TABLE D1. Classifications for combined hormonal contraceptives, including pill, patch, and ring.

Condition	CHC		Clarification/Evidence/Comment
Personal Characteristics and Reproductive History
Pregnancy	NA		Clarification: Use of CHCs is not required. No known harm to the patient, the course of pregnancy, or the fetus occurs if CHCs are inadvertently used during pregnancy.
Age			Evidence: Evidence is inconsistent about whether CHC use affects fracture risk (36–47), although three recent studies demonstrate no effect (36,37,47). CHC use might decrease BMD in adolescents, especially in those choosing very low-dose formulations (COCs containing <30 µg ethinyl estradiol) (48–61). CHC use has little to no effect on BMD in premenopausal women (62–76) and might preserve bone mass in those who are perimenopausal (77–85). BMD is a surrogate marker for fracture risk that might not be valid for premenopausal women and therefore might not accurately predict current or future (postmenopausal) fracture risk (86–88). Comment: The risk for cardiovascular disease increases with age and might increase with CHC use. In the absence of other adverse clinical conditions, CHCs can be used until menopause.
a. Menarche to <40 years	1
b. ≥40 years	2
Parity
a. Nulliparous	1		—
b. Parous	1		—
Breastfeeding
a. <21 days postpartum	4		Clarification (breastfeeding): Breastfeeding provides important health benefits for breastfeeding parent and infant. The U.S. Dietary Guidelines for Americans and American Academy of Pediatrics recommend that infants be exclusively breastfed for about the first 6 months with continued breastfeeding while introducing appropriate complementary foods for 1 year or longer (89) or up to age 2 years or longer (90). Evidence (breastfeeding): Clinical studies demonstrate conflicting results regarding effects on breastfeeding continuation or exclusivity in women exposed to COCs during lactation. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs 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 (91). Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97). Comment: Risk factors for breastfeeding difficulties include previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and preterm birth. For all breastfeeding persons, with or without risk factors for breastfeeding difficulties, discussions about contraception should include information about risks, benefits, and alternatives.
b. 21 to <30 days postpartum
i. With other risk factors for VTE (e.g., age ≥35 years, previous VTE, thrombophilia, immobility, transfusion at delivery, peripartum cardiomyopathy, BMI ≥30 kg/m2, postpartum hemorrhage, postcesarean delivery, preeclampsia, or smoking)	3		Clarification: For persons with other risk factors for VTE, these risk factors might increase the classification to a category 4. Clarification (breastfeeding): Breastfeeding provides important health benefits for breastfeeding parent and infant. The U.S. Dietary Guidelines for Americans and American Academy of Pediatrics recommend that infants be exclusively breastfed for about the first 6 months with continued breastfeeding while introducing appropriate complementary foods for 1 year or longer (89) or up to age 2 years or longer (90). Evidence (breastfeeding): Clinical studies demonstrate conflicting results regarding effects on breastfeeding continuation or exclusivity in women exposed to COCs during lactation. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs 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 (91). Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97). Comment: Risk factors for breastfeeding difficulties include previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and preterm birth. For all breastfeeding persons, with or without risk factors for breastfeeding difficulties, discussions about contraception should include information about risks, benefits, and alternatives.
ii. Without other risk factors for VTE	3		Clarification (breastfeeding): Breastfeeding provides important health benefits for breastfeeding parent and infant. The U.S. Dietary Guidelines for Americans and American Academy of Pediatrics recommend that infants be exclusively breastfed for about the first 6 months with continued breastfeeding while introducing appropriate complementary foods for 1 year or longer (89) or up to age 2 years or longer (90). Evidence (breastfeeding): Clinical studies demonstrate conflicting results regarding effects on breastfeeding continuation or exclusivity in women exposed to COCs during lactation. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs 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 (91). Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97). Comment: Risk factors for breastfeeding difficulties include previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and preterm birth. For all breastfeeding persons, with or without breastfeeding difficulties, discussions about contraception should include information about risks, benefits, and alternatives.
c. 30–42 days postpartum
i. With other risk factors for VTE (e.g., age ≥35 years, previous VTE, thrombophilia, immobility, transfusion at delivery, peripartum cardiomyopathy, BMI ≥30 kg/m2, postpartum hemorrhage, postcesarean delivery, preeclampsia, or smoking)	3		Clarification: For persons with other risk factors for VTE, these risk factors might increase the classification to a category 4. Clarification (breastfeeding): Breastfeeding provides important health benefits for breastfeeding parent and infant. The U.S. Dietary Guidelines for Americans and American Academy of Pediatrics recommend that infants be exclusively breastfed for about the first 6 months with continued breastfeeding while introducing appropriate complementary foods for 1 year or longer (89) or up to age 2 years or longer (90). Evidence (breastfeeding): Clinical studies demonstrate conflicting results regarding effects on breastfeeding continuation or exclusivity in women exposed to COCs during lactation. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs 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 (91). Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97). Comment: Risk factors for breastfeeding difficulties include previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and preterm birth. For all breastfeeding persons, with or without breastfeeding difficulties, discussions about contraception should include information about risks, benefits, and alternatives.
ii. Without other risk factors for VTE	2		Clarification (breastfeeding): Breastfeeding provides important health benefits for breastfeeding parent and infant. The U.S. Dietary Guidelines for Americans and American Academy of Pediatrics recommend that infants be exclusively breastfed for about the first 6 months with continued breastfeeding while introducing appropriate complementary foods for 1 year or longer (89) or up to age 2 years or longer (90). Evidence (breastfeeding): Clinical studies demonstrate conflicting results regarding effects on breastfeeding continuation or exclusivity in women exposed to COCs during lactation. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs 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 (91). Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97). Comment: Risk factors for breastfeeding difficulties include previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and preterm birth. For all breastfeeding persons, with or without breastfeeding difficulties, discussions about contraception should include information about risks, benefits, and alternatives.
d. >42 days postpartum	2		Clarification (breastfeeding): Breastfeeding provides important health benefits for breastfeeding parent and infant. The U.S. Dietary Guidelines for Americans and American Academy of Pediatrics recommend that infants be exclusively breastfed for about the first 6 months with continued breastfeeding while introducing appropriate complementary foods for 1 year or longer (89) or up to age 2 years or longer (90). Evidence: Clinical studies demonstrate conflicting results regarding effects on breastfeeding continuation or exclusivity in women exposed to COCs during lactation. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs 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 (91). Comment: Risk factors for breastfeeding difficulties include previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and preterm birth. For all breastfeeding persons, with or without breastfeeding difficulties, discussions about contraception should include information about risks, benefits, and alternatives.
Postpartum (nonbreastfeeding)
a. <21 days postpartum	4		Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97). Risk for pregnancy during the first 21 days postpartum is very low but increases after that point; ovulation before first menses is common (98).
b. 21–42 days postpartum
i. With other risk factors for VTE (e.g., age ≥35 years, previous VTE, thrombophilia, immobility, transfusion at delivery, peripartum cardiomyopathy, BMI ≥30 kg/m2 postpartum hemorrhage, postcesarean delivery, preeclampsia, or smoking)	3		Clarification: For persons with other risk factors for VTE, these risk factors might increase the classification to a category 4. Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97).
ii. Without other risk factors for VTE	2		Evidence: One study examined use of CHCs during the postpartum period and found that VTE rates were higher for CHC users compared with nonusers at all time points postpartum (92). Rates were significantly different only after 13 weeks postpartum; however, the numbers needed to harm were lowest in the first 6 weeks postpartum. VTE risk is increased during pregnancy and the postpartum period; this risk is most pronounced in the first 3 weeks after delivery, decreasing to near baseline levels by 42 days postpartum (93–97).
c. >42 days postpartum	1		—
Postabortion (spontaneous or induced)
a. First trimester abortion			Clarification: CHCs may be started immediately after abortion completion or at time of medication abortion initiation. Evidence: Evidence suggests that there is no increased risk for adverse events when CHCs are initiated after first trimester procedural or medication abortion (immediately or delayed) (99). Immediate initiation of COCs after first trimester procedural or medication abortion did not cause clinically significant changes in coagulation parameters compared with placebo, a hormonal IUD, a nonhormonal contraceptive method, or delayed COC initiation (100).
i. Procedural (surgical)	1
ii. Medication	1
iii. Spontaneous abortion with no intervention	1
b. Second trimester abortion			Clarification: CHCs may be started immediately after abortion completion or at time of medication abortion initiation. Evidence: Limited evidence suggests that there is no increased risk for adverse events when CHCs are initiated after second trimester procedural abortion (immediately or delayed) (99).
i. Procedural (surgical)	1
ii. Medication	1
iii. Spontaneous abortion with no intervention	1
c. Immediate postseptic abortion	1		Clarification: CHCs may be started immediately after abortion completion or at time of medication abortion initiation.
Past ectopic pregnancy	1		Comment: The risk for future ectopic pregnancy is increased among those who have had an ectopic pregnancy in the past. CHCs protect against pregnancy in general, including ectopic gestation.
History of pelvic surgery	1		—
Smoking			Evidence: COC users who smoked were at increased risk for cardiovascular diseases, especially myocardial infarction, compared with those who did not smoke. Studies also demonstrated an increased risk for myocardial infarction with increasing number of cigarettes smoked per day (101–113).
a. Age <35 years	2
b. Age ≥35 years
i. <15 cigarettes per day	3
ii. ≥15 cigarettes per day	4
Obesity			Clarification: Risk for thrombosis increases with multiple risk factors, such as obesity, older age (e.g., ≥40 years), diabetes, smoking, family history of thrombosis, and dyslipidemia. When a person has multiple risk factors, any of which alone would increase risk for thrombosis, use of CHCs might increase thrombosis risk to an unacceptable level. However, a simple addition of categories for multiple risk factors is not intended; for example, a combination of two category 2 risk factors might not necessarily warrant a higher category. Evidence: Although the absolute risk for VTE in healthy women of reproductive age is small, COC use and higher BMI independently increase risk for VTE, with the greatest relative risks among those with both risk factors. From a systematic review, COC users with obesity consistently had a relative risk for VTE of 5–8 times that of nonusers with obesity (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Research examining the interaction between COCs and BMI on VTE risk is limited, particularly for those in the highest BMI categories (BMI ≥35 kg/m2). Comparative studies on the risk for VTE among contraceptive patch or ring users by weight or BMI were not identified (114–116). Limited evidence suggests that COC users with obesity do not have a higher risk for acute myocardial infarction or stroke than do nonusers with obesity (114) (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Limited evidence suggests that effectiveness of certain COC formulations might decrease with increasing BMI; however the observed reductions in effectiveness are minimal and evidence is conflicting (117–124). Effectiveness of the patch might be reduced in women with BMI ≥30 kg/m2 or weight >90 kg (125).
a. BMI ≥30 kg/m2	2
b. Menarche to <18 years and BMI ≥30 kg/m2	2
History of bariatric surgery This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Restrictive procedures: decrease storage capacity of the stomach (vertical banded gastroplasty, laparoscopic adjustable gastric band, or laparoscopic sleeve gastrectomy)	1		Evidence: Limited evidence demonstrated no substantial decrease in effectiveness of oral contraceptives among women who underwent laparoscopic placement of an adjustable gastric band (126).
b. Malabsorptive procedures: decrease absorption of nutrients and calories by shortening the functional length of the small intestine (Roux-en-Y gastric bypass or biliopancreatic diversion)	COCs: 3 Patch and ring: 1		Evidence: Limited evidence demonstrated no substantial decrease in effectiveness of oral contraceptives among women who underwent a biliopancreatic diversion; however, evidence from pharmacokinetic studies reported conflicting results of oral contraceptive effectiveness among women who underwent a jejunoileal bypass (126). Comment: Bariatric surgical procedures involving a malabsorptive component have the potential to decrease oral contraceptive effectiveness, perhaps further decreased by postoperative complications, such as long-term diarrhea or vomiting.
Surgery
a. Minor surgery without immobilization	1		—
b. Major surgery
ii. Without prolonged immobilization	2		—
i. With prolonged immobilization	4		—
Cardiovascular Disease
Multiple risk factors for atherosclerotic cardiovascular disease (e.g., older age, smoking, diabetes, hypertension, low HDL, high LDL, or high triglyceride levels)	3/4		Clarification: When a person has multiple major risk factors, any of which alone would substantially increase risk for cardiovascular disease, use of CHCs might increase risk to an unacceptable level. However, a simple addition of categories for multiple risk factors is not intended; for example, a combination of two category 2 risk factors might not necessarily warrant a higher category. Clarification: The recommendations apply to known pre-existing medical conditions or characteristics. Few if any screening tests are needed before initiation of contraception. See U.S. SPR (https://www.cdc.gov/contraception/hcp/usspr/HYPERLINK) (127).
Hypertension Systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg are associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Adequately controlled hypertension	3		Clarification: For all categories of hypertension, classifications are based on the assumption that no other risk factors exist for cardiovascular disease. When multiple risk factors do exist, risk for cardiovascular disease might increase substantially. A single reading of blood pressure level is not sufficient to classify a person as hypertensive. Clarification: Persons adequately treated for hypertension are at reduced risk for acute myocardial infarction and stroke compared with untreated persons. Although no data exist, CHC users with adequately controlled and monitored hypertension should be at reduced risk for acute myocardial infarction and stroke compared with untreated hypertensive CHC users. Evidence: Among women with hypertension, COC users were at higher risk than nonusers for stroke, acute myocardial infarction, and peripheral arterial disease (101,103,110–113,128–142). Discontinuation of COCs in women with hypertension might improve blood pressure control (143).
b. Elevated blood pressure levels (properly taken measurements)			Clarification: For all categories of hypertension, classifications are based on the assumption that no other risk factors exist for cardiovascular disease. When multiple risk factors do exist, risk for cardiovascular disease might increase substantially. A single reading of blood pressure level is not sufficient to classify a person as hypertensive. Evidence: Among women with hypertension, COC users were at higher risk than nonusers for stroke, acute myocardial infarction, and peripheral arterial disease (101,103,110–113,128–142). Discontinuation of COCs in women with hypertension might improve blood pressure control (143).
i. Systolic 140–159 mm Hg or diastolic 90–99 mm Hg	3
ii. Systolic ≥160 mm Hg or diastolic ≥100 mm Hg	4
c. Vascular disease	4
History of high blood pressure during pregnancy (when current blood pressure is measurable and normal)	2		Evidence: Women with a history of high blood pressure in pregnancy who also used COCs had a higher risk for myocardial infarction and VTE than did COC users who did not have a history of high blood pressure during pregnancy. The absolute risks for acute myocardial infarction and VTE in this population remained small (112,129,141,142,144–150).
Deep venous thrombosis/ Pulmonary embolism This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Current or history of DVT/PE, receiving anticoagulant therapy (therapeutic dose) (e.g., acute DVT/PE or long-term therapeutic dose)	3		Clarification: Persons using anticoagulant therapy are at risk for gynecologic complications of therapy, such as heavy or prolonged bleeding and hemorrhagic ovarian cysts. CHCs can be of benefit in preventing or treating these complications. When a contraceptive method is used as a therapy, rather than solely to prevent pregnancy, the risk/benefit ratio might differ and should be considered on a case-by-case basis. Clarification: When a patient discontinues therapeutic dose of anticoagulant therapy, careful consideration should be given to transitioning from CHCs to a progestin-only or nonhormonal method, if acceptable to the patient. Evidence: Limited evidence was identified on use of CHCs among women with DVT/PE receiving anticoagulant therapy (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). In one study among women with a history of acute VTE currently receiving therapeutic anticoagulant therapy (i.e., rivaroxaban or enoxaparin/vitamin K antagonist [warfarin or acenocoumarol]), the incidence of recurrent VTE was similar among estrogen users (CHC or estrogen-only pills), POC users, and women not on hormonal therapy (151).
b. History of DVT/PE, receiving anticoagulant therapy (prophylactic dose)			Clarification: Persons using anticoagulant therapy are at risk for gynecologic complications of therapy, such as heavy or prolonged bleeding and hemorrhagic ovarian cysts. CHCs can be of benefit in preventing or treating these complications. When a contraceptive method is used as a therapy, rather than solely to prevent pregnancy, the risk/benefit ratio might differ and should be considered on a case-by-case basis.
i. Higher risk for recurrent DVT/PE (one or more risk factors)	4
• Thrombophilia (e.g., factor V Leiden mutation; prothrombin gene mutation; protein S, protein C, and antithrombin deficiencies; or antiphospholipid syndrome)     • Active cancer (metastatic, receiving therapy, or within 6 months after clinical remission), excluding nonmelanoma skin cancer     • History of recurrent DVT/PE
ii. Lower risk for recurrent DVT/PE (no risk factors)	3
c. History of DVT/PE, not receiving anticoagulant therapy
i. Higher risk for recurrent DVT/PE (one or more risk factors)	4		—
• History of estrogen-associated DVT/PE      • Pregnancy-associated DVT/PE      • Idiopathic DVT/PE      • Thrombophilia (e.g., factor V Leiden mutation; prothrombin gene mutation; protein S, protein C, and antithrombin deficiencies; or antiphospholipid syndrome)      • Active cancer (metastatic,      receiving therapy, or within 6 months after clinical remission), excluding nonmelanoma skin      cancer      • History of recurrent DVT/PE
ii. Lower risk for recurrent DVT/PE (no risk factors)	3		—
d. Family history (first-degree relatives)	2		Comment: Certain conditions that increase the risk for DVT/PE are heritable.
Thrombophilia (e.g., factor V Leiden mutation; prothrombin gene mutation; protein S, protein C, and antithrombin deficiencies; or antiphospholipid syndrome) This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	4		Clarification: Routine screening in the general population before contraceptive initiation is not recommended. Clarification: If a person has current or history of DVT/PE, see recommendations for DVT/PE. Clarification: Classification of antiphospholipid syndrome includes presence of a clinical feature (e.g., thrombosis or obstetric morbidity) and persistently abnormal antiphospholipid antibody test on two or more occasions at least 12 weeks apart (152). Evidence: Among women with factor V Leiden mutation, prothrombin gene mutation, antithrombin deficiency, and protein C deficiency, COC users had an increased risk for venous and arterial thrombosis compared with nonusers. Evidence was inconsistent on risk for thrombosis among women with protein S deficiency using COCs. No evidence was identified on COC use among persons with antiphospholipid syndrome (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
Superficial venous disorders
a. Varicose veins	1		Evidence: One study suggested that among women with varicose veins, the rate of VTE and superficial venous thrombosis was higher in oral contraceptive users compared with nonusers; however, statistical significance was not reported and the number of events was small (153).
b. Superficial venous thrombosis (acute or history)	3		Clarification: Superficial venous thrombosis might be associated with an increased risk for VTE. If a person has risk factors for concurrent DVT (e.g., thrombophilia or cancer) or has current or history of DVT, see recommendations for DVT/PE. Superficial venous thrombosis associated with a peripheral intravenous catheter is less likely to be associated with additional thrombosis and use of CHCs may be considered. Evidence: One study demonstrated that among women with superficial venous thrombosis, the risk for VTE was higher in oral contraceptive users compared with nonusers (153).
Current and history of ischemic heart disease This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	4		—
Stroke (history of cerebrovascular accident) This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	4		—
Valvular heart disease Complicated valvular heart disease is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Uncomplicated	2		—
b. Complicated (pulmonary hypertension, risk for atrial fibrillation, or history of subacute bacterial endocarditis)	4		Comment: Among persons with valvular heart disease, CHC use might further increase the risk for arterial thrombosis; persons with complicated valvular heart disease are at greatest risk.
Peripartum cardiomyopathy This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).			Evidence: No direct evidence exists about the safety of CHCs among women with peripartum cardiomyopathy. Limited indirect evidence from noncomparative studies of women with cardiac disease demonstrated few cases of hypertension and transient ischemic attack in women with cardiac disease using COCs. No cases of heart failure were reported (154). Comment: COCs might increase fluid retention in healthy persons; fluid retention might worsen heart failure in persons with peripartum cardiomyopathy. COCs might induce cardiac arrhythmias in healthy persons; persons with peripartum cardiomyopathy have a high incidence of cardiac arrhythmias.
a. Normal or mildly impaired cardiac function (New York Heart Association Functional Class I or II: no limitation of activities or slight, mild limitation of activity) (155)
i. <6 months	4
ii. ≥6 months	3
b. Moderately or severely impaired cardiac function (New York Heart Association Functional Class III or IV: marked limitation of activity or should be at complete rest) (155)	4
Renal Disease
Chronic kidney disease This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Current nephrotic syndrome	4		Evidence: No direct evidence was identified on CHC use among persons with CKD with current nephrotic syndrome (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Persons with severe CKD or nephrotic syndrome are at higher risk for thrombosis than the general population (156–158). Use of CHCs might further elevate risk for thrombosis among those with CKD with current nephrotic syndrome. Comment: A person might have CKD without current nephrotic syndrome but might have other conditions often associated with CKD (e.g., diabetes, hypertension, and SLE). See recommendations for other conditions if they apply.
b. Hemodialysis	4		Evidence: No direct evidence was identified on CHC use among persons with CKD on hemodialysis (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Persons with CKD on dialysis are at higher risk for thrombosis than the general population (156–158). Use of CHCs might further elevate risk for thrombosis among those with CKD on dialysis. Comment: A person might have CKD without hemodialysis, but might have other conditions often associated with CKD (e.g., diabetes, hypertension, and SLE). See recommendations for other conditions if they apply.
c. Peritoneal dialysis	4		Evidence: No direct evidence was identified on CHC use among persons with CKD on peritoneal dialysis (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Persons with CKD on dialysis are at higher risk for thrombosis than the general population (156–158). Use of CHCs might further elevate risk for thrombosis among those with CKD. Comment: A person might have CKD without peritoneal dialysis, but might have other conditions often associated with CKD (e.g., diabetes, hypertension, and SLE). See recommendations for other conditions if they apply.
Rheumatic Diseases
Systemic lupus erythematosus This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Positive (or unknown) antiphospholipid antibodies	4		Clarification: Persons with SLE are at increased risk for ischemic heart disease, stroke, and VTE. Categories assigned to such conditions in U.S. MEC should be the same for persons with SLE who have these conditions. For all subconditions of SLE, classifications are based on the assumption that no other risk factors for cardiovascular disease are present; these classifications must be modified in the presence of such risk factors (159–177). Evidence: Antiphospholipid antibodies are associated with a higher risk for both arterial and venous thrombosis (178,179).
b. Severe thrombocytopenia	2		Clarification: Persons with SLE are at increased risk for ischemic heart disease, stroke, and VTE. Categories assigned to such conditions in U.S. MEC should be the same for persons with SLE who have these conditions. For all subconditions of SLE, classifications are based on the assumption that no other risk factors for cardiovascular disease are present; these classifications must be modified in the presence of such risk factors (159–177).
c. Immunosuppressive therapy	2		Clarification: Persons with SLE are at increased risk for ischemic heart disease, stroke, and VTE. Categories assigned to such conditions in U.S. MEC should be the same for persons with SLE who have these conditions. For all subconditions of SLE, classifications are based on the assumption that no other risk factors for cardiovascular disease are present; these classifications must be modified in the presence of such risk factors (159–177).
d. None of the above	2		Clarification: Persons with SLE are at increased risk for ischemic heart disease, stroke, and VTE. Categories assigned to such conditions in U.S. MEC should be the same for persons with SLE who have these conditions. For all subconditions of SLE, classifications are based on the assumption that no other risk factors for cardiovascular disease are present; these classifications must be modified in the presence of such risk factors (159–177).
Rheumatoid arthritis			Evidence: Limited evidence demonstrates no consistent pattern of improvement or worsening of rheumatoid arthritis with use of oral contraceptives, progesterone, or estrogen (180).
a. Not receiving immunosuppressive therapy	2
b. Receiving immunosuppressive therapy	2
Neurologic Conditions
Headaches
a. Nonmigraine (mild or severe)	1		Clarification: Classification depends on accurate diagnosis of those severe headaches that are migraines and those headaches that are not, as well as diagnosis of ever experiencing aura. Aura is a specific focal neurologic symptom. For more information about headache classification see the International Headache Society’s International Classification of Headache Disorders, 3rd ed. (https://ichd-3.org) (181). Any new headaches or marked changes in headaches should be evaluated.
b. Migraine			Clarification: Classification depends on accurate diagnosis of those severe headaches that are migraines and those headaches that are not, as well as diagnosis of ever experiencing aura. Aura is a specific focal neurologic symptom. For more information about headache classification see the International Headache Society’s International Classification of Headache Disorders, 3rd ed. (https://ichd-3.org) (181). Any new headaches or marked changes in headaches should be evaluated. Clarification: Classification is for persons without any other risk factors for stroke (e.g., age, hypertension, and smoking). Evidence: Among women with migraine, oral contraceptive use is associated with about a threefold increased risk for ischemic stroke compared with nonuse, although most studies did not specify migraine type or oral contraceptive formulation. The only study to examine migraine type found that the risk for ischemic stroke among women with migraine with aura was increased to a similar level among both oral contraceptive users and nonusers, compared with women without migraine (182). The risk for ischemic stroke is increased among women using COCs, compared with women not using COCs (101,183). The risk for ischemic stroke is also increased among women with migraine with aura, compared with women without migraine (184–186). One older meta-analysis found that migraine without aura was associated with an increased risk for ischemic stroke, while two more recent meta-analyses did not find such an association (184–186). Comment: Menstrual migraine is a subtype of migraine without aura. For more information, see the International Headache Society’s International Classification of Headache Disorders, 3rd ed. (https://ichd-3.org) (181).
i. Without aura (includes menstrual migraine)	2
ii. With aura	4
Epilepsy This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	1		Clarification: If a person is taking anticonvulsants, see recommendations for Drug Interactions. Certain anticonvulsants lower COC effectiveness. The extent to which patch or ring use is similar to COC use in this regard remains unclear.
Multiple sclerosis			Evidence: Limited evidence suggests that use of COCs or oral contraceptives (type not specified) among women with multiple sclerosis does not worsen the clinical course of disease (187). Comment: No data exist that evaluate the increased risk for VTE among persons with multiple sclerosis using CHCs. However, persons with multiple sclerosis are at higher risk for VTE than those without multiple sclerosis.
a. Without prolonged immobility	1
b. With prolonged immobility	3
Depressive Disorders
Depressive disorders	1		Clarification: If a person is receiving psychotropic medications or St. John’s wort, see recommendations for Drug Interactions. Evidence: COC use was not associated with increased depressive symptoms in women with depression or scoring above threshold levels on a validated depression screening instrument compared with baseline or with nonusers with depression. One small study of women with bipolar disorder found that oral contraceptives did not significantly change mood across the menstrual cycle (188).
Reproductive Tract Infections and Disorders
Vaginal bleeding patterns
a. Irregular pattern without heavy bleeding	1		Comment: Irregular menstrual bleeding patterns are common among healthy persons.
b. Heavy or prolonged bleeding (includes regular and irregular patterns)	1		Clarification: Unusually heavy bleeding should raise the suspicion of a serious underlying condition. Evidence: A Cochrane Collaboration Review identified one RCT evaluating the effectiveness of COC use compared with naproxen and danazol in treating menorrhagia. Women with menorrhagia did not report worsening of the condition or any adverse events related to COC use (189).
Unexplained vaginal bleeding (suspicious for serious condition) before evaluation	2		Clarification: If pregnancy or an underlying pathological condition (e.g., pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation. Comment: No conditions that cause vaginal bleeding will be worsened in the short-term by use of CHCs.
Endometriosis	1		Evidence: A Cochrane Collaboration Review identified one RCT evaluating the effectiveness of COC use compared with a gonadotropin-releasing hormone analog in treating the symptoms of endometriosis. Women with endometriosis did not report worsening of the condition or any adverse events related to COC use (190).
Benign ovarian tumors (including cysts)	1		—
Severe dysmenorrhea	1		Evidence: Risk for side effects with COC use was not higher among women with dysmenorrhea than among women not using COCs. Certain COC users had a reduction in pain and bleeding (191,192).
Gestational trophoblastic disease This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).			Clarification: For all subconditions of gestational trophoblastic disease, classifications are based on the assumption that persons are under close medical supervision because of the need for monitoring of β-hCG levels for appropriate disease surveillance. Evidence: After molar pregnancy evacuation, the balance of evidence found COC use did not increase the risk for postmolar trophoblastic disease, and β–hCG levels regressed more rapidly in certain COC users than in nonusers (193). Limited evidence suggests that use of COCs during chemotherapy does not significantly affect the regression or treatment of postmolar trophoblastic disease compared with women who used a nonhormonal contraceptive method or DMPA during chemotherapy (193).
a. Suspected gestational trophoblastic disease (immediate postevacuation)
i. Uterine size first trimester	1
ii. Uterine size second trimester	1
b. Confirmed gestational trophoblastic disease (after initial evacuation and during monitoring)
i. Undetectable or nonpregnant β-hCG levels	1
ii. Decreasing β-hCG levels	1
iii. Persistently elevated β-hCG levels or malignant disease, with no evidence or suspicion of intrauterine disease	1
iv. Persistently elevated β-hCG levels or malignant disease, with evidence or suspicion of intrauterine disease	1
Cervical ectropion	1		Comment: Cervical ectropion is not a risk factor for cervical cancer, and restriction of CHC use is unnecessary.
Cervical intraepithelial neoplasia	2		Evidence: Among women with persistent human papillomavirus infection, long-term COC use (≥5 years) might increase the risk for carcinoma in situ and invasive carcinoma (194). Limited evidence on women with low-grade squamous intraepithelial lesions found use of the vaginal ring did not worsen the condition (9).
Cervical cancer (awaiting treatment)	2		Comment: Theoretical concern exists that CHC use might affect prognosis of the existing disease. While awaiting treatment, persons may use CHCs. In general, treatment of this condition can render a person infertile.
Breast disease Breast cancer is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Undiagnosed mass	2		Clarification: Evaluation of mass should be pursued as early as possible.
b. Benign breast disease	1		—
c. Family history of cancer	1		Evidence: Women with breast cancer susceptibility genes (e.g., BRCA1 and BRCA2) have a higher baseline risk for breast cancer than women without these genes. The baseline risk for breast cancer also is higher among women with a family history of breast cancer than among those who do not have such a history. However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs (195–212).
d. Breast cancer			Comment: Breast cancer is a hormonally sensitive tumor, and the prognosis for persons with current or recent breast cancer might worsen with CHC use.
i. Current	4
ii. Past and no evidence of current disease for 5 years	3
Endometrial hyperplasia	1		—
Endometrial cancer This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	1		Comment: COC use reduces the risk for endometrial cancer; whether patch or ring use reduces the risk for endometrial cancer is not known. While awaiting treatment, patients may use CHCs. In general, treatment of this condition can render a person infertile.
Ovarian cancer This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	1		Comment: COC use reduces the risk for ovarian cancer; whether patch or ring use reduces the risk for ovarian cancer is not known. While awaiting treatment, patients may use CHCs. In general, treatment of this condition can render a person infertile.
Uterine fibroids	1		Comment: COCs do not appear to cause growth of uterine fibroids, and patch and ring also are not expected to cause growth.
Pelvic inflammatory disease			Comment: COCs might reduce the risk for PID among persons with STIs but do not protect against HIV infection or lower genital tract STIs. Whether use of patch or ring reduces the risk for PID among persons with STIs is unknown; however, they do not protect against HIV infection or lower genital tract STIs.
a. Current PID	1
b. Past PID
i. With subsequent pregnancy	1
ii. Without subsequent pregnancy	1
Sexually transmitted infections
a. Current purulent cervicitis or chlamydial infection or gonococcal infection	1		—
b. Vaginitis (including Trichomonas vaginalis and bacterial vaginosis)	1		—
c. Other factors related to STIs	1		—
HIV
High risk for HIV infection	1		Evidence: Low-to-moderate-quality evidence from 11 observational studies suggested no association between COC use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition. No studies of patch or ring were identified (213,214).
HIV infection For persons with HIV infection who are not clinically well or not receiving ARV therapy, this condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	1		Clarification: Drug interactions might exist between hormonal contraceptives and ARV drugs; see recommendations for Drug Interactions. Evidence: Overall, evidence does not support an association between COC use and progression of HIV. Limited direct evidence does not support an association between COC use and transmission of HIV to noninfected partners; studies measuring genital viral shedding as a proxy for infectivity have had mixed results. Studies measuring whether hormonal contraceptive methods affect plasma HIV viral load generally have found no effect (215–217).
Other Infections
Schistosomiasis Schistosomiasis with fibrosis of the liver is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Uncomplicated	1		Evidence: Among women with uncomplicated schistosomiasis, COC use had no adverse effects on liver function (218–224).
b. Fibrosis of the liver (if severe, see recommendations for Cirrhosis)	1		—
Tuberculosis This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).			Clarification: If a person is taking rifampin, see recommendations for Drug Interactions. Rifampin is likely to decrease COC effectiveness. The extent to which patch or ring use is similar to COC use in this regard remains unclear.
a. Nonpelvic	1
b. Pelvic	1
Malaria	1		—
Endocrine Conditions
Diabetes Insulin-dependent diabetes; diabetes with nephropathy, retinopathy, or neuropathy; diabetes with other vascular disease; or diabetes of >20 years’ duration are associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. History of gestational disease	1		Evidence: The development of non–insulin-dependent diabetes in women with a history of gestational diabetes is not increased by use of COCs (225–232). Likewise, lipid levels appear to be unaffected by COC use (233–235).
b. Nonvascular disease			Evidence: Among women with insulin-dependent or non–insulin-dependent diabetes, COC use had limited effect on daily insulin requirements and no effect on long-term diabetes control (e.g., glycosylated hemoglobin levels) or progression to retinopathy. Changes in lipid profile and hemostatic markers were limited, and most changes remained within normal values (236–245).
i. Non-insulin dependent	2		—
ii. Insulin dependent	2		—
c. Nephropathy, retinopathy, or neuropathy	3/4		Clarification: The category should be assessed according to the severity of the condition.
d. Other vascular disease or diabetes of >20 years’ duration	3/4		Clarification: The category should be assessed according to the severity of the condition.
Thyroid disorders
a. Simple goiter	1		—
b. Hyperthyroid	1		—
c. Hypothyroid	1		—
Gastrointestinal Conditions
Inflammatory bowel disease (ulcerative colitis or Crohn’s disease)	2/3		Clarification: For persons with mild IBD and with no other risk factor for VTE, the benefits of CHC use generally outweigh the risks (category 2). However, for persons with IBD who are at increased risk for VTE (e.g., those with active or extensive disease, surgery, immobilization, corticosteroid use, vitamin deficiencies, or fluid depletion), the risks of CHC use generally outweigh the benefits (category 3). Evidence: Risk for disease relapse was not significantly higher among women with IBD using oral contraceptives (most studies did not specify type) than among nonusers (246). Absorption of COCs among women with mild ulcerative colitis and no or small ileal resections was similar to the absorption among healthy women (246). Findings might not apply to women with Crohn’s disease or more extensive bowel resections. No data exist that evaluate the increased risk for VTE among women with IBD using CHCs. However, women with IBD are at higher risk than unaffected women for VTE (246).
Gallbladder disease			Comment: CHCs might cause a small increased risk for gallbladder disease. CHCs might worsen existing gallbladder disease.
a. Asymptomatic	2
b. Symptomatic
i. Current	3
ii. Treated by cholecystectomy	2
iii. Medically treated	3
History of cholestasis
a. Pregnancy related	2		Comment: History of pregnancy-related cholestasis might predict an increased risk for COC-related cholestasis.
b. Past COC related	3		Comment: History of COC-related cholestasis predicts an increased risk with subsequent COC use.
Viral hepatitis	Initiation	Continuation	—
a. Acute or flare	3/4	2	Clarification (initiation): The category should be assessed according to the severity of the condition. Evidence: Limited evidence was identified on COC use among persons with acute viral hepatitis. Data suggest that in women with chronic viral hepatitis, COC use does not increase the risk or severity of fibrosis, nor does it increase the risk for hepatocellular carcinoma. For women with chronic viral hepatitis, COC use does not appear to trigger severe liver dysfunction (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Comment: Hepatic metabolism of exogenous hormones might be impaired in persons with liver dysfunction, which could lead to increased estrogen levels in circulation and estrogen-related side effects and adverse events (e.g., thrombosis).
b. Chronic	1	1	Evidence: Data suggest that in women with chronic viral hepatitis, COC use does not increase the risk or severity of fibrosis, nor does it increase the risk for hepatocellular carcinoma. For women with chronic viral hepatitis, COC use does not appear to trigger severe liver dysfunction (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
Cirrhosis Decompensated cirrhosis is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Compensated (normal liver function)	1		Evidence: No direct evidence was identified on CHC use among persons with compensated cirrhosis (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
b. Decompensated (impaired liver function)	4		Evidence: No direct evidence was identified on CHC use among persons with decompensated cirrhosis (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). Comment: Hepatic metabolism of exogenous hormones might be impaired in persons with liver dysfunction, which could lead to increased estrogen levels in circulation and estrogen-related side effects and adverse events (e.g., thrombosis). Any estrogen-related hepatotoxicity might be less tolerated in persons with existing liver dysfunction.
Liver tumors Hepatocellular adenoma and malignant liver tumors are associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. Benign
i. Focal nodular hyperplasia	2		Evidence: Limited evidence suggests that COC use does not influence either progression or regression of focal nodular hyperplasia (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
ii. Hepatocellular adenoma	4		Evidence: Evidence suggests that COC use is associated with progression of hepatocellular adenoma growth, while COC discontinuation is associated with stability or regression (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
b. Malignant (hepatocellular carcinoma)	4		Evidence: No direct evidence was identified on CHC use among persons with hepatocellular carcinoma (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
Respiratory Conditions
Cystic fibrosis This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	1		Clarification: Persons with cystic fibrosis are at increased risk for diabetes, liver disease, gallbladder disease, and VTE (particularly related to use of central venous catheters) and are frequently prescribed antibiotics. Categories assigned to such conditions in U.S. MEC should be the same for persons with cystic fibrosis who have these conditions. For cystic fibrosis, classifications are based on the assumption that no other conditions are present; these classifications must be modified in the presence of such conditions. Clarification: Certain drugs to treat cystic fibrosis (e.g., lumacaftor) might reduce effectiveness of hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives. Evidence: Limited evidence suggests that use of COCs or oral contraceptives (type not specified) among women with cystic fibrosis is not associated with worsening of disease severity. Very limited evidence suggests that cystic fibrosis does not impair the effectiveness of hormonal contraception (247).
Hematologic Conditions
Thalassemia	1		Comment: Anecdotal evidence from countries where thalassemia is prevalent indicates that COC use does not worsen the condition.
Sickle cell disease This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).	4		Evidence: Persons with sickle cell disease are at higher risk for stroke and venous thrombosis than the general population (248–251). CHC use might further elevate risk for thrombosis among persons with sickle cell disease, but evidence is limited (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
Iron deficiency anemia	1		Comment: CHC use might decrease menstrual blood loss.
Solid Organ Transplantation
Solid organ transplantation This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 3).
a. No graft failure	2		Clarification: Persons with transplant due to Budd-Chiari syndrome should not use CHCs because of the increased risk for thrombosis. Evidence: Limited evidence among CHC users indicated no adverse events and no overall changes in biochemical parameters (e.g., blood pressure, cholesterol) and no pregnancies (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). However, one study reported discontinuations of COC use in two (8%) of 26 women as a result of serious medical complications, including acute graft rejection (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
b. Graft failure	4		Evidence: Limited evidence among CHC users indicated no adverse events and no overall changes in biochemical parameters (e.g., blood pressure, cholesterol) and no pregnancies (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516). However, one study reported discontinuations of COC use in two (8%) of 26 women as a result of serious medical complications, including acute graft rejection (Supplementary Appendix, https://stacks.cdc.gov/view/cdc/156516).
Drug Interactions
Antiretrovirals used for prevention (PrEP) or treatment of HIV infection			Comment: These recommendations generally are for ARV agents used alone. However, most persons receiving ARV therapy are using multiple drugs in combination. In general, whether interactions between ARVs and hormonal contraceptives differ when ARVs are given alone or in combination is unknown.
See the following guidelines for the most up-to-date recommendations on drug-drug interactions between hormonal contraception and ARVs: 1) Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States (https://clinicalinfo.hiv.gov/en/guidelines/perinatal/prepregnancy-counseling-childbearing-age-overview?view=full#table-3) (252) and 2) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/drug-interactions-overview?view=full) (253).
a. Nucleoside reverse transcriptase inhibitors (NRTIs)
i. Abacavir (ABC)	1		Evidence: NRTIs do not appear to have significant risk for interactions with hormonal contraceptive methods (254–259).
ii. Tenofovir (TDF)	1
iii. Zidovudine (AZT)	1
iv. Lamivudine (3TC)	1
v. Didanosine (DDI)	1
vi. Emtricitabine (FTC)	1
vii. Stavudine (D4T)	1
b. Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
i. Efavirenz (EFV)	2		Clarification: Evidence suggests drug interactions between EFV and certain hormonal contraceptives. These interactions might reduce the effectiveness of the hormonal contraceptive. Evidence: Two studies suggested that pregnancy rates might be higher among women using COCs and EFV compared with COCs alone, although one study found no difference in pregnancy rates (260–262). Two studies found conflicting results on ovulations in women receiving COCs and EFV compared with EFV alone (263,264). Two pharmacokinetic studies demonstrated decreases in ethinyl estradiol and progestin concentrations in women receiving COCs and EFV compared with COCs alone (264,265). Pharmacokinetic studies demonstrated generally no changes in EFV concentrations with concomitant COC use (264–266).
ii. Etravirine (ETR)	1		Evidence: One study demonstrated no clinically relevant pharmacokinetic or pharmacodynamic changes in women using COCs and ETR compared with COCs alone (267).
iii. Nevirapine (NVP)	1		Evidence: Five studies found no significant differences in pregnancy rates among women using COCs and NVP compared with women using COCs alone (260–262,266,268). Three studies reported no ovulations among women receiving COCs and NVP (263,268,269). Two pharmacokinetic studies demonstrated decreased concentrations of ethinyl estradiol and progestin among women using COCs and NVP compared with COCs alone, and one study found no change in contraceptive hormone concentrations (263,269,270). Pharmacokinetic studies demonstrated generally no changes in NVP concentrations with concomitant COC use (263,270,271).
iv. Rilpivirine (RPV)	1		Evidence: One study demonstrated no clinical significant pharmacokinetic changes or adverse events in women using COCs and RPV compared with COCs alone (272).
c. Ritonavir-boosted protease inhibitors
i. Ritonavir-boosted atazanavir (ATV/r)	2		Clarification: Theoretically, drug interactions might occur between certain ritonavir-boosted protease inhibitors and certain hormonal contraceptives that might reduce the effectiveness of the hormonal contraceptive. Evidence: One pharmacokinetic study demonstrated decreased estrogen but increased progestin concentrations in women using COCs and ATV/r compared with COCs alone (273).
ii. Ritonavir-boosted darunavir (DRV/r)	2		Clarification: Theoretically, drug interactions might occur between certain ritonavir-boosted protease inhibitors and certain hormonal contraceptives that might reduce the effectiveness of the hormonal contraceptive. Evidence: One pharmacokinetic study demonstrated no change in follicle-stimulating hormone or luteinizing hormone but decreases in ethinyl estradiol and norethindrone in women using COCs with DRV/r compared with COCs alone (274).
iii. Ritonavir-boosted fosamprenavir (FPV/r)	2		Clarification: Theoretically, drug interactions might occur between certain ritonavir-boosted protease inhibitors and certain hormonal contraceptives that might reduce the effectiveness of the hormonal contraceptive. Evidence: Information from the package label states that both ethinyl estradiol and norethindrone concentrations decreased with concurrent administration of COCs and FPV/r (275).
iv. Ritonavir-boosted lopinavir (LPV/r)	1		Evidence: One study demonstrated a nonsignificant increase in pregnancy rates among women using COCs and LPV/r compared with COCs alone (260). One study demonstrated no ovulations in women using the combined hormonal patch and LPV/r compared with combined hormonal patch alone; ethinyl estradiol concentrations for COC and patch users decreased but norelgestromin concentrations increased with use of the patch (276).
v. Ritonavir-boosted saquinavir (SQV/r)	2		Clarification: Theoretically, drug interactions might occur between certain ritonavir-boosted protease inhibitors and certain hormonal contraceptives that might reduce the effectiveness of the hormonal contraceptive. Evidence: One pharmacokinetic study demonstrated no change in SQV concentrations in women using COC and SQV compared with COCs alone (277).
iv. Ritonavir-boosted tipranavir (TPV/r)	2		Clarification: Theoretically, drug interactions might occur between certain ritonavir-boosted protease inhibitors and certain hormonal contraceptives that might reduce the effectiveness of the hormonal contraceptive. Evidence: Information from the package label states that ethinyl estradiol concentrations decrease but norethindrone concentrations increased with concurrent administration of COCs and TPV/r (278).
d. Protease inhibitors without ritonavir
i. Atazanavir (ATV)	2		Clarification: Theoretical concern exists that increased levels of ethinyl estradiol because of interactions with ATV might increase the risk for adverse events. Evidence: Information from the package label states that there are inconsistent changes in ethinyl estradiol concentrations and increases in progestin concentrations with concurrent administration of two different COCs and ATV (279). Comment: When ATV is administered with cobicistat, theoretical concern exists for a drug interaction with hormonal contraceptives. Cobicistat is an inhibitor of CYP3A and CYP2D6 and could theoretically increase contraceptive hormone levels. However, its effects on CYP enzymes and drug levels might vary when combined with other ARVs.
ii. Fosamprenavir (FPV)	3		Clarification: Concern exists that interactions between FPV and hormonal contraceptives leading to decreased levels of FPV might diminish effectiveness of the ARV drug. Evidence: Information from the package label states that amprenavir concentrations decreased with concurrent administration of COCs and amprenavir. Norethindrone concentrations increased and ethinyl estradiol concentrations did not change (275).
iii. Indinavir (IDV)	1		Evidence: One small study found no pregnancies in women using COCs and IDV (262).
iv. Nelfinavir (NFV)	2		Clarification: Evidence suggests drug interactions between certain protease inhibitors and certain hormonal contraceptives. These interactions might reduce the effectiveness of the hormonal contraceptive. Evidence: One small study suggested that women using COCs and NFV might have had higher pregnancy rates than those using COCs alone (262).
e. CCR5 co-receptor antagonists
i. Maraviroc (MVC)	1		Evidence: COC concentrations were not altered by co-administration with MVC (280).
f. HIV integrase strand transfer inhibitors
i. Raltegravir (RAL)	1		Evidence: One pharmacokinetic study demonstrated increased concentrations of norgestimate and no change in ethinyl estradiol among women using COCs and RAL compared with COCs alone (281).
ii. Dolutegravir (DTG)	1		Evidence: One study demonstrated no clinically relevant pharmacokinetic or pharmacodynamic changes in women using COCs and DTG compared with COCs alone (282).
iii. Elvitegravir (EVG)	1		Evidence: Information from the package label states that ethinyl estradiol concentrations decreased and norgestimate concentrations increased with concurrent administration of COCs and EVG (283). Comment: When EVG is administered with cobicistat, theoretical concern exists for a drug interaction with hormonal contraceptives. Cobicistat is an inhibitor of CYP3A and CYP2D6 and could theoretically increase contraceptive hormone levels. However, its effects on CYP enzymes and drug levels might vary when combined with other ARVs.
g. Fusion inhibitors
i. Enfuvirtide	1		—
Anticonvulsant therapy
a. Certain anticonvulsants (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine)	3		Clarification: Although the interaction of certain anticonvulsants with CHCs is not harmful, it is likely to reduce the effectiveness of CHCs. Use of other contraceptives should be encouraged for persons who are long-term users of any of these drugs. When a COC is chosen, a preparation containing a minimum of 30 μg ethinyl estradiol should be used. Evidence: Use of certain anticonvulsants might decrease the effectiveness of COCs (284–288).
b. Lamotrigine	3		Clarification: The recommendation for lamotrigine applies only for situations where lamotrigine monotherapy is taken concurrently with COCs. Anticonvulsant treatment regimens that combine lamotrigine and non–enzyme-inducing antiepileptic drugs (e.g., sodium valproate) do not interact with COCs. Evidence: Pharmacokinetic studies demonstrate levels of lamotrigine decrease significantly during COC use (288–293). Certain women who used both COCs and lamotrigine experienced increased seizure activity in one trial (289).
Antimicrobial therapy
a. Broad-spectrum antibiotics	1		Evidence: Most broad-spectrum antibiotics do not affect the contraceptive effectiveness of COCs (294–330), patch (331), or ring (332).
b. Antifungals	1		Evidence: Studies of antifungal agents have demonstrated no clinically significant pharmacokinetic interactions with COCs (333–342) or ring (343).
c. Antiparasitics	1		Evidence: Studies of antiparasitic agents have demonstrated no clinically significant pharmacokinetic interactions with COCs (218,344–348).
d. Rifampin or rifabutin therapy	3		Clarification: Although the interaction of rifampin or rifabutin therapy with CHCs is not harmful, it is likely to reduce the effectiveness of CHCs. Use of other contraceptives should be encouraged for persons who are long-term users of either of these drugs. When a COC is chosen, a preparation containing a minimum of 30 μg ethinyl estradiol should be used. Evidence: The balance of the evidence suggests that rifampin reduces the effectiveness of COCs (349–363). Data on rifabutin are limited, but effects on metabolism of COCs are less than with rifampin, and small studies have not demonstrated evidence of ovulation (351,357).
Psychotropic medications			Comment: For many common psychotropic agents, limited or no theoretical concern exists for clinically significant drug interactions when co-administered with hormonal contraceptives. However, either no or very limited data exist examining potential interactions for these classes of medications. For psychotropic agents that are CYP1A2 substrates (e.g., duloxetine, mirtazapine, ziprasidone, olanzapine, clomipramine, imipramine, and amitriptyline), co-administration with CHCs could theoretically yield increased concentrations of the psychotropic drug. For agents with narrow therapeutic windows (e.g., tricyclic antidepressants), increased drug concentrations might pose safety concerns that could necessitate closer monitoring.
a. Selective serotonin reuptake inhibitors (SSRIs)	1		Evidence: Limited clinical and pharmacokinetic data do not demonstrate concern for SSRIs decreasing the effectiveness of oral contraceptives. Limited evidence suggests that for women taking SSRIs, the use of hormonal contraceptives was not associated with differences in effectiveness of the SSRI for treatment or in adverse events when compared with women not taking hormonal contraceptives (364). Comment: Drugs that are inhibitors of CYP3A4 or CYP2C9 theoretically have the potential to increase levels of contraceptive steroids which might increase adverse events. Fluvoxamine is an SSRI known to be a moderate inhibitor of both CYP3A4 and CYP2C9; however, no clinical or pharmacokinetic studies were identified to explore potential drug-drug interactions.
St. John’s wort	2		Evidence: Although clinical data are limited, studies with pharmacokinetic and pharmacodynamics outcomes raise concern that St. John’s wort might decrease effectiveness of hormonal contraceptives, including increased risk for breakthrough bleeding and ovulation and increased metabolism of estrogen and progestins. Any interactions might be dependent on the dose of St. John’s wort, and the concentration of active ingredients across types of St. John’s wort preparations might vary (365).

Abbreviations: ARV = antiretroviral; BMD = bone mineral density; BMI = body mass index; CHC = combined hormonal contraceptive; CKD = chronic kidney disease; COC = combined oral contraceptive; CYP = cytochrome P450; DMPA = depot medroxyprogesterone acetate; DVT = deep venous thrombosis; hCG = human chorionic gonadotropin; HDL = high-density lipoprotein; IBD = inflammatory bowel disease; IUD = intrauterine device; LDL = low-density lipoprotein; NA = not applicable; PE = pulmonary embolism; PID = pelvic inflammatory disease; POC = progestin-only contraceptive; PrEP = pre-exposure prophylaxis; RCT = randomized clinical trial; SLE = systemic lupus erythematosus; SSRI = selective serotonin reuptake inhibitor; STI = sexually transmitted infection; U.S. MEC = U.S. Medical Eligibility Criteria for Contraceptive Use; U.S. SPR = U.S. Selected Practice Recommendations for Contraceptive Use; VTE = venous thromboembolism.