Acceptability of misoprostol-only medical termination of pregnancy compared with vacuum aspiration: an international, multicentre trial.

OBJECTIVE: To compare women's acceptance of misoprostol-only medical termination of pregnancy (TOP) with surgical TOP. DESIGN: Prospective cohort study. SETTING: Termination of pregnancy clinics in New Delhi, Mumbai, Hanoi, Tbilisi, Trivandrum and Yerevan. POPULATION: Women requesting TOP, at 63 days of gestation or less, at study sites where both medical and surgical methods were available. METHODS: Serial surveys eliciting measures of women's satisfaction and acceptance of TOP method were administered. Data were analysed using cross-tabulation and logistic regression to determine if TOP method was predictive of acceptability. MAIN OUTCOME MEASURES: Patient acceptance. RESULTS: High acceptability of both surgical and misoprostol-only TOP. CONCLUSIONS: Where medical TOP with mifepristone is not available, misoprostol-only medical TOP is acceptable to women who have the choice between medical or surgical techniques.

Copper T380A intrauterine device for emergency contraception: a prospective, multicentre, cohort clinical trial.

OBJECTIVE: To determine the effectiveness of the Copper T380A (CuT380A) intrauterine device (IUD) as an emergency contraceptive in women. DESIGN: Prospective, multicentre, cohort clinical trial. SETTING: Eighteen family planning clinics in China. SAMPLE: A cohort of 1963 women, aged 18-44 years, requesting emergency contraception within 120 hours of unprotected sexual intercourse. METHODS: Women requesting emergency contraception were followed at 1, 3 and 12 months after the insertion of CuT380A. MAIN OUTCOME MEASURES: Efficacy of CuT380A as emergency contraception and for up to 12 months of postinsertion use. Insertion complication rates, reported side-effects and continuation rates at 12 months were also recorded. RESULTS: No pregnancies occurred prior to or at the first follow-up visit, making CuT380A 100% effective as emergency contraception in this study. The pregnancy rate over the 12-month period was 0.23 per 100 women. In all, 29 (1.5%) women experienced a difficult IUD insertion process, requiring local anaesthesia or prophylactic antibiotics. No uterine perforations occurred. The main side-effects were increased menstrual bleeding and menstrual disturbances. The 12-month postinsertion continuation rate was 94.0 per 100 woman-years. CONCLUSIONS: CuT380A is a safe and effective method for emergency contraception. The advantages of CuT380A include its ability to provide effective, long-term contraception.

Misoprostol dose and route after mifepristone for early medical abortion: a randomised controlled noninferiority trial.

OBJECTIVE: To compare 400 and 800 microg sublingual or vaginal misoprostol 24 hours after 200 mg mifepristone for noninferiority regarding efficacy in achieving complete abortion for pregnancy termination up to 63 days of gestation. DESIGN: Placebo-controlled, randomised, noninferiority factorial trial, stratified by centre and length of gestation. Misoprostol 400 or 800 microg, administered either sublingually or vaginally, with follow up after 2 and 6 weeks. SETTING: Fifteen obstetrics/gynaecology departments in ten countries. POPULATION: Pregnant women (n = 3005) up to 63 days of gestation requesting medical abortion. METHODS: Two-sided 95% CI for differences in failure of complete abortion and continuing pregnancy, with a 3% noninferiority margin, were calculated. Proportions of women with adverse effects were recorded. OUTCOME MEASURES: Complete abortion without surgical intervention (main); continuing live pregnancies, induction-to-abortion interval, adverse effects, women's perceptions (secondary). RESULTS: Efficacy outcomes analysed for 2962 women (98.6%): 90.5% had complete abortion after 400 microg misoprostol, 94.2% after 800 microg. Noninferiority of 400 microg misoprostol was not demonstrated for failure of complete abortion (difference: 3.7%; 95% CI 1.8-5.6%). The 400-microg dose showed higher risk of incomplete abortion (P < 0.01) and continuing pregnancy (P < 0.01) than 800 microg. Vaginal and sublingual routes had similar risks of failure to achieve complete abortion (P = 0.47, difference in sublingual minus vaginal -0.7%, 95% CI -2.6-1.2%). A similar pattern was observed for continuing pregnancies (P = 0.21). Fewer women reported adverse effects with vaginal than sublingual administration and with the 400-microg dose than the 800-microg dose. Of the women, 94% were satisfied or highly satisfied with the regimens, 53% preferred the sublingual route and 47% preferred the vaginal route. CONCLUSIONS: A 400-microg dose of misoprostol should not replace the 800-microg dose when administered 24 hours after 200 mg mifepristone for inducing abortion in pregnancies up to 63 days. Sublingual and vaginal misoprostol have similar efficacy, but vaginal administration is associated with a lower frequency of adverse effects.

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.

Expanding access to emergency contraception.

Emergency contraception (EC) is safe and has the potential to prevent unwanted pregnancies. However, use remains low in most settings, due to a range of barriers to access. This paper reviews key issues related to EC and describes recommendations reached during the Women's Health Alliance pre-Congress workshop, held in advance of the FIGO 2006 World Congress. The working group concluded that national societies of obstetrics and gynecology can play an important role in increasing access to this unique contraceptive method.

Cervical priming with misoprostol prior to transcervical procedures.

Cervical priming with misoprostol has shown to facilitate transcervical procedures and to reduce side-effects. Cervical priming is recommended by several evidence-based guidelines prior to surgical abortion, dilatation and curettage, hysteroscopy and intrauterine device insertion. It is effective in pregnant as well as in non-pregnant women while the results in post-menopausal women are conflicting. Misoprostol is the best suited prostaglandin for a number of reasons: it has a short half-life, few side effects, it is stable at room temperature, it is relatively cheap and the dosage can easily be adjusted according to the clinical need. Various doses, routes, and time intervals between misoprostol application and the intervention have been evaluated. A single dose of 400 microg given sublingually or vaginally 3h before the intervention has given the best efficacy with the least side effects. Higher doses or longer intervals do not improve the effect on the cervix. Pain is a frequent side effect, but usually responds well to NSAIDs. Other side effects are rare.

Impact of bodyweight/body mass index on the effectiveness of emergency contraception with levonorgestrel: a pooled-analysis of three randomized controlled trials.

OBJECTIVE: A pooled analysis of two randomized controlled trials (RCTs) suggested that increased bodyweight and body mass index (BMI) may be associated with a greater probability of pregnancy. To address this issue we investigated whether higher bodyweight and/or BMI negatively impacted the risk of pregnancy in women receiving LNG-EC (levonorgestrel - emergency contraception) after unprotected sexual intercourse in a pooled analysis of three large multinational RCTs conducted by the World Health Organization (WHO). METHODS: A pooled analysis of three double-blind, multinational RCTs conducted by the WHO to investigate the efficacy of LNG-EC in the general population. All analyses were done on the per-protocol set (PPS) which included 5812 women who received LNG-EC within 72 hours following unprotected sexual intercourse. The analysis was based on logistic regression, with pregnancy as the outcome. BMI and weight were represented in the same model. RESULTS: A total of 56 pregnancies were available for analysis in the PPS. Increasing bodyweight and BMI were not correlated with an increased risk of pregnancy in the studied population. A limitation of this study is that despite the large study population in the pooled analysis there were relatively small numbers of women in the high-BMI and high-bodyweight subgroups. CONCLUSION: LNG-EC is effective for preventing pregnancy after unprotected intercourse or contraceptive failure and no evidence was found to support the hypothesis of a loss of EC efficacy in subjects with high BMI or bodyweight. Therefore, access to LNG-EC should not be limited only to women of lower bodyweight or BMI.

Body size at birth and blood pressure among children in developing countries.

BACKGROUND: Studies in developed countries have shown that reduced fetal growth is related to raised blood pressure in childhood and adult life. Little is known about this association in developing countries, where fetal growth retardation is common. METHODS: In 1994-1995, we measured blood pressure in 1570 3-6-year-old children living in China, Guatemala, Chile, Nigeria and Sweden. We related their blood pressure to patterns of fetal growth, as measured by body proportions at birth. The children were all born after 37 weeks gestation and weighed more than 2.5 kg at birth. RESULTS: In each country, blood pressure was positively related to the child's current weight. After adjusting for this and gender, systolic pressure was inversely related to size at birth in all countries except Nigeria. In Chile, China and Guatemala, children who were proportionately small at birth had raised systolic pressure. For example, in Chile, systolic pressure adjusted for current weight increased by 4.9 mmHg (95% CI : 2.1, 7.7) for every kilogram decrease in birthweight, by 1 mmHg (95% CI : 0.4, 1.6) for every centimetre decrease in birth length, and by 1.3 mmHg (95% CI : 0.4, 2.2) for every centimetre decrease in head circumference at birth. In Sweden, systolic pressure was higher in children who were disproportionately small, that is thin, at birth. Systolic pressure increased by 0.3 mmHg (95% CI : 0.0, 0.6) for every unit (kg/m3) decrease in ponderal index at birth. These associations were independent of the duration of gestation. CONCLUSIONS: Raised blood pressure among children in three samples from China, Central and South America is related to proportionate reduction in body size at birth, which results from reduced growth throughout gestation. The relation between fetal growth and blood pressure may be different in African populations. Proportionately reduced fetal growth is the prevalent pattern of fetal growth retardation in developing countries, and is associated with chronic undernutrition among women. Improvement in the nutrition and health of girls and young women may be important in preventing cardiovascular disease in developing countries.

Multicenter study of the lactational amenorrhea method (LAM) III: effectiveness, duration, and satisfaction with reduced client-provider contact.

The objective of this effort was to assess the use and efficacy of the Lactational Amenorrhea Method (LAM) with reduced numbers of client-provider contacts. A co-sponsored multicenter study of LAM was performed to test the efficacy and acceptability of the method under "post-marketing" conditions, with investigator-initiated contact occurring only twice: at the time of intake and then again at month 7 of postpartum. These data are assumed to provide an assessment of LAM's use, efficacy, and performance that more closely reflects the prevailing conditions of these populations during normal use. Three hundred and sixty-two subjects were recruited through centers that had participated in the previous, more contact-intensive studies. Using a cooperatively developed protocol, data were gathered prospectively on at least 10 and up to 50 LAM acceptors at nine sites, and entered and cleaned on site. Data were further cleaned and analyzed at the Georgetown University Institute for Reproductive Health (IRH) and the Department of Nutrition at the University of Connecticut. Using country-level and pooled data, descriptive statistics and life tables were produced. LAM efficacy in this sample is 100% because there were no pregnancies at any of the participating sites. Satisfaction with the method was high, and the rate of continuation on to another method after LAM was 66.7% at 7 months postpartum. Of the women who had never used family planning prior to LAM, 63.0% went on to use another method of family planning in a timely manner. LAM can be highly effective as an introductory postpartum family planning method when offered in a variety of cultures, health care settings, and industrial and developing country locales. Under conditions of limited client-provider contact, LAM remains effective and leads to acceptance of another method by about two-thirds of the acceptors. Women are able to use LAM effectively without extensive counseling or follow-up, with a high level of user satisfaction.

Multicenter study of the Lactational Amenorrhea Method (LAM): I. Efficacy, duration, and implications for clinical application.

A multicenter study of the Lactational Amenorrhea Method (LAM) was carried out to test the acceptability and efficacy of the method. Additionally, the data are used to test new constructs for improvement of method criteria. A protocol was designed at the Institute for Reproductive Health (IRH), Department of Obstetrics and Gynecology, Georgetown University Medical Center, a World Health Organization (WHO) Collaborating Center, and was reviewed and modified in collaboration with the co-sponsors, the World Health Organization and the South to South Cooperation for Reproductive Health, and the principal investigators from each site. Data were gathered prospectively on LAM acceptors at 11 sites. Data were entered and cleaned on-site and further cleaned and analyzed at IRH, using country-level and pooled data to produce descriptive statistics and life tables. The 98+% efficacy of LAM is confirmed in a wide variety of settings. In addition, the results yield insight on the possibility of continued use beyond 6 months. LAM is found to be highly effective as an introductory postpartum method when offered in a variety of cultures, health care settings, socio-economic strata, and industrial and developing country locales. In addition, LAM acceptance complements breastfeeding behaviors without ongoing breastfeeding support services. The parameters studied yield high efficacy and method continuation. Therefore, the basic tenets of the 1995 Bellagio consensus on LAM is reconfirmed and it is recommended that LAM be reconfirmed and it is recommended that LAM be incorporated into hospital, maternity, family planning, maternal and child health, and other primary health care settings.

Multicenter study of the Lactational Amenorrhea Method (LAM): II. Acceptability, utility, and policy implications.

A multicenter study of the Lactational Amenorrhea Method (LAM) was carried out to determine acceptability, satisfaction, and utilization in 10 different populations, and to confirm the efficacy of the method. Efficacy data are presented in a companion paper. A protocol was designed at the Institute for Reproductive Health (IRH), Department of Obstetrics and Gynecology, Georgetown University Medical Center, and reviewed and modified in collaboration with the co-sponsors, the World Health Organization, the South-to-South Cooperation for Reproductive Health, and the principal investigators from each site. Data were gathered prospectively on LAM users at 11 sites. Data were entered and cleaned on-site, and further cleaned and analyzed at IRH, using country-level and pooled data to produce descriptive statistics. The overall satisfaction with LAM was 83.6%, and continuation with another method of family planning was shown to be 67.6% at 9 months postpartum, in most cases exceeding previous use of contraception prior to use of LAM. Knowledge and understanding of the method at discontinuation were high, ranging from 78.4 to 88.6% for the three criteria. LAM can be used with a high level of satisfaction and success by women in a variety of cultures, health care settings, socio-economic strata, and industrial and developing country settings. The results confirm that LAM is acceptable and ready for widespread use, and should be included in the range of services available in maternal and child health, family planning, and other primary health care settings.

[Effects of mifepristone of different doses on emergency contraception, a randomized double-blind study].

OBJECTIVE: To compare the effects of mifepristone of different doses on emergency contraception. METHODS: 3,052 healthy women with regular menstrual cycle who visited the 10 family planning institutes and hospitals in Beijing, Shanghai, Shangdong, Sichuan, Tianjin, Guangdong, and Liaoning for emergency contraception within the period of 120 hours after a single act of unprotected sex were given a single dose of 10 mg or 25 mg mifepristone randomly and double-blindly. They were asked to record the vaginal hemorrhage that would occur and not to have unprotected sex until the next menstrual onset when they were followed up. The trial for a specific subject ended when she menstruated. If the menstruation was irregular or a specific subject failed to menstruate on time a blood or urine human chorionic gonadotropin (hCG) test was made. If the hCG test was negative, an appointment was made to follow up once one week later. If the hCG test was positive ultrasound examination was made to detect pregnancy. If the subject still failed to menstruate and the hCG test was still negative follow-up for this subject could be finished. RESULTS: Twenty-two of the 3,052 subjects were lost to follow up. Among the remaining 3,030 women 1,516 were in the 10 mg group and 1 514 in the 25 mg group. Seventeen pregnancies occurred in each group, with a pregnancy rate of 1.1% for both groups. The relative risk of pregnancy of treatment of 25 mg mifepristone in comparison with treatment of 10 mg mifepristone was 1.0 (95% CI: 0.51-1.95). Both doses prevented about 85% approximately 86% of the anticipated pregnancy if no measure had been adopted. The pregnancy rate nearly doubled in the women who had unprotected sex after treatment of mifepristone. The efficacy of mifepristone decreased along with the delay of mifepristone administration. Side effects were uncommon and mild. Delay of 7 days or more in the onset of next menstruation occurred in 9%-10% of the women. CONCLUSION: Mifepristone of the dose of 10 mg is safe and effective for emergency contraception. Earlier administration is preferable, although the method can be used effectively up to five days after the unprotected sex.

Research on regimens for early medical abortion.

Until recently the medical abortion regimen of mifepristone followed by a suitable prostaglandin analogue two days later has been available in only a few countries. Limited access to the drug has hampered research and forced investigators without access to seek alternatives. Where mifepristone has not been available, investigators have tested repeated doses of the prostaglandin misoprostol alone or in combination with methotrexate. However, these regimens cannot compete in efficacy, safety, and convenience with the mifepristone-prostaglandin regimen. The development of the mifepristone-prostaglandin regimen has continued since approval, and a more effective and better tolerated medical method than was available ten years ago can now be offered to women. Several randomized double-blind studies have demonstrated that the dose of mifepristone can be lowered to 200 mg, one-third of the original dose, without compromising efficacy. Misoprostol has now largely replaced other prostaglandin analogues in the regimen, and this has made medical abortion simpler and more cost effective. Although women prefer oral administration of drugs, recent evidence suggests that to achieve sufficient efficacy, misoprostol has to be administered vaginally in women beyond 49 days' gestation. This medical abortion regimen has proved to be acceptable to women and safe when provided under proper conditions.

Research on mifepristone and levonorgestrel in comparison with the Yuzpe regimen.

Women should be informed that it is possible to prevent unwanted pregnancy after intercourse in most cases by effective emergency contraception (EC). The currently used hormonal method, the Yuzpe regimen, however, has unpleasant side effects. The UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research training in Human Reproduction has worked on developing improved methods of EC for the last ten years. This research has focused on levonorgestrel and mifepristone. Now that results from large clinical studies are becoming available, they suggest that both these compounds are better tolerated and appear even more effective than the Yuzpe regimen. The challenge now is to implement the research results by making better emergency contraceptives a reality for women.

Emergency contraception.

The term 'emergency contraception', as employed in this paper, refers to methods that are used as emergency procedures to prevent pregnancy following unprotected intercourse. Alternative, less appropriate, terms are postcoital and 'morning-after' contraception. References to postcoital preparations can be found as far back as 1500 BC in Egyptian papyri, but it was not until fairly recently that contraceptive research has been able to at least partially fulfill that need. The development of hormonal methods of emergency contraception goes back to the 1960s when the first human trials of postcoitally administered high-dose oestrogens were undertaken. Combined oestrogen- progestogen combination therapy (the so-called Yuzpe regimen) was introduced in the early 1970s, while the postcoital insertion of an intrauterine contraceptive device (IUD) for emergency contraception was first reported in 1976. Other compounds that have been tested more recently include levonorgestrel, the antiprogestogen mifepristone, and danazol. Although there is some debate about the magnitude of the protective effect, few people question the important role that emergency contraception can play in preventing unwanted pregnancy and hence maternal mortality and morbidity resulting from unsafe abortion. Given that the most often used methods of emergency contraception, namely the Yuzpe regimen and postcoital insertion of an IUD, rely on technology that has been available for some 30 years, family planning programmes that claim to be concerned with improving women's reproductive health, cannot really be excused if they do not provide emergency contraception as part of their routine services.

Clinical uses of antiprogestogens.

Antiprogestogens, which block the action of progesterone at the cellular level through binding to the progesterone receptor, are proving to be one of the most significant developments in endocrinology in recent years. Several hundreds of such compounds have been synthesized, but only a few of them have been evaluated to any significant extent in biological screening models and, to our knowledge, only three compounds, namely mifepristone, lilopristone (ZK 98.734) and onapristone (ZK 98.299) have been given to humans. Most of the clinical research to date has focused on the use of mifepristone given in combination with prostaglandin for termination of early pregnancy, an indication for which the compound is being used routinely in four countries so far, i.e. China, France, the UK and Sweden. The gynaecological and obstetrical applications in which antiprogestogens have been shown to be of value to date include ripening of the pregnant cervix prior to pregnancy termination, sensitization of the uterus to prostaglandins in second-trimester abortion, and induction of labour. Available data suggest that antiprogestogens have no place in the conservative treatment of ectopic pregnancy or in the treatment of premenstrual tension. In fertility regulation, the sequential combination regimen of mifepristone plus prostaglandin as used for inducing abortion has proved to be effective also for menses induction and can be expected to be an efficacious once-a-month contraceptive. Mifepristone alone, without adjuvant prostaglandin, has yielded promising results as an anti-implantation agent and in emergency contraception. Other potential uses include once-a-week contraception, ovulation inhibition (in a sequential regimen with a progestogen), and as a daily mini-pill. Mifepristone, and other antiprogestogens for which biological data have been reported also bind to the cellular receptors for glucocorticoid hormones and, consequently, possess antiglucocorticoid in addition to their antiprogestational activity. Because of this antiglucocorticoid effect, mifepristone has been employed successfully in the palliative treatment of hypercortisolism due to Cushing's syndrome, and its use has been proposed for treating certain forms of depression and of glaucoma, and in wound healing. However, for scientific and practical reasons, it would be preferable if molecules were developed that have only the antiprogestational or the antiglucocorticoid activity rather than both.

Research on new methods of emergency contraception.

PIP: The ideal emergency contraceptive would be highly effective (surpassing the 75% effectiveness rate of the Yuzpe method), free of side effects, non-disruptive of the menstrual cycle, easily administered, interceptive, and affordable. Prevention of fertilization rather than ovulation would be an important advance since it would increase the window of time after unprotected intercourse that a drug can be administered. Recent research in this area has focused on levonorgestrel alone, danazol, anti-estrogens, gonadotropin-releasing hormone antagonists, and progesterone inhibition. Crucial to further advances is basic research on embryonic development and signaling before implantation, tubal transport and milieu, endometrial development before implantation, and the inter-relationships between the embryo and uterus during implantation. Until more knowledge is amassed about these physiological mechanisms, no new methods are likely to emerge. In the interim, an emphasis is being placed on the evaluation of anti-progestogens such as RU-486 that are easier to administer and associated with fewer side effects than the Yuzpe method.^ieng