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Oral Contraceptives

By

Frances E. Casey

, MD, MPH, Virginia Commonwealth University Medical Center

Last full review/revision May 2020| Content last modified May 2020
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Oral contraceptives (OCs) mimic ovarian hormones. Once ingested, they inhibit the release of gonadotropin-releasing hormone (GnRH) by the hypothalamus, thus inhibiting the release of the pituitary hormones that stimulate ovulation. OCs also affect the lining of the uterus and cause the cervical mucus to thicken, making it impervious to sperm. If used consistently and correctly, OCs are an effective form of contraception.

OCs may be started at any time in a woman's life up until menopause.

OCs may be a combination of the hormone estrogen and a progestin or a progestin alone.

Combination oral contraceptives

For most combination oral contraceptives, an active pill (estrogen plus progestin) is taken daily for 21 to 24 days. Then, an inactive (placebo) pill is taken daily for 4 to 7 days to allow for withdrawal bleeding. In some products, the placebo pill contains iron and folate (folic acid); in others, this pill is not truly inactive but contains 10 mcg of ethinyl estradiol. Combination OCs are also available as extended-cycle products (with 84 active pills, one to be taken each day, followed by 7 days of placebo pills) or as continuous-use products (active pills every day, with no placebo pills).

Most combination OCs contain 10 to 35 mcg of ethinyl estradiol. This dose is considered low. Low-dose OCs are usually preferred to high-dose OCs (50 mcg of estrogen) because low-dose OCs appear equally effective and have fewer adverse effects, except for a higher incidence of irregular vaginal bleeding during the first few months of use. Estradiol valerate may be used instead of ethinyl estradiol. The doses of estrogen and progestin are the same throughout the month in some combination OCs (monophasic pills); they change throughout the month in others (multiphasic pills).

All combination OCs have similar efficacy; the pregnancy rate after 1 year is 0.3% with perfect use and about 9% with typical (ie, inconsistent) use.

However, combination OCs must be used with caution in some women (for more information, see the US Medical Eligibility Criteria for Contraceptive Use, 2016). Use of combination OCs is contraindicated by the following:

  • < 21 days postpartum or < 42 days postpartum if risk of venous thromboembolism is high

  • Smoking > 15 cigarettes/day in women > 35

  • Current or past breast cancer

  • Severe decompensated cirrhosis, hepatocellular adenoma, or liver cancer

  • Venous thromboembolism (deep venous thrombosis or pulmonary embolism), thrombogenic mutation, or systemic lupus erythematosus (SLE) with unknown or positive antiphospholipid antibody status

  • Migraine with aura or migraine of any type in women > 35

  • Hypertension

  • Ischemic heart disease

  • Peripartum cardiomyopathy

  • Diabetes for > 20 years or with vascular disease (eg, neuropathy, nephropathy, retinopathy)

  • Valvular heart disorders with complications

  • Solid-organ transplantation with complications

  • Current or medically treated gallbladder disease or a history of contraceptive-related cholestasis

  • Hypertriglyceridemia

  • Acute viral hepatitis

Progestin-only oral contraceptives

To be effective, progestin-only OCs must be taken at the same time of day, every day. No inactive pills are included. Progestin-only OCs provide effective contraception primarily by thickening the cervical mucus and preventing sperm from passing through the cervical canal and endometrial cavity to fertilize the egg. In some cycles, these OCs also suppress ovulation, but this effect is not the primary mechanism of action. Common adverse effects include breakthrough bleeding. Progestin-only OCs are commonly prescribed when women wish to take OCs but estrogen is contraindicated. Pregnancy rates with perfect and typical use of progestin-only OCs are similar to those with combination OCs.

Adverse Effects of Oral Contraceptives

Although oral contraceptives may have some adverse effects, the overall risk of these effects is small.

OCs may cause breakthrough bleeding (which may resolve with time or when the estrogen dose is increased) or amenorrhea; amenorrhea, if not acceptable, may resolve when the progestin dose is decreased.

In some women, ovulation remains inhibited for a few months after they stop taking OCs. OCs do not adversely affect the outcome of pregnancy when conception occurs during or after their use.

Estrogens increase aldosterone production and cause sodium retention, which can cause dose-related, reversible increases in blood pressure (BP) and in weight (up to about 2 kg). Weight gain may be accompanied by bloating and edema.

Most progestins used in OCs are related to 19-nortestosterone and are androgenic. Norgestimate, etonogestrel, and desogestrel are less androgenic than levonorgestrel, norethindrone, norethindrone acetate, and ethynodiol diacetate. Androgenic effects may include acne, nervousness, and an anabolic effect resulting in weight gain. If a woman gains > 4.5 kg/year, a less androgenic OC should be used. Newer 4th-generation antiandrogenic progestins include dienogest and drospirenone (related to spironolactone, a diuretic).

The incidence of deep venous thrombosis Deep Venous Thrombosis (DVT) Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more Deep Venous Thrombosis (DVT) and thromboembolism Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more (eg, pulmonary embolism) increases as the estrogen dose is increased. With OCs that contain 10 to 35 mcg of estrogen, risk is 2 to 4 times the risk at baseline. However, this increased risk is still much lower than the risk associated with pregnancy. A wide variety of progestins in combination OCs may also affect this risk. OCs that contain levonorgestrel appear to lower this risk, and OCs that contain drospirenone or desogestrel may increase it. Risk is probably increased because production of clotting factors in the liver and platelet adhesion are increased. If deep vein thrombosis or pulmonary embolism is suspected in a woman taking OCs, OCs should be stopped immediately until results of diagnostic tests can confirm or exclude the diagnosis. Also, OCs should be stopped at least 1 month before any major surgery that requires immobilization for a long time and should not be taken again until 1 month afterward. Women with a family history of idiopathic venous thromboembolism should not use OCs that contain estrogen.

Risk of breast cancer Breast Cancer Breast cancer most often involves glandular breast cells in the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more Breast Cancer is not increased by current use of OCs nor by former use in women aged 35 to 65. Also, risk is not increased in high-risk groups (eg, women with certain benign breast disorders or a family history of breast cancer).

Risk of cervical cancer Cervical Cancer Cervical cancer is usually a squamous cell carcinoma caused by human papillomavirus infection; less often, it is an adenocarcinoma. Cervical neoplasia is asymptomatic; the first symptom of early... read more Cervical Cancer is slightly increased in women who have used OCs for > 5 years, but this risk decreases to baseline 10 years after stopping OCs. Whether this risk is related to a hormonal effect or to behaviors (ie, not using barrier contraception) is unclear.

Although increased stroke Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more Ischemic Stroke risk has been attributed to OCs, low-dose combination OCs do not appear to increase risk of stroke in healthy, normotensive, nonsmoking women. Nonetheless, if focal neurologic symptoms, aphasia, or other symptoms that may herald stroke develop, OCs should be stopped immediately. Smokers over 35 should not use contraceptives that contain estrogen because of the increased risk of myocardial infarction and/or stroke.

CNS effects of OCs include nausea, vomiting, headache, depression, and sleep disturbances.

Although progestins may cause reversible, dose-related insulin resistance, use of OCs with a low progestin dose rarely results in hyperglycemia.

Serum high-density lipoprotein (HDL) cholesterol levels may decrease when OCs with a high progestin dose are used but usually increase when OCs with low progestin and estrogen doses are used. The estrogen in OCs increases triglyceride levels and can exacerbate preexisting hypertriglyceridemia. Most alterations in serum levels of other metabolites are not clinically significant. Thyroxine-binding globulin capacity may increase in OC users; however, free thyroxine levels, thyroid-stimulating hormone levels, and thyroid function are not affected.

Levels of pyridoxine, folate, B complex vitamins, ascorbic acid, calcium, manganese, and zinc decrease in OC users; vitamin A levels increase. None of these effects is clinically significant, and vitamin supplementation is not advised as an adjunct to OC use.

Risk of developing gallstones does not appear to be increased by use of low-dose OCs.

Rarely, benign hepatic adenomas Hepatocellular adenoma Benign liver tumors are relatively common. Most are asymptomatic, but some cause hepatomegaly, right upper quadrant discomfort, or intraperitoneal hemorrhage. Most are detected incidentally... read more , which can spontaneously rupture, develop. Incidence increases as duration of use and OC dose increase; adenomas usually regress spontaneously after OCs are stopped.

Melasma Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition. (See also Overview of Pigmentation Disorders.) Focal... read more occurs in some women; it is accentuated by sunlight and disappears slowly after OCs are stopped. Because treatment is difficult, OCs are stopped when melasma first appears. OCs do not increase risk of melanoma.

Benefits of Oral Contraceptives

OCs have some very important health benefits. High- and low-dose combination OCs decrease the risk of endometrial cancer Endometrial Cancer Endometrial cancer is usually endometrioid adenocarcinoma. Typically, postmenopausal vaginal bleeding occurs. Diagnosis is by biopsy. Staging is surgical. Treatment requires hysterectomy, bilateral... read more and ovarian cancer Ovarian Cancer Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography... read more by about 50% for at least 20 years after OCs are stopped. They also decrease the risk of benign ovarian tumors Benign Ovarian Masses Benign ovarian masses include functional cysts and tumors; most are asymptomatic. Treatment varies depending on the patient's reproductive status. There are 2 types of functional cysts: Follicular... read more , abnormal uterine bleeding Abnormal Uterine Bleeding Due to Ovulatory Dysfunction (AUB-O) Abnormal uterine bleeding due to ovulatory dysfunction (AUB-O) is abnormal uterine bleeding that, after examination and ultrasonography, cannot be attributed to the usual causes (structural... read more due to ovulatory dysfunction, dysmenorrhea Dysmenorrhea Dysmenorrhea is uterine pain around the time of menses. Pain may occur with menses or precede menses by 1 to 3 days. Pain tends to peak 24 hours after onset of menses and subside after 2 to... read more , osteoporosis Osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more Osteoporosis , premenstrual dysphoric disorder Premenstrual dysphoric disorder Depressive disorders are characterized by sadness severe enough or persistent enough to interfere with function and often by decreased interest or pleasure in activities. Exact cause is unknown... read more , iron deficiency anemia Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more Iron Deficiency Anemia , benign breast disorders Evaluation of Breast Disorders Breast symptoms (eg, masses, nipple discharge, pain) are common, accounting for > 15 million physician visits/year. Although > 90% of symptoms have benign causes, breast cancer is always a concern... read more Evaluation of Breast Disorders , and functional ovarian cysts Functional cysts Benign ovarian masses include functional cysts and tumors; most are asymptomatic. Treatment varies depending on the patient's reproductive status. There are 2 types of functional cysts: Follicular... read more . Ectopic pregnancy Ectopic Pregnancy In ectopic pregnancy, implantation occurs in a site other than the endometrial lining of the uterine cavity—ie, in the fallopian tube, uterine cornua, cervix, ovary, or abdominal or pelvic cavity... read more and salpingitis Acute salpingitis Pelvic inflammatory disease (PID) is a polymicrobial infection of the upper female genital tract: the cervix, uterus, fallopian tubes, and ovaries; abscess may occur. PID may be sexually transmitted... read more , which can impair fertility, occur less frequently in OC users.

Drug Interactions of Oral Contraceptives

Although OCs can slow the metabolism of certain drugs (eg, meperidine), these effects are not clinically important.

Some drugs can induce liver enzymes (eg, cytochrome P-450 enzymes) that accelerate transformation of OCs to less biologically active metabolites. Women who take these drugs should not be given OCs concurrently unless other contraceptive methods are unavailable or unacceptable. These drugs include certain antiseizure drugs (most commonly phenytoin, carbamazepine, barbiturates, primidone, topiramate, and oxcarbazepine), ritonavir-boosted protease inhibitors, rifampin, and rifabutin. Lamotrigine should not be used with OCs because OCs can decrease lamotrigine levels and affect seizure control.

Initiation of Oral Contraceptives

Before oral contraceptives are started, clinicians should take a thorough medical, social, and family history to check for potential contraindications to use. Blood pressure (BP) is measured, and a urine pregnancy test is done. OCs should not be prescribed unless BP is normal and results of the urine pregnancy test are negative. A physical examination, although often done when OCs are started, is not required. However, a physical examination is recommended within 1 year of OC initiation. A follow-up visit in 3 months may be useful for discussing potential adverse effects and for rechecking BP. OCs can be prescribed for 13 months at a time.

OCs may be started on the same day as the contraceptive office visit (often called the quick-start method). The day of the week and time in the menstrual cycle are not important to when OCs are started. However, if OCs are started > 5 days after the first day of menses, women should use a backup contraceptive method (eg, condoms) for the first 7 days of OC use.

Progestin-only OCs must be taken every day, at the same time every day. If > 27 hours elapse between doses of a progestin-only OC, women should use a backup contraceptive method for 7 days in addition to taking the OC daily.

For combination OC, timing is not as stringent. However, if combined OC users miss taking a pill, they are advised to take 2 pills the next day. If they forget to take a pill for 2 days, they should resume taking the OC each day and should use a backup contraceptive method for 7 days. If they forget to take a pill for 2 days and have had unprotected sex in the 5 days before forgetting to take the pill, they can consider taking emergency contraception.

The timing for starting combination OCs after pregnancy varies:

  • After a 1st-trimester spontaneous or induced abortion: Started immediately

  • For deliveries at 12 to 28 weeks gestation: Started within 1 week

  • After a delivery at > 28 weeks: Not started until > 21 days after delivery because risk of thromboembolism is additionally increased during the postpartum period

  • If women are exclusively breastfeeding (feeding on demand including night feedings and not supplementing with other foods) or if their risk of venous thromboembolism is increased (eg, because of a recent cesarean delivery): Delayed 42 days.

In 98% of women who are exclusively breastfeeding and in whom menses does not resume, pregnancy does not occur for 6 months postpartum even when no contraception is used. However, these women are often advised to start using contraception within 3 months after delivery.

Progestin-only OCs may be used immediately postpartum.

If women have a history of a liver disorder, tests to confirm normal liver function should be done before OCs are prescribed. Women at risk of diabetes (eg, those who have a family history, who have had gestational diabetes, who have had high-birth-weight infants, or who have physical signs of insulin resistance such as acanthosis nigricans) require plasma glucose screening and a complete serum lipid profile annually. Use of low-dose OCs is not contraindicated by abnormal glucose or lipid test results, except for triglycerides > 250 mg/dL (2.8 mmol/L). Most women with diabetes mellitus may take combination OCs; exceptions are those who have vascular complications (eg, neuropathy, retinopathy, nephropathy) and those who have had diabetes for > 20 years.

Key Points

  • All combination oral contraceptives (estrogen plus a progestin) are equally effective; formulations with a low estrogen dose are preferred because they have fewer adverse effects.

  • Progestin-only OCs may cause irregular bleeding and must be taken at the same time every day.

  • Women may take OCs continuously until menopause if they have no contraindications.

  • Combination OCs increase the risk of thrombotic disorders, but this risk is less than that associated with pregnancy.

  • OCs do not increase the overall risk of breast cancer.

  • Before OCs are prescribed, a thorough patient history is required; a physical examination is not required but ideally should be done within 1 year after OCs are started.

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