Vasectomy and cardiovascular deaths in Korean men: a community-based case-control study.

This community-based case-control study was carried out in four cities in South Korea to examine whether vasectomy is associated with a long-term increased risk of cardiovascular death in Korean men. Our results coincide with those from epidemiological studies conducted in Western countries as well as the one study conducted in China and do not support the vasectomy--atherosclerosis hypothesis originating from animal research.

PIP: Researchers compared data on 413 35-65 year old men who died between October 1982-September 1983 with data on 413 healthy 35-65 year old men. Both cases and controls were from Seoul, Pusan, or Incheon, South Korea. Interviewers spoke only to wives as proxies of the deceased. 36 cases and 26 controls had undergone a vasectomy, but none of their counterparts had undergone a vasectomy. This paired analysis revealed a statistically nonsignificant odds ratio (OR) of 1.38. The researchers then controlled for all confounding variables while conducting a multivariate analysis. They found the adjusted OR to be 1 for vasectomy. None of the 3 underlying causes of death ORs (cerebrovascular disease, ischemic heart disease, and hypertensive disease) different significantly from unity. The leading cause of death was stroke (71.4%). Just 7% died from ischemic heart disease. Limitations of the study included problematic diagnosis of underlying causes of death, heterogeneous cardiovascular deaths, and the lack of distinction between thrombotic or hemorrhagic stroke, and small number of cases when stratified by length of exposure to vasectomy or by cause of death. Nevertheless, like other epidemiologic studies, this community-based study did not find an association between cardiovascular deaths and vasectomy, even though animal research in the late 1970s-early 1980s found that vasectomy in monkeys brought on a progression of atherosclerosis.

Rare events occurring at insertion of an intrauterine device--a review of an international experience.

Events occurring at the time of insertion of an intrauterine device (IUD) are rarely studied, especially for parous women for whom, in theory, IUD contraception is most suitable. These events, although rare, cause personal distress, embarrassment and inconvenience and can have a negative impact on IUD acceptance. Sixty million women worldwide are using IUDs. Thus, even a rare event may have important public health implications. To avoid such occurrences, the risk factors of these rare events need to be delineated. The large international IUD data set compiled by Family Health International (FHI) since 1972 provides a unique opportunity to achieve this purpose. Four IUD insertion-related rare events have been studied, namely: insertion failure, uterine perforation, syncope and other vasovagal reactions, and severe insertional pain. This review paper summarizes the important findings from these as well as other relevant studies. This broad experience should form the basis by which health personnel inserting IUDs can improve the quality of care for women requesting a device for contraception.

Pregnancy following minilaparotomy tubal sterilization--an update of an international data set.

Seventeen pregnancies were reported from an international tubal sterilization data set comprising 1,862 minilaparotomy cases between 1978 and 1984. Of these 17, seven (41.2%) were diagnosed as luteal phase pregnancies. Of the 10 pregnancies due to sterilization failure, one was an ectopic pregnancy which occurred much later (20 months poststerilization) than the intrauterine pregnancies (10 months or less). Poststerilization pregnancy risk was greater among gravid women (those undergoing sterilization at the time of abortion or soon after childbirth) than among non-gravid women (those undergoing interval sterilization). These findings are, in general, consistent with those of previous studies using a much larger data set of primarily laparoscopic sterilizations. Pregnancies occurred with every type of mechanical tubal occlusion techniques included for study (the tubal ring, the Rocket Clip, the Secuclip and the Filshie Clip), and a frequently reported reason for failure was incorrect placement of the device. No pregnancies occurred in women sterilized with the non-mechanical Pomeroy/modified Pomeroy techniques. Findings of this analysis suggest that in minilaparotomy sterilization, for the mechanical tubal occlusion techniques to be as effective as the Pomeroy/modified Pomeroy techniques, more care and skill are required for the operator.

PIP: 17 pregnancies were reported from an international tubal sterilization data set comprising 1,862 minilaparotomy cases between 1978 and 1984. Of these 17, 7 (41.2%) were diagnosed as luteal phase pregnancies. Of the 10 pregnancies due to sterilization failure, 1 was an ectopic pregnancy which occurred much later (20 months poststerilization) than the intrauterine pregnancies (10 months or less). Poststerilization pregnancy risk was greater among gravid women (those undergoing sterilization at the time of abortion or soon after childbirth) than among non-gravid women (those undergoing interval sterilization). These findings are, in general, consistent with those of previous studies using a much larger data set of primarily laparascopic sterilizations. Pregnancies occurred with every type of mechanical tubal occlusion technic included for study (the tubal ring; the Rocket Clip; the Secuclip; and the Filshie Clip), and a frequently reported reason for failure was incorrect placement of the device. No pregnancies occurred in women sterilized with the non-mechanical Pomeroy/modified Pomeroy technics. Findings of this analysis suggest that in minilaparotomy sterilization, for the mechanical tubal occlusion technics to be as effective as the Pomeroy/modified Pomeroy technics, more care and skill are required for the operation.

A clinical trial of Neo Sampoon vaginal tablets and Emko foam in Alexandria, Egypt.

Results are reported for a comparative 12-month study of Neo Sampoon foaming vaginal tablets containing 60 mg of the spermicide, menfegol, and Emko vaginal foam containing an 8.0% concentration of the spermicide, nonoxynol-9. Conducted in cooperation with the Family Planning Association in Alexandria, Egypt, the trial included 349 women who were randomly allocated to use one of the two contraceptive products. The twelve-month cumulative life-table rate for accidental pregnancy (per 100 women) was 2.8 for Neo Sampoon tablet users and 2.1 for Emko foam users. The 12-month continuation rates were 77.6 and 77.2 per 100 women for the tablet and foam groups, respectively. In both groups, the majority of discontinuations from the study were for personal reasons, including lack of confidence in the method, messiness, partner's objection and a burning sensation. Few women reported a product-related complaint while using their assigned contraceptive method. The most commonly reported complaint for both methods was that use of the product led to an uncomfortable burning sensation for the woman and/or her partner. This complaint, however, was cited by less than 5% of the women in each group. Thus, a combination of low pregnancy rates, few complications and complaints and high continuation rates confirm the relative acceptability, effectiveness and short-term safety of these methods of contraception among this sample of Egyptian women.

PIP: Results are reported for a 12-month study of Neo Sampoon foaming vaginal tablets containing 60mg of the spermicide, menfegol, and EMKO vaginal foam containing an 8.0% concentration of the spermicide, nonoxynol-9. Conducted in cooperation with the Family Planning Association in Alexandria, Egypt, the trial included 349 women randomly allocated to use 1 of 2 contraceptive products. The 12-month cumulative life-table rate for accidental pregnancy (per 100 women) was 2.8 for Neo Sampoon tablet users and 2.1 for Emko foam users. The 12-month continuation rates were 77.6 and 77.2/100 women for the tablet and foam groups, respectively. In both the majority of discontinuations from the study were for personal reasons, including lack of confidence in the method, messiness, partner's objection and a burning sensation. Few women reported a product-related complaint while using their assigned contraceptive method. The most commonly reported complaint for both methods was that use of the product led to an uncomfortable burning sensation for the woman and/or her partner. This complaint, however, was cited by 5% of the women in each group. Thus, a combination of low pregnancy rates, few complications and complaints and high continuation rates confirm the relative acceptability, effectiveness and short-term safety of these methods of contraception among this sample of Egyptian women.

[Vasectomy and cardiovascular deaths in Korean men].

PIP: This community-based case-control study was carried out in 4 cities in South Korea to investigate whether vasectomy is associated with a long-term increased risk of cardiovascular death. The cases are 413 men who died at ages 35-65 between October 1982 and September 1983 with an underlying cause of death, as reported in the death certificate, of ischemic heart disease (29 men), nontraumatic cerebrovascular disease (295 men), or hypertensive disease (89 men). Each case was matched for age and parity to a living male from the same neighborhood. Wives of cases and controls were interviewed at home as surrogates. Univariate analysis of the association between vasectomy and cardiovascular death revealed an odds ration of 1.4. Multivariate logistic regression analysis, controlling for potentially confounding variables, revealed a lower adjusted odds ratio of 1. The authors did not detect an association between vasectomy and cardiovascular death in Korean men; nor did they find a statistically significant increased risk for those subjects who had a vasectomy 15 years or more previously. These results concur with those from Western epidemiologic studies and do not support the vasectomy-atherosclerosis hypothesis originating from animal research.^ieng

Severe pain at interval IUD insertion: a case-control analysis of patient risk factors.

This investigation, using a case-control analysis approach on an IUD data set from a less-developed country center, delineated four risk factors in patient characteristics that are associated with severe pain at interval IUD insertion. They are: higher education (greater than or equal to seven years), low-parity (1-2 live births), longer open interval (greater than or equal to 13 months) between the end of the last pregnancy and insertion, and non-breastfeeding at the time of insertion. Adjusted relative risks estimated by odds ratios are 2.1, 2.7, 2.7 and 5.0, respectively. For women with a combination of the above risk factors, they have a further increased (additive in nature) risk of suffering severe insertion pain. Similar analysis was also performed on a developed country center data set for which only the effect of education and parity could be studied; an odds ratio of 5.0 for nulliparity was obtained. The plausibility of these findings as well as their clinical and programmatic implications are discussed.

PIP: This investigation, using a case-control analysis approach on an intrauterine device (IUD) data set from a less-developed country center, delineated 4 risk factors in patient characteristics that are associated with severe pain at interval IUD insertion. They are: higher education ( or = 7 years) low parity (1-2 live births), longer open interval ( or = 13 months) between the end of the last pregnancy and insertion, and non-breast feeding at the time of insertion. Adjusted relative risks estimated by odds ratios are 2.1, 2.7, 2.7, and 5.0 respectively. For women with a combination of the above risk factors, they have a further increased (additive in nature) risk of suffering severe insertion pain. Similar analysis was also performed on a developed country center data set for which only the effect of education and parity could be studied; an odds ratio of 5.0 for nulliparity was obtained. Better educated women are probably less inhibited to complain of pain than less-educated women. A tighter uterine cervix and a smaller uterine cavity in women of low parity may account for IUD insertion pain. Postpartum involution of the uterus could explain pain upon insertion for women with a long open interval. These findings support the hypothesis that cervical stretching and direct endometrial pressure are probably the most important factors for IUD insertion pain.

Clinical evaluation of drugs used in fertility regulation.

The clinical evaluation of drugs used in fertility regulation is initially assessed in Phase I, II and III trials. The design of each phase and the investigative staff must be adequate. In Phase I, normal, healthy human volunteers meeting specific guidelines are usually studied. Numbers vary between 20 and 80 and the purpose is to determine the acute toxicity of the compound. In Phase II, efficacy and safety are examined in a clinical target population, and emphasis may be placed on pharmacological and mechanistic studies. Usually between 50 and 200 patients are involved. In Phase III, large-scale clinical studies for local registration and the introduction of drugs to various countries are included. This paper describes the evaluation of various drugs used in contraception, including NORPLANT implants, and considers the efficiency, safety and acceptability of such drugs. Phase IV studies are usually needed to reveal chronic toxicities or rare events.

PIP: The nature of clinical studies in Phases I to III of various drugs used in contraception, including Norplant implants, are described. International ethical standards generally agree that subjects should give informed consent before entering a study. Study subjects in Phase I of clinical evaluation are generally normal human volunteers who meet very specific selection guidelines. In special cases a target population of patients might be studied. Typically, the number of subjects studied in this phase ranges from 20-80 depending upon the specific product and the specific study objectives. The primary purpose of Phase I studies is to determine the acute toxicity potential of the product. In addition, one may want to determine the pharmacological or metabolic effects of the product. Family Health International (FHI) currently is planning the development of a new vaginal contraceptive product (FD 100). Initial studies will focus on safety parameters associated with the vaginal route. A subsequent Phase I study of FD 100 will provide an initial assessment of efficacy as well as safety. Phase II studies typically provide an opportunity to examine issues of efficacy and safety in a clinical target population and often permit a determination of the dose and dose intervals which will be most appropriate for that particular population and allow for a more definitive evaluation of the pharmacokinetics and, perhaps, bioavailability of a particular formulation. Typically, between 50-200 subjects are enrolled in a series of Phase II studies. The Program for Applied Research on Fertility Regulation and FHI recently have conducted a Phase II evaluation of a norethindrone (NET) pellet implant system. The most important side effect associated with this implant system consisted of changes in menstrual patterns. The Norplant subdermal implant system is in advanced stages of Phase III evaluation in the US and in selected other countries. In all study countries, the principal investigators are specialists in obstetrics and gynecology and the implants are offered to 400-600 healthy, nonlactating women who want to limit their family size. Beyond a typical study of product safety and efficacy, the novel nature of this implant technology has required the incorporation of special approaches into the multinational Phase III evaluation of the Norplant system. The Today-TM contraceptive sponge was approved for marketing by the Food and Drug Administration in 1983 based largely upon a multicenter study conducted by FHI in the US.

IUD insertion at cesarean section--the Chinese experience.

This review reports the experience of nine studies in Chinese maternity hospitals with insertions of an intrauterine device (IUD) at the time of cesarean section. In contrast to the usually high expulsion rates associated with immediate postpartum vaginal insertions, all nine studies reported low expulsion rates, thus resulting in high continuation rates with this procedure, comparable to those with interval insertions. This immediate post-cesarean section insertion procedure was also found to be safe. These findings are of programmatic importance for postpartum family planning delivery services and may eventually lead to an understanding of the expulsion mechanism in postpartum IUD contraception. Results of these reports have been synthesized in this review. Seven of these nine reports were originally in Chinese and were translated into English for the benefit of a broad international audience. Future research directions on this insertion procedure are also discussed.

Syncope and other vasovagal reactions at interval insertion of Lippes Loop D--who is most vulnerable?

Syncope and other vasovagal reactions occasionally occur at or immediately after IUD insertion. This analysis, using an international data set comprised of interval insertions of Lippes Loop D, found that women who are primiparous (as compared to those who are multiparous), and/or those who want more children are at higher risk for vasovagal reactions and deserve more careful counseling and gentler cervical manipulation. Moderate to severe pelvic pain at insertion is closely associated with the development of vasovagal reaction. Measures to alleviate or prevent pain at insertion could reduce the incidence of vasovagal reactions.

Where next with long-acting steroids?

PIP: A new generation of steroidal contraceptives is undergoing clinical trials or has reached the stage of national drug authority approval. In November 1983, Norplant contraceptive implants were approved for marketing in Finland as a longacting contraceptive. Norplant continues to be evaluated in large-scale clinical trials in a number of developing and developed countries. A continuous low dose of levonorgestrel is released into the woman's blood from 6 small silastic capsules implanted under the skin of the arm. A variation using 2 implants is under study. The implant systemmay be used for up to 5 years. The mechanism of action of levonorgestrel has 3 components: inhibition of ovulation in about 1/2 of cycles, suppression of the endometrium, and alteration of the cervical mucus to make it less permeable to sperm. The annual pregnancy rate is about .5/100 women. Fertility returns rapidly after removal, and the implant system has a good safety profile. The most frequent side effects in the 1st months of use are apparently menstrual irregularity or spotting, but total blood loss may be decreased. The steroid does not influence blood pressure and hasno unfavorable effect on blood lipids. The Population Council, developer of Norplant, is expected to seek US Food and Drug Administration approval on the basis of specific clinical experience. A vaginal ring consisting of a 3-layer ring of silastic containing levonorgestrel and estradiol has also been developed by the Population Council. The 2 hormones are released into the vagina at a constant rate and absorbed into the woman's blood, resulting in inhibition of ovulation. The rings imitate the action of combined oral contraceptives but do not require daily administration. The World Health Organization is also developing a vaginal ring which contains only a progestogen and is worn without a 1-week break in use. A new sustained-release formulation of norethindrone (NET) is entering expanded clinical trials in the US and developing countries. The system consists of biodegradable polymeric microspheres containing NET which are injected intramuscularly as a suspension. Depending on the size of the microspheres the product can provide 30,90, or 180 day contraceptive protect ive with a single dose. The availability of the 3 formulations each with different durations of action will serve the contraceptive needs of varied populations. Most longacting steroidal contraceptives give rise to menstrual irregularities, but they have the convenience of long action and the physiological advantage of low doses delivered directly to the systemic circulation. Use by millions of women for 1-2 decades will be required before they are completely understood.^ieng

Influence of cefoperazone on ethanol and acetaldehyde metabolism in vitro.

The effect of cefoperazone on ethanol and acetaldehyde metabolism was studied in rat liver homogenates and with a purified aldehyde dehydrogenase. Rat liver homogenates were incubated with ethanol (30 mM) alone or in combination with cefoperazone (15 or 150 micrograms/g liver). Ethanol and acetaldehyde concentrations were determined at 6, 12, 18 and 24 minutes. Cefoperazone added to the incubation medium inhibited ethanol and acetaldehyde metabolism in a concentration-dependent manner. The addition of cefoperazone to rat liver homogenates incubated with acetaldehyde (300 microM), however, did not inhibit acetaldehyde disappearance for a period of 15 minutes. Purified aldehyde dehydrogenase was incubated with 300 microM acetaldehyde. When cefoperazone was added, acetaldehyde disappearance was significantly slower than without cefoperazone. The data indicate that cefoperazone inhibits ethanol metabolism in rat liver homogenates in a concentration-dependent manner. The effect of the antibiotic on acetaldehyde elimination in liver homogenate, however, depends on the concentration of acetaldehyde in the medium. The acetaldehyde dehydrogenase obtained from yeast is inhibited by cefoperazone.

Influence of lactation on rate of disappearance of ethanol in the rat.

The rate of blood ethanol disappearance was significantly increased in lactating rats compared to virgin controls and parturient rats that had their offspring removed in birth. Liver but not kidney size was also increased in lactating rats.

Cross-tolerance between delta9-tetrahydrocannabinol and ethanol: the role of drug disposition.

Acute challenge doses of delta9-tetrahydrocannabinol (THC), 10.1 mg/kg, administered intragastrically by gavage (IG), or ethanol, 1.24 g/kg, IP, reduced the rotarod performance of female rats by 50%. Daily treatment of the animals with THC, 10.1 mg/kg, IG, or ethanol, 4 g/kg, IG, resulted in tolerance development to the impairing effects of the challenge doses of each drug on rotarod performance. THC-tolerant animals were cross-tolerant to the challenge dose of ethanol, but ethanol-tolerant rats did not show complete cross-tolerance to the challenge dose of THC. THC-tolerant animals initially had higher blood levels of 14C-THC than controls after IG drug administration. Following IV injection, the rates of 14C-THC disappearance were equivalent in the latter groups. 14C-THC disappearance was not altered in ethanol-tolerant animals. The rates of ethanol disappearance were not significantly modified in THC- or ethanol-tolerant animals. In conclusion, THC-tolerant female rats demonstrated cross-tolerance to ethanol as shown previously for males. Furthermore, the development of tolerance and cross-tolerance was not a function of changes in drug disappearance.