Table C1. Classifications for Progestin-Only Contraceptives

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TABLE C1. Classifications for progestin-only contraceptives, including implants, depot medroxyprogesterone acetate, and progestin-only pills
Condition Category Clarifications/Evidence/Comments
Implants DMPA POPs
Personal Characteristics and Reproductive History
Pregnancy NA NA NA Clarification: Use of POCs is not required. No known harm to the woman, the course of her pregnancy, or the fetus occurs if POCs are inadvertently used during pregnancy. However, the relation between DMPA use during pregnancy and its effects on the fetus remains unclear.
Age Evidence: Most studies have found that women lose BMD during DMPA use but recover BMD after discontinuation. Limited evidence shows a weak association with fracture. However, one large study suggests that women who choose DMPA might be at higher risk for fracture before initiation (1). It is unclear whether adult women with long durations of DMPA use can regain BMD to baseline levels before entering menopause and whether adolescents can reach peak bone mass after discontinuation of DMPA. The relationship between these changes in BMD during the reproductive years and future fracture risk is unknown. Studies generally find no effect of POCs other than DMPA on BMD (148).
a. Menarche to <18 years 1 2 1
b. 18–45 years 1 1 1
c. >45 years 1 2 1
Parity
a. Nulliparous 1 1 1
b. Parous 1 1 1
Breastfeeding
a. <21 days postpartum 2 2 2 Clarification: Breastfeeding provides important health benefits for mother and infant. The U.S. Department of Health and Human Services recommends increasing the proportion of infants initially breastfed, exclusively breastfed through 6 months of life, and continuing breastfeeding through at least 1 year of life as key public health goals (49).
Evidence: Two small, randomized controlled trials found no adverse impact on breastfeeding with initiation of etonogestrel implants within 48 hours postpartum. Other studies found that initiation of POPs, injectables, and implants at ≤6 weeks postpartum compared with nonhormonal use had no detrimental effect on breastfeeding outcomes or infant health, growth, and development in the first year postpartum. In general, these studies are of poor quality, lack standard definitions of breastfeeding or outcome measures, and have not included premature or ill infants (50,51).
Comment: Certain women might be at risk for breastfeeding difficulties, such as women with previous breastfeeding difficulties, certain medical conditions, and certain perinatal complications and those who deliver preterm. For these women, as for all women, discussions about contraception for breastfeeding women should include information about risks, benefits, and alternatives.
b. 21 to <30 days postpartum Clarification: Breastfeeding provides important health benefits for mother and infant. The U.S. Department of Health and Human Services recommends increasing the proportion of infants initially breastfed, exclusively breastfed through 6 months of life, and continuing breastfeeding through at least 1 year of life as key public health goals (49).Evidence: Two small, randomized controlled trials found no adverse impact on breastfeeding with initiation of etonogestrel implants within 48 hours postpartum. Other studies found that initiation of POPs, injectables, and implants at ≤6 weeks postpartum compared with nonhormonal use had no detrimental effect on breastfeeding outcomes or infant health, growth, and development in the first year postpartum. In general, these studies are of poor quality, lack standard definitions of breastfeeding or outcome measures, and have not included premature or ill infants (50,51).Comment: Certain women might be at risk for breastfeeding difficulties, such as women with previous breastfeeding difficulties, certain medical conditions, and certain perinatal complications and those who deliver preterm. For these women, as for all women, discussions about contraception for breastfeeding women should include information about risks, benefits, and alternatives.
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) 2 2 2
ii. Without other risk factors for VTE 2 2 2
c. 30–42 days postpartum Clarification: Breastfeeding provides important health benefits for mother and infant. The U.S. Department of Health and Human Services recommends increasing the proportion of infants initially breastfed, exclusively breastfed through 6 months of life, and continuing breastfeeding through at least 1 year of life as key public health goals (49).Evidence: Two small, randomized controlled trials found no adverse impact on breastfeeding with initiation of etonogestrel implants within 48 hours postpartum. Other studies found that initiation of POPs, injectables, and implants at ≤6 weeks postpartum compared with nonhormonal use had no detrimental effect on breastfeeding outcomes or infant health, growth, and development in the first year postpartum. In general, these studies are of poor quality, lack standard definitions of breastfeeding or outcome measures, and have not included premature or ill infants (50,51).Comment: Certain women might be at risk for breastfeeding difficulties, such as women with previous breastfeeding difficulties, certain medical conditions, and certain perinatal complications and those who deliver preterm. For these women, as for all women, discussions about contraception for breastfeeding women should include information about risks, benefits, and alternatives.
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) 1 1 1
ii. Without other risk factors for VTE 1 1 1
d. >42 days postpartum 1 1 1 Clarification: Breastfeeding provides important health benefits for mother and infant. The U.S. Department of Health and Human Services recommends increasing the proportion of infants initially breastfed, exclusively breastfed through 6 months of life, and continuing breastfeeding through at least 1 year of life as key public health goals (49).
Evidence: Overall, studies found that initiation of POPs, injectables, and implants at >6 weeks postpartum compared with nonhormonal use had no detrimental effect on breastfeeding outcomes or infant health, growth, and development in the first year postpartum. In general, these studies are of poor quality, lack standard definitions of breastfeeding or outcome measures, and have not included premature or ill infants (51).
Comment: Certain women might be at risk for breastfeeding difficulties, such as women with previous breastfeeding difficulties, certain medical conditions, and certain perinatal complications and those who deliver preterm. For these women, as for all women, discussions about contraception for breastfeeding women should include information about risks, benefits, and alternatives.
Postpartum (nonbreastfeeding women)
a. <21 days postpartum 1 1 1
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) 1 1 1
ii. Without other risk factors for VTE 1 1 1
c. >42 days postpartum 1 1 1
Postabortion
a. First trimester 1 1 1 Clarification: POCs may be started immediately postabortion.Evidence: Limited evidence suggests that no adverse side effects occur when implants (Norplant) or progestin-only injectables (NET-EN) are initiated after first trimester abortion (5255).
b. Second trimester 1 1 1 Clarification: POCs may be started immediately postabortion.
c. Immediate postseptic abortion 1 1 1 Clarification: POCs may be started immediately postabortion.
Past ectopic pregnancy 1 1 2 Comment: POP users have a higher absolute rate of ectopic pregnancy than do users of other POCs but still lower than women using no method.
History of pelvic surgery 1 1 1
Smoking
a. Age <35 years 1 1 1
b. Age ≥35 years
i. <15 cigarettes per day 1 1 1
ii. ≥15 cigarettes per day 1 1 1
Obesity
a. BMI ≥30 kg/m2 1 1 1
b. Menarche to <18 years and BMI ≥30 kg/m2 1 2 1 Evidence: Among adult women, generally no association has been found between baseline weight and weight gain among DMPA users compared with nonusers. Evidence is mixed for adolescent DMPA users, with some studies observing greater weight gain among obese compared with normal weight users but other studies showing no association; methodologic differences across studies might account for the differences in findings. Data on other POC methods and other adverse outcomes including weight gain are limited (5673).
History of bariatric surgery
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Restrictive procedures: decrease storage capacity of the stomach (vertical banded gastroplasty, laparoscopic adjustable gastric band, or laparoscopic sleeve gastrectomy) 1 1 1 Evidence: Limited evidence demonstrated no substantial decrease in effectiveness of oral contraceptives among women who underwent laparoscopic placement of an adjustable gastric band (74).
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) 1 1 3 Evidence: Limited evidence demonstrated no substantial decrease in effectiveness of oral contraceptives among women who underwent a biliopancreatic diversion; however, evidence from pharmacokinetic studies suggested conflicting results regarding oral contraceptive effectiveness among women who underwent a jejunoileal bypass (74).
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, vomiting, or both.
Cardiovascular Disease
Multiple risk factors for atherosclerotic cardiovascular disease (e.g., older age, smoking, diabetes, hypertension, low HDL, high LDL, or high triglyceride levels) 2 3 2 Clarification: When multiple major risk factors exist, risk for cardiovascular disease might increase substantially. Certain POCs might increase the risk for thrombosis, although this increase is substantially less than with COCs. The effects of DMPA might persist for some time after discontinuation.
Clarification: The recommendations apply to known preexisting medical conditions or characteristics. Few if any screening tests are needed before initiation of contraception. See the U.S. Selected Practice Recommendations for Contraceptive Use (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/usspr.htm).
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 2).
a. Adequately controlled hypertension 1 2 1 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 woman as hypertensive.
Clarification: Women adequately treated for hypertension are at lower risk for acute myocardial infarction and stroke than are untreated women. Although no data exist, POC users with adequately controlled and monitored hypertension should be at lower risk for acute myocardial infarction and stroke than are untreated hypertensive POC users.
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 woman as hypertensive.Evidence: Limited evidence suggests that among women with hypertension, those who used POPs or progestin-only injectables had a small increased risk for cardiovascular events compared with women who did not use these methods (75).
i. Systolic 140–159 mm Hg or diastolic 90–99 mm Hg 1 2 1
ii. Systolic ≥160 mm Hg or diastolic ≥100 mm Hg 2 3 2
c. Vascular disease 2 3 2 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 woman as hypertensive.
Comment: Concern exists about hypoestrogenic effects and reduced HDL levels, particularly among users of DMPA. However, little concern exists about these effects with regard to POPs. The effects of DMPA might persist for some time after discontinuation.
History of high blood pressure during pregnancy (when current blood pressure is measurable and normal) 1 1 1
Deep venous thrombosis/Pulmonary embolism
a. History of DVT/PE, not receiving anticoagulant therapy
i. Higher risk for recurrent DVT/PE (one or more risk factors)

• History of estrogen-associated DVT/PE

• Pregnancy-associated DVT/PE

• Idiopathic DVT/PE

• Known thrombophilia, including antiphospholipid syndrome

• Active cancer (metastatic, receiving therapy, or within 6 months after clinical remission), excluding nonmelanoma skin cancer

• History of recurrent DVT/PE

2 2 2
ii. Lower risk for recurrent DVT/PE (no risk factors) 2 2 2
b. Acute DVT/PE 2 2 2 Evidence: No direct evidence exists on use of POCs among women with acute DVT/PE. Although findings on the risk for venous thrombosis with use of POCs in otherwise healthy women is inconsistent, any small increased risk is substantially less than that with COCs (7577).
c. DVT/PE and established anticoagulant therapy for at least 3 months Evidence: No direct evidence exists on use of POCs among women with DVT/PE receiving anticoagulant therapy. Although findings on the risk for venous thrombosis with use of POCs is inconsistent in otherwise healthy women, any small increased risk is substantially less than that with COCs (7577).Limited evidence indicates that intramuscular injections of DMPA in women receiving chronic anticoagulation therapy does not pose a significant risk for hematoma at the injection site or increase the risk for heavy or irregular vaginal bleeding (78).
i. Higher risk for recurrent DVT/PE (one or more risk factors)

• Known thrombophilia, including antiphospholipid syndrome

• Active cancer (metastatic, receiving therapy, or within 6 months after clinical remission), excluding nonmelanoma skin cancer

• History of recurrent DVT/PE

2 2 2
ii. Lower risk for recurrent DVT/PE (no risk factors) 2 2 2
d. Family history (first-degree relatives) 1 1 1
e. Major surgery
i. With prolonged immobilization 2 2 2
ii. Without prolonged immobilization 1 1 1
f. Minor surgery without immobilization 1 1 1
Known thrombogenic mutations (e.g., factor V Leiden; prothrombin mutation; and protein S, protein C, and antithrombin deficiencies)
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
2 2 2 Clarification: Routine screening is not appropriate because of the rarity of the conditions and the high cost of screening.
Superficial venous disorders
a. Varicose veins 1 1 1
b. Superficial venous thrombosis (acute or history) 1 1 1
Current and history of ischemic heart diseaseThis condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2). Initiation Continuation Initiation Continuation Comment: Concern exists about hypoestrogenic effects and reduced HDL levels, particularly among users of DMPA. However, little concern exists about these effects with regard to POPs. The effects of DMPA might persist for some time after discontinuation.
2 3 3 2 3
Stroke (history of cerebrovascular accident)
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
Initiation Continuation Initiation Continuation Comment: Concern exists about hypoestrogenic effects and reduced HDL levels, particularly among users of DMPA. However, little concern exists about these effects with regard to POPs. The effects of DMPA might persist for some time after discontinuation.
2 3 3 2 3
Valvular heart disease
Complicated valvular heart disease is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Uncomplicated 1 1 1
b. Complicated (pulmonary hypertension, risk for atrial fibrillation, or history of subacute bacterial endocarditis) 1 1 1
Peripartum cardiomyopathy
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
Evidence: No direct evidence exists on the safety of POCs among women with peripartum cardiomyopathy. Limited indirect evidence from noncomparative studies of women with cardiac disease demonstrated few cases of hypertension, thromboembolism, and heart failure in women with cardiac disease using POPs and DMPA (79).Comment: Progestin-only implants might induce cardiac arrhythmias in healthy women; women 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: patients with no limitation of activities or patients with slight, mild limitation of activity) (80)
i. <6 months 1 1 1
ii. ≥6 months 1 1 1
b. Moderately or severely impaired cardiac function (New York Heart Association Functional Class III or IV: patients with marked limitation of activity or patients who should be at complete rest) (80) 2 2 2
Rheumatic Diseases
Systemic lupus erythematosus
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
Initiation Continuation
a. Positive (or unknown) antiphospholipid antibodies 3 3 3 3 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 women 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. Many women with SLE can be considered good candidates for most contraceptive methods, including hormonal contraceptives (8199).
Evidence: Antiphospholipid antibodies are associated with a higher risk for both arterial and venous thrombosis (100,101).
b. Severe thrombocytopenia 2 3 2 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 women 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. Many women with SLE can be considered good candidates for most contraceptive methods, including hormonal contraceptives (8199).
Comment: Severe thrombocytopenia increases the risk for bleeding. POCs might be useful in treating menorrhagia in women with severe thrombocytopenia. However, given the increased or erratic bleeding that might be seen on initiation of DMPA and its irreversibility for 11–13 weeks after administration, initiation of this method in women with severe thrombocytopenia should be done with caution.
c. Immunosuppressive therapy 2 2 2 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 women 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. Many women with SLE can be considered good candidates for most contraceptive methods, including hormonal contraceptives (8199).
d. None of the above 2 2 2 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 women 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. Many women with SLE can be considered good candidates for most contraceptive methods, including hormonal contraceptives (8199).
Rheumatoid arthritis
a. Receiving immunosuppressive therapy 1 2/3 1 Clarification (DMPA): DMPA use among women receiving long-term corticosteroid therapy with a history of, or with risk factors for, nontraumatic fractures is classified as category 3. Otherwise, DMPA use for women with rheumatoid arthritis is classified as category 2.
Evidence: Limited evidence shows no consistent pattern of improvement or worsening of rheumatoid arthritis with use of oral contraceptives, progesterone, or estrogen (102).
b. Not receiving immunosuppressive therapy 1 2 1 Evidence: Limited evidence shows no consistent pattern of improvement or worsening of rheumatoid arthritis with use of oral contraceptives, progesterone, or estrogen (102).
Neurologic Conditions
Headaches
a. Nonmigraine (mild or severe) 1 1 1
b. Migraine Evidence: No studies directly examined the risk for stroke among women with migraine using POCs (103). Limited evidence demonstrated that women using POPs, DMPA, or implants do not have an increased risk for ischemic stroke compared with nonusers (104).Comment: Menstrual migraine is a subtype of migraine without aura. For more information, see The International Headache Society Classification, 3rd edition (http://www.ihs-classification.org/_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdfpdf iconexternal icon).
i. Without aura (This category of migraine includes menstrual migraine.) 1 1 1
ii. With aura 1 1 1
Epilepsy
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
1 1 1 Clarification: If a woman is taking anticonvulsants, see Drug Interactions section. Certain anticonvulsants lower POC effectiveness.
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 (105).
Comment: Women with multiple sclerosis might have compromised bone health from disease-related disability, immobility, and use of corticosteroids. Use of DMPA, which has been associated with small changes in BMD, might be of concern.
a. With prolonged immobility 1 2 1
b. Without prolonged immobility 1 2 1
Depressive Disorders
Depressive disorders 1 1 1 Clarification: If a woman is taking psychotropic medications or St. John’s wort, see Drug Interactions section.
Evidence: The frequency of psychiatric hospitalizations for women with bipolar disorder or depression did not significantly differ among women using DMPA, LNG-IUD, Cu-IUD, or sterilization (106).
Reproductive Tract Infections and Disorders
Vaginal bleeding patterns
a. Irregular pattern without heavy bleeding 2 2 2 Comment: Irregular menstrual bleeding patterns are common among healthy women. POC use frequently induces an irregular bleeding pattern. Implant use might induce irregular bleeding patterns, especially during the first 3–6 months, although these patterns might persist longer.
b. Heavy or prolonged bleeding (includes regular and irregular patterns) 2 2 2 Clarification: Unusually heavy bleeding should raise the suspicion of a serious underlying condition.
Unexplained vaginal bleeding
(suspicious for serious condition) before evaluation
3 3 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: POCs might cause irregular bleeding patterns, which might mask symptoms of underlying pathologic conditions. The effects of DMPA might persist for some time after discontinuation.
Endometriosis 1 1 1
Benign ovarian tumors (including cysts) 1 1 1
Severe dysmenorrhea 1 1 1
Gestational trophoblastic disease
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
Clarification: For all subconditions of gestational trophoblastic disease, classifications are based on the assumption that women are under close medical supervision because of the need for monitoring of β-hCG levels for appropriate disease surveillance.
a. Suspected gestational trophoblastic disease (immediate postevacuation)
i. Uterine size first trimester 1 1 1
ii. Uterine size second trimester 1 1 1
b. Confirmed gestational trophoblastic disease (after initial evacuation and during monitoring)
i. Undetectable/nonpregnant β–hCG levels 1 1 1
ii. Decreasing β–hCG levels 1 1 1
iii. Persistently elevated β-hCG levels or malignant disease, with no evidence or suspicion of intrauterine disease 1 1 1
iv. Persistently elevated β-hCG levels or malignant disease, with evidence or suspicion of intrauterine disease 1 1 1
Cervical ectropion 1 1 1
Cervical intraepithelial neoplasia 2 2 1 Evidence: Among women with persistent human papillomavirus infection, long-term DMPA use (≥5 years) might increase the risk for carcinoma in situ and invasive carcinoma (107).
Cervical cancer
(awaiting treatment)
2 2 1 Comment: Theoretical concern exists that POC use might affect prognosis of the existing disease. While awaiting treatment, women may use POCs. In general, treatment of this condition can render a woman sterile.
Breast disease
Breast cancer is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Undiagnosed mass 2 2 2 Clarification: Evaluation should be pursued as early as possible.
b. Benign breast disease 1 1 1
c. Family history of cancer 1 1 1
d. Breast cancer Comment: Breast cancer is a hormonally sensitive tumor, and the prognosis for women with current or recent breast cancer might worsen with POC use.
i. Current 4 4 4
ii. Past and no evidence of current disease for 5 years 3 3 3
Endometrial hyperplasia 1 1 1
Endometrial cancer
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
1 1 1 Comment: While awaiting treatment, women may use POCs. In general, treatment of this condition renders a woman sterile.
Ovarian cancer
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
1 1 1 Comment: While awaiting treatment, women may use POCs. In general, treatment of this condition can render a woman sterile.
Uterine fibroids 1 1 1 Comment: POCs do not appear to cause growth of uterine fibroids.
Pelvic inflammatory disease Comment: Whether POCs, like COCs, reduce the risk for PID among women with STDs is unknown; however, they do not protect against HIV or lower genital tract STDs.
a. Past PID
i. With subsequent pregnancy 1 1 1
ii. Without subsequent pregnancy 1 1 1
b. Current PID 1 1 1
Sexually transmitted diseases
a. Current purulent cervicitis or chlamydial infection or gonococcal infection 1 1 1
b. Vaginitis (including Trichomonas vaginalis and bacterial vaginosis) 1 1 1
c. Other factors related to STDs 1 1 1
HIV
High risk for HIV 1 2 1 Clarification (DMPA): There continues to be evidence of a possible increased risk of acquiring HIV among progestin-only injectable users. Uncertainty exists about whether this is due to methodological issues with the evidence or a real biological effect. In many settings, unintended pregnancies and/or pregnancy-related morbidity and mortality are common, and progestin-only injectables are among the few types of methods widely available. Women should not be denied the use of progestin-only injectables because of concerns about the possible increased risk. Women considering progestin-only injectables should be advised about these concerns, about the uncertainty over whether there is a causal relationship, and about how to minimize their risk of acquiring HIV.
Evidence: Evidence from 13 observational studies of DMPA, NET-EN or non-specified progestin-only injectables, which were considered to be “informative but with important limitations”, continues to show some association between use of progestin-only injectables and risk of HIV acquisition, but it remains unclear whether this results from a causal relationship or methodological limitations (108a).One additional randomized pilot feasibility trial, published subsequently to the systematic review, found no statistically significant difference in risk of HIV acquisition between progestin-only injectable users (DMPA or NET-EN) and copper IUD users; this study had several limitations including lack of power to assess differences in HIV acquisition rates, and problems with ascertainment of hormonal contraception exposure and HIV acquisition outcomes (108b).
Two small studies assessing levonorgestrel implants, which were considered to be “informative but with important limitations”, did not suggest an elevated risk, although the risk estimates were imprecise. One study reported no association between use of progestin-only pills and HIV acquisition (108a).
HIV infection
For women with HIV infection who are not clinically well or not using ARV therapy, this condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
1 1 1 Clarification: Drug interactions might exist between hormonal contraceptives and ARV drugs; see Drug Interactions section.
Evidence: Overall, evidence does not support an association between POC use and progression of HIV. Limited direct evidence on an association between POC use and transmission of HIV to noninfected partners, as well as 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 (109111).
Other Infections
Schistosomiasis
Schistosomiasis with fibrosis of the liver is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Uncomplicated 1 1 1 Evidence: Among women with uncomplicated schistosomiasis, limited evidence showed that DMPA use had no adverse effects on liver function (112).
b. Fibrosis of the liver (if severe, see Cirrhosis section) 1 1 1
Tuberculosis
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
Clarification: If a woman is taking rifampin, see Drug Interactions section. Rifampin is likely to decrease the effectiveness of some POCs.
a. Nonpelvic 1 1 1
b. Pelvic 1 1 1
Malaria 1 1 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 2).
a. History of gestational disease 1 1 1 Evidence: POCs had no adverse effects on serum lipid levels in women with a history of gestational diabetes in two small studies (113,114). Limited evidence is inconsistent about the development of noninsulin-dependent diabetes among users of POCs with a history of gestational diabetes (115118).
b. Nonvascular disease Evidence: Among women with insulin-dependent or non–insulin-dependent diabetes, limited evidence on use of POCs (POPs, DMPA, and LNG implant) suggests that these methods have little effect on short-term or long-term diabetes control (e.g., glycosylated hemoglobin levels), hemostatic markers, or lipid profile (119122).
i. Non-insulin dependent 2 2 2
ii. Insulin dependent 2 2 2
c. Nephropathy, retinopathy or neuropathy 2 3 2 Comment: Concern exists about hypoestrogenic effects and reduced HDL levels, particularly among users of DMPA. The effects of DMPA might persist for some time after discontinuation. Some POCs might increase the risk for thrombosis, although this increase is substantially less than with COCs.
d. Other vascular disease or diabetes of >20 years’ duration 2 3 2 Comment: Concern exists about hypoestrogenic effects and reduced HDL levels, particularly among users of DMPA. The effects of DMPA might persist for some time after discontinuation. Some POCs might increase the risk for thrombosis, although this increase is substantially less than with COCs.
Thyroid disorders
a. Simple goiter 1 1 1
b. Hyperthyroid 1 1 1
c. Hypothyroid 1 1 1
Gastrointestinal Conditions
Inflammatory bowel disease (ulcerative colitis or Crohn’s disease) 1 2 2 Evidence: Risk for disease relapse among women with IBD using oral contraceptives (most studies did not specify formulation) did not increase significantly from that for nonusers (123).
Comment: Absorption of POPs among women with IBD might be reduced if the woman has substantial malabsorption caused by severe disease or small bowel surgery.Women with IBD have a higher prevalence of osteoporosis and osteopenia than the general population. Use of DMPA, which has been associated with small changes in BMD, might be of concern.
Gallbladder disease
a. Symptomatic
i. Treated by cholecystectomy 2 2 2
ii. Medically treated 2 2 2
iii. Current 2 2 2
b. Asymptomatic 2 2 2
History of cholestasis
a. Pregnancy related 1 1 1
b. Past COC related 2 2 2 Comment: Theoretical concern exists that a history of COC-related cholestasis might predict subsequent cholestasis with POC use. However, this has not been documented.
Viral hepatitis
a. Acute or flare 1 1 1
b. Carrier 1 1 1
c. Chronic 1 1 1
Cirrhosis
Severe cirrhosis is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Mild (compensated) 1 1 1
b. Severe (decompensated) 3 3 3
Liver tumors
Hepatocellular adenoma and malignant liver tumors are associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Benign
i. Focal nodular hyperplasia 2 2 2 Evidence: Limited direct evidence suggests that hormonal contraceptive use does not influence either progression or regression of liver lesions among women with focal nodular hyperplasia (124).
ii. Hepatocellular adenoma 3 3 3 Comment: No evidence is available about hormonal contraceptive use among women with hepatocellular adenoma. COC use in healthy women is associated with development and growth of hepatocellular adenoma; whether other hormonal contraceptives have similar effects is not known.
b. Malignant (hepatoma) 3 3 3
Respiratory Conditions
Cystic fibrosis
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
1 2 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 women 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 (125).
Comment: Women with cystic fibrosis have a higher prevalence of osteopenia, osteoporosis, and fragility fractures than the general population. Use of DMPA, which has been associated with small changes in BMD, might be of concern.
Anemias
Thalassemia 1 1 1
Sickle cell disease
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
1 1 1 Evidence: Among women with sickle cell disease, POC use did not have adverse effects on hematologic parameters and, in some studies, was beneficial with respect to clinical symptoms (126133).
Iron deficiency anemia 1 1 1 Comment: Changes in the menstrual pattern associated with POC use have little effect on hemoglobin levels.
Solid Organ Transplantation
Solid organ transplantation
This condition is associated with increased risk for adverse health events as a result of pregnancy (Box 2).
a. Complicated: graft failure (acute or chronic), rejection, or cardiac allograft vasculopathy 2 2 2
b. Uncomplicated 2 2 2
Drug Interactions
Antiretroviral therapy Comment: These recommendations generally are for ARV agents used alone. However, most women 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.
a. Nucleoside reverse transcriptase inhibitors (NRTIs)
i. Abacavir (ABC) 1 1 1 Evidence: NRTIs do not appear to have significant risk for interactions with hormonal contraceptive methods (134139).
ii. Tenofovir (TDF) 1 1 1
iii. Zidovudine (AZT) 1 1 1
iv. Lamivudine (3TC) 1 1 1
v. Didanosine (DDI) 1 1 1
vi. Emtricitabine (FTC) 1 1 1
vii. Stavudine (D4T) 1 1 1
b. Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
i. Efavirenz (EFV) 2 1 2 Clarification: Evidence suggests drug interactions between EFV and certain hormonal contraceptives. These interactions might reduce the effectiveness of the hormonal contraceptive.
Evidence: One study found that women using etonogestrel implants with EFV had a higher pregnancy rate than women not using ARVs, although confidence intervals overlapped and absolute pregnancy rates were still lower than for other hormonal methods; another study found that etonogestrel levels were decreased and 5% of women had presumptive ovulation while using etonogestrel implants with EFV (140,141). Three studies of women using LNG implants showed increased pregnancy rates for women using EFV-containing ARV therapy compared with no ARV use, although absolute pregnancy rates were still lower than for other hormonal methods in one study (141143); another study of LNG implant users found no difference in pregnancy rates with EFV compared with no EFV (144). No significant effects were found on pregnancy rates, DMPA levels, EFV levels, or HIV disease progression in women using DMPA and EFV compared with DMPA alone (141,144148). No significant effects were found on HIV disease progression in women using LNG implants and EFV compared with no ARVs (143). No data have assessed effectiveness of contraceptive implants during later years of use when progestin concentrations are lower and risk for failure from drug interactions might be greater.
ii. Etravirine (ETR) 1 1 1
iii. Nevirapine (NVP) 1 1 1 Evidence: Five studies found no significant increase in pregnancy rates among women using implants and NVP compared with implants alone (141144,149). Four studies found no significant increase in pregnancy rates among women using DMPA or other contraceptive injectables and NVP compared with DMPA or other contraceptive injectables alone (141,144,147,150). One study found no ovulations or changes in DMPA concentrations (145). No effect was found on HIV disease progression with use of NVP and DMPA or LNG implants (143,145,147149,151). No data have assessed effectiveness of contraceptive implants during later years of use when progestin concentrations are lower and risk for failure from drug interactions might be greater.
iv. Rilpivirine (RPV) 1 1 1
c. Ritonavir-boosted protease inhibitors
i. Ritonavir-boosted atazanavir (ATV/r) 2 1 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. Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA.
Evidence: One pharmacokinetic study demonstrated increased progestin concentrations with use of POPs and ATV/r compared with POPs alone (152).
ii. Ritonavir-boosted darunavir (DRV/r) 2 1 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. Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA.
iii. Ritonavir-boosted fosamprenavir (FPV/r) 2 1 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. Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA.
iv. Ritonavir-boosted lopinavir (LPV/r) 1 1 1 Evidence: One study demonstrated no pregnancies, no ovulations, no change in LPV/r level, and no change in HIV disease progression in women using DMPA (153); another study found a small increase in pregnancy rate in women using DMPA with LPV/r compared with no ARV therapy, however confidence intervals overlapped (141). Two studies found no increased risk for pregnancy in women using implants (141,142). Two studies found contraceptive hormones increased in women using LPV/r with DMPA or etonogestrel implants (140,153).
v. Ritonavir-boosted saquinavir (SQV/r) 2 1 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. Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA.
vi. Ritonavir-boosted tipranavir (TPV/r) 2 1 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. Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA.
d. Protease inhibitors without ritonavir
i. Atazanavir (ATV) 1 1 1 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) 2 2 2 Clarification: Theoretical concern exists that interactions between FPV and hormonal contraceptives leading to decreased levels of FPV might diminish effectiveness of the ARV drug. The drug interaction likely involves CYP3A4 pathways; POCs have less effect on CYP3A4 enzymes than CHCs.
iii. Indinavir (IDV) 1 1 1
iv. Nelfinavir (NFV) 2 1 2 Clarification: Theoretically, drug interactions might occur between certain protease inhibitors and certain hormonal contraceptives that might reduce the effectiveness of the hormonal contraceptive. Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA. Concern exists that interactions between NFV and POCs might decrease NFV levels.
Evidence: One study found no pregnancies, no ovulations, no change in DMPA concentrations and no change in HIV disease progression with use of DMPA and NFV compared with DMPA alone; NFV concentrations were decreased with concomitant DMPA use (145,147).
e. CCR5 co-receptor antagonists
i. Maraviroc (MVC) 1 1 1
f. HIV integrase strand transfer inhibitors
i. Raltegravir (RAL) 1 1 1
ii. Dolutegravir (DTG) 1 1 1
iii. Elvitegravir (EVG) 1 1 1 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 may vary when combined with other ARVs.
g. Fusion inhibitors
i. Enfuvirtide 1 1 1
Anticonvulsant therapy
a. Certain anticonvulsants (phenytoin, carbamazepine, barbiturates, primidone, topiramate, and oxcarbazepine) 2 1 3 Clarification: Although the interaction of certain anticonvulsants with POPs and etonogestrel implants is not harmful to women, it is likely to reduce the effectiveness of POPs and etonogestrel implants. Whether increasing the hormone dose of POPs alleviates this concern remains unclear. Use of other contraceptives should be encouraged for women who are long-term users of any of these drugs. Use of DMPA is a category 1 because its effectiveness is not decreased by use of certain anticonvulsants.
Evidence: Use of certain anticonvulsants might decrease the effectiveness of POCs (154156).
b. Lamotrigine 1 1 1 Evidence: No drug interactions have been reported among women with epilepsy receiving lamotrigine and POCs (157).
Antimicrobial therapy
a. Broad-spectrum antibiotics 1 1 1
b. Antifungals 1 1 1
c. Antiparasitics 1 1 1
d. Rifampin or rifabutin therapy 2 1 3 Clarification: Although the interaction of rifampin or rifabutin with POPs and etonogestrel implants is not harmful to women, it is likely to reduce the effectiveness of POPs and etonogestrel implants. Use of other contraceptives should be encouraged for women who are long-term users of any of these drugs. Use of DMPA is a category 1 because its effectiveness is not decreased by use of rifampin or rifabutin. Whether increasing the hormone dose of POPs alleviates this concern remains unclear.
Psychotropic medications Comment: For many common psychotropic agents, limited or no theoretical concern exits 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.
a. SSRIs 1 1 1 Evidence: No evidence specifically examined the use of POCs with SSRIs. 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 (158).
Comment: Drugs that are inhibitors of CYP3A4 or CYP2C9 theoretically have the potential to increase levels of contraceptive steroid, which might increase adverse events. Fluvoxamine is an SSRI known to be a moderate inhibitor of both 3A4 and 2C9; however, no clinical or pharmacokinetic studies were identified to explore potential drug-drug interactions.
St. John’s wort 2 1 2 Evidence: No evidence specifically examined the use of POCs with St John’s wort. 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 progestin. 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 may vary (159).
Comment: Any potential effect on contraceptive effectiveness is likely to be lower with DMPA than with other POCs because of the higher dose of DMPA.

Abbreviations: ARV = antiretroviral; BMD = bone mineral density; BMI = body mass index; COC = combined oral contraceptive; DMPA = depot medroxyprogesterone acetate; DVT = deep venous thrombosis; hCG = human chorionic gonadotropin; HDL = high-density lipoprotein; HIV = human immunodeficiency virus; IBD = inflammatory bowel disease; LDL = low-density lipoprotein; LNG = levonorgestrel; NA = not applicable; NET-EN = norethisterone enantate; PE = pulmonary embolism; PID = pelvic inflammatory disease; POC = progestin-only contraceptive; POP = progestin-only pill; SSRI = selective serotonin reuptake inhibitor; STD = sexually transmitted disease; VTE = venous thromboembolism

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