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Am Fam Physician. 1999;60(7):2073-2084

Oral contraceptive pills are widely used and are generally safe and effective for many women. The World Health Organization has developed a risk classification system to help physicians advise patients about the safety of oral contraceptive pills. The choice of pill formulation is influenced by clinical considerations. By choosing appropriately from the available pill formulations, family physicians can minimize negative side effects and maximize noncontraceptive benefits for their patients. Additional monitoring and follow-up are necessary in special populations, such as women over 35 years of age, smokers, perimenopausal women and adolescents. Third-generation progestins are additional options for achieving noncontraceptive benefits, but their use has raised new questions about thrombogenesis. The U.S. Food and Drug Administration has labeled emergency postcoital contraception for use following unprotected coitus. Oral contraceptive pills are associated with few clinically significant drug interactions, although consideration of interactions remains important.

Oral contraceptive pills are combined formulations of a progestin and a synthetic estrogen (Table 1).1 These pills have been widely used in the United States for almost 40 years. Recent data indicate that oral contraceptive pills are used annually by approximately 10 million U.S. women.2

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Unlike other commonly prescribed drugs, oral contraceptive pills are taken by healthy women for long periods of time. Thus, it is important for family physicians to be familiar with the most recent information on the side effect profiles of oral contraceptive pills and their risk-to-benefit ratios. Armed with this information, family physicians should be able to help patients choose a primary method of contraception, as well as a backup method.3 Fortunately, the safety of oral contraceptive pills for most women is now well documented.4

Efficacy Rates and Patterns of Oral Contraceptive Pill Use

Efficacy data, or failure rates, for oral contraceptive use can be analyzed based on information about the “perfect” user and the “typical” user. The perfect user never misses taking a pill, takes the pill at the same time each day and never vomits or has diarrhea. The “typical” user's behavior results in the failure rates reported for the general population. Whereas only one of 1,000 women who take oral contraceptive pills “perfectly” becomes pregnant within a year, 50 of 1,000 women who take the pills “typically” become pregnant within one year.4

Benefits of Oral Contraceptive Pills

High efficacy (with proper use), ease of use, separation of pill administration from coitus, reversibility and noncontraceptive benefits are among the reasons women and their sexual partners may choose oral contraceptive pills over other forms of contraception.

Contraceptive methods such as the intra-uterine device and subdermal contraceptive implants do not require daily administration. However, many women find swallowing a pill easier than manipulating a diaphragm. Likewise, the separation of administration from the coital act allows many oral contraceptive pill users to feel more spontaneous about sexual activity.

Reversibility data are clear. Despite a possible few months' lag in the return of normal menstrual cycles, most women resume their previous level of fertility once they stop taking oral contraceptive pills.4

The noncontraceptive benefits (and favorable side effect profiles) of oral contraceptive pills are so important that some patients use the pills exclusively for those reasons.5 Labeled and unlabeled indications for oral contraceptive pills include acne, dysmenorrhea, premenstrual syndrome (PMS) and endometriosis5 (Table 2).4

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Drawbacks of and Fears About Oral Contraceptive Pill Use

Patients may decide not to use oral contraceptive pills for a number of reasons. One reason is that this form of contraception provides no protection against infection. In addition, some women are concerned about the side effects of systemic hormonal medications, and others have actual contraindications to the use of oral contraceptive pills.

If a patient's sexual practice puts her at risk for sexually transmitted infections, counseling about the use of male or female condoms is appropriate. It is also reasonable to add an oral contraceptive pill for effective pregnancy prevention. For the typical user who feels that 50 pregnancies in 1,000 oral contraceptive pill users is an unacceptably high failure rate, adding a second contraceptive method increases efficacy. Barrier contraceptive methods should be recommended for all women to decrease the spread of human herpesvirus, human immunodeficiency virus and human papillomavirus infections.

Fears about the side effects of oral contraceptive pills vary widely and depend on a woman's exposure to sensational media reports, stories from friends and family members, and personal values and beliefs. Well-written patient information handouts can enhance a balanced presentation of information on oral contraceptive pills and allow patients time to consider the broader issues related to contraceptive practice.

World Health Organization Precautions

The World Health Organization (WHO) and many U.S. leaders in the field of family planning now promote a graded scheme of “precautions,” rather than “contraindications,” in considering which patients should not use oral contraception6 (Table 3).4

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Women with WHO category 4 diagnoses should not be given oral contraceptive pills.4,6 (WHO category 4 is comparable to the “Who should not take oral contraceptives” category in the Physicians' Desk Reference.7) WHO category 3 conditions are those for which the physician should “exercise caution” in prescribing oral contraceptive pills “and carefully monitor for adverse effects.”6

WHO category 2 conditions are those in which the “advantages [of oral contraceptive pills] generally outweigh theoretical or proven disadvantages.”6 Oral contraceptive pills can generally be prescribed without restriction to patients with these conditions. Category 1 conditions are essentially unrelated to the metabolism of oral contraceptive agents. Women with these conditions have no restrictions on the use of oral contraceptive pills.

A careful personal and family medical history (with particular attention to cardiovascular risk factors) and an accurate blood pressure measurement are recommended before the initiation of oral contraceptive pills. In the United States, a physical examination and a Papanicolaou smear (with screening genital cultures as indicated) are usually performed at the time oral contraceptive pills are initially prescribed.8 However, many U.S. leaders in family planning circles believe that the risk of pregnancy and the safety of oral contraceptive pills (based on the WHO guidelines) allow an initial prescription to be written before a physical examination and a Pap test are performed in healthy young women.4

Oral Contraceptive Pill Formulations

The formulations of oral contraceptive pills have changed dramatically over the years. The first oral contraceptive pill, introduced in 1960, contained high doses of norethynodrel (progestin) and mestranol (estrogen). Norethynodrel is one of the first-generation prog estins called “estranes.” This class includes the current agents norethindrone, norethindrone acetate and ethynodiol diacetate. Levonorgestrel, a more potent, second-generation progestin, was developed in about 1970. Over the past several decades, the dose of the estrogen component of oral contraceptive pills has decreased from the original 150 μg to 50 μg and then to 20 to 35 μg. These changes were made to lower the risk of thromboembolic complications associated with the use of oral contraceptive pills.

Originally, most combination oral contraceptive pill formulations were monophasic, with each active tablet containing a fixed dose of estrogen and progestin throughout the cycle. Multiphasic preparations (biphasic and triphasic) were developed in the 1980s to reduce the total dosage of progestin throughout the cycle without increasing the risk of breakthrough bleeding.

Five years ago, third-generation progestins from the gonane class were incorporated into oral contraceptive pill formulations to reduce the androgenic and metabolic side effects that occur with older agents. These new progestins include desogestrel, gestodene (not available in the United States) and norgestimate.

Oral contraceptive pills containing third-generation progestins reportedly have several benefits.9 Androgenicity associated with older progestins has been linked to adverse lipoprotein and carbohydrate changes, weight gain, acne, hirsutism, mood changes and anxiety.5 The third-generation progestins have minimal impact on blood glucose levels, plasma insulin concentrations and the lipid profile. Thus, they are suitable to use in patients with lipid disorders or diabetes.

Third-generation progestins have also been shown to resolve or reduce acne and hirsutism. Furthermore, they do not adversely affect weight or blood pressure. In addition, fewer incidences of contraceptive discontinuation because of lack of cycle control (i.e., breakthrough bleeding, spotting and amenorrhea) have been reported with the newer progestins.9

Although third-generation progestins may have a better side effect profile in selected patients, no evidence exists to show that these agents are clinically superior to first- or second-generation progestins. Therefore, switching to a third-generation progestin is not necessarily indicated, and use of older oral contraceptive pill formulations can be continued. However, products containing third-generation progestins are indicated for use in patients who are unable to tolerate other combination oral contraceptive pills.

Progestin-only pills, or minipills, contain no estrogen and also have a lower dose of progestin. These oral contraceptive pills have been marketed in the United States for the past 30 years. Norethindrone (Norlutin) and norgestrel (Ovrette) are currently available in this country, but they account for only 0.2 percent of the total oral contraceptive pill market. These agents are recommended for women with contraindications to the use of combined oral contraceptives and women who are breast-feeding.10

Cardiovascular Effects of Oral Contraceptive Pills

MYOCARDIAL INFARCTION AND STROKE

The relationship between oral contraceptive pills and cardiovascular disease has been extensively studied. Women who do not smoke and do not have hypertension or diabetes are at no increased risk of acute myocardial infarction when they are taking oral contraceptive pills.11 However, regular assessment of blood pressure to diagnose hypertension is important.

The risk of ischemic stroke is 1.5 times higher in women with hypertension who are taking oral contraceptive pills.12 Women who use this contraceptive method but are less than 35 years of age, do not smoke and are normotensive have no increased risk of hemorrhagic stroke, although the incidence of this event increases with age.13 Women who are taking oral contraceptive pills with higher estrogen doses are at greater risk for ischemic stroke. Hypertension and smoking are independent and additive risk factors for myocardial infarction, ischemic stroke and hemorrhagic stroke in patients taking oral contraceptive pills.4,11

The risk of myocardial infarction, ischemic stroke and hemorrhagic stroke does not become higher with increasing duration of oral contraceptive pill use or because of past use.

The risk of mortality from cardiovascular disease attributable to oral contraceptive pill use is up to 10 times higher in women 40 to 44 years of age than in women 20 to 24 years of age.14 Despite the increased cardiovascular risk in older women, the risk of pregnancy is still greater in women who use no other form of contraception. At any given age, women who smoke but do not use oral contraceptives are at greater risk of death from arterial disease than nonsmoking oral contraceptive pill users.

VENOUS THROMBOEMBOLISM

Venous thromboembolism, including pulmonary embolism and deep venous thrombosis, is the most common serious cardiovascular event among women who use oral contraceptive pills. Despite a low absolute risk (15 cases per 100,000 cardiovascular events per year), women who are taking oral contraceptive pills have a three to six times greater risk of venous thromboembolism than women who do not use this contraceptive method.15

The absolute risk of venous thromboembolism associated with oral contraceptive pills increases with age, obesity, recent surgery and some forms of thrombophilia. This risk is highest during the first year of use and is not related to the estrogen component of currently available pill formulations.16

Whether oral contraceptive pills containing desogestrel and gestodene are associated with a greater risk of venous thromboembolism than other combination oral contraceptives remains a point of controversy.17,18 Insufficient data are available to determine whether norgestimate potentially increases the risk of venous thromboembolism. The dose and type of progestin may influence the effect of an oral contraceptive on lipid metabolism as well as coagulation and fibrinolytic markers. The association between third-generation progestins and risk of venous thromboembolism has not been documented persuasively enough to recommend discontinuation.

The blood of women with an inherited antithrombin III defect or factor V Leiden mutation has abnormally increased coagulability. Women with these conditions who take oral contraceptive pills are at increased risk for venous thromboembolism.14,19 Progestin-only pills should be considered for use in these patients. When inexpensive tests become available, some experts believe that all first-time oral contraceptive pill users will be screened for factor V Leiden.19

Product Selection and Practice Guidelines

The wide variety of available pill formulations allows the family physician to optimize individual patient responses.4,20,21 Factors to consider when starting or switching oral contraceptive pill formulations are listed in Table 4.4

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Premature discontinuation of oral contraceptive pills most commonly occurs because of the following real or perceived side effects: breakthrough bleeding, nausea, headache, breast tenderness, acne, hirsutism, mood swings and weight gain.20 Patients should be counseled that many side effects subside over the first few months of oral contraceptive pill use.

Nausea, breast tenderness and vascular headaches are estrogen mediated, whereas acne, oily skin, hirsutism and, possibly, weight gain are androgen mediated (Table 5).1 Breakthrough bleeding is related to the ratio of estrogen to progestin in a pill formulation. Many women perceive that oral contraceptive pills cause weight gain (the progestational and androgenic effects may affect appetite), but actual studies of currently available formulations demonstrate little or no change in weight.20,22

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Mood changes are a common complaint among women who take oral contraceptive pills. However, the role of pill components as distinct from reactions to life events has not yet been adequately defined in the literature.4,20 Premenstrual mood changes (i.e., PMS) may actually improve in many women who use monophasic oral contraceptive pills.4

It is important for the family physician to educate women about the initiation of oral contraceptive pills, the handling of missed pills and situations when other forms of contraception are needed. Instructions on the use of oral contraceptive pills are provided in Table 6.4

Initiation of use (choose one):
The patient begins taking the pills on the first day of menstrual bleeding.
The patient begins taking the pills on the first Sunday after menstrual bleeding begins.
The patient begins taking the pills immediately if she is definitely not pregnant and has not had unprotected sex since her last menstrual period.
Missed pill
If it has been less than 24 hours since the last pill was taken, the patient takes a pill right away and then returns to normal pill-taking routine.
If it has been 24 hours since the last pill was taken, the patient takes both the missed pill and the next scheduled pill at the same time.
If it has been more than 24 hours since the last pill was taken (i.e., two or more missed pills), the patient takes the last pill that was missed, throws out the other missed pills and takes the next pill on time. Additional contraception is used for the remainder of the cycle.
Additional contraceptive method
The patient uses an additional contraceptive method for the first 7 days after initially starting oral contraceptive pills.
The patient uses an additional contraceptive method for 7 days if she is more than 12 hours late in taking an oral contraceptive pill.
The patient uses an additional contraceptive method while she is taking an interacting drug (see Table 9) and for 7 days thereafter.

Special Populations

WOMEN OVER 35 YEARS OF AGE

In healthy women over 35 years of age who do not smoke, the benefits of oral contraceptive pills generally exceed the risks.4,23 In fact, nonsmokers with no cardiovascular disease may continue using this contraceptive method until menopause. In addition to effective contraception, benefits include the prevention of ovarian and endometrial cancers, an increase in bone mass and the reduction of perimenopausal symptoms.

Cardiovascular complications are the major concerns in older women who take oral contraceptive pills (Table 7). Venous thromboembolism occurs more often in women who use this form of contraception, regardless of age (i.e., four to 21 cases per 100,000 cases per year).17 Although the overall risk of myocardial infarction increases with age, current data on low-dose oral contraceptive pills indicate that the excess risk of this event resulting from pill use is less than about one case per 100,000 healthy nonsmoking women.23

1. Check for any reason (WHO criteria [see Table 3]) that the patient should not take oral contraceptive pills.
2. Ask the patient about a history of headaches, hypertension and diabetes; ask about a family history of premature cardiovascular disease.
3. Measure the patient's blood pressure; in addition, measure the patient's fasting blood sugar, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride cholesterol levels.
4. Record the patient's height and weight; perform a breast examination, and consider mammography.
5. Ask the patient about smoking habits.
6. If the patient is 50 to 52 years of age, assess the follicle-stimulating hormone level during a pill-free interval.

Smoking dramatically increases the risk of myocardial infarction at the ages when the overall risk of this event begins to rise steeply. The combination of oral contraceptive pill use and smoking has a greater effect on risk than the simple addition of the two factors. Thus, oral contraceptive pills generally are not prescribed to smokers over 35 years of age. Strong smoking cessation assistance should be provided to women who wish to use oral contraceptive pills.

MENOPAUSAL WOMEN

In the United States, the average age of menopause is 48 to 52 years of age. Women past menopause are no longer at risk of pregnancy and do not need contraception. Thus, oral contraceptive pill use can be discontinued after menopause is documented.23

How can the physician determine if a woman is menopausal and can safely discontinue oral contraception? Menopause is generally indicated by a serum follicle-stimulating hormone (FSH) level greater than 30 mIU per mL (30 IU per L), measured on the sixth day of a seven-day pill-free interval. In some women, the FSH level may not rise sufficiently during the pill-free interval; in others, there is a slight chance of a late ovulation, even with one high FSH level.4

One conservative approach is to have women continue taking oral contraceptive pills until the age of 50 to 52 years. Then they are instructed to use a back-up contraceptive method for the pill-free period required to check (and possibly recheck) the FSH level. The FSH level is measured after seven pill-free days; if this level is greater than 30 mIU per mL, the FSH level is checked again in six weeks. Menopause can be diagnosed and contraception may be safely discontinued if the following criteria are met: both measured FSH levels are greater than 30 mIU per mL, vasomotor symptoms occur and no withdrawal bleeding occurs after oral contraceptive pills are discontinued.4,24

If no contraindications exist, estrogen replacement therapy should be strongly considered once oral contraceptive pills are discontinued. Estrogen replacement therapy is helpful for treating menopausal symptoms and preventing osteoporosis. The estrogen potency of low-dose oral contraceptive pills is about four (20-μg of ethinyl estradiol) to seven times (35-μg of ethinyl estradiol) that of most estrogen replacement products (e.g., 0.625 mg of conjugated estrogens).

ADOLESCENTS

Girls under 19 years of age are at high risk for sexually acquired infections and unintended pregnancy. Teenage girls and their sexual partners have the highest rates of sexually acquired infections of any age group, and they do not usually establish long-term mutually monogamous relationships. Hence, use of a barrier method for protection from infection should be advocated and prescribed with oral contraceptive pills for all sexually active teenage girls.

Adolescents may be more likely to discontinue oral contraceptive pill use because of early or minor side effects, such as nausea or breakthrough bleeding. Therefore, the family physician needs to provide thorough counseling before this form of contraception is initiated and should be prepared to respond to complaints after a teenage girl starts taking the pill.4

No evidence exists that epiphyses close prematurely in very young oral contraceptive pill users, and bone density is well preserved.4,25 Furthermore, many teenage girls appreciate the noncontraceptive benefits of having shorter menses, more regular periods and relief from dysmenorrhea. Counseling that these benefits evaporate when pills are discontinued helps to encourage compliance when the primary purpose of oral contraceptive pill use is to relieve a physiologic condition. Acne and hirsutism may be improved with the use of more estrogenic formulations and the newest progestin formulations.

The American Academy of Family Physicians has published a policy position statement regarding contraceptive advice in adolescents.26

Emergency Postcoital Contraception

The use of “emergency” contraception in the first 72 hours after unprotected sexual intercourse has been studied for almost two decades. Only recently, however, has the U.S. Food and Drug Administration labeled certain oral contraceptive pills for this indication.27,28 The pill formulations with such labeling contain norgestrel or levonorgestrel and ethinyl estradiol. Postcoital contraception reduces the risk of pregnancy by 75 percent. This is much less than the risk reduction achieved with regular prophylactic use of oral contraceptive pills or other contraceptive methods.29

Emergency contraception frequently causes nausea and vomiting. When this treatment is needed, it may be helpful to administer an antiemetic drug 60 minutes before the initial dose of oral contraceptive.3,29

Several ethinyl estradiol and levonorgestrel regimens are used for emergency contraception (Table 8).4 The first oral contraceptive pill dose should be taken within 72 hours of unprotected intercourse. The second dose is taken 12 hours later. Regular oral contraceptive pill use can be started after the second dose.3

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Drug Interactions

A number of clinically significant interactions between oral contraceptive pills and other medications have been reported (Table 9). Hepatic enzyme–inducing antiepileptic drugs lower oral contraceptive pill hormone levels by approximately 40 percent, thereby increasing the risk of unplanned pregnancy in women with seizure disorders.30 These agents include carbamazepine (Tegretol), phenytoin (Dilantin), phenobarbital, primidone (Mysoline) and ethosuximide (Zarontin). Troglitazone (Rezulin) has also been shown to reduce the efficacy of oral contraceptive pills by reducing plasma estrogen and progestin concentrations. An alternate method of contraception is recommended for patients taking any of these interacting medications.

Drug decreases effectiveness of oral contraceptive pills
Amoxicillin
Ampicillin
Carbamazepine (Tegretol)
Ethosuximide (Zarontin)
Metronidazole (Flagyl)
Phenobarbital
Phenytoin (Dilantin)
Primidone (Mysoline)
Rifampin (Rifadin)
Tetracycline
Troglitazone (Rezulin)
Oral contraceptive pills decrease effectiveness of drug
Clofibrate (Atromid-S)
Lorazepam (Ativan)
Oxazepam (Serax)
Salicylates
Temazepam (Restoril)
Oral contraceptive pills potentiate effect of drug
Benzodiazepines*
Beta blockers
Caffeine
Corticosteroids
Theophylline
Tricyclic antidepressants

In contrast, valproic acid (Depakene) and gabapentin (Neurontin) do not interfere with the effectiveness of oral contraceptive pills. Lamotrigine (Lamictal) and vigabatrin (Sabril) have not been thoroughly studied.

The possibility that some antibiotics decrease the effectiveness of oral contraceptive pills has been widely reported. Unfortunately, the literature supporting an oral contraceptive pill–antibiotic interaction consists of anecdotal reports or descriptive studies that included no controls or gave questionable historical control rates.31

Rifampin (Rifadin) is the only antibiotic that has been shown to decrease estrogen and progestin levels by hepatic enzyme induction and to significantly reduce the efficacy of oral contraceptive pills. Retrospective case studies indicate a weak association between ampicillin, amoxicillin, metronidazole (Flagyl) and tetracycline and ineffectiveness of oral contraceptive pills. Only isolated case reports have linked oral contraceptive pill failure to griseofulvin (Gris-Peg), clindamycin (Cleocin), cephalexin (Keflex), dapsone, isoniazid (INH), trimethoprim (both alone [Proloprim] and combined with sulfamethoxazole [Bactrim, Septra]) and erythromycin.31

More importantly, antibiotic-related diarrhea may be associated with decreased absorption of oral contraceptive pills and a diminished therapeutic effect.

It is important to realize that the inherent failure rate of oral contraceptive pills is much higher than the small, theoretically increased failure rate in women who are taking antibiotics. Nevertheless, it may be prudent for women to use a back-up contraceptive method during antibiotic therapy and for seven days after completing the antibiotic course or having the last episode of vomiting and diarrhea.4

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