Oral Contraceptive Pills

Mechanism of Action

Progesterone is primarily responsible for preventing pregnancy. The main 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 the secretion of follicle-stimulating hormone (FSH) and decreases the secretion of luteinizing hormone (LH). If the follicle isn’t developing, there is no increase in the estradiol levels (the follicle makes estradiol). The progestogen negative feedback and lack of estrogen positive feedback on LH secretion stop the mid-cycle LH surge. With no follicle developed and no LH surge to release the follicle, ovulation is prevented.

Estrogen has some effect with inhibiting follicular development because of its negative feedback on the anterior pituitary with slowed FSH secretion; it’s just not as prominent as the 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, but there is no proof that this occurs.

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 progestin component and dose of estrogen and progestin component. 

• Estrogen component: Estradiol, Ethinylestradiol, or Estetrol
• 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 (POP)

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, decreasing the mid-cycle LH and FSH peaks, which slows the movement of the ovum through fallopian tubes, and alters endometrium thickness. Some progestin compounds have more potent antiandrogenic properties and, therefore more effective in treating polycystic ovary syndrome, hirsutism, and acne.[7]

Administration

Combined Oral Contraceptive

Choice of COC: Usually, Ethinyl estradiol dose is 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 withdrawal bleeding desired by the patient and clinically recommended, it can be prescribed as a cyclic (monthly bleeding), extended cyclic (every three months bleeding), or continuous dosing(no bleeding). 

• Cyclic formulations: The cyclic formulations have active hormone pills for 21-24 days, followed by 7-4 days of hormone-free pills.
• Extended cycle formulations: extended cycle formulations have active hormone pills every day for three months, followed by a placebo week.
• Continous use formulation:  can be manipulated by using the only active pills from monthly formulations for one year period, which will functionally stop all menstrual bleeding. The most common complication from the extended cycle is break-through bleeding. Any formulation of a combined oral contraceptive pill can be used in this manner, but typically the monophasic pills are the easiest to manipulate.

Initiation: Combined oral contraceptive pills are to be taken daily at approximately the same time each day. Avoid taking them greater than 24 hours apart as this could affect efficacy. There are two methods of initiating COC for women per their priority as follow:[8]

• First-day start: Pills are started on the first day of menses, and this is considered the best strategy as it attains contraceptive efficacy faster than other methods.
• 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 seven days, and an additional form of birth control is recommended.
• 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 not protected from pregnancy in the first seven days. An additional way of birth control is recommended during this period.[8]
• Abortion/lost pregnancy: After abortion or losing a pregnancy in the first two trimesters, start OC pills within the first seven 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. 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/m, smoking, preeclampsia, immobility, thrombophilia, transfusion at delivery, peripartum cardiomyopathy, history of VTE, postpartum hemorrhage, or postcesarean delivery are at risk of VTE.
• Breastfeeding women: Avoid COC for the first 42 days following postpartum if a woman is breastfeeding as hormones impact lactation.[9] introducing estrogen before three 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 two tablets in a row in the first or second week, take two tablets the day the patient remembers and two 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 if it occurs.

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

Progesterone Only Pill (POP)

Choice of POP: CDC has provided guidelines for users of POPs who have other medical conditions. POP can be used by most women, and it 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 the dose used in COC pills. It comes in a packet of 28 hormone pills, which should be taken continuously, and there are no hormone-free pills in the pack. 
• Drospirenone is commercially available as 4 mg drospirenone, and the package contains 24 hormone tablets with four 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 five days from the onset of menses. It 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 (e.g., condoms) method for the first 48 hours following initiation if POP is started within the first five days of menses.

Missed dose: Women who miss taking a norethindrone POP dose by more than three hours or had vomiting or severe diarrhea within three 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. Use of additional contraception (e.g., condoms) for 48 hours after the late dose is also recommended.

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

Adverse Effects

Most side effects of OCP's are mild and disappear with continued use or switching to another pill formulation. The most common adverse effect of combined oral contraceptive pills 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. The majority of the 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. For the first six months, OC progestogens can impair glucose metabolism in healthy adult women. Women with diabetes mellitus might need to increase insulin intake to regulate blood glucose levels within the desired range. 

Oral contraceptive pills can cause hypertension in 4-5% of healthy women and exacerbate hypertension in about 9-16% of women with pre-existing hypertension.

Four studies on teenage women found a small negative effect of combined oral contraceptive pills on the acquisition of bone mineral density. In addition, COC use increases the risk of venous thrombotic events (VTE), especially during the first year of initiation. VTE risk increases with high Ethinyl Estradiol dose and 3rd and 4th generation progestin.[12]

Stroke and/or Myocardial infarction: 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 type pr 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 micrograms of estrogen. Most preparation now contains less than 50 micrograms of estrogen, making COC substantially safer to use. COC pill containing 30μg of estrogen and levonorgestrel is the safest oral form of combined oral contraceptive pills.[13]

These pills do not protect against any sexually transmitted diseases (STDs). Thus, using a condom is highly recommended, especially if the partner is a stranger. Regular monitoring of the patient is necessary to ensure that she is not developing any serious side effects.[14][15]

In one study, women who used COC for one year of "continuous use" were monitored for return of fertility, and 97 percent of women had spontaneous menses within 90 days after discontinuation of COCs.

In women with a history of hereditary angioedema, exogenous estrogen components may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in subjects with a known history of chloasma gravidarum. If Women have a tendency 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 lesser 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, and hence 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 are summarized below, and CDC criteria are listed in The 2016 U.S. Medical Eligibility Criteria for Contraceptive Use.

Combined Oral Contraceptive

• There are a few absolute and relative contraindications of oral contraceptive use. For example, women with uncontrolled hypertension should not initiate oral contraceptive use until their hypertension is being managed; people with diabetes may experience some hyperglycemia when starting OC’s, but these are issues that can be addressed. 
• However, OCP’s are contraindicated in smokers (more than 15 cigarettes per day) over age 35 due to significant risk for cardiovascular events and specifically deep vein thromboembolism. The risk of venous thromboembolism increases among OC users 3-9/10,000 woman-years compared with nonusers who are not pregnant and not taking hormones (1-5/10,000 woman-years). The risk is even greater in those over 35 and smoking.[18]
• Women with hypertension (systolic BP ≥140 mmHg 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.
• 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 OC’s as these conditions represent unacceptable health risks to the users.
• Women who have two or more risk factors for cardiovascular diseases such as older age, diabetes, hypertension, or smoking should also not use COC as the risk outweighs benefits.
• Women with thrombogenic mutations like prothrombin mutation, factor V Leiden, protein C, protein S,  and antithrombin deficiencies should not use COC. There are too many available alternatives for the patient to prevent pregnancy and not increase the patients’ health risk.

Progesterone Only Pill

• Women with suspected or known pregnancy
• Patient with undiagnosed abnormal uterine bleeding
• Patient with breast cancer or suspected
• Acute liver disease, benign or malignant liver tumors, or severe cirrhosis
• History of bariatric surgeries
• Women taking certain antiseizure medicine

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 have an annual visit with her primary care provider 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 is usually dose-dependent.

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

Drospirenone: It has an anti-mineralocorticoid activity which 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 which 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. Medicines 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 inhibitor concomitantly administered with OC should be monitored for serum potassium levels. Strong CYP3A4 inhibitors include protease inhibitors (e.g., indinavir, boceprevir), azole antifungals (e.g., ketoconazole, voriconazole, itraconazole), and clarithromycin.[19]

Toxicity

If a patient takes too many oral contraceptive pills at one time, the most likely complications will be severe headaches, nausea, or vomiting. There is no antidote to treat this condition, just treating the symptoms with antiemetics and analgesics. If the patient has other risk factors significant for increased venous thromboembolism, one may temporarily consider a prophylactic anticoagulant medication. High doses of estrogen and progesterone (the same types found in the combined OC’s) are even treatment options for menorrhagia that have led to severe or symptomatic anemia.[20][21][22]

There have been no reports of serious ill effects 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 to follow 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 put them at increased risk for taking combined OC or progestin  OC, the prescriber should inform patients of many alternatives to prevent pregnancy. OC's are a choice made by the patient and her clinician after adequate counseling of risks and benefits. There are significant non-contraceptive uses of hormonal contraceptives, and these should be considered when counseling the patient about her options. Many OC formulations can provide menstrual regularity, treating both menorrhagia and dysmenorrhea. They can even be utilized to induce amenorrhea for lifestyle considerations.

The birth control pill is prescribed by many healthcare workers, including the physician assistant, nurse practitioner, physicians, obstetricians, internists, and gynecologists. Patients' health benefits can influence the choice of contraceptive pills, so pharmacists should guide prescribers to choose affordable options for individual patients. Nurses should inform the patient about the potential adverse reactions and monitor patient vitals at each visit.[14][15] Pharmacists should perform medication reconciliation and counsel patients thoroughly for oral contraceptive use, start method, missed dose, and emphasize using a backup contraceptive method for recommended medicine if contraception is desired. All healthcare providers working as an interprofessional team can achieve maximum therapeutic benefit for women who desire to use oral contraceptive medicines. [Level 5]