Efficacy and acceptability of a mifepristone-misoprostol combined regimen for early induced abortion among women in Mexico City.

OBJECTIVE: To evaluate the experience of women receiving mifepristone-misoprostol for early induced abortion in public sector facilities in the Federal District of Mexico City. METHODS: An open-label prospective study was conducted with 1000 pregnant women who sought induced abortion with a pregnancy of up to 63days of gestation, as measured from the date of their last menstrual period. The study was conducted in three public sector healthcare facilities: two secondary level hospitals and one primary care clinic. Women ingested 200mg mifepristone on day 1, followed by 800µg buccal misoprostol 24hours later, and they returned for follow-up on day 8. The primary outcome was complete abortion without recourse to surgical intervention. RESULTS: A total of 971 women received mifepristone-misoprostol and were included in the analysis for efficacy of treatment. The overall efficacy of the combined medical abortion regimen studied was 97.3% (n=945); the success rate did not vary significantly by gestational age (95.9%-100%; P=0.449). Most women (n=922, 95.0%) had a successful induced abortion with only one dose of misoprostol. CONCLUSION: The combined mifepristone and buccal misoprostol regimen was found to be highly effective and acceptable among Mexican women. www.ClinicalTrials.gov: NCT00386282.

Mifepristone for uterine fibroids.

BACKGROUND: Uterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competitively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristone has been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associated adverse effects as described in randomised controlled trials. OBJECTIVES: To determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women. SEARCH METHODS: We searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertility Review Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE, EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists, databases of ongoing trials and the Internet. There were no language restrictions. SELECTION CRITERIA: Only truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal women with confirmed uterine fibroids were included. DATA COLLECTION AND ANALYSIS: Four authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomous data and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed using the fixed-effect model. MAIN RESULTS: Three studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo (Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I(2) = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardised mean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24; 95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in the mifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I(2) = 0%). Only one study (Bagaria 2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebo group; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women in the mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes. AUTHORS' CONCLUSIONS: Mifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.

Emergency contraception in Cuba with 10 mg of mifepristone.

BACKGROUND: Mifepristone in a dose of 10 mg is an effective emergency contraceptive when administered up to 120 hours after unprotected coitus. METHODS: Between May 2003 and February 2005, we conducted in Cuba a single-arm trial to evaluate the effectiveness of 10 mg mifepristone for emergency contraception up to 6 days after unprotected coitus. A total of 635 women who requested emergency contraception after a single act of unprotected intercourse were included in the study. RESULTS: After treatment there were 7/635 (1.1%) pregnancies (95% CI 0.4-2.3%). Pregnancy that might have occurred was prevented in 88.0% of the cases (95% CI 77.1-95.1%). The most common side effects reported by participants were fatigue (10.7%), dizziness (6.1%) and nausea (4.9%); vomiting was only reported by 0.6%. In 38/635 (6.0%) women menstruation was delayed more than 7 days. CONCLUSIONS: Mifepristone 10 mg administered is an effective emergency contraceptive with an acceptable profile of side effects up to five days, but greater studies are necessary to verify its efficacy up to 6 days after unprotected intercourse.

[Medical termination of pregnancy at 9-14 weeks gestation. Prospective study of 105 cases in Saint-Laurent-du-Maroni (French Guyana)]. / L'interruption volontaire de grossesse médicamenteuse de 9 à 14 semaines d'aménorrhée: étude prospective de 105 cas à Saint-Laurent-du-Maroni (Guyane française).

OBJECTIVES: To demonstrate the effectiveness and safety of mifepristone 600mg with misoprostol 800 mg, for termination of pregnancy at 9-14 weeks gestation. PATIENTS AND METHODS: This prospective study included 105 women at 9 to 14 weeks gestation given 800 mg of vaginal misoprostol, 2 or 3 days after a single dose of 600 mg of mifepristone for pregnancy termination. Outcomes measures included mean expulsion time, the interval between fotal and placental expulsion, adverse effects, vaginal bleeding, requirement for analgesia, and hospital stay, analyzed by parity and gestational age. RESULTS: Pregnancy termination was successful in 92.4% of the patients without requirement for surgery. The mean time to expulsion was 6 hours. The fetus and placenta were expelled together in 79% of the cases. In 15% the conception products were retained in the cervical canal, and removed with a ring forceps. Additional misoprostol doses were necessary in 33% and analgesia (nalbuphine sublingually, mean dose was 10mg) in 56%. Significant bleeding was observed in 7.5%, leading to curettage in 2 patients. No statistically significant differences were found between the rate of success and term (9-12 versus 12-14) or parity. CONCLUSION: Combining oral mifepristone and vaginal misoprostol is a successful alternative to surgical termination of pregnancy, even after 9 weeks' gestation. The use of nalbuphine for analgesia improves acceptability; sublingual administration helps avoid invasive procedures. Before 14 weeks gestation, the legal limit for termination of pregnancy in France, the choice between the surgical and medical alternatives should be left to the patient.

[Medical methods for pregnancy termination. A review of literature and its potential role in Mexico and Latin America]. / Medicamentos para la interrupción de la gestación: una revisión de la literatura y sus posibles implicaciones para México y América Latina.

In this document, we review the relevant aspects of the different medical methods of abortion. We describe the principal medical regimens currently used in North America, Europe, and a growing number of developing countries. We also describe specific treatment regimens (which usually involve a combination of two drugs), physiological methods of action, potential side effects and complications, method requirements, including follow-up visits, any existing contraindication, and acceptability of these methods among patients. Finally, we comment on the potential role of medical abortion in Mexico and throughout Latin America.

How safe is emergency contraception?

Emergency contraception is used to prevent pregnancy after unprotected sex but before pregnancy begins. Currently, women can use emergency contraception by taking higher doses of the active ingredients found in ordinary oral contraceptive pills [either combined estrogen-progestogen (progestin) or progestogen-only formulations], or by having providers insert copper-bearing intrauterine devices (IUDs). The antiprogestogen mifepristone also has an excellent efficacy and safety profile as emergency contraception, but it is currently available for this indication only in China. Many studies have documented providers' and women's fears about the individual and public health safety risks of emergency contraception. Some of these concerns include potentially increased risks of cardiovascular events (including arterial and venous disease), worries about possible effects on future fertility, feared teratogenic consequences following method failure or inadvertent use during pregnancy, exaggerated or extreme fears of adverse tolerability, and concerns about drug interactions with other medications. Wider public health questions include feared reductions in the use of ongoing, more effective contraception, possible 'abuse' of emergency contraception through overly frequent use, and potential increases in risky sexual encounters (owing to the existence of a back-up, postcoital method) and therefore in rates of sexually transmitted infections, including HIV/AIDS. These fears can each be generally allayed. Direct and indirect investigations of emergency contraception in the biomedical and social science literature, the extensively documented safety profile of ordinary oral contraceptives, and more than 30 years of clinical experience since hormonal emergency contraception was first described, give strong evidence for its safety. This review confirms declarations by the World Health Organization and the US Food and Drug Administration, and shows that emergency contraception has an excellent safety profile in nearly all women. Finally, emergency contraception allows women a second chance to avoid unwanted pregnancies. Whether pregnancy is carried to term or terminated, the condition has inherent risks that are greater than any posed by emergency contraception.

Side effects of mifepristone-misoprostol abortion versus surgical abortion. Data from a trial in China, Cuba, and India.

Although serious adverse events of early abortion have been studied, little attention has been paid to the more common side effects experienced by early medical or surgical abortion clients. Using data from a multicenter comparative trial of women < or = 56 days' gestation in China, Cuba, and India (n = 1373), side effects experienced by mifepristone-misoprostol medical abortion and surgical abortion clients were analyzed at the different stages of their abortions. Data on side effects came from women's reports at each clinic visit, providers' observations during the clinic visits, and symptom diaries maintained during the study period. Medical abortion clients at all sites experienced more side effects than their surgical counterparts. The disparity between the two groups was particularly pronounced for bleeding and pain. Despite more reports of side effects among medical abortion clients, however, assessments of well-being and reports of satisfaction at the exit interview were similar in both treatment groups.

Mifepristone-misoprostol medical abortion: home administration of misoprostol in Guadeloupe.

Mifepristone-misoprostol medical abortion promises to revolutionize reproductive health-care. Several simplifications of the standard three clinic visit regimen may be possible, however. Particularly in developing countries, access to the method can be greatly increased by eliminating the longest clinic visit. Indeed, shortly after mifepristone's introduction in Guadeloupe, a semi-developed Caribbean territory administered by France, in 1991, two of the authors conducted a small prospective study of a one treatment-visit regimen. The study regimen was subsequently adopted as the standard of care for medical abortion on the island. Women (n = 92) with amenorrhea of < or = 49 days received 600 mg mifepristone under clinical supervision and were given 400 micrograms oral misoprostol for home administration 2 days later, returning 2 weeks later for follow-up. The success rate (95.4%) is comparable to rates found when both drugs are administered in the clinic and to rates from a similar study conducted recently in the United States. Adverse events were also comparable to protocols requiring in-clinic administration of misoprostol. Protocol adherence appeared to be excellent and loss to follow-up was rare. We suggest that home administration of misoprostol can be safe and effective in most nonindustrialized settings.

PIP: This paper presents a prospective study of home administration and a one-treatment-visit regimen of mifepristone-misoprostol for medical abortion in Guadeloupe. The administration of this contraceptive method usually requires a standard 3-clinic visit regimen, which would sometimes lead to discontinuation of the abortion process. The study consisted of 92 medical abortion cases conducted over a 13-month period. The intervention involved a 1-day treatment visit with patients receiving 600 mg of mifepristone and instructions on ingesting 2 tablets (400 mcg) of misoprostol orally after 2 days and another 200 mcg misoprostol if bleeding had not occurred within 6-12 hours. A follow-up was conducted among these women after 10-15 days of initial clinic visit and contraceptive administration. The total success rate was 95.4% in comparison with those who received a 3-clinic visit regimen and the statistical result of a study conducted in the US. Several adverse effects have been associated with the administration of abortive methods, which include bleeding (19.6% in mifepristone users and 68.2% in misoprostol users) and vomiting. Strict monitoring of mifepristone and misoprostol distribution and patient follow-up was ensured by French legislators. The authors conclude that home administration of misoprostol must be made available to women in developing countries.

Effects of long-term low-dose mifepristone on reproductive function in women.

Low-dose antiprogestin administration has been proposed as a new contraceptive modality to interference with endometrial receptivity without disturbing ovarian function. The effects of 1 mg/day mifepristone for 150 days on the menstrual cycle were assessed in 21 surgically sterilized women. The aim was to study each woman for one control cycle and during months 1, 3 and 5 of treatment. Ovulation, endometrial thickness, serum oestradiol and progesterone, urinary luteinizing hormone, endometrial morphology and cervical mucus were assessed. Luteal phase progesterone concentrations were observed in 36 of the 60 treated months assessed and less frequently as treatment progressed. The bleeding pattern was regular in most biphasic cycles, while prolonged interbleeding intervals or no bleeding were associated with monophasic cycles. Altered endometrial morphology was found in all cases irrespective of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were observed in 25 and 34% respectively of the monophasic cycles. Mifepristone, 1 mg/day, interferes with endometrial development while allowing the occurrence of biphasic ovarian cycles and regular bleeding. However, it also prevents ovarian cyclicity in a high proportion of treated months, and this is associated with increased endometrial growth in some women, which may be of concern.

PIP: Low-dose antiprogestin administration has been proposed as a new contraceptive modality that interferes with endometrial receptivity without disturbing ovarian function. To explore this potential, the effects on the menstrual cycle of 1 mg/day of mifepristone for 150 days were assessed in 21 surgically sterilized women from Santiago, Chile. Control cycles were biphasic in all 21 women and ovulatory in 20 women. Luteal phase progesterone concentrations were observed in 36 of the 60 treatment months (1, 3, and 5) assessed. The proportion of ovulatory cycles was highest during month 1 and decreased progressively with treatment. 40% of treatment cycles were monophasic and bleeding cyclicity was altered in 57%. Prolonged inter-bleeding intervals or no bleeding occurred in monophasic cycles. Endometrial morphology was altered in all cases, regardless of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were recorded in 25% and 34%, respectively, of the monophasic cycles. These findings suggest that 1 mg of mifepristone interferes with endometrial development while allowing biphasic ovarian cycles and regular bleeding. Whether these endometrial alterations are sufficient to prevent implantation remains to be established. The long-term effect of prevention of ovarian cyclicity and the associated increased endometrial growth recorded in some women require further investigation.

Fertility impairment after mifepristone treatment to rats at proestrus. Actions on the hypothalamic-hypophyseal-ovarian axis.

Accumulated evidence indicates that the antigestagen mifepristone affects the reproductive axis acting on hypothalamic, pituitary, ovarian, and uterine tissues. The purpose of this study was to further investigate which reproductive functions are impaired by the antagonist, critically compromising the reproductive process, leading to unsuccessful pregnancy. Circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling rats receiving a single dose of mifepristone (1 or 10 mg/kg subcutaneously) at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Mifepristone-treated rats had decreased preovulatory surges of LH and prolactin (PRL), and hypersecretion of LH, PRL, and progesterone at estrus. The sexual receptivity was dramatically affected by the antagonist as indicated by the profound decrease in the lordosis response evaluated on the night of proestrus. The number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus were not affected by mifepristone. The low number of rats that succeeded in mating with potent males became pregnant. However, they delivered an average of only two pups at parturition, indicating a failure in the implantation of the fertilized ova, as ovulation was not affected by the antagonist at the dose used. We conclude that a dramatic inhibition of the sexual receptivity and unsuccessful implantation, preceded by a reduction on LH and PRL secretion, are the major components leading to fertility impairment after a single dose of mifepristone administered before the preovulatory surge of LH.

PIP: Mifepristone has been demonstrated to act on hypothalamic, pituitary, ovarian, and uterine tissue. To further investigate impairments in reproductive function triggered by this antagonist, circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling Wistar rats receiving a single dose (1 or 10 mg/kg subcutaneously) of mifepristone at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Treated rats had decreased preovulatory LH and prolactin (PRL) surges and hypersecretion of LH, PRL, and progesterone as estrus. A profound decrease in the lordosis response on the night of proestrus indicated a dramatic effect on sexual receptivity. There was no affect on the number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus. The few rats who succeeded in mating with potent males became pregnant, but they delivered an average of only two pups, indicating a failure in the implantation of the fertilized ova. These findings suggest that the dramatic inhibition of sexual receptivity and unsuccessful implantation, preceded by a reduction in LH and PRL secretion, are the major factors producing fertility impairment after a single dose of mifepristone before the preovulatory LH surge. factors such as smoking and parity.