Interruption of early pregnancy with mifepristone in combination with gemeprost. Misoprostol alone for early abortion: an evaluation of seven potential regimens. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. I: Efficacy. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: A randomized trial. A randomised controlled trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion up to 13 weeks of gestation. Efficacy of mifepristone followed on the same day by misoprostol for early termination of pregnancy: report of a randomised trial. Double-blind randomized trial of mifepristone in combination with vaginal gemeprost or misoprostol for induction of abortion up to 63 days gestation. The effect of dose of mifepristone and gestation on the efficacy of medical abortion with mifepristone and misoprostol. Tamoxifen compared to methotrexate when used with misoprostol for abortion. Randomised controlled trial comparing the efficacy of same-day administration of mifepristone and misoprostol for termination of pregnancy with the standard 36 to 48 hour protocol. Lowering the doses of mifepristone and gameprost for early abortion: a randomised controlled trial. World Health Organization Task Force on Post-ovulatory Methods for Fertility Regulation. Regimens of misoprostol with mifepristone for early medical abortion: a randomised trial. Are two doses of misoprostol after mifepristone for early abortion better than one? A comparison of tamoxifen and misoprostol to misoprostol alone for early pregnancy termination. Two mifepristone doses and two intervals of misoprostol administration for termination of early pregnancy: a randomised factorial controlled equivalence trial. Efficacy of two intervals and two routes of administration of misoprostol for termination of early pregnancy: a randomised controlled equivalence trial. Termination of early human pregnancy with RU 486 (mifepristone) and the prostaglandin analogue sulprostone: a multi-centre, randomized comparison between two treatment regimens. A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy. Therapeutic abortion in early pregnancy with antiprogestogen RU486 alone or in combination with prostaglandin analogue (gemeprost). A randomized trial comparing misoprostol three and seven days after methotrexate for early abortion. Two-pill regimens of misoprostol after mifepristone medical abortion through 63 days' gestational age: a randomized controlled trial of sublingual and oral misoprostol. Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. Comparison of two doses of mifepristone in combination with misoprostol for early medical abortion: a randomised trial. Early abortion induction by a combination of mifepristone and oral misoprostol: a comparison between two dose regimens of misoprostol and their effect on blood pressure. A prospective randomized study on the measured blood loss in medical termination of early pregnancy by three different misoprostol regimens after pretreatment with mifepristone. Methotrexate pharmacokinetics and effects in women receiving methotrexate 50 mg and 60 mg per square meter for early abortion. A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation. [Prevent from bleeding after medical abortion through prolonged application of mifepristone with misoprostol for terminating early pregnancy]. Mifepristone 100 mg in abortion regimens. Mifepristone and misoprostol administered simultaneously versus 24 hours apart for abortion: a randomized controlled trial. Methotrexate and misoprostol vs misoprostol alone for early abortion. A randomized controlled trial. A randomized comparison of misoprostol 6 to 8 hours versus 24 hours after mifepristone for abortion. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. Randomized, double-blind, controlled trial of mifepristone in capsule versus tablet form followed by misoprostol for early medical abortion. The antiprogestational agent RU 486 as an abortifacient in early human pregnancy: a comparison of three dose regimens. Methotrexate and misoprostol used alone or in combination for early abortion. Oral methotrexate and vaginal misoprostol for early abortion. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. RU 486 (mifepristone): clinical trials in China. Randomized trial of misoprostol and cervagem in combination with a reduced dose of mifepristone for induction of abortion. Effect of oral prostaglandin E2 on uterine contractility and outcome of treatment in women receiving RU 486 (mifepristone) for termination of early pregnancy. Pregnancy termination with mifepristone and gemeprost: a multicenter comparison between repeated doses and a single dose of mifepristone. World Health Organization. Randomized trial of mifepristone and buccal or vaginal misoprostol for abortion through 56 days of last menstrual period. Misoprostol alone vs. methotrexate followed by misoprostol for early abortion. Induction of early abortion with mifepristone (RU486) and two different doses of prostaglandin pessary (gemeprost). Oral methotrexate and vaginal misoprostol for early abortion. Termination of early pregnancy by two regimens of mifepristone with misoprostol and mifepristone with PG05--a multicentre randomized clinical trial in China. Comparing vaginal and buccal misoprostol when used after methotrexate for early abortion. Oral methotrexate compared with injected methotrexate when used with misoprostol for abortion. Randomized trial of oral versus vaginal misoprostol at one day after mifepristone for early medical abortion.
Mifepristone in combination with prostaglandin has been used since 1988 for induction of early abortion. The aim of the present investigation was to assess the tolerance and efficacy of 600 mg. mifepristone orally followed by gemeprost 1 mg. vaginally either 24 hours (group one) or 48 hours (group two) later.
                Sixty-four healthy women applying for abortion within the first 8 weeks of pregnancy were randomly allocated to one of the two treatment groups. Intrauterine pregnancy and gestational age were verified by ultrasonography. Symptoms after administration of mifepristone and gemeprost were recorded, and the patients observed at the hospital for at least three hours after prostaglandin-insertion. Blood samples for blood group, hemoglobin, beta-chorion-gonadotrophin, aspartate-aminotransferase and creatinine were drawn.
                Outcome was established by gynecological examination, the level of beta-hCG and ultrasonography, at visits one, two and if necessary three to four weeks later. Surgical curettage was performed in case of incomplete abortion, of which there were four in the 24-hour interval group and five in the 48-hour interval group with a success rate (complete abortion) of 55 out of 64 patients (86%).
                There was no difference in efficacy or side effects whether the prostaglandin was administered 24 or 48 hours after mifepristone intake, which suggests that the treatment period can be reduced from the conventional 48 hours. A growing body of literature has shown that misoprostol alone could be effective for early medical abortion. We evaluated seven potential regimens in women up to 56 days of gestation in order to potentially identify an optimal regimen.
                In phase I of the study, women requesting early abortion were randomized to one of three misoprostol regimens (4x400 microg po every 3 h, 2x800 microg po every 6 h, 1x600 pv microg); in phase II, women were randomized to one of two regimens (2x800 microg po every 3 h, 1x800 pv microg). In phase III, we consecutively tested two regimens (800 microg pv wetted with saline repeated after 24 h if intact gestational sac, 2x800 microg pv wetted with saline) to validate previously published results.
                Although most women experienced some side effects, all regimens were tolerable and acceptable. Five of the seven regimens resulted in complete abortion rates of 60% or less. Only repeated doses of 800 microg pv misoprostol resulted in efficacy exceeding 60%.
                Misoprostol-alone abortion regimens using oral misoprostol are too ineffective for clinical use or further investigation. Regimens with repeated dosing of misoprostol 800 microg pv warrant further study to find the optimal treatment protocol. To compare the efficacy of oral and vaginal administration of misoprostol after a single oral dose of 200 mg of mifepristone and to investigate whether the efficacy can be improved and the duration of bleeding shortened by continuing oral misoprostol for one week.
                Double blind, randomised controlled trial.
                Fifteen gynaecological clinics in 11 countries.
                A total of 2219 healthy pregnant women requesting medical abortion with < or =63 days of amenorrhoea.
                Mifepristone 200 mg administered orally on day one, followed by 0.8 mg misoprostol either orally or vaginally on day three. The oral group and one of the vaginal groups continued with 0.4 mg of oral misoprostol twice daily for seven days.
                Complete abortion was the main outcome. Secondary outcomes were side effects, timing of expulsion and duration of bleeding.
                The crude complete abortion rate was 92.3% in the oral plus continued oral misoprostol group, in the vaginal-only group it was 93.5%, and it was 94.7% in the vaginal group that continued with oral misoprostol, when considering undetermined cases as failures. Among women with amenorrhoea length > or =57 days, the risk of failure of complete abortion was almost three times higher in the oral plus continued oral misoprostol group (RR = 2.8, 95% CI 1.3 to 5.8), and over two times higher in the vaginal-only group (RR = 2.2, 95% CI 1.0 to 4.7), when compared with the vaginal plus continued oral misoprostol group. Among women with amenorrhoea length < 57 days, the differences were not significant. Timing of expulsions and duration of bleeding were similar in the three groups.
                For amenorrhoea length > or =57 days, vaginal misoprostol is more effective than oral when continued with 0.4 mg oral misoprostol twice daily for seven days. Misoprostol continuation improved the efficacy in this amenorrhoea group compared with a single dose of vaginal misoprostol on day three, but it did not shorten the duration of bleeding. No differences in efficacy were observed when amenorrhoea length was < 57 days. The conventional timing of misoprostol administration after mifepristone for medical abortion is 2 days, but more flexible intervals, which may make the regimen more convenient, have not been studied.
                To determine whether vaginal misoprostol administered 1, 2, or 3 days after mifepristone influences safety or effectiveness for abortion at up to 56 days' gestation.
                Prospective, randomized, open-label trial conducted from March 1998 to June 1999.
                Sixteen US primary care and referral abortion facilities.
                A total of 2295 healthy patients aged 18 years or older who were 56 or fewer days pregnant. Forty (1.7%) were lost to follow-up.
                Patients received 200 mg of oral mifepristone and were randomly assigned to self-administer 800 microg of vaginal misoprostol at home 1 (n = 745), 2 (n = 778), or 3 (n = 772) days later. Women returned to the clinic up to 8 days after mifepristone for ultrasonographic evaluation. A second dose of misoprostol was administered if the abortion was not complete. Patients with continuing pregnancy, excessive bleeding, or retained pregnancy tissue 5 weeks later received an aspiration curettage.
                Effectiveness of the procedure (ie, a complete medical abortion without surgical intervention), adverse effects, acceptability of the procedure based on patient questionnaires, reasons for surgical intervention, and adverse outcomes, compared among the study groups.
                Of the 2255 women completing follow-up, complete medical abortion rates were 98% (95% confidence interval [CI], 97%-99%) among those using misoprostol after 1 day, 98% (95% CI, 97%-99%) for those using misoprostol after 2 days, and 96% (95% CI, 95%-97%) among those using misoprostol after 3 days. Fifty-five subjects aborted before taking misoprostol, 9 had early surgery, and 103 did not take misoprostol on their assigned day. No blood transfusions were required. Cramping and nausea were the most common adverse effects reported, with similar percentages of patients in all 3 groups reporting such effects. Thirteen unexpected or serious adverse events occurred: 6 in those using misoprostol after 1 day; 4 in those using it after 2 days; and 3 in those using it after 3 days. Nearly all women (>90%) found the procedure to be acceptable.
                Our results suggest that vaginal misoprostol, 800 microg, can be used from 1 to 3 days after mifepristone, 200 mg, for early medical abortion, and need not be administered strictly 48 hours after mifepristone. JAMA. 2000;284:1948-1953. To assess women's acceptability, the efficacy and side effects of sublingual versus vaginal administration of misoprostol in combination with mifepristone for medical abortion up to 13 weeks of gestation.
                Randomised controlled trial.
                Aberdeen Royal Infirmary.
                Women undergoing medical abortion under the terms of the 1967 Abortion Act.
                Mifepristone (200 mg) was given orally followed 36-48 hours later by misoprostol administration (sublingual: 600 microg; vaginal: 800 microg). A second dose of misoprostol 400 microg was given 3 hours later (sublingually or vaginally). Women between 9 and 13 weeks of gestation received a further (third) dose of misoprostol 400 microg (sublingually or vaginally), 3 hours later if abortion had not occurred.
                Women's acceptability, efficacy of the regimen and side effects experienced.
                A total of 340 women were recruited (171 sublingual and 169 vaginal). A total of 70% of women in the sublingual group expressed satisfaction with the route of misoprostol administration; 18% answered 'Don't know' while 12% were dissatisfied, compared with 68%, 28% and 4%, respectively, in the vaginal group (P= 0.02). There was no significant difference in the need for surgical evacuation for women in the sublingual (3/158, 1.9%) and vaginal groups (4/156, 2.6%) (P= 0.70). Women receiving misoprostol sublingually were more likely to experience diarrhoea (P < 0.01), shivering (P < 0.01) and unpleasant mouth taste (P < 0.01).
                Sublingual administration of misoprostol is an effective alternative to vaginal administration for medical abortion up to 13 weeks of gestation. The prevalence of prostaglandin-related side effects, however, was higher with this route of administration. 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.
                Prospective, randomised trial.
                Clinical research office.
                Eighty-six women, requesting elective termination of a pregnancy which has a gestational age of < or = 49 days.
                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.
                Rate of complete abortion 24 hours after administration of misoprostol.
                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.
                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. Gemeprost and misoprostol are two of the most widely used prostaglandins in combination with mifepristone for medical abortion in early pregnancy. However, the efficacy and side-effects of those two drugs given vaginally have not been assessed in a randomized trial.
                Randomized double-blind controlled trial involving 999 women undergoing an abortion at gestational age < or =63 days who received either 0.5 mg gemeprost (group I, n = 499) or 800 microg misoprostol (group II, n = 500) vaginally approximately 48 h after taking 200 mg mifepristone by mouth. The rate of complete abortion and the side-effects were compared between the groups.
                A total of 89 cases was excluded from full analysis of outcome because either they aborted after mifepristone alone (n = 2), had an ectopic pregnancy (n = 1), or because the outcome was uncertain as they failed to attend their follow-up appointment (n = 86). The rate of complete abortion was very high (>95%) in both groups but significantly higher after treatment with misoprostol than with gemeprost [436/453 (98.7%) versus 451/457 (96.2%), P = 0.019, difference 2.5%, confidence interval 0.4-4.7%] and there were fewer ongoing pregnancies (n = 1 versus n = 8, P < 0.018). Surgical intervention rose significantly with gestation in women who received gemeprost (P < 0.03) but not with misoprostol. The incidence of side-effects such as diarrhoea (13.7 versus 16.4%) and vomiting (27.8 versus 29.7%) was similar in women who received misoprostol or gemeprost respectively, as was the duration and amount of bleeding.
                (i) Both regimens using a reduced dose of mifepristone are highly effective methods of inducing abortion in early pregnancy; (ii) vaginal misoprostol is the preferred prostaglandin because it is it is associated with fewer failures than low-dose gemeprost, particularly at gestation > or =49 days. Although it has been demonstrated that a combination of mifepristone and a prostaglandin is an effective method of inducing abortion in early pregnancy, the optimum dose of the antigestogen is unknown. Women (n = 220) requesting abortion in early pregnancy (< or = 63 days amenorrhoea) were randomized to receive a single dose of either 600 or 200 mg mifepristone followed 48 h later by a single dose of 600 micrograms misoprostol by mouth. The percentage of women who had a complete abortion (93.6% confidence interval 90.4-95.5%) was identical in the two groups. There was no significant difference in the number of women who passed the fetus within 4 h of receiving the prostaglandin (64 versus 74%), the days of bleeding (14.6 +/- 1.1 versus 15.3 +/- 0.9) nor in the onset of the next period (39.7 +/- 1.3 versus 36.7 +/- 1.3) respectively between the groups receiving 200 or 600 mg mifepristone. However, the complete abortion rate was significantly higher in women < or = 49 days compared to women 50-63 days amenorrhoea (97.5 versus 89.1% respectively; P < 0.02). There was no difference in any of the other parameters at different weeks of gestation. We conclude: (i) that the recommended dose of mifepristone could be reduced from 600 to 200 mg without loss of clinical efficacy, (ii) that the combination of mifepristone and 600 micrograms misoprostol is a highly effective alternative to vacuum aspiration for inducing abortion in women < 50 days amenorrhoea and (iii) at gestation > 56 days, this combination may result in too many incomplete abortions to be clinically acceptable. The purpose of this study was to compare tamoxifen to methotrexate, with respect to effectiveness, when followed by misoprostol to induce abortion. In the first phase, 198 women presenting for medical abortion at < 7 weeks gestation were randomized to receive either 40 mg of tamoxifen, followed 2 to 3 days later by 800 micrograms of misoprostol self-administered vaginally or 50 mg/m2 of methotrexate, followed 5 to 7 days later by the same dose of misoprostol. In the second phase, 200 women were randomized to receive 20 mg tamoxifen twice daily for 4 days, followed by 800 micrograms misoprostol or the same regimen of methotrexate and misoprostol as in phase 1. The main outcome measure was success rate determined by the number of women who aborted without surgery. In phase 1, the success rate was higher in the methotrexate group (93.0%) compared to the tamoxifen group (85.7%) (p = 0.045). In the tamoxifen group, nine of 98 women had incomplete abortions with symptoms requiring a surgical aspiration, compared to one of 100 women in the methotrexate group. In phase 2, the success rates were 90.9% in the methotrexate group compared to 84.7% in the tamoxifen group (p = 0.20). The side effects were less in the tamoxifen group in phase 1 but not in phase 2. When tamoxifen is given as a single dose, it is less effective than methotrexate but when it is given 20 mg twice daily for 4 days, there is no significant difference. Tamoxifen does not appear to have any benefits over methotrexate. To determine the efficacy of oral mifepristone followed by vaginal misoprostol 6 hours later compared with the standard 36- to 48-hour regimen for medical termination of pregnancy.
                Single centre, two arm, parallel, open randomised controlled trial.
                Medical termination service at a teaching hospital.
                Four hundred and fifty women undergoing medical termination of pregnancy at up to 63 days of gestation.
                Eligible women were randomised to receive mifepristone 200 mg orally followed by vaginal misoprostol 800 micrograms either 6 hours (n=225) or 36-48 hours (n=225) later. All participants were invited to attend for a follow-up pelvic ultrasound scan within 7 days following the misoprostol administration. For those women in whom products of conception remained at the follow-up ultrasound scan, expectant management ensued with weekly follow-up ultrasound scans until the termination was complete. They could elect to undergo an evacuation of uterus at any stage following the scan. Those women with a nonviable gestation sac at the follow-up scan were offered a further dose of vaginal misoprostol 800 micrograms or suction termination of pregnancy. Women with a continuing pregnancy were managed with surgical termination.
                Successful medical abortion defined as no requirement for medical or surgical intervention beyond the initial dose of misoprostol.
                One hundred and sixty-five women (79%) in the 6-hour group and 197 women (92%) in the 36- to 48-hour group had a successful termination at first follow-up ultrasound or presumed on the basis of other considerations (those not seen for ultrasound but deemed successful by negative pregnancy test, products passed on ward or long-term assessment of notes). Twenty-two women (10%) in the 6-hour regimen required up to three further ultrasound scans after 7 days following the mifepristone administration in order to ensure that the termination process was complete. None of these women required a suction evacuation of uterus. In the 36- to 48-hour regimen, ten (5%) women had up to two further ultrasound scans to confirm a complete termination without the need for a surgical evacuation of uterus. Therefore, the overall successful termination rate in the 6-hour regimen was 89% (187/210) compared with 96% (207/215) in the 36- to 48-hour regimen (relative risk=0.92, 95% CI 0.84-0.98). Repeat administration of misoprostol or surgical treatment was required in 23 women (11%) in the 6-hour group and 8 women (4%) in the 36- to 48-hour group. A viable pregnancy was found in five women (2%) in the 6-hour group and in three women (1%) in the 36- to 48-hour group.
                Oral mifepristone 200 mg followed by vaginal misoprostol 800 micrograms after 6 hours is not as effective at achieving a complete abortion compared with the 36- to 48-hour protocol. To test the efficacy of lower doses of mifepristone and gemeprost for medical induction of early abortion.
                Randomised controlled trial. Participants were blinded as to the therapy and physicians to the dose of mifepristone.
                Thirteen hospital gynaecological units in different continents.
                1,224 healthy pregnant women requesting medical abortion at <57 days from last menses.
                Random allocation to one of four regimens: mifepristone 50 mg by mouth followed by either 0.5 mg or 1.0 mg gemeprost vaginally on day 3; mifepristone 200 mg by mouth followed by either 0.5 mg or 1.0 mg gemeprost vaginally. We concealed the allocation sequence from clinicians enrolling participants, and maintained double blinding throughout.
                Incidence of complete abortion; subordinate outcome measures included side effects such as vomiting and fall in haemoglobin, as well as the need for emergency curettage and blood transfusion.
                The success rate was significantly related to the dose of mifepristone. The relative risk of failure to have a complete abortion with the lower dose of mifepristone was 1.6 (95% CI: 1.1-2.3) times that with the higher dose. The relative risk of failure with the lower dose of gemeprost (1.3; 95% CI: 0.9-1.8) did not reach statistical significance.
                A single dose of mifepristone 50 mg followed by gemeprost is inadequate for early medical abortion. There was no significant difference in side effects between the four treatment groups. To compare the efficacy, adverse effects and acceptability of the three most common misoprostol regimens used with mifepristone for medical abortion.
                Randomised nonblinded trial.
                Three clinics associated with major research universities in Canada; two in major urban areas and one in a periurban area.
                Women of reproductive age.
                Consenting women presenting for abortion services with gestations less than 56 days and who met inclusion criteria were given 200 mg mifepristone orally and then randomised into three misoprostol study groups: (group I) 400 micrograms of oral misoprostol, (group II) 600 micrograms of oral misoprostol, and (group III) 800 micrograms of vaginal misoprostol. Misoprostol was self-administered at home 24-48 hours following mifepristone, and participants were instructed to take a second similar misoprostol dose at 24 hours after the initial dose if bleeding was less than a normal menstrual period.
                Successful abortion without surgery was 94.1%, with no significant differences across the three study groups (94.7% in group I, 93.4% in group II, and 94.3% in group III; P= 0.975).
                Efficacy and adverse effects did not differ significantly across the three study groups. Pain increased significantly across the study and the gestational age groups and was associated with lower acceptability.
                There appears to be a range of safe and effective options for early medical abortion with mifepristone including a choice between oral and vaginal administration of misoprostol. OBJECTIVE: The objective of this study was to determine if a repeat dose of misoprostol following mifepristone or a single dose of misoprostol increases the efficacy of medical termination of pregnancy. DESIGN: Randomised, placebo controlled trial. SETTING: K.E.M. Hospital, Pune, India, and the Health Centre, Larsen and Toubro Limited, Mumbai, India. SAMPLE: A total of 300 women seeking an abortion with amenorrhoea of 8 weeks or less. Methods Women were randomised to receive one or two doses of 400 microgram oral misoprostol at the clinic 48 hours after administration of 200 mg mifepristone. Main outcome measure Complete abortion without surgical intervention. Results The repeat administration of misoprostol 400 microgram improved the complete abortion rate from 86 to 92% and significantly reduced the rate of continuing pregnancy from 7 to 1%. Almost all the women who were administered the additional dose of misoprostol were either very satisfied (58%) or satisfied (37%) with the method. Conclusion While an additional oral dose of 400 microgram misoprostol did not significantly increase the rate of complete abortion without surgical intervention, the additional dose did significantly reduce the rate of continuing pregnancies without compromising the acceptability and ease of use of the method. A study was undertaken to determine whether the combination of oral tamoxifen and moistened misoprostol administered vaginally was superior to that of placebo and moistened misoprostol administered vaginally for elective termination of early pregnancies.A clinical trial was conducted with a study group of 150 healthy women with pregnancies of </=56 days gestational age who desired pregnancy termination. Subjects were randomized to ingest either 20 mg of tamoxifen (group 1) or placebo (group 2) twice daily for 1 day, followed 48 h later by vaginal administration of 800 micrograms of saline-moistened misoprostol. This dose of misoprostol was repeated 24 h later and 8 days later if an abortion had not occurred. The main outcome measures were incidence of complete abortion, hemoglobin levels, duration of vaginal bleeding, and incidence of side effects. Complete abortion occurred in 709 (93.3%) in group 1 and 68 (90.7%) in group 2. There were no differences in either group between earlier (</=49 days) and later (50-56 days) gestations. The mean duration of uterine bleeding was 7.9 days and 8.2 days in group 1 and group 2, respectively. In group 1, 94.3% who aborted bled for <14 days, and in group 2, 95.6%. No subject required a blood transfusion. There were no significant differences in side effects between the two groups. These data suggest that pretreatment with tamoxifen is not necessary when using moistened vaginal misoprostol for abortion of pregnancies of </=56 days of gestation. To compare the efficacy of 100 mg and 200 mg of mifepristone and 24- and 48-hour intervals to administration of 800 microg vaginal misoprostol for termination of early pregnancy.
                Placebo-controlled, randomized, equivalence trial, stratified by centre.
                13 departments of obstetrics and gynecology in nine countries.
                2,181 women with 63 days or less gestation requesting medical abortion.
                Two-sided 95% CI for the risk differences of failure to complete abortion were calculated and compared with 5% equivalence margin between two doses of mifepristone and two intervals to misoprostol administration. Proportions of women with adverse effects were compared between the regimens using standard testes for proportions.
                Rates of complete abortion without surgical intervention and adverse effects associated with the regimens.
                Efficacy outcome was analysed for 2,126 women (97.5%) excluding 55 lost to follow up. Both mifepristone doses were found to be similar in efficacy. The rate of complete abortion was 92.0% for women assigned 100 mg of mifepristone and 93.2% for women assigned 200 mg of mifepristone (difference 1.2%, 95% CI: -1.0 to 3.5). Equivalence was also evident for the two intervals of administration: the rate of complete abortion was 93.5% for 24-hour interval and 91.7% for the 48-hour interval (difference -1.8%, 95% CI: -4.0 to 0.5). Interaction between doses and interval to misoprostol administration was not significant (P = 0.92). Adverse effects related to treatments did not differ between the groups.
                Both the 100 and 200 mg doses of mifepristone and the 24- and 48-hour intervals have a similar efficacy to achieve complete abortion in early pregnancy when mifepristone is followed by 800 micrograms of vaginally administered misoprostol. The most effective route and best interval between several doses of misoprostol to induce abortion have not been defined. Our aim was to assess the effects of the interval between multiple doses of misoprostol and the route of administration to terminate pregnancy.
                2066 healthy pregnant women requesting medical abortion with 63 days or less of gestation were randomly assigned within 11 gynaecological centres in six countries to the four treatment groups (three doses of 0.8 mg misoprostol given sublingually at 3-h intervals, vaginally 3 h, sublingually 12 h, and vaginally 12 h), stratifying by gestational age. This was an equivalence trial with a 5% margin of equivalence. The primary endpoints were efficacy of treatment to achieve complete abortion and to terminate pregnancy. The main efficacy analysis excluded women lost to follow-up. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN10531821.
                Efficacy outcomes were analysed for 2046 women (99%), excluding 20 lost to follow-up. Complete abortion rates at 2-week follow-up were recorded for 431 (84%) in the sublingual and for 434 (85%) women in the vaginal group when misoprostol was given at 3-h intervals (difference 0.4%, 95% CI -4.0 to 4.9, p=0.85 equivalence shown), and for 399 (78%) in the sublingual and for 425 (83%) in the vaginal 12-h groups (4.6%, -0.2 to 9.5, p=0.06, equivalence not shown). In the 3-h groups, pregnancy continued in 29 (6%) women after sublingual and in 20 (4%) women after vaginal administration (difference 1.8%, 95% CI -0.8 to 4.4, p=0.19, equivalence shown); in the 12-h groups it continued in 47 (9%) after sublingual and in 25 (5%) after vaginal administration (4.4%, 1.2-7.5, p=0.01, vaginal better than sublingual). Differences for complete abortion between intervals for sublingual and vaginal routes were 6% (95% CI 1.0-10.6, p=0.02, 3 h better than 12 h) and 2% (-2.9 to 6.1, p=0.49, equivalence not shown), respectively; for continuing pregnancies they were 4% (0.4-6.8, p=0.03, 3 h better than 12 h) and 1% (-1.5 to 3.5, p=0.44, equivalence shown), respectively.
                Administration interval can be chosen between 3 h and 12 h when misoprostol is given vaginally. If administration is sublingual, the intervals between misoprostol doses need to be short, but side-effects are then increased. With 12-h intervals, vaginal route should be used, whereas with 3-h intervals either route could be chosen. A multi-centre, randomized trial was conducted to compare the efficacy and side-effects of two combination regimens of the antiprogestin RU 486 and the intramuscular PGE2 analogue sulprostone for termination of early pregnancy (amenorrhoea up to 49 days). Women in the 3-day group (n = 125) received 25 mg RU 486 twice daily for 3 days plus a single injection of 0.25 mg sulprostone in the morning of the third day of antiprogestin treatment. In the 4-day group (n = 126), RU 486 was given for 4 days and the sulprostone injection in the morning of the fourth day. Treatment outcome in the two groups was similar. Overall, 88.8% had a complete abortion, 6.8% an incomplete abortion and 2.4% were treatment failures; in the remaining 2% treatment outcome could not be determined. Only three of the six women with treatment failure still had detectable fetal heart activity when the pregnancy was terminated by vacuum aspiration two weeks after the start of treatment. Five of the 17 interventions for incomplete abortion were carried out as emergency procedures because of heavy bleeding; two of these five women were given a blood transfusion. The majority of the curettages (10/17) were performed in one centre. If the data from this centre and the women with undetermined treatment outcome were excluded, the rates for complete abortion, incomplete abortion and treatment failure in the remaining six centres were 93.6, 3.7 and 2.7%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) Vaginal misoprostol has been shown to be an effective single agent for medical abortion. This randomized, double-blinded, placebo-controlled trial compared a regimen of mifepristone and misoprostol with misoprostol alone for termination of early pregnancy.
                250 women with gestations < or = 56 days were randomized by a random number table to receive either 200 mg mifepristone orally or placebo followed 48 h later by 800 microg vaginal misoprostol. Administration of misoprostol was repeated every 24 h up to three doses if abortion failed to occur. Abortion success was defined as complete abortion without the use of surgical aspiration.
                Successful medical abortions occurred in 114 out of 119 subjects (95.7%) after mifepristone followed by vaginal misoprostol. In all, 110 out of 125 subjects (88.0%) successfully aborted after placebo and vaginal misoprostol. The higher success rate of complete abortion with the mifepristone and misoprostol regimen was statistically significant compared with the placebo and misoprostol regimen (P < 0.05).
                A regimen of mifepristone and misoprostol was significantly more effective for termination of pregnancies < or = 56 days than misoprostol alone. The 88% efficacy obtained with vaginal misoprostol alone may be clinically acceptable when mifepristone is not available. Abortion was attempted in 39 women in early pregnancy (less than 56 days amenorrhea) with the progesterone antagonist RU486 alone (150 mg per day for 4 days) or in combination with a PG analogue, 16,16-dimethyl-trans-delta 2-PGE1 (Gemeprost) in the form of a 1 mg vaginal pessary. Complete abortion was also attempted in 5 women who received RU486 together with 2 X 1 mg PG pessaries. Vaginal bleeding followed by complete abortion occurred in 18 of 19 women who received RU486 + 1 mg PG pessary as compared to only 12 of 20 women who received RU486 alone (P less than 0.01). All women who received RU486 + 2 mg Gemeprost had a complete abortion. The onset of crampy abdominal pain (median: 3 vs 4 days) and vaginal bleeding (3 vs 3 days) was similar in the RU486 and RU486 + PG groups, respectively. Slightly less than half the patients in both groups had nausea and/or vomiting, but the incidence did not differ from that occurring prior to treatment. The mean duration (range) of vaginal bleeding [RU486 alone: 10 (0,29) days and RU486 + PG: (5,34) days], and the measured blood loss [RU486: 53 (2,227) ml and RU486 + PG: 81 (32,222) ml] did not differ significantly between the two treatments. It is concluded that the combination of RU486 and a single PG vaginal pessary is a highly effective means of inducing therapeutic abortion in early pregnancy and offers an alternative to surgery. Our purpose was to determine whether vaginal misoprostol 7 days rather than 3 days after methotrexate injection increases the percent of successful abortions on the day of misoprostol administration.
                A randomized controlled trial was performed in women requesting an abortion at < or = 56 days' gestation. Eighty-six women were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days (group 1) or 7 days (group 2) later by vaginal misoprostol 800 micrograms. The misoprostol dose was repeated if the abortion did not occur.
                Complete abortion occurred in 38 of 46 (83%) patients in group 1 and 39 of 40 (98%) in group 2 (p = 0.033). Of the women with complete abortions, 30 of 46 (65%) in group 1 and 27 of 40 (68%) in group 2 aborted the same day as the first or second dose of misoprostol (p = 0.823). Vaginal bleeding lasted 14 +/- 5 (mean +/- SD) days in group 1 and 17 +/- 9 days in group 2. The remaining women aborted after a delay of 24 +/- 6 days in group 1 and 28 +/- 13 days in group 2. For these women vaginal bleeding lasted 18 +/- 17 and 14 +/- 7 days, respectively, and the human chorionic gonadotropin-beta level was < or = 25 IU/L by 22 +/- 7 days after the abortion in group 1 and 19 +/- 9 days in group 2. Treatment failures in group 1 were four continuing pregnancies (9%), two incomplete abortions (4%), and two women who requested surgical termination after receiving both medications (4%). The treatment failure in group 2 was an incomplete abortion. Methotrexate and misoprostol side effects were infrequent.
                Methotrexate and vaginal misoprostol are more effective abortifacients when the misoprostol is given 7 days rather than 3 days after methotrexate. This treatment regimen may offer an alternative to surgical abortion or the use of antiprogestins and prostaglandin for medical abortion. A 400 mcg dose of sublingual misoprostol has high efficacy and few side effects when used with 200 mg mifepristone for medical abortion through 63 days' gestation.
                Eligible and consenting women (n=480) were randomized to 400 mcg of misoprostol sublingually or orally, 24 h after 200 mg of mifepristone. Abortion status was assessed two weeks later.
                Complete abortion occurred in 98.7% of the sublingual group and 94.0% of the oral group (p value=.006, RR: 1.05, 95% CI=1.01--1.09). Over 90% of women in both arms expressed high satisfaction with the method. Side effects were similar in both groups, with only fever or chills reported by significantly more women in the sublingual arm.
                The sublingual route appears superior to the regimen of 400 mcg misoprostol used orally and may be a good option for mifepristone medical abortion. Medical termination of pregnancy can be successfully performed with a combination of mifepristone (RU 486) and a prostaglandin analogue. We conducted a prospective, randomized trial to compare oral with vaginal administration of the prostaglandin E1 analogue misoprostol for first-trimester abortion in women treated initially with mifepristone.
                The study population consisted of 270 women seeking abortion within 63 days after the onset of amenorrhea. The dose of mifepristone was 600 mg, and the dose of misoprostol was 800 micrograms. The study had two primary end points: expulsion of the conceptus without the need for a surgical procedure, and abortion within four hours after the administration of misoprostol.
                Expulsion of the conceptus without the need for a surgical procedure occurred in 95 percent of the women who received misoprostol vaginally and in 87 percent of those who received it orally (P = 0.03). The rate of continued pregnancy was 7 percent with the oral regimen and 1 percent with the vaginal regimen (P = 0.01). Ninety-three percent of the women receiving misoprostol vaginally had abortions within four hours, as compared with only 78 percent of the women receiving the drug orally (P < 0.001). Vomiting and diarrhea were reported more frequently by the women who received oral misoprostol than by those who received vaginal misoprostol (P = 0.04 and P = 0.002, respectively).
                After the administration of mifepristone, vaginal administration of misoprostol is more effective and better tolerated than oral administration for the induction of first-trimester abortion. To compare the efficacy of two different regimens of mifepristone followed by misoprostol for medical abortion in women with menstrual delay of < or = 35 days.
                Double-blind, randomised controlled trial.
                Seventeen centres internationally.
                We enrolled 1,589 healthy pregnant women with menstrual delay of < or = 35 days who were requesting nonsurgical abortion.
                Within gestational age strata, we randomly assigned women to receive a single oral dose of mifepristone, either 200 mg or 600 mg, followed in 48 h by misoprostol 400 microg by mouth. We concealed the allocation assignments from investigators and participants and maintained double-blinding throughout the study.
                Complete abortion was the principal outcome measure. We also compared rates of side effects such as abdominal pain.
                The complete abortion rate with the lower dose of mifepristone was similar to that with the higher dose (89.3% vs 88.1%) The crude relative risk of failure to achieve complete abortion with the 200 mg dose compared with the 600 mg dose was 0.9 (95% CI 0.7 to 1.2). The likelihood of complete abortion was inversely related to gestational age, although this finding is exploratory in nature. Among failures the percentage of women with continuing pregnancies increased from 1.4% at menstrual delay of two weeks or less to 9.0% when the delay was 4-5 weeks. Low efficacy led to stopping enrolment at 29 to 35 days' menstrual delay. Stopping criteria were also met at completion of the study in the group with 22-28 days' menstrual delay. No significant differences emerged in the frequency of side effects between the two mifepristone groups.
                Both regimens had similar efficacy. Women with a menstrual delay of four to five weeks had twice the risk of failure to abort compared with those who received treatment within two weeks of the expected menses. The efficacy of the mifepristone-prostaglandin regimen was not reduced by decreasing the dose of mifepristone from 600 mg to 200 mg. The regimens of 600 mg or 200 mg of mifepristone, followed by a single oral dose of misoprostol 400 microg 48 hours later, were not sufficiently efficient in inducing abortion when the menstrual delay was > 21 days. 1. To investigate the efficacy of 800 micrograms misoprostol (a PGE1 analogue) when administered to women pretreated with mifepristone for early pregnancy termination. 2. To establish means of minimising gastrointestinal side effects by comparing two different misoprostol regimens. The impact of these regimens on blood pressure was investigated in a subgroup of patients.
                A randomised study of 150 women of 56 days gestation, or less, allocated to receive oral misoprostol either in a single dose of 800 micrograms or as two doses of 400 micrograms administered sequentially 2 h apart; in each case misoprostol was administered 36 to 48 h after receiving mifepristone 200 mg orally.
                Complete abortion rates, the frequency and severity (patients' perception) of gastrointestinal side effects, and blood pressure changes in response to prostaglandin administration.
                The overall success rate was 93%. Seventy-one (95%) women who received a single dose of misoprostol and sixty-nine (92%) who received the sequential dose aborted completely. There were two ongoing pregnancies in the first group (2.5%) and three (4%) in the second. The overall ongoing pregnancy rate was 3%. The incidence of diarrhoea was significantly lower for women receiving the sequential dose, and no significant differences were found in the incidence of the other gastrointestinal side effects. The only noted significant change in blood pressure was in diastolic pressure 4 h after the administration of the higher dose of prostaglandin, but this was slight.
                The combination of mifepristone and oral misoprostol provides an alternative method to inducing abortion of pregnancies of up to eight weeks gestation. Patients receiving the single dose of 800 micrograms were more troubled by diarrhoea than those on the sequential regimen. The ongoing pregnancy rate was higher than previously reported with vaginal or parenteral administration of prostaglandin. Prolonged vaginal bleeding is a common complaint after medical abortion. The effect of a 1 week course of daily oral misoprostol after medical abortion with mifepristone and misoprostol on the amount of post-abortal blood loss was studied.
                A total of 150 women (gestation <or=63 days) were randomized to three groups using computer-generated tables. They received 200 mg oral mifepristone, followed 48 h later by 0.8 mg oral misoprostol and vaginal placebo in group A, and 0.8 mg vaginal misoprostol and oral placebo in groups B and C. In groups A and B, the women continued with oral misoprostol 0.4 mg twice daily on days 4-10, while the women in group C took placebo. The actual blood loss was measured by the alkaline haematin method.
                No significant difference in the median amount (82.8, 94.7 and 88.5 ml for A, B and C respectively) and duration (16, 15 and 16 days respectively) of vaginal bleeding was observed. The incidence of diarrhoea was significantly higher (66, 55.1 and 12.5% respectively) in the groups with oral misoprostol after abortion.
                A 1 week course of oral misoprostol (0.4 mg twice daily) could not decrease the duration and amount of vaginal bleeding. Further studies with a larger sample size are needed to assess whether the complete abortion rate can be improved with this regimen. Our goal was to evaluate the pharmacokinetics and safety of methotrexate in doses of 50 mg/m2 and 60 mg/m2 in regimens for early abortion.
                A randomized controlled trial was performed in women requesting an abortion at < or = 49 days' gestation. Twenty women were treated with intramuscular methotrexate 50 mg/m2 (group 1) or 60 mg/m2 (group 2). Methotrexate levels were determined serially for the first 24 hours, then every 24 hours for 7 days. On the seventh day misoprostol 800 microg was administered vaginally. The misoprostol dose was repeated 24 hours later if abortion did not occur.
                Complete abortion occurred in 9 of 10 (90%, 95% confidence interval 56% to 100%) patients in group 1 and all 10 (100%, 95% confidence interval 69% to 100%; p = 0.99) in group 2. Methotrexate levels peaked within 1 to 2 hours and were nondetectable within 48 hours in all patients in group 1 and 72 hours in group 2. Both the maximum concentration of methotrexate and the area under the curve were significantly greater for group 2. Methotrexate clearance rates were 7.89 +/- 1.98 L/hr and 5.55 +/- 0.83 L/hr (p = 0.003), respectively.
                The serum levels of intramuscular methotrexate with 50 mg/m2 and 60 mg/m2 regimens indicate that these are safe treatment doses. Methotrexate 50 mg/m2 intramuscularly has the same clearance rates when administered during pregnancy as in a nonpregnant state, and maximum concentrations do not reach sustained toxic levels. A combination of mifepristone and misoprostol provides an effective method of medical abortion for early pregnancy. This is the first randomized trial comparing the use of sublingual misoprostol with vaginal misoprostol in combination with mifepristone for termination of early pregnancies up to 63 days.
                A total of 224 women who requested legal termination of pregnancy up to 63 days were randomized by computer- generated list into two groups and given 200 mg of oral mifepristone followed 48 h later by either 800 micro g of sublingual (n = 112) or vaginal (n = 112) misoprostol.
                Complete abortion occurred in 98.2% (95% CI: 93-99) of women in the sublingual group and 93.8% (95% CI: 88-97) in the vaginal group. There were three ongoing pregnancies in the vaginal group but none in the sublingual group. The median duration of vaginal bleeding was 17 days. There was no serious complication. Fever, chills and gastrointestinal side-effects (nausea, vomiting and diarrhoea) were significantly more common in the sublingual group.
                The combination of mifepristone and misoprostol is effective for medical abortion up to 63 days. Both the sublingual and vaginal are effective routes of administration. Further randomized trials are required to find out the optimal dose of sublingual misoprostol that can give the highest complete abortion rate and lowest incidence of side-effects. To find out the optimal doses regimen of mifepristone with misoprostol for termination early pregnancy.
                A randomized comparative study in 1,621 women requesting medical abortion at < or = 49 days from 9 hospitals was conducted in Hebei, women were randomly divided into 2 groups by 2:1 ratio. Study group (n = 1,118) women took mifepristone 50 mg immediately, then 25 mg b. i. d(total amount of 300 mg), plus misoprostol 600 micrograms at 8:00 in the morning on 3th day, and plus misoprostol 200 micrograms respectively at 8:00 in the morning on 4th, 5th, 6th day. In control group (n = 494), mifepristone 50 mg immediately, then, 25 mg b. i. d (total amount of 150 mg), plus misoprostol 600 micrograms at 8:00 in the morning on 3th day.
                In study group and control group, the complete abortion rate was 98.39% and 88.06% respectively, bleeding duration was (8.2 +/- 2.8) days and (12.3 +/- 3.9) days. There was no difference of side effects between the two groups.
                Mifepristone taken 300 mg plus misoprostol 1,200 micrograms orally for 6 days is an optimal dose regimen for termination of early pregnancy. 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.
                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.
                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.
                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. Mifepristone and oral misoprostol are typically used for medical abortion in women up to 49 days of gestation, with a 36- to 48-hour interval between the medications. Alternative routes of misoprostol administration allow for use beyond 49 days of gestation. We designed this randomized, noninferiority trial to compare the efficacy, adverse effects, and acceptability of misoprostol 800 mcg vaginally administered simultaneously with, or 24 hours after, mifepristone 200 mg orally for abortion in women up to 63 days of gestation.
                The 1,128 participants swallowed mifepristone 200 mg and were then randomized to self-administer misoprostol intravaginally immediately in the office (group 1) or 24 hours later at home (group 2). Subjects returned for an evaluation, including transvaginal ultrasonography, 7+/-1 days after initiating treatment. Women who had not aborted were offered a second dose of misoprostol and returned for another evaluation in approximately 1 week. A phone contact was also attempted approximately 5 weeks after treatment. Treatment was considered a failure if a suction aspiration was performed for any indication.
                The complete abortion rate for group 1 (95.1%, 95% confidence interval [CI] 93.0-96.8%) was statistically noninferior to that for group 2 (96.9%, 95% CI 95.1-98.2%) (P=.003). The abortion rates between groups did not significantly differ by gestational age. Adverse effects were mostly similar, although nausea, diarrhea, and warmth or chills were significantly more common in group 1.
                Mifepristone 200 mg and misoprostol 800 mcg vaginally used simultaneously is as effective for abortion as compared with regimens using a 24-hour dosing interval.
                ClinicalTrials.gov, www.clinicaltrials.gov, NCT00269568
                I. To compare the safety and efficacy of early abortion by administration of methotrexate and misoprostol vs administration of misoprostol alone.
                Randomized controlled trial.
                San Francisco (Calif) General Hospital.
                Pregnant women at 56 days' gestation or less seeking elective abortion. Sixty-three women volunteered for the trial; 61 completed the study and are included in the analysis.
                Intramuscular administration of 50 mg of methotrexate per square meter of body surface area followed 3 days later by vaginal administration of 800 micrograms of misoprostol (group 1) or the same dose of misoprostol given alone (group 2). The misoprostol dose was repeated 24 hours later if abortion had not occurred.
                Successful abortion, duration of vaginal bleeding, side effects, and change in beta-human chorionic gonadotropin (beta-hCG) level. An abortion was considered successful if the pregnancy ended without requiring a surgical procedure.
                Complete abortion occurred in 28 (90%) of 31 patients in group 1 and 14 (47%) of 30 patients in group 2 (P < .001). Seventeen (61%) of the 28 women in group 1 who aborted did so the same day as misoprostol administration; vaginal bleeding lasted a mean (+/- SD) of 10 (+/- 4) days, and beta-hCG level was less than or equal to 10 IU/L by a mean of 31 (+/- 6) days after methotrexate administration. The 11 other women in group 1 who aborted did so after a mean delay of 29 (+/- 11) days; vaginal bleeding lasted 7 (+/- 4) days, and beta-hCG level was less than or equal to 10 IU/L by a mean of 24 (+/- 11) days after the abortion. There were three treatment failures in group 1: two ongoing pregnancies (6%) and one incomplete abortion (3%). For the 14 women with successful abortions in group 2, vaginal bleeding lasted a mean of 10 (+/- 6) days and beta-hCG level was less than or equal to 10 IU/L by mean of 39 (+/- 18) days after the misoprostol. There were 16 treatment failures in group 2: eight ongoing pregnancies (27%), and eight incomplete abortions (27%). Methotrexate side effects were minimal. Misoprostol side effects were diarrhea in 18% and nausea and vomiting in 5%.
                Methotrexate and vaginal misoprostol are more effective than misoprostol alone. Both drugs are available throughout the United States, and both drugs are inexpensive. This combination may offer an alternative to the use of antiprogestin and prostaglandin for medical abortion. To demonstrate equivalence between mifepristone 200 mg followed 6 to 8 hours later and 24 hours later by misoprostol 800 microg vaginally for abortion in women up to 63 days of gestation.
                Mifepristone 200 mg was swallowed by 1,080 women after which they were randomly assigned to self-administer misoprostol intravaginally 6 to 8 hours later (group 1) or 23 to 25 hours later (group 2) at home. Participants returned for an evaluation, including transvaginal ultrasonography, 7 +/- 1 days after initiating treatment. Subjects who had not aborted were offered a second dose of misoprostol. All participants returned approximately 2 weeks after receiving mifepristone. Telephone contact was also attempted approximately 5 weeks after treatment. Treatment was considered a failure if a suction aspiration was performed for any indication.
                Complete abortion rates for groups 1 and 2 were 503 of 525 (95.8%, 95% confidence interval 93.7%, 97.3%) and 521 of 531 (98.1%, 95% confidence interval 96.6%, 99.1%), respectively, which were statistically equivalent. Side effects were significantly more common after mifepristone administration for women in group 2. Nausea, vomiting, and heavy bleeding were also significantly greater for women in group 2 after misoprostol treatment. Pain and subject acceptability were similar between groups.
                Mifepristone 200 mg followed 6 to 8 hours later by misoprostol 800 microg vaginally is as effective for abortion and has significantly fewer side effects as compared with regimens using a 24-hour dosing interval. Women receiving mifepristone and vaginal misoprostol for abortion can have the flexibility to administer the misoprostol as soon as 6 hours after using the mifepristone. To compare the side effect profiles of regimens of oral and vaginal administration of misoprostol after a single oral dose of 200 mg of mifepristone and to investigate patients' perceptions of medical abortion.
                Double-blind, randomised controlled trial.
                Fifteen gynaecological clinics in 11 countries.
                A total of 2219 healthy pregnant women requesting medical abortion with < or =63 days of amenorrhoea. Two thousand women were asked about their perceptions of the method.
                Mifepristone 200 mg orally on day one, followed by 0.8 mg misoprostol either orally or vaginally on day three. The oral group (O/O group) and one of the vaginal groups (V/O group) continued with 0.4 mg of oral misoprostol, and the vaginal-only group (V-only group) with oral placebo, twice daily for seven days. Side effects were recorded daily by women and reported at each visit. After misoprostol administration at the clinic, side effects were recorded at 1-hour interval up to 3 hours. Patients' perceptions were asked at the second follow up visit, six weeks after treatment.
                The outcome measures were the following: pregnancy-related symptoms (nausea, vomiting, breast tenderness, fatigue, dizziness, headache), drug-related side effects (diarrhoea, fever, rash and blood pressure change), side effects related to the abortion process (lower abdominal pain) and women's perceptions of the method.
                The pregnancy-related symptoms decreased in all groups after misoprostol, and breast tenderness decreased already after mifepristone. Oral administration of misoprostol was associated with a higher frequency of nausea and vomiting than vaginal administration at 1 hour after administration. With oral misoprostol, diarrhoea was more frequent at 1, 2 and at 3 hours after administration than with vaginal administration. Misoprostol induced fever during at least 3 hours after administration in up to 6% of the women, this peak being slightly higher and taking place later with the vaginal route. Lower abdominal pain peaked at 1 and 2 hours after oral misoprostol, while it did so at 2 and 3 hours after vaginal misoprostol. In the two groups that continued misoprostol, 27% of women had diarrhoea between the misoprostol visit and the two-week follow up visit, compared with 9% in the placebo group. Among the women studied, 84% would choose medical abortion again, 9% would choose surgical abortion and 7% did not know. Twenty-three percent of the women would choose to have a possible future abortion at home, 70% at a health facility and 7% did not know.
                The pregnancy-related symptoms decrease significantly with time during medical abortion. Nausea, vomiting and diarrhoea were more frequent after oral administration of misoprostol. Pain related to the abortion process occurs earlier after oral misoprostol. Should a need arise, a majority of women would choose medical abortion again and would prefer to have it at a health facility rather than at home. To compare the efficacy and side-effects of mifepristone 75 mg in capsule form versus 150 mg in tablet form followed by misoprostol for medical termination of early pregnancy.
                In a prospective randomized, double-blind, placebo-controlled trial, a total of 480 women who were 49 days or less pregnant were randomized by means of a random number table to receive either two tablets in the morning and one tablet 12 h later for 2 days (group A) or three capsules orally twice daily for 2 days, the first dose being double all subsequent doses (group B). After a further 48 h, 600 microg misoprostol was given orally. Successful abortion was defined as complete abortion with no need for surgical aspiration.
                There were no significant differences between the two study groups in the rates of complete abortion (95.4% in group A versus 96.3% in group B), incomplete abortion (3.8% in group A, 3.3% in group B) and continued pregnancy (0.8% in group A, 0.4% in group B). No significant difference in the duration and amount of vaginal bleeding was observed. The incidence of side-effects, such as vomiting, nausea, headache, diarrhea and lower abdominal pain was similar in the two groups.
                Our results indicate that 75 mg mifepristone in capsule form combined with 600 microg misoprostol is as effective and safe as 150 mg mifepristone in tablet form for the termination of pregnancy up to 49 days. Three different regimens of RU 486, a progesterone receptor blocking agent, were compared for their ability to terminate early human pregnancy. One-hundred-fifty-three healthy women with a gestational length less than 49 days from the last menstrual period were recruited to the study and randomly allocated to one of three treatment regimens: 1) RU 486 10 mg x 2 for seven days; 2) RU 486 25 mg x 2 for seven days; or 3) RU 486 50 mg x 2 for seven days. No significant difference in efficacy was seen between the three dose regimens. Treatment with 10 mg x 2 x VII resulted in 73 per cent complete abortions, 25 mg x 2 x VII in 66 per cent and 50 mg x 2 x VII in 64 per cent complete abortions. Response to treatment, measured as reported onset of bleeding and passage of products of conception, however, occurred significantly later on the 10 mg x 2 regimen than on the other two dose regimens. In each treatment group, women who subsequently aborted completely had significantly lower pretreatment levels of hCG than women with incomplete abortion or continuing pregnancy. The treatment was well tolerated by the women and except for one woman who experienced a profound bleeding necessitating a blood transfusion, no serious side effects were seen. The purpose of this study was to compare the outcome and side effects of using the drugs methotrexate and misoprostol, alone or in combination, to induce abortion. A total of 108 subjects who had requested elective termination of pregnancy and medical abortion at 9 weeks gestation or less were randomized into three groups. The first group received 50 mg/m2 intramuscular (i.m.) methotrexate on day 1 and, if the hCG level had risen by > 50% of the initial level on day 4, a second dose was given. They were then followed-up at weekly intervals up to day 21. Group 2 received 800 micrograms vaginal misoprostol on day 1 and, if ultrasound showed a gestational sac on day 4, they received a repeat dose and were re-examined on day 7. Group 3 received 50 mg/m2 methotrexate intramuscularly followed 3 days later by 800 micrograms vaginal misoprostol and were re-examined on day 7. Complete abortion occurred in 25 (69%) of the 36 subjects in group 1, 21 (58%) of the 36 subjects in group 2, and 32 (89%) of the 36 subjects in group 3. The complete abortion rate in group 3 was significantly higher than that of both group 1 and group 2 (p < 0.05). The incomplete abortion rate was significantly higher in group 2 as compared with both of the other groups (p < 0.05). There were significant differences between the mean gestational age of the successful abortions and the failures in group 1 (no abortion occurred at more than 49 days gestation), but not in groups 2 or 3. Vaginal bleeding in subjects who successfully aborted began within 16 +/- 4 days in group 1 after the first dose, and within 24 h in 18 (86%) of the 21 subjects in group 2 and 27 (84%) of the 32 subjects in group 3 after the misoprostol dose. The drugs caused no serious or prolonged side effects. The combination of methotrexate and misoprostol is a more effective abortifacient regimen than when either drug is used alone. 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. To study the efficacy, safety, and acceptability of oral immediately swallowed and buccal misoprostol 800 mcg after mifepristone 200 mg for terminating pregnancy through 63 days since the last menstrual period (LMP).
                This seven-site study randomly assigned 966 women seeking abortions to oral or buccal misoprostol 800 mcg 24-36 hours after mifepristone 200 mg with 7-14-day follow-up.
                Success rates in the oral and buccal groups were 91.3% (389 of 426) and 96.2% (405 of 421), respectively (P=.003; relative risk [RR] 0.95, 95% confidence interval [CI] 0.92-0.98). Ongoing pregnancy occurred in 3.5% (15 of 426) of women who took oral misoprostol compared with 1.0% (4 of 421) of women in the buccal group (P=.012; RR 3.71, 95% CI 1.24-11.07). Through 49 days since the LMP, oral and buccal regimens performed similarly, but success with oral misoprostol decreased as pregnancy advanced. In pregnancies of 57-63 days since the LMP, success with oral misoprostol fell below 90%, whereas that with buccal remained high (oral 85.1% [97 of 114], buccal 94.8% [109 of 115], P=.015, RR 0.90, 95% CI 0.82-0.98). Furthermore, in this gestational age group, there were significantly more ongoing pregnancies among women who took misoprostol orally (7.9% [9 of 114]) compared with buccally (1.7% [2 of 115]; P=.029, RR 4.54, 95% CI 1.0-20.55). Adverse effect profiles were similar, although fever and chills were reported approximately 10% more often among women who took buccal misoprostol. Satisfaction and acceptability were high for both methods.
                Buccal misoprostol 800 mcg after mifepristone 200 mg is a good option for medical abortion through 63 days since the LMP. Oral misoprostol 800 mcg is also a safe and effective alternative, although success rates diminish with increasing gestational age.
                ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386867
                I. Four multicentre clinical trials on interruption of early pregnancy (less than or equal to 49 days of amenorrhea) using RU 486 have been conducted in China, including 2321 subjects. The data from trials 1, 2 and 4 are presented here. RU 486 (600 mg as a single dose) was given to 299 women. A further 422 women were given RU 486 (600 mg) plus a vaginal suppository containing the Chinese domestic prostaglandin PGO5 (1 mg) 36-60 hours later. Complete abortion was achieved in 63.5% of patients receiving RU 486 alone and in 94.1% of patients receiving RU 486 plus PG (p less than 0.001). RU 486 given alone showed decreasing efficacy as the duration of amenorrhea increased. However, RU 486 combined with PG was equally effective at all time points studied (less than or equal to 35 days of amenorrhea: 98.1%, 36-42 days: 92%, 42-49 days: 87.4%). When compared with RU 486 alone Ru 486 + PG also produced a shorter bleeding time and a lower volume of blood loss (n = 21, 52 ml vs n = 13, 117 ml). Two patients from the RU 486+PG group and 4 given RU 486 alone suffered heavy bleeding, necessitating emergency curettage. No transfusions were required. The time elapsed between RU 486 intake and expulsion of the conceptus was significantly shorter in the RU 486+PG group (n = 97, 31 days) than that in the RU 486 alone group (n = 95, 4.4 4.4 days). Main side effects, nausea/vomiting and headache/dizziness, were mainly due to RU 486. PG increased the incidence of diarrhea and uterine cramp.(ABSTRACT TRUNCATED AT 250 WORDS) Mifepristone (600 mg) in combination with a prostaglandin has been demonstrated to be a safe, acceptable alternative to vacuum aspiration for induction of abortion in the first 9 weeks of pregnancy. However, the efficacy and side-effects of different prostaglandins used in combination with mifepristone have not been assessed in a randomized trial. In this study, 800 women seeking an abortion at gestational age < or = 63 days amenorrhoea were randomized to receive either 0.5 mg gemeprost by vaginal pessary (group I) or 600 micrograms misoprostol (group II) by mouth approximately 48 h after taking 200 mg mifepristone by mouth. The side-effects and number of complete abortions were used as measures of efficacy. There was no significant difference in the rate of complete abortion between group I [96.7%; 95% confidence interval (CI) 94.9-98.5%, n = 391] and group II (94.6%; 95% CI 92.3-96.9, n = 386). It was not possible to assess the outcome with certainty in the remaining 23 women. However, there were significantly more ongoing pregnancies in the women who received misoprostol than in those who received gemeprost (nine versus one, P < 0.01) and in eight of these 10 women the gestation was > 49 days. Fewer women in group II required analgesia than in group I (48 versus 60%, P < 0.001) although the number requesting opiate was similar in each group (6.9 versus 5.2%, P > 0.4). The incidence of nausea and vomiting after misoprostol (47.8 and 21.9% respectively) was higher (P < 0.001) than after gemeprost (33.9 and 12% respectively).(ABSTRACT TRUNCATED AT 250 WORDS) It has been shown that the antiprogestin RU 486 (mifepristone) increases the sensitivity of the early pregnant human uterus to the stimulatory action of synthetic prostaglandin E (PGE) analogues. To examine if RU 486 also increases uterine sensitivity to the naturally occurring PGE2 given orally, two investigative approaches were used in the present studies: (i) direct registration of uterine contractions before and after PGE2 administration in untreated and RU 486-treated early pregnant women; and (ii) a double-blind, randomized, controlled efficacy trial involving treatment of pregnant women (amenorrhoea of less than or equal to 49 days) with RU 486 (25 mg twice daily for 4 days) and PGE2 (1 mg once or twice) or placebo on the last day of RU 486 treatment. The results indicate that oral PGE2 at the doses employed had little or no stimulatory effect on uterine contractility and that it did not improve the rate of complete abortion achieved with RU 486 alone. Overall, 25 of 42 women (59%) had a complete abortion, 15 women (36%) did not abort and the remaining two had incomplete abortions. Women with complete abortions had significantly lower pretreatment levels of progesterone and a longer duration of induced bleeding than those who did not abort. Thus oral PGE2, when given in clinically acceptable doses, is not a suitable alternative to synthetic PGE analogues for use in combination with RU 486 for termination of early pregnancy. To compare two regimens of mifepristone plus gemeprost for early pregnancy termination.
                A prospective, randomized, multicenter trial.
                Ten gynecological services, mostly in academic hospitals.
                Three hundred eighty-five healthy women up to 35 years of age with amenorrhea less than or equal to 49 days requesting pregnancy termination.
                Mifepristone, 25 mg five times at 12-hour intervals (n = 192) or 600 mg as a single dose (n = 193) followed by 1 mg gemeprost 60 hours after the start of mifepristone.
                Pregnancy outcome, time of onset and duration of vaginal bleeding, subjective complaints, and hormone changes during treatment and 6-week follow-up.
                Treatment outcome was identical in both groups with an overall complete abortion rate of 92.7% among the 385 women included in the analysis. The frequency of complaints, bleeding patterns, and changes in hemoglobin, beta-human chorionic gonadotropin, estradiol, and progesterone were also similar in both groups. Cortisol (at 12 and 36 hours after mifepristone) and prolactin (at 12 hours) were significantly higher in the single 600-mg dose group.
                When used for early pregnancy termination with prostaglandin, a lower dose of mifepristone than the currently recommended single 600-mg dose may suffice. Mifepristone-misoprostol medical abortion has been approved in the United States since 2000. U.S. providers have preferred to use vaginal misoprostol because of evidence that such a regimen is more effective in later gestations. Buccal administration of misoprostol may be equally effective and more acceptable to some women.
                This open-label, randomized trial was conducted at two sites in Rochester, NY, and involved healthy women with pregnancies through 56 days since the last menstrual period (LMP) as indicated by sonogram. Women received mifepristone 200 mg orally and were randomized to use 800 mug of misoprostol either buccally or vaginally 1 to 2 days later. They returned within 15 days for repeat sonogram. If the woman's pregnancy had not been completely aborted by day 36, a suction abortion was performed. The primary outcome was a complete abortion without surgical intervention.
                Four hundred forty-two women were enrolled in the study, and complete data were available on 429. The efficacy rate was 95% (205/216) in the buccal group and 93% (199/213) in the vaginal group (chi(2)=0.43, p=.51). Nausea was the most commonly reported side effect, affecting 70% in the buccal group and 62% in the vaginal group. There were no differences in the satisfaction with the overall procedure between the buccal (92%) and the vaginal groups (95%) (chi(2)=1.87, p=.17).
                Buccal administration of misoprostol after low-dose mifepristone for medical abortion appears to be a highly effective and acceptable alternative compared with vaginal administration for medical abortion in pregnancies through 56 days LMP. nan One-hundred-and-twenty women of less than 56 days amenorrhoea were treated with a single dose of 600 mg of mifepristone in combination with half or a whole 1 mg gemeprost vaginal pessary. Complete abortion was induced in 119 (99%) women and there were no continuing pregnancies. There were few gastro-intestinal side effects following prostaglandin. The smaller dose of prostaglandin caused significantly less severe pain. This study confirmed the effectiveness of mifepristone and prostaglandin for the induction of early abortion but suggests that more research should be carried out to determine the lowest effective doses of both drugs. A prospective trial including 300 pregnant women seeking elective abortion was conducted to evaluate the safety and efficacy of methotrexate and misoprostol for abortion at < or = 63 days' gestation. Subjects received methotrexate 50 mg orally and were randomly allocated to receive 800 micrograms of misoprostol vaginally 3, 4, or 5 days after administration of the methotrexate. The misoprostol dose was repeated 48 and 96 h later if abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure) and side effects. Complete abortion occurred in 273 of 300 patients (91%, 95%, CI 87, 94%) patients. No significant statistical differences were found in the success rates when misoprostol was given days 3, 4, or 5 after the administration of methotrexate (p = 0.69). Vaginal bleeding lasted 7.1 +/- 3.8 days, spotting 4.1 +/- 2.5 days, and total bleeding 11.2 +/- 4.1 days. Side effects for methotrexate were minimal, whereas, for misoprostol they were mild and transient except for pain. The use of methotrexate and misoprostol together could be an alternative to the intramuscular use of methotrexate or the use of antiprogestins and prostaglandin for medical abortion. A multicentre randomized open clinical trial was conducted to compare the efficacy and side effects of two regimens of mifepristone with misoprostol, and mifepristone with PG05 for termination of early pregnancy (amenorrhoea < = 49 days). Six-hundred women in early pregnancy, who requested medical abortion were randomly allocated into 3 groups. In group 1 (n = 301), an initial dose of mifepristone 50 mg was given, followed by 25 mg every 12 hours up to a total dose of 150 mg mifepristone, plus a single oral dose of misoprostol 600 micrograms in the morning of the third day. In group 2 (n = 150), the same regimen of mifepristone was given, but dl-15-methyl PGF2 alpha (PG05) 1 mg vaginal suppository was inserted on the third day. In group 3 (n = 149), a single dose of mifepristone 200 mg was given and misoprostol 600 micrograms was used as in group 1. The complete abortion rate were 94.4%, 97.3%, and 94.6% for group 1, 2 and 3, respectively. 3.0, 2.0 and 2.7% of women had incomplete abortion, and 1.7, 0.7 and 2.0% of women in the 3 groups were treatment failures; in the remaining 1% in group 1 and 0.7% in group 3, treatment outcome could not be determined. There were no significant differences among the 3 groups. Lower abdominal pain was the main complaint which was reported by 82% of the subjects after PGs administration. The incidence of diarrhoea in PG05 group (38.7%) was significantly higher than that in the other two groups (21.6 and 20.1%) (P < 0.001), and so was vomiting. It was concluded that misoprostol, as an orally effective prostaglandin, in combination with mifepristone for induced abortion of early pregnancy was as effective as PG05 vaginal suppository. Besides, it has advantages of convenience of use, less side effects, easy storage and transfer, and low cost. The primary objective of this study was to determine if buccal misoprostol was as effective as vaginal misoprostol in medical abortions. The secondary objectives were to compare side effects and acceptability.
                This was a randomized controlled trial of 600 microg misoprostol by the buccal or vaginal routes used 3 to 6 days after 50 mg/m2 methotrexate. The participants were women presenting for abortion at 49 days or less gestation. The outcome measures were the number of women who had aborted by Day 8, side effects and acceptability.
                Day 8 completion rate was 53.5% for the buccal route and 67.5% for the vaginal route (p = 0.012). Side effects were similar in the two groups except that there was more burning with the buccal route. Overall acceptability and route acceptability were similar in the two groups.
                When used after methotrexate for early abortion, the vaginal route for misoprostol is more effective and preferred to the buccal route. This study was undertaken to compare oral to injected methotrexate with respect to effectiveness, side effects, and acceptability.
                One hundred women in an urban primary care practice were randomly assigned in phase 1 to receive 50 mg/m(2) methotrexate by either the oral or the injected route. In phase 2 another 87 women were allowed to choose between the oral and injected routes. In both phases and in all groups the methotrexate was followed 5 to 7 days later by misoprostol administered vaginally by the patient. The main outcome was the success rate (the number whose pregnancies aborted without surgery); other outcomes included side effects and acceptability.
                There were no differences in rates of success, side effects, or acceptability between groups receiving oral and injected methotrexate. Among the women in phase 2 the oral form was chosen by 57.5%.
                This study indicates that for medical abortions induced with methotrexate and misoprostol it is possible to offer both the oral and injected routes of methotrexate without sacrificing efficacy and that about half of the women offered a choice will choose the oral route. Mifepristone was recently approved in the United States. Regimens with shorter intervals may be more acceptable. The objective of this study was to determine whether the oral route of misoprostol was as effective as the vaginal route of misoprostol 1 day after mifepristone. A prospective, open-labeled, randomized trial of healthy adult women up to 63 days pregnant and wanting a medical abortion were randomized to use either two doses of oral misoprostol 400 microg taken 2 h apart or misoprostol 800 microg vaginally. Women self-administered misoprostol 1 day after taking one-third of the standard dose of mifepristone (200 mg) orally. Women then returned to the clinic up to 5 days later for a repeat sonogram evaluation. A dose of vaginal misoprostol was administered to women with a continuing pregnancy who then returned 1 day later to Day 15. The primary outcome measures were a complete medical abortion by the first or by the second follow-up visits. Surgical intervention was indicated for continuing pregnancy at the second follow-up visit, excessive bleeding, or persistent products of conception 5 weeks later. One thousand one hundred sixty-eight women were enrolled. Of the 1144 (98%) women who complied with their random assignment, two oral doses of misoprostol (800 microg total) were 90% effective at inducing an abortion by the first follow-up visit, compared with one dose of misoprostol by vagina of 97% (chi(2) = 23.95, p = 0.001). By the second follow-up visit, the complete abortion rate was 95% for oral misoprostol and 99% for vaginal misoprostol (chi(2) = 21.76, p = 0.001). There were minimal differences in side effects. Women preferred the oral route. The trial demonstrated that although two doses of oral misoprostol were effective, the vaginal misoprostol was more effective at inducing an early medical abortion at 1 day after low-dose mifepristone, and the regimen could be extended to 63 days gestation.