The efficacy, safety and acceptability of medical termination of pregnancy provided by standard care by doctors or by nurse-midwives: a randomised controlled equivalence trial.

OBJECTIVE: To assess nurse-midwife provision of early medical termination of pregnancy (TOP) in a high-resource setting where ultrasound examination for dating of pregnancy is part of the protocol. DESIGN: Randomised controlled equivalence trial. SETTING: Out-patient family planning unit at a university hospital. POPULATION: Women seeking early medical TOP. METHODS: A total of 1180 women were randomised, without any prior examination, to counselling, examination, and treatment by either nurse-midwife or gynaecologist. Ultrasound was performed in all cases by the allocated provider. MAIN OUTCOME MEASURES: The primary outcome was efficacy, defined as the successful completion of TOP without need for vacuum aspiration. Secondary outcomes were safety, defined as need for hospitalisation or blood transfusion, and acceptability, defined as preferred provider were the women to have a medical TOP in the future. RESULTS: A total of 481 women in the nurse-midwife group and 457 women in the doctor group were available for the final analysis. The effectiveness of provision of medical TOP by nurse-midwife providers was superior to that provided by doctors (risk difference 1.6%, 95% confidence interval 0.2-3.0%, which was within the set margin of equivalence). There were no significant differences in safety parameters. Women examined and counselled by a nurse-midwife were significantly more likely (P < 0.001, 95% confidence interval 0.308-0.394) to prefer seeing a nurse-midwife for the consultation were they to have another medical TOP in the future. CONCLUSIONS: These findings show that nurse-midwife provision of early medical TOP in a high-resource setting, where ultrasound is part of the protocol, is effective, and can be safely implemented with high acceptability among women.

Effects of oral and vaginal administration of levonorgestrel emergency contraception on markers of endometrial receptivity.

BACKGROUND: The standard regimen of the levonorgestrel-only pill (1.5 mg either in a single dose or in a dose of 0.75 mg twice, 12 h apart) administered orally for emergency contraception (EC) has been shown to have no effect on endometrial development and markers of endometrial receptivity. We aimed to explore whether repeated oral and single vaginal administration of levonorgestrel affect the endometrium and thus potentially increase the EC efficacy, compared with the standard regimen. METHODS: Endometrial biopsies were taken from non-smoking, healthy women with proven fertility on cycle days LH + 6 to LH + 8 in control and levonorgestrel treatment cycles (each woman serving as her own control). Levonorgestrel was administered either orally (0.75 mg x 4, at 24 h intervals on LH + 1 to LH + 4; n = 8) or vaginally (a single dose of 1.5 mg on LH + 2; n = 7). Immunohistochemistry and real-time RT-PCR was performed to compare the levels of protein and mRNA for sex steroid receptors, interleukin-1beta, leukaemia inhibitory factor (LIF), vascular endothelial growth factor, cyclooxygenase-2, tumour necrosis factor-alpha, integrin alpha(v)beta(3) and mucin 1 in endometrial cells. RESULTS: Following the repeated oral treatment, the immunoreactivity of both progesterone receptor (PR)-A and PR-B declined in glandular epithelium (P = 0.03 and P = 0.02, respectively), whereas stromal immunoreactivity and mRNA expression of LIF increased compared with control (P < 0.001 and P = 0.03, respectively). However, vaginal levonorgestrel did not cause any significant endometrial changes. CONCLUSIONS: The two regimens of levonorgestrel caused either only minor or no alterations in markers of endometrial receptivity. New agents targeting the endometrial development should be explored in order to increase EC efficacy.

Two mifepristone doses and two intervals of misoprostol administration for termination of early pregnancy: a randomised factorial controlled equivalence trial.

OBJECTIVE: 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. DESIGN: Placebo-controlled, randomized, equivalence trial, stratified by centre. SETTING: 13 departments of obstetrics and gynecology in nine countries. POPULATION: 2,181 women with 63 days or less gestation requesting medical abortion. METHODS: 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. OUTCOME MEASURES: Rates of complete abortion without surgical intervention and adverse effects associated with the regimens. RESULTS: 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. CONCLUSIONS: 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.

A randomised controlled trial of intravaginal dinoprostone, intravaginal misoprostol and transcervical balloon catheter for labour induction.

OBJECTIVE: To compare the efficacy and safety of induction of labour by vaginal application of dinoprostone or misoprostol or transcervical insertion of a balloon (Bard) catheter. DESIGN: A non-blinded, randomised, controlled trial. SETTING: A tertiary level Swedish hospital. POPULATION: A total of 592 women who had undergone full-term pregnancies, not previously been subjected to a caesarean section, and required induction of labour for common, routine indications. METHODS: Women were randomly assigned to induction of labour using intravaginal dinoprostone (2 mg once every 6 hours) or misoprostol (25 micrograms once every 4 hours) or a transcervical balloon catheter. MAIN OUTCOME MEASURES: The time interval between induction to delivery in general and vaginal delivery in particular, the mode of delivery, maternal and neonatal parameters of outcome. RESULTS: Of the 588 subjects included in the final intention-to-treat analysis, 191 were assigned to treatment with dinoprostone, 199 with misoprostol and 198 with the balloon catheter. The shortest mean induction-to-delivery interval was obtained with the catheter (12.9 hours versus 16.8 and 17.3 hours for dinoprostone and misoprostol, respectively). The efficacies of the two prostaglandins were similar. The maternal and neonatal outcomes associated with each of the three procedures were similar. CONCLUSIONS: Induction of labour with a transcervical balloon catheter is effective and safe and can be recommended as the first choice. The two prostaglandins, dinoprostone and misoprostol, were shown to be equally effective and safe, while misoprostol costs significantly less and is easier to store.

Quality of family planning services at primary care facilities in an urban area of East Azerbaijan, Iran.

OBJECTIVE: To determine the quality of family planning (FP) services at primary care facilities in Tabriz, Iran, and to identify areas for improvement. METHODS: Structured observations of 469 client-provider interactions and some clinical procedures at 34 facilities. Exit interviews with 416 of the observed clients. RESULTS: The providers treated the clients respectfully in more than 80% of the consultations and discussed a return visit in 89%. Privacy was not assured in one-third of the cases. Over two-thirds of the clients were not encouraged to ask questions or raise concerns, and 54% were not satisfied with the amount of information given. The use of educational audio-visual and printed materials was very infrequent. Reported waiting time was less than 30 minutes in 89%. Most new clients received their preferred contraceptive method, but were informed about neither other available methods, nor common side effects and warning symptoms due to the chosen method. Provider performance in some clinical procedures, such as the implementation of hand hygiene, was insufficient. CONCLUSIONS: All elements of the FP services need improvement. Special attention should be paid to interactive communication, information given to clients, privacy and confidentiality, as well as to infection prevention procedures. Multifaceted interventions seem necessary to improve the quality.

Cervical priming with sublingual misoprostol prior to insertion of an intrauterine device in nulliparous women: a randomized controlled trial.

BACKGROUND: The copper intrauterine device (IUD) is a highly effective and safe contraceptive method, also in nulliparous women. However, insertion of an IUD through a narrow cervix may be technically difficult. Misoprostol has been shown to be effective for cervical priming in non-pregnant women prior to hysteroscopy. METHODS: Eighty nulliparous women requesting an IUD were randomly allocated to receive sublingually 400 microg misoprostol and 100 mg diclofenac (misoprostol group) or 100 mg diclofenac alone (control group) 1 h prior to IUD insertion. Cervical dilatation was measured prior to insertion using Hegar pins. Ease of insertion was judged by the investigator. Pain, bleeding and side effects were recorded at insertion and until follow-up performed one month later. RESULTS: Following treatment with misoprostol, insertion was significantly easier than in the control group [P = 0.039, difference 19.36%, confidence interval (CI) -0.013, 39.99]. Pain estimated on a visual analogue scale (1-10) showed no evidence of a difference between the groups. The overall distribution of side effects did not differ. However, shivering was more common in the misoprostol group (P = 0.0084, difference 23.27%, CI 6.64, 39.90). CONCLUSIONS: Misoprostol facilitates insertion of an IUD, and reduces the number of difficult and failed attempts of insertions in women with a narrow cervical canal. The optimal regimen of misoprostol remains to be defined.

Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception.

An emergency contraceptive method is used after coitus but before pregnancy occurs. The use of emergency contraception is largely under-utilized worldwide. One of the main barriers to widespread use is concern about the mechanism of action. Recently, treatment with either 10 mg mifepristone or 1.5 mg of levonorgestrel has emerged as the most effective hormonal method for emergency contraception with very low side-effects. However, the knowledge of the mechanism of action of mifepristone and levonorgestrel in humans, when used for contraceptive purposes and especially for emergency contraception, remains incomplete. The objective of this review is to summarize available data on the effects of mifepristone and levonorgestrel on female reproductive functions relevant to the emergency use of the compounds. When summarized, available data from studies in humans indicate that the contraceptive effects of both levonorgestrel and mifepristone, when used in single low doses for emergency contraception, involve either blockade or delay of ovulation, due to either prevention or delay of the LH surge, rather than to inhibition of implantation.

Pregnancy termination.

During pregnancy, the antiprogestin mifepristone will induce uterine contractions, increase the sensitivity of the myometrium to prostaglandin, and ripen the cervix. These effects indicate that mifepristone can be used for termination of pregnancy. The clinical experience has shown that mifepristone is sufficiently effective for this purpose only if combined with a suitable prostaglandin, e.g. gemeprost or misoprostol. The combined treatment has been used for termination of early pregnancy (up to 63 days of amenorrhea) and for termination of second trimester pregnancy. During early pregnancy, the recommended dose of mifepristone is 600 mg (although 200 mg seems sufficient), followed 36-48 h later by 0.4-0.8 mg misoprostol administered either orally or vaginally, or vaginal administration of 1.0 mg gemeprost. For termination of second trimester pregnancy, the treatment with mifepristone is most commonly combined with 1.0 mg gemeprost repeated at 3-6-h intervals. The combined treatment is as effective and safe during early pregnancy as is the alternative vacuum aspiration and is also equally acceptable if the woman is allowed to choose the method she prefers. During the second trimester, the pretreatment will significantly reduce the duration of labor, dose of prostaglandin, and the frequency of side effects.

Medical termination of early pregnancy: the Swedish experience.

Abortion has been legal up to the 22nd week of gestation in Sweden since 1975. Most women terminate their pregnancies early; 96% before the 12th week and 75% in less than 63 days. Termination of early pregnancy (up to 63 days' gestation) using mifepristone followed by gemeprost was approved in Sweden in 1992. Use of the medical method has slowly but steadily increased since then. Currently about 40% of the women eligible for the procedure choose it. Both the surgical (vacuum aspiration) and the medical methods are regarded as effective and safe. The medical method will not replace vacuum aspiration, but be an alternative to it.

Contraceptive efficacy of daily administration of 0.5 mg mifepristone.

The antiprogestin mifepristone has shown potential to be used as a contraceptive. If 200 mg mifepristone is administered immediately after ovulation, the endometrium shows sufficient impairment of secretory development to prevent implantation. Low daily doses of mifepristone have been shown to reduce several of the local factors regarded as crucial for implantation in human endometrium. To find out if this regimen is sufficient to prevent pregnancy, 32 women were recruited for a study where 0.5 mg mifepristone was administered daily. A total of 141 cycles were studied. Five pregnancies occurred, which was significantly less than if no contraceptive method had been used. However, the dose chosen did not seem sufficient to act as a contraceptive although it is probably not possible to increase the dose without disturbing ovulation and bleeding pattern.

Expression of cyclo-oxygenase in human endometrium during the implantation period.

Prostaglandins (PG) are known to be involved in the process of human implantation. In several animal species treatment with prostaglandin synthesis inhibitors will prevent implantation. Cyclo-oxygenase (COX) is the rate-limiting enzyme in the synthesis of PGs and exists in two isoforms, COX-1 and COX-2. Defective implantation in COX-2-deficient mice has been demonstrated recently. In the present study, the expression of COX-1 and COX-2 was studied during the implantation period in healthy fertile women before and after treatment with the antiprogesterone, mifepristone. The study consisted of one control cycle and one treatment cycle. The subjects served as their own control. During the treatment cycle the subjects received 200 mg of mifepristone 2 days after the luteinizing hormone (LH) surge. Endometrial biopsies were obtained in the mid-luteal phase (LH + 6 to LH + 8) in both cycles. Using polyclonal antibodies against COX-1 and COX-2, immunostaining for COX-1 was found mainly in the glandular and luminal epithelium and for COX-2 mainly in the luminal epithelium and the perivascular cells. After treatment with mifepristone, expression of COX-1 in glandular epithelium and COX-2 in luminal epithelium significantly decreased whilst the immunostaining for COX-2 in the perivascular cells remained strong. This study shows the expression of both COX-1 and COX-2 during the implantation period and also indicates that treatment with mifepristone in early luteal phase impairs glandular epithelial function and endometrial receptivity.

Contraceptive use of antiprogestin.

OBJECTIVES: To study the effect of antiprogestin on ovarian function and endometrial development during the menstrual cycle and the possibility of using these compounds for contraceptive purposes. METHODS: Administration of different doses of the antiprogestin mifepristone during the menstrual cycle; intermittent measurements of luteinizing hormone, progestin and estrogen in blood and/or urine; endometrial morphology and concentration of markers for endometrial receptivity; efficacy trials of the contraceptive effect of mifepristone. RESULTS: A high dose of mifepristone administered in the follicular phase will inhibit follicular development. If mifepristone is given immediately after ovulation, the secretory development of the endometrium and the expression of, for instance, leukemia inhibitory factor and integrins will be inhibited. Similar effects on the endometrium are obtained with small weekly doses (2.5 or 5.0 mg) or small daily doses (0.5 mg) of mifepristone, which do not inhibit ovulation. Once-monthly administration of 200 mg mifepristone on the day after ovulation, and emergency postcoital treatment, are highly effective methods for preventing pregnancy. Even 5 mg once weekly has a significant contraceptive effect. CONCLUSIONS: The antiprogestin mifepristone has a number of effects during the menstrual cycle which makes the compound suitable for contraceptive use. Treatment after a single act of unprotected intercourse, and once-a-month treatment immediately after ovulation, have shown high contraceptive efficacy. A low-dose regimen which does not influence ovulation also has a contraceptive effect, but the efficacy needs to be improved before routine clinical use.

Comparison between oral and vaginal administration of misoprostol on uterine contractility.

OBJECTIVE: To compare the degree of absorption and the effect on uterine contractility of the prostaglandin E1 analogue misoprostol after vaginal and oral administration. METHODS: Thirty women with a normal intrauterine pregnancy between 8 and 11 weeks' gestation who requested termination of pregnancy were given either 0.2 mg (orally n = 5; vaginally n = 6) or 0.4 mg (orally n = 10; vaginally n = 9) of misoprostol. Intrauterine pressure was recorded using a Grass polygraph connected to a pressure transducer 30 minutes before misoprostol was given and for 4 hours thereafter. At the end of the recording, suction curettage was performed. Blood samples were obtained at 0, 0.5, 1, 2, 4, and 6 hours for measurement of misoprostol, which was assayed by high-pressure liquid chromatography-mass spectrometry. RESULTS: In all patients, the first effect was an increase in uterine tonus. After 0.4 mg of misoprostol administered orally, uterine tonus started to increase after a mean (+/- standard deviation) time of 7.8+/-3.0 minutes and reached its maximum after 25.5+/-5.0 minutes. The corresponding times after vaginal administration were 20.9+/-5.3 minutes and 46.3+/-20.7 minutes, respectively. The initial increase in tonus was also more pronounced after oral than after vaginal administration. After vaginal administration, all patients developed uterine contractions; the activity, measured in Montevideo units, increased continuously during the observation period. This was not the case after oral administration. Plasma levels of misoprostol were measured in 18 patients. The highest levels were found 30 minutes after oral treatment and 1-2 hours after vaginal administration. CONCLUSION: The long-lasting and continuously increasing uterine contractility after vaginal administration can be explained only in part by a direct effect of misoprostol. The longer period of elevated plasma levels of misoprostol may also have initiated the prolonged events leading to increased uterine contractility.

Contraceptive efficacy of low doses of mifepristone.

OBJECTIVE: To determine whether a 5-mg dose of mifepristone is sufficient to prevent pregnancy. DESIGN: Clinical study. SETTING: Academic research center. SUBJECT(S): Healthy, fertile, sexually active female volunteers. INTERVENTION: Volunteers received a 5-mg dose of mifepristone once weekly, starting on cycle day 2, for up to 6 months. This was their only contraceptive method. MAIN OUTCOME MEASURE(S): Number of pregnancies. RESULT(S): The treatment resulted in a significant decrease in pregnancy rate without affecting the menstrual cycle or causing disturbing side effects. CONCLUSION(S): A low dose of mifepristone, which does not inhibit ovulation, reduces fertility significantly by affecting the endometrium. However, the contraceptive effect needs to be improved for the drug to compete with other contraceptive methods.

PIP: Clinical research has demonstrated that the effect of mifepristone on the endometrium is sufficient to prevent pregnancy. The efficacy of a low dose of mifepristone in preventing implantation was investigated in 18 healthy, fertile women with normal menstrual cycles from Stockholm, Sweden. Study participants received 5 mg of mifepristone once/week, starting on cycle day 2, and were followed for 1-6 months. Three pregnancies occurred in the 63 treatment cycles observed. The mean frequency of sexual intercourse was 2.2 times/week. If ovulation occurred 14 days before the onset of menstruation, at least 1 coital act took place during the period 3 days before and 1 day after ovulation in at least 45 cycles, resulting in a probability of pregnancy of 0.067. Without treatment, 14 pregnancies would have been expected. Although ovulation was not measured objectively, the regular bleeding pattern recorded in all cycles but one makes it unlikely that the contraceptive effect of mifepristone was due to ovulation inhibition. Although the failure rate of 5 mg of mifepristone is unacceptably high for a contraceptive regimen, other treatment schedules merit investigation.

The effect of antiprogestin on integrin expression in human endometrium: an immunohistochemical study.

Integrins are cell surface receptors for the extracellular matrix and connect extracellular cell adhesion proteins to cytoskeletal components. Several investigators have recently described the expression of different integrins in the human endometrium as markers of receptivity. In the present study we investigated the effect of various doses of the antiprogestin mifepristone on the endometrial expression of integrins during the implantation phase. Endometrial biopsies from healthy fertile women were obtained in the midluteal phase. The study included one control and one, two or three treatment cycles. In treatment cycles either 2.5 (n = 9) or 5 mg (n = 5) of mifepristone was administered once weekly, 0.5 mg daily (n = 5), or 200 mg as a single dose administered on day 2 after the luteinizing hormone surge (day LH + 2; n = 8). By using polyclonal antibodies against integrin alpha(v)beta3, subunit beta3 and subunit alpha4 we found reduced immunostaining for alpha4 and beta3 subunit in glandular epithelium after treatment with mifepristone while alpha(v)beta3, expression appeared to be unaffected. No differences between treatment groups were noted. This study demonstrates that treatment with mifepristone interferes with integrin distribution during the implantation window. This may imply that the contraceptive effect of mifepristone is primarily due to impaired endometrial receptivity. However, since no effect was shown on the distribution of the vitronectin receptor, this integrin might be regulated differently by other factors such as cytokines.

Six cases of massive feto-maternal bleeding causing intra-uterine fetal death.

Six patients in whom intra-uterine fetal death (IUFD) near term resulted from massive feto-maternal hemorrhage are reported. Two of the mothers were Rh-negative, which necessitated the administration of large volumes of anti-D. In order to detect such patients, the Kleihauer-Betke test should be performed in all cases of IUFD of unknown etiology.

Left ventricular output during postnatal circulatory adaptation in healthy infants born at full term.

Left ventricular output was measured non-invasively at predefined time intervals from less than 15 minutes to 72 hours after birth in 16 infants who had been born at full term. The blood flow velocity in the ascending aorta was measured by a range gated Doppler technique and multiplied by the cross sectional diameter measured by cross sectional and M mode echocardiography. Left ventricular output remained high in the first two hours, 235-243 ml/min/kg, despite a 10% decrease in heart rate. The fall in heart rate was compensated for by a 15% increase in stroke volume. Between 2 and 24 hours there was a significant fall in mean (SD) left ventricular output to 187 (35) ml/min/kg caused mainly by a reduction in stroke volume. The fall in left ventricle output after two hours may reflect an adaptation to the decreased demand on the left ventricle as the ductus constricts.