Continuing Education Activity

Currently, 3 types of oral contraceptive pills are broadly prescribed: combined estrogen-progesterone, progesterone-only, and continuous or extended-use pills. The birth control pill is the most commonly prescribed form of contraception in the US. Approximately 25% of women aged 15 to 44 who currently use contraception reported using the pill as their method of choice. The most commonly prescribed pill is the combined hormonal pill with estrogen and progesterone. Progesterone is the hormone that prevents pregnancy, and the estrogen component controls menstrual bleeding. Birth control pills are widely used to avoid pregnancy; however, given their side effects in populations at risk, several other methods of contraception are in use as well. Each of these methods is considered based on prior history, medications in use, and concurrent medical diseases such as clotting disorders.

This activity reviews the indications and contraindications, pharmacology, and various formulations of oral contraceptives and highlights the role of the interprofessional team in educating patients about birth control. Given the process of matching patients with the preferred method of contraception, the team consisting of primary care or ob/gyn is likely the most effective in recommending OCPs.

Objectives:

• Differentiate between types and formulations of oral contraceptives, considering factors such as hormonal composition, dosage, and administration schedule.

• Screen patients for potential contraindications, including medical conditions, medications, and lifestyle factors affecting oral contraceptive safety and efficacy.

• Apply strategies to optimize oral contraceptive effectiveness, such as counseling on correct pill-taking techniques and addressing common misconceptions or concerns.

• Collaborate with an interprofessional team, such as gynecologists, pharmacists, and nurses, to ensure comprehensive and coordinated patient care using oral contraceptives.

Indications

The birth control pill is the most commonly prescribed form of contraception in the US. Approximately 25% of women aged 15 to 44 who currently use contraception reported using the pill as their method of choice. Oral contraceptive pills (OCPs) are either combined estrogen-progesterone (also called combined oral contraceptive pill-COC) or progesterone-only pill (POP).

The most commonly prescribed pill is the COC pill. Progesterone is the hormone that prevents pregnancy, and the estrogen component controls menstrual bleeding.[1] Birth control pills are primarily used to avoid pregnancy. The type of medicine used estimates the effectiveness of these oral contraceptive medicines.

• Perfect use, in which the method is used consistently and correctly every time, means less than one woman out of 100 will become pregnant in the first year. 

• Typical use, meaning the method may not always be used consistently or correctly, results in a failure rate of 9 women out of 100 that will become pregnant during the first year of using this method. Unfortunately, due to human error, the quoted failure rate for COC pills is typically 9%.

Most women take OCPs to prevent pregnancy, but 14% use them for non-contraceptive reasons. OCPs can be used to address other health conditions, particularly menstrual-related disorders such as menstrual pain, irregular menstruation, fibroids, endometriosis-related pain, and menstrual-related migraines.[2][3] The FDA has formally approved combined pills for acne for specific brands.[4]

Strong epidemiologic evidence supports a 50% reduction in the risk of endometrial cancer among women who have used COCs compared with those who have never used COCs. This effect lasts for up to 20 years. COC use decreases the risk of ovarian cancer by 27%; the longer the duration of use, the greater the risk reduction. OCs have also been reported to reduce the risk of colon cancer by 18%. Some formulations have indications for the treatment of acne and hirsutism.[5][6]

Mechanism of Action

Progesterone is primarily responsible for preventing pregnancy. The primary mechanism of action is the prevention of ovulation; they inhibit follicular development and prevent ovulation.[1] Progestogen-negative feedback works at the hypothalamus to decrease the pulse frequency of the gonadotropin-releasing hormone. This, in turn, will reduce follicle-stimulating hormone (FSH) secretion and decrease luteinizing hormone (LH). If the follicle isn't developing, an increase in the estradiol levels (the follicle makes estradiol) does not occur. The progestogen-negative feedback and lack of estrogen-positive feedback on LH secretion stop the mid-cycle LH surge. Ovulation is prevented when no follicle develops, and no LH surge occurs to release the follicle.

Estrogen has some effect on inhibiting follicular development because of the negative feedback on the anterior pituitary with slowed FSH secretion; it is just not as prominent as progesterone's effect. Another primary mechanism of action is progesterone's ability to inhibit sperm from penetrating through the cervix and upper genital tract by making the cervical mucous unfriendly.[1] Progesterone-induced endometrial atrophy should deter implantation.

Combined Oral Contraceptive (COC)

The usual estrogen component is combined with a different generation of progestin components with varying degrees of androgenic and progestogenic potential. The combination is prescribed based on desirable effects and risk of adverse events with the progestin component and dose of estrogen and progestin levels. 

• Estrogen component: Estradiol, ethinylestradiol, estetrol, mestranol

• First-generation progestin: Norethindrone acetate, ethynodiol diacetate, lynestrenol, norethynodrel

• Second-generation progestin: Levonorgestrel, dl-norgestrel

• Third-generation progestin: Norgestimate, gestodene, desogestrel

• Unclassified progestin: Drospirenone, cyproterone acetate

Progesterone-Only Pill

While multiple types of progestin pills are available in the US, most frequently, formulations have drospirenone or norethindrone. Drospirenone suppresses ovulation and also has anti-mineralocorticoid activity. While norethindrone primarily acts by thickening cervical mucus to inhibit sperm penetration, suppressing ovulation, and decreasing the mid-cycle LH and FSH peaks, it slows the ovum's movement through fallopian tubes and alters endometrium thickness. Some progestin compounds have more potent antiandrogenic properties and, therefore, are more effective in treating polycystic ovary syndrome, hirsutism, and acne.[7]

Administration

Combined Oral Contraceptive

Choice of COC: The ethinyl estradiol dose is usually less than 50 mcg in this combination of pills. The pills can be either monophasic (same dose of both components in the active pills) or multiphasic (varying doses weekly of both or either component in the active pills). Depending on the withdrawal bleeding desired by the patient and clinically recommended, it can be prescribed as a cyclic (monthly bleeding), extended cyclic (every 3 months bleeding), or continuous dosing(no bleeding). 

• Cyclic formulations: The cyclic formulations have active hormone pills for 21 to 24 days, followed by 7 to 4 days of hormone-free pills.

• Extended cycle formulations: The extended cycle formulations have active hormone pills daily for 3 months, followed by a placebo week.

• Continuous use formulation:  This can be manipulated by using only active pills from monthly formulations for 1 year, which will functionally stop all menstrual bleeding. The most common complication from the extended cycle is breakthrough bleeding. Any combined oral contraceptive pill formulation can be used in this manner, but typically, monophasic pills are the easiest to manipulate.

Initiation: Combined OCPs are recommended at approximately the same time each day. Avoid taking them greater than 24 hours apart as this could affect efficacy. Two methods of initiating COC for women are recognized per their priority as follows:

• First-day start: Pills are started on the first day of menses, and this is considered the best strategy as contraceptive efficacy is faster than other methods.[8]

• Quick start: Pills are started on any day medicine is given to women. When patients initiate this method, they are not protected from pregnancy in the first 7 days, and an additional form of birth control is recommended.[8]

• Sunday start: Pills are started on the first Sunday after the period begins. When patients initiate the contraceptive pills on the Sunday start method, they are unprotected from pregnancy in the first 7 days. An additional form of birth control is recommended during this period.[8]

• Abortion/lost pregnancy: After abortion or losing a pregnancy in the first 2 trimesters, start OC pills within the first 7 days if contraception is desired.

• Postpartum: Avoid COC for the first 21 days following postpartum, as this group has a higher risk of venous thromboembolism (VTE). Postpartum women with a higher risk of VTE should not be started on COC for the first 42 days following delivery, irrespective of breastfeeding. Women age 35 years and above, BMI 30 kg/m², smoking, preeclampsia, immobility, thrombophilia, transfusion at delivery, peripartum cardiomyopathy, history of VTE, postpartum hemorrhage, or postcesarean delivery are at risk of VTE.

• Breastfeeding considerations: Avoid COC for the first 42 days following postpartum if a woman is breastfeeding, as hormones impact lactation.[9] Introducing estrogen before 3 weeks of postpartum might increase the risk of thromboembolism in these women. In breastfed infants, cases of breast enlargement are reported mostly with estrogen doses higher than are currently used, which were reversible. WHO recommends performing a risk-benefit assessment for using COC between 6 weeks to 6 months postpartum in breastfeeding women. 

Missed doses: If a patient misses a tablet, take the missed tablet as soon as they remember and the next tablet at the usual time (taking two pills in 1 day). If the patient misses 2 tablets in a row in the first or second week, take 2 tablets the day the patient remembers and 2 pills the next day, then resume 1 per day. Use additional forms of contraception until the patient begins a new cycle.[10] Check the package insert for accurate information on managing missed doses.

Emergency contraception: Emergency contraception is recommended in the first week of the cycle if unprotected intercourse occurs and two or more COC pills are missed (except ulipristal acetate). 

Progesterone Only Pill

Choice of progesterone pill: The CDC has provided guidelines for users of progesterone-only pills (POPs) who have other medical conditions. Most women can use POP, which appears to be chosen for women who have contraindications to COC or want to avoid the estrogen component in the contraceptive pill.[11]

• Norethindrone is commercially available as 0.35 mg tablets, and the dose is lower than that of COC pills. The drug is available in a packet of 28 hormone pills, which should be taken continuously, and no hormone-free pills are in the pack. 

• Drospirenone is commercially available as 4 mg drospirenone, and the package contains 24 hormone tablets with 4 hormone-free pills.

Initiation: The pill must be taken at the same time each day to maximize contraceptive efficacy. Use backup contraception if the patient starts POPs more than 5 days from the onset of menses. POP can be started on any day of the menstrual cycle, but recommendations exist to begin on the first day of menses. Use a backup contraceptive (eg, condoms) method for the first 48 hours following initiation if POP is started within the first 5 days of menses.

Missed dose: Women who miss taking a norethindrone POP dose by more than 3 hours or had vomiting or severe diarrhea within 3 hours of taking a POP are advised to take the missed pill as soon as they remember and the next tablet at the scheduled time. Additional contraception (eg, condoms) for 48 hours after the late dose is also recommended.

Emergency contraception: Emergency contraception can be offered (except ulipristal acetate) to women who have unprotected intercourse within 48 hours of initiating POP or missed pills where backup contraception or abstinence was advised.[8]

Adverse Effects

Most side effects of OCPs are mild and disappear with continued use or switching to another pill formulation. The most common adverse effect of combined OCPs is breakthrough bleeding. Women will also complain of nausea, headaches, abdominal cramping, breast tenderness, and increased vaginal discharge or decreased libido. Nausea can be avoided by taking the medication at night before sleep. Most other consequences will resolve with time or switching OCP to a different preparation.

Women who have a pre-existing cardiovascular condition or smoke should not use OCs. OC progestogens can impair glucose metabolism in healthy adult women for the first 6 months of therapy. Women with diabetes might need to increase insulin intake to regulate blood glucose levels within the desired range. OCPs can cause hypertension in 4% to 5% of healthy women and exacerbate hypertension in about 9% to 16% of women with pre-existing hypertension.

Four studies on teenage women found a small negative effect of combined OCPs on the acquisition of bone mineral density. In addition, COC use increases the risk of VTE, especially during the first year of initiation. VTE risk increases with high ethinyl estradiol dose and 3rd and 4th generation progestin.[12]

In a meta-analysis, which included 28 publications, reported COC users were at higher risk of ischemic stroke (relative risk 1.7, 95% CI 1.5 to 1.9) and myocardial infarction (relative risk 1.6, 95% CI 1.2 to 2.1) when compared with non-users. The risks did not depend on the type or generation of progestagen. Data analysis showed the risk of ischemic stroke or myocardial infarction increases with higher doses of estrogen. This risk was highest when pills had more than 50 μg of estrogen. Most preparations now contain less than 50 μg of estrogen, making COC substantially safer. COC pill containing 30 μg of estrogen and levonorgestrel is the safest oral form of combined oral contraceptive.[13]

These pills do not protect against any sexually transmitted infections (STIs). Thus, using a condom is highly recommended, especially if a new partner is involved. Regular patient monitoring is necessary to ensure serious side effects are mitigated.[14][15] In one study, women who used COCs for one year of "continuous use" were monitored for return of fertility, and 97% of women had spontaneous menses within 90 days after discontinuing COCs. Exogenous estrogen components may induce or exacerbate symptoms of angioedema in women with a history of hereditary angioedema. Chloasma may occasionally occur, especially in subjects with a known history of chloasma gravidarum. If women tend to develop chloasma, avoid exposure to ultraviolet radiation and the sun while taking COCs.

POP users have reported acne flare and follicular ovarian cysts. Changes in menses and unscheduled, irregular bleeding are the most commonly reported adverse effects of POPs.[16] Progestogen-only OCs have fewer systemic side effects than combined OCs but often cause menstrual changes. Their long-term effects are not yet known.[1] Both COC and POP have significant drug interactions, so patient medication history should be taken thoroughly before prescribing OC, including supplements. For example, co-administering OC with antiseizure medicines (phenytoin, carbamazepine, oxcarbazepine, lamotrigine, barbiturates) can result in a lower level of OC in blood and reduce the effectiveness of OC.[17]

Contraindications

CDC and WHO have set criteria for women who want to initiate COC or POP. Patients need to be screened for contraindications before starting COC or POP, summarized below, and CDC criteria are listed in The 2016 U.S. Medical Eligibility Criteria for Contraceptive Use.

Combined Oral Contraceptive

• A few absolute and relative contraindications of oral contraceptive use are recognized. For example, women with uncontrolled hypertension should not initiate oral contraceptive use until their hypertension is managed; people with diabetes may experience some hyperglycemia when starting OCs, but these are issues that can be addressed. 

• However, OCPs are contraindicated in smokers (more than 15 cigarettes per day) over age 35 due to a significant risk for cardiovascular events, specifically deep vein thromboembolism. The risk of VTE increases among OC users 3 to 9/10,000 woman-years compared with nonusers who are not pregnant and not taking hormones (1-5/10,000 woman-years). The risk is more significant in those aged over 35 and smoking.[18]

• Women with hypertension (systolic BP greater than or equal to 140 mm Hg or diastolic BP ≥90 mmHg as per the CDC), breast cancer,  known ischemic heart disease, migraines with auras, endometrial cancer, cirrhosis, hepatocellular adenoma, or malignant hepatoma are contraindicated to use combined hormone contraceptive pill.[19]

• Women with a history of VTE, stroke, breast or endometrial cancer, and valvular heart disease (history of subacute bacterial endocarditis, the risk for atrial fibrillation, or pulmonary hypertension) should not use OCPs as these conditions represent unacceptable health risks to the users.

• Women who have 2 or more risk factors for cardiovascular diseases, such as older age, diabetes, hypertension, or smoking, should also not use COC as the risk outweighs the benefits.

• Women with thrombogenic mutations like prothrombin mutation, factor V Leiden, protein C, protein S,  and antithrombin deficiencies should not use COC. Too many alternatives are available for the patient to prevent pregnancy and not increase the patient’s health risk.

Progesterone Only Pill

• Women with suspected or known pregnancy

• Patient with undiagnosed abnormal uterine bleeding

• Patients with breast cancer or suspected

• Acute liver disease, benign or malignant liver tumors, or severe cirrhosis

• History of bariatric surgeries

• Women taking certain antiseizure medications

Monitoring

COC

The patients should be counseled thoroughly on potential adverse reactions before initiating hormone contraceptive pills and informed to report signs and symptoms of serious adverse reactions to achieve better adherence and treatment outcomes. A healthy woman taking COCs should visit her primary care clinician annually for a blood pressure check and routine medical care. Monitor blood pressure in women with well-controlled hypertension being managed medically. Monitor prediabetic and diabetic women periodically, as hormone contraceptives may impair glucose intolerance and are usually dose-dependent.

POP

Prescribers should monitor baseline weight and BMI before initiating the POP.

Drospirenone

It has an anti-mineralocorticoid activity that might cause hyperkalemia in high-risk patients (3 mg drospirenone has comparable anti-mineralocorticoid activity as 25 mg dose of spironolactone), so women with diseases that predispose to hyperkalemia or who are taking medications that increase serum potassium concentration should be monitored for serum potassium level in the first treatment cycle.

Medications that may increase serum potassium levels include potassium supplementation, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, aldosterone antagonists, heparin, and non-steroidal anti-inflammatory drugs. In addition, long-term users of CYP3A4 inhibitors concomitantly administered with OC should be monitored for serum potassium levels. Potent CYP3A4 inhibitors include protease inhibitors (eg, indinavir, boceprevir), azole antifungals (eg, ketoconazole, voriconazole, itraconazole), and clarithromycin.[20]

Toxicity

If a patient takes too many OCPs, the most likely complications are severe headaches, nausea, or vomiting. No antidote is available to treat this condition; the symptoms are treated with antiemetics and analgesics. If the patient has other risk factors significant for increased VTE, one may temporarily consider a prophylactic anticoagulant medication. High doses of estrogen and progesterone are treatment options for menorrhagia that have led to severe or symptomatic anemia.[21][22][23]

No reports of severe effects are apparent from an overdose, including ingestion by children. However, overdosage may cause withdrawal bleeding in females and nausea. Drospirenone is a spironolactone analog with anti-mineralocorticoid properties, so monitor serum concentration of potassium and sodium and evidence of metabolic acidosis in overdose cases. Contact the local poison control center for the protocol if an overdose is suspected or confirmed.

Enhancing Healthcare Team Outcomes

Oral contraceptive pills provide patients with the option to prevent pregnancy. If the patient has medical conditions that increase their risk of taking combined OC or progestin OC, the prescriber should inform patients of many alternatives to prevent pregnancy. OCs are a choice made by the patient and her clinician after adequate counseling of risks and benefits. Significant non-contraceptive uses of hormonal contraceptives should be considered when counseling the patient about her options. Many OC formulations can provide menstrual regularity, treating both menorrhagia and dysmenorrhea. They can be utilized to induce amenorrhea for lifestyle considerations. The birth control pill is prescribed by many healthcare professionals, including physicians, advanced practice practitioners, and specialists like obstetricians, internists, and gynecologists.

Patients' health benefits can influence the choice of contraceptive pills, so pharmacists should help prescribers choose affordable options for individual patients. Nurses should educate the patient regarding the potential adverse reactions, monitor the patient's vitals at each visit, and collaborate with the prescribing clinician regarding any concerns.[14][15] Pharmacists should perform medication reconciliation, counsel patients thoroughly about proper oral contraceptive dosing and use, various start methods, how to address missed doses, and emphasize using a backup contraceptive method for recommended medicine if contraception is desired. The interprofessional team can achieve maximum therapeutic benefit for women who want to use oral contraceptive drugs, leading to optimal outcomes with the fewest adverse events.