According to the 2002 National Survey of Family Growth (NSFG) approximately one-half of all pregnancies in the United States were unintended and almost one-half of these occurred in women using some form of reversible contraception. These rates have remained relatively unchanged since the previous survey reported in 1995. Addressing family planning and contraception is an important issue for providers of care to reproductive-age women. An increasing number of contraceptive options are becoming available on the US market. It is dependent on physicians and other health care providers to maintain currency with the recent advances in information concerning counseling, efficacy, safety, and side effects.

According to the 2002 NSFG, the combined oral contraceptive pill is the leading contraceptive method among women, with 19% of women between the ages of 15 and 44 choosing the pill. The introduction of lower-dose combination oral contraceptives (COCs) (<50 μg ethinyl estradiol) has provided many women a highly effective, safe, and tolerable method of contraception.

COCs suppress ovulation by diminishing the frequency of gonodotropin-releasing hormone pulses and halting the luteinizing hormone surge. They also alter the consistency of cervical mucous, affect the endometrial lining, and alter tubal transport. Most of the antiovulatory effects of COCs derive from the action of the progestin component. The estrogen doses are not sufficient to produce a consistent antiovulatory effect. The estrogenic component of COCs potentiates the action of the progestin and stabilizes the endometrium so that breakthrough bleeding is minimized. When administered correctly and consistently, they are greater than 99% effective at preventing pregnancy. However, failure rates are as high as 8%-10% during the first year of typical use. Noncompliance is the primary reason cited for the difference between these rates, frequently secondary to side effects such as abnormal bleeding and nausea.

Hormonal Content

The estrogenic agent most commonly used in COCs is ethinyl estradiol (EE), in doses ranging from 20 to 35 μg. Mestranol, which is infrequently used, is less potent than ethinyl estradiol such that a 50-μg dose of mestranol is equivalent to 30-35 μg of ethinyl estradiol. It appears that decreasing the dose of estrogen to 20 μg reduces the frequency of estrogen-related side effects, but increases the rate of breakthrough bleeding. In addition, there may be less margin for error with low-dose preparations such that missing pills may be more likely to result in breakthrough ovulation.

Multiple progestins are used in COC formulations. Biphasic and triphasic oral contraceptives, which vary the dose of progestin over a 28-day cycle, were developed to decrease the incidence of progestin-related side effects and breakthrough bleeding, although there is no convincing evidence that multiphasics indeed cause fewer adverse effects. The most commonly used progestins include norgestrel, levonorgestrel, and norethindrone. As with estrogens, some progestins (norethindrone and levonorgestrel) are biologically active, while others are pro-drugs that are activated by metabolism. Norethindrone acetate is converted to norethindrone and norgestimate is metabolized into several active steroids including levonorgestrel. Progestins that do not require hepatic transformation tend to have better bioavailability and a longer serum half-life. For example, levonorgestrel has a longer half-life than norethindrone. Norgestimate and desogestrel, have lower androgenic potential than other progestins.

Drospirenone, a derivative of spironolactone, differs from other progestins because it has mild antimineralocorticoid activity. Contraceptive efficacy, metabolic profile, and cycle control are comparable to other COCs. The clinical implications of the diuretic-like potential of drospirenone are not yet clear. Because of its antimineralocorticoid effects and the potential for hyperkalemia, drospirenone should not be used in women with severe renal disease or hepatic dysfunction.

COC are traditionally dosed cyclically with 21 days of hormone and 7 days of placebo during which a withdrawal bleed occurs. To address the potential of escape ovulation in the lowest estrogen formulations (20 μg), many regimens reduce the number of hormone free days to 2-4 days. Extended cycle regimens or continuous hormonal regimens are safe and acceptable forms of contraception and may be more efficacious than cyclic regimens. Extended cycle regimens result in fewer scheduled bleeding episodes, however they also result in more unscheduled bleeding and/or spotting episodes that decrease with time. Women who may particularly benefit from these regimens are those who have symptoms exacerbated by their menses. These include women who have seizure disorders, endometriosis, menstrual headaches, premenstrual dysphoric disorder, menorrhagia, or dysmenorrhea. There are several extended cycle regimens approved by the FDA (Seasonal, Seasonique, Lybrel); however, traditionally packaged COCs may also be prescribed as extended cycle regimens. Women are advised to use the active pills and then start a new pack, ignoring the placebo pills. This regimen gives women the option of cycling as she desires, modifying the timing of individual periods on a month-by-month basis for personal reasons. Based on a Cochrane review there are no differences between the traditional and extended cycles in satisfaction, compliance, pregnancy rates, and safety.

Side Effects

Side effects may be due either to the estrogen component, the progestin component, or both. Side effects attributable to progestin include androgenic effects, such as hair growth, male-pattern baldness, and nausea. Switching to an agent with lower androgenic potential may decrease or resolve these problems. Estrogenic effects include nausea, breast tenderness, and fluid retention. Weight gain is commonly thought to be a side effect of COCs, however, multiple studies have failed to confirm a significant effect. Weight gain can be managed by switching to a different formulation, however, appropriate diet and exercise should be emphasized.

Bleeding irregularities is the side effect most frequently cited as the reason for discontinuing COCs. Patients should be counseled that irregular bleeding/spotting is common in the first 3 months of COC use and will diminish with time. Spotting is also related to missed pills. Patients should be counseled regarding the importance of taking the pill daily. If the bleeding does not appear to be related to missed pills, the patient should be evaluated for other pathology such as infection, cervical disease, or pregnancy. If this evaluation is negative the patient may be reassured. Another approach would be to change the pill formulation to increase the estrogen or progestin component. The doses can be tailored to the time in the cycle when the bleeding occurs. If the bleeding precedes the menses, consider a triphasic pill that increases the dose of estrogen (Estrostep) or progestin (eg, Ortho-Novum 7/7/7) sequentially through the cycle. If the bleeding follows the menses consider Mircette which has only 2 hormone-free days. Increase the estrogen and/or the progestin midcycle for midcycle bleeding (eg, Triphasil).

Combined oral contraceptives may cause a small increase in blood pressure in some patients. The risk increases with age. The hypertension usually resolves within 3 months if the COC is discontinued. Both estrogens and progestins are known to affect blood pressure. Therefore, switching to a lower-estrogen formulation or a progestin-only pill may not resolve the problem.

Major Sequelae

Use of most oral contraceptives with less than 50 μg of estrogen approximately triples one’s risk of venous thromboembolism. Before 1995, the progestin component of COCs was not generally thought to contribute to the risk of thrombosis. However, more recent studies with formulations containing gestodene (not available in the United States) or desogestrel have shown approximately a sevenfold increased risk of thrombosis compared with nonusers of COCs. Bias and confounding in these studies do not explain the consistent epidemiologic findings of an increased risk. Obesity and increasing age are contributing risk factors. The factor V Leiden mutation is another risk factor. As compared with the baseline risk for women who do not use COCs and who do not carry the mutation, the risk of venous thromboembolism is increased by a factor of 35 in women who carry the mutation and also use COCs. The best approach to identify women at higher risk of venous thromboembolism before taking COCs is controversial. Universal screening for factor V Leiden is not cost-effective. Furthermore, family history of venous thromboembolism has unsatisfactory sensitivity and positive predictive value for identifying carriers of other common defects.

The risk of thrombotic or ischemic stroke among users of COCs appears to be relatively low. There is no evidence that the type of progestin influences risk or mortality associated with ischemic stroke. The risk of ischemic stoke does appear to be directly proportional to estrogen dose, but even with the newer low-estrogen preparations there is still a slightly increased risk compared with nonusers. Hypertension, cigarette smoking, and migraine headaches interact with COC use to substantially increase the risk of ischemic stroke. The risk of hemorrhagic stroke in young women is low and is not increased by the use of COCs in the absence of risk factors. The major risk factors are hypertension and cigarette smoking. History of migraine without focal neurologic signs is not a contraindication to hormonal contraception.

Current use of COCs is associated with an increased risk of acute myocardial infarction (AMI) among women with known cardiovascular risk factors (diabetes, cigarette smoking, hypertension) and among those who have not been effectively screened for risk factors, particularly for blood pressure. There is no increased risk for AMI with increasing duration of use or with past use of COCs.

Many epidemiologic studies have reported an increased risk of breast cancer among COC users. For current users of COCs, the relative risk of breast cancer compared with never-users is 1.24. This small risk persists for 10 years, but essentially disappears after this time period. Although COC users have a modest increase in risk of breast cancer, the disease tends to be localized. The pattern of disappearance of risk after 10 years coupled with the tendency toward localized disease suggests that the overall effect may represent detection bias or perhaps a promotional effect. A population- based, case-control study with over 8000 women enrolled was conducted to evaluate risk of breast cancer in COC users later in life when the risk of cancer is higher. This study, reported in 2002, showed that among women from 35 to 64 years of age, current or previous contraceptive use was not associated with a significantly increased risk of breast cancer.

Noncontraceptive Health Benefits

Most studies evaluating the relationship between COCs and ovarian cancer have shown a protective effect for oral contraceptives. There appears to be a 40%-80% overall decrease in risk among users, with protection beginning 1 year after starting use, with a 10%-12% decrease annually in risk for each year of use. Protection persists between 15 and 20 years after discontinuation. The mechanisms by which COCs may produce these protective effects include suppression of ovulation and the suppression of gonadotropins.

The use of COCs conveys protection against endometrial cancer as well. The reduction in risk of up to 50% begins 1 year after initiation, and persists for up to 20 years after COCs are discontinued. The mechanism of action is likely reduction in the mitotic activity of endometrial cells because of progestational effects.

A number of epidemiologic studies demonstrate that the use of COCs will reduce the risk of salpingitis by 50%-80% compared with the risk to women not using contraception or who use a barrier method. There is no protective effect against the acquisition of lower genital tract sexually transmitted diseases. The purported mechanism for protection include progestin-induced thickening of the cervical mucus, so that ascent of bacteria is inhibited, and a decrease in menstrual flow, resulting in less retrograde flow to the fallopian tubes. Other noncontraceptive benefits of COCs include decreased incidence of benign breast disease, relief from menstrual disorders (dysmenorrhea and menorrhagia), reduced risk of uterine leiomyomata, protection against ovarian cysts, reduction of acne, improvement in bone mineral density, and a reduced risk of colorectal cancer.

A transdermal contraceptive patch containing norelgestromin, the active metabolite of norgestimate, and ethinyl estradiol is marketed by Ortho-McNeil under the trade name “Ortho-Evra.” The system is designed to deliver 150 μg of norelgestromin and 20 μg of ethinyl estradiol daily directly to the peripheral circulation. The treatment regimen for each cycle is three consecutive 7-day patches (21 days) followed by 1 patch-free week so that withdrawal bleeding can occur. The patch can be applied to one of four sites on a woman’s body: abdomen, buttocks, upper outer arm, or torso (excluding the breast).

Ortho Evra’s efficacy is comparable to that of COCs. Compliance with the patch is much higher than with COC, which may result in fewer pregnancies overall. However, pregnancy is more likely to occur in women weighing greater than 198 lb. Breakthrough bleeding, spotting, and breast tenderness are slightly higher for Ortho-Evra than COCs in the first two cycles, but there is no difference in later cycles. Amenorrhea occurs in only 0.1% of patch users. Patch-site reactions occur in 2%-3% of women.

Initiation of patch use is similar to initiation of COC use. Women apply the first patch on day 1 of their menstrual cycle. Another option is to apply the first patch on the Sunday after their menses begins. This becomes their patch change day. Subsequently, they change patches on the same day of the week. After three cycles they have a patch-free week during which they can expect their menses. A backup contraceptive should be used for the first 7 days of use.

The US Food and Drug Administration (FDA) requires labeling on the Ortho Evra patch to warn health care providers and patients that this product exposes women to higher levels of estrogen than most birth control pills. Average concentration at steady state for ethinyl estradiol is approximately 60% higher in women using Ortho Evra compared with women using an oral contraceptive containing 35 μg of ethinyl estradiol. In contrast, peak concentrations for ethinyl estradiol are approximately 25% lower in women using Ortho Evra. In general, increased estrogen exposure may increase the risk of blood clots. The potential risks related to increased estrogen exposure with the patch should be balanced against the risk of pregnancy if patients have difficulty following the daily regimen associated with typical birth control pills.