P.F.A. Van Look

Termination of pregnancy with reduced doses of mifepristone

OBJECTIVES To compare the abortifacient efficacy and side effects of three doses of the antiprogestin mifepristone plus prostaglandin for termination of early pregnancy. DESIGN Randomised, double blind multicentre trial. SETTING 11 departments of obstetrics and gynaecology and of family planning, mostly in university hospitals, in seven countries. SUBJECTS 1182 women with an early pregnancy (menstrual delay of 7-28 days) requesting abortion. INTERVENTIONS Single doses of 200 mg, 400 mg, or 600 mg mifepristone followed, 48 hours later, by vaginal pessary of 1 mg of the prostaglandin E1 analogue gemeprost. MAIN OUTCOME MEASURES Outcome of treatment; duration and subjective amount of menstrual bleeding; side effects and complications; and concentrations of haemoglobin. RESULTS Outcome was similar with the three doses of mifepristone. Of the 1151 women with known outcome, 95.5% had a complete abortion (364 (93.8%) of those given 200 mg mifepristone, 368 (94.1%) of those given 400 mg, and 367 (94.3%) of those given 600 mg), 3.7% had an incomplete abortion (14 (3.6%), 15 (3.8%), and 14 (3.6%)), 0.3% had a missed abortion (three (0.8%), one (0.3%), and none), and 0.4% had a continuing live pregnancy (two (0.5%), two (0.5%), and one (0.3%)). Of the 43 women who had incomplete abortion, 23 underwent emergency uterine curettage (usually for haemostatic purposes) and three of these women were given a blood transfusion. The numbers of reported complaints, bleeding patterns, and changes in blood pressure and haemoglobin concentrations were similar with the three treatments. CONCLUSIONS For termination of early pregnancy a single dose of 200 mg mifepristone is as effective as the currently recommended dose of 600 mg when used in combination with a vaginal pessary of 1 mg gemeprost.

Pharmacokinetic study of RU 486 and its metabolites after oral administration of single doses to pregnant and non-pregnant women

RU 486 and three of its metabolites (RU 42633-monodemethyl, RU 42848-didemethyl, and RU 42698-hydroxymetabolite) were determined by HPLC in plasma from nine non-pregnant and 36 pregnant women. Each non-pregnant subject took an oral dose of RU 486 (25, 100, 400 and 600 mg consecutively) once per menstrual cycle. Six of the nine women also received a dose of 200 mg. The 36 pregnant women were randomized into four groups which were given a single dose of 25, 100, 400 or 600 mg RU 486. Blood samples were taken up to 120 h after dosing. Peak concentrations of RU 486 occurred on most occasions within 2 h. Plasma concentrations at 1 h and at 24 h increased in proportion to log dose. There was a wide variability (up to ten-fold) in the pharmacokinetic parameters within each dose group. Plasma concentrations of RU 42633 were similar to those of RU 486 but concentrations of RU 42848 and RU 42698 were much lower. As with RU 486, the plasma concentrations of the metabolites were maintained at high levels for up to 48-72 h after dosing. The findings were consistent with a rapid metabolism of RU 486 to RU 42633; removal of the second methyl group leading to RU 42698 occurred much more slowly and to a much less extent than removal of the first. There appeared to be no significant differences between the non-pregnant and pregnant women in either the plasma concentrations or pharmacokinetic parameters of RU 486 and its metabolites.

Lactational amenorrhea method for family planning

In December 1995 a conference on the lactational amenorrhea method (LAM) for family planning was held in Bellagio Italy to review the findings of studies expressly designed to test the consensus of the 1988 meeting on LAM also held in Bellagio and findings of other relevant research. At the 1988 meeting on LAM participants came to a conclusion now referred to as the Bellagio consensus: women who are not using family planning but are fully or nearly fully breast feeding and amenorrheic face a risk of pregnancy less than 2% during the first six months postpartum. 1995 conference participants found that the findings clearly confirmed the Bellagio consensus. The criteria to meet LAM guidelines are amenorrhea full or nearly full breast feeding and the first six months postpartum. The 1995 participants concluded that it is impossible to eliminate the amenorrhea criterion. It may be possible to relax the criterion of full or nearly full breast feeding and to extend LAM beyond six months postpartum. They defined the end of amenorrhea to be two consecutive days of bleeding/spotting or of the womans perception that her menses have returned. The LAM guidelines advise women who no longer meet any of these criteria or no longer wish to use LAM that they should immediately begin using another family planning method to avoid pregnancy. Family planning programs and policies should support LAM so it can be available worldwide. Programmatic research needs are studies on the LAM performance under a wide range of field conditions impact of LAM on family planning use LAM use in mothers who are separated from their babies for a prolonged period each day and in mothers of premature babies integration of LAM into family planning and other health services and the level and nature of support needed for effective LAM use. Biomedical research needs are studies on the factors that determine whether a woman ovulates before or after her return to menses the levels and patterns of infant feeding needed to maintain low pregnancy rates and the relative importance of the various factors that contribute to lactational infertility.

Pharmacokinetic study of orally administered RU 486 in non-pregnant women

A method based on HPLC was devised for the estimation of RU 486 in blood and utilised to study the pharmacokinetics of a single dose of 50 mg RU 486 administered orally to 12 women on day 7 of the cycle. The dose was rapidly absorbed with peak plasma concentration between 1 and 2 hours. Distribution was also rapid (mean t1/2 alpha: 1.4h), whereas elimination was slow (mean t1/2 beta: 28.3 h). RU 486 was still detectable in some women at 72 h after administration. The plasma concentrations fitted the equation for a two-compartment open model from which the pharmacokinetic parameters were calculated. The mean total plasma clearance was 3.0 l/h, and the comparison of our data with those published studies suggests that the pharmacokinetics of RU 486 in Chinese women are similar to those of other populations.

A multicenter clinical study on two types of levonorgestrel tablets administered for postcoital contraception

Contraceptive efficacy, cycle control and side effects of two types of 0.75 mg levonorgestrel tablets taken postcoitally during the periovulatory period of one cycle were studied in a multicenter trial involving 361 women. No significant differences were found between the two types of levonorgestrel pills in terms of contraceptive efficacy, cycle control and side effects. The failure rate observed (1.4% per treated cycle) was similar to that reported for other hormonal approaches to emergency postcoital contraception. Intermenstrual bleeding or spotting occurred in 11.5% of the cycles and anovulation as assessed from BBT charts in 14.4% of cycles. One or more side effects were reported by 22.2% of subjects. The relatively frequent occurrence of cycle disturbances and subjective side effects make it unlikely that the repeated postcoital use of levonorgestrel would be an acceptable routine method of contraception for most women.

Comparative cross-over pharmacokinetic study on two types of postcoital contraceptive tablets containing levonorgestrel

A pharmaceutical and pharmacokinetic study was carried out on levonorgestrel tablets from two different sources (Hungarian- and Chinese-made). Both preparations contained 0.75 mg levonorgestrel and had been shown to have similar contraceptive efficacy and side effects when used for postcoital contraception. Absorption and bioavailability of the Hungarian-made tablets were greater as evidenced by higher serum concentrations of levonorgestrel, a greater area under the concentration-time curve during the first 24 hours, and a more marked suppressive effect on SHBG levels. These differences most probably reflect differences in their pharmaceutical formulation, in particular the extent of tablet dissolution and the degree of micronisation of levonorgestrel.

The use of prostaglandins and antiprogestins for pregnancy termination.

Although vacuum aspiration could be regarded as a simple procedure, complications do occur and attempts have been made to develop non‐surgical procedures for termination of pregnancy during the first 3–4 weeks following the first missed menstrual period. A variety of prostaglandin (PG) analogs have been developed which are equally effective as vacuum aspiration to induce abortion during early pregnancy. However, the widespread acceptance of PG treatment is limited by a relatively high incidence of gastrointestinal side effects and uterine pain. Treatment with presently available antiprogestins alone is not sufficiently effective to compete with vacuum aspiration. However, administration of these compounds induces uterine contractions and increases the sensitivity of the myometrium to prostaglandin. These effects allow the development of sequential treatment with RU 486 and a low dose of PG analogs administered intramuscularly or vaginally which is highly effective and is seemingly associated with a lower frequency of side effects than if PG analogs are used alone. It can be concluded that this medical abortion method has the capacity to compete with vacuum aspiration for termination of early pregnancy. Randomized studies comparing the two procedures are, however, needed to confirm this statement.

Lactational amenorrhoea method for family planning

1 Weintraub WS, King SB III, Douglas JS Jr, Kosinski AS. Percutaneous transluminal coronary angioplasty as a first revascularization procedure in single-, doubleand triple-vessel coronary artery disease. J Am Coil Cardiol 1995;26:142-51. 2 Currier JW, Faxon DP. Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target?JAm CoU Cardiol 1995;25:516-20. 3 Pocock SJ, Henderson RA, Rickards AF, Hampton JR, King SB III, Hamm CW, et al. Meta-analysis ofrandomised trials comparing coronary angioplasty with bypass surgery. Lancet 1995;346:1 184-9. 4 Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N EnglJ Med 1987;316:701-6. 5 Serruys PW, Strauss BH, Beatt KJ, Bertrand ME, Puel J, Rickards AF, et al. Angiographic follow-up after placement of a self-expanding coronary artery stent. N Engi Y Med 1991;324:13-7. 6 Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al for the Benestent Study Group. A comparison ofballoon expandable stent implantation with balloon angioplasty in patients with coronary artery disease. NEnglJMed 1994;331:489-95. 7 Fischman DL, Leon MB, Baim D, Schatz RA, Savage MP, Penn I, et al for the Stent Restenosis Study Investigators. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. NEnglJMed 1994;331:496-501. 8 Schatz RA, Baim DS, Leon MB, Goldberg S, Hirshfeld JW, Cleman MW, et al. Clinical experience with Palmaz-Schatz coronary stent: initial results of a multicenter study. Circulation 1991;83:148-161 9 George BS, Voorhess WD, Roubin GS, Fearnot NE, Pinkerton CA, Raizner AE, et al. Multicenter investigation of coronary stenting to treat acute or threatened closure after percutaneous transluminal coronary angioplasty: clinical and angiographic outcomes. JAm Cog Cardiol 1993;22:135-43. 10 Popma JJ, Satler LF, Pichard AD, Kent KM, Campbell A, Chuang YC, et al. Vascular complications after balloon and new device angioplasty. Circulation 1993;88: 1569-78. 11 Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1891-7. 12 Morice MC, Zemour G, Beneviste E, Biron Y, Bourdonnec C, Faivre R, et al. Intracoronary stenting without coumadin: one month results of a French multicenter study. Cathet Cardiovasc Diag 1995;35:1-7. 13 Hall P, Nakamura S, Maiello L, Itoh A, Blengino S, Martini G, et al. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 1996;93: 215-22. 14 Nakamura S, Colombo A, Gaglione S, Almagor Y, Goldberg SL, Maiello L, et al. Intracoronary ultrasound observations during stent imnplantation. Circulation 1994;89:2026-34. 15 Serruys PW, Emanuelsson H, van der Giessen W, Lunn AC, Kiemeneij F, Macaya C, et al for the Benestent-II Study Group. Heparin-coated Palmaz-Schatz stents in human coronary arteries. Early outcome of the Benestent-II pilot study. Circulation 1996;93: 412-22.

Cervical ripening with mifepristone (RU 486) in late first trimester abortion

In order to further evaluate the usefulness of the antiprogestogen, mifepristone, as a cervical ripening agent, a double-blind multicentre study was undertaken of 230 primigravid women with 10-12 weeks amenorrhoea who were randomly assigned to receive either 0 (placebo) or 200 mg of mifepristone 36 hours before surgical pregnancy termination. Fifteen women who did not fulfil all of the selection criteria were excluded from analysis. In the mifepristone group (N = 105) 12 women experienced some pre-operative vaginal bleeding as compared with only one subject in the placebo group (N = 110), but only one of these 12 women described the bleeding as more than her usual menstrual flow. In mifepristone-treated women the cervix was about 1 mm more dilated at operation and further mechanical dilatation was needed less frequently than in placebo-treated controls. High resistance during further mechanical stretching was encountered significantly more often and at a smaller cervical diameter in the placebo group than in the women given mifepristone. Also, dilatation was reported by the operating surgeons to be easier in women given the antiprogestogen. Other significant differences included a shorter operation time, lower peroperative blood loss and less frequent use of analgesic drugs post-operatively in the mifepristone group. Post-operative complications, the duration of post-operative bleeding and the interval to the first menstruation were similar in both groups. The results confirm that the antiprogestogen, mifepristone, is an effective cervical ripening agent which deserves further study in comparison with the currently used methods, i.e. prostaglandins and osmotic dilators.

Demographic aspects of induced abortion

Abstract Every day some 150 000 unwanted pregnancies, close to 53 million in a year, are terminated by induced abortion. One third of these abortions are performed under unsafe conditions, resulting in about 500 deaths every day — or approximately 180 000 in 1 year. The majority of these deaths occur in countries in the developing part of the world, where access to abortion is restricted either by law or because existing services are inadequate. The trend towards liberalisation of abortion started in Europe in the 1930s and continues today. Currently, some 63% of the worlds people live in countries where abortion is available on request or where social factors can be taken into consideration when evaluating a womans request for pregnancy termination. Liberalisation of abortion does not inevitably lead to an increase in the number of abortions, as illustrated by the example of the Netherlands which has the lowest reported abortion rate in the world despite its liberal law. Other factors such as universal sex education in schools and easily accessible family planning services, including services for adolescents and the provision of emergency contraception, influence a countrys abortion rate to a much greater extent than the degree of liberalness of its law. This is also reflected by the demographic characteristics of the women who most often utilise abortion. In English-speaking countries, especially the USA, and in Scandinavia, young unmarried women make up the largest proportion of those who obtain abortion and the major challenge in these countries, therefore, is to improve sexual education and contraceptive use and hence reduce unintended pregnancy amongst this group. In most other developed countries, including those in Central and Eastern Europe, that have reliable abortion statistics, and probably also in most of the developing world, married women with children constitute the largest group of abortion users and thus the greatest need here is to provide contraceptive services and supplies and encourage their use. But neither the family planning methods currently available nor the people who use them are perfect, and it would be unrealistic to believe, therefore, that unplanned pregnancy and induced abortion are totally preventable.