Reducing maternal mortality due to elective abortion: Potential impact of misoprostol in low-resource settings.

Over 99% of deaths due to abortion occur in developing countries. Maternal deaths due to abortion are preventable. Increasing the use of misoprostol for elective abortion could have a notable impact on maternal mortality due to abortion. As a test of this hypothesis, this study estimated the reduction in maternal deaths due to abortion in Africa, Asia and Latin America. The estimates were adjusted to changes in assumptions, yielding different possible scenarios of low and high estimates. This simple modeling exercise demonstrated that increased use of misoprostol, an option for pregnancy termination already available to many women in developing countries, could significantly reduce mortality due to abortion. Empirical testing of the hypothesis with data collected from developing countries could help to inform and improve the use of misoprostol in those settings.

The androgenicity of progestins.

All steroid hormones are structurally similar, but relatively minor differences cause profound alterations in biochemical activity. The 21-carbon series (pregnane nucleus) includes the corticoids and the true progestins (e.g., medroxyprogesterone acetate). The 19-carbon series (androstane nucleus) includes all the androgens, among them the progestins used in most oral and parenteral contraceptives. The removal of carbon 19 from testosterone changes the major hormonal effect from androgenic to progestogenic, but these "19-nor" steroids retain varying degrees of androgenic activity. (They can also have limited estrogenic activity, but this is insignificant at the low doses used for contraception.) Some of the 19-nortestosterone progestins are metabolized to other compounds (e.g., norethynodrel, ethynodiol diacetate, and lynestrenol to norethindrone), and some (levonorgestrel, desogestrel) are active unchanged. The lingering androgenic effects of 19-nor progestins are dose-related, opposed by estrogen, and are manifested metabolically (e.g., glucose tolerance, lipoprotein synthesis) and symptomatically (e.g., acne, weight gain). The effect of 19-nortestosterones on lipoproteins prompted the development of less androgenic compounds, but the obvious benefit of the new progestins (desogestrel, gestodene, norgestimate) is a reduction in the symptoms associated with the androgenicity of the older compounds. Mitigation of androgenic effects on lipoprotein and carbohydrate metabolism could have long-term benefits, especially for women who are at risk of arteriosclerotic vascular disease; however, these effects remain to be epidemiologically demonstrated.

PIP: This paper reports the results of a review of current literature on progestin androgenicity and any progress made to reduce androgenicity. Structurally synthetic, steroid hormones are similar. The 19-carbon structure series includes all the androgens, including the progestins used in most oral and parenteral OC formulations. Some 19-nortestosterone progestins are metabolized to other compounds and some are active as they are. Androgenic effects of 19-nor progestins are dose-related, opposed by estrogen, and are manifested metabolically or symptomatically. Effects on lipoprotein and carbohydrate metabolism may play a role in the development of vascular disease. This has lead researchers to develop safer, less androgenic compounds characterized by fewer androgenic side effects.

Sonographically guided extraction of a submucous myoma.

Under ultrasonographic guidance, a 5-cm, symptomatic submucous myoma was removed from the uterus during a second-trimester pregnancy termination. The procedure was rapid and well tolerated and suggests that intraoperative sonography may provide a transvaginal alternative to laparotomy in the treatment of submucous myomata.

Cervical dilation before first-trimester elective abortion: a controlled comparison of meteneprost, laminaria, and hypan.

Preoperative cervical dilation makes first-trimester abortion safer, but increases costs and inconvenience to patients if extra visits are required. Eighty-four pregnant primigravid volunteers who requested first-trimester abortion were assigned randomly to one of four study groups: placebo, 16 dimethyl prostaglandin E2 (PGE2) vaginal suppository, 4-mm hypan plastic dilator, or small Laminaria japonica tent. This grouping was done to determine which of three modalities is most effective for cervical dilation within three hours before abortion. After three to four hours of treatment, hypan achieved greater cervical dilation among primigravid women and only modestly increased side effects, as compared with 16 dimethyl PGE2 suppositories or laminaria tents.

Massive exudative ascites produced from a tubal pseudocyst in chronic pelvic inflammatory disease.

A case of massive exudative hemorrhagic ascites occurring as a serious complication of chronic pelvic inflammatory disease (PID) is presented. The clinical manifestations, simulating diffuse carcinomatosis in a young female patient, are described.

Emergency contraception: advance provision in a young, high-risk clinic population.

OBJECTIVE: To assess whether advance provision of emergency contraception increases its use and whether it has secondary effects on regular contraceptive use. METHODS: We conducted a controlled trial of female clients, aged 16-24 years, who attended a publicly funded family planning clinic. Women were systematically assigned to receive an advance provision of emergency contraception and education (treatment) or education only (control). Among 263 participants enrolled (133 treatment, 130 control), follow-up was completed in 213 (111 treatment, 102 control). The main outcome measures were emergency contraception knowledge and use, frequency of unprotected sex, and pattern of contraceptive use in the past 4 months. RESULTS: Participants were aware of emergency contraception at follow-up, but the treatment group was three times as likely to use it (P =.006). Although the treatment group did not report higher frequencies of unprotected sex than the control group, women in the treatment group (28%) were more likely than those in the control group (17%) to report using less effective contraception at follow-up compared with enrollment (P =.05). The proportion of women in both groups who reported consistent pill use increased from enrollment to follow-up (34% versus 45%); however, the control group (58%) was more likely than the treatment group (32%) to report consistent pill use at follow-up (P =.03). CONCLUSION: Use of emergency contraception was increased by providing it in advance, but not by education alone. Changes to less effective contraceptive methods and patterns of pill use were potentially negative effects that need to be explored in relation to observed benefits.

A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.

OBJECTIVE: To compare the efficacy and acceptability of oral misoprostol, vaginal misoprostol, and laminaria tents for cervical dilation before surgical abortion. METHODS: We conducted a randomized, double-blind, placebo-controlled trial comparing oral misoprostol 400 microg, vaginal misoprostol 400 microg, and one medium laminaria for dilating the cervix over 4 hours before surgical abortion. The study sample consisted of 106 women at 7-14 weeks' gestation who presented to San Francisco General Hospital requesting abortion. The primary outcome was the amount of cervical dilation measured by Pratt dilators. Secondary outcomes were the proportion of subjects needing further manual dilation, difficulty of dilation, duration of the procedure, blood loss, and side effects. RESULTS: The vaginal-misoprostol group had a significantly greater mean dilation (28.0 mm) than the oral misoprostol group (24.2 mm; P < .05) and a greater mean dilation than the laminaria group (25.9 mm), although this difference did not reach significance. Women who received laminaria reported significantly more pain at the time of placement (85.7% reported at least "a little" pain) compared with women who received misoprostol by either route (28.9% of oral-misoprostol and 34.0% of vaginal-misoprostol subjects reported "a little" pain; P < .01). The proportion of subjects who required further manual dilation, ease of dilation, duration of the procedure, and blood loss were not significantly different among the groups. There was no difference in side effects during the 4-hour waiting period among the three groups, and gastrointestinal side effects were rare in all groups. CONCLUSION: Vaginal misoprostol is superior to oral misoprostol and is an acceptable alternative to laminaria tents for cervical dilation before surgical abortion in pregnancies of 7-14 weeks' gestation. It is inexpensive and easy to administer, and achieves equal or greater dilation with less pain on insertion and no increase in side effects compared with laminaria.

Uterine perforation during second-trimester abortion by cervical dilation and instrumental extraction: a review of 15 cases.

Review of the records of 15 women who had uterine perforations at the time of second-trimester abortion by dilation and evacuation showed that unexpected pain (but not excessive bleeding) was the most prominent sign. All patients required laparotomy, but in no case was laparotomy necessary as an emergency procedure. Laparoscopy was not helpful. Two-thirds had bowel injuries and two required hysterectomy. Errors in estimating gestational duration, inadequate cervical dilation, and failure to use sonography characterized these complicated cases.

Levonorgestrel capsule implants in the United States: a 5-year study.

OBJECTIVE: To measure effectiveness, adverse event experience, and acceptability of the Food and Drug Administration-approved variant of levonorgestrel capsule implants in the United States through 5 years and to examine determinants of these outcomes. METHODS: In a prospective, multicenter study, 511 sexually active women selecting contraceptive implants were monitored four times in the 1st year, then semiannually through 5 years. Adverse events were elicited by query and physical examination, and their incidence was measured. Lifetable analyses computed pregnancy and other discontinuation rates. Cox regression models examined effects of age, parity, and preadmission desire for more children on continuation. Removal times were analyzed by analysis of variance. RESULTS: Three pregnancies occurred, yielding a 5-year cumulative rate of 1.3+/-0.8 per 100 users, an average annual rate of three per 1000 women, and an ectopic pregnancy rate of 0.6 per 1000 woman years. No pregnancies occurred to women weighing less than 79 kg. Prolonged or irregular menstrual bleeding, followed distantly by headache, weight gain, and mood changes, was the most frequent medical conditions leading to removal. Weight gain averaged 1 kg per year. Each annual continuation rate was above 80 per 100, for a cumulative 5-year rate of 39 per 100. Continuation was age-dependent, with younger women (younger than 25 years at entry) having lower 5-year continuation rates than older subjects (P < .01). Tissue trauma from deeply placed or poorly aligned implants or severe reactions to local anesthetic affected subjects in 3.1% of removals (nine cases). CONCLUSION: As measured by annual continuation rates of 80 per 100 or higher and annual pregnancy rates below one per 100, implant contraception in the United States was found to be highly acceptable and effective, year after year, regardless of the woman's age or family formation status. The cumulative 5-year pregnancy rate, 1.3 per 100, is comparable to that of tubal ligation.

Absorption kinetics of misoprostol with oral or vaginal administration.

OBJECTIVE: To compare the pharmacokinetics of vaginal and oral administration of the prostaglandin E1 analogue, misoprostol. METHODS: Twenty women received 400-micrograms doses of misoprostol either orally or as tablets placed in the vagina. Serum levels of principal metabolite, misoprostol acid, were measured at 7.5, 15, 30, 45, 60, 90, 120, and 240 minutes. The first ten women were pregnant and undergoing first-trimester abortions, and the last ten were not pregnant and had additional blood sampling at 360 minutes. We compared the pharmacokinetics of misoprostol acid after oral and vaginal administration. RESULTS: All 20 subjects completed the study. The maximum mean (+/- standard deviation [SD]) of misoprostol acid differed significantly between the oral and vaginal groups (277 +/- 124 compared with 165 +/d- 86 pg/mL, respectively; P = .03, analysis of variance), as did the mean +/- SD time to peak levels (34 +/- 17 compared with 80 +/- 27 minutes, respectively; P < .001) and areas under the misoprostol concentration versus time curve (mean +/- SD) up to 4 hours (n = 20,273.3 +/- 110.0 compared with 503.3 +/- 296.7 pg.hour/mL, respectively; P = .033) and up to 6 hours (n = 10, 300.0 +/- 103.3 compared with 956.7 +/- 541.7 pg.hour/mL, respectively; P = .029). The extent of absorption was highly variable among subjects in each group. CONCLUSION: There are significant differences in the pharmacokinetics of misoprostol administered by vaginal and oral routes that may explain the difference observed in clinical efficacy. Assuming that the pharmacologic effect of misoprostol is related to its concentration in the plasma, our observation of the prolonged serum concentrations in the vaginal group suggests that vaginal administration could be dosed at longer intervals than oral.

Medical abortion with oral methotrexate and vaginal misoprostol.

OBJECTIVE: To evaluate the safety and efficacy of oral methotrexate and vaginal misoprostol for medical abortion. METHODS: A prospective multicenter trial involved 300 women up to 49 days' gestation seeking elective abortion. Subjects received methotrexate 50 mg orally followed 5-6 days later by misoprostol 800 micrograms vaginally. The misoprostol dose was repeated if abortion did not occur. RESULTS: Complete abortion occurred in 273 of 299 women (91.3%; 95% confidence interval [CI] 87.5, 94.2%); one woman was lost to follow-up. Abortion occurred within 8 days of the methotrexate in 233 women (77.9%; 95% CI 72.8, 82.5%); the remaining 13.4% of women who aborted did so after a delay of 23.5 +/- 9.8 days (median 23 days, range 10-45). Vaginal bleeding lasted an average of 15 and 11 days in immediate and delayed-success abortions, respectively. Complete abortion rates decreased linearly with increasing body surface area. After methotrexate and misoprostol administration, nausea was reported in 37% and 33%, vomiting in 11% and 18%, diarrhea in 12% and 18%, and subjective fever or chills in 15% and 31% of subjects, respectively. CONCLUSION: Oral methotrexate followed by vaginal misoprostol is effective for abortion and represents an acceptable alternative to intramuscular methotrexate in regimens for medical abortion.

Digoxin to facilitate late second-trimester abortion: a randomized, masked, placebo-controlled trial.

OBJECTIVE: To examine the efficacy of digoxin for decreasing operative time, difficulty, and pain of late second-trimester surgical abortions. METHODS: We performed a randomized, double-masked, placebo-controlled trial of intra-amniotic digoxin for second-trimester dilation and evacuation (D&E) involving 126 consecutive women at an inner-city public hospital. Eligible women had gestational ages of 20-23.1 weeks, spoke English or Spanish, and were at least 16 years old. Digoxin (1 mg) or saline was injected intra-amniotically 24 hours before the procedure, at cervical laminaria insertion. The primary outcome was procedure duration. Sample size was based on 80% power to detect a difference of 3.5 minutes between groups. RESULTS: The two groups were similar in demographic factors, obstetric histories, and gestational duration. The average gestational length was 22.5 weeks. There was no difference in procedure duration (mean +/- standard deviation) between groups (placebo 14.7 +/- 7.0, digoxin 15.4 +/- 8.0). There were no differences in blood loss estimated by surgeons, pain scores, procedure difficulty scores, or complications between groups. Vomiting was significantly more common in those who received digoxin (placebo 3.1%, digoxin 16.1%). Most subjects (91%) reported that they preferred their fetuses were dead before the abortions. CONCLUSION: Although digoxin did not increase efficacy of late second-trimester abortion, patient preference might justify its use.

Implant contraception.

The experience of 6 million Norplant users has led to several more advanced implants. Implanon is a single-rod implant system containing a low androgenic progestin and requires 1 to 2 minutes for insertion and removal. Like other implants, Implanon prevents pregnancy by changing the character of the cervical mucus and interfering with luteal function. Unlike Norplant, though, Implanon is designed to prevent ovulation for the full duration of use. Implant contraception has several advantages over other types of contraception including high efficacy, minimal required maintenance, absence of estrogen, and rapid return of fertility after discontinuation. Implants can be a good choice for adolescents; women with hypertension, diabetes, anemia, endometriosis, or other medical problems; and women who are breast-feeding. Irregular bleeding is the most common adverse effect of implants and can be treated with several medication regimens. Preinsertion counseling, however, is the most important factor in ensuring satisfaction with implants. Unfortunately, no implant system is currently available in the United States since August 2000, but Implanon is expected to reach the U.S. market within the next 2 years.

Evaluation of a 1-year levonorgestrel-releasing contraceptive implant: side effects, release rates, and biodegradability.

OBJECTIVE: To determine the release rates, effects on ovulation, and side effects of two lengths of a biodegradable, subdermal contraceptive implant containing levonorgestrel in a caprolactone capsule. DESIGN: Phase II randomized clinical trial. SETTING: Public family planning clinic at an urban general hospital. PARTICIPANTS: Forty-eight healthy, parous, ovulating volunteers. INTERVENTION: Subjects were randomly assigned either a 2.5- or a 4.0-cm contraceptive capsule that was worn under the skin of the upper arm for 1 year if not removed earlier for other reasons. MAIN OUTCOME MEASURES: Serum concentrations of levonorgestrel, progesterone, estradiol, and lipoproteins were measured as were metabolic parameters. Vaginal bleeding and other side effects were recorded. After implant removal, remaining levonorgestrel, capsule viscosity, and molecular weight were measured. RESULTS: The 4-cm implant provided serum concentrations of levonorgestrel ranging from 0.65 ng/mL shortly after insertion to 0.20 ng/mL at 12 months, but the 2.5-cm implant resulted in levels too low for contraception. The 4-cm implant suppressed ovulation in approximately 80% of cycles over 1 year of use, but the 2.5-cm implant failed to suppress ovulation. The implants were rapidly and easily inserted and removed. They retained structural integrity through 1 year of use. Of 48 subjects, 32 had abnormal bleeding patterns; the mean number of days of bleeding per month was 7 with 23 days between episodes. Women using capronor maintained normal metabolic parameters except that low-density lipoprotein decreased slightly. CONCLUSIONS: The 4.0-cm implant is a promising contraceptive. There were no important metabolic effects, but there were bothersome minor side effects typical of progestin-only contraception.

Safety and efficacy of a triphasic oral contraceptive containing desogestrel: results of three multicenter trials.

This report combines the data obtained in three multicenter efficacy studies with a new triphasic oral contraceptive combination containing desogestrel (DSG) and ethinyl estradiol (EE). The studies were conducted at 40 investigational sites in the United States (38 centers) and Canada (2 centers) in support of the FDA approval of the product. In total, 1,095 subjects were exposed to the study medication for 11,231 cycles, corresponding to approximately 864 woman-years of use. Of these subjects, 414 completed at least 13 cycles of treatment. Contraceptive efficacy was high; six pregnancies occurred during the in-treatment period (two due to method failure and four due to user failure), corresponding to Pearl Indices of 0.23 and 0.46, respectively. The incidence of irregular bleeding was low, and the acceptability was excellent as evidenced by the low incidence of drug-related drop-outs. No drug-related serious adverse experiences were reported, and the incidence of other drug-related adverse experiences was generally low and decreased with continued use. No effects were seen on blood pressure, body mass index, laboratory parameters, cervical cytology and breast nodularity. These studies demonstrate that triphasic DSG/EE is an effective and acceptable triphasic oral contraceptive preparation with excellent cycle control and no significant physiologic effects.

Methotrexate and misoprostol for early abortion.

Methotrexate is cytotoxic to trophoblast and, in low doses, has minimal side effects. It is used to treat both gestational trophoblastic neoplasia and ectopic pregnancy. The cytotoxic effects of methotrexate on intrauterine trophoblast should be equivalent. To test this hypothesis, ten pregnant women, < 8 weeks' gestation were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days later by misoprostol, a prostaglandin E1 analogue. The first 4 patients received misoprostol 600 micrograms orally; none aborted soon after the misoprostol. Two patients aborted 25 and 26 days after the methotrexate injection and two elected a suction abortion after 14 days (one by choice and one because the pregnancy was still viable). The last 6 patients received misoprostol 800 micrograms vaginally and aborted within 3-8 hours. One patient had an incomplete abortion requiring a suction curettage 34 days after the misoprostol. Vaginal bleeding for these 6 patients lasted an average of 29 +/- 11 days (range, 12-42 days). No methotrexate side effects were observed. Vaginal misoprostol (800 micrograms) was significantly more effective (p = 0.005) than oral misoprostol (600 micrograms) in effecting abortion after intramuscular methotrexate.

Acceptability of manual versus electric aspiration for first trimester abortion: a randomized trial.

This study was conducted to compare the acceptability of manual and electric vacuum aspiration for first trimester elective abortion. Eighty-four women seeking abortions at less than 10 weeks gestation were randomized to abortion by manual or electric vacuum aspiration. Post-procedure questionnaires were administered to patients to assess pain, noise disturbance and overall satisfaction with the abortion procedure. Physicians reported procedural difficulty, their perceptions of patient discomfort and their overall acceptance of the procedure. Other outcomes included amounts of anesthesia required and complication rates. There were no significant differences in pain levels or satisfaction reported by patients; however, significantly more women in the electric group were bothered by noise (19% vs. 2%, p = 0.03). There were no differences in physician assessments of procedural difficulty; however, there were significantly more times in the electric group that physicians would have preferred manual aspiration (43% vs. 17%, p = 0.02). There were four crossovers from manual to electric, and none from electric to manual. It is concluded that physicians and patients find manual vacuum aspiration as acceptable as electric vacuum aspiration for elective abortions performed at less than 10 weeks gestation.

Knowledge and willingness to use emergency contraception among low-income post-partum women.

We performed a multivariate analysis to determine factors associated with knowledge and willingness to use emergency contraception in a consecutive sample of 371 post-partum women from an inner-city public hospital. Women were queried about previous contraceptive use, pregnancy history including abortions and unplanned pregnancies, and demographic characteristics. Outcomes included knowledge of emergency contraception and willingness to use it. Questionnaires were conducted in person, in English or Spanish.Of 371 women, 3% had used emergency contraception, 36% had heard of it, and 7% knew the correct timing for use. Two-thirds of the population indicated a willingness to use emergency contraception in the future. Factors positively associated with knowledge included being a teenager or more than 30 years old, prior use of condoms, and history of an elective abortion. Being multiparous, monolingual Spanish-speaking, or Asian were negatively associated with knowledge. Willingness to use emergency contraception was positively associated with being multiparous and negatively associated with a higher income, moral or religious objections to the use of emergency contraception, a belief that it is unsafe or a perception that it is an abortificient. Knowledge about emergency contraception, especially correct timing, remains low. Multiparous women should receive increased education given their lack of knowledge but willingness to use emergency contraception. In order to increase the acceptability of emergency contraception, educational efforts must include accurate information about its mechanism of use and safety.

Cervical neoplasia risk in women provided hormonal contraception without a Pap smear.

The study was conducted to determine whether women using a demonstration program providing hormonal birth control without concurrent pelvic examination (First Stop) are at higher risk of cervical neoplasia compared to women using traditional family planning clinics. Using retrospective ion of medical charts, we compared risk factors for cervical neoplasia among 400 First Stop clients and 400 traditional site clients matched on age, race, and contraceptive method. We determined prevalence of these factors: previous abnormal cervical smear, <16 years at first intercourse, multiple sexual partners, high parity, history of sexually transmitted infections, and current cigarette smoking. First Stop clients were not at greater likelihood of having any risk factor for cervical neoplasia except high parity. First Stop clients who failed to follow through on a referral to a traditional clinic were not more likely to be of higher risk than those who did follow through. Of 13 First Stop clients with the highest risk profiles (previous abnormal cervical smear plus one other risk factor), one did not follow through with referral. First Stop clients choosing hormonal contraception without a pelvic examination do not appear to be at substantially higher risk of cervical neoplasia. Future research should quantify more precisely the risks and benefits of the general application of this strategy on a population level.

Serum concentrations of estradiol, progesterone, and levonorgestrel are not determinants of endometrial histology or abnormal bleeding in long-term Norplant implant users.

The objective of this study was to determine the relevance of serum estradiol, progesterone and levonorgestrel concentrations to endometrial histology and uterine bleeding associated with long-term Norplant implants use. Eighteen five-year users of Norplant implants had endometrial biopsies and determinations of serum estradiol, progesterone and levonorgestrel concentrations. Correlations among these factors and uterine bleeding were calculated. Proliferative endometrium (but not sex steroid levels) was associated with abnormal bleeding. Neither ovarian steroid nor levonorgestrel concentrations was a predictor of abnormal bleeding. Hyperplastic changes were not seen even with high estradiol and low levonorgestrel levels.

PIP: At the gynecologic clinic of San Francisco General Hospital in California, 18 women aged 27-44 who had used Norplant contraceptive implants for the full 5 years of effectiveness and who had at least 1 year of recurrent episodes of vaginal bleeding agreed to have an endometrial biopsy and a venipuncture for determination of serum estradiol, progesterone, and levonorgestrel levels. Investigators wanted to learn whether hormonal factors contributed to abnormal bleeding patterns in women who had used levonorgestrel-releasing contraceptive implants for 5 years. At the time of biopsy and venipuncture, 13 (72%) women had normal bleeding patterns. Two women had no apparent follicular activity. Six other women (44%) had a low estradiol level (i.e., 100 pg/ml). 14 women (77%) had no signs of luteal development (i.e., progesterone level 3 ng/ml). None of the women had hyperplastic endometrium. The endometrial index was used to describe endometrial histology and ranged from secretory to proliferated characteristics of the endometrium. It differed significantly between Norplant users with normal bleeding and those with abnormal bleeding (0.32 [a mixture of secretory and proliferative characteristics, but especially secretory characteristics] vs. 0.9 [close to full proliferation of the endometrium]; p 0.01). Serum estradiol, progesterone, and levonorgestrel levels were not significantly different between the two groups. These findings suggest that a proliferative endometrium, rather than sex steroid levels, was linked to abnormal bleeding. Thus, abnormal bleeding among long-term Norplant users is probably not a risk factor for developing endometrial cancer.