Oral Contraception

   Oral  Contraception

 

  The oral contraceptives (OCs) first introduced in the 1950s contained doses of estrogen and progestin nearly 10 times as high as those in today's pills. Over the years, old synthetic ovarian steroids like mestranol and chlormadinone were largely replaced by newer compounds with fewer adverse physiologic effects. More recently, pill administration schedules have been changed from the traditional and arbitrary 3 weeks on and 1 week off to a variety of regimens that increase efficacy and convenience and reduce side effects.
  As birth control pill doses, steroids, and schedules evolved, knowledge of the physiologic and epidemiologic effects of pill use burgeoned. No drug has been as thoroughly evaluated as the combined oral contraceptive. Improved preparations and prescribing practices have dramatically reduced the morbidity and mortality associated with oral contraceptives so that today, on balance, the use of OCs has a substantial positive effect on public and individual health.

Mechanism of Action

 

 The combination pill, consisting of estrogen and progestin, was the first hormonal contraceptive and was packaged to be taken daily for 3 out of every 4 weeks in order to mimic the menstrual cycle. Additional regimens, such as taking estrogen alone during the usual placebo week or taking a combination pill every day for 3 months, have been marketed more recently.
 The combination pill prevents ovulation by inhibiting gonadotropin secretion via an effect on both pituitary and hypothalamic centers. The progestational agent in the pill primarily suppresses luteinizing hormone (LH) secretion (preventing ovulation), and the estrogenic agent inhibits follicle-stimulating hormone (FSH) secretion (suppressing the emergence of a dominant follicle). Therefore, the estrogenic component significantly contributes to the contraceptive efficacy. However, even if follicular growth and development were not suppressed, the progestational component would prevent the surge-like release of LH necessary for ovulation.
  The estrogen in the pill serves two other purposes. It provides stability to the endometrium so that irregular shedding and unwanted bleeding is minimized, and it potentiates the action of the progestational agents. The latter function of estrogen allows reduction of the progestational dose in the pill. The mechanism for this action is probably estrogen's effect in increasing the concentration of intracellular progesterone receptors. Therefore, a minimal pharmacologic level of estrogen is necessary to maintain the efficacy of the combination pill.
  Because the effect of a progestational agent always takes precedence over estrogen unless the dose of estrogen is greatly increased, the endometrium, cervical mucus, and tubal function reflect progestational stimulation. The progestin in the combination pill produces an endometrium that is a decidualized bed with exhausted and atrophied glands and is therefore not receptive to ovum implantation. The cervical mucus becomes thick and impervious to sperm transport. It is possible that progestational influences on secretion and peristalsis within the fallopian tubes provide additional contraceptive effects. Even if there is some ovarian follicular activity as with the lowest dose products, these other actions serve to ensure good contraceptive efficacy.

Efficacy

 

  The contraceptive effectiveness of the new oral contraceptive regimens (multiphasic formulations and products with the lowest estrogen dose) is the same as that of older monophasic birth control pills in both the low-dose (<50 μg estrogen) and higher dose formulations. Although carefully monitored studies with motivated subjects achieve an annual failure rate of 0.1%, typical use is associated with a 7.6% failure rate during the first year of use. Contraceptive failure rates have been estimated using the data from the 1995 National Survey of Family Growth, correcting for the known underreporting of induced abortion.


Patterns of Pill Taking
 
  Effective contraception is present during the first cycle of pill use, provided the pills are started no later than the fifth day of the woman's cycle and that no pills are missed. Starting oral contraception on the first day of menses ensures immediate protection. In the United States, most clinicians and patients use the Sunday-start packages, beginning on the first Sunday following menstruation. This can be easier to remember, and it usually prevents menstrual bleeding on weekends. It is probable, but not totally certain, that even if a dominant follicle should emerge in occasional patients after a Sunday start, an LH surge and ovulation would still be prevented.
  The conventional approach to starting oral contraceptives, either with menses or on Sunday, carries with it a delay in achieving contraception for many women, so some clinicians advocate an immediate start on the day the patient receives her prescription, regardless of the patient's day in her cycle. Combined with a backup method for the first week, preferably condoms, an immediate start can prevent unwanted pregnancies occurring during the delay before initiating oral contraception with the conventional methods. In some instances, a sensitive pregnancy test is a wise precaution. Women who use the immediate, or quick-start, method do not experience an increase in breakthrough bleeding.
  Postponement of a menstrual period can be easily achieved by omitting the 7-day hormone-free interval.
  There is no rationale for recommending a pill-free interval to “rest,” because this practice all too often results in unwanted pregnancies. The serious side effects are not eliminated by pill-free intervals.
  Although the effects of fixed schedules are not well studied, there is reason to believe that precise pill taking minimizes breakthrough bleeding. In addition, compliance is improved by a fixed schedule that is habit forming.

Avoiding Menstrual Bleeding

  More and more women are embracing the idea that fewer menstrual periods provide a welcome relief from bleeding and menstrual symptoms. A regimen (Seasonale) is available that supplies a package containing the number of pills required for 84 days of daily administration, reducing menstrual frequency to four menses per year. However, clinicians for years have prescribed continuous daily oral contraceptives to treat conditions such as endometriosis, bleeding disorders, menstrual seizures, and menstrual migraine headaches, as well as to prevent bleeding in athletes and busy women. Many women do not require the periodic experience of vaginal bleeding to assure themselves they are not pregnant and can choose how frequently to have withdrawal bleeding.
  Any combination OC can be used on a daily basis; even the lowest estrogen dose formulations provide acceptable bleeding and side effect profiles in a continuous regimen.  A further benefit of continuous use is simplification of the pill-taking schedule with the potential of better compliance and a lower failure rate. When breakthrough bleeding occurs, patients can be reassured that it is almost always temporary. When breakthrough bleeding is persistent, a 3- or 4-day interruption without pill taking has been reported to be helpful.

Missed Pills

 

  Irregular pill taking is a common occurrence. An electronic monitoring device demonstrates that consistency of pill taking is even worse than what patients report; only 33% of women were documented to have missed no pills in cycle 1, and by cycle 3, about one third of the women missed 3 or more pills with many episodes of consecutive days of missed pills. These data indicate that women become less careful over time, emphasizing the importance of repeatedly reviewing with patients what to do when pills are missed.
  Studies have questioned whether missing pills has an impact on contraception. One study demonstrated that skipping four consecutive pills at varying times in the cycle did not result in ovulation. Studies in which women deliberately lengthen their pill-free interval up to 11 days have failed to show signs of ovulation.  So far, there is no evidence that moving to lower doses has had an impact on the margin of error. Despite greater follicular activity with the lowest-dose oral contraceptives, ovulation is still effectively prevented. The progestational effects on endometrium and cervical mucus serve to ensure good contraceptive efficacy.
  The most prevalent identifiable problems associated with apparent oral contraceptive failures are vomiting and diarrhea.  Even if no pills have been missed, patients should be instructed to use a backup method for at least 7 days after an episode of gastroenteritis.

Clinical Problems Associated with Oral Contraceptive Use

Breakthrough Bleeding

 

  There are two characteristic breakthrough bleeding problems: irregular bleeding in the first few months after starting oral contraception, and unexpected bleeding after many months of use. Effort should be made to manage the bleeding problem in a way that allows the patient to remain on low-dose oral contraception. There is no evidence that the onset of bleeding is associated with decreased efficacy, no matter what oral contraceptive formulation is used, even the lowest-dose products. Indeed, in a careful study, breakthrough bleeding did not correlate with changes in the blood levels of the contraceptive steroids. On starting oral contraception, patients need to be fully informed about breakthrough bleeding.
  The most commonly encountered breakthrough bleeding occurs in the first few months of use. The incidence is greatest in the first 3 months, ranging from 10% to 30% in the first month to less than 10% in the third month. Breakthrough bleeding rates are higher with the lowest-dose OCs, but not dramatically higher.  Breakthrough bleeding rates are higher in women who smoke and in smokers who use formulations with 20 mg ethinyl estradiol. However, the differences among the various formulations currently available are of minimal clinical significance. The basic pattern is the same, highest in the first month and a greater prevalence in smokers, especially in later cycles.
  Breakthrough bleeding that occurs after many months of oral contraceptive use is a consequence of the progestin-induced decidualization. This endometrium and the blood vessels within the endometrium tend to be fragile and prone to breakdown and asynchronous bleeding.
  Two recognized factors (both preventable) are associated with a greater incidence of breakthrough bleeding. Inconsistent use and smoking increase spotting and bleeding, but inconsistency of pill taking is more important and has a greater effect in later cycles, whereas smoking exerts a general effect at any time. Reinforcement of consistent pill taking can help minimize breakthrough bleeding. Cervical infection can be another cause of breakthrough bleeding; the prevalence of cervical chlamydial infections is higher among oral contraceptive users who report breakthrough bleeding.

Thrombotic Complications
 
  The administration of pharmacologic amounts of estrogen as in high-dose oral contraceptives causes an increase in the production of clotting factors such as factor V, factor VIII, factor X, and fibrinogen. The progestin component also influences the clotting factor responses. Some studies of the blood coagulation system have concluded that monophasic and multiphasic low-dose OCs have no significant clinical impact on the coagulation system. Slight increases in thrombin formation are offset by increased fibrinolytic activity.  Other studies of formulations containing 30 or 35 mg of ethinyl estradiol indicate an increase in clotting factors associated with an increase in platelet activity. However, these changes are essentially all within normal ranges, and their clinical significance is unknown.
  Smoking produces a shift to hypercoagulability. A 20-μg estrogen formulation has been reported to have no effect on clotting parameters, even in smokers.  One study comparing a 20-μg product with a 30-μg product found similar mild procoagulant and fibrinolytic activity, although there was a trend toward increased fibrinolytic activity with the lower dose. These mixed reports make it essential to base clinical decisions on the epidemiologic studies of clinical events.
There is no evidence of an increase in risk of cardiovascular disease among past users of oral contraception.  In the Nurses' Health Study, the Royal College of General Practitioners' Study, and the Oxford Family Planning Association Study, long-term past use of oral contraceptives was not associated with an increase in overall mortality.  Part of the concern for a possible lingering effect of oral contraceptive use was based on a presumed adverse impact on the atherosclerotic process, which would then be added to the effect of aging and thus would be manifested later in life. Instead, the findings have been consistent with the contention that cardiovascular disease due to oral contraception is secondary to acute effects, specifically estrogen-induced thrombosis, a dose-related event.

Venous Thrombosis

Venous Thromboembolism

 

   Older epidemiologic evaluations of oral contraceptives and vascular disease indicated that venous thrombosis was caused by estrogen, limited to current users, with a disappearance of the risk by 3 months after discontinuation. Thromboembolic disease was believed to be a consequence of the pharmacologic administration of estrogen, and the level of risk was believed to be related to the estrogen dose. Smoking was documented to produce an additive increase in the risk of arterial thrombosis, but it had no effect on the risk of venous thromboembolism.
   In the first years of oral contraception, the available products, containing 80 and 100 mg ethinyl estradiol (extremely high doses), were associated with a sixfold increased risk of venous thrombosis, the same risk seen in pregnant women. Because of the increased risks of venous thrombosis, myocardial infarction, and stroke, lower-dose formulations (<50 mg estrogen) came to dominate the market, and clinicians became more careful in their screening of patients and prescribing of oral contraception. Because of these two factors, the Puget Sound study in the United States documented a reduction in venous thrombosis risk to twofold.

Venous Thromboembolism and the Factor V Leiden Mutation

 

  A risk of idiopathic venous thrombosis persists with low-dose oral contraceptives at a level of approximately threefold to fourfold greater than the normal, general incidence.  However, an inherited resistance to activated protein C, the factor V Leiden mutation, might account for a significant portion of the patients who experience venous thrombosis while taking oral contraceptives ( Table 1 - 2 ).

TABLE 1 - 2   - RELATIVE RISK AND ACTUAL INCIDENCE OF VENOUS THROMBOEMBOLISM

Population	Relative Risk	Incidence (no. per 100,000/year)
Young women (general population)	1	4-5
Pregnant women	12	48-60
High-dose oral contraceptives	6-10	24-50
Low-dose oral contraceptives	3-4	12-20
Leiden mutation carrier	5-8	20-40
Leiden carrier and oral contraceptives	10-30	40-150
Leiden mutation, homozygous	80	320-400

  An inherited resistance to activated protein C, the factor V Leiden mutation, is the most common inherited coagulation problem transmitted in an autosomal-dominant fashion.  Heterozygotes have a 5- to 8-fold increased risk of venous thromboembolism, and homozygotes have an 80-fold increased risk. Oral contraceptive users who have this mutation have been reported to have a 30-fold increased risk of venous thrombosis.  Some have argued, however, that this increase has been overestimated, and it may be closer to 10- to 15-fold. The risk of developing venous thrombosis is greatest in the initial months of use, and it has been suggested that venous thrombosis occurring in the first month of exposure should make the clinician suspect the presence of a clotting disorder.
  Combination oral contraception is contraindicated in women who have a history of idiopathic venous thromboembolism, as well as in women who have a close family history (parent or sibling) of idiopathic venous thromboembolism. These women will have a higher incidence of congenital deficiencies in important clotting measurements, especially antithrombin III, protein C, protein S, and resistance to activated protein C. Such a patient who screens negatively for an inherited clotting deficiency might still consider using oral contraceptives, but this would be a difficult decision with unknown risks for both patient and clinician, and it is more prudent to consider other contraceptive options. Other risk factors for thromboembolism that should be considered by clinicians include an acquired predisposition, such as lupus anticoagulant or malignancy, and immobility or trauma. Varicose veins are not a risk factor unless they are very extensive.

Arterial Thrombosis

 

   The incidence of cerebral thrombotic attacks (thrombotic strokes and transient ischemic attacks) among young women is higher than that of venous thromboembolism and myocardial infarction, and death and disability are more likely. Because of the higher incidence and risk, cerebral arterial thrombosis is the most important possible side effect of oral contraceptives. A very low incidence of stroke in young women carries with it little increase in absolute risk. However, because the incidence of cerebral thrombotic attacks is higher in women older than 40 years, oral contraceptive users older than 40 years must be in good health and without significant risk factors for cardiovascular disease (especially hypertension, migraine with aura, and smoking).
  The synergy of smoking and oral contraception in causing myocardial infarction is well documented ( Table 1 - 3 ). It has been difficult to establish arterial thrombosis dose-response relationships with estrogen because these events are so rare. Nevertheless, the estrogen dose is an important factor for the risk of myocardial infarction and thrombotic strokes.

TABLE 1 - 3  - INCIDENCE OF MYOCARDIAL INFARCTION IN REPRODUCTIVE-AGE WOMEN

Population	Incidence (no. per 100,000/year)
Overall	5
WOMEN YOUNGER THAN 35 YEARS
Nonsmokers	4
Nonsmokers taking OCs	4
Smokers	8
Smokers taking OCs	43
WOMEN 35 YEARS AND OLDER
Nonsmokers	10
Nonsmokers taking OCs	40
Smokers	88
Smokers taking OCs	485

OC, oral contraceptive. Note: These incidences are estimates based on oral contraceptive use paired with cardiovascular risk factors prevalent in the general population. Effective screening would produce smaller numbers. The increased risks in the smokers and OC groups reflect the impact of undetected cardiovascular risk factors, especially hypertension.

Arterial Thrombosis—Stroke

 

  Older case-control and cohort studies indicated an increased risk of cerebral thrombosis among current users of high-dose oral contraceptives.  However, thrombotic stroke did not appear to be increased in healthy, nonsmoking women who used oral contraceptives containing less than 50 mg ethinyl estradiol.  A case-control study of all 794 women in Denmark who suffered a cerebral thromboembolic attack during the period 1985 to 1989 concluded that there was an almost twofold increased relative risk associated with oral contraceptives containing 30 to 40 mg estrogen, and the risk was significantly influenced by both smoking and the dose of estrogen in additive (not synergistic) fashion. A case-control analysis of data collected by the Royal College of General Practitioners' Oral Contraception Study concluded that current users were at increased risk for stroke (with a persisting effect in former users); however, this outcome was limited mainly to smokers and to formulations with 50 mg or more of estrogen.
  A population-based, case-control study of 408 strokes from the California Kaiser Permanente Medical Care Program found no increase in risk for either ischemic stroke or hemorrhagic stroke. The identifiable risk factors for ischemic stroke were smoking, hypertension, diabetes, elevated body weight, and low socioeconomic status. The risk factors for hemorrhagic stroke were the same plus greater body mass and heavy use of alcohol. Current users of low-dose oral contraceptives did not have an increased risk of ischemic or hemorrhagic stroke compared with former users and with never users. There was no evidence for an adverse effect of increasing age or for smoking (for hemorrhagic stroke, there was a suggestion of a positive interaction between current oral contraceptive use and smoking, but the numbers were small, and the result was not statistically significant). Table 1 - 4 summarizes current results.

TABLE 1 - 4  - INCIDENCE OF STROKE IN REPRODUCTIVE-AGE WOMEN

Population	Incidence (no. per 100,000/year)
ISCHEMIC STROKE
Overall	5
Women < 35 y	1-3
Women ≥ 35 y	10
HEMORRHAGIC STROKE
Overall	6
EXCESS DUE TO OC USE[*]
Low-dose OC	2
Low-dose OC, <35 y	1
High-dose OC	8

OC, oral contraceptive.

*	Includes women who smoke and women with hypertension.

Arterial Thrombosis—Current Assessment

 

   There has been no evidence with respectable statistical power that the new (third generation) progestins have an appreciable difference in risk of arterial disease, an event not increased with low-dose older-type progestin oral contraceptives. It is possible that as these studies continue and acquire greater statistical power, a difference will emerge, but the difference will be minor and probably clinically insignificant even if this is the case.
  Most importantly, the new studies fail to find any substantial risk of ischemic or hemorrhagic stroke with low-dose oral contraceptives in healthy young women. The WHO study did find evidence for an adverse impact of smoking in women younger than 35 years; the Kaiser study did not. This difference is explained by the confounding effect of hypertension, the major risk factor identified. In the WHO study, a history of hypertension was based on whether a patient reported ever having had high blood pressure (other than in pregnancy) and was not validated by medical records. In the Kaiser study, women were classified as having hypertension if they reported using antihypertensive medication (less than 5% of oral contraceptive users had treated hypertension, and there were no users of higher-dose products). In the WHO study, the effect of using oral contraceptives in the presence of a high-risk factor is apparent in the different odds ratios when European women who received good screening from clinicians were compared with women in developing countries who received little screening; therefore, more women with cardiovascular risk factors in developing countries were using oral contraceptives.
 Oral contraceptives containing less than 50 mg ethinyl estradiol do not increase the risk of myocardial infarction or stroke in healthy nonsmoking women, regardless of age. The effect of smoking in women younger than 35 years is, as we have long recognized, not detectable in the absence of hypertension. After age 35 years, the subtle presence of hypertension makes analysis difficult, but the Kaiser study indicates that increasing age and smoking by themselves have little impact on the risk of stroke in low-dose oral contraceptive users. The screening of patients in the Kaiser program was excellent, resulting in few women with hypertension using oral contraceptives. The new studies indicate that hypertension should be a major concern, especially with regard to the risk of stroke.

Hypertension

 

  Oral contraceptive–induced hypertension was observed in approximately 5% of users of higher-dose pills. More-recent evidence indicates that small increases in blood pressure can be observed even with 30-mg estrogen monophasic pills, including those containing the new progestins. However, an increased incidence of clinically significant hypertension has not been reported. The lack of clinical hypertension in most studies may be due to the rarity of its occurrence. The Nurses' Health Study observed an increased risk of clinical hypertension in current users of low-dose oral contraceptives, providing an incidence of 41.5 cases per 10,000 women per year. Therefore, an annual assessment of blood pressure is still an important element of clinical surveillance, even when low-dose oral contraceptives are used. Postmenopausal women in the Rancho Bernardo Study who had previously used oral contraceptives (probably high-dose products) had slightly higher (2 to 4 mm Hg) diastolic blood pressures. Because past users do not demonstrate differences in incidence or risk factors for cardiovascular disease, it is unlikely this blood pressure difference has an important clinical effect.
Low-dose oral contraceptives are very safe for healthy young women. Screening for smoking and cardiovascular risk factors, especially hypertension, in women older than 35 years can nearly eliminate increased risk of arterial disease associated with low-dose oral contraceptives. There is no increased risk of cardiovascular events associated with duration of use (long term). In large cohort studies, the risk of overall mortality comparing users and nonusers of oral contraceptives is identical.

Breast Cancer

 

  Current and recent use of oral contraceptives, in case-control studies, may be associated with about a 20% increased risk of early (before age 35 years) premenopausal breast cancer, essentially limited to localized disease. This modest increase in relative risk is predicted to be associated with a very small increase in the actual number of cases (so small, there would be no major impact on incidence figures). The finding of a modest increase in relative risk in young women may be partly or entirely due to detection and surveillance bias and accelerated growth of already present malignancies, a situation similar to the effects of pregnancy and postmenopausal hormone therapy on the risk of breast cancer. Further comfort can be derived from the fact that the increase in breast cancer in American women was greater in older women from 1973 to 1994, those who did not have the opportunity to use oral contraception. In women younger than 50 years, there was only a slight increase during this time period. The large American case-control study of women age 35 to 64 years was totally negative and very reassuring.
  There is no effect of past use or duration of oral contraceptive use (up to 15 years of continuous use) on the risk of breast cancer, and there is no evidence indicating that higher-dose oral contraceptives increased the risk of breast cancer. In fact, previous oral contraceptive use may be associated with a reduced risk of metastatic breast cancer later in life and possibly with a reduced risk of postmenopausal breast cancer.
  Oral contraceptive use does not further increase the risk of breast cancer in women with positive family histories of breast cancer or in women with proven benign breast disease. However, the clinician should not fail to take every opportunity to direct attention to all factors that affect breast cancer. Breastfeeding and control of alcohol intake are good examples and are also components of preventive health care. Especially important is this added motivation to encourage breastfeeding. The protective effect of breastfeeding is exerted mainly on premenopausal breast cancer, the cancer of concern to younger women using oral contraception.

Carbohydrate Metabolism

 

   With the older high-dose oral contraceptives, many women had impaired glucose tolerance: plasma levels of insulin as well as the blood sugar were elevated in a glucose tolerance test. Generally, the effect of oral contraception is to produce an increase in peripheral resistance to insulin action. Most women can meet this challenge by increasing insulin secretion, and there is no change in the glucose tolerance test, although 1-hour values may be slightly elevated.
Insulin sensitivity is affected mainly by the progestin component of the pill. The derangement of carbohydrate metabolism may also be affected by estrogen influences on lipid metabolism, hepatic enzymes, and elevation of unbound cortisol. The glucose intolerance is dose related: effects are less with the low-dose formulations. Insulin and glucose changes with low-dose monophasic and multiphasic oral contraceptives are so minimal that it is now believed they are of no clinical significance.  These studies include long-term evaluation with measurement of hemoglobin A1c (Hb_A1c).

Liver

 

   The liver is affected in more ways and with more regularity and intensity by the sex steroids than any other extragenital organ. Estrogen influences the synthesis of hepatic DNA and RNA, hepatic cell enzymes, serum enzymes formed in the liver, and plasma proteins. Estrogenic hormones also affect hepatic lipid and lipoprotein formation, the intermediary metabolism of carbohydrates, and intracellular enzyme activity. Nevertheless, an extensive analysis of the prospective cohorts of women in the Royal College of General Practitioners' Oral Contraception Study and the Oxford Family Planning Association Contraceptive Study could detect no evidence of an increased incidence or risk of serious liver disease among oral contraceptive users.
  The active transport of biliary components is impaired by estrogens as well as some progestins. The mechanism is unclear, but cholestatic jaundice and pruritus were occasional complications of higher dose oral contraception. As in the recurrent jaundice of pregnancy, the cholestasis was benign and reversible. The incidence of this complication with lower dose oral contraception is unknown, but it must be very rare.
  The only absolute hepatic contraindication to oral contraceptive use is acute or chronic cholestatic liver disease. Cirrhosis and previous hepatitis are not aggravated. Once recovered from the acute phase of liver disease, a woman can use oral contraception.

Oral Contraceptive Use and Medical Problems

Metabolic Disorders

Diabetes Mellitus

 

Oral contraception may be used by diabetic women younger than 35 years old who do not smoke and are otherwise healthy (especially an absence of diabetic vascular complications). A case-control study could find no evidence that oral contraceptive use by young women with insulin-dependent diabetes mellitus increased the development of retinopathy or nephropathy. In a 1-year study of women with insulin-dependent diabetes mellitus who were using a low-dose oral contraceptive, no deterioration could be documented in lipoprotein or hemostatic biochemical markers for cardiovascular risk. And finally, no effect of oral contraceptives on cardiovascular mortality could be detected in a group of women with diabetes mellitus. Women with diabetes and vascular disease or major cardiovascular risk factors should avoid pharmacologic doses of exogenous estrogen.

Gallbladder Disease

 

Oral contraception use might precipitate a symptomatic attack in women known to have stones or a positive history for gallbladder disease and, therefore, should either be used very cautiously or not at all.

Hyperlipidemia

  Because low-dose oral contraceptives have negligible impact on the lipoprotein profile, hyperlipidemia is not an absolute contraindication, with the exception of very high levels of triglycerides (which can be further elevated by estrogen). In women with triglyceride levels greater than 250 mg/dL, estrogen should be provided with great caution. If vascular disease is already present, oral contraception should be avoided. If other risk factors are present, especially smoking, oral contraception is not recommended. Dyslipidemic patients who begin oral contraception should have their lipoprotein profiles monitored monthly for a few visits to ensure no adverse impact. If the lipid abnormality cannot be controlled, an alternative method of contraception should be used.
 Oral contraceptives containing the less androgenic synthetic progestins—desogestrel, noregestimate, or gestodene—can increase high-density lipoprotein (HDL) levels, but it is not known if this change is clinically significant. If hypertriglyceridemia is the only concern, keep in mind that the triglyceride response to estrogen is rapid. A repeat level should be obtained in 2 to 4 weeks.     A level greater than 750 mg/dL represents an absolute contraindication to estrogen treatment because of the risk of pancreatitis.

Hepatic Disease

 

  Oral contraception may be used when liver function tests return to normal. Follow-up liver function tests should be obtained after 2 to 3 months of OC use.

Obesity

 

  An obese woman who is otherwise healthy may use low-dose oral contraception. However, there are special considerations associated with obesity.
  Obesity is an independent risk factor for venous thrombosis, and case-control studies have indicated that this risk adds to that associated with oral contraceptives.
   Recent evidence suggests that hormonal contraceptive failure is increased in overweight women (weight greater than 155 pounds).  Clinical trials have excluded women with high body weight, and for this reason, the effect of body weight on contraception was not well studied. Selecting a 50-mg estrogen product for overweight women might overcome the failure rate, but this would add the risks of venous thrombosis associated with a higher dose of estrogen to those already linked with obesity. Keep in mind that the conclusions regarding failure rates and weight were based on differences of only 2 to 4 pregnancies per 100 women per year. Efficacy in overweight women is still greater than that with barrier methods.

Polycystic Ovaries and Insulin Resistance

  Because older, high-dose oral contraceptives increased insulin resistance, it has been suggested that this treatment should be avoided in anovulatory, overweight women. However, low-dose oral contraceptives have minimal effects on carbohydrate metabolism, and the majority of hyperinsulinemic, hyperandrogenic women can be expected to respond favorably to treatment with oral contraceptives.
  Insulin and glucose changes with low-dose (<50 mg ethinyl estradiol) oral contraceptives are so minimal that it is now believed that they are of no clinical significance. Long-term follow-up studies have failed to detect any increase in the incidence of diabetes mellitus or impaired glucose tolerance (even in past and current users of high-dose pills). Furthermore, there is no evidence of an increase in risk of cardiovascular disease among past users of oral contraceptives.  In addition, low-dose oral contraceptives have been administered to women with recent gestational diabetes without an adverse impact, and in women with insulin-dependent diabetes mellitus, low-dose oral contraceptives have not produced deterioration of lipid and biochemical markers for cardiovascular disease or increased the development of retinopathy or nephropathy. The administration of a low-dose oral contraceptive to women with extreme obesity and very severe insulin resistance resulted in only a mild deterioration of glucose tolerance.
  Impressively, in a follow-up study (about 10 years) of women with polycystic ovaries and hyperinsulinism, comparing oral contraceptive users with nonusers, the metabolic parameters not only did not worsen in the users, but they actually improved, including body weight, glucose tolerance, insulin levels, and HDL-cholesterol levels, which was in striking contrast to the metabolic worsening observed in the nonusers. This experience supports the safety of estrogen-progestin contraceptive treatment for anovulatory, hyperandrogenic, hyperinsulinemic women.

Eating Disorders

 

  In patients with eating disorders, bone density correlates with body weight. The response of bone density to hormone therapy will be impaired as long as an abnormal weight is maintained. The failure to respond to estrogen treatment with an increase in bone density may be due to the adverse bone effects of the hypercortisolism associated with stress disorders. Furthermore, because the pubertal gain in bone density is so significant, patients who fail to experience this adolescent increase can continue to have a deficit in bone mass despite hormone treatment. Reduced menstrual function for any reason early in life (even beyond adolescence) can leave a residual deficit in bone density that cannot be totally retrieved with resumption of menses or with hormone treatment.

Cardiovascular Disorders

Hypertension

 

  Low-dose oral contraception may be used in women younger than 35 years who have hypertension well controlled by medication and who are otherwise healthy and do not smoke. We recommend the lowest estrogen dose formulations. Nevertheless, a cross-sectional study in Brazil reported worse control of hypertension in users of oral contraceptives. Certainly a woman with controlled hypertension who has additional medical problems or who smokes should not use estrogen-progestin contraceptives (including the transdermal and vaginal methods). In a young woman with controlled hypertension who is otherwise healthy, very frequent and close monitoring of the blood pressure is essential. Because myocardial infarction and stroke become more common after age 35 years, combined estrogen-progestin contraception should not be used by women who have controlled hypertension after age 35. Progestin-only methods are acceptable.

Mitral Valve Prolapse

Oral contraception use in women with mitral valve prolapse is limited to nonsmoking patients who are asymptomatic (no clinical evidence of mitral regurgitation). There is a small subset of patients with mitral valve prolapse who are at increased risk for thromboembolism. Patients with atrial fibrillation, migraine headaches, or clotting factor abnormalities should consider progestin-only methods or intrauterine contraception (prophylactic antibiotics should cover insertion if mitral regurgitation is present).

Smoking

 

Oral contraception is absolutely contraindicated in smokers older than 35 years. In patients 35 years and younger, heavy smoking (15 or more cigarettes per day) is a relative contraindication. The relative risk of cardiovascular events is increased for women of all ages who smoke and use oral contraceptives; however, because the actual incidence of cardiovascular events is so low at a young age, the absolute risk is very low for young women, although it increases with age. An ex-smoker (for at least 1 year) should be regarded as a nonsmoker. Risk is only linked to active smoking. In the absence of any other risk factors, low-dose oral contraceptives might be appropriate for a light smoker or the user of a nicotine patch. A 20-mg estrogen formulation may be a better choice for smoking women, regardless of age, because this dose of estrogen has no impact on clotting factors and platelet activation. Smoking continues to be a difficult problem, not only for patient management but also for analysis of data. In large U.S. surveys in 1982 and 1988, the decline in the prevalence of smoking was similar in users and nonusers of oral contraception; however, 24.3% of 35- to 45-year-old women who used oral contraceptives were smokers! In this group of smoking, oral contraceptive–using women, 85.3% smoked 15 or more cigarettes per day (heavy smoking). Despite the widespread teaching and publicity that smoking is a contraindication to oral contraceptive use in women older than 35 years, more older women who used oral contraceptives smoked and smoked heavily, compared with young women. This strongly suggests that older smokers are less than honest with clinicians when requesting oral contraception, and this further raises serious concern over how well this confounding variable can be controlled in case-control and cohort studies. A former smoker must have stopped smoking for at least 12 consecutive months to be regarded as a nonsmoker. Women who have nicotine in their bloodstream obtained from patches or gum should be regarded as smokers.

Congenital Heart Disease or Valvular Heart Disease

 

Oral contraception is contraindicated only if there is marginal cardiac reserve or a condition that predisposes to thrombosis.

Pregnancy-Associated Diseases

 

Pregnancy-Induced Hypertension

Women with pregnancy-induced hypertension may use oral contraception as soon as the blood pressure is normal in the postpartum period.

Gestational Diabetes

 

Low-dose formulations do not produce a diabetic glucose tolerance response in women with previous gestational diabetes, and there is no evidence that combined oral contraceptives increase the incidence of overt diabetes mellitus.  Women with previous gestational diabetes may use oral contraception with annual assessment of the fasting glucose level.

Cholestatic Jaundice in Pregnancy

 

Not all patients who have cholestatic jaundice in pregnancy will develop jaundice while taking oral contraception. Jaundice is especially unlikely with the low-dose formulations.

Benign Tumors

Uterine Leiomyoma

The risk of leiomyomas decreased by 31% in women who used higher dose oral contraception for 10 years. However, case-control studies with lower-dose oral contraceptives have found neither a decrease nor an increase in risk, although the Nurses' Health Study reported a slightly increased risk when oral contraceptives were first used in early teenage years. One case-control study indicated a decreasing risk of uterine myomas with increasing duration of oral contraceptive use. The administration of low-dose oral contraceptives to women with leiomyomas does not stimulate fibroid growth, and it is associated with a reduction in menstrual bleeding.

Benign Breast Disease

 

   Benign breast disease is not a contraindication for oral contraception. With 2 years of use, the condition sometimes improves.

Pituitary Prolactin-Secreting Adenomas

 

   Estrogen stimulates prolactin secretion and causes growth of pituitary lactotrophs, but oral contraceptives do not increase the risk of pituitary adenomas and may be used in the presence of microadenomas without affecting their rate of growth.

Neurologic and Psychiatric Disorders

Migraine Headaches

 

Some women report an improvement in their headaches with oral contraceptives. Low-dose oral contraception (the lowest estrogen dose formulations) may be used with careful surveillance in women with migraine headaches without aura. Daily administration can prevent menstrual migraine headaches. Oral contraception is best avoided in women with migraine headaches with aura or if additional risk factors for stroke are present (especially older age, smoking, and hypertension).

Seizure Disorders

 

Oral contraceptives do not exacerbate epilepsy, and in some women, seizure control has improved. Antiepileptic drugs that affect liver metabolism, however, can decrease the effectiveness of oral contraception. Some clinicians advocate the use of higher -ose (50 mg estrogen) products; however, no studies have been performed to demonstrate that this higher dose is necessary. Another problem is that moving to a higher-dose product increases the estrogen dose (and the risk of side effects) but does not significantly change the progestin dose, the component that inhibits ovulation. A wiser course is to consider intrauterine contraception, long-acting progestin methods, or sterilization.

Depression

 

  Low-dose oral contraceptives have minimal, if any, impact on mood.

Hematopoietic Disorders 

Sickle Cell Disease

 

Women with sickle cell trait may use oral contraception. The potentiation of risk of thrombosis with sickle cell disease or sickle C diseases is a theoretical (and medicolegal) possibility. However, we believe effective protection against pregnancy in these patients warrants the use of low-dose oral contraception. In the only long-term (10 years) follow-up report of women with sickle cell disease using oral contraceptives at a time when higher dose products were prevalent, no apparent adverse effects were observed. A study of erythrocyte deformability in women with sickle cell anemia could detect no adverse effects of contraceptive steroids. Keep in mind that depot-medroxyprogesterone acetate (DMPA) used for contraception is associated with inhibition of sickling and improvement in anemia in patients with sickle cell disease.

Hemorrhagic Disorders

 

 Women with hemorrhagic disorders and women taking anticoagulants may use oral contraception. Inhibition of ovulation can prevent the serious problem of a hemorrhagic corpus luteum in these patients. A reduction in menstrual blood loss provides an additional benefit.

 Inflammatory and Immune Conditions

Systemic Lupus Erythematosus

 

 Oral contraceptive use can exacerbate systemic lupus erythematosus, and the vascular disease associated with lupus, when present, represents a contraindication to estrogen-containing contraceptives. The progestin-only methods are a good choice. However, in patients with stable or inactive disease, without renal involvement or high antiphospholipid antibodies, low-dose oral contraception may be considered.

Infectious Mononucleosis

 

Oral contraception may be used as long as liver function tests are normal.

Ulcerative Colitis

 

 There is no association between oral contraception and ulcerative colitis. Women with this problem may use oral contraceptives. Oral contraceptives are absorbed mainly in the small bowel.

Regional Enteritis (Crohn's Disease)

 

  In a prospective cohort of women with Crohn's disease, no adverse impact of oral contraceptives could be detected on the clinical course, specifically on flare-ups.

Elective Surgery

 

   The recommendation that oral contraception should be discontinued 4 weeks before elective major surgery to avoid an increased risk of postoperative thrombosis is based on data derived from high-dose pills. If possible, it is safer to follow this recommendation when a period of immobilization is expected. With major surgery and immobilization, prophylactic anticoagulation should be considered for a current or recent user of oral contraceptives. It is prudent to maintain contraception right up to the performance of a sterilization procedure, and this short outpatient operation carries minimal risk.

  Noncontraceptive Benefits of Oral Contraception

 

  The noncontraceptive benefits of low-dose oral contraception can be grouped into two main categories: benefits that incidentally accrue when oral contraception is specifically used for contraceptive purposes and benefits that result from the use of oral contraceptives to treat problems and disorders. The noncontraceptive incidental benefits are listed in Table 1 - 5 .

TABLE 1 - 5 - NONCONTRACEPTIVE BENEFITS OF ORAL CONTRACEPTIVES

EFFECTIVE CONTRACEPTION

Less need for induced abortion    Less need for surgical sterilization

MORE REGULAR MENSES

Less flow    Less dysmenorrhea    Less anemia

OTHER

Less endometrial cancer    Less ovarian cancer    Fewer ectopic pregnancies    Less salpingitis    Increased bone density    Probably less endometriosis    Possibly less benign breast disease    Possibly less rheumatoid arthritis    Possibly protection against atherosclerosis    Possibly fewer fibroids    Possibly fewer ovarian cysts

Special Uses of Oral Contraception

The Progestin-Only Minipill

 

   The minipill contains a small dose of a progestational agent and must be taken daily, in a continuous fashion.  There is no evidence for any major differences in clinical behavior among the available minipill products except that desogestrel suppresses ovulation more reliably than the others.
All of them (listed in Table 1 - 6 ) could probably be used in high doses (10 to 20 pills) as emergency contraception, but only levonorgestrel has been proved effective.

TABLE 1 - 6 - MINIPILLS AVAILABLE WORLDWIDE

Brand	Composition
Micronor, Nor-QD, Noriday, Norod	0.350 mg norethindrone
Microval, Noregeston, Microlut	0.030 mg levonorgestrel
Ovrette, Neogest	0.075 mg norgestrel (equivalent to 0.0375 mg levonorgestrel)
Exluton	0.500 mg lynestrenol
Femulen	0.500 mg ethynodial diacetate
Cerazette	0.075 mg desogestrel

Mechanism of Action

 

After taking a progestin-only minipill, the small amount of progestin in the circulation (about 25% of that in combined oral contraceptives) will have a significant effect only on tissues very sensitive to progesterone. The contraceptive effect is more dependent on effects on endometrial and cervical mucus because gonadotropins are not consistently suppressed. The cervical mucus becomes thick and impermeable to sperm, and the endometrium involutes and becomes hostile to implantation. Approximately 40% of patients ovulate normally.  Tubal physiology might also be affected, but this is speculative. The progestin-only minipill containing 0.075 mg desogestrel appears to be more effective, probably because it exerts a greater inhibition of ovulation than the other progestins.
Because of the low dose, the minipill must be taken every day at the same time of day. The change in the cervical mucus requires 2 to 4 hours to take effect, and, most importantly, the impermeability diminishes 22 hours after administration, and by 24 hours sperm penetration is essentially unimpaired.
Ectopic pregnancy is not prevented as effectively as intrauterine pregnancy. Although the overall incidence of ectopic pregnancy is not increased (it is still much lower than the incidence in women not using a contraceptive method), when pregnancy occurs, the clinician must suspect that it is more likely to be ectopic. A previous ectopic pregnancy should not be regarded as a contraindication to the minipill; however, women at risk for subsequent ectopic pregnancy require the protection provided by methods, like the combined pill, that prevent fertilization.
There are no significant metabolic effects (lipid levels, carbohydrate metabolism, and coagulation factors remain unchanged),  and there is an immediate return to fertility on discontinuation, unlike the delay seen with the combination oral contraceptive.

Efficacy

 

Failure rates have been documented to range from 1.1 to 9.6 per 100 women in the first year of use. The failure rate is higher in younger women (3.1 per 100 woman-years) compared with women older than 40 years (0.3 per 100 woman-years). In motivated women, the failure rate is comparable to the rate (<1 per 100 woman-years) with combination oral contraception.

Patterns of Pill Taking

 

 The minipill should be started on the first day of menses, and a backup method must be used for the first 7 days because some women ovulate as early as 7 to 9 days after the onset of menses. Taking the pill should be keyed to a daily event to ensure regular administration at the same time of the day. If pills are forgotten or gastrointestinal (GI) illness impairs absorption, the minipill should be resumed as soon as possible, and a backup method should be used immediately and until the pills have been resumed for at least 2 days. If two or more pills are missed in a row and there is no menstrual bleeding in 4 to 6 weeks, a pregnancy test should be obtained. If the pill is taken more than 3 hours late, a backup method should be used for 48 hours.

Problems

 

  In view of the unpredictable effect on ovulation, it is not surprising that irregular menstrual bleeding is the major clinical problem. The daily progestational impact on the endometrium also contributes to this problem. Patients can expect to have normal ovulatory cycles (40% to 50%); short, irregular cycles (40%); or a total lack of cycles ranging from irregular bleeding to spotting and amenorrhea (10%). Abnormal bleeding is the major reason women discontinue the minipill method of contraception.
  Women on progestin-only contraception develop more functional ovarian follicular cysts than those using methods that more profoundly suppress gonadotropins. This is not a clinical problem because all or nearly all regress. Women who have experienced frequent ovarian cysts would be happier with methods that effectively suppress ovulation (combined oral contraceptives or DMPA).
  The levonorgestrel minipill may be associated with acne. The mechanism is similar to that seen with Norplant (see later). The androgenic activity of levonorgestrel decreases the circulating levels of sex hormone–binding globulin (SHBG).Therefore, free steroid levels (levonorgestrel and testosterone) will be increased despite the low dose. This is in contrast to the action of combined oral contraception, in which the effect of the progestin is countered by the estrogen-induced increase in SHBG.
  Progestin-only minipills achieve efficacy comparable to combined pills in women older than 40 years and in women who are breastfeeding. There is no evidence for any adverse effect on breastfeeding as measured by milk volume and infant growth and development.  In fact, there is a modest positive effect; women using the minipill breastfeed longer and add supplementary feeding later. Because of the slight positive impact on lactation, the minipill can be started immediately after delivery. A study investigating the effect of early initiation found no adverse effects on breastfeeding.
  The minipill is a good choice in situations where estrogen is contraindicated, such as patients with serious medical conditions (diabetes with vascular disease, severe systemic lupus erythematosus, cardiovascular disease). The freedom from complications caused by estrogen, although likely, is presumptive. On the other hand, it is logical to conclude that any of the progestin effects associated with the combination oral contraceptives are found with the minipill, but a dose-response relationship should reduce adverse effects. The World Health Organization case-control study and the Transnational case-control study found no indication of increased risks of stroke, myocardial infarction, or venous thromboembolism with oral progestin-only contraceptives, but relatively small numbers have chosen to use this method of contraception and were included in these studies, which focused on combined OCs. No impact can be measured on the coagulation system. The minipill can probably be used in women with previous episodes of thrombosis, and the package insert in the United States was revised, eliminating vascular disease as a contraindication.
  The minipill is a good alternative for the occasional woman who reports diminished libido on combination oral contraceptives, presumably due to decreased androgen levels. The minipill should also be considered for the few patients who report unacceptable levels of minor side effects (GI upset, breast tenderness, headaches) with the combination oral contraceptive.
 Because of the relatively low doses of progestin administered, patients using medications that increase liver metabolism should avoid this method of contraception and other low-dose progestin methods, such as implants. These drugs include carbamazepine (Tegretol), felbamate, nevirapine, oxcarbazepine, phenobarbital, phenytoin (Dilantin), primidone (Mysoline), rifabutin, rifampicin (Rifampin), topiramate, St. John's wort, vigabatrin, and possibly ethosuximide, griseofulvin, and troglitazone. These medications can also limit the efficacy of combined pills.
  Because of the relatively small numbers of users, we do not know if minipills confer the same benefits as combined oral contraceptives. The progestin impact on cervical mucus, endometrium, and ovulation leads one to think the benefits will be present (reduced risks of pelvic infection, endometrial cancer, and ovarian cancer). Although limited by small numbers, one case-control study indicated that protection against endometrial cancer was even greater with progestin-only pills than with combination oral contraceptives.
  Good efficacy with the minipill requires regularity of administration, taking the pill at the same time each day. There is less room for forgetting, and therefore the minipill is probably not a good choice for a disorganized adult or for the average adolescent.

Emergency Postcoital Contraception

  The use of large doses of estrogen to prevent implantation was pioneered by Morris and van Wagenen at Yale in the 1960s. The initial work in monkeys led to the use of high doses of diethylstilbestrol (25 to 50 mg/day) and ethinyl estradiol in women. It was quickly appreciated that these extremely large doses of estrogen were associated with a high rate of GI side effects. Albert Yuzpe developed a method using a combination oral contraceptive, resulting in an important reduction in dosage. The following treatment regimens have been documented to be effective ( Table 1 - 7 ):

	•	Ovral: 2 tablets followed by 2 tablets 12 hours later (0.5 mg norgestrel and 50 mg ethinyl estradiol per tablet)
	•	Alesse: 5 tablets followed by 5 tablets 12 hours later (100 mg levonorgestrel and 20 mg ethinyl estradiol per tablet)
	•	Lo Ovral, Nordette, Levlen, Triphasil (yellow tablets), Trilevlen (yellow tablets): 4 tablets followed by 4 tablets 12 hours later.

TABLE 1 -7  - EMERGENCY CONTRACEPTION

	DOSE PER TABLET
Brand Name	Ethinyl Estradiol	Levonorgestrel	Norgestrel	First Dose	Second Dose (12 hr Later)
Alesse	20 μg	0.10 mg	—	5 tablets	5 tablets
Levlen	30 μg	0.15 mg	—	4 tablets	4 tablets
Lo Ovral	30 μg	—	0.3 mg	4 tablets	4 tablets
Nordette	30 μg	0.15 mg	—	4 tablets	4 tablets
Ovral	50 μg	—	0.5 mg	2 tablets	2 tablets
Plan B[*]	none	0.75 mg	—	1-2 tablets	0-1 tablets
Trilevlen	30 μg	0.125 mg	—	4 tablets	4 tablets
Triphasil	30 μg	0.125 mg	—	4 tablets	4 tablets
Ovrette, Neogest	none	—	0.075 mg	20 tablets	20 tablets

*	Package only as emergency contraception; taken in one or two doses.

  Levonorgestrel in a dose of 0.75 mg given twice, 12 hours apart, or in a single 1.5 mg dose, is more successful and better tolerated than the combination oral contraceptive method.  In many countries, special packages of two 0.75 mg levonorgestrel tablets (Plan B, Postinor, Norlevo, Vikela) are available for emergency contraception. In others, 20 levonorgestrel-containing mini pills are used to obtain an equivalent dose. Greater efficacy and fewer side effects make levonorgestrel alone the treatment of choice.
  This method has been commonly called postcoital contraception or the morning after treatment. Emergency contraception (EC) is a more accurate and appropriate name, indicating one-time protection. It is an important option for patients and should be considered when condoms break, when sexual assault occurs, when diaphragms or cervical caps dislodge, or with the lapsed use of any method. In studies at abortion units, 50% to 60% of the patients would have been suitable candidates for emergency contraception and would have used it if it were readily available.  In the United States, it is estimated that emergency contraception could annually prevent 1.7 million unintended pregnancies, and the number of induced abortions would decrease by about 40%.
Many women do not know of this method, and it has been difficult to obtain.  Even if women are aware of it, accurate and detailed knowledge is lacking. Women who have used emergency contraception are very satisfied with the method, and most importantly, they do not express an intention to substitute this method for regular contraception.
  Clinicians should consider providing emergency contraceptive kits to patients (a kit can simply be an envelope containing instructions and the appropriate number of oral contraceptives) to be taken when needed. In studies of self-administration, women in Scotland and young women in California increased the use of emergency contraception without adverse effects, such as increasing unprotected sex or contracting sexually transmitted disease.
  Progestin-only emergency contraception is now available without a prescription in many countries including the United States, where patients 18 and older can obtain it without first seeing a clinician. Younger patients, who are mostly likely to need it, must still have a prescription except in a few states that have more permissive laws. Women are able to use this nonprescription access effectively and do not develop a reliance on emergency contraception as a regular method. Adolescents use it in the same way as do older women.

Mechanism and Efficacy

   The mechanism of action is not known with certainty, but it is believed with justification that this treatment combines delay of ovulation with a local effect on the endometrium and prevention of fertilization. How much a postfertilization effect contributes to efficacy is not known, but it is not believed to be the primary mechanism.
  Efficacy has been confirmed in large clinical trials and summarized in complete reviews of the literature. Treatment with high doses of estrogen or with levonorgestrel yields a failure rate of approximately 1%; failure rate with the combination oral contraceptive is approximately 2% to 3%. The failure rate is lowest with high doses of ethinyl estradiol given within 72 hours (0.1%), but the negative side effects make this method a poor choice. In general clinical use, the method using oral contraceptives can reduce the risk of pregnancy by about 75%; this degree of reduction in probability of conception (given the relatively low chance, about 8%, for pregnancy associated with one act of coitus) yields the 2% failure rate measured in clinical studies.
  Results with levonorgestrel are even better, approximately an 85% reduction in the risk of pregnancy; in the worldwide World Health Organization study, the risk of pregnancy was 60% lower with the levonorgestrel-only method compared with the oral contraceptive method, with less than half as much nausea and vomiting.

Treatment Method

Treatment should be initiated as soon after exposure as possible, but no later than 120 hours. Careful assessment of the reported experience with emergency contraception indicates that the method is equally effective when started on the first, second, or third day after intercourse (which would allow user-friendly scheduling) and that efficacy might extend beyond 72 hours.  Data from the World Health Organization randomized clinical trial, however, support the importance of timing; this trial found a reduction in efficacy after 72 hours, and the greatest protection occurred when the medication was taken within 24 hours of intercourse. Postponing the dose by 12 hours raises the chance of pregnancy by almost 50%. For this reason, the treatment should be initiated as soon as possible after sexual exposure, an important argument in favor of advance provision of emergency contraception.
  In case the patient is already pregnant, there is no evidence that exposure to the amounts of estrogen and progestin in oral contraceptives is teratogenic.  Furthermore, emergency contraception will be ineffective in the presence of an established pregnancy. A delay in menses after treatment warrants testing for pregnancy and consideration of the possibility of an ectopic pregnancy.
  When using combined oral contraceptives for emergency contraception, it is worth adding an antiemetic to the treatment; a long-acting nonprescription agent, 25 or 50 mg meclizine (Bonine, Dramamine II, Antivert) is recommended, to be taken 1 hour before the emergency contraception treatment. Side effects reflect the high doses used: nausea (50%), vomiting (20%), breast tenderness, headache, and dizziness. If a patient vomits within an hour after taking pills, additional pills must be administered as soon as possible. Nausea and vomiting with the levonorgestrel-only method is so uncommon that an antiemetic is not necessary.
  The UK General Practice Research Database could find no evidence for an increased risk of venous thromboembolism with the short-term use of oral contraceptives for emergency contraception. Indeed, no cases were found for as long as 60 days after use in more than 100,000 episodes of use.
  A norethindrone–ethinyl estradiol combination was found to be equally effective to the levonorgestrel–ethinyl estradiol formulation, and it is likely that any combination oral contraceptive would be successful. However, this is a moot point because the levonorgestrel-only method is now the treatment of choice.
  The three major problems with the available methods of emergency contraception are the high rate of side effects, the need to start treatment promptly after intercourse, and the small, but important, failure rate. Use of the progesterone antagonist mifepristone in a single oral dose of 600 mg is associated with markedly less nausea and vomiting than is the use of combination oral contraceptives and has an efficacy rate of nearly 100%.  In randomized trials, 10 mg mifepristone was as effective as 25 mg, 50 mg, or 600 mg, preventing about 80% to 85% of expected pregnancies (the same efficacy as with the levonorgestrel method), with a slight decrease in efficacy when treatment was delayed to 5 days after intercourse. Because the next menstrual cycle is delayed after mifepristone, contraception should be initiated immediately after treatment. Ironically, mifepristone, around which swirls the abortion controversy, can make an effective contribution to preventing unwanted pregnancies and induced abortions.