RISKS AND SIDE EFFECTS ASSOCIATED WITH ESTROGEN-PROGESTIN

CONTRACEPTIVES
Risks and side effects associated with estrogen-progestin
contraceptives
Authors
Kathryn A Martin, MD
Pamela S Douglas, MD
Section Editors
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD
Disclosures: Kathryn A Martin, MD Employee of UpToDate, Inc. Pamela
S Douglas, MD Grant/Research/Clinical Trial Support: Abiomed [Heart
failure (Right ventricular percutaneous assist device)]; Atritech/Boston
Scientific [Atrial fibrillation (Left atrial appendage occlude device)]; Bristol
Meyers Squibb [Hepatitis]; David H Murdock Research Institute; Gilead
[Hepatitis (Sofusbivir)]; Edwards Lifesciences [Aortic Stenosis (Percutaneous
heart valve)]; HeartFlow [Coronary artery disease (CTA analysis software)];
Ikaria [Heat failure (Sodium alginate)]; Merck; Novartis; ResMed [Heart
failure (Ventilator)]; Roche [Heart failure]; Stealth Peptides [Heart failure (Darginyl-2,6-dimethyl-L-tyrosyl- L lysyl- L phenylalaninamide)].
Consultant/Advisory Boards: Boston Scientific [Atrial fibrillation (Left atrial
appendage occlude device)]; CardioDx [Coronary artery disease (Blood
diagnostic with gene expression)]; Interleukin Genetics; Pappas Ventures;
Omicia [Genomics]; Third Point, LLC; Genome Magazine [Genomics]; US
Diagnostic Standards [Genomic testing]. Equity Ownership/Stock Options:
CardioDx [Coronary artery disease (Blood diagnostic with gene expression)];
Omicia [Genomics].Robert L Barbieri, MD Nothing to disclose. William F
Crowley, Jr, MD Consultant/Advisory Boards: Quest Diagnostics
[endocrinology (diagnostic laboratory testing)].
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Literature review current through: Jan 2015. | This topic last
updated: Nov 11, 2014.
INTRODUCTION Oral contraceptives (OCs) are a reliable form of
contraception with a theoretical failure rate of 0.1 percent and, due to
problems with compliance, an actual failure rate of 2 to 3 percent. They also
have noncontraceptive benefits, being useful in the treatment of a variety of
disorders including hyperandrogenism, dysmenorrhea, and menorrhagia.

Currently available preparations are shown in the table (table 1). There are,
however, several contraindications to their use. (See"Overview of the use of
estrogen-progestin contraceptives".)
Concern about toxicity (such as thromboembolic events and cardiovascular
disease) initially limited the long-term use of these drugs. However, the
decrease in both estrogen and progestin content since the introduction of
the pill in 1960 has led to a reduction in both side effects and cardiovascular
complications [1]. As a result, these preparations are a reasonable
contraceptive option for most women.
While the US Food and Drug Administration (FDA) had previously set upper
age limits for OC use as 35 years for smokers and 40 years for nonsmokers,
the age limit was removed in 1989 for healthy, nonsmoking women. Thus,
OCs can be given until menopause in such women. Caution is still needed in
prescribing OCs for women who smoke and an effort to induce smoking
cessation should be made first.
Certain forms of toxicity remain a concern. This topic will review the side
effects and major potential risks associated with OC administration. The
noncontraceptive benefits of estrogen-progestin contraceptives and other
types of contraception are reviewed separately. (See "Overview of the use of
estrogen-progestin contraceptives", section on 'Noncontraceptive
benefits' and "Overview of contraception".)
SIDE EFFECTS Early side effects of oral contraceptives (OCs) include
bloating, nausea, and breast tenderness [2]. Although they may be
bothersome enough to lead to discontinuation of the OC, these side effects
usually subside in several months. Abnormal bleeding is a common problem
that often resolves. Weight gain is not a consistent finding with low-dose
pills. (See 'Weight' below.)
Breakthrough bleeding Breakthrough bleeding is the most common
side effect of OCs. Its occurrence does not indicate a decrease in efficacy,
but reflects tissue breakdown as the endometrium adjusts to a new thin
state in which it is fragile and atrophic. Breakthrough bleeding is more of a
problem with lower doses of estrogen because estrogen stabilizes the
endometrium. In addition, bleeding is more common with extended and
continuous regimens, although most women eventually develop
amenorrhea.
The most common cause of breakthrough bleeding is thought to be missed
pills [3]. Women should be cautioned that missing pills results in an increase
in breakthrough bleeding as well as a decrease in contraceptive efficacy.
Follicular development with increased estrogen concentrations may also
occur with the lower dose preparations [4]. Other causes include smoking
[5] and drug interactions. (See "Overview of the use of estrogen-progestin
contraceptives", section on 'Drug interactions'.)
Although contraceptive efficacy appears to be similar for different
progestins, limited data suggest that the third-generation progestins may be
associated with less intermenstrual bleeding than earlier progestins [6].
However, we do not consider this to be a reason to choose third-generation
progestins over earlier ones.

Our approach to treatment of bleeding starts with patient reassurance and

encouragement to take the OC for at least three cycles before making any
changes. If the bleeding does not stop, a cervical examination pelvic
ultrasound to rule out structural causes of bleeding, such as uterine fibroids
or polyps, should be considered.
Amenorrhea Amenorrhea is the goal with the continuous and extended
estrogen-progestin regimens. However, amenorrhea may also occur with the
standard preparations containing 21 days of hormone and seven days of
placebo, most commonly with the lower dose pills containing 20 mcg.
Amenorrhea is the desired outcome with the extended regimens, but it is a
bothersome problem with the standard cyclic regimens because of the
monthly concern that pregnancy might have occurred.
If the woman is on a low dose (20 mcg OC), switching to a 30 to 35 mcg
preparation often restores menses. Our most common approach is to simply
reassure the patient that the amenorrhea is not a sign of a new endocrine
problem, nor does it mean that she is not getting reliable contraception.
Post-pill amenorrhea It had previously been thought that women who
used OCs were at risk of developing subsequent irregular menses or
amenorrhea. However, data suggest that the incidence and endocrinologic
findings in women with amenorrhea occurring after the use of cyclic OC
regimens are the same as in women with spontaneous amenorrhea [7]. This
appears to be true for continuous pill regimens, as well, as illustrated in a
report of 187 women using the continuous pill for one year [8]. After
stopping the pill, the median time to return to menses was 32 days, and
spontaneous menses or pregnancy occurred at day 90 in 185 of 187
women (98.9 percent).
Thus, women who do not menstruate three months after discontinuing an
OC should undergo the same evaluation for amenorrhea as any woman with
amenorrhea. (See"Etiology, diagnosis, and treatment of primary
amenorrhea" and "Etiology, diagnosis, and treatment of secondary
amenorrhea".)
DRUG INTERACTIONS The metabolism of oral contraceptives (OCs) is
accelerated by any drug that increases liver microsomal enzyme activity
such asphenobarbital, phenytoin, and rifampin. This topic is reviewed in
detail separately. (See "Overview of the use of estrogen-progestin
contraceptives", section on 'Drug interactions'.)
CONTRAINDICATIONS The absolute and relative contraindications to the
use or estrogen-progestin contraceptives are reviewed in detail separately
(table 2). (See"Overview of the use of estrogen-progestin contraceptives",
section on 'Contraindications'.)
CARDIOVASCULAR DISEASE The greatest concern surrounding the use
of estrogen-progestin contraceptives has been the increase in
cardiovascular morbidity and mortality that occurred with the early highdose pills. However, the reduction in estrogen content has increased safety
substantially. Because myocardial infarction (MI) is an extremely rare event
in otherwise healthy women of reproductive age, even a doubling of the risk

would result in an extremely low attributable risk. Risk in older women who
smoke outweighs the risk of an unwanted pregnancy [9].
Much of what is known about the potential risks of oral contraceptives (OCs)
comes from four large cohort studies: the Royal College of General
Practitioners (RCGP) Study, the Oxford Family Planning Association Study,
the Walnut Creek Contraceptive Drug Study, and the Group Health
Cooperative of Puget Sound Study [10,11].
Coronary heart disease A number of epidemiologic studies have
reported an increase in MI, thought to be related to a thrombotic mechanism
rather than the development of atherosclerotic plaques [12], and an
increase in cardiovascular mortality in estrogen-progestin contraceptive
users over age 35 years who smoke [13,14]. These studies included women
who used both high (50 mcg ethinyl estradiol [EE]) and low-dose (35 mcg
EE) OCs. However, the absolute risk of an MI in a nonsmoker using a pill
containing 20 to 40 mcg of EE is very low [12,15].
Newer "third-generation" OCs (eg, those containing desogestrel,
norgestimate, or gestodene) have more favorable effects on the lipid profile
than second generation preparations, but this did not translate into a lower
risk of MI in two case-control studies [16,17]. In a third study, the risk of MI
appeared to be lower in women using third rather than second generation
(relative risk [RR] 2.5) OCs (RR 1.3 versus 2.5, respectively), but the
difference was not significant [18].
A meta-analysis of 10 studies calculated an overall doubling of
cardiovascular mortality risk (due to coronary heart disease [CHD]) in
women using OCs with less than 50 mcg EE [19]. However, because MI is an
extremely rare event in otherwise healthy women of reproductive age, even
a doubling of the risk would result in an extremely low attributable risk.
The largest cohort study of hormonal contraception and arterial thrombosis
risk was published after the meta-analysis, and included the entire
population of Danish women ages 15 to 49 years, followed from 1995 to
2009, with nearly 500 MIs and over 1000 strokes in current users of
hormonal contraception. In an analysis adjusted for differences in progestin
type and age, OCs containing EE doses of 20 mcg or 30 to 40 mcg were
associated with an increased risk of MI (RR 1.4 and 1.88, respectively) [12].
Risks did not differ significantly between type of progestin. In spite of the
apparent excess risk of MI, the absolute risk of an event with OCs is very
low; the authors estimated that among 10,000 women who use a pill
containing EE 20 mcg with desogestrel for one year, two will have arterial
thrombosis (MI or thrombotic stroke) (versus 6.8 with venous thrombosis)
[15]. (See 'Stroke' below and 'Venous thromboembolic disease' below.)
The number of MIs was too low to estimate risk for the contraceptive patch
and vaginal ring. No excess risk was seen with any of the progestin-only
formulations.
Theoretically, the increase in MI risk may be more clinically relevant in
women with polycystic ovary syndrome (who are thought to be at higher risk
of cardiovascular disease) [19]. However, there are no clinical data on the
risk of MI with OC use in this group of patients. (See "Diagnosis of polycystic

ovary syndrome in adults" and"Treatment of polycystic ovary syndrome in

adults".)
A consensus panel reviewing the issue of OCs in women over 35 years who
smoke suggested that OCs should not be given to those who smoke more
than 15 cigarettes per day, but they can be considered in women who
smoke fewer than 15 cigarettes per day, since the risks of pregnancy in this
age group are greater than the risks associated with OC use [20]. World
Health Organization (WHO) guidelines agree with this approach. However,
patients often underreport the number of cigarettes smoked per day and,
therefore, we agree with the American College of Obstetricians and
Gynecologists (ACOG) that the risk of OC use is unacceptable for women
over 35 years who smoke at all.
On the other hand, for younger women, the benefits of OCs appear to
outweigh the risks, even among heavy smokers, as long as there is no
family history of thromboembolic disease.
Women who have taken an OC are not at increased risk for CHD later in life
[21,22].
In summary, some, but not all, studies report that OCs may be associated
with an increased risk of MI. However, because MI is an extremely rare event
in otherwise healthy women of reproductive age, even a doubling of the risk
would result in an extremely low attributable risk. Risk in older women who
smoke outweighs the risk of an unwanted pregnancy.
Hypertension OCs frequently cause a mild elevation in blood pressure
within the normal range; however, overt hypertension can occur. Early
reports suggesting an incidence of hypertension of 5 percent involved
preparations containing at least 50 mcg of estrogen and 1 to 4 mg of
progestin. The effect of current low-dose OCs was assessed in a report from
the Nurses' Health Study, which prospectively evaluated almost 70,000
nurses aged 25 to 42 years [23]. After adjustment for age, weight, smoking,
family history, and other risk factors, the RR of hypertension compared with
women who never used OCs was 1.8 for current users and 1.2 for previous
users. Overall, only 41.5 cases per 10,000 person-years could be attributed
to OC use; this risk rapidly declined with cessation of therapy. (See "Effect of
oral contraceptives and postmenopausal hormone therapy on blood
pressure".)
Although OC-induced hypertension is not common, its recognition is
important, as hypertensive OC users appear to be at increased risk of MI
and stroke relative to nonusers [24].
Stroke OC use has been associated with a small but significant increase
in ischemic stroke risk in many [25-27], but not all [28-30], studies. This was
a particular concern with early OC preparations that contained high doses of
estrogen [31]. OC preparations containing less than 50 mcg of EE are
associated with a lower risk of stroke than high-dose preparations. Of note is
that in otherwise healthy young women (non-smokers without
hypertension), the attributable risk is extremely low because baseline risk of
ischemic stroke is so low in this population [32]. In all of these studies,
the absolute risk of stroke was very low in young women (11.3 per 100,000

patients per year) [28,29]. Stroke risk appears to be similar across different
progestins [27,33].
Ischemic A meta-analysis of 16 epidemiologic studies found that a
nonsmoking, normotensive woman's annual stroke risk would be expected
to increase from 4.4 to 8.5 per 100,000 with use of low estrogen OCs [32].
Thus, treatment of 24,000 women would lead to one additional ischemic
stroke each year.
A second meta-analysis of 20 studies (four cohort and 16 case-control,
including many of the studies described above [25-29]), reported an
increased risk of thrombotic stroke in the case-control studies (odds ratio
[OR] 2.74, 95% CI 2.24-3.35), but not the cohort studies (OR 0.95, 95% CI
0.51-1.78) [34]. The authors argue that the association, if it exists, is very
small, and perhaps nonexistent (due to heterogeneity of the studies, ORs
less than 1.0 in the cohort studies, and methodological limitations including
potential biases and confounders, which were not adequately addressed).
In the large Danish cohort study described above [12], use of combined OCs
was associated with an excess risk of thrombotic stroke in addition to MI
when compared with non-use (see 'Coronary heart disease' above). In the
analysis adjusted for differences in progestin type and age, preparations
containing EE doses of 20 mcg or 30 to 40 mcg, the RRs of thrombotic
stroke risk were 1.6 and 1.75, respectively. Risks did not differ significantly
between type of progestin. As described above, the absolute risk of a
thrombotic stroke or MI is very low. (See 'Coronary heart disease' above.)
The risk of thrombotic stroke also appeared to be increased for other routes
of administration: for the contraceptive patch (RR 3.15, 95% 0.79-12.6) and
the vaginal ring (RR 2.49, 95% CI 1.41-4.41) [12]. No excess risk was seen
with any of the progestin-only formulations.
If a woman on an OC has a stroke, the pill should be discontinued and not
resumed.
Hemorrhagic OCs do not appear to be associated with an excess risk of
hemorrhagic stroke [35]. However, we suggest alternate forms of
contraception in women who have had such a stroke.
Additional risk factors with OC use In addition to older age, smoking,
hypertension, and migraine headaches with aura, other factors that further
increase stroke risk in women taking OCs include obesity, dyslipidemia, and
prothrombotic mutations [33,36].
The Risk of Arterial Thrombosis In Relation to Oral Contraceptives study
(RATIO) found that women using OCs who were heterozygous for factor V
Leiden had an 11-fold excess risk of ischemic stroke compared with women
not using OCs (OR 11.2, 95% CI, 4.229.0) [37]; lupus anticoagulant
conferred even greater risk in women using OCs (OR 201, 95% CI, 22.11828), but this estimate was based upon a small number of events [38].
The question of whether women should be screened for thrombophilia
before starting hormonal contraception is addressed below. (See 'Screening
for thrombophilia'below.)
VENOUS THROMBOEMBOLIC DISEASE An increase in the risk of
venous thromboembolic disease (VTE) is seen with both high and low dose

estrogen oral contraceptive (OC) preparations [39-42]. Although the

reduction in steroid content of OCs has improved the safety and side effect
profile of the pill, the increased risk of venous thrombosis has not been
eliminated [40,43,44].
A pooled analysis of studies regarding the use of OCs found that the risk
ratios for thromboembolism in women taking non-third generation OCs
compared with women who did not take an OC ranged from 1.1 to 4.8
(depending upon the type of study) [43]. However, the absolute risk of
thromboembolism is very low in healthy women, and the potential risk of
VTE with the use of OCs is far less than the risks associated with unintended
pregnancy.
Obesity Obesity further increases risk. Among OC users in two casecontrol studies, obese women had a two- [45] to 24-fold [46] higher risk of
VTE as non-obese women. In a third case-control study of 454 consecutive
patients with a first episode of objectively diagnosed deep vein thrombosis
(DVT), the risk of thrombosis among those with both obesity and OC use was
increased 10-fold compared with women with neither risk factor; the
increase in risk was lower (2.3- to 4.6-fold) with either risk factor alone [47].
Age Increasing age is also associated with increased risk. In a pooled
analysis of two case-control studies, the risk of VTE rose sharply after age
39 years among women taking estrogen-progestin OCs. The estimated
incidence in women over age 39 years, when compared with adolescents,
was 100 versus 25 cases of VTE per 100,000 person-years, respectively
[48].
Type of progestin
Third generation There have been concerns that newer progestins may
be associated with a greater risk of VTE when compared with earlier
progestins. A number of observational studies, initially published in the mid1990s, reported that women taking OCs containing third generation
progestins (desogestrel and gestodene, but not norgestimate) were at
greater risk for VTE when compared with women taking OCs
containing levonorgestrel, a second generation progestin (odds ratios [ORs]
ranging from 1.5 to 2.6) [49-52]. Similar results were later reported in a
meta-analysis of seven studies that compared the effects of different OCs on
VTE risk; the overall adjusted odds ratio for VTE with third versus second
generation OCs was 1.7 [53].
Although not all epidemiologic studies have confirmed these findings
[54,55], a large 2011 registry-based cohort study reported an excess risk of
VTE with OCs containing desogestrel or gestodene compared with those
containing levonorgestrel [56].
Acquired resistance to activated protein C has been suggested as one
mechanism by which the third generation OCs could predispose to VTE
[57,58]. In addition, third generation and second generation progestins have
different effects on the anticoagulant pathway [59,60]. It has been
suggested that second generation progestins, such as levonorgestrel, are
more effective than third generation progestins, such as desogestrel, in
counteracting the thrombotic effects of estrogen [61].

In summary, most studies suggest that the third generation progestins,

desogestrel and gestodene (but not norgestimate), may be associated with
a higher risk of VTE when compared with levonorgestrel, a second
generation progestin. However, the absolute excess risk is small, and may
be outweighed by the many benefits of OCs, including prevention of an
unwanted pregnancy, and a reduction in ovarian and endometrial cancer
risk. (See 'Ovarian cancer' below and 'Endometrial cancer' below.)
Antiandrogens
Cyproterone acetate Data on the impact of OCs containing cyproterone
acetate, a progestin and antiandrogen, on the risk of VTE are conflicting. In
two studies, a higher risk of VTE was seen when compared with
contraceptives containing levonorgestrel [62,63], while a lower risk was
reported in a report from the Danish National Register of Patients (absolute
risk 4.2 and 3.1 per 10,000 woman-years for levonorgestrel
and cyproterone acetate, respectively) [64].
Drospirenone Drospirenone, a progestin that also has antiandrogen and
antimineralocorticoid properties, has been associated with a greater risk of
VTE when compared with levonorgestrel in some, but not all studies. In
2012, based upon available data, the US Food and Drug Administration
(FDA) added revised labeling to all OCs containing drospirenone, stating that
they may be associated with up to a threefold higher risk of VTE compared
with OCs with levonorgestrel and some other progestins [65].
The FDA does not advise women to stop drospirenone-containing OCs, but
does suggest that an individuals risk of VTE be assessed before starting one
in a new OC user, or before considering using one in a woman who has been
on an OC not containing drospirenone. Lastly, the warning notes that the
VTE risk with drospirenone is small and still lower than the risk of VTE during
pregnancy.
The FDA based its decision on the following data:
Two initial observational studies reported that OCs containing drospirenone
were associated with an excess risk of VTE (similar in magnitude to the third
generation progestins [52,66]).
Two subsequent large, prospective, surveillance studies of new users of
drospirenone-containing OCs subsequently reported that the
thromboembolism risk was no different from that for other OCs [67,68]. It
was estimated that 9000 women would need to be treated with a
drospirenone OC to see one additional case of VTE [68].
After the publication of the two surveillance studies, two additional casecontrol studies [69,70] and a registry-based cohort study [56] reported a
two- to threefold increased risk of VTE with OCs containing drospirenone
compared with levonorgestrel.
An FDA-sponsored study published after the Drug Safety Communication
utilized computerized data files from two integrated medical care programs
and two state Medicaid programs to obtain data regarding the risk of several
cardiovascular endpoints in combined hormonal contraceptives users [71].
The authors identified a final cohort that included 189,210 person-years of
exposure to drospirenone. In adjusted analyses, drospirenone use was

associated with a significantly higher risk of VTE relative to low-estrogen

comparators (relative risk [RR] 1.74, 95% CI 1.42-2.14). When the analysis
was restricted to new users only, drospirenone was associated with a higher
risk of both arterial thrombotic events (RR 2.01, 95% CI 1.06-3.81) and VTE
(RR 1.77, 95% CI 1.33-2.35).
In 2011, the European Medicines Agency also concluded that drospirenonecontaining birth control pills carry a higher risk of VTE, but noted the overall
risk of blood clot from any birth control method remains small and stopped
short of advising women to stop taking pills containing drospirenone [72].
Contraceptive patch Data are conflicting on whether the risk of VTE is
higher in users of the transdermal contraceptive patch (Ortho Evra) than
users of OCs. (See"Transdermal contraceptive patch", section on 'Risk of
thrombotic events'.)
Injectables Oral and injectable progestin-only preparations for
contraception do not appear to be associated with an increased risk of
thromboembolism. (See"Overview of contraception", section on 'Injectable
contraceptives'.)
Thrombophilias Use of OCs significantly increases the risk of thrombosis
in women with hereditary thrombophilia [73,74]:
In one study of 155 consecutive premenopausal women with deep venous
thrombosis, the risk of thrombosis among those with both OC use and the
factor V Leiden mutation was increased more than 30-fold compared with
women with neither risk factor; the increase in risk was lower (four- to
eightfold) with either risk factor alone [73]. (See "Factor V Leiden and
activated protein C resistance: Clinical manifestations and diagnosis",
section on 'DVT'.)
In a retrospective family cohort study, women with hereditary deficiencies
of protein S, protein C, or antithrombin who were taking an OC had an
annual incidence of VTE of 3.5 percent, increasing to 12 percent if an
additional thrombophilic defect was present [74].
Screening for thrombophilia Some have argued that all women should
be screened for the Factor V mutation before pregnancy or OC therapy.
However, the cost efficacy of this approach is questionable [40,75]. Over
500,000 women would need to be screened for Factor V Leiden to avoid one
death from pulmonary embolism, as only 5 percent of women have the
mutation, and venous thrombosis-related mortality is low in young women
[40]. The World Health Organization (WHO) does not recommend routine
screening for thrombogenic mutations. (See "Contraceptive counseling for
women with inherited thrombophilias", section on 'Indications for screening
for inherited thrombophilias'.)
Other risk factors for VTE are discussed in detail elsewhere. (See "Overview
of the causes of venous thrombosis".)
Cerebral vein thrombosis Carriers of hereditary thrombophilias (Factor
V Leiden, the prothrombin gene mutation, and deficiencies of protein S,
protein C, and antithrombin) and subjects with hyperhomocysteinemia who
take an OC are at higher risk of cerebral vein thrombosis [76-79].
(See "Prothrombin gene mutation: Thrombotic risk and diagnosis".)

Surgical risk The potential perioperative risk of VTE due to OCs and the
indications for stopping OCs prior to surgery are discussed separately.
(See "Perioperative medication management", section on 'Oral
contraceptives'.)
Summary In summary, even low dose OCs cause a modest increase in
risk of VTE. Some studies suggest that the risk of VTE is higher with OCs
containing third generation progestins (desogestrel and gestodene), when
compared with OCs containing levonorgestrel [49-51,80]. However, this area
remains controversial [53,55,81-83].
OCs containing drospirenone also appear to be associated with a higher risk
of VTE compared with OCs containing levonorgestrel. As of 2012, these OCs
carry revised labeling to reflect this possible excess risk.
It is important to take a careful personal and family history of deep venous
thrombosis to detect those women who might be at high risk before
prescribing an OC. Women with antiphospholipid antibodies or the nephrotic
syndrome also may be at increased risk [84,85].
WHO strongly discourages the use of OCs or other hormonal contraception
in women with either an underlying thrombophilia or a history of a previous
venous thromboembolic event [86]. However, they do not recommend
routine screening for underlying thrombogenic mutations.
Although there are no data specifically addressing the risk of recurrent deep
venous thrombosis with OCs, data in postmenopausal women suggest that
even low dose estrogen use increases risk of a recurrent event [87].
RISK OF CANCER
Overall cancer risk Oral contraceptive (OC) use has been associated
with an increased risk of certain types of cancer and a decrease in others.
However, it appears that the pill is not associated with an overall increased
risk of cancer. This was illustrated in the Royal College of General
Practitioners' (RCGP) cohort study, which included nearly 50,000 women
followed for a mean of 24 years. In pill users compared with nonusers, risks
were significantly lower for colorectal, uterine, and ovarian cancer [88]. The
incidence of breast cancer was similar in pill users and never users, but
there were significant trends of increasing risk of cervical and central
nervous system cancer in pill users. Depending upon the data set used,
there was either a nonsignificant or significant reduction in overall cancer
risk among users compared with nonusers, with an estimated absolute risk
reduction between 10 and 45 per 100,000 woman-years.
Breast cancer Available data on breast cancer risk with OC use are
conflicting.
Epidemiologic studies have generally not demonstrated an association
between OC use and the risk of breast cancer later in life [89-94].
In three large prospective cohort studies, including the Nurses' Health
Study, the RCGP study, and the Oxford-Family Planning Association
contraceptive study, neither long-term past OC use nor current use was
associated with an increased breast cancer risk [88,91,95].
A population-based, case-control study evaluated women ages 35 to 64
years (4574 women with breast cancer and 4682 controls), over 75 percent

of whom were using or had used OCs [92]. The relative risks (RRs) of breast
cancer for current or previous OC use were 1.0 (95% CI 0.8-1.2) and 0.9
(95% CI 0.8-1.0), respectively. Breast cancer risk was not associated with
estrogen dose, duration of use, initiation at a young age (<age 20 years), or
race.
A meta-analysis of prospective cohort studies (13 studies, involving 11,722
cases and over 850,000 women) reported a nonsignificant increase in ever
users of OCs compared with non users. (RR 1.08, 95% CI 0.99-1.17) [96].
Data on breast cancer risk in OC users with a family history of breast cancer
are also conflicting. In one case-control study [92], the risk was not
increased in women with a family history of breast cancer [92]. In contrast,
a review of women taking OCs prior to 1975 (high dose formulations) found
an increase in breast cancer risk in those who had a first-degree relative
with breast cancer (RR 3.3, 95% CI 1.6-6.7) [97]. However, the small number
of breast cancer cases and the high dose formulations used prior to 1975
limit the generalizability of this report to current OC use.
Data on breast cancer risk with OC use in women who are carriers
of BRCA1 mutations are inconsistent [96]. (See "BRCA1 and BRCA2:
Prevalence and risks for breast and ovarian cancer".)
Cervical cancer There appears to be an increased risk for developing
cervical cancer among women who have taken OCs [88,94,98-100]. A
systematic review of 28 studies, including over 12,000 women with cervical
cancer, found that the risk increased with increasing duration of oral OC use
(table 3) [101]. Although there was considerable variation in study designs,
the increased risk of cervical cancer was demonstrated after adjusting for
the number of sexual partners, previous cervical smears, smoking, histology
(adenocarcinoma or squamous cell), human papillomavirus (HPV) status,
and use of barrier methods. Adjustment for HPV status may not have been
reliable since HPV testing at regular intervals was not routinely performed;
thus, some HPV infections could have been missed [101].
The best available evidence comes from The Collaborative Group on
Epidemiological Studies of Cervical Cancer, which reanalyzed and pooled
individual participant data from 24 epidemiologic studies that included
16,573 women [102]. The risk of invasive cervical cancer increased with
increasing duration of use (RR for five or more years of use 1.90, 95% CI
1.69-2.13). The risk decreased after use ceased, returning to that of
nonusers after 10 years.
Similar patterns of risk were seen for invasive and in-situ cancer, and for
women who tested positive for high-risk HPV. The absolute increase in risk is
very low: the authors estimate that 10 years of use between ages 20 and 30
years would increase the cumulative incidence of cervical cancer from 7.3 to
8.3 per 1000 and 3.8 to 4.5 per 1000 in less developed and more developed
countries, respectively. It is still unclear whether the relationship between
OC use and cervical cancer is a causal one because their use is also
associated with exposure to human papillomavirus, the known cause of
cervical cancer.

Some studies indicate HPV-negative OC users do not have an increased risk

of cervical cancer [101,103]. The mechanism for an increased cervical
cancer risk in HPV-positive OC users noted in some studies may be related
to a metabolite of estradiol, 16 alpha-hydroxyestrone, which can act as a
cofactor with oncogenic HPV to promote cell proliferation [100,103-105].
Ovarian cancer Epidemiologic studies have consistently shown that
prolonged use of OCs reduces the risk of ovarian cancer [94]. An analysis of
45 epidemiological studies from 21 countries found that, compared with
women who had never used OCs, any use of OCs was associated with a
significant reduction in risk of developing ovarian cancer (RR 0.73, 95% CI
0.70-0.76) [106]. Importantly, the protective effect persisted for 30 years
after cessation of OCs. Low dose OCs are as effective as higher dose OCs.
This topic is reviewed in detail separately. (See "Epithelial carcinoma of the
ovary, fallopian tube, and peritoneum: Histopathology".)
The use of OCs to reduce the risk of ovarian cancer in women at high risk of
this disease (BRCA1 or BRCA2 mutations) is reviewed separately. (See "Riskreducing bilateral salpingo-oophorectomy in women at high risk of epithelial
ovarian and fallopian tubal cancer".)
Endometrial cancer The use of OC pills decreases the risk of
endometrial cancer [88,94,107]. In one study, women using combination OC
pills for at least 12 months had an RR of endometrial cancer of 0.6 (95% CI
0.3-0.9) compared with nonusers [107]. The protective effect of OCs
persisted for at least 15 years after cessation of use. This benefit is likely
related to the progestin effect of OCs, which suppress endometrial
proliferation. (See "Endometrial carcinoma: Epidemiology and risk factors".)
Melanoma The impact of OCs on the risk of melanoma has been unclear.
In a prospective cohort study of premenopausal Caucasian women, current
OC use was associated with a twofold increase in risk, particularly in current
users with 10 or more years of use [108]. However, a systematic metaanalysis that included 18 case-control studies showed no evidence for an
increased risk of melanoma with the use of OCs [109]. (See "Risk factors for
the development of melanoma", section on 'Other factors'.)
OVERALL MORTALITY As described above, oral contraceptive (OC) use
in women over age 35 years who smoke is associated with an increased risk
of death from cardiovascular events. However, overall mortality rates are
not increased, and may actually be decreased, among ever users of OCs
compared with never users, as illustrated by the following observations:
In the Oxford Family Planning cohort study of 17,032 women of
reproductive age followed for 32 years, the rate ratio for death from any
cause in those who had ever used OCs was 0.89 compared with never users
(after adjusting for smoking, age, parity, social class, and duration of use)
[110].
In the Nurses Health Study, there was no adverse effect of OC use on
overall long-term mortality (relative risk [RR] of mortality 0.93 for ever users
versus never users; RR 1.06 for 10 years of use) [111].
A possible mortality benefit was reported in the Royal College of General
Practitioners' (RCGP) prospective cohort study of over 46,000 women

followed for up to 39 years [112]. Ever users of OCs had a significantly lower
rate of death from any cause (RR 0.88). Lower rates of death were also seen
for all cancers combined, individual cancers (colorectal, uterine, ovarian),
cardiovascular disease, and coronary heart disease (CHD). The estimated
absolute reduction in all cause mortality for ever users of OCs was 52 per
100,000 woman years.
The majority of women in this study had taken OCs containing higher doses
of estrogen than are typically used today (50 mcg versus 20 to 35 mcg
ethinyl estradiol [EE]). These data should reassure young, nonsmoking
women that current use of OCs is not associated with an increased longterm risk of death, and may actually provide a small benefit.
OTHER EFFECTS Oral contraceptives (OCs) have a variety of other
effects.
Carbohydrate and lipid metabolism Abnormal glucose tolerance tests
were fairly common in women taking high-dose OCs, but few women
developed diabetes [113]. Women taking low-dose OCs have normal glucose
tolerance, but these pills do cause mild insulin resistance [113]. In a study of
Hispanic women with recent gestational diabetes who were breast feeding,
the use of progestin-only OCs was associated with an increased risk of type
2 diabetes [114]; the applicability of these findings to other women is
unclear, but progestin-only OCs should be used with caution in breastfeeding women with a history of gestational diabetes mellitus. Other
information on contraception options for diabetic women is found elsewhere.
(See "Pregestational diabetes: Preconception counseling, evaluation, and
management".)
The effect of OCs on serum lipid values depends upon the estrogen dose
and the androgenicity of the progestin (see "Overview of the use of
estrogen-progestin contraceptives"). In general, serum triglyceride
concentrations rise slightly, but there are no consistent changes in serum
high-density (HDL) or low-density (LDL) lipoprotein cholesterol
concentrations [115,116]:
The estrogen component of OCs increases serum triglycerides and HDL
concentrations and lowers serum LDL cholesterol concentrations.
Oral but not transdermal preparations are associated with an increase in
serum triglycerides [117-119].
The progestin usually increases serum LDL cholesterol and lowers serum
HDL cholesterol concentrations, particularly the androgenic progestins
(norgestrel andlevonorgestrel).
Contraceptives with low-dose norethindrone lower serum LDL cholesterol
and raise serum HDL cholesterol concentrations because of the dominant
effects of estrogen and the relatively low androgenicity of norethindrone
[116].
The newer progestins, such as desogestrel, tend to raise serum HDL
cholesterol and lower LDL cholesterol concentrations. In a meta-analysis of
18 studies, administration of a desogestrel-containing OC increased the
former by 5.8 mg/dL (0.2 mmol/L) and reduced the latter by
4.5 mg/dL (0.1 mmol/L) [115].

Increased binding proteins The estrogen component of OC pills, like

any estrogen taken orally, raises the serum concentrations of thyroxinebinding globulin (TBG), cortisol-binding globulin (CBG), and sex hormonebinding globulin (SHBG). As a result, the serum concentrations of total
thyroxine, triiodothyronine, cortisol, estradiol, and testosterone increase, but
the serum concentrations of free thyroxine, triiodothyronine, cortisol,
estradiol, and testosterone do not change (see "Euthyroid
hyperthyroxinemia and hypothyroxinemia"). This effect of oral estrogen
administration needs to be considered when evaluating tests of thyroid,
adrenal, and gonadal function in women taking any estrogen orally.
Low doses of estrogen administered transdermally or vaginally (eg,
postmenopausal doses) do not cause such changes, although a transdermal
contraceptive patch, which contains a much higher dose of estrogen, does
increase SHBG. (See "Transdermal contraceptive patch".)
Pregnancy and fertility Inadvertent OC administration during early
pregnancy has not been associated with an increase in risk of congenital
anomalies. A possible exception is congenital urinary tract abnormalities,
the frequency of which was increased in one study [120].
When OCs are discontinued, several months may elapse before ovulatory
cycles return, but there is no increased risk of infertility. To the contrary, the
risk of primary infertility may be reduced in women who have taken an OC
[121].
Use during lactation The World Health Organization (WHO) and the
American College of Obstetricians and Gynecologists (ACOG) have made
recommendations for nonhormonal and hormonal contraception during
lactation. This topic is reviewed in detail elsewhere. (See "Postpartum and
postabortion contraception", section on 'Contraceptive choices during
lactation'.)
Sexual function Data on the impact of estrogen-progestin
contraceptives on female sexuality are conflicting. Although OCs suppress
serum testosterone concentrations, there are no definitive data that they
have a negative impact on libido. (See "Sexual dysfunction in women:
Epidemiology, risk factors, and evaluation", section on 'Hormonal
contraceptives'.)
Uterine fibroids Use of low dose OCs does not cause fibroids to grow;
therefore, administration of these drugs is not contraindicated in women
with fibroids. (See"Epidemiology, clinical manifestations, diagnosis, and
natural history of uterine leiomyomas (fibroids)", section on 'Hormonal
contraception'.)
Liver disorders A number of liver disorders have been thought to be
associated with OC use. Evidence for an association with hepatic adenoma
is good, while evidence for an association with focal nodular hyperplasia and
hepatocellular carcinoma is inconclusive. Estrogen-progestin contraceptives
containing 35 mcg of ethinyl estradiol (EE) have not been shown to have
an adverse effect on liver function tests; this includes pills containing early
generation progestins, third generation progestins, and drospirenone [122-

124]. The eligibility criteria for women with known liver disease (or past
disease) are outlined in the table (table 2).
Focal nodular hyperplasia The use of OCs is not required for the
development of focal nodular hyperplasia (FNH), but they may be a risk
factor, although data are inconsistent. (See "Focal nodular hyperplasia".)
Hepatic adenomas OCs are associated with the development of hepatic
adenomas; risk correlates with dose and duration of use. Most of the
available incidence data are based upon early OC preparations with high
estrogen and progestin content; the incidence is thought to be decreasing
with lower dose OC preparations, but data are limited. This topic is
discussed in detail separately. (See "Hepatic adenoma".)
Hepatocellular carcinoma Studies evaluating whether OCs increase the
risk of hepatocellular carcinoma (HCC) have produced mixed results. No
significant relationship was detected in a meta-analysis of 12 studies (odds
ratio [OR] 1.45, 95% CI 0.932.27) [125]. Six of the 12 studies reported a
possible increased risk of HCC in women using OCs long-term (>5 years, OR
range 2 to 20), but the studies had potentially important methodologic
limitations. Thus, any association between long-term OC use and HCC
remains uncertain. (See "Epidemiology and etiologic associations of
hepatocellular carcinoma".)
Pancreatitis Oral exogenous estrogen raises serum triglyceride
concentrations, and has been associated with hypertriglyceridemia-induced
acute pancreatitis [126]. We recommend against the use of OCs in women
whose serum triglyceride levels are >500 mg/dL due to a heightened risk of
this complication. (See"Hypertriglyceridemia-induced acute pancreatitis",
section on 'Secondary hypertriglyceridemia'.)
Weight Many women and their clinicians believe that OCs cause weight
gain. However, available data suggest that this is not the case. As an
example, in a study of 49 healthy women initiating treatment with an OC
containing 30 mcg EE plus 75 mcg gestodene, anthropometric
measurements before and after the initiation of OC use were compared with
those in 31 age- and weight-matched women [127]. Baseline body mass
index (BMI), percent fat, percent water, and waist-to-hip (WHR) ratio did not
change significantly after six cycles in the OC users. A similar number of
women gained weight in both groups (30.6 percent of users, 35.4 percent of
controls); the typical weight gain in the OC group was only 0.5 kg. The
weight gain in these women was due to accumulation of fat, not body water.
Approximately 20 percent of women in both groups lost weight.
A systematic review of 49 trials (only four of which had a placebo group), did
not find evidence supporting a causal relationship between use of
combination OCs (or contraceptive patch) and weight gain [128]. The
majority of trials that compared pills of variable types and doses (EE doses
20 to 50 mcg) showed no significant difference in weight between groups.
The authors concluded that the available data exclude a large, but not a
small, effect of OCs on weight.
Headaches Headache is among the most common side effects that are
reported with OC use, and is a frequently cited reason for discontinuation

[129]. In a systematic review of OCs and headache, quantitative analysis

was not possible because of differences in study populations, pill
formulations, trial endpoints, and trial durations [130]. However, the authors
made several conclusions, including the following:
There does not appear to be a strong relationship between OC use and
headache for most women. In controlled trials, increases in headache
frequency were sometimes seen in early cycles of pill use, with
improvement in subsequent cycles.
Women with a strong personal or family history of troublesome headaches
(in particular, migraine) did appear to be at higher risk for new-onset
headache related to OC use. However, most women with this history
reported no change in overall headache history.
The dose or type of progestin did not appear to affect headache risk. The
effect of estrogen dose was unclear.
Regardless of cause, when headaches started or worsened with OC use,
they tended to improve despite continued use. The authors estimated that
women who experience headache in the first cycle of pill use have a one in
three and 1 in 10 chance of experiencing headache in the second and third
cycle, respectively.
Thus, it appears that concerns about headache should not be a major factor
in the decision about whether to use OCs. However, OCs should not be used
in women with pseudotumor cerebri (idiopathic intracranial hypertension) or
migraines with focal symptoms. The association of pseudotumor cerebri with
prothrombotic abnormalities (antithrombin III deficiency and
antiphospholipid antibodies), and an increased risk of cerebral vein
thrombosis, represents an unacceptable risk for using combined estrogenprogestin contraceptives [131]. (See "Idiopathic intracranial hypertension
(pseudotumor cerebri): Clinical features and diagnosis".)
Migraine headaches Migraine headaches have been reported to
worsen, improve, or not change in women taking an OC [132-135]. If
migraines occur during OC therapy, it is typically during the hormone-free
interval. Use of extended cycle OC regimens or OCs with a shortened pillfree interval (four days) appear to result in fewer and less severe migraines
when compared with standard OCs with a seven-day pill-free interval
[136,137]. (See "Estrogen-associated migraine".)
Accumulating evidence supports an association between migraine,
particularly migraine with aura, and ischemic stroke risk (see "Headache,
migraine, and stroke", section on 'Migraine and stroke risk'). However, the
absolute increase in the risk of stroke is small. Although there are concerns
that studies of stroke risk in women with migraine headaches have
significant methodological limitations [1], the best evidence for an
association comes from a meta-analysis of 11 case-control studies and three
cohort studies [138]. The pooled relative risk (RR) for ischemic stroke among
women with any type of migraine was 2.16. In a pooled analysis of three of
the studies, the RR among women with migraines who were also taking OCs
was 8.72 [138]. Migraine with aura appears to be associated with a greater

risk of stroke than migraine without aura [138,139]. (See "Headache,

migraine, and stroke", section on 'Migraine and stroke risk'.)
WHO [140] and ACOG conclude from the literature that women with a
history of migraine headaches who take OCs are at increased risk for
cerebral thromboembolism, and that the risks of OC use usually outweigh
the benefits in women over age 35 years with migraines. In addition, they
suggest that for women of any age with migraines associated with aura or
focal symptoms, the risk of OC use is unacceptable. (See "Headache,
migraine, and stroke", section on 'Migraine and stroke risk'.)
In women with migraines without aura, other modifiable risk factors for
stroke such as smoking, hypertension, and dyslipidemia should be identified
and treated before considering using an OC [141,142].
Approximately 25 percent of women with migraine headaches have auras,
which are usually visual. The International Headache Societys definition of
aura is reviewed separately. (See "Pathophysiology, clinical manifestations,
and diagnosis of migraine in adults".)
In women with migraines with aura but no other risk factors, the frequency
and severity of the aura is likely to be important. For example, a patient who
experienced only one to two aura in the distant past may be a reasonable
candidate for an OC, while a patient who experiences a prolonged aura with
every migraine would not be [143]. A consensus statement from headache
and stroke experts suggests screening for and treatment of stroke risk
factors in women with migraine. However, it does not state that low-dose OC
use is contraindicated [142].
Inflammatory bowel disease The literature is conflicting with regard to
a possible role of OCs in predisposing to the development of inflammatory
bowel disease [144]. Given the uncertainty, it is reasonable to continue the
OC in women with inflammatory bowel disease who are doing well [144].
However, cessation should be considered in those women who remain
symptomatic despite conventional drug therapy. (See "Definition,
epidemiology, and risk factors in inflammatory bowel disease", section on
'Oral contraceptives and hormone replacement therapy'.)
Systemic lupus erythematosus The potential risk of developing or
worsening of systemic lupus erythematosus is discussed in detail elsewhere.
(See "Menstrual function, menopause, and hormonal contraceptives in
women with systemic lupus erythematosus".)
Angioedema OCs or postmenopausal hormone therapy appear to induce
or exacerbate symptoms of hereditary angioedema in some patients. In a
study of 516 women with recurrent angioedema, 228 (44 percent) had used
one of the two hormone therapies. Of these 228 patients, postmenopausal
hormone therapy led to angioedema attacks in 46 (20 percent), including 20
of 32 (63 percent) and 24 of 39 (64 percent) of the women with hereditary
angioedemas types I and III, respectively. Only 2 of 50 women with
idiopathic angioedema were affected [145]. (See "Hereditary angioedema:
Prevention of attacks".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient
education materials, The Basics and Beyond the Basics. The Basics

patient education pieces are written in plain language, at the 5 th to 6th grade
reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want
a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10 th to 12th grade reading
level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
patient info and the keyword(s) of interest.)
Basics topics (see "Patient information: Hormonal birth control (The
Basics)" and "Patient information: Choosing birth control (The Basics)")
Beyond the Basics topics (see "Patient information: Long-term methods of
birth control (Beyond the Basics)" and "Patient information: Hormonal
methods of birth control (Beyond the Basics)" and "Patient information: Birth
control; which method is right for me? (Beyond the Basics)")
SUMMARY
Early side effects of oral contraceptives (OCs) include bloating, nausea,
and breast tenderness. Although they may be bothersome enough to lead to
discontinuation of the OC, these side effects usually subside in several
months. (See 'Side effects' above.)
Breakthrough bleeding is the most common side effect of OCs. The most
common cause of breakthrough bleeding is thought to be missed pills, but it
is common in women who do not miss pills. Its occurrence does not indicate
a decrease in efficacy, but reflects tissue breakdown as the endometrium
adjusts to a new thin state in which it is fragile and atrophic. Breakthrough
bleeding is more of a problem with lower doses of estrogen because
estrogen stabilizes the endometrium. In addition, bleeding is more common
with extended and continuous regimens, although most women eventually
develop amenorrhea. (See 'Breakthrough bleeding' above.)
OC use does not cause subsequent menstrual cycle disorders, including
amenorrhea. Women who do not menstruate three months after
discontinuing an OC should undergo the same evaluation for amenorrhea as
any woman with amenorrhea. (See 'Post-pill amenorrhea' above.)
Most data suggest that weight gain is not a consistent finding with OCs.
(See 'Weight' above.)
OCs may be associated with an increased risk of myocardial infarction
(MI). However, because MI is an extremely rare event in otherwise healthy
women of reproductive age, even a doubling of the risk would result in an
extremely low attributable risk. Risk in older women who smoke outweighs
the risk of an unwanted pregnancy. Low-dose OCs may be associated with a
small increase in stroke risk. If present, the absolute increase in risk is
extremely low, particularly in healthy women under age 35 years (nonsmokers without hypertension). Risk appears to be similar for different

progestins, and the risk of hemorrhagic stroke does not appear to be

increased. (See 'Cardiovascular disease' above.)
An increase in the risk of venous thromboembolic disease (VTE) is seen
with both high and low dose estrogen OC preparations. Although the
reduction in steroid content of OCs has improved the safety and side effect
profile of the pill, the increased risk of venous thrombosis has not been
eliminated. Risk is affected by patient age, weight, and thrombophilia
status. The type of progestin also affects risk. A pooled analysis of studies
regarding the use of OCs found that the risk ratios for thromboembolism in
women taking non-third generation OCs compared with women who did not
take an OC ranged from 1.1 to 4.8 (depending upon the type of study).
However, the absolute risk of thromboembolism is very low in healthy
women, and the potential risk of VTE with the use of OCs is far less than the
risks associated with unintended pregnancy. (See 'Venous thromboembolic
disease' above.)
The risk of ovarian and endometrial cancer are both reduced with OC use.
The risk of cervical cancer appears to be increased, while data on breast
cancer are conflicting. (See 'Risk of cancer' above.)
The World Health Organization (WHO) and American College of
Obstetricians and Gynecologists (ACOG) conclude from the literature that
women with a history of migraine headaches who take OCs are at increased
risk for cerebral thromboembolism, and that the risks of OC use usually
outweigh the benefits in women over age 35 years with migraines. In
addition, they suggest that for women of any age with migraines associated
with aura or focal symptoms, the risk of OC use is unacceptable.
(See 'Migraine headaches' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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