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Oral Contraception

Article in The Medical clinics of North America · February 2015

Impact Factor: 2.61 · DOI: 10.1016/j.mcna.2015.01.004

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Eliza L. Sutton
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Oral Contraception
a, b
Ginger Evans, MD *, Eliza L. Sutton, MD

KEYWORDS
 Oral contraception  Ethinyl estradiol  Levonorgestrel  Venous thromboembolism
 Medical eligibility criteria

KEY POINTS
 Oral contraceptives (OC) offer noncontraceptive benefits, including improvement of acne,
hirsutism, and dysmenorrhea.
 Many OC formulations exist; ethinyl estradiol at 20 to 30 mcg with levonorgestrel seems to
confer a lower risk of venous thromboembolism than OCs with other progestins.
 Medical eligibility criteria, developed by the World Health Organization and adapted by in-
dividual countries, provide a resource to assess patients’ medical situations for contrain-
dications to OCs.
 Blood pressure measurement is the only physical examination or testing needed before
OC prescription.
 Continuous daily use of OCs and extended (3 month) cycles are reasonable alternatives to
cyclic monthly use and can further improve menstrual-associated symptoms.

INTRODUCTION

The development of hormonal contraception marked a breakthrough in the technol-

ogy of pregnancy prevention and planning. Hormonal contraception relies on a pro-
gestin to
 Thicken cervical mucus, forming a mechanical barrier
 Suppress ovulation by suppressing the midcycle surge of follicle-stimulating hor-
mone (FSH) and luteinizing hormone (LH)
 Keep the endometrium thin and thus inhospitable for implantation
Estrogen contributes to ovulation suppression and also prevents sloughing of the
endometrium, thus reducing irregular bleeding, which can be a limiting side effect of
progestin-only methods.

Disclosure: No financial relationships to disclose.

a
VA Puget Sound Health Care System, 1660 South Columbian Way, S-123-PCC, Seattle, WA
98108, USA; b Women’s Health Care Center, University of Washington, 4245 Roosevelt Way
Northeast, Box 354765, Seattle, WA 98105, USA
* Corresponding author.
E-mail address: [email protected]

Med Clin N Am 99 (2015) 479–503

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480 Evans & Sutton

HISTORY AND SAFETY OF THE PILL

In 1960, the Food and Drug Administration (FDA) approved the first oral contraceptive
(OC), a pill containing mestranol 150 mcg and norethynodrel, 3 years after its approval
for the treatment of menstrual disorders.1 The pill has been popular, but the early high-
dose formulation was associated with increased mortality from venous thromboembo-
lism (VTE) and arterial vascular events.2,3 With the development of other formulations,
the effect of the estrogen dose and the specific progestin on thromboembolism risk
were recognized,4 leading to the development of lower-dose, lower-risk formulations.
Current formulations of combination OCs (COCs) contain one-third to one-fifth of the
amount of estrogen in the first COC, plus any of 8 synthetic progestins in a dizzying
array of patterns (Table 1).
In 1973, a progestin-only pill (POP), popularly called the mini pill, became available.
The sole active ingredient in the only POP available in the United States and Canada is
norethindrone. The POP is less effective than other hormonal methods of contracep-
tion and commonly causes irregular bleeding, but it is safer than combined hormonal
contraceptives (CHCs) for women in whom exogenous estrogen is contraindicated.
In 1996, the World Health Organization (WHO) developed and began a periodic re-
view called Medical Eligibility Criteria for Contraceptive Use (hereafter referred to as
MEC); the fourth edition of MEC was released in 20096 with subsequent updates.
The MEC suggests a weighing of risks and benefits ranging from level 1 to level 4
(Box 1) for each form of contraception with regard to specific patient factors and med-
ical conditions and has been adopted and adapted by individual countries for their
own use. Free resources to assist in the clinical use of the MEC are available for down-
load at the Centers for Disease Control and Prevention’s Web site.7

PREGNANCY PREVENTION

Modern CHCs are effective for contraception, with perfect use theoretically resulting in
only 0.3 pregnancies per 100 women in the first year. Actual effectiveness depends
significantly on adherence. Typical use of COCs results in about 9 pregnancies per
100 women in the first year, performing significantly better than barrier methods, spermi-
cides, withdrawal, and fertility awareness (rhythm) methods but not as well as intrauter-
ine devices (IUDs), progestin implants or injections, or sterilization.8 For comparison,
85% of sexually active heterosexual women conceive in 1 year without contraception.8

NONCONTRACEPTIVE HEALTH BENEFITS

Since the original introduction of COCs, many noncontraceptive benefits have been
discovered and used; in addition, benefits have been attributed to COCs that are
not currently substantiated by research (Box 2). Because patients are frequently un-
aware of the noncontraceptive benefits, health care providers have an important op-
portunity to debunk myths and educate patients on the real and relevant benefits.9–11
Acne is an important consideration to many young adult patients. All COCs are
effective for relief of acne in clinical trials.12,22 In general, about half (50%–90%) of pa-
tients will experience improvement in acne after 6 to 9 months, with an average of 30%
to 60% reduction in inflammatory lesions.29,30 The estrogen component of a COC de-
creases circulating free androgen via 2 mechanisms: (1) suppression of LH-driven
androgen production by ovaries and (2) induction of hepatic synthesis of sex hormone
binding globulin (SHBG), which leads to lower levels of free testosterone.
The comparative effectiveness against acne between formulations of COCs is un-
clear.12,22 The ring and patch may not be as effective against acne as OCs because
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Table 1
Ingredients and formulations of hormonal contraceptives available in the United States

Estrogen Progestin Phasing Cycle

Forms and Doses Forms Number of Days at Each Dose of Active Medication Number of Active Pills Per Pill Pack
EE First-generation Monophasic (estrogen and progestin dose stable over 21 d) 21-d Pack
10 mcga Ethynodiol diacetate Multiphasic (progestin dose changes over 21 d) 21
20 mcg Norethindrone Biphasic (10 1 11) 28-d Pack
25 mcg Norethindrone acetate Triphasic (7 1 7 1 7) 21
30 mcg Second-generation Estrophasic (estrogen dose changes over 21 d) 24c
35 mcg Levonorgestrel 20/30/35 mcg EEc (5 1 7 1 9; monophasic in progestin) 28
40 mcga Norgestrel 30/40/30 mcg EE (6 1 5 1 10; also triphasic in progestin) 91-d Pack
50 mcg Third-generation 3/2/1 mg EVc (2 1 5 1 17 1 2 1 2; also multiphasic in progestin) 84
EVa,b Desogestrel Estrophasic (estrogen dose changes over 84 d) 84 1 7 of 10 mcg EE
3 mg Etonorgestrelc (ring, implant) 20/25/30/10 mcg EE (42 1 21 1 21 1 7; monophasic in progestin)5
2 mg Norelgestrominc (patch)
1 mg Norgestimate
Mestranol Fourth-generation
(EE prodrug) Dienogestb
50 mcg Drospirenone

This information is current as of September 2014. New brands with new synthetic hormones and formulations, and generics of previously approved brands,
become available frequently.
Bold indicates recommended first-line COC.
Italics indicate progestins available only in nonoral contraceptives.

Oral Contraception
Abbreviations: EE, ethinyl estradiol; EV, estradiol valerate.
a
Available only within an estrophasic formulation (as of September 2014).
b
As a component of OC, available only as brand name (as of September 2014).
c
Available only as brand name (as of September 2014).

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Box 1
Key: MEC for contraceptive use

Level Definition/Meaning
1 Level 1 medical conditions present no contraindication to the contraceptive method;
the method may be used without restriction
2 Advantages of method generally outweigh proven and/or theoretic risks for women
with level 2 medical conditions.
3 Proven and/or theoretic risks usually outweigh advantages for women with level 3
medical conditions.
4 Health risk from the method is considered unacceptable for women with level 4
medical conditions; the method is contraindicated.

Adapted from Centers for Disease Control and Prevention. U S. medical eligibility criteria for
contraceptive use, 2010. MMWR Recomm Rep 2010;59(RR-4):2.

they bypass first-pass hepatic metabolism, so do not induce SHBG synthesis.22,30

POPs are not effective against acne because they lack the therapeutic estrogen
component. The progestin component of COCs binds androgen receptors, which
could worsen acne. However, in a COC, the androgen-reducing effect of the estrogen
component outweighs the proandrogenic effect of the progestin component resulting
in an overall decrease in acne. Multiple different progestin formulations are available

Box 2
Proven benefits and unproven/disproven noncontraceptive effects of COCs

Proven Benefits
Acne
 All COCs are effective.12
 New antiandrogenic progestins (eg, drospirenone) are superior in some trials.12–14
PCOS
 COCs are effective for associated menstrual disorders, acne, and hirsutism.15
Primary dysmenorrhea16–18
Secondary dysmenorrhea from endometriosis15,19,20
PMDD21
 Only drospirenone-containing COCs have demonstrated a benefit
 Trials of other COCs have not shown a benefit over placebo
Menorrhagia22,23
Reduction in risk of endometrial, ovarian, and colon cancer24
Unproven or disproven effects of COCs
PMS25,26
Leiomyoma growth22
Functional ovarian cysts (treatment)27
Bone mineral density28

Abbreviations: PCOS, polycystic ovary syndrome; PMDD, premenstrual dysphoric disorder; PMS,
premenstrual syndrome.
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Oral Contraception 483

(see Table 1). Later-generation progestins are less androgenic, including drospire-
none, which was derived from spironolactone and, therefore, has antiandrogenic
and antimineralocorticoid properties. Drospirenone was superior for the treatment
of acne to triphasic norgestimate/ethinyl estradiol (EE) and nomegestrol acetate/
17b-estradiol in comparative trials12–14 but also can cause hyperkalemia (because
of its antimineralocorticoid effect), necessitating laboratory monitoring in some
women.22 It is not known how COCs compare with other acne therapy.12
For primary dysmenorrhea, nonsteroidal antiinflammatory drugs are generally the
first-line treatment; but COCs are also effective.16 Based on small trials, the response
could be as high as 80%,17 and the magnitude of benefit was significant (with a pain
score decrease in one trial from 60 out of 100 to 20 out of 100 on a visual analogue
scale) after only one cycle of therapy.18 There is no evidence for the benefit of one
COC over another.16 COCs may also be used for menorrhagia, with an anticipated
decrease in blood flow of about 40% to 50%.22,23 Continuous administration could
theoretically decrease this further given the fewer number of scheduled bleeding ep-
isodes. Secondary dysmenorrhea associated with endometriosis is also an indication
for COCs.15,20
COCs address the effects of anovulation and androgenic excess in women with
polycystic ovary syndrome (PCOS), reducing acne and hirsutism associated with
this condition.15 COCs are associated with higher high-density lipoprotein and triglyc-
eride levels in women with PCOS without affecting metabolic measures, including
glucose and insulin, in a clinically significant manner.31
Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syn-
drome (PMS). Only OCs containing drospirenone are FDA approved for the treatment
of PMDD based on clinical trials.21,22 The benefit is uncertain for milder symptoms
(PMS).25 PMS symptoms not severe enough to meet the definition of PMDD may be
treated with nonhormonal measures, such as exercise, relaxation, and selective sero-
tonin reuptake inhibitors.26
OCs are not effective for the treatment of functional ovarian cysts.27 COCs can pre-
vent formation of functional ovarian cysts,32 particularly corpus luteum cysts; howev-
er, multiphasic COCs and the lower-dose COCs currently in use (EE 35 mcg) may be
less effective than higher-dose monophasic COCs.33
OCs may improve bleeding symptoms associated with leiomyomas, but they do not
positively or negatively affect their growth.22
Lastly, the use of OCs for prophylaxis against menstrual migraine (without aura) has
mixed evidence.34 Continuous/extended use of COCs, or tetraphasic preparations
that gradually step down estrogen doses, may prevent the premenstrual decrease
in estrogen levels that may precipitate headaches.34–37

RISKS AND CONTRAINDICATIONS

Pregnancy is associated with a higher risk of morbidity and mortality than contracep-
tion; however, women in modern times are typically exposed to contraception for
more of their lives than to pregnancy. The risks of CHC are essentially a subset of
the risks of pregnancy via the estrogenic effect on (1) the coagulation system,
increasing the risks of venous and arterial thrombosis and thromboembolism, and
(2) estrogen-dependent tissues, particularly breast and liver. For clinical decision mak-
ing, the risk comparison should include the risks and efficacy of different methods of
contraception.
Relative and absolute contraindications to CHCs are listed in Table 2, including
several conditions in which the US MEC and UK MEC assign different levels of risk.
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484
Evans & Sutton
Table 2
Conditions in which the risks of COCs outweigh the benefits

Condition Risk Level 4 Risk Level 3

VTE (DVT and/or PE) Current VTE X —
Higher risk of VTE History of VTE with higher risk recurrence X —
Known thrombogenic mutation X —
Major surgery with prolonged X —
immobilization
Postpartum <21 d X —
Systemic lupus erythematosus with X —
positive or unknown antiphospholipid
antibody status
Budd-Chiari syndrome: should not use X —
COCs40 but not listed by MEC level
Lower risk of VTE History of VTE with lower risk recurrence — X
Post partum 21–42 d with other risk for — X
VTE (including age 35 y, smoking, BMI
30, preeclampsia, cesarean section,
postpartum hemorrhage)39
Inflammatory bowel disease with — X
increased risk VTE
Obesity (BMI 35 kg/m2 is level 3 in UK) — Level 3 in UK MEC,
MEC based on VTE risk and level 2 in US MEC
cardiovascular risk38 but level 2 in US
MEC40
Family history of VTE in a first-degree — Level 3 in UK MEC,
relative before 45 y of age is level 3 in Level 2 in US MEC
UK MEC38 but family history of VTE in
first-degree relatives is level 2 in US
MEC40
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Arterial thrombosis Diabetes Duration >20 ya X X

(particularly Known vascular diseasea X X
cardiovascular) Nephropathy, neuropathy, retinopathya X X
Hypertension Controlled hypertension (systolic blood — X
pressure <140 and diastolic blood
pressure <90)
Systolic blood pressure 140–150 or — X
diastolic blood pressure 90–99
Systolic blood pressure 160 or diastolic X —
blood pressure 100
Cardiovascular risks, including age, Lower risk based on number & severity of — X
diabetes, hypertension, hyperlipidemia factors
Higher risk based on number & severity of X —
factors
Current or past ischemic heart disease X —
History of stroke X —
Migraine With aura, any age X —
Without aura, 35 y (For COC (For COC initiation)
continuation)
Smoking, age 35 y 15 Cigs/d X —
<15 Cigs/d — X
Vascular disease X —
Complicated valvular heart disease X —
Complicated congenital heart disease38 X —
Peripartum cardiomyopathy Moderate to severely impaired cardiac X —
function, <6 or 6 mo post partum
<6 mo Post partum and normal to mildly X —
reduced cardiac function

Oral Contraception
6 mo Post partum and normal to mildly — X
reduced cardiac function

(continued on next page)

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Table 2
(continued )
Condition Risk Level 4 Risk Level 3
Liver or biliary disease Hepatic adenoma or hepatocellular X —
carcinoma
Severe (decompensated) cirrhosis X —
Viral hepatitisa (acute or flare) X X
Current or medically treated gallbladder — X
disease
History of cholestasis caused by COC use — X
Breast neoplasm Current breast cancer X —
History of breast cancer, clinically disease- — X
free for 5 y
Undiagnosed breast mass38 — For COC initiation,
in UK MEC
Other or combined risks Complicated organ transplant X —
Lactation39 (see also <21 d Post partum X —
Table 3 and VTE risk 21 to <30 d Post partum — X
section of this table)
Lack of efficacy because History of bariatric surgery with intestinal — X
of malabsorption bypass

Pregnancy poses risk in the disease conditions listed earlier.

Information is from US MEC40 except where otherwise noted.
UK MEC determination is given where condition is not mentioned in US MEC or listing differs significantly.
Abbreviations: BMI, body mass index; Cigs, cigarettes; DVT, deep vein thrombosis; PE, pulmonary embolism.
a
Level 3 or 4 based on severity and other risk factors.
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Oral Contraception 487

Table 3
Initiating OC in the postpartum period

Days Post CHC POP

Partum Breastfeeding Not Breastfeeding Breastfeeding Not Breastfeeding
<21 4 4 2 1
a
21–29 3 3 If other VTE risk 2 1
2 If no other VTE risk
30–42 3 If other VTE riska 3 If other VTE riska 1 1
2 If no other VTE risk 2 If no other VTE riska
a

>42 2 1 1 1
a
VTE risk here also includes smoking, obesity, and complications of recent pregnancy, including
preeclampsia, caesarian delivery, or postpartum hemorrhage.
Adapted from Centers for Disease Control and Prevention. Update to CDC’s U.S. medical eligi-
bility criteria for contraceptive use, 2010: revised recommendations for the use of contraceptive
methods during the postpartum period. MMWR Morb Mortal Wkly Rep 2011;60(26):882.

Misconceptions about the risks of hormonal contraception and lack of knowledge

about the benefits are common among women who are potential candidates for OC
use.9,41 In addition, CHCs are sometimes prescribed for women with level 3 and 4 con-
traindications. Analysis of data from a national health survey in the United States found
that 23.7% of nearly 3000 women aged 18 to 44 years who took CHCs had level 3 or 4
conditions (see Box 1, Table 2), including 9% who had level 4 conditions in which
CHCs are contraindicated; the most common conditions were (1) migraine and an
age of 35 years or older or migraine with aura, (2) hypertension, and (3) multiple risk
factors for cardiovascular disease.42
VTE remains the major risk of COCs, occurring at 3.5 times more than the baseline
risk of approximately 0.37 per 1000 user-years for nonpregnant women5 but still a
significantly lower risk than during pregnancy and the postpartum period. VTEs attrib-
utable to OCs occur at about 0.63 per 1000 user-years, with excess deaths from VTE
attributable to OCs occurring in about 5 women per 1 million user-years.43
Cancer may be a concern for some women considering CHCs. In fact, OC use is
associated with lifetime reduction in 3 types of cancer:
 Endometrial cancer incidence: OR 0.57 (95% CI 0.43 – 0.77)24
 Ovarian cancer incidence: OR 0.73 (95% CI 0.66 – 0.81), related to duration of
use (OR 0.91 for use 12 months and OR 0.42 for use >10 years)44
 Colorectal cancer incidence: OR 0.86 (95% CI 0.79 – 0.95)24
On the other hand, OC use is associated with increased likelihood of 2 or 3 types of
cancer:
 Breast cancer incidence overall: OR 1.08 (95% CI 1.00–1.17)24
 Longer use and current use are associated with higher risk in women 20–44,
with OR 1.5 (95% CI 1.1-2.2) for current use 5 years and OR 1.6 (95% CI
1.1-2.5) for lifetime use 15 years.45
 OC initiation before age 20–25 is associated with higher risk of diagnosis by
age 40 for women with BRCA1, for OC initiation before age 20 (OR 1.40,
95% CI 1.14-1.70) and possibly from age 20–25 (OR 1.19, 95% CI 0.99-
1.42), compared with older ages.46
 Cervical cancer and precancer incidence is increased in setting of persistent hu-
man papillomavirus infection and OC use, however risk estimation is limited by
the heterogeneity of studies24
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488 Evans & Sutton

 The increased risk of cervical cancer is observed with current or recent OC use
and may either persist24 or decline to baseline47 after cessation of OCs.
 Benign liver tumors (focal nodular hyperplasia and hepatic adenoma) are associ-
ated with OC use, and incidence of hepatocellular carcinoma may be increased
(OR 1.57, 95% CI 0.96 – 2.54, from heterogeneous studies).48 For comparison, in
men hepatic adenomas occur less often, but the risk of transformation to hepa-
tocellular carcinoma is about 10-fold higher49

PRESCRIBING ORAL CONTRACEPTIVES

Prescribers may find the number of different formulations challenging to navigate and
may incorrectly think breast and pelvic examinations are necessary before initial pre-
scription and subsequent refills.
A basic medical history should be obtained before CHC prescription. Relative and
absolute contraindications to CHCs are listed in Table 2 and include hypertension,
vasculopathy, advanced liver disease, and breast cancer, with the last 2 also contra-
indications to POP.40 In pulmonary hypertension, pregnancy is contraindicated
because of the 30% to 50% maternal mortality risk; however, CHCs are generally
not advised50: Acute or chronic VTEs can cause or exacerbate pulmonary hyperten-
sion; drug-drug interactions may reduce the efficacy of systemic hormonal ap-
proaches,51,52 and estrogen might play an etiologic role in the condition.50

Venous Thromboembolism Risk Factors by History

Risk factors for VTE should be reviewed before prescription of a CHC, including family
medical history. However, family history of VTE is a poor means of screening for
thrombophilia in women who are candidates for CHCs. The sensitivity of a positive
family history of VTE for detecting thrombophilic laboratory findings in patients is
11% for affected first-degree relatives and 16% for affected first- and second-
degree relatives; the positive predictive value for finding such a thrombophilic defect
is 8% and 9%, respectively.53 A negative family history, thus, fails to accurately assess
patients’ risk of thrombophilia and may be falsely reassuring. A positive family history
(especially of late-life or provoked VTE in single or distant relatives) could unduly limit
the prescription of effective contraception.
Despite limitations in predicting known thrombophilic mutations, a positive family
history does modestly predict a woman’s overall risk of future VTE. In an observa-
tional study of young women, a positive family history for VTE was associated with
2.4-fold increased risk of VTE even in the absence of a prothrombin gene mutation
or factor V Leiden.54 In a case-control study of people with a first episode of VTE, fam-
ily history of a first-degree relative affected before 45 to 50 years of age or a family
history of several affected relatives was associated with 2- to 4-fold increased risk
of VTE.55
Family history of VTE is considered level 2 for use of CHCs in the WHO MEC6 and
the US MEC40 because the absolute risk of VTE is low and because of the poor per-
formance of family history as a screening tool. However, in the UK MEC, family history
of VTE in a first-degree relative before 45 years of age is level 3.56
Given the uncertainties and the discrepant guidelines discussed earlier, the low ab-
solute risk for VTE even for women on CHCs, and the availability of other effective
methods of contraception, the authors concur with the recommendations that a family
history of young or multiple relatives with VTE warrants discussion with patients of
their potentially heightened relative risk of VTE on a CHC, plus consideration of other
contraceptive options and/or testing for thrombophilic conditions.57,58
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Oral Contraception 489

Testing for thrombophilic conditions is not cost-effective for the general population
of women starting CHCs.57,59

Physical Examination
Physical examination60 and testing60,61 other than blood pressure measurement is not
required before prescription. Blood pressure should be measured before initiation of
CHC; hypertension is a contraindication to CHCs though not to POPs (see
Table 2).40,60 Given the lack of need for a physical examination and testing, in
September 2014, Planned Parenthood began offering to women in Minnesota and
Washington online video visits for prescription of hormonal contraception, with pa-
tients required to obtain a blood pressure reading in the community.62
Body mass index (BMI) may be taken into consideration. In the WHO6 and US
MEC,40 a BMI of 30 kg/m2 or greater is level 2, whereas in the UK MEC, a BMI of
30 to 35 kg/m2 is level 2 and a BMI of 35 kg/m2 or greater is level 3 because of the
risk of cardiovascular disease and VTE (see Table 2).38

Generic Versus Brand Name Drugs

To gain FDA approval, generic formulations of brand medications must be therapeu-
tically equivalent to the brand (same active ingredients at same doses) and must
demonstrate bioequivalence (mean area under the drug concentration-time curve
within 90% confidence level of brand in crossover studies). In one study, initiation
of generic or insurance-preferred brand medications (including OCs) was associated
with 62% and 30% greater odds, respectively, of patients having adequate adherence
(>80% of medication doses taken) than patients started on higher-tier medications.63
On the other hand, concerns about side effects and the perceived possibility of lower
efficacy of medications may affect the acceptability of a generic OC for some women.
The American Congress of Obstetricians and Gynecologists (ACOG)64 supports a low
threshold for use of whichever oral contraceptive patients and clinicians think will be
most effective based on various considerations, including cost and patient preference.

Medication Interactions
OCs can interact with medications of several classes, reducing the efficacy either of
the contraceptive or of the other medications. The interactions significant enough to
warrant consideration of either a different approach to contraception or a different
medication for the underlying condition are listed next, all level 3 for CHCs and for
POP except where noted:
 Rifamycin-class antibiotics (rifampin, rifabutin, and rifapentine)40
 Some antiepileptic medications: barbiturates, carbamazepine, phenytoin, primi-
done, oxcarbazepine, and topiramate40
 Lamotrigine (level 3 for CHCs; level 1 for POP)40
 Ritonavir-boosted antiretroviral therapy (highly active antiretroviral therapy
including ritonavir to inhibit CYP3A4)40
 St John’s wort65 (not listed in MEC)
 Armodafinil and modafinil66 (not listed in MEC)
 Dual endothelin receptor antagonist bosentan51,52 (not listed in MEC)
Other highly active antiretroviral therapy medications affect the serum levels of hor-
mones in CHCs; however, the clinical relevance of these effects remains murky.67
Thinking regarding the effect of antibiotics on efficacy of OCs has changed over
time, except for antibiotics in the rifamycin class. Some studies show no overall effect
on nonrifamycin antibiotics on blood levels of steroid hormones,68 and the MEC
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490 Evans & Sutton

classifies all nonrifamycin antibiotics as level 1.40 However, the interaction may be
clinically significant in some individuals, particularly with the use of tetracyclines and
penicillins69; a 2011 population study in the Netherlands found that OC users who
conceived had an odds ratio of 2.21 (95% confidence interval: 1.03–4.75) of having
taken antibiotics around the time of conception.70

CHOOSING BETWEEN MANY COMBINATION ORAL CONTRACEPTIVE OPTIONS

See Box 3 for tips on selecting from among COCs. Because the side effect profile and
noncontraceptive benefits are largely similar between different formulations of COCs,
patient preference can strongly influence the choice. The cost difference between
generic and brand name formulations can be marked, which may be a consideration
for some patients.
Monophasic COC preparations should be first-line agents, as there is insufficient
evidence to demonstrate that triphasic preparations are better in terms of effective-
ness, bleeding patterns, or discontinuation rates.72
In a 2014 Cochrane Review,5 researchers recommended 30 mg of EE with levonor-
gestrel (LNG) as the first-line COC. This recommendation was based on a meta-
analysis of 26 studies examining the differential VTE risk between various formulations
of COCs, with the VTE risk found to depend on both the dose of EE and the type of
progestin. The lowest COC dose of EE (20 mg) has the lowest VTE risk but may also
increase unscheduled bleeding that can adversely affect compliance. Of the proges-
tins, LNG (20 mg or 30 mg) had the lowest VTE risk (other types carried a 50%–80%
higher risk).

CYCLIC VERSUS CONTINUOUS USE OF COMBINATION ORAL CONTRACEPTIVES

When the COC was first introduced in 1960, it was formulated with 21 active pills, fol-
lowed by a 7 days of placebo. The withdrawal bleed on placebo pills was meant to
mimic a woman’s natural cycle and, thus, increase acceptability among users.73–75
Continuous or extended use of COCs was recommended by some practitioners
long before the FDA approval in 2003 of SeasonaleÒ, the first brand formulated for
withdrawal bleeding every 3 months (once per season). Since that formulation was
approved, the method has become more widely used, both for the treatment of
menstrual-related symptoms (eg, menstrual migraine and endometriosis) and for con-
venience. Several COCs packaged for extended-cycle use and for continuous use are

Box 3
Tips for selecting a COC

 Patient preference should be strongly considered.64

 Generic formulations cost less than brand name formulations and are bioequivalent.71
 Monophasic preparations are preferred.72
 Of the available progestins, LNG (with 20 mg or 30 mg EE) increases the VTE risk the least.5
 20 mg EE may increase the VTE risk less than higher dosages of estrogen.5
 30 mg EE results in less unscheduled bleeding and lower discontinuation rates.12
 Even relatively androgenic progestins, like LNG, tend to improve acne.12

Abbreviation: LNG, levonorgestrel.

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Oral Contraception 491

currently on the market, but any monophasic COC can be used continuously by hav-
ing patients take only the active pills from each pack and beginning the next pack
directly, without 7 days of no pill or placebo every 28 days. However, third-party
payers may not cover the additional pack required every 12 weeks to use cyclic
COCs in this manner.
Multiple researchers have demonstrated that most women prefer to have less or no
bleeding if given the opportunity,76,77 which can be achieved in several ways:
 Continuous use of active monophasic COCs indefinitely
 Continuous use of active monophasic COCs for periods of time longer than
28 days (for example, 84 days) followed by a scheduled withdrawal bleed
 Continuous use of active monophasic COCs until persistent unscheduled
bleeding begins, at which time patients initiate a hormone-free interval of
7 days or less and, thus, a withdrawal bleed
Advocates of continuous use argue that the hormone-free interval serves no biolog-
ical purpose and could theoretically lead to decreased effectiveness because of the
rare possibility of escape ovulation, decreased compliance, and more missed pills;
worsened quality of life; and more menstrual-related symptoms and work
absenteeism.
Critics of continuous use articulate 2 main concerns: (1) a lack of long-term data
supporting its safety and (2) overmedicalization of normal menstruation. In other
words, they voice concern that continuous-use COCs might recruit more users that
are looking for lifestyle benefits (amenorrhea) without necessarily needing/desiring
the contraceptive benefits and, therefore, exposing themselves to risks of COCs
without a strong indication.78

Efficacy
Studies monitoring signs of ovulation have demonstrated follicular development
occurring in the hormone-free interval of cyclic COCs.79 Delay in initiation of the
next cycle of active pills after a placebo week can lead to contraceptive failure.
Some researchers have postulated that continuous use of COCs may be more effec-
tive than cyclic use,80 but the authors of a recent Cochrane review concluded that
contraceptive efficacy of extended-cycle COC use was similar to cyclic COC use in
8 randomized controlled trials (RCTs).81

Bleeding and Endometrial Effect

Extended-cycle COC use results in less scheduled bleeding with variable reports on
the frequency of spotting or unscheduled bleeding. Most studies show a similar num-
ber of days with bleeding between cyclic COCs and extended-cycle COCs and similar
discontinuation rates,81 with the unscheduled bleeding of extended use declining over
the first several months of use81,82 and fewer menstrual symptoms with extended-
cycle use.81
Sonographic studies of the endometrial lining in continuous and extended-cycle
COC users have demonstrated normal endometrial stripes, and biopsies have
confirmed a lack of hyperplasia.73,80,81,83

Return to Fertility
Median time to return of menses is 32 days after stopping continuous COCs,73,84,85
and 99% of women return to spontaneous menses or pregnancy within 90 days of
stopping COCs.84 Furthermore, within the confines of a 1-year study, the duration
of use was not related to time to return to menses.84
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492 Evans & Sutton

PATIENT COUNSELING
Initiation
There are 3 methods for initiation of CHCs and POP:
 Start on same day the CHC is prescribed (called quick start, same day start, or
immediate start)
 Start on first day of next menses
 Start on the first Sunday on or after the start of next menses (Sunday start)
The quick-start method is acceptable if patients are unlikely to be pregnant. Ovula-
tion is inhibited after 7 days of use. Compared with the other approaches, the quick-
start method may result in higher initial continuation rates86; but that difference is lost
over time for COCs.86,87 Bleeding rates and pregnancy rates are similar.86,87 The
quick-start method is used when OCs are begun in amenorrheic patients in the post-
partum period.

Common Minor Side Effects, Including Management

Breast tenderness and nausea with or without vomiting are commonly reported with
initiation of CHCs, are attributed to the estrogen component, and are less problematic
with 20 mcg EE COCs than with higher EE doses.88 Nausea can be managed by taking
the pill at bedtime or switching to a 20-mcg EE formulation.
On the other hand, breakthrough bleeding (BTB) is more common with 20-mcg
EE COCs than with higher EE doses and leads to more frequent discontinuation
of the lower-dose pills.88 BTB is also common on POP. For low-dose EE COCs
and for POP, taking the pill at the same time every day can reduce the chance of
BTB.
All of these side effects tend to improve over several months with continued use;
counseling patients to expect them and that they should resolve within a few months
can improve OC continuation rates.
If BTB on COC does not resolve with time (and another cause is not found) or if pa-
tients do not find waiting 3 months acceptable, BTB can be managed by increasing
the EE dose from 20 mcg EE to 30 to 35 mcg EE or switching to a COC with a different
progestin. If patients have been taking the COC as an extended cycle, stopping the
active hormone for 4 to 7 days to allow a withdrawal bleed, then resuming extended
use, may be effective for several months, at which time it can be repeated.
Potential for weight gain on COC may be a concern for some women; however,
studies show no significant effect and no difference in discontinuation rates for weight
gain between COC and placebo.89

Potential Major Side Effects

Any symptom suggestive of VTE or arterial thrombosis should be evaluated promptly.
Headaches can occur with initiation of CHCs. New or worsened migraines, severe
headaches, or headaches associated with neurologic signs or symptoms should
prompt discontinuation of the CHC and initiation of appropriate medical evaluation.

Methods to Improve Adherence

For OCs, the quick-start method (also called immediate start or same-day start) is
associated with better initial adherence86 as discussed earlier. Daily text messages
improve OC continuation rates,90 and special counseling can help patients identify
cues to daily dosing.91 Several dozen smartphone applications are available, varying
in reminder methods (light, sound, vibration, and/or pop-up reminders) and also in
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Oral Contraception 493

technical reliability.92 Dispensing a larger quantity of pill packs at once is associated

with fewer pregnancies but more “pill wastage.”93
Although not the focus of this article, the contraceptive patch and ring are relevant to
a discussion of adherence to hormonal contraception. Adherence is better with the
CHC patch than the COC pill in weeks in which it is used,94,95 but side effects may
result in a greater chance of discontinuation of the patch.95 The CHC ring has been
associated with better adherence compared with the patch and ring in some studies.96
Advice for Missed Pills
Ovulation is most likely to occur when pills are missed in the first or last week of active
hormone in cyclic use or any other lapse that results in a hormone-free stretch of more
than 7 days. Estrogen dose matters; missing 1 to 4 doses of COC results in more follic-
ular activity in women who have been on 20-mcg EE formulations than in women who
have been on 30-mcg EE pills.97 Patients should be given advice on aids to adherence
as well as clear instructions on what to do if 1 or more doses is missed (Fig. 1).

Follow-up
No routine follow-up is needed after the initiation of POP or CHC; however, women
should be encourage to return for follow-up should side effects or any other issues

Fig. 1. Recommended actions after late or missed COC doses. (From Centers for Disease Con-
trol and Prevention. U.S. Selected Practice Recommendations for Contraceptive Use, 2013:
adapted from the World Health Organization selected practice recommendations for con-
traceptive use, 2nd edition. MMWR Recomm Rep 2013;62(RR-05):1–60.)
 Author's personal copy
494 Evans & Sutton

or concerns arise.60 Significant changes in health status that may increase the risk or
reduce the efficacy of the contraceptive method should prompt a reevaluation of its
use.60 As is advised for all adults, women on CHC60 should have blood pressure
measured periodically.

CONSIDERATIONS FOR SPECIAL POPULATIONS

A woman’s fertility may span 30 or more years of her life, during which adjustments in
the best choice of contraception should be expected. She will likely experience
changes in her own menstrual cycle, menstrual-associated symptoms, comorbidities,
parity, desire for future fertility, timing or frequency of sexual activity, other copre-
scribed medications, and so forth. All of these may influence the balance of benefit
and risk for a woman choosing a contraceptive method. The following are a few sub-
groups for which questions commonly arise.

Teenage Years
Compared with the 1990s, adolescents in the United States are less likely to report be-
ing sexually active and more likely to report using effective forms of contraception; but
the teen pregnancy rate remains higher than in other developed countries,98 and about
78% of teen pregnancies are unintended.99 In 2009, teens aged 15 to 19 years in the
United States had 705,000 pregnancies and 410,000 live births.98
During 2006 to 2010, 43% of teens aged 15 to 19 years reported having had sex,
which represents a 16% decline from a prior finding of 51% in 1995.100 Almost 80%
of female teenagers who had sex reported having used contraception for the first in-
tercourse, with 68% of those using condoms, 16% using OC, and 6% using injection,
patch, ring, or emergency contraception.101 Among female teenagers who had sex in
the prior month but were not pregnant, postpartum, or seeking pregnancy, overall
48% used a hormonal method or IUD without a condom; 12% used a hormonal
method or IUD with a condom; 16% used condoms alone or a method of similar effi-
cacy; 6% used a less effective method, such as withdrawal; and 18% did not use any
contraception.100 Compared with 1995, this reflects a 26% increase in the use of more
effective methods and a 7% decrease in the use of no contraceptive method.100
Age, itself, is not a contraindication to any reversible form of contraception. Teens
should be counseled that condoms are needed to protect against sexually transmitted
infections; but given their high contraceptive failure rate with typical use, an additional
contraceptive method should also be strongly considered. Although outside the scope
of this article, Long-acting reversible contraceptives (LARCs) are highly efficacious
and safe in this population but are underused, with about 2.5% of teens using
IUDs102 and about 0.5% using progestin implant.103 The ACOG recommends that ad-
olescents be encouraged to consider LARC methods.103 CHCs also remain a reason-
able choice for contraception for teens and offer control of irregular and/or heavy
periods. COCs have the additional noncontraceptive benefit of improving acne.
Adolescents face some unique barriers to obtaining and optimally using contracep-
tion that should be considered by health care practitioners.104
Confidentiality can be a significant concern. Policies need to be in place to maintain
confidentiality of medical records, reimbursements, and so forth; patients should be
repeatedly reassured about efforts to maintain confidentiality.
Misinformation can be prevalent and should be corrected. Providing accurate infor-
mation on sex and contraceptive choices to adolescents does not lead to increased
rates of sexual activity, earlier onset of intercourse, or a greater number of part-
ners.104,105 Patients may have exaggerated concern or inaccurate information about
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Oral Contraception 495

risks of COCs; practitioners can help by dispelling myths about weight gain, mood
swings, or acne. Teens should also be reassured that a pelvic examination is typically
not needed before prescribing OCs.60
Adherence to user-dependent hormonal contraceptive methods is a significant
challenge in this population. Typical-use failure rates for COCs are about 8% in the
general population but 15% to 26% in teenagers,104 hence, the recommendation to
consider LARC or injection. When OCs are chosen, the clinician should counsel pa-
tients on the importance of not missing pills, emphasize the noncontraceptive benefits
of OCs, offer (but not require) frequent follow-up, and troubleshoot ways to keep use
confidential from a parent or other adult if that is important to patients. Alternatively, if
patients are open to involving their mother, this can increase compliance.104 Lastly,
emergency contraception should also be proactively discussed and prescribed so it
is readily available if the need should arise.

Postpartum
Effective contraception in the postpartum period is important. Unintended pregnan-
cies can have long-lasting detrimental effects on the mother-child relationship.106
Interpregnancy intervals less than 6 months adversely affect fetal health by increasing
preterm birth and neonatal death.106,107 Cross-culturally, about half (ranging about
32%–60%) of mothers have resumed sexual activity by 6 weeks post par-
tum.1–4,6,7,40,108 Contraceptive counseling by practitioners before and after delivery
significantly increases the percentage of women who choose a highly effective
method of contraception.109
When considering OC options in the postpartum period, the main consideration for
nonbreastfeeding mothers is the risk of VTE, which is 11-fold110 to 50-fold111 higher in
the first 3 months post partum than in nonpregnant women and as much as 84-fold
higher111 in the first 6 weeks post partum compared with the nonpregnant state.
Coagulation and fibrinolysis variables are altered post partum, potentially as a mech-
anism for reducing the risk of postpartum hemorrhage.40 MEC recommendations for
the postpartum period are given in Table 3.
Additional considerations with breastfeeding include (1) hormone uptake into breast
milk and its effect on the infant and (2) effect of hormones on breast milk production.
Although the estrogen component of COCs may decrease milk production, POPs do
not have a demonstrable effect on milk production. Exogenous progestin is trans-
ferred to breast milk112; however, no long-term effects have been detected with obser-
vation of breastfed children whose mothers took POPs up to 8 years.113 COCs have
not been shown to have adverse effects on infants.40,114

Perimenopause
Perimenopause includes several years of decreasing fertility during the menopausal
transition and ends 12 months after the final menstrual period.115,116 There is a wide
range of experiences and symptoms related to perimenopause; but physiologic
changes, cycle changes, and perimenopausal symptoms can last more than 6 years117
and commonly intensify over the 4 years preceding the final menstrual period.118
Contraception is indicated for pregnancy prevention during perimenopause. Fecun-
dity is variable from woman to woman and affected by genetics, comorbidities, smoking,
coital frequency, and male fertility. Although fertility rates decrease starting in a woman’s
late 20s, the annual chance of pregnancy in heterosexual cohabitating women in their mid
40s, not using any contraception, can still be estimated around 10%119; pregnancy can
occur into the sixth decade of life. It is estimated that only about half of couples are truly
sterile at 45 years of age.120 Furthermore, when pregnancies do occur in this period, there
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496 Evans & Sutton

is a higher risk of miscarriage (about 33% by 45 years of age),120,121 pregnancy compli-

cations, and perinatal mortality (about 1.0%–1.4% to women 40 years and older).122
The full spectrum of options for contraception is available to women in perimeno-
pause; age, itself, is not a contraindication to any of the options. The US MEC catego-
rizes 40 years of age and older as level 2 with the comment that cardiovascular risk
factors increase with age and advises that “[i]n the absence of other adverse clinical
conditions, CHCs can be used until menopause.”40
The estrogen component of COCs can have noncontraceptive benefits for
perimenopause-related symptoms commonly experienced at this time,118 including
irregular cycles, heavy menstrual bleeding, and vasomotor symptoms.
The most concerning potential complications of COCs are detailed in prior sections
but are generally VTE and cardiovascular disease (heart attack and stroke). The pres-
ence of comorbidities that contribute to these diseases increases with age (eg, dia-
betes, hypertension); age is an independent risk factor for VTE. COCs should
generally not be prescribed to women aged 35 years and older who smoke or to
women with multiple risk factors for cardiovascular disease, of which age is one.40
Although outside the scope of this article, LARC options (IUDs and progestin
implant) should also be considered for women in this age group, especially those
who have relative or absolute contraindications to exogenous estrogen.
Deciding when to stop hormonal contraception should be an individualized deci-
sion. In a healthy, nonsmoking woman who has continued COCs throughout perimen-
opause, it would be ideal to stop COCs shortly after menopause has begun (after her
final natural menstrual period would have occurred). This timing is, of course, difficult
to identify prospectively and complicated by the suppression of her natural menses by
the COCs. Continued withdrawal bleeds do not mean menopause has not developed;
likewise, amenorrhea while on cyclic COCs does not necessarily predict meno-
pause.119 The most common method of stopping is to have a woman who is
approaching 50 years old stop her COC while using a nonhormonal backup method.
If this trial period is not feasible for a particular woman, practitioners can check an FSH
level at the end of each hormone-free interval and presume menopause has devel-
oped if FSH is 30 IU/L or greater. However, this approach can be misleading, failing
to identify menopause even though it has developed.119

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