The effects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors.

OBJECTIVE: This study was undertaken to evaluate the effects on hemostatic factors of a low-dose preparation of levonorgestrel and ethinyl estradiol in a 12-cycle study. STUDY DESIGN: Thirty healthy women began taking 100 microg levonorgestrel and 20 microg ethinyl estradiol on the first day of the menstrual cycle, continued to take the preparation for the next 21 days, and then took placebo for 7 days. Mean changes in prothrombin time, partial thromboplastin time, and levels of factors VII and X, antithrombin, plasminogen, fibrinogen, protein S, thrombin-antithrombin complexes, and D-dimer were analyzed at baseline and at cycles 3, 6, and 12 with paired Student t tests. RESULTS: Factor X, plasminogen antigen and activity, and D-dimer levels were significantly increased (P

Cycle control with oral contraceptives containing 20 micrograms of ethinyl estradiol. A multicenter, randomized comparison of levonorgestrel/ethinyl estradiol (100 micrograms/20 micrograms) and norethindrone/ethinyl estradiol (1000 micrograms/20 micrograms).

A randomized, open-label, multicenter study was undertaken to compare the effects of oral contraceptives (OC) containing 100 micrograms levonorgestrel (LNG)/20 micrograms ethinyl estradiol (EE) (Aless/Loette) and 1000 micrograms norethindrone acetate (NETA)/20 micrograms EE (Loestrin Fe 1/20) on menstrual cycle control over four cycles of use. A total of 84 evaluable women provided 274 cycles of exposure in the LNG/EE group, and 89 women provided 289 cycles of exposure in the NETA/EE group. Overall, the LNG/EE group achieved a consistently higher percentage of normal menstrual cycles as well as a lower rate of intermenstrual bleeding and amenorrhea than the NETA/EE group. In cycle 4, 63.8% of cycles were normal in the LNG/EE group compared with 41.9% in the NETA/EE group (p < 0.005). Of the total cycles in the NETA/EE group, 10% were amenorrheic, compared with 1.1% in the LNG/EE group. The occurrence of bleeding and/or spotting was significantly lower in cycles 2 and 3 in the LNG/EE group (41.7% and 34.8%, respectively) compared with the NETA/EE group (62.3% and 56.3%; p < 0.05). Other cycle variables were generally similar between groups, as was the incidence of adverse events. These results demonstrate that good cycle control was achieved with an OC containing 20 micrograms EE and that 100 micrograms LNG/20 micrograms EE produces better cycle control than 1000 micrograms NETA/20 micrograms EE.

Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive.

Analogous to recommendations for treatment of side effects of early pregnancy and premenstrual syndrome, use of vitamin B6 has been recommended for the treatment of side effects of oral contraceptive (OC) use. A randomized, triple-blinded controlled trial of 124 women was done to evaluate the effect of taking 150 mg of vitamin B6 daily for 30 days on the severity of nausea, headache, vomiting, dizziness, depression, and irritability associated with the initiation of low-dose (30 micrograms norgestrel and 30 micrograms ethinyl estradiol) OG use. The severity of the symptoms was measured on a scale from 0 to 3 (not present to severe), and was evaluated at one month after admission. The two treatment groups (vitamin B, and placebo) had comparable baseline characteristics. From admission to follow up, there was a decrease in the severity of all symptoms in both groups. There was no statistically significant difference in the reductions found in the vitamin B6 and the placebo groups, although reductions in the severity of headache and dizziness were greater in the B6 group. The decrease in the severity of all OC side effects can be explained more by a placebo effect than by a marginal pharmacological effect of the vitamin B6.

PIP: Use of vitamin B-6 has been recommended for the treatment of side effects associated with combined oral contraceptive (OC) use. To evaluate this recommendation, a randomized, triple-blinded controlled trial of 124 women recruited from 2 health centers in Zacatecas, Mexico, was conducted. 62 women received 150 mg of vitamin B-6 daily for 30 days, while the remaining 62 received a placebo. All cases and controls were new or continuing users of an OC containing 30 mcg of norgestrel and 30 mcg of ethinyl estradiol. Women rated the severity of 6 common OC side effects (nausea, headache, vomiting, dizziness, depression, and irritability) on a scale from 0 to 3 at baseline and 30 days after admission. There was a decrease in the severity of all 6 symptoms in both groups. Although higher proportions of women in the vitamin B-6 group reported decreases in OC-related side effect severity between admission and the 30-day follow-up visit, these differences were appreciable only for headache and dizziness and none was statistically significant. No evidence of vitamin B-6 toxicity was observed. However, this study failed to substantiate a clinically important pharmacologic effect of vitamin B-6 on OC side effects.

Pre-introductory clinical trials of Norplant implants: a comparison of seventeen countries' experience.

This report summarizes the data collected in pre-introductory Norplant implants clinical trials in 17 countries in Latin America, Asia and Africa that were coordinated by either the Population Council or Family Health International (FHI) between 1984 and 1991. A total of 16,282 women between the ages of 18 and 40 years participated in the studies with semi-annual or annual follow-up visits for up to 5 years. Gross cumulative pregnancy rates were < 0.6 per 100 women in the first year and < 1.5 in the second year in all countries. Significant differences in cumulative 5-year pregnancy rates were observed between weight groups 40-49 and 50-59 kg and between 50-59 and 60-69 kg body weight but not between 60-69 kg and those > or = 70 kg. Total cumulative discontinuation rates after five years of Norplant implants use ranged from 35.8 to 60.0 per 100 women. Younger age and low parity were associated with a higher discontinuation rate. Cumulative discontinuation rates for menstrual reasons more than doubled between the end of the first year and second year of use in 13 of 17 countries. This analysis and one previous review provide the only comparison of Norplant contraceptive system study results across a wide diversity of countries; thus allowing an appreciation of the range of clinical experience with Norplant implants and the regional differences in that experience.

A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.

A non-comparative study of a progestin-only oral contraceptive (POC) containing 75 micrograms norgestrel was conducted at 22 sites in 14 countries. This study was designed to evaluate safety, contraceptive efficacy, and the overall acceptability of a POC in breastfeeding women. A total of 4,088 women entered the study over a three-year period and 29,399 woman-months of experience was gathered. Women had follow-up visits at 2, 6, and 11 months after admission. Headaches and vaginal discharge were the medical complaints most commonly reported by women, both prior to and after admission. Menstrual problems were reported by 59% of the women after admission. Of the 3,714 women who returned for at least one follow-up visit, 1,101 (29.6%) discontinued through month 11. The 11-month total discontinuation percentage, including those lost to follow-up (25.3%) was 51.6%. The most common reason given for discontinuation was a woman's desire for a change in contraceptive method. Only 4.9% discontinued pill use for menstrual problems, a percentage far below those generally reported for POCs. Twenty-nine unintended pregnancies occurred through 11 months giving a gross cumulative life table rate of 1.2 per 100 women (Pearl Index = 1.4). The POC appears to be a safe, effective and acceptable contraceptive option for postpartum breastfeeding women.

Experimental methods of contraception.

While most new contraceptives currently in development incorporate existing contraceptive agents into new delivery systems, several types of contraceptives with novel mechanisms of action are making steady progress. The antiprogestin mifepristone (better known as RU 486) is being tested as an ovulation inhibitor, as a once-a-month pill, and as a postcoital contraceptive. An antiestrogen, Centchroman (Hindustan Latex, India), is in use in India as a once-a-week, nonsteroidal pill. The development of more potent pituitary gonadotropin antagonists has improved their potential to block ovulation in women and to inhibit spermatogenesis in men (which requires concurrent administration of testosterone). Another promising male contraceptive is an intraluminal vas occlusion plug tested extensively in China that can be removed with no apparent detriment to future fertility. Finally, several types of immunocontraceptives could become the most specific form of fertility control by directing an antibody response against the fertilized or unfertilized egg or against sperm.

Insertion site complications during the first year of NORPLANT use.

Although review articles have provided much information on the NORPLANT system, information on insertion site complications based on multi-country trials has been limited to infection rates. This paper examines 2,674 NORPLANT acceptors from seven countries who were enrolled and followed for one year. The one-year incidence rates of infection (0.8%), expulsion (0.4%) and local reaction (4.7%) varied widely among countries and clinics within a country. In contrast to previous reports that insertion site complications occur during the first few weeks of use, these data show that a substantial proportion of insertion site infections (34.6%) and implant expulsions (64.3%) were reported after the first two months of use, while 35.7% of local reactions were reported after 4.5 months of use. Of the 16 women with infections who did not have the implants immediately removed, 8 eventually required or requested removal, indicating that the ICCR recommendation for immediate removal in case of infection appears appropriate. An awareness of the frequency of insertion site complications, distribution of the time of onset post-insertion and potential sequelae of complications will aid clinicians in better client counseling and complication management.

PIP: Although review articles have provided much information on the NORPLANT system, information on insertion site complications based on multi- country trials has been limited to infection rates. This paper examines 2,674 NORPLANT acceptors from 7 countries (Bangladesh, Haiti, Nepal, Nigeria, Philippines, Singapore, Sri Lanka) at 19 sites who were enrolled and followed for 1 year. The 1 year incidence rates of infection (0.8%), expulsion (0.4%) and local reaction (4.7%) varied widely among countries and clinics within a country. In contrast to previous reports that insertion site complications occur during the 1st few weeks of use, these data show that a substantial proportion of insertion site infections (34.6%) and implant expulsions (64.3%) were reported after the first 2 months of use, while 35.7% of local reactions were reported after 4.5 months of use. Of the 16 women with infections who did not have the implants immediately removed, 8 eventually required or requested removal, indicating The Population Council's International Committee for Contraception Research (ICCR) recommendation for immediate removal in case of infection appears appropriate. An awareness of the frequency of insertion site complications, distribution of the time on onset post-insertion and potential sequelae of complications will aid clinicians in better client counseling and complication management.

A comparative evaluation of the safety and contraceptive effectiveness of 65 mg and 100 mg of 90-day norethindrone (NET) injectable microspheres: a multicenter study.

The first of a second generation of slow-release injectable contraceptives is the norethindrone (NET) microspheres with a 90-day duration of action. It was evaluated at 65-mg and 100-mg doses for safety and contraceptive effectiveness in two randomized, single-blind trials among 131 women: 94 women for 12 months and 37 women for 6 months. The 6-month trial included additional evaluations of ovarian function and serum NET values. In the 6-month trial, no indication of ovulation was detected in the 100-mg dose group, while 3 of the 19 women in the 65-mg group showed signs of ovulation (progesterone greater than 3 ng/ml). No pregnancies were reported in the 100-mg group and one pregnancy in the 65-mg group resulted in a life-table pregnancy rate for that dose of 2.6 per 100 woman-years (95% confidence interval, 0 to 7.5). Days of vaginal bleeding were analyzed for 30 days before treatment and in 90-day reference periods after treatment. The mean number of vaginal bleeding and spotting days increased initially after the first injection in both dose groups, but decreased to below baseline in both dose groups after 6 months. The two doses appear comparable in clinical safety, side effects, vaginal bleeding patterns, and laboratory measures. With the preliminary estimate of efficacy, the 65-mg dose would be the minimally effective dose for the NET 90-day injectable contraceptive.

Bleeding patterns and acceptability among Norplant users in two Asian countries.

Changes in menstrual bleeding patterns are the most frequent reason for discontinuing NORPLANT during the first year of use. Although NORPLANT is used by more women in Asia than in any other region, the changes that occur among these women are not well documented. In pre-introductory clinical trials of NORPLANT in the Philippines and Sri Lanka, 175 women were enrolled with greater than 95% continuing the method after one year. Daily menstrual bleeding calendars were kept by 94% of subjects for nine months and by 66% for one year. In contrast to findings in previous studies which showed that approximately 60% of NORPLANT users had bleeding disruptions in the first year of use, almost all of these women experienced bleeding disruptions. In a one-year study of menstrual pattern changes, increased bleeding was found to occur with the same frequency as reduced bleeding. However, the changes experienced by the Asian women tended to be decreases, rather than increases, in menstrual bleeding.

Case-fatality rates for tubal sterilization in U.S. hospitals, 1979 to 1980.

To update a 1977 to 1978 case-fatality estimate for tubal sterilization in U.S. hospitals, we reviewed the medical records of women reported by the Commission on Professional and Hospital Activities to have died after tubal sterilization procedures in 1979 or 1980. We project that the most reasonable case-fatality rate estimate is slightly greater than 9 per 100,000 sterilizations if all deaths associated with the procedure are considered. Rate estimates that assume minimum and maximum numbers of all associated deaths in our sample are approximately 6 per 100,000 and 10 per 100,000 sterilizations, respectively. However, when only deaths that can be attributed to sterilization per se are considered, the most reasonable case-fatality rate is estimated at between 1 and 2 per 100,000 procedures, a lower rate than previously reported. Rate estimates that assume minimum and maximum numbers of attributable deaths in our sample are approximately 1 per 100,000 and 5 per 100,000 sterilizations, respectively. These results further indicate that death attributable to tubal sterilization is rare.

PIP: The medical records of women reported by the US Commission on Professional and Hospital Activities to have died after tubal sterilization procedures in 1979-80 were reviewed to obtain current case-fatality estimates. The previous estimate, which used data from 1977 and 1978, was 3.6/100,000 procedures. The Commission identified 53 women who had tubal sterilization and who died during hospitalization; however, permission to review medical records was obtained for only 37 of these women. Of these 37 deaths, 28 were associated with sterilization and 9 involved coding errors. Of the 28 sterilization-associated deaths, 17 were attributable to concurrent cesarean section and 7 were attributable to other concurrent procedures. Of the 3 women whose deaths were clearly related to the sterilization procedure, 2 had no underlying illnesses and 1 had severe congenital heart disease (which may have contributed to her death). In the 4th case, the probable cause of death was intracranial hemorrhage caused by pregnancy-induced hypertension. The 28 sterilization-associated deaths occurred among a total population of 433,744 women who received tubal sterilizations in US hospitals in 1979 and 1980. Since 28 of the 37 deaths reviewed were associated with sterilization, it was assumed that 76% of the unreviewed deaths were sterilization-associated. This assumption results in a total number of 40 deaths and a case-fatality rate of 9.2/100,000 procedures. Use of the same procedure suggests a sterilization-attributable case-fatality rate of 1.5/100,000. In view of the small number of deaths involved, the decline in sterilization-attributable deaths from 1977-78 and 1979-80 should not be interpreted as a trend over time. However, these results confirm the belief that death attributable to tubal sterilization is a rare event.

A comparison of two cause-of-death classification systems for deaths among women of reproductive age in Menoufia, Egypt.

Mortality data ascertained from sources other than a death registration system can validate the accuracy of the system, but this information is rarely obtained. Data on 1979 deaths among reproductive age women were collected in the 1981-1983 Reproductive Age Mortality Survey (RAMOS) in the governorate of Menoufia, Egypt, and compared with data on these deaths as recorded by the Egyptian death registration system. Although the distribution of the causes of death were similar, there were substantial differences between classification systems for deaths due to particular causes. Over half of the deaths classified differently by the systems were those assigned to circulatory disease on the death certificate. In contrast, there was a high rate of agreement between systems in the classification of trauma deaths. About half (52.4%) of cancer deaths had the same site-specific cancer diagnosis assigned by RAMOS. The percentage of deaths assigned to maternal causes was three times higher in RAMOS (19.2%) than on death certificates (6.1%). Reported mortality rates for this often-preventable cause of death have been substantially underestimated in national death registration systems. Such underreporting masks the need for additional prenatal care and maternal health programmes.

Complications of vasectomies in the United States.

Physicians in the United States were surveyed in 1983 to gather information concerning the number of vasectomies they performed in 1982 as well as their use of anesthesia and complications of those vasectomies. Most urologists performed vasectomies, whereas family physicians and general surgeons were less likely to do so. As expected, most physicians used local anesthesia, occasionally in combination with a sedative; however, 22 percent of physicians reported using general anesthesia for at least some vasectomies. Complication rates were in the ranges reported by previous case series. Physicians who performed between one and ten vasectomies in 1982 had higher rates of hematoma and hospitalization for treatment of a complication than physicians who performed more vasectomies. Maintenance of surgical skills appears to be important in preventing complications of this usually low-risk procedure.

Women's perceptions of the pill's potential health risks in Sri Lanka.

PIP: The 1985-86 Rural Family Planning Survey was confined to the rural sector and covered 17 of the 24 districts of Sri Lanka. Multistage stratified random sampling with probability in proportion to size was used in selecting the sample. A total of 3253 respondents were successfully interviewed between August 1985 and February 1986. 98.6% of the respondents had heard about oral contraception (the pill). Of those who had heard of it, 2/3 believed that pill-taking had harmful effects on women's health and body. This perception was constant across all social, economic, and educational groups. 3 characteristics were associated with small but interesting differences in the perception of risk of pill-taking. A slightly higher but significant percentage of those who work outside the home on an irregular basis were more likely to say that the pill detrimentally affects women's health. Those who have ever used traditional contraceptive methods (mainly calendar rhythm and withdrawal) were more likely to have a negative perception than those who had never used any traditional or modern method except the pill. Women living in developed areas were more likely to think that the pill had detrimental effects on health than women living in less developed areas. 1/3 of the women believed that the pill causes heart attacks, cancer, and birth defects. 16-18% thought that the pill causes weight gain and stroke/paralysis. About 17% thought the pill causes permanent sterility, and 10% thought it causes sexually transmitted diseases. Women's education and their status of pill use were the 2 most powerfully and consistently related factors identifying the women who gave "yes" responses from those who gave "no" responses to each of the 7 specified health problems. The results also showed that when the effects of all the variables were considered simultaneously, neither the husband's education nor the respondent's work status remained a significant variable discriminating the subgroups of women who have correct versus incorrect perceptions. 1 out of 3 women thought that childbearing was safer than pill-taking. This perception did not vary significantly across many subgroups, except for women's work status, contraceptive use, couple's wealth status, and the area development level. 1 of the most surprising findings of this study was that there is generally an inverse relationship between the modernity status of the women and their correct perceptions of the potential health risk of OC use with regard to cardiovascular disease and stroke.^ieng

Human papillomavirus and cervical neoplasia: epidemiological considerations.

Recent clinical research using new diagnostic and laboratory techniques indicates that human papillomavirus (HPV) infection may play a key role in the development of cervical neoplasia. Cervical HPV infection is found in 1-3% of routine Papanicolaou smears, and preliminary data suggest that women with cervical HPV infection have about a tenfold greater risk of developing cervical intraepithelial neoplasia (CIN) compared with those with no HPV infection. This paper discusses how epidemiological studies can reduce misclassification of cervical HPV infection and CIN through selective use of research advances in cytologic, histologic and colposcopic techniques. These studies can also assess whether certain potential cocarcinogens interact synergistically with HPV. Since an estimated 2-10% of women with cervical HPV lesions develop associated CIN within a year, it appears feasible to conduct prospective studies of the risk of malignant transformation of cervical HPV lesions.

Luteal phase pregnancy and tubal sterilization.

The effectiveness of several measures that may reduce the risk of luteal phase pregnancies after interval tubal sterilization was analyzed. Using data from the Collaborative Review of Sterilization on 5495 women, 18 luteal phase pregnancies were identified. Women who underwent sterilization after their estimated date of ovulation had a low risk of having a luteal phase pregnancy if they used oral contraceptives or an intrauterine device in the month before sterilization. Of the 18 luteal phase pregnancies, 14 (78%) occurred among the 16.8% of the women who were sterilized after their estimated date of ovulation and who had used barrier, rhythm, or withdrawal methods of contraception in the month before sterilization. The use of concurrent dilatation and curettage in these women at increased risk of luteal phase pregnancy did not lower their risk to that of women who were sterilized before their estimated date of ovulation.

Regret after decision to have a tubal sterilization.

To determine characteristics associated with regretting sterilization that can be determined preoperatively, we analyzed data from the Collaborative Review of Sterilization (CREST), a multicenter, prospective, observational study. Of 5022 women, 2.0% regretted having had a tubal sterilization at 1 year after the procedure and 2.7% did so after 2 years. Using a multivariate analysis to identify risk factors for regret, we found that almost all characteristics were more closely associated with regret at 1 year than at 2 years postoperatively. Of the characteristics we examined that could be objectively determined preoperatively, we considered only age less than 30 years and (for whites) a concurrent cesarean section to be risk factors for regret at 2 years after sterilization. However, in absolute terms, less than 10% of women with both those risk factors regretted having the procedure.

PIP: To determine characteristics associated with regretting sterilization that can be determined preoperatively, the authors analyzed data from the Collaborative Review of Sterilization (CREST), a multicenter, prospective, observational study. Of 5022 women, 2.0% regretted having had a tubal sterilization at 1 year after the procedure, and 2.7% did so after 2 years. Using a multivariate analysis to identify risk factors for regret, the authors found that almost all characteristics were more closely associated with regret at 1 year than at 2 years postoperatively. Of the characteristics examined that could be objectively determined preoperatively, only age less than 30 years and (for whites) a concurrent cesarean section were considered to be risk factors for regret at 2 years after sterilization. However, in absolute terms, less than 10% of women with both those risk factors regretted having the procedure.

Contraceptive use before tubal sterilization.

A woman's decision to undergo tubal sterilization may be affected by her experience with temporary contraception. To examine this issue we analyzed data from the Collaborative Review of Sterilization, a multicenter, prospective study of the health effects of sterilization operations on women aged 15-44 years. Data on contraceptive use by a comparison group of nonsterilized women were drawn from a random, population-based sample of women aged 20-44 years who were controls in a large study of cancer and steroid hormone use. Sterilized women reported ever using a higher average number of contraceptive methods than did nonsterilized women. As compared with nonsterilized women, a higher percentage of sterilized women reported ever using contraceptives (99% versus 91%), especially two types, barrier and rhythm or withdrawal. Prior to selecting sterilization as a permanent contraceptive method, the sterilized women had more extensive experience with temporary contraceptives, particularly the less effective ones, than did the comparable nonsterilized women.

PIP: This study compared contraceptive use histories in women undergoing tubal sterlization to those obtained from women who had not sought sterilization. The 6080 tubal sterilization cases were drawn from the Collaborative Review of Sterilization (CREST) study; 412 nonsterilized controls were drawn from the control group of the Cancer and Steroid Hormone (CASH) study. 4 types of contraceptive methods were evaluated: oral contraceptives (OCs), IUDs, barrier methods (diaphragm, foam, or condom), and traditional methods (withdrawal and rhythm). Ever-use rates were standardized by age, race, years of education, and gravidity. Compared with nonsterilized women, a higher percentage of women undergoing tubal sterilization reported ever-use of IUDs (35.1% of sterilized women versus 24% of nonsterilized women), barrier methods (66/.1% versus 15.9%, respectively), and rhythm or withdrawl (29.4% versus 14.6%, respectively). Rates of OC use were similar (87.1% among sterilized women versus 84.3% among nonsterilized controls). Further analysis indicated that 1.4% undergoing tubal sterilization compared to 11.9% of the nonsterilized women had never used any contraceptive method. 39.6% of the women in the sterilization group but only 6.2% of the controls had used 3-4 different contraceptive methods. The former group of women were more likely to have higher gravidity and a history of abortion than those who had used fewer methods before their tubal sterilization. These findings suggest that experience with temporary contraceptives may affect the decision to undergo tubal sterilization.