predictors of success, including regimen, is difficult because of regimen variability and a lack of direct comparisons. This meta-analysis estimates rates of primary clinical outcomes of medical abortion (successful abortion, incomplete abortion, and viable pregnancy) and compares them by regimen and gestational age. We identified 54 studies published from 1991 to 1998 using mifepristone with misoprostol (18), mifepristone with other prostaglandin analogues (23), and methotrexate with misoprostol (13). Data abstracted from studies included regimen details and clinical outcomes by gestational age. We found that efficacy decreases with increasing gestational age (p<0.001), and differences by regimen are not statistically significant except at gestational age > or =57 days. For gestations < or =49 days, mean rates of complete abortion were 94-96%, incomplete abortion 2-4%, and ongoing (viable) pregnancy 1-3%. For gestations of 50-56 days, the mean rate of complete abortion was 91% (same for all regimens), incomplete abortion 5-8%, and ongoing pregnancy 3-5%. For > or =57 days, success was lower for mifepristone/misoprostol (85%, 95% confidence interval 78-91%) than for mifepristone/other prostaglandin analogues 95% (CI 91-98%, p = 0.006). For mifepristone/misoprostol, using > or =2 prostaglandin analogue doses seems to be better than a single dose for certain outcomes and gestational ages. We conclude that both mifepristone and methotrexate, when administered with misoprostol, have high levels of success at < or =49 days gestation but may have lower efficacy at longer gestation.

PIP: Multiple clinical studies demonstrate the efficacy of medical abortion with mifepristone or methotrexate followed by a prostaglandin analogue. However, assessing predictors of success, including regimen, is difficult because of regimen variability and a lack of direct comparisons. This meta-analysis estimates rates of primary clinical outcomes of medical abortion (successful abortion, incomplete abortion, and viable pregnancy) and compares them by regimen and gestational age. The authors identified 54 studies published from 1991 to 1998 using mifepristone with misoprostol (18), mifepristone with other prostaglandin analogues (23), and methotrexate with misoprostol (13). Data abstracted from studies included regimen details and clinical outcomes by gestational age. The authors found that efficacy decreases with increasing gestational age (p 0.001), and differences by regimen are not statistically significant except at gestational age 57 days or more. For gestations of 49 or fewer days, mean rates of complete abortion were 94-96%, incomplete abortion 2-4%, and ongoing (viable) pregnancy 1-3%. For gestations of 50-56 days, the mean rate of complete abortion was 91% (same for all regimens), incomplete abortion 5-8%, and ongoing pregnancy 3-5%. For 57 days or more, success was lower for mifepristone/misoprostol (85%; 95% CI, 78-91%) than for mifepristone/other prostaglandin analogues (95%; 95% CI, 91-98%; p = 0.006). For mifepristone/misoprostol, using 2 or more prostaglandin analogue doses seems to be better than a single dose for certain outcomes and gestational ages. The authors conclude that both mifepristone and methotrexate, when administered with misoprostol, have high levels of success at 49 or fewer days.

Meclizine for prevention of nausea associated with use of emergency contraceptive pills: a randomized trial.

OBJECTIVE: We conducted a randomized trial to determine whether pretreatment with meclizine reduces the incidence of nausea and vomiting associated with the Yuzpe regimen of emergency contraception. METHODS: We randomly assigned 343 women aged 18-45 years who were not at risk for pregnancy to pretreatment with 50 mg of meclizine, placebo, or no drug 1 hour before the first of two doses of emergency contraceptive pills. We asked participants to complete three questionnaires over the following 48 hours. RESULTS: The incidence of nausea was 47% in the group pretreated with meclizine and 64% in the other two groups (relative risk adjusted for center 0.7, 95% confidence intervals 0.6, 0.9 for comparisons of meclizine with both placebo and no drug). The severity of nausea and the incidence of vomiting were also significantly lower in the meclizine pretreatment group than in the other two groups. Drowsiness was reported by about twice as many women in the meclizine pretreatment group (31%) than in the other two groups (13% in the placebo group, 16% in the no-pretreatment group; P < .01 for both comparisons). CONCLUSION: Meclizine is effective for preventing nausea and vomiting associated with the Yuzpe regimen of emergency contraceptive pills. Women using this drug should be cautioned to anticipate drowsiness.