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    NEGATIVE EFFECTS OF CONTRACEPTIVES

    NEGATIVE EFFECTS OF CONTRACEPTIVES



    Pregnancy and childbirth carry risks of morbidity and mortality. Although the contraceptives that couples use to avoid pregnancy have their own health risks, they also have substantial noncontraceptive health benefits. Information about these risks and benefits is necessary for informed decision making. Oral contraceptives, for example, not only prevent pregnancy, but they also reduce the risk of endometrial and ovarian cancer and protect against acute pelvic inflammatory disease and ectopic pregnancies. However, oral contraceptives increase the risk of cardiovascular disease. IUDs provide effective contraception but increase the potential for infection in certain high-risk groups. Barrier methods of contraception provide less effective contraception, but they protect against sexually transmitted infections including human immunodeficiency virus (HIV).

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    Cardiovascular Diseases
    Cardiovascular diseases are a major cause of death in developed countries, where most research on the association between OC use and cardiovascular diseases has been conducted. These diseases are less common in developing countries, so alteration in their occurrence by OC use may not be as substantial as in industrialized countries.

    OC use increases the risk of cardiovascular disease, in particular the risk of venous thromboembolism, myocardial infarction, and stroke (Stadel, 1986; Prentice and Thomas, 1987; Vessey, 1980). The risk of serious illness or death attributable to OC use from adverse cardiovascular effects is concentrated primarily among older women over age 30 and women who smoke cigarettes or have other cardiovascular risk factors. The excess risk of cardiovascular diseases seems to be directly related to both the estrogen and progestin content of the pill. And the risks may be substantially lower with newer low-dose preparations.

    Venous thrombosis is the blockage of a vein by a blood clot particle. Thromboembolism occurs when the blood clot moves from a primary site to another, such as to the lungs or the brain. It is a major source of illness that may lead to death. Although the risk of venous thromboembolism is increased for current OC users, the increased risk does not persist among former users and is not related to duration of use (Vessey, 1980). The higher the estrogen content of the OC, the greater is the risk of venous thromboembolism, both for superficial and deep vein thrombosis (Stadel, 1986). The risk of venous thromboembolism among pill users appears to be unrelated to cigarette smoking. Mechanisms underlying increases in venous thromboembolism involve effects of estrogen or blood clotting factors that increase the coagulability of blood.

    Myocardial infarction and stroke are much more important causes of mortality attributable to OCs. The risk is strongly influenced by age and by the presence of other cardiovascular risk factors, including cigarette smoking, hypertension, and diabetes. The annual risk of myocardial infarction attributable to current OC use rises from about 4 cases per 100,000 among nonsmoking OC users ages 30 to 39 to 185 cases per 100,000 among heavy-smoking OC users ages 40 to 44 (Stadel, 1986). Current OC use has been found to slightly elevate blood pressure in most women, possibly a contributing factor to the pathogenesis of myocardial infarction and stroke among current OC users. OC use leads to a three- to sixfold increase in the risk of overt hypertension, increasing with a woman's age and duration of OC use. It must be remembered that these risks pertain to use of the relatively high-dose pills of the 1960s and 1970s and their patterns of use in relation to such factors as age and smoking.



    Other Possible Health Effects

    Metabolic Effects
    Metabolic changes may underlie the effects of OCs on myocardial infarction. Estrogens have the apparently desirable effect of increasing HDL-cholesterol (high density lipoprotein) concentration. Depending on type, progestins may either increase, decrease, or have no effect on HDL-cholesterol (for a complete discussion of changes in HDL-cholesterol, see Vessey, 1980). The net effect of different OC formulations on HDL-cholesterol is a function of both the dose of estrogen and the dose and type of progestin (Stadel, 1986).

    Current OC use has been found to decrease glucose tolerance in most women, although this decrease appears to be small and unrelated to duration of use. This decrease is directly related to the estrogen content of the OCs (Stadel, 1986).


    Neoplastic Diseases
    The forms of neoplasia that are of greatest concern with the potential effects of OC use are breast cancer, cervical cancer, endometrial cancer, and ovarian cancer. There are two main reasons for the concern. First, these cancers are major causes of morbidity and mortality, particularly breast cancer in developed countries and cervical cancer in some developing countries.1 Second, the breast, the uterus, and the ovaries are endocrine-dependent organs, and a large body of research shows that hormonally related factors, such as age at menarche and age at first birth, affect the risk of developing neoplastic diseases. Thus, any factor that alters hormones requires careful scrutiny as a possible carcinogen or anticarcinogen for these organs. In addition, cervical cancer is caused by the human papiloma virus, and contraception may modify transmission.

    Complex methodological problems make the study of possible relationships between OC use and these cancers difficult. Such problems include a possible long latency period and the difficulty of evaluating factors that might alter the effects of OCs, such as age at first pregnancy for breast cancer and the number of sexual partners for cervical cancer. In fact, some studies on breast and cervical cancer among OC users have found no effect on cancer risk and others have suggested increases. Since breast and cervical cancer are two of the most common cancers affecting women, the debate has taken on an urgency unlike that of other health risks. Family planning programs in the least developed countries generally lack the resources to monitor and respond adequately to these cancers. For example, Papanicolaou (Pap) screening, which is routine in developed countries, is not commonly performed in many developing countries. Although OC use clearly provides protection from the development of endometrial and ovarian cancer, its effect on other malignancies is generally unclear.

    The relationship between OC use and breast cancer is controversial. The Cancer and Steroid Hormone study, the largest study to date, was conducted in eight regions of the United States from 1980 to 1982 (Centers for Disease Control and National Institute of Child Health and Human Development, 1986). This study found no increased risk of breast cancer among pill users, regardless of length of use or OC formulation. Even groups known to be at high risk, such as women with prior benign breast disease or a family history of breast cancer, nulliparous women, or those who had a late age at first full-term pregnancy, were unaffected by OC use. Controversy centers on long-term OC use, use at an early age, or use before the first full-term pregnancy. One study showed a higher rate of premenopausal breast cancer among women who used ''high-progestin'' OCs before age 25. Another study of women with long-term OC use before the birth of their first child found the risk of breast cancer as much as doubled in some cases (Pike et al., 1983; McPherson et al., 1983; Meirik et al., 1986). Although a subsequent analysis of the CASH data that replicated the analysis made by Pike and McPherson contradicted their findings, a recent analysis of the data from the CASH study suggests that very long-term OC use may decrease the age of onset of breast cancer for a small subset of nulliparous women without an appreciable impact for women in the aggregate (Stadel et al., 1988).

    Breast cancer is uncommon among women in developing countries, and premenopausal breast cancer in these populations is rare. While there may be increased risk in small, select subgroups, in the aggregate there is probably no appreciable increase in risk. McPherson et al. (1983) have suggested that any possible risk of breast cancer associated with OC use at early ages may not become apparent until at least 20 years after that use, in which case researchers may not be able to detect such a relationship at the present time. The CASH study has found no increased risk of breast cancer within 10 to 15 years after use, even when use began at early ages (Schlesselman et al., 1988). The preponderance of epidemiologic studies suggest that OCs do not increase the risk of breast cancer, and any increase that may exist for certain subgroups of women is not great. Moreover, the inconsistencies among studies suggest that there may be methodological problems in the investigation of this complex disease.

    According to available data, cancer of the cervix is the most frequent malignancy among women in developing countries (Lunt, 1984). No definite causal relationship has been established between OC use and cervical cancer. Some of the major epidemiologic studies conducted have found no increased risk and some have found significantly increased risk, at least in certain subgroups (Piper, 1985; Brinton et al., 1986; Ebeling et al., 1987; Irwin et al., 1988). A large study by the World Health Organization, which included many developing countries, found some indication of increased risk with prolonged OC use (World Health Organization, 1985a), but these studies have serious methodological problems, most notably a detection bias mused by increased Pap screening of OC users compared with nonusers and differences in sexual behavior among users and nonusers of OCs (Piper, 1985; Swan and Petitti, 1982). More recent studies have attempted to address these methodological problems, but the results remain conflicting. While OCs probably do not dramatically increase the overall risk of cervical dysplasia or cancer, long-term OC use or use by specific subgroups of women may increase the risk. Two large British cohort studies have shown a higher incidence of cervical neoplasia among oral contraceptive users (Vessey et al., 1983; Beral et al., 1988). The most important conclusion from the conflict over these results is the importance of annual Pap screening in the prevention of invasive cervical cancer.

    OCs have been associated with malignant melanoma (skin cancer), but the association is rather weak and possibly confounded by differences in exposure to sunlight (Stadel, 1986). Some studies do suggest an increase within certain subgroups of women, particularly those with long-term use (Bain et al., 1982; Beral et al., 1984; Holly et al., 1983; Ramcharan et al., 1981). Due to the rarity of this malignancy in developing countries, however, the attributable risk is quite low and not very important for public health policy.

    Recent case-control studies have found an increased risk of hepatocellular carcinoma (liver cancer) among OC users, largely confined to long-term users (Forman et al., 1986; Neuberger et al., 1986; Henderson et al., 1983). Unfortunately, these studies all had small sample sizes and methodological problems that may have biased the results. Since hepatocellular carcinoma is extremely rare in developed countries, the attributable risk is very low. The disease is a much more common problem in many developing countries, especially where there is a high prevalence of chronic hepatitis B. The interrelationships among OC use, hepatitis B, and liver cancer are not well understood. The World Health Organization is conducting a multicenter case-control study in three developing countries to address the question.

    It is clear that OC use increases the risk of hepatocellular adenoma (HCA), a rare, benign tumor of the liver that can cause serious intra-abdominal hemorrhage and death. The case fatality rate is approximately 8 percent (Rooks et al., 1979). The risk attributable to OC use is very low, estimated to be about 2 cases of HCA per 100,000 users per year among women who have used OCs five years or more (Stadel, 1986).


    Other Effects
    It has been suggested that OC use might accelerate the appearance of gall bladder disease in susceptible women (Royal College of General Practitioners, 1982), although evidence for this hypothesis is limited. Early studies (Boston Collaborative Drug Surveillance Program, 1974; Royal College of General Practitioners, 1982) suggested that the risk of gall bladder disease might be increased in OC users. Recent studies and further analysis of information from British studies, which had first shown an increased risk of gallbladder disease in OC users (Layde et al., 1982; Wingrave and Kay, 1982), have failed to confirm this association.

    There have been extensive studies of the effects on pregnancy outcome of hormonal contraceptive use prior to or during pregnancy. Although there are some reports of adverse effects, the majority of studies show no increased risks, and several comprehensive reviews of the literature have concluded that in utero exposure to synthetic steroids at the doses used for contraception does not result in significant deleterious effects on fetal growth or development (Wilson and Brent, 1981; World Health Organization, 1981; Simpson, 1985).

    Even at low doses, the estrogen component of combination OCs has been shown to suppress milk volume in lactating mothers. Progestin-only contraceptives, including the minipill and long-acting methods discussed below, do not suppress milk production and can be used by breastfeeding women (World Health Organization, 1981). Although the synthetic hormones of the pill do pass on to the suckling infant, no adverse effects have been observed. Some reports have postulated an association between birth defects and the use of hormonal contraceptives prior to or during pregnancy. However, the majority of studies show no increased risks of deleterious effects on fetal growth or development (wilson and Brent, 1981; World Health Organization, 1981; Simpson, 1985).



    Barrier Methods
    Because they may prevent transmission of sexually transmitted diseases, including the human immunodeficiency virus (HIV), a great deal of attention is being focused on spermicides and barrier methods of contraception, principally condoms, diaphragms, and sponges. The United Nations estimates that 48 million women or their partners use these methods, but this number may be growing rapidly (United Nations, 1989). The effectiveness of these methods is highly dependent on user motivation and compliance. As a result, average failure rates tend to be higher than for any other modern method of contraception.


    Condoms are a very safe method of birth control, but their effectiveness as a contraceptive and as a disease prophylactic depends on consistent and proper use. Failure rates are estimated to be as high as 12 percent per year in practice (Tressell and Kost, 1987). A number of in vitro studies have demonstrated that latex condoms are effective barriers to herpes simplex virus type 2, chlamydia trachomarls, cytomegalovirus, and HIV. Condoms evidently reduce the transmission of organisms present in the semen, such as Neisseria gonorrhoeae, hepatitis B virus, and Trichomonas vaginalis (Conant et al., 1984; Judson et al., in press; Katznelson et al., 1984; Conant et al., 1986; Stone et al., 1986).
    Data regarding in vivo condom use and STDs is limited. Several studies have found a lower frequency of gonorrhea and HIV infection among condom users and/or their partners (Barlow, 1977; Hart, 1974; Hooper et al., 1978; Fischl et al., 1987; Centers for Disease Control, 1987). However, these studies are confounded by the fact that condom users are likely to differ from nonusers in many important characteristics (Feldblum and Fortney, 1988). Still, while the evidence is inconclusive, available data suggest that condoms may be quite effective STD prophylactics (Horsburgh et al., 1987). Their failure to protect is explained more probably by misuse than by product failure (Centers for Disease Control, 1988).


    Spermicides are chemical agents that inactivate sperm in the vagina before they can move into the upper genital tract. The contraceptive sponge with spermicides may provide some protection against STDs, although, as with other barrier methods, the effectiveness of this contraceptive is highly dependent on user compliance. Failure rates in the first year of use may be as high as 18 percent among nulliparous women and close to 30 percent among parous women (Trussell and Kost, 1987). Laboratory and clinical evidence suggests that their virucidal effects may inhibit the growth of Neisseria gonorrhoeae (Cowan and Cree, 1973; Singh et al., 1972), herpes simplex virus type 2 (Singh et al., 1976), and HIV (Hicks et al., 1985). Although evidence is sparse, there is some indication that spermicides also protect against cervical cancer, which has been associated with the human papilloma virus (Spring and Gruber, 1985).


    The sponge also has attendant health risks. Sponge users may be at increased risk of vaginal candidiasis, because normal bacterial growth is suppressed by certain types of spermicide, which leads to the overgrowth of candida (Rosenberg et al., 1987). There is also an association between the sponge and toxic shock syndrome (TSS), which in severe cases can lead to shock, coma, or death. Sponge users are apparently at 10.5 times greater risk of TSS than women using no barrier method (Schwartz et al., 1989). However, the attributable risk is low, since TSS is an extremely rare disease.
    The diaphragm (with spermicide), like the condom, if used correctly and consistently, can be an effective contraceptive. Because of inadequate motivation, improper fitting, or inconsistent use, the average failure rate is roughly 18 percent per year (Trussell and Kost, 1987). The diaphragm appears to reduce the risk of gonorrhea, PID, and tubal infertility (Jick et al., 1982; Kelaghan et al., 1982; Cramer et al., 1987). Several studies have shown cervical dysplasia and cervical neoplasia to be less common among users (Wright et al., 1978; Harris et al., 1980; Celentano et al., 1987). Since diaphragms and sponges are almost always used with spermicides, it is difficult to separate the specific effects of each.


    As with the sponge, the risk of TSS is significantly increased for diaphragm users (Schwartz et al., 1989). Still, the attributable risk is only about 0.2 percent annually. A less serious, but more frequent, complication associated with diaphragm use is urinary tract infections, occurring 2 to 3 times more often among users than nonusers (Foxman and Frerichs, 1985; Fihn et al., 1985; Vessey et al., 1987).
    Long-acting Contraceptives
    Several long-acting contraceptive methods have been developed, consisting mainly of injectables and implants. Usage is still relatively low, with just over 6 million women estimated to be using injectables (United Nations, 1989). These methods are highly effective and convenient to use and give protection from pregnancy from one month to five years. All contain a progestin, which may lead to a disturbance of the menstrual cycle.


    Injectables
    Two injectable progestins, Depo-Provera (DMPA) and Noristerat (NET), have been approved in over 90 countries worldwide.2 Estimated failure rates in the first year of use are between 0.3 and 0.4 percent, depending on the kind of progestin used (Trussell and Kost, 1987). Injections are usually given every 8 to 12 weeks. Injectables prevent pregnancy by inhibiting ovulation, thickening cervical mucous, and altering the endometrial lining, which inhibits implantation (Liskin and Quillin, 1982).


    The relationship between the risk of cancer and the use of injectables, particularly DMPA, remains controversial. The largest epidemiologic study yet published is an ongoing case-control study conducted by the World Health Organization. This study has found no increased risk of breast and endometrial cancer, and an analysis of invasive cervical cancer was deemed inconclusive. Final results concerning breast and cervical cancer are expected in the near future from this study and from a study in New Zealand. These and other studies have been hindered by small sample sizes and short durations of exposure. Animal data suggest that DMPA may increase the risk of breast and endometrial cancer (World Health Organization, 1986a).


    Reported metabolic effects of the use of injectables include changes in blood pressure and insulin, cholesterol, and triglyceride levels (Liskin et al., 1987; WHO, 1986b). Various studies of DMPA and NET users have found both increases and decreases in total cholesterol and HDL-cholesterol. The findings are thus inconsistent and none has shown clear clinical significance (Liskin et al., 1987). No studies have been published on the possible associations between DMPA or NET use and the risk of cardiovascular disease. Unlike OCs, injectables appear to have little effect on the coagulation and fibrinolytic systems that affect blood clotting.


    Amenorrhea or irregular, unpredictable bleeding episodes are the most commonly reported problems with injectables and the primary reason for terminating use (World Health Organization, 1978; Swenson et al., 1980; World Health Organization, 1987b). One-half to two-thirds of users have no regular menstrual cycles in the first year of use (Liskin et al., 1987). After one year of use, as many as 50 percent of users will be amenorrheac. The occurrence of heavy bleeding is rare, occurring in 0.5 percent of users. Conversely, since bleeding is often lighter than normal, increased hemoglobin levels have been reported (World Health Organization, 1986b).


    Injectables appear to have no permanent effect on fertility, although ovulation may be inhibited for four to nine months or more after the last injection (Liskin et al., 1987; Pardthaisong et al., 1980; Affandi et al., 1987). Injectables may protect against PID by causing changes in the cervical mucus (Gray, 1985).


    Injectable progestins may protect against endometrial and ovarian cancers. A WHO case-control study found a reduced risk of endometrial cancer in DMPA users, but the sample was quite small and results are inconclusive (World Health Organization, 1986a). There are even fewer data regarding ovarian cancer. However, since injectables prevent ovulation, as do OCs, it is hypothesized that injectables will also decrease the incidence of ovarian cancer; preliminary results from the WHO study support this possibility.


    Implants
    The Norplant subdermal implant system is another highly effective progestational contraceptive. One-inch-long plastic rods are surgically implanted under the skin of the upper arm and are left in place for several years. The progestin levonorgestrel is slowly released and remains effective for three to five years. The implants have a cumulative five-year net pregnancy rate of less than 2 percent in most studies (Segal, 1988).


    Like injectables, the most common side effect of implants is disturbance of the menstrual cycle. Episodes of abnormal bleeding diminish with duration of use but, unlike injectables, the implants can be removed if there are extreme complications. Norplant users are generally protected from ectopic pregnancy since ovulation is suppressed. Transient ovarian cysts occur in a small percentage of women using Norplant, although the cysts eventually regress (Salah et al., 1987; Diaz et al., 1987). Permanent infertility appears not to be a problem (Sivin et al., 1983; Diaz et al., 1987; Affandi et al., 1987). Several studies have shown that fecundity quickly returns after the implants are removed. No changes have been found in liver function, carbohydrate metabolism, blood coagulation, blood pressure, or body weight (Liskin et al., 1987). Of particular importance in the use of implants is the very low blood level of progestogen, which is much lower than with other steroid contraceptives.

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