ORAL CONTRACEPTIVES

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• ACRONYMS AND DEFINITIONS

• Breakthrough bleeding - bleeding that occurs while taking active pills (between menstrual cycles)
• Monophasic - only one dose of hormones is given over a course of therapy
• Biphasic - two different doses of hormones are given over one course of therapy
• Combined OCPs - OCPs that contain both an estrogen and a progestin
• CVD - Cardiovascular disease
• EE - Ethinyl estradiol
• Extended-cycle OCPs - OCPs that are dosed so that menses occurs less frequently than once a month
• HRT - Hormone replacement therapy
• Triphasic - three different doses of hormones are given over one course of therapy
• Quadriphasic - four different doses of hormones are given over one course of therapy
• OCPs - Oral contraceptive pills
• Progestin - synthetic version of progesterone
• Progestin-only OCPs - OCPs that only have a progestin component
• Spotting - bleeding that occurs while taking active pills (between menstrual cycles)
• VTE - Venous thromboembolism (deep vein thrombosis and pulmonary embolism)
• Withdrawal bleeding - bleeding that occurs at the end of a cycle (normal period or bleeding while taking inactive pills)

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• OVERVIEW

• History
• Combined oral contraceptive pills were first introduced in the 1960s. The first OCPs were monophasic and contained much higher doses of estrogen (150 mcg vs 20 mcg or less today), which were associated with a greater risk of VTE. As time went by, estrogen concentrations declined, and safety improved. Today, OCPs are the most common type of birth control in the developed world. [1]
• OCPs prevent pregnancy through the following mechanisms: (1) inhibition of ovulation by suppressing FSH and LH release from the pituitary, (2) cervical mucus changes that inhibit sperm penetration, (3) endometrial changes that reduce the likelihood of implantation.


• Effectiveness
• When used correctly, OCPs are very effective
• Pregnancy rate with perfect use in first year - 0.3%
• Pregnancy rate with typical use in the first year - 8%
• Other methods:
• Female sterilization (tubal ligation) - 0.5% failure in first year
• Copper IUD - 0.6% failure in first year with perfect use
• Condom - 5.0% failure in first year with perfect use [1]

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• OCP PHASES

• Overview
• OCPs are divided into phases based on the number of hormone doses given in one cycle. The component that varies may be the estrogen, progestin, or both. See OCP chart for OCPs grouped by phase.
• Monophasic - only one dose of hormones is given over a cycle of therapy
• Biphasic - two different doses of hormones are given over a cycle of therapy
• Triphasic - three different doses of hormones are given over a cycle of therapy
• Quadriphasic - four different doses of hormones are given over a cycle of therapy

• Comparing OCPs of different phases
• A series of Cochrane meta-analyses evaluated trials comparing OCPs of different phases. Those studies are summarized below.
• Monophasic vs Biphasic - The review found one study that met inclusion criteria. In that study, the odds of having breakthrough bleeding was slightly higher for the biphasic pills (OR 1.29; 95% CI 0.99 to 1.69). No other measures were found to be significantly different. [2]
• Monophasic vs Triphasic - The review found 23 trials that met inclusion criteria, but a meta-analysis was not possible due to differences between trials in progestin type and hormone dose. Half of the trials reported less breakthrough bleeding and more withdrawal bleeding with triphasic pills. There was no significant difference in discontinuation rates between the two phases. Differences in efficacy could not be assessed. [3]
• Monophasic vs Quadriphasic - The review found one trial that met inclusion criteria. No significant difference was found in effectiveness or breakthrough bleeding. More women in the monophasic group had withdrawal bleeding, and more women in the quadriphasic group complained of breast pain. There was no significant difference in discontinuation rates. [4]
• Biphasic vs Triphasic - The review found one relevant study. Biphasic pills containing norethindrone had more breakthrough bleeding and less withdrawal bleeding than triphasic pills containing levonorgestrel. When biphasic pills containing norethindrone were compared to triphasic pills containing norethindrone, there was no significant difference. [5]

• Summary
• Based on the available data, it is not possible to draw meaningful conclusions about differences in effectiveness or side effects between OCPs of different phases

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• HIGH VS LOW ESTROGEN PILLS

• Overview
• Estrogen stabilizes the endometrium for better bleeding control while working with progestin to inhibit ovulation. Most modern pills contain ethinyl estradiol, with doses ranging from 0.010 mg - 0.050 mg. Pills with more than 0.020 mg of EE are considered high estrogen pills, while pills with 0.020 mg or less are considered low (see OCPs with .020 mg EE and OCPs with .010 mg EE for a list of low estrogen pills).

• Comparing high (> 0.020 mg EE) and low (≤ 0.020 mg EE) estrogen pills
• The observational studies summarized below compared outcomes between high and low pills
• Side effects
• A Cochrane meta-analysis evaluated trials where low EE pills (≤ 0.020 mg) were compared to high EE pills (> 0.020 mg)
• The following effects were seen:
• It was not possible to do a formal meta-analysis because of heterogeneity between trials, but some general trends were noted
• There was no significant difference in effectiveness between high and low pills
• Low pills generally had more irregular bleeding patterns (breakthrough bleeding, prolonged bleeding, no withdrawal bleeding, etc.) than high pills
• Low pills had a lower incidence of breast pain and nausea in some trials [6]
• Risk of blood clots (thromboembolism)
• Several cohort studies have compared the risk of blood clots between high EE (> 0.020 mg) and low EE (≤ 0.020 mg) pills
• A registry study in Danish women found that the relative risk of blood clots was 18% lower with low pills compared to high pills. [19] Another study involving the same database found that the relative risk of blood clots was 17 - 23% lower with OCPs containing 0.020 mg of EE compared to those with 0.030 mg. The lower risk was only true for OCPs with desogestrel and gestodene and not for those with drospirenone. [20]
• A French cohort study found that the relative risk of pulmonary embolism was lower with low pills compared to high pills (RR 0.75, 95%CI [0.67 to 0.85]) [66]
• Risk of heart attack and stroke
• A French cohort study found that the relative risk of stroke (RR 0.82, 95%CI [0.70 to 0.96]) and myocardial infarction (RR 0.56, 95%CI [0.39 to 0.79]) was lower for OCPs with 0.020 mg of EE compared to those with 0.030 - 0.040 mg of EE [66]

• Summary
• Based on a limited amount of observational data, the following may be true:
• Low pills may have a higher incidence of irregular bleeding than high pills
• Low pills may have a lower incidence of nausea and breast pain
• Low pills appear to have a slightly lower risk of blood clots, heart attacks, and strokes. While the risk with high pills may be greater, it's important to note that the overall risk is still very low.

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• EXTENDED CYCLE OCPs

• Overview
• In recent years, OCP prescribing that leads to fewer periods (extended cycle) has become popular. Extended cycles can be achieved by skipping placebo pills and continuing with active pills in the next package or by prescribing products that are marketed for this purpose.
• While some women prefer fewer menses, others worry that not having periods is unnatural and can lead to endometrial thickening. This concern is mostly unfounded as the progestin component helps to keep the endometrium thin. See extended-cycle OCPs for a list of pills that are packaged for this purpose.
• Several observational studies comparing extended-cycle and normal cycle OCPs are presented below

• STUDY
  VTE Risk with Extended-Cycle (84/7), Continuous-Cycle (365/0), or Traditional-Cycle (21/7) OCPs, JAMA IM (2018) [PubMed abstract]
• Design: Retrospective propensity score-matched cohort study (N=733,007 | average exposure - 0.7 person-years) in women initiating continuous/extended or traditional cyclic OCPs containing ethinyl estradiol and levonorgestrel of any dose
• Exposure: Extended-Cycle (84/7), Continuous-Cycle (365/0), or Traditional-Cycle (21/7) OCPs
• Primary outcome: First hospitalization for VTE
• Results:
• Primary outcome (cases per 1000 person-years): Continuous/extended - 1.44, Traditional cycle - 1.09 (HR 1.32 95%CI [1.07 - 1.64])
• Findings: Holding the progestogen type constant (levonorgestrel), we observed a slightly elevated VTE risk in association with continuous/extended COC use when compared with cyclic COC use. However, due to the small absolute risk difference and potential residual confounding, our findings did not show strong evidence supporting a VTE risk difference between continuous/extended and cyclic COC use.

• STUDY
  Continuous or Extended Cycle vs Cyclic use of OCPs, Cochrane meta-analysis (2005) [PubMed abstract]
• A Cochrane meta-analysis evaluated trials where extended-cycle OCPs (> 28 days) were compared to traditional OCPs (21 days of hormone followed by 7 days of placebo)
• The following effects were seen:
• A formal meta-analysis was not possible due to differences in drug regimens and drug doses
• There was no significant difference in pregnancy rates between the two regimens, although the studies were not powered to assess this
• In three studies, endometrial thickness was measured by ultrasound in a subset of patients. No significant difference between traditional and extended cycles was found in any of the studies.
• Menstrual-associated symptoms (bloating, headache, tiredness, etc.) were less with the extended cycles in some studies and not significantly different in others
• Days with bleeding (spotting or other) were not significantly different in some trials and were less with extended cycles in others [7]

• Summary
• Extended cycles appear to be safe and effective
• Women are likely to have fewer spotting and bleeding days with extended cycles, although this was not the case in all trials
• Extended cycles do not appear to cause uterine lining build-up (endometrial thickening)
• Extended cycle may confer a slightly higher risk of VTE, but the effect is very small

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• 24-DAY OCPs

• Overview
• Traditional OCP regimens provide 21 days of active hormone and 7 days of placebo, while 24-day OCPs provide 24 days of hormone and 3 days of placebo. See 24-day OCPs for a list of these products.
• 24-day OCPs are theoretically supposed to reduce withdrawal bleeding and limit the side effects of menses. Trials that have compared 24-day OCPs to traditional OCPs have generally not found a significant difference in bleeding patterns between the two. [1,9]
• A large cohort study found that 24-day OCPs had a lower unintended pregnancy rate than 21-day pills. [10]

• Summary
• It's unclear if 24-day OCPs offer any advantage over 21-day pills

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• PROGESTIN COMPONENT

• Progestin categories
• Progestins in OCPs are categorized in two different ways. One way groups them into generations based on when they were introduced, and the other is by their chemical structure and whether it is related to progesterone, testosterone, or spironolactone. The table below shows these groupings.

• Progestin comparisons
• Few quality studies have compared outcomes between OCPs with different progestins. Drospirenone has received the most extensive evaluation because of concerns it may carry a higher risk of VTE (see venous thromboembolism below).
• Findings from a cohort study and a Cochrane meta-analysis are summarized below
• Studies
• A cohort study encompassing over 52,000 OCP users found that OCPs containing drospirenone had a lower rate of unintended pregnancies than pills with other progestins. The authors hypothesized that this is secondary to drospirenone's half-life (30 hours), which is substantially longer than other progestins (8 - 12 hours). [10]
• A Cochrane meta-analysis that looked at studies comparing OCPs with different progestins found that the quality of existing trials was low. Based on limited evidence, the authors came to the following conclusions:
• Fewer women discontinued second-generation progestins than first-generation progestins
• Women on third-generation progestins had less breakthrough bleeding than women on second-generation progestins
• Women taking drospirenone were more likely to complain of breast tenderness and nausea than women taking desogestrel [8]

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• SIDE EFFECTS

• Common side effects
• Common side effects of OCPs are listed below. In general, randomized trials comparing OCPs to placebo have found no significant difference in the incidence of these complaints. One exception is irregular bleeding, which appears to occur more with low estrogen pills (EE ≤0.020 mg). [6,11,12]
• Common side effects reported with OCP use include:
• Irregular menstrual bleeding
• Nausea
• Headache / Migraine
• Breast tenderness
• Mood disorders
• Decreased libido

• Weight gain
• Weight gain is a common complaint with OCPs and one that women are frequently concerned about. That being said, there is no evidence from placebo-controlled trials that OCPs cause weight gain. [11,12,13]

• Increase in blood pressure
• Combined OCPs may raise blood pressure in some women. The effect is thought to be secondary to the estrogen component, which increases the hepatic production of angiotensinogen.
• In controlled trials, the effect of OCPs on blood pressure has been mixed. Some studies have shown no significant effect, while others have shown a slight increase of 1 - 2 mmHg on average. Older OCPs containing higher amounts of estrogen were sometimes found to increase systolic blood pressure by 7 - 8 mmHg.
• The progestin drospirenone is structurally similar to spironolactone, an aldosterone antagonist used to treat hypertension. Drospirenone-containing OCPs have been shown to lower blood pressure by 1 - 4 mmHg in some studies, while others have found no significant effect.
• In summary, women with hypertension, prehypertension, or multiple risk factors for hypertension should monitor their blood pressure when starting or changing OCPs. [78,79,80,81,82,83]

• Diabetes and glucose intolerance
• Early OCPs with higher doses of estrogen were shown to cause insulin resistance. Modern OCPs with less estrogen have not been shown to increase the risk of diabetes or glucose intolerance. [15,16]

• High potassium (Drospirenone)
• Drospirenone is structurally related to the mineralocorticoid antagonist spironolactone, which blocks aldosterone receptors in the kidney and can raise potassium levels (nephron diagram).
• The manufacturers of drospirenone-containing OCPs warn that it may cause hyperkalemia in women with kidney disease and those taking medications that raise potassium (see potassium-raising medications)
• Clinical studies
• Cohort studies and randomized trials examining the incidence of hyperkalemia among women taking drospirenone-containing OCPs have found that they do not increase the risk of hyperkalemia compared to other OCPs. Hyperkalemia risk also does not appear to be elevated when taken with other potassium-raising medications, including spironolactone. [17,29,30,69]
• Summary
• Drospirenone-induced hyperkalemia is uncommon even when taken with other potassium-raising medications
• Spironolactone is increasingly used to treat acne in young women, and the American Academy of Dermatology states that it is safe to use with drospirenone-containing OCPs. [69]

• Liver adenomas
• OCPs have been associated with the development of hepatic adenomas. This side effect is rare, with an estimated incidence of 3.3 cases per 100,000 users. [17]

• Photosensitivity
• OCPs may cause photosensitivity and skin reactions. Limiting sun exposure and using sunscreen can help prevent these reactions. [63]

• Melasma (chloasma)
• Melasma (also called chloasma) is darkening of the skin that typically affects the forehead, cheeks, and upper lip. It is associated with hormonal changes and is most often seen in pregnant women. OCPs may also cause melasma, and women with a history of pregnancy-induced melasma are at greater risk. Limiting sun exposure and wearing sunscreen may help to prevent it.

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• LONG-TERM RISKS

• Venous thromboembolism (VTE)
• The estrogen in combined OCPs increases the risk of VTE. When discussing this risk, it's important to note that pregnancy and the postpartum period carry a much higher risk of VTE than OCP use. In this regard, OCPs may actually lower a woman's risk of VTE.
• The incidences of VTE in different populations of women are listed below. Given the high risk of VTE during the postpartum period (42 days after delivery), specific recommendations for birth control during this time have been issued by the CDC and are available here - postpartum birth control recommendations.


• Non-pregnant, non-OCP user: 1 - 5 blood clots per 10,000 women annually
• Combined OCP user: 3 - 9 blood clots per 10,000 women taking for a year
• Non-oral combined hormone contraceptive user (e.g. patch): 3 - 12 blood clots per 10,000 women using for a year
• Pregnant female: 5 - 20 blood clots per 10,000 pregnant women annually
• Postpartum (first 12 weeks after delivery): 40 - 65 blood clots per 10,000 postpartum women annually. The risk appears to be greatest during the first 6 weeks, after which it decreases significantly. [17,18,58]

• Drospirenone
• Some observational studies have found that drospirenone-containing OCPs carry a higher risk of VTE, while other studies have found no such link. The FDA reviewed the issue and concluded that drospirenone-containing OCPs might be associated with higher VTE risk, but the evidence is inconclusive. See FDA statement on drospirenone for more.

• Heart attack and stroke
• The estrogen component in combined OCPs causes a slight increase in the risk of heart attack and stroke. Women with other risk factors for CVD (e.g. smoking, older, diabetes, hypertension) are at the greatest risk, and combined OCPs are contraindicated in some of these patients (see contraindications below).
• OCPs with higher levels of EE (0.030 - 0.040 mg) may also carry a higher risk compared to lower EE pills
• Migraine headache with aura is a risk factor for stroke, and OCPs are contraindicated in these patients.
• Estrogen-free forms of contraception (e.g. IUD, depo shot, progestin-only pills) may be preferred in these patients [1,14,56]

• Breast cancer
• OCPs are contraindicated in women with current or past breast cancer. It is unclear if OCP use increases the risk of developing breast cancer, as observational studies that have examined this association have had mixed results. [1,17,74,75,84]

• Cervical cancer
• Some observational studies have found a slightly increased risk of cervical cancer in OCP users. Since cervical cancer is strongly associated with the sexually-contracted HPV virus, it's unclear if OCPs have an actual effect or if differences in sexual activity between users and nonusers are the reason.

• Fracture risk
• Studies that have examined the association between OCP use and fracture risk have had conflicting results, with some studies showing increased risk, some showing a protective effect, and others showing no effect. [26,27,28]

• Gallbladder disease
• Older OCPs with high estrogen content were associated with an increased risk of gallbladder disease. Today's formulations do not appear to carry this risk. [14]

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• HORMONE THERAPY AFTER VTE

• Overview
• Combined OCPs and estrogen-containing hormone replacement products are not recommended in women with a history of VTE. Whether anticoagulated women can safely take them is a subject of debate. Two professional organizations have issued conflicting guidance on the topic, and no randomized controlled trial has evaluated the matter. In 2016, a post-hoc analysis of the EINSTEIN DVT/PE studies was published that helped shed some light on the issue. EINSTEIN compared rivaroxaban to vitamin K antagonists in patients with VTE, and the analysis looked at the subgroup of women who took hormones while they were anticoagulated. Results from the study are detailed below.

• STUDY
  Risk of Recurrent VTE Among Women Receiving Hormonal Therapy in the EINSTEIN DVT/PE Study, Blood (2016) [PubMed abstract]
• In the EINSTEIN DVT/PE study, 1888 women less than 60 years old were randomized to rivaroxaban or a vitamin K antagonist following a VTE. Of these women, 705 were using hormone therapy before randomization and 1183 were not. After randomization, 400 hormone users continued or restarted hormones, and 75 nonusers initiated hormonal therapy.
• Estrogen therapy, defined as estrogen-only pills and combined estrogen-progestin contraceptives (e.g. pills, patches, vaginal rings), was taken by 306 women, and progestin-only therapy (e.g. pills, implants, IUD) was used by 217 women.
• A total of 7 recurrent VTEs occurred during periods of hormone therapy use, and 38 occurred during no use.
• The incidence of recurrent VTE was as follows:
• No hormone use: 4.7%/year (95% CI [3.3% - 6.4%])
• Estrogen-containing therapy: 3.7%/year (95% CI [1.0% - 9.4%])
• Progestin-only therapy: 3.8%/year (95% CI [0.8% - 11.2%])
• The incidence of uterine bleeding leading to transfusion was as follows:
• No hormone use: 2.5%/year (95% CI [1.5% - 4.0%])
• Estrogen-containing therapy: 1.9%/year (95% CI [0.2% - 6.9%])
• Progestin-only therapy: 1.3%/year (95% CI [0.0% - 7.2%]) [65]
• Findings: In conclusion, there is no indication that the use of estrogen-containing or progestin-only hormonal therapy is associated with an increased risk of recurrent VTE in pre- or postmenopausal women on anticoagulant treatment. The finding that use of rivaroxaban was associated with an increased rate of abnormal uterine bleeding needs further mechanistic exploration. Physicians should pay special attention to women with anemia or those with uterine fibroids or adenomyosis who start anticoagulant therapy.

• Professional recommendations
• The World Health Organization guidelines published in 2010 state that estrogen-containing contraceptives should not be used in women who are anticoagulated after a VTE
• The International Society on Thrombosis and Haemostasis guidelines published in 2012 recommend that women diagnosed with a hormone-associated VTE continue oral contraceptive and estrogen-replacement therapy while they are anticoagulated. The authors argue that the prothrombotic effect of hormones will be neutralized by anticoagulation, and the elevated risk of menorrhagia from anticoagulation will be reduced with hormone therapy. [65]

• Summary
• The post-hoc analysis of the EINSTEIN DVT/PE study found that neither estrogen nor progestin therapy increased the risk of recurrent VTE in anticoagulated women. The study is limited by its observational design, and it was underpowered to analyze specific treatments (e.g. OCPs, HRT, speicifc estrogens, specific progestins).
• In conclusion, anticoagulated women who have a strong preference or need for estrogen-containing hormonal therapy may take these medications with the understanding that there is limited data on their safety

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• BENEFITS OF OCPs

• Endometrial cancer
• A number of observational studies have shown that women who use OCPs have a lower risk of endometrial cancer. In some studies, the risk has been reduced by as much as 50% and remained reduced for up to 20 years after OCPs were stopped. [31,72,75,84]

• Ovarian cancer
• Observational studies have found that women who use OCPs have a lower risk of ovarian cancer [32,72,75,77,84]
• A review that combined data from 45 studies encompassing over 100,000 women found that OCP use reduced the relative risk of ovarian cancer by 27%. The reduction persisted for up to 30 years after OCPs were stopped, and longer use was associated with greater reduction. [PMID 18294997]

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• CONTRAINDICATIONS

• Combined OCPs are contraindicated in patients with the following conditions:
• Women who smoke and are ≥ 35 years old
• History of blood clots (see hormone therapy after VTE above)
• History of heart disease or cerebrovascular disease (stroke)
• Atrial fibrillation
• Heart valve disorders that are thrombogenic (ex. significant mitral valve prolapse, endocarditis)
• Hypercoagulable disorders (Factor V Leiden mutation, Protein C and S deficiency, etc.)
• Uncontrolled hypertension or hypertension with vascular disease
• Diabetes with vascular disease
• Headaches with focal neurological symptoms
• Migraine with aura
• Any migraine headache and > 35 years old
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Breast cancer or other estrogen- or progestin-sensitive cancer (e.g. endometrial cancer), now or in the past
• Liver tumors (benign and malignant)
• Acute viral hepatitis or decompensated liver disease
• Undiagnosed abnormal uterine bleeding

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• PRECAUTIONS

• Migraine headache
• Evidence from observational studies suggests that women with migraine headaches have an increased risk of stroke. The association appears to be strongest for migraines preceded by an aura. Because OCPs can also increase the risk of stroke, it's recommended that they not be taken by women who have migraine headaches with aura and women older than 35 years with any migraine.
• It's important to note that although OCPs may enhance the risk of stroke in these women, the overall risk is still very low, with 5 - 10 strokes per 100,000 women annually in those less than 45 years old. Women with migraines who have a strong preference or need for combined OCPs may find the benefits outweigh the risks. [24,25,85]

• Obesity
• OCP failure
• Some studies have found that obese women have higher rates of OCP failure than average-weight women, while others have found no such association. A randomized controlled trial that directly measured ovulation rates between normal and obese women on OCPs found no significant difference between the groups. [PMID 20664386]
• There is no conclusive evidence that OCPs are less effective in obese women [33,34]
• Venous thromboembolism (VTE)
• Obesity is a risk factor for VTE, and combined OCPs may enhance the risk (see venous thromboembolism above). Estrogen-free contraceptives (e.g. IUD, depo shot) may be preferred in obese women.

• Postpartum (after childbirth)
• After childbirth, a woman's risk of VTE is elevated for up to 42 days, with the highest risk occurring during the first 21 days. Estrogen-containing birth control methods can enhance the risk, so the CDC has issued guidelines regarding their use in postpartum women. Those recommendations are provided below.


• CDC recommendations for women who are breastfeeding
• First 30 days after delivery - all women should avoid combined hormonal contraceptives
• Days 30 - 42 after delivery
• Women with risk factors for blood clots (see below) - do not use combined hormonal contraceptives
• Women without risk factors for blood clots - the advantages of combined hormonal contraceptives generally outweigh the risk
• > 42 days after delivery - the advantages of combined hormonal contraceptives generally outweigh the risks in all appropriate patients
• Breastfeeding and combined hormonal contraceptives - the CDC states that there is conflicting evidence about the effects of estrogen-containing birth control on breast milk production. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to combined hormonal contraceptives through breast milk have not been demonstrated; however, studies have been inadequately designed to determine whether a risk for either serious or subtle long-term effects exists. [67]


• CDC recommendations for women who are NOT breastfeeding
• First 21 days after delivery - all women should avoid combined hormonal contraceptives
• Days 21 - 42 after delivery
• Women with risk factors for blood clots (see below) - do not use combined hormonal contraceptives
• Women without risk factors for blood clots - the advantages of combined hormonal contraceptives generally outweigh the risk
• > 42 days after delivery - combined hormonal contraceptives may be used in all appropriate patients [67]

• Risk factors for blood clots inlude:
• ≥ 35 years old
• Previous VTE (pulmonary embolism, deep vein thrombosis)
• Hypercoagulable disorders
• Immobility
• Transfusion at delivery
• Peripartum cardiomyopathy
• BMI ≥ 30
• Postpartum hemorrhage
• Postcesarean delivery
• Preeclampsia
• Smoking [67]

• Hypertension
• Combined OCPs are contraindicated in women with uncontrolled hypertension. See increase in blood pressure above for a review of OCP effects on blood pressure.

• Liver disease
• OCPs are contraindicated in women with a history of hepatic tumors, decompensated liver disease (Child-Pugh B and C), and acute viral hepatitis. The effects of compensated liver disease (Child-Pugh A) on OCP metabolism have not been studied extensively, and caution should be used in these patients.

• Kidney disease
• Most OCPs have not been studied in women with kidney disease, and manufacturers offer little guidance. In 2020, the Italian Society of Nephrology issued guidelines for contraceptive use in women with chronic kidney disease. Those guidelines are summarized below.


• Any woman with hypertension or a thrombophilic state (e.g. lupus with antiphospholipid antibodies, nephrotic proteinuria)
• Avoid combined OCPs
• Progestin-only contraceptives and IUDs are acceptable
• CKD stages 1, 2, and 3a (GFR ≥ 44 ml/min)
• Combined OCPs, progestin-only contraceptives, and IUDs are acceptable
• CKD stages 3b, 4, and 5 (GFR < 44 ml/min)
• Avoid combined OCPs
• Progestin-only contraceptives and IUDs are acceptable [86]
• See stages of kidney disease

• Thyroid hormone
• OCPs can cause an increase in thyroid-binding globulin (TBG) which leads to a reduction in the clearance of triiodothyronine (T3) and thyroxine (T4). T3 and T4 exist in two forms, inactive and active. The inactive form is bound to TBG, and the active form is unbound or "free." OCPs increase T3 and T4 levels by reducing their clearance, but the amount of free T3 and free T4 remains the same because TBG increases proportionately. The net effect in most women is that thyroid activity is unchanged. [39]

• Surgery
• The prescribing information for combined OCPS states that they should be discontinued at least 4 weeks before major surgery or other surgeries known to have an elevated risk of VTE. Guidelines from SPAQI state that it is okay to continue them before surgery (see preoperative medication management).

• Fetal exposure to OCPs
• Occasionally, women will inadvertently take OCPs after they have become pregnant. Observational studies examining the effects of OCPs on the developing fetus have found no conclusive evidence that OCPs increase the risk of fetal demise or birth defects. [40,42,60,64]

• Hereditary angioedema
• Exogenous estrogens may exacerbate angioedema. Use caution in susceptible women.

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• DRUG INTERACTIONS

• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).


• All OCPs
• Acetaminophen (Tylenol®) - acetaminophen may increase blood level of ethinyl estradiol. OCPs may decrease levels of acetaminophen.
• Antibiotics - see antibiotics below
• Anticonvulsants - see anticonvulsants below
• Ascorbic acid (Vitamin C) - some studies have found that ascorbic acid increases blood levels of ethinyl estradiol
• Atorvastatin (Lipitor®) - atorvastatin may increase blood levels of EE by approximately 20 - 25% [71]
• Benzodiazepines (alprazolam, Xanax®, triazolam, temazepam, etc.) - OCPs have been shown to both increase and decrease blood levels of benzodiazepines [38]
• Bile acid sequestrants (Welchol®, etc.) - bile acid sequestrants can block the absorption of EE. In one study, colesevelam decreased the absorption of EE when EE was taken one hour before colesevelam. When EE was taken 4 hours before colesevelam, no interaction occurred. [PubMed abstract]
• Cyclosporine - OCPs may increase blood levels of cyclosporine
• CYP3A4 Inducers - CYP3A4 inducers can decrease blood levels of OCPs
• CYP3A4 Inhibitors - CYP3A4 inhibitors can increase blood levels of OCPs. The significance of this effect is unknown. Patients taking CYP3A4 inhibitors with OCPs may want to take a low ethinyl estradiol pill (<0.030 mg).
• GLP-1 analogs
• GLP-1 analogs slow gastric emptying, which can affect the absorption of OCPs. The manufacturers of exenatide and lixisenatide give recommendations on taking OCPs with their products.
• OCPs should be taken 1 hour before exenatide (Byetta®, Bydureon®) is injected [55]
• OCPs should be taken at least 1 hour before lixisenatide (Soliqua®) administration or at least 11 hours after the last dose of lixisenatide [73]
• Griseofulvin (Gris-Peg®) - griseofulvin may decrease blood levels of OCPs
• HIV/Hepatitis C medications - many of the protease inhibitors and NNRTIs used to treat HIV and hepatitis C are CYP3A4 inducers and inhibitors that can alter OCP exposure.
• Mavyret® (glecaprevir + pibrentasvir) - DO NOT COMBINE. Concomitant therapy may increase the risk of ALT elevations.
• Morphine - OCPs may decrease blood levels of morphine
• Pioglitazone (Actos®) - pioglitazone is a CPY3A4 inducer. Pioglitazone may decrease OCP blood levels.
• Pramlintide (Symlin®) - pramlintide slows gastric emptying and may affect the absorption of OCPs
• Prednisolone - OCPs may increase blood levels of prednisolone
• Rosuvastatin (Crestor®) - rosuvastatin may increase blood levels of EE by approximately 20 - 25% [71]
• Technivie® (ombitasvir, paritaprevir, and ritonavir) - OCPs with ethinyl estradiol should not be taken with the hepatitis C drug Technivie. ALT elevations > 5 - 20 ULN have been seen in some patients.
• Theophylline (Theo-Dur®) - OCPs may increase blood levels of theophylline
• Thyroid hormone - OCPs may cause an increase in blood levels of thyroid hormone and thyroid-binding globulin. The amount of active (free) thyroid hormone is generally unchanged (see thyroid hormone above).
• Tizanidine (Zanaflex®) - OCPs may increase blood levels of tizanidine
• Ulipristal (Ella®) - ulipristal is a progesterone agonist/antagonist emergency contraceptive agent. The effectiveness of progestin-containing contraceptives and ulipristal may be decreased if progestin-containing contraceptives are taken within 5 days of ulipristal dosing. Therefore, if a woman wishes to use a progestin-containing contraceptive after using ulipristal, she should do so no sooner than 5 days after the intake of ulipristal, and she should use a reliable barrier method for subsequent acts of intercourse until her next menstrual period.
• Viekira-Pak™ (ombitasvir, paritaprevir, ritonavir, and dasabuvir) - OCPs with ethinyl estradiol should not be taken with the hepatitis C drug Viekira Pak. ALT elevations > 5 - 20 ULN have been seen in some patients.
• Voriconazole - OCPs may increase blood levels of voriconazole

• Anticonvulsants
• Nowadays, anticonvulsants are used to treat a wide range of conditions besides seizure disorders (e.g. migraines, pain, bipolar disorder, depression). Some anticonvulsants are CYP3A4 enzyme inducers and may theoretically decrease the effectiveness of OCPs by lowering hormone levels. The significance of this effect is unknown as studies have shown that women who take OCPs with CYP3A4-inducing anticonvulsants still have very low pregnancy rates.
• Other forms of contraception (IUD, barrier) should be considered in women taking CYP3A4-inducing anticonvulsants. If OCPs are still desired, products with at least 0.030 mg of ethinyl estradiol should be used.
• Estrogen-containing OCPs have been shown to decrease blood levels of lamotrigine (Lamictal®) by up to 50%, and they may also lower valproic acid levels. During concomitant therapy, lamotrigine and valproic acid levels should be monitored closely, particularly when stopping or starting OCPs. [35,36,70,87]


• Anticonvulsants that induce CYP3A4
• Carbamazepine (Tegretol®)
• Cenobamate (Xcopri™)
• Clobazam (Onfi®)
• Eslicarbazepine (Aptiom®)
• Felbamate (Felbatol®)
• Oxcarbazepine (Trileptal®)
• Phenobarbital
• Phenytoin (Dilantin®)
• Primidone (Mysoline®)
• Topiramate (Topamax®)


• Anticonvulsants that do NOT induce CYP3A4
• Ethosuximide (Zarontin®)
• Gabapentin (Neurontin®)
• Lamotrigine (Lamictal®) - Estrogen-containing OCPs have been shown to reduce lamotrigine levels by as much as 50%
• Levetiracetam (Keppra®)
• Tiagabine (Gabitril®)
• Valproic acid (Depakote®)
• Zonisamide (Zonegran®)


• Anticonvulsants that may be affected by OCPs
• Lamotrigine (Lamictal®) - Estrogen-containing OCPs have been shown to reduce lamotrigine levels by as much as 50%
• Valproic acid (Depakote®) - OCPs may reduce valproic acid levels

• Antibiotics
• It has long been suggested that antibiotics may interact with OCPs, causing OCP failure and unintended pregnancies. Outside of rifampin (a CYP3A4 inducer), supportive evidence for this belief is weak or nonexistent.
• Studies evaluating the direct effects of antibiotics on blood levels of hormones have generally found that they do not significantly affect hormone levels. However, a small number of patients in these studies did show significant variations in hormone levels when taking antibiotics. It's possible that a small subpopulation of patients are predisposed to some type of antibiotic-OCP interaction, the mechanism of which has not been elucidated. [37,76]
• CDC statement on antibiotics and combined hormonal contraceptives
• Most broad-spectrum antibiotics do not affect the contraceptive effectiveness of combined OCPs, the patch, or vaginal ring
• Although the interaction of rifampin or rifabutin therapy with combined hormonal contraceptives is not harmful to women, it is likely to reduce the effectiveness of combined hormonal contraceptives. Use of other contraceptives should be encouraged for women who are long-term users of either of these drugs. When a combined hormonal contraceptive is desired, a preparation containing a minimum of 0.030 mg of ethinyl estradiol should be used. [87]

• Metabolism and clearance
• All OCPs
• CYP3A4 - sensitive substrate and weak inhibitor
• CYP1A2 - moderate inhibitor

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• DOSING

• Overview
• All OCPs are taken once daily. Patients should try to take the pill at the same time every day, and they can be taken without regard to food.

• Starting OCPs (combined and progestin-only)
• Traditional method
• OCPs should be started on the first day of the menstrual cycle, or they can be started on the first Sunday after the start of a menstrual cycle. The Sunday start is for convenience since it makes the start of a new packet coincide with the beginning of a new week.
• If an OCP is started later than the first day of the menstrual cycle, it should not be considered effective until 7 consecutive days of pills have been taken. Barrier contraception should be used during those 7 days.
• Immediate start
• Some women may wish to start OCPs immediately, regardless of menses
• Sexually active women should be aware that urine pregnancy tests can take up to 2 weeks to become positive
• If this approach is used, an alternative barrier method should be used for at least 7 days after starting the pills and possibly longer
• Inadvertent OCP use during pregnancy does not appear to harm the fetus [40]
• Postpartum
• Combined oral contraceptives - the CDC has issued specific guidelines for combined oral contraceptives in the postpartum period (see postpartum above)
• Progestin-only pills - may be started immediately after giving birth [43]

• Missed doses (combined OCPs)
• Each OCP product comes with an insert that explains how to handle missed doses for that specific product
• The guidelines below are general guidelines for missed doses. When available, OCP users should follow the instructions specific to their product.
• Miss 1 day
• If one day is missed, take 2 pills on the following day
• Backup contraception is not needed
• Miss 2 days in a row
• If two days in a row are missed (days 1 and 2), take two pills on day 3, and two pills on day 4
• Use backup contraception until 7 consecutive days of OCPs have been taken
• Miss 3 days in a row
• If three days in a row are missed, throw out the current packet (monthly packets only) and start a new package immediately or on Sunday if you are a Sunday starter
• Use backup contraception until 7 consecutive days of OCPs have been taken

• Missed doses (progestin-only)
• Missed dose or more than 3 hours late taking a pill
• Take the pill as soon as remembered, then go back to taking pills at regular time
• Use backup contraception for 48 hours

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• PROGESTIN-ONLY PILLS

• Overview
• Progestin-only pills only contain a progestin and no estrogen. In the U.S., three progestins are available for contraceptive use - norethindrone, levonorgestrel, and drospirenone. Norethindrone and drospirenone are used for daily contraception, and levonorgestrel is approved for emergency contraception. Progestin-only pills are primarily used in breastfeeding women (see breastfeeding below) and those with a contraindication to estrogen.

• Dosing and dosage form
• Progestin-only pill dosing and dosage form chart

• Effectiveness
• Pharmacokinetic studies have shown that the metabolism of progestins can vary widely among individuals. This has led some experts to conclude that progestin-only pills are not as effective as combined OCPs and that they should be taken at the same time every day. Clinical evidence supporting these beliefs is mostly nonexistent. A Cochrane meta-analysis that looked at trials comparing the effectiveness of progestin-only contraceptives to combined OCPs found that there was insufficient data to draw conclusions. It also found no trials evaluating the effects of daily variations in dose timing. [45]

• Breastfeeding
• Progestin-only contraceptives are often used during breastfeeding because estrogens are believed to suppress breast milk production A Cochrane meta-analysis that evaluated this issue found that the available evidence was limited and of poor quality, and no recommendation could be made. [46] Furthermore, a trial that randomized postpartum breastfeeding women to progestin-only pills or combined OCPs found no significant difference in breastfeeding continuation rates and infant growth parameters between the pills. [PMID 22143258]
• The CDC postpartum OCP recommendations state that there is conflicting evidence about the effects of combined birth control methods on breast milk production, and no consistent effects on infant growth or illness have been reported [67]

• Bleeding patterns
• Norethindrone products contain an active pill every day of the cycle. Bleeding patterns for norethindrone products vary widely among women, with some having no bleeding and others reporting frequent irregular bleeding. About 40% of women on progestin-only pills have regular monthly menses. [48]
• The drospirenone product Slynd® has 4 inert tablets at the end of the cycle, and the prescribing information states that "menses may occur" during this period. In Slynd® trials, unscheduled bleeding occurred in 64.4% of women during cycle 1 and dropped to 40.3% by cycle 13.

• Risks
• Unlike combined OCPs, progestin-only pills have not been found to increase the risk of VTE, stroke, or heart attack. For these reasons, they may be safer in certain populations (e.g. history of VTE, CVD, migraine with aura). [45,49,56]

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• EMERGENCY CONTRACEPTION

• Overview
• Emergency contraception, also known as the morning-after pill, is taken within days of unprotected intercourse to help prevent pregnancy. The pills contain hormones, typically progestins (e.g. levonorgestrel, ulipristal), that work by inhibiting or delaying ovulation. Traditionally, emergency contraception was recommended up to 72 hours after intercourse, but studies have shown it to be effective up to 120 hours, and this is the interval the World Health Organization recommends. The hormonal agent may be a combination OCP, levonorgestrel, or a progesterone agonist/antagonist (e.g. ulipristal).
• In the U.S., Plan B® and Plan B One-Step® can be bought over-the-counter by a male or female who is 17 years of age or older, while ulipristal (Ella®) requires a prescription.
• Emergency contraception can also be achieved by inserting a copper IUD within 5 days of unprotected intercourse (see ParaGard® for more). In 2021, a study was published that found the Mirena IUD to be as effective as the copper IUD for emergency contraception. [PMID 33503342]

• Timing
• Studies have shown that emergency contraception is effective up to 120 hours (5 days) after unprotected intercourse, and the World Health Organization recommends this interval [40,42]

• Effectiveness
• A study that compared the Yuzpe method to levonorgestrel (0.75 mg, repeated 12 h later) within 72 hours of unprotected intercourse found that levonorgestrel was superior with a pregnancy rate of 1.1% (11/976) vs 3.2% (31/979) with Yuzpe. [PMID 9708750]
• Results from a study that compared ulipristal 30 mg to levonorgestrel 1.5 mg for emergency contraception within 5 days of unprotected intercourse are presented in the table below.

• Obese women
• Some studies have found that emergency contraception is less effective in obese women
• In one study, the incidence of pregnancy after emergency contraception with levonorgestrel was 1.4% in women weighing 154 - 165 pounds (70 - 75 kg) and 6.4% in women weighing 165 - 187 pounds (75 - 85 kg). [PMID 25528415] Another study found that serum levonorgestrel levels after a single dose of 1.50 mg were 50% lower in obese women (median BMI 39) when compared to non-obese women. When the obese women were given 3 mg, they achieved similar levels to non-obese women. [PMID 27000996] Contrarily, another study found that double-dose levonorgestrel (3 mg) was no better than the standard dose (1.5 mg) for inhibiting or prolonging ovulation in obese women. [PMID 35849455]
• Pregnancy rates with ulipristal have also been higher in obese women. In a pooled analysis or ulipristal trials, women with a BMI > 30 had a pregnancy rate of 3.1%, which was not significantly different from the expected rate of 4.5% without emergency contraception. [88]
• Summary: Overall, emergency contraception is less effective in obese women (BMI ≥ 30). There is some indication that ulipristal may be more effective than levonorgestrel in this population, but this has not been proven in a randomized controlled trial. Women with a BMI ≥ 30 may want to take ulipristal or use a levonorgestrel dose of 3 mg instead of 1.5 mg. [90]

• Side effects
• In a trial that compared ulipristal to levonorgestrel 1.5 mg (N=2221), the incidence of reported side effects was similar between groups and included the following: headache (19%), dysmenorrhea (14%), nausea (13%), fatigue (6%), dizziness (5%), and abdominal pain (5 - 7%) [89]
• Vaginal bleeding after emergency contraception may be irregular, or it may occur at the expected time [40]

• Fetal effects
• The overall effects of emergency contraception on a developing fetus are unknown, but studies examining fetal outcomes in women who received emergency contraception during pregnancy have not found a definitive association between emergency contraception and fetal harm. [40,42,60,88]

• Contraindications
• The only contraindication to emergency contraception is known pregnancy [40,42,88]

• Progestin-only regimens
• Levonorgestrel 1.50 mg one time
• Available in one pill (levonorgestrel 1.50 mg) as Plan B One-Step® and as a generic
• The World Health Organization recommends this regimen [42]
• Obese women may require a 3 mg dose. See obese women above.
• Levonorgestrel 0.75 mg every twelve hours for 2 doses total
• Levonorgestrel 0.75 mg pills are available as generics
• See progestin-only dosing chart

• Ulipristal (Ella®)
• Dosage form: 30 mg tablet
• Dosing: Take one tablet orally as soon as possible within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure
• May take without regard to food
• If vomiting occurs within 3 hours of intake, consideration should be given to repeating the dose
• May be taken at any time during the menstrual cycle
• Ulipristal is a progesterone agonist/antagonist

• Progestin + Ethinyl Estradiol regimens (Yuzpe regimens)
• Ethinyl estradiol 0.100 mg + levonorgestrel 0.5 mg every 12 hours for 2 doses total
• Doses can be accomplished with a number of OCP products
• In trials, this regimen has not been found to be as effective as the progestin-only regimens [41]
• Has a high incidence of nausea and vomiting [40]

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• USE IN OTHER CONDITIONS

• Menorrhagia (heavy periods)
• The progestin in OCPs helps to keep the endometrium thin, reducing menstrual bleeding. See abnormal uterine bleeding for more.

• Ovarian cysts
• OCPs are often given to women with functional ovarian cysts based on the belief that OCPs can hasten their resolution. A Cochrane meta-analysis that looked at studies comparing combined OCPs to no treatment in women with functional ovarian cysts found that OCPs did not affect cyst resolution. Most cysts resolved without treatment within a few cycles, and cysts that persisted for several months were more likely to be endometriomas or paraovarian cysts. [PMID 24782304]

• Dysmenorrhea (painful menstrual cramps)
• OCPs are often used to treat dysmenorrhea. A Cochrane meta-analysis of trials comparing combined OCPs to other combined OCPs, placebo, or no management found that combined OCPs appeared to benefit some women with dysmenorrhea, although the evidence was weak. There was no conclusive evidence that one OCP preparation was better than another. [PMID 19821293]

• Acne
• Combined OCPs have been shown to improve acne. Proposed mechanisms for their beneficial effect include the following: (1) suppression of ovarian androgen production, (2) increase in sex hormone-binding globulin which reduces free testosterone, (3) reduction in 5-alpha-reductase activity, (4) blockade of androgen receptors. An improvement is typically seen after 3 cycles. [59,68]
• A Cochrane meta-analysis of trials comparing combined OCPs to placebo or other active treatments found that OCPs significantly reduced inflammatory and non-inflammatory facial lesions. There was no evidence that one preparation was better than another. [PMID 22786490]
• A list of OCPs that are FDA-approved to treat acne is available here - OCPs approved for acne [53,59]

• Endometriosis
• Endometriosis is a condition where endometrial tissue is found outside of the uterus. It can be painful and is associated with infertility. Endometrial pain is often treated with OCPs. A Cochrane meta-analysis of trials comparing combined OCPs to placebo or other treatments for endometrial pain found insufficient data to evaluate OCP effectiveness. [PMID 29786828]

• Polycystic ovarian syndrome (PCOS)
• PCOS is a syndrome characterized by cystic ovaries, insulin resistance, anovulation, high levels of testosterone, and obesity. Combined OCPs suppress testosterone production and are the recommended first-line treatment for PCOS. See Endocrine Society PCOS recommendations for more.

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