Management of pain associated with up-to-9-weeks medical termination of pregnancy (MToP) using mifepristone-misoprostol regimens: expert consensus based on a systematic literature review.

Evidence-based guidelines on the management of pain associated with first-trimester medical abortion are lacking. Most published clinical trials have failed to report on this important aspect of the procedure. The aim of this comprehensive work was to provide clinical advice based on a comprehensive literature review, supplemented by the clinical experience of a group of European experts in case no evidence is available. Pain level ranged from 5 to 8 in 80% of studies where pain was measured on a 0-10 visual analogue scale; severe pain was reported by 20-80% of women. Pain assessment was rarely reported in studies. Pain treatment should be preventive and avoidance of unnecessary uterine contractions should be considered. Analgesic treatment should follow the WHO three-step ladder, starting with the use of NSAIDs and allowing for easily available back-up treatment with weak opioids.

Dosing interval between mifepristone and misoprostol in second and third trimester termination.

OBJECTIVE: To compare several strategies for second trimester labor induction for termination of pregnancy (TOP) using misoprostol and mifepristone and to determine which one is more effective in accelerating the time to delivery. METHOD: This was a retrospective study in which pregnancies that underwent second and third trimester TOP due to fetal anomalies between 2007 and 2017 were classified into a group that received misoprostol alone, a group that received mifepristone followed by misoprostol on the same day, one where misoprostol was given 1 day after mifepristone and one where the medications were administered 2 days apart. The primary outcome measure was the induction to delivery interval. RESULTS: 481 pregnancies fulfilled the inclusion criteria. In 140 cases, mifepristone was not administered. 341 women received mifepristone prior to induction, which was administered on the day of induction in 85 cases, and 1 or 2 days prior to induction in 140 and 19 cases. Median time interval between first induction and delivery was 15.0 (IQR 10.0-24.1) h in case no mifepristone was given and 13.2 (9.7-18.2) h if mifepristone was given on the same day and 9.3 (6.6-14.9) and 10.5 (7.2-22.3) h, if mifepristone was given 1 or 2 days prior to induction. After 24 h, the proportion of terminated pregnancies in each of the four groups was 75.0, 83.5, 93.2 and 78.9%. CONCLUSION: A 1 day interval between mifepristone and misoprostol is more effective in second and third trimester TOP compared to other strategies in terms of reducing the induction to abortion interval.

Progesterone Decreases in vitro Indoleamine 2, 3-dioxygenase Expression in Dendritic and CD4+ Cells from Maternal-Fetal Interface of Rats.

PROBLEM: Several mechanisms contribute to the tolerogenic state observed during pregnancy, such as the activity of the enzyme indoleamine 2, 3-dioxygenase (IDO). This initializes the catabolism of tryptophan, inducing T cells to apoptosis due to its deprivation and by the action of its catabolites in the placental microenvironment. Progesterone plays an important part on immunological tolerance mechanisms during pregnancy; however, there is no evidence it is related to IDO activity. Thus, this study aimed to investigate progesterone influence on the maternal-fetal interface of pregnant Wistar rats, by identifying IDO positive cells by immunophenotyping and flow cytometry under exogenous progesterone supplementation. METHOD OF STUDY: Placenta and embryo cells were cultured and separated into groups that received interferon γ or progesterone, supplemented or not with mifepristone. After 2 and 24 h, these were labeled with an anti-IDO and a series of antibodies specific to leucocytes and progesterone receptor and processed through flow cytometry analysis. RESULTS: Progesterone induced a significant decrease in the expression of IDO in dendritic cells and CD4+ lymphocytes. CONCLUSION: The blocking of progesterone receptor on these cells by mifepristone restored IDO expression levels and may constitute evidence of the participation of this hormone through a direct route in these cells.

Roles of Mifepristone on the Regulation of Cytotoxic Lymphocytes and Regulatory T Cells.

OBJECTIVE: To investigate the immunologic function of mifepristone, which acts as a contraceptive drug at the level of the decidua. SETTING: In our hospital, 60 women (less than 63 days of amenorrhea) volunteered to terminate their pregnancies by the uterine suction evacuation method. Immunohistochemically, the transcription factor forkhead box P3 and granzyme B staining were performed to identify regulatory T cells and cytotoxic lymphocytes (CLs) in all operational subjects. CD8 (cytotoxic T cells marker) and CD56 (natural killer cells marker) staining were further performed in order to characterize the CLs subpopulations. RESULT: A significantly increased number of CLs was found in the decidua treated with mifepristone. CONCLUSION: Mifepristone increases the expression of CLs in the decidua, and it provides new insights into the immunologic function of mifepristone as a drug used for pregnancy termination.

Management of Medical Termination of Pregnancy (MToP) up until the 7th week of gestation in the Czech Republic.

OBJECTIVE: In the Czech Republic (CR), it is possible, to carry out Medical Termination of Pregnancy (MToP) in the 1st trimester since June 2014, in case a woman submits a written request for it and in case the ultrasound examination confirms an intrauterine singleton prosperous pregnancy, between day 42 and 49 of gestation, crown-rump length (CRL) of the embryo 2-9 mm. The aim of the study is to analyze the management of MToP up until the 7th week of gestation in five centres in the CR. DESIGN: Multicenter cohort (prospective) study. SETTING: Department of Obstetrics and Gynecology, Palacky University Olomouc, Faculty of Medicine and Dentistry, University Hospital Olomouc; The Institute for the Care of Mother and Child, Charles University in Prague, Third faculty of Medicine; Department of Gynecology and Obstetrics, Charles University in Prague, First faculty of Medicine, General University Hospital in Prague; Department of Gynecology and Obstetrics, Charles University in Prague, First faculty of Medicine, Hospital Na Bulovce, Prague; Department of Gynecology and Obstetrics, Masaryk University, Faculty of Medicine, University Hospital Brno. METHODS: In 2014-2016, a total of 1820 pregnant women requested MToP. The diagnosis of an intrauterine singleton prosperous pregnancy was set by transvaginal ultrasound, CRL 2-9 mm. MToP was carried out by combination of mifepristone (600 mg orally) and misoprostol (400 mcg orally) within 48 hours. MToP follow up (exclusion of ongoing pregnancy) after 2-3 weeks was carried out by transvaginal ultrasound as well. RESULTS: In 11.0% of women (201/1820) who requested MToP, CRL > 9 mm, unprosperous, multiple or ectopic pregnancy was diagnosed. In the remaining 1619 women MToP was carried out, but in 221 cases (13.7%) at least one additional pre-first visit was needed before the diagnosis of intrauterine singleton prosperous pregnancy CRL 2-9 mm could be established, in 19 cases (1.2%) two pre-first visits and in 5 cases (0.3%) even three. Gestational age was 42-49 days (average 47.1, median 47), the women were 14-47 years of age (average 30.7, median 30). In 20.8% of women (336/1619) MToP follow up was missed and of the remaining 1283 women, ongoing pregnancy (MToP failure) was diagnosed in 1.6% (24/1283), incomplete abortion in 6.5% (83/1283) and complete abortion in 91.9% (1179/1283). A subsequent surgical intervention was carried out in 7.1 % of women (91/1283). CONCLUSION: A medical facility performing MToP in the 1st trimester should develop its own methodology in accordance with the legislation in force, Summaries of Product Characteristics, and recommendations of professional associations. The methodology should also include a method of evaluation of the result and management. The subsequent surgical intervention should only be performed in indicated cases. The main goal of MToP follow up is to exclude ongoing pregnancy (MToP failure), and the patient should be informed in detail about the risks involved and possibilities of their solution, it is necessary to obtain an informed consent.

Abscess formation in ovarian endometriomas after failure of mifepristone-induced abortion.

OBJECTIVE: To report a case of abscess formation in bilateral ovarian endometriomas after failure of mifepristone-induced abortion. CASE REPORT: A-36-year-old multiparous woman with bilateral ovarian endometriomas conceived spontaneously and received mifepristone to induce an abortion at 35 days' gestation. Fever and lower abdominal pain occurred 28 days after the abortion. The patient then underwent surgical curettage for an incomplete abortion complicated by endometritis. Her symptoms and signs became aggravated, and computed tomography showed a large ovarian abscess. She underwent laparoscopic drainage of the abscess plus the enucleation of the ovarian endometriomas, and received intravenous antibiotic treatment. She resumed menstruation one month later and was doing well at the 11-month follow-up. CONCLUSION: This case demonstrates the importance of combining antibiotic therapy with mifepristone to induce abortions in women with known ovarian endometriomas.

Safety, efficacy and acceptability of outpatient mifepristone-misoprostol medical abortion through 70 days since last menstrual period in public sector facilities in Mexico City.

Extensive evidence exists regarding the efficacy and acceptability of medical abortion through 63 days since last menstrual period (LMP). In Mexico City's Secretariat of Health (SSDF) outpatient facilities, mifepristone-misoprostol medical abortion is the first-line approach for abortion care in this pregnancy range. Recent research demonstrates continued high rates of complete abortion through 70 days LMP. To expand access to legal abortion services in Mexico City (where abortion is legal through 12 weeks LMP), this study sought to assess the efficacy and acceptability of the standard outpatient approach through 70 days in two SSDF points of service. One thousand and one women seeking pregnancy termination were enrolled and given 200 mg mifepristone followed by 800 µg misoprostol 24-48 hours later. Women were asked to return to the clinic one week later for evaluation. The great majority of women (93.3%; 95% CI: 91.6-94.8) had complete abortions. Women with pregnancies ≤ 8 weeks LMP had significantly higher success rates than women in the 9th or 10th weeks (94.9% vs. 90.5%; p = 0.01). The difference in success rates between the 9th and 10th weeks was not significant (90.0% vs. 91.2%; p = 0.71). The majority of women found the side effects (82.9%) and the use of misoprostol (84.4%) to be very acceptable or acceptable. This study provides additional evidence supporting an extended outpatient medical abortion regimen through 10 weeks LMP.

Assessment of effects of mifepristone administration to lactating mice on the development and fertility of their progeny.

AIM: Mifepristone, a synthetic steroid compound that induces abortion, was recently found to potentially pass into human milk. This study aimed to determine the effects of mifepristone administration to lactating mice on the development and reproduction of their progeny. METHODS: Lactating mice were gavage fed with mifepristone (8 mg/kg) daily for 4 days either from days 1-4 or from days 7-10 of lactation; controls received only peanut oil. Growth, mortality rate, organ weight to bodyweight ratio, sex hormone at 20, 40 and 60 days, fertility of these F1 progeny and litter size, sex ratio and mortality rate of the second generation were recorded. RESULTS: No significant differences were observed in the average bodyweight, mortality rate of the female or male pups, and organ coefficient of uterus and ovaries of females in adulthood in comparison with the controls. However, the organ coefficient of testis at day 20 and 40 and testosterone concentration at day 60 were increased in male pups. Moreover, the reproductive capacity of the F1 pups was unaffected by 4 days exposure to mifepristone via their mother's milk: time to birth of F2 pups, litter size, sex ratio and mortality rate were similar to control F1 pups. CONCLUSION: The study showed that treating lactating mice with 8 mg/kg mifepristone influenced only the organ coefficient of testis at day 40 and the testosterone concentration in male pups at day 60, however, it did not affect the development and fertility of female and male pups.

Effects of steroid ablation and progestin replacement on the transcriptome of the primate corpus luteum during simulated early pregnancy.

Previous microarray analyses indicated that a portion of the transcriptome in the macaque corpus luteum (CL) of the menstrual cycle was regulated indirectly by luteinizing hormone via the local actions of steroid hormones, notably progesterone (P). The current study was designed to investigate this concept in the CL of early pregnancy by analyzing chorionic gonadotrophin (CG)-regulated genes that are dependent versus independent of local steroid action. Exogenous human chorionic gonadotropin treatment simulating early pregnancy (SEP) began on Day 9 of the luteal phase in female rhesus monkeys with and without concurrent administration of the 3-ß-hydroxysteroid dehydrogenase inhibitor trilostane (TRL) with or without the synthetic progestin R5020. Compared with SEP treatment alone, TRL altered 50 mRNA transcripts on Day 10, rising to 95 on Day 15 (P<0.05, ≥2-fold change in gene expression). Steroid-sensitive genes were validated; notably effects of steroid ablation and P replacement varied by day. Expression of some genes previously identified as P-regulated in the macaque CL during the menstrual cycle were not significantly altered by steroid ablation and P replacement during CG exposure in SEP. These data indicate that the majority of CG-regulated luteal transcripts are differentially expressed independently of local steroid actions. However, the steroid-regulated genes in the macaque CL may be essential during early pregnancy, based on previous reports that TRL treatment initiates premature structural regression of the CL during SEP. These data reinforce the concept that the structure, function and regulation of the rescued CL in early pregnancy differs from the CL of the menstrual cycle in primates.

Interplacental uterine expression of genes involved in prostaglandin synthesis during canine pregnancy and at induced prepartum luteolysis/abortion.

BACKGROUND: In the non-pregnant dog, ovarian cyclicity is independent of a uterine luteolysin. This is in contrast to pregnant animals where a prepartum increase of luteolytic PGF2α occurs, apparently originating in the pregnant uterus. Recently, the placenta as a source of prepartum prostaglandins (PGs) was investigated, indicating fetal trophoblast cells as the likely main source. However, the possible contribution of uterine interplacental tissues to the production of these hormones has not yet been thoroughly examined in the dog. METHODS: Several key factors involved in the production and/or actions of PGs were studied: cyclooxygenase 2 (COX2, PTGS2), PGF2α-synthase (PGFS/AKR1C3), PGE2-synthase (PGES), and the respective receptors FP (PTGFR), EP2 (PTGER2) and EP4 (PGTER4), 15-hydroxyprostaglandin dehydrogenase (HPGD), PG-transporter (PGT, SLCO2A1) and progesterone receptor. Their expression and localization patterns were assessed by Real Time PCR and immunohistology in the interplacental uterine sites from pregnant dogs during the pre-implantation period (days 8-12), post-implantation (days 18-25), mid-gestation (days 35-40) and during antigestagen-induced luteolysis/abortion. RESULTS: Whereas only low COX2 expression was observed in uterine samples at all the selected time points, expression of PGFS/AKR1C3 strongly increased post-implantation. A gradual increase in PGES-mRNA expression was noted towards mid-gestation. FP-mRNA expression decreased significantly with the progression of pregnancy until mid-gestation. This was associated with clearly detectable expression of HPGD, which did not change significantly over time. The expression of FP and EP2-mRNA decreased significantly over time while EP4-mRNA expression remained unaffected. The antigestagen-treatment led to a significant increase in expression of COX2, PGES, EP2 and PGT (SLCO2A1) mRNA. COX2 was localized predominantly in the myometrium. The expression of PGFS/AKR1C3, which was unchanged, was localized mostly to the surface luminal epithelium. The expression of EP4, PGT and HPGH did not change during treatment, they were co-localized with PGES and EP2 in all uterine compartments. CONCLUSIONS: The data clearly demonstrate the basic capability of the canine pregnant uterus to produce and respond to PGs and suggests their functions both as local regulatory factors involved in the establishment and maintenance of pregnancy, as well as potential contributors to the process of parturition, supporting the myometrial contractility associated with fetal expulsion.

Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

Modulation of free corticotrophin-releasing hormone, adrenal and placental steroid hormone levels induced by mifepristone during pregnancy.

UNLABELLED: Mifepristone is a progesterone receptor antagonist widely used in obstetrics. The aim of the study was to focus on free corticotrophin-releasing hormone (CRH) and also describe modulation of adrenal and placental steroid hormone concentrations induced by mifepristone. METHODS: Twenty-six women were enrolled in the study. They received mifepristone for termination of pregnancy. Maternal blood samples were retrieved before administration of mifepristone (600 mg) and 48 h after, just before induction of labor. Bound and free CRH levels were determined in maternal blood concomitantly with cortisol, estriol, progesterone and SDHEA levels. Also paired fetal cord blood samples were collected. RESULTS: Maternal plasmatic CRH level did not change after mifepristone absorption but free CRH increased significantly (0.500 ± 0.326 vs. 0.388 ± 0.303 ng/ml, p = 0.040). A significant decrease of progesterone was observed (83.6 ± 49.3 vs. 95.6 ± 54.9 ng/ml, p = 0.001) with a lower progesterone/estriol ratio (26.9 ± 15.7 vs. 40.7 ± 31.1, p = 0.004). There was a strong association between maternal and fetal free CRH (r² = 0.675, p = 0.001), cortisol (r² = 0.570, p = 0.019), and positive but modest correlation for progesterone (r² = 0.341, p = 0.046) and estriol (r² = 0.379, p = 0.025) levels. CONCLUSION: Mifepristone has an effect on free CRH level and changes the estriol-progesterone balance.

Betamethasone, progesterone and RU-486 (mifepristone) exert similar effects on connexin expression in trophoblast-derived HTR-8/SVneo cells.

Connexins (Cx) are membrane proteins able to influence cell trophoblast responses, such as proliferation, differentiation, migration and invasiveness. Likewise, glucocorticoids are also known to modulate many factors involved in implantation, including trophoblast gap-junction intercellular communication, although their influence on pregnancy is controversial. In order to investigate the effects of betamethasone, a synthetic glucocorticoid, on Cx and glucocorticoid receptor (GR) expression and localisation, as well as on cell proliferation, the extravillous trophoblast-derived HTR-8/SVneo cell line was used as a model. The results, confirmed by means of immunofluorescence, demonstrate that betamethasone selectively modifies GR and Cx expression, enhancing the GRα isoform without affecting GRß, and inhibiting Cx40 expression whilst increasing that of Cx43 and Cx45. Furthermore, betamethasone was shown to exert an inhibitory action on cell proliferation. In this model the abortion drug RU-486 (mifepristone), reported to be a GR antagonist, did not counteract this effect of betamethasone. On the contrary, it induced responses similar to those of the hormone. Knowing that RU-486 is also a potent progesterone-receptor antagonist, the effect of progesterone alone and in combination with the drug on Cx expression and cell proliferation was then tested. Progesterone showed the same effect as betamethasone on Cx expression, but it did not affect proliferation. Based on these results, neither the abortion effects of RU-486 nor the protective action of betamethasone and progesterone are exerted by modulation of Cx. RU-486 did not antagonise the progesterone effect, suggesting that its abortive action does not involve alteration of trophoblast Cx expression.

Mifepristone regulates macrophage-mediated natural killer cells function in decidua.

Mifepristone has been used for first-trimester abortion and contraception. Nevertheless, its functional mechanism still needs to be elucidated. Decidua tissues were collected from 40 pregnant women who received (20 patients) or did not receive (20 patients) mifepristone. Immunofluorescence was used to analyze the effect of mifepristone on the quantity of CD56 and CD206 in decidua. in vitro assay, NK cells were isolated from decidua tissue and macrophages were induced from THP-1 cells. NK cells were co-cultured with macrophages pre-treated different concentrations of mifepristone (0 nmol/L, 200 nmol/L, 1800 nmol/L, and 25000 nmol/L); the cells' cytotoxicity and migration ability were analyzed using MTT assay and transwell assay, respectively. Si-TGF-ß1, which was utilized to knock down the TGF-ß1 expression in macrophages and human recombinant TGF-ß1 were used to verify whether TGF-ß1 was involved in the mifepristone regulation of NK cells function. The quantity of CD56 and CD206 decreased after mifepristone treatment. Moreover, the NK cells' cytotoxicity and migration ability were significantly increased by macrophages pre-treated with mifepristone in a dose-dependent manner. Moreover, compared with the si-NC group, the MTT absorbance rate of NK cells was significantly increased in the si-TGF-ß1 group and was decreased in the human recombinant TGF-ß1 group. Our data suggest that mifepristone, which regulates NK cells function through macrophages, was associated with the changes in TGF-ß1 secreted by macrophages. This may be one of the mechanisms of mifepristone acting as contraceptive and abortion drugs at the maternal-fetal interface.

Expression and regulation of tumor necrosis factor (TNF) and TNF-receptor family members in the macaque corpus luteum during the menstrual cycle.

Members of the tumor necrosis factor (TNF)-receptor (R) family may be involved in the tissue remodeling that occurs in the primate corpus luteum (CL) during development and regression. As a first step towards addressing this issue, studies assessed TNF ligand-R expression and regulation in CL collected from monkeys during the early (ECL, Days 3-5), mid (MCL, Days 7-8), mid-late (MLCL, Days 10-11), late (LCL, Days 14-16), and very late (VLCL, menses) luteal phase of the menstrual cycle. CL were also collected after gonadotropin and/or steroid ablation and replacement (with hLH and the progestin R5020) for 3 days at mid-late luteal phase. TNF-alpha, -beta, FAS ligand (FASL), and TNF-R1 mRNA levels were two- to sixfold greater (P < 0.05) at the MLCL or LCL phase as compared to earlier (ECL, MCL). In contrast, TNF-R2 and FAS mRNA levels did not change during the luteal phase. Immunohistochemical staining for TNF-beta, TNF-R1, TNF-R2, FAS, and FASL was observed in luteal cells, whereas only TNF-beta staining was observed in endothelial cells. Several TNF-R components were influenced by LH and/or steroid ablation; notably, steroid ablation reduced (P < 0.05) luteal TNF-alpha, but not TNF-beta, mRNA levels, which was prevented by progestin treatment. In contrast, steroid ablation increased (P < 0.05) luteal cell immunostaining for FAS and FASL, which was reduced by progestin treatment. Thus, several members of the TNF R-ligand family are expressed in the primate CL in an LH- and/or progestin-dependent manner. Peak expression in the late luteal phase may signify a role for the TNF-R system in death receptor-mediated apoptosis during luteolysis.

Frequency and risk factors for repeat abortions after surgical compared with medical termination of pregnancy.

OBJECTIVE: To compare the frequency and risk factors for repeat abortions after surgical compared with medical termination of pregnancy. METHODS: Frequency of and risk factors for repeat abortions after medical (performed with mifepristone alone, or with a combination of mifepristone and misoprostol or other prostaglandins) compared with surgical (dilation and curettage, or vacuum aspiration) termination of pregnancy were studied using Finnish national health registries. The cohort consisted of 40,360 women undergoing termination of pregnancy between 2000 and 2005 (19,841 medical and 20,519 surgical abortions) with duration of gestation of 63 days or less. Univariable and multivariable association models were used in connection with various factors associated with repeat abortion. The mean (+/-standard deviation) follow-up times were 3.0 (+/-1.5) and 4.3 (+/-1.9) years, respectively. RESULTS: Women choosing surgical and medical abortion differed subtly, but significantly in several respects. The total number of repeat terminations was 37.9 per follow-up year per 1,000 after surgical termination of pregnancy and 40.4 after medical termination of pregnancy (P=.01). However, medical termination of pregnancy was not linked to an increased risk of another abortion when compared with surgical methods (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.93-1.04). In multivariable analysis, the risk factors for repeat abortion were parity (HR 1.99, 95% CI 1.85-2.14), previous abortion(s) (HR 1.70, 95% CI 1.60-1.82), low socioeconomic status (HR 1.22, 95% CI 1.06-1.39), and being unmarried but cohabiting (HR 1.14, 95% CI 1.03-1.25) or single (HR 1.25, 95% CI 1.15-1.36). The risk of repeat termination of pregnancy decreased with age, among women living in rural areas, and when intrauterine devices or sterilization were planned for future contraception. CONCLUSION: The risk of repeat abortion is associated with various sociodemographic characteristics. The method of abortion used is not a risk factor for repeat termination of pregnancy. LEVEL OF EVIDENCE: II.

Contragestion and other clinical applications of RU 486, an antiprogesterone at the receptor.

RU 486, a steroid with high affinity for the progesterone receptor, is the first available active antiprogesterone. It has been used successfully as a medical alternative for early pregnancy interruption, and it also has other potential applications in medicine and for biochemical and pathophysiological endocrine research.

Uterine activity after oral mifepristone administration in human pregnancies beyond 41 weeks' gestation.

BACKGROUND/AIM: To examine the effect of oral mifepristone on uterine activity in postterm human pregnancies. METHODS: As part of a randomized, placebo-controlled trial comparing 200 mg oral mifepristone to placebo for preinduction cervical ripening in women with well-dated pregnancies beyond 41 weeks' gestation with unfavorable cervices, uterine activity was continuously recorded with external tocodynamometry and contraction frequency tabulated. RESULTS: Ninety-seven women received mifepristone and 83 women received placebo. Uterine activity (uterine contractions/hour) was greater in the mifepristone than in the placebo group between 7 h (8.03 +/- 0.48 vs. 5.90 +/- 0.39, p = 0.001) and 24 h (8.53 +/- 0.68 vs. 6.61 +/- 0.46, p = 0.02) after dosing. CONCLUSION: Oral mifepristone administration to women with pregnancies beyond 41 weeks increases uterine activity in the absence of externally administered uterotonic agents.

Prostaglandin-Endoperoxide Synthase 1 Mediates the Timing of Parturition in Mice Despite Unhindered Uterine Contractility.

Cyclooxygenase (COX)-derived prostaglandins stimulate uterine contractions and prepare the cervix for parturition. Prior reports suggest Cox-1 knockout (KO) mice exhibit delayed parturition due to impaired luteolysis, yet the mechanism for late-onset delivery remains unclear. Here, we examined key factors for normal onset of parturition to determine whether any could account for the delayed parturition phenotype. Pregnant Cox-1KO mice did not display altered timing of embryo implantation or postimplantation growth. Although messenger RNAs of contraction-associated proteins (CAPs) were differentially expressed between Cox-1KO and wild-type (WT) myometrium, there were no differences in CAP agonist-induced intracellular calcium release, spontaneous or oxytocin (OT)-induced ex vivo uterine contractility, or in vivo uterine contractile pressure. Delayed parturition in Cox-1KO mice persisted despite exogenous OT treatment. Progesterone (P4) withdrawal, by ovariectomy or administration of the P4-antagonist RU486, diminished the delayed parturition phenotype of Cox-1KO mice. Because antepartum P4 levels do not decline in Cox-1KO females, P4-treated WT mice were examined for the effect of this hormone on in vivo uterine contractility and ex vivo cervical dilation. P4-treated WT mice had delayed parturition but normal uterine contractility. Cervical distensibility was decreased in Cox-1KO mice on the day of expected delivery and reduced in WT mice with long-term P4 treatment. Collectively, these findings show that delayed parturition in Cox-1KO mice is the result of impaired luteolysis and cervical dilation, despite the presence of strong uterine contractions.

Mifepristone in second-trimester medical abortion: a randomized controlled trial.

OBJECTIVE: To investigate the adjunctive use of mifepristone in second-trimester induction abortions using misoprostol 1 day after feticidal digoxin. METHODS: This is a randomized, placebo-controlled, double-blind trial of mifepristone in second-trimester induction termination using misoprostol after feticidal digoxin. Women seeking abortion between 18 and 23 weeks of gestation were offered enrollment. At the time of digoxin amnioinfusion, participants received a randomly allocated, identical-appearing capsule containing either mifepristone, 200 mg, or placebo. Patients returned the following day for induction with buccal misoprostol. The primary outcome was the time interval from the first misoprostol dose to abortion. Analysis utilized survival curves with log-rank testing. RESULTS: Of 64 women, 32 received mifepristone and 32 received placebo. The groups did not differ by ethnicity, age, parity, reason for termination, or gestational age. Median procedure time was significantly shorter for those who received mifepristone, 10 hours (95% confidence interval [CI] 8-12), than those who did not, 18 hours (95% CI 15-22), P<.01, and those parous, 10 hours (95% CI 9-14), compared with nulliparous, 16 hours (95% CI 12-22, P=.02). Other findings in the mifepristone compared with placebo group included rates of placental retention, 3.1% compared with 6.3% (P=.61), length of hospitalization, 0.66 days compared with 0.8 days (P=.23), and analgesic requirements, 27.2 mg compared with 39.3 mg morphine (P=.22). Side effects during induction were similar between groups. CONCLUSION: Addition of mifepristone in second-trimester termination inductions using misoprostol significantly reduces the abortion time interval. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00382538 LEVEL OF EVIDENCE: I.