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.

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.

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.

Misoprostol for medical evacuation of early pregnancy failure.

OBJECTIVE: To determine whether misoprostol (a prostaglandin E1 analogue) 400 micrograms orally (group 1) or 800 micrograms vaginally (group 2) will cause complete uterine evacuation in women with early pregnancy failure. METHODS: Twenty subjects were recruited for a prospective, non-blinded, randomized clinical trial. Early pregnancy failure was diagnosed by transvaginal ultrasound examination; only women with a closed cervical os and minimal vaginal bleeding were enrolled. Subjects returned 24 hours after misoprostol administration for a transvaginal ultrasound examination. If the gestational sac was still present, the misoprostol dose was repeated and the subject returned again 24 hours later. Subjects who failed to expel the pregnancy were offered a suction curettage. RESULTS: Twelve and eight women were randomized to groups 1 and 2, respectively. Complete uterine evacuation occurred in three of 12 [25%, 95% confidence interval (CI) 1%, 50%] and seven of eight (88%, 95% CI 65%, 100%, P = .010) subjects in groups 1 and 2, respectively. Vomiting occurred in 30% and 13%, respectively, and diarrhea in 50% and 38%, respectively. CONCLUSION: Vaginal misoprostol 800 micrograms is more effective than oral misoprostol 400 micrograms for uterine evacuation of early pregnancy failure and may be an effective alternative to dilation and curettage.

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.

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.

Medical abortion with oral methotrexate and vaginal misoprostol.

OBJECTIVE: To evaluate the safety and efficacy of oral methotrexate and vaginal misoprostol for medical abortion. METHODS: A prospective multicenter trial involved 300 women up to 49 days' gestation seeking elective abortion. Subjects received methotrexate 50 mg orally followed 5-6 days later by misoprostol 800 micrograms vaginally. The misoprostol dose was repeated if abortion did not occur. RESULTS: Complete abortion occurred in 273 of 299 women (91.3%; 95% confidence interval [CI] 87.5, 94.2%); one woman was lost to follow-up. Abortion occurred within 8 days of the methotrexate in 233 women (77.9%; 95% CI 72.8, 82.5%); the remaining 13.4% of women who aborted did so after a delay of 23.5 +/- 9.8 days (median 23 days, range 10-45). Vaginal bleeding lasted an average of 15 and 11 days in immediate and delayed-success abortions, respectively. Complete abortion rates decreased linearly with increasing body surface area. After methotrexate and misoprostol administration, nausea was reported in 37% and 33%, vomiting in 11% and 18%, diarrhea in 12% and 18%, and subjective fever or chills in 15% and 31% of subjects, respectively. CONCLUSION: Oral methotrexate followed by vaginal misoprostol is effective for abortion and represents an acceptable alternative to intramuscular methotrexate in regimens for medical abortion.

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.

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.

Laboratory criteria for menopause in women using oral contraceptives.

OBJECTIVE: To evaluate laboratory criteria for menopause in women talking oral contraceptives (OC). DESIGN: Prospective, uncontrolled pilot study. SETTING: San Francisco General Hospital, San Francisco, California, and Magee-Womens Hospital, Pittsburgh, Pennsylvania. PATIENTS: Twenty-eight menopausal women. INTERVENTIONS: Fourteen menopausal women received triphasic 35 micrograms ethinyl E2 and 180-215-250 micrograms norgestimate, and 14 menopausal women received monophasic 30 micrograms ethinyl E2-150 micrograms desogestrel. MAIN OUTCOME MEASURES: Serum FSH, LH, and E2 levels were evaluated on days 14 and 28 (day 7 of the pill-free interval) of the third cycle of pills. RESULTS: Twelve women in each group completed the study. Fifteen (62.5%) subjects still had a serum FSH < 30 mIU/mL (30 IU/L) on the 7th day of the pill-free interval of the third pill package. All subjects had a serum FSH:LH ratio > 1 and 20 of 21 (95%) subjects had E2 < 20 pg/mL (73 pmol/L) at the end of the pill-free interval of the third cycle. CONCLUSIONS: Measuring FSH on the 7th day of the pill-free interval is not a sensitive test for menopause. Serum FSH:LH ratio > 1 or E2 < 20 pg/mL (73 pmol/L) on the 7th day of the pill-free interval may be a more appropriate marker of menopause in women using OC in the later reproductive years.

PIP: Health workers recruited 28 women aged 35-65 attending San Francisco General Hospital in California or Magee-Women's Hospital in Pittsburgh, Pennsylvania, for a prospective study designed to evaluate the laboratory criteria for menopause in women using oral contraceptives (OCs). The first 14 women received three cycles of a triphasic OC containing 35 mcg ethinyl estradiol and 180, 215, and 250 mcg norgestimate (Orth Tri-Cyclen-28). They comprised group 1. The remaining 14 women received three cycles of a monophasic OC containing 30 mcg ethinyl estradiol and 150 mcg desogestrel (Ortho-Cept-28). They comprised group 2. 12 women in each group completed the study. The mid-cycle luteinizing hormone (LH) level was much higher in group 1 than in group 2 (8.8 vs. 3.6 mIU/ml; p = 0.02). The serum follicle stimulating hormone (FSH) level of 62.5% of the women was still less than 30 mIU/ml on day 28 of the third pill package. All the women had an FSH:LH ratio of 1 at baseline and on day 28 of the third OC package, indicative of menopause. This ratio was significantly higher on day 7 of the pill-free interval than at baseline or mid-cycle (2.82 vs. 1.99 and 2.26, respectively; p 0.0001). The proportion of women with estradiol levels of 25 pg/ml was 90% at baseline and in the middle of the third cycle and 95% at the end of the pill-free interval of the third cycle. These findings suggest that the mid-cycle FSH:LH ratio and measuring FSH on the seventh day of the pill-free interval are not reliable indicators of menopause. Instead, a serum FSH:LH ratio of 1 or an estradiol level of 20 pg/ml on the seventh day of the pill-free interval may be a more reliable indicator of menopause in women using OCs in their later reproductive years.

Cost of ectopic pregnancy management: surgery versus methotrexate.

OBJECTIVE: To estimate the potential annual cost savings of methotrexate (MTX) therapy for ectopic pregnancy (EP) at our institution and nationally. DESIGN: Retrospective. SETTING: San Francisco General Hospital. PATIENTS: All patients treated for EP in 1991. INTERVENTIONS: Medical records and billing statements were reviewed. MAIN OUTCOME MEASURES: Direct costs were determined from billing statements, and indirect costs were estimated based on published data. Potential annual national cost savings from MTX treatment were then extrapolated using national statistics on the incidence of EP. RESULTS: Fifty EPs were treated with an average direct cost of $7,972 per case. Direct and indirect costs totaled > $500,000. Fifteen (30%) of the cases would have been eligible for MTX treatment with a resultant cost savings of > $160,000. The potential annual national cost savings would be in excess of $280 million. CONCLUSIONS: If preliminary findings suggesting the effectiveness of MTX as an alternative therapy for EP are confirmed, appropriate use of MTX will not only reduce morbidity but also the substantial cost.

Medical treatment of ectopic pregnancy with methotrexate.

OBJECTIVE: To review our experience with low-dose IM methotrexate for the medical management of ectopic pregnancy (EP). DESIGN: Retrospective chart review. SETTING: Magee-Womens Hospital, Pittsburgh, Pennsylvania. PATIENT(S): The first 50 women treated by the resident service in whom EP was diagnosed and treated with methotrexate. INTERVENTION(S): Intramuscular methotrexate, 50 mg/m2. Serum beta-hCG was evaluated 4 and 7 days after treatment and then weekly thereafter. The dose was repeated if the beta-hCG level did not drop > or = 15% between days 4 and 7 or if a plateau or rise was noted during weekly follow-up evaluation. Surgery was performed if significant abdominal pain occurred in the presence of hemodynamic instability or signs of peritoneal irritation on physical examination. MAIN OUTCOME MEASURE(S): Resolution of the EP without surgical intervention. RESULT(S): Two patients were lost to follow-up and one was treated without a certain diagnosis of EP. Forty-three of the remaining 47 women (91.5%; 95% confidence interval, 83.5%, 99.5%) were treated successfully with methotrexate. Of these, 36 women were treated with a single dose, and 7 required a second dose. Four women were treated surgically after medical management failed. The time from initiation of treatment to cure in women who were treated successfully was 25 +/- 15 days (mean +/- SD). Thirteen patients (27.7%) made additional visits to the emergency department because of increased abdominal pain. CONCLUSION(S): As medical therapy for EP becomes common practice, familiarity with its side effects may lead to greater success rates. The decision to abandon medical treatment and proceed with surgery should be based on defined guidelines, such as the development of peritoneal signs, decreasing hemoglobin levels, or hemodynamic instability.

Screening for factor V Leiden mutation before prescribing combination oral contraceptives.

OBJECTIVE: To evaluate the cost-effectiveness of screening for factor V Leiden mutation in women in the United States who use combination oral contraceptives. DESIGN: Cost-effectiveness analysis. SETTING: A national research reference laboratory, a university medical center, and an academic health center managed care organization. PATIENT(S): Women of reproductive age in the United States. INTERVENTION(S): Baseline risk estimates of venous thromboembolic disease in the general population and in carriers of factor V Leiden mutation were calculated using available data. MAIN OUTCOME MEASURE(S): The number of women who would require factor V Leiden testing and the cost of identifying this cohort to prevent one death caused by venous thromboembolic disease before prescribing combination oral contraceptives. RESULT(S): To prevent one venous thromboembolic death attributable to the use of oral contraceptives in women with factor V Leiden mutation, >92,000 carriers would need to be identified and stopped from using these pills. The estimated charge to prevent this one death would exceed $300 million. If the price of testing were discounted to 34.5% of current charges, the cost still would be between $105 million and $130 million. CONCLUSION(S): Screening for factor V Leiden mutation before prescribing combination oral contraceptives is not a cost-effective use of U.S. health care dollars. The best and most cost-effective screening tool we have is taking a thorough personal and family history related to venous thromboembolic events.

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.

Methotrexate for abortion at < or = 42 days gestation.

Methotrexate is cytotoxic to trophoblast and, in low doses, has minimal side effects. It is used to treat gestational trophoblastic neoplasia and ectopic pregnancy and has recently been shown to have similar effects on intrauterine trophoblast. A prior study suggested that methotrexate may successfully cause abortion of an early pregnancy without prostaglandin. To test this hypothesis, ten pregnant women at < or = 42 days gestation were treated with methotrexate 50 mg/m2 intramuscularly. Vaginal bleeding started 24 +/- 10 (mean +/- standard deviation) days after the injection and lasted 10 +/- 3 days. Methotrexate side effects occurred in 4 patients and were limited to the first 4 days after the injection. Methotrexate alone appears sufficient to abort a very early intrauterine pregnancy.

Methotrexate and misoprostol for abortion at 57-63 days gestation.

Methotrexate and misoprostol have been shown in preliminary studies to be effective for abortion at < or = 56 days gestation with minimal side effects. RU-486 is used in combination with prostaglandin for abortion < or = 49 days gestation in France but < or = 63 days gestation in England. This pilot study was performed to evaluate if methotrexate and misoprsotol may also be effective up to 63 days gestation. Ten pregnant women between 57-63 days gestation were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days later by misoprostol 800 micrograms vaginally. Abortion occurred in 6 women; abortion occurred in one of the women after a repeat dose of misoprostol 24 hours after the first dose. The remaining 4 women all had a surgical abortion. In the successfully treated women, vaginal bleeding lasted 14 +/- 4 (mean +/- standard deviation) days and serum beta-hCG was < or = 25 IU/L by 32 +/- 5 days after the methotrexate injection. No methotrexate side effects occurred. Methotrexate and misoprostol do not appear to be as effective for medical abortion between 57 and 63 days gestation as compared to < or = 56 days gestation.

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.

Oral methotrexate and vaginal misoprostol for early abortion.

Intramuscular methotrexate followed by vaginal misoprostol has been shown to be effective for abortion at < or = 49 days gestation. Oral dosing of the methotrexate may offer advantages over parenteral dosing. This pilot study was performed to evaluate if oral methotrexate would be effective when combined with vaginal misoprostol to effect abortion at < or = 49 days gestation. Twenty pregnant women were randomized to receive methotrexate 25 mg or 50 mg followed 7 days later by misoprostol 800 micrograms vaginally. The misoprostol dose was repeated the next day if the abortion did not occur. Complete abortion occurred in all subjects in both groups within 20 days after the methotrexate. However, women in the 50 mg group passed the pregnancy within 24 hours of the first or second dose of methotrexate more often than women in the 25 mg group (80% vs. 50%, p = 0.35). Vaginal bleeding lasted 12.1 +/- 3.1 days and 9.4 +/- 4.5 days in immediate success and delayed success patients, respectively. Oral methotrexate may be an effective alternative to intramuscular methotrexate in treatment regimens for nonsurgical abortion.

PIP: At the Magee-Women's Hospital in Pittsburgh, Pennsylvania, a clinical investigator compared data on 10 healthy women who received 25 mg oral methotrexate (group 1) with data on 10 other healthy women who received 50 mg oral methotrexate (group 2) to determine whether these two doses followed 7 days later by 800 mcg vaginal misoprostol could safely induce abortion at or less than 49 days gestation. If the women did not experience an abortion, they received a repeat misoprostol dose the next day. All 20 women experienced a complete abortion without a need for surgical procedure within 20 days after oral methotrexate administration. Group 1 had a higher immediate success rate (i.e., abortion within 24 hours of the first dose of misoprostol) than did group 2 (80% vs. 50%), but due to the small sample size the difference was not statistically different (p = 0.35). Vaginal bleeding of women who experienced immediate success lasted longer than those who experienced delayed success (12.1 vs. 9.4 days). Nausea was more common with oral methotrexate than with intramuscular methotrexate reported in another study (45% vs. 19%). On the other hand, vomiting and diarrhea rates were similar. These findings indicate that oral methotrexate may be an effective alternative to intramuscular methotrexate in regimens for nonsurgical abortion.

Medical abortion with methotrexate 75 mg intramuscularly and vaginal misoprostol.

Methotrexate (50 mg/m2 intramuscularly and 50 mg orally) followed by vaginal misoprostol have proven to be > 90% effective at causing abortion in women at less than 49 days' gestation. Although the effectiveness of the oral dose (which has a lower serum bioavailability) demonstrates that a methotrexate dose of 50 mg/m2 may be more than necessary, an intramuscular regimen is more advantageous because it is less costly. This trial was designed to investigate the potential effectiveness of a single dose of methotrexate, 75 mg intramuscularly, in a regimen for early abortion. One hundred subjects received 75 mg methotrexate intramuscularly followed 5 to 6 days later by 800 micrograms misoprostol vaginally. The misoprostol dose was repeated if the abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure), duration of vaginal bleeding, and side effects. One subject was lost to follow-up. Complete abortion occurred in 94 of 99 (94.9%, 95% CI 90.6, 99.3%) patients. The complete abortion rate was no different for earlier gestations: 38 of 40 (95.0%, 95% CI 88.2, 100%) at up to 42 days' gestation and 56 of 59 (94.9%, 95% CI 89.3, 100%) at more than 42 days' gestation (p = 0.99). Abortion occurred in the 24 h following the initial or repeat misoprostol dose (immediate success) in 70.7%; the remaining 24.2% of women who aborted did so after a delay of 22 +/- 10 days (mean + standard deviation). Vaginal bleeding lasted 17 +/- 8 days and 11 +/- 7 days in immediate success and delayed success patients, respectively. Overall, 77.8%, 86.9%, and 91.9% of patients had passed the pregnancy by 14, 28, and 35 days, respectively, after receiving methotrexate. This preliminary evaluation demonstrates that a medical abortion regimen using 75 mg methotrexate intramuscularly appears to have similar effectiveness to one with 50 mg/m2 methotrexate.

PIP: The effectiveness for early abortion of a single dose (75 mg intramuscularly) of methotrexate, followed 5-6 days later by 800 mcg of misoprostol vaginally, was investigated in 99 women presenting to a Pittsburgh, Pennsylvania (US), hospital with pregnancies under 50 days' gestation. Complete abortion occurred in 94 patients (94.9%). There were no significant differences in this rate by gestation (up to 42 days vs. 43-49 days). In 70 cases (70.7%), abortion occurred in the 24 hours following the initial or repeat misoprostol dose. Overall, 77.8%, 86.9%, and 91.9% of women had expelled the fetus by 14, 28, and 35 days, respectively, after receiving methotrexate. Vaginal bleeding lasted an average of 17 days in women who aborted in 24 hours and 11 days in those with delayed abortion. Side effects associated with methotrexate included nausea (47%), warmth/hot flashes (43%), diarrhea (22%), dizziness (21%), headache (16%), and vomiting (12%). These results are comparable to those obtained with an intramuscular dose of 50 mg/sq. m or an oral dose of 50 mg of methotrexate. The lowest effective dose of methotrexate, when combined with misoprostol for abortion, remains to be determined.