The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical practice

Hormonal Contraception in Women

of Older Reproductive Age
Andrew M. Kaunitz, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.

A healthy, lean 46-year-old woman who is a nonsmoker requests advice about contraception. She notes that her menstrual periods are less regular than previously, and she
also reports intermittent bothersome hot flashes. She is in a new relationship after a
divorce, and she is sexually active. She asks if she can begin to use an oral contraceptive. What would you advise?

The Cl inic a l Probl e m

From the Department of Obstetrics and
Gynecology, University of Florida College
of MedicineJacksonville, Jacksonville.
N Engl J Med 2008;358:1262-70.
Copyright 2008 Massachusetts Medical Society.

During the transition toward their final spontaneous menses, many perimenopausal women have menstrual-cycle alterations and vasomotor symptoms. Although
sporadic ovulation continues until menopause,1,2 fecundity declines as the final
menses approaches. For instance, in one study involving women undergoing insemination with frozen donor sperm, the fecundity of women older than 40 years of age
was less than half that of those 35 years of age or younger.3
Women of older reproductive age are more likely than younger women to have
adverse consequences when they do conceive. In the United States, pregnancyrelated mortality ratios (deaths per 100,000 live births) among women 40 years of
age or older are five times those of women between 25 and 29 years of age; coexisting conditions during pregnancy, including diabetes and hypertension, also increase
with maternal age.4,5 In 2001, there were 304 induced abortions per 1000 live
births among women 40 years of age or older in the United States; this ratio was
higher than that among all other age groups except adolescents.6 These data underscore the importance of effective contraception for women of older reproductive age.
A previous Clinical Practice article addressed long-acting methods of contraception.7 The present review focuses on hormonal contraception, primarily the use of
combination estrogenprogestin contraceptives, in women of older reproductive
age (Tables 1 and 2).

S t r ategie s a nd E v idence
CONTRACEPTIVE EFFICACY

Women of older reproductive age are less fecund and more likely to use contraceptives correctly and consistently than younger women. Accordingly, women in this age
group have lower rates of contraceptive failure than do younger women.8
SAFETY

Venous Thromboembolism

Older age and obesity are independent risk factors for venous thromboembolism
among women using combination oral contraceptives, and obesity is increasingly
1262

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

clinical pr actice

Table 1. Oral Contraceptives Available in the United States.*

Formulation

Regimens

Pregnancy Rate
(First Year of
Typical Use)

Comments

%
Combination estrogenprogestin

Most formulations available as generics

21 active tablets and 7 placebo

tablets
Ethinyl estradiol, 20 g

Levonorgestrel, 0.1 mg (Aviane,

Lutera)
Norethindrone acetate, 1 mg
(Junel 21 1/20)

Ethinyl estradiol, 25 g

Norgestimate, 0.18 mg, 7 tablets;

norgestimate, 0.215 mg, 7 tablets;
and norgestimate, 0.25 mg, 7 tablets (Ortho Tri-Cyclen Lo)

Ethinyl estradiol, 30 g

Levonorgestrel, 0.15 mg (Portia)

Ethinyl estradiol, 35 g

Norethindrone, 1 mg (Necon 1/35)

More unscheduled bleeding than formulations

with higher estrogen dose; data do not
confirm greater safety than formulations
containing 30 or 35 g of ethinyl estradiol

28-day with reduced hormonefree interval

Ethinyl estradiol, 20 g desogestrel,

0.15 mg, 21 tablets; 2 placebo
tablets and ethinyl estradiol,
10 g, 5 tablets (Kariva)
Ethinyl estradiol, 20 g drospirenone, 3 mg,
24 tablets; and 4 placebo tablets (Yaz)

Greater suppression of ovarian follicular

activity than with 7day placebo interval

Extended oral contraceptives

Ethinyl estradiol, 30 g levonorgestrel,

0.15 mg, 84 tablets; and 7 placebo
tablets (Quasense)

Initially more unscheduled bleeding than with

monthly regimens; scheduled bleeding
episodes each 3 mo

Progestin-only, 28 active tablets

Norethindrone, 0.35 mg (Camila,

Errin)

More unscheduled bleeding than with combined oral contraceptives; dose may be
inadequate to suppress ovulation; failure
rate may be higher than with combination
estrogenprogestin oral contraceptives

* This list is not exhaustive. Progestins found in U.S. oral-contraceptive formulations include desogestrel, drospirenone, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, and norgestrel.
Pregnancy rates are expected to be lower among contraceptive users of older reproductive age (data are from Trussell8).
This is a generic drug.
Data are from Gallo et al.9
There is no generic version of this drug in the United States.

common with older age. The risk of venous

thromboembolism rises sharply after 39 years of
age among women who receive combination oral
contraceptives, with an estimated incidence of
more than 100 cases per 100,000 person-years
among women who are older than 39 years of age,
as compared with 25 cases per 100,000 personyears among adolescents.12 The risk is nearly
twice as high among obese women as it is among
nonobese women who receive oral contraceptives.13 Thus, combination contraceptives should
be used with caution in women of older reproductive age who are obese; progestin-only contraceptives or intrauterine devices are generally preferred in these women.14
The estrogen component of combination oral
contraceptives is considered to be the major con-

tributor to the risk of venous thromboembolism

associated with the use of oral contraceptives,
with higher doses of estrogen associated with a
greater risk.13 However, the progestin component
may also affect the risk of venous thromboembolism. For example, oral contraceptives formulat
ed with the progestin desogestrel are associated
with a risk of venous thromboembolism that is
about twice the risk associated with oral contraceptives formulated with the progestins levonorges
trel and norgestimate.15 Although oral contraceptives containing 20 g of estrogen are increasingly
prescribed in women of older reproductive age,
evidence is lacking to confirm that these formulations are safer than those containing 30 to 35
g of estrogen.9
Women with familial thrombophilic syn-

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

1263

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 2. Nonoral Hormonal Contraceptives.*

Type of Contraceptive

Daily Hormone
Release

Schedule of Use

Bleeding Profile

Pregnancy Rate
(First Year of
Typical Use)
%

Combination estrogenprogestin
Transdermal patch (Ortho Evra)

Ethinyl estradiol,
20 g; norelges
tromin, 150 g

Use 1 patch/week for

3 weeks, remove
for 1 week, repeat
with new patch

Bleeding during patch-free week

Vaginal ring (NuvaRing)

Ethinyl estradiol,
15 g; etonogestrel, 120 g

Insert ring for 3 weeks, Bleeding during ring-free week

remove for 1 week,
repeat with new ring

Approximately 20 g

Up to 5 yr

Initial increase in days of bleeding and

spotting; 12 mo after insertion, 20
50% of users amenorrheic

0.1

Etonogestrel implant (Implanon) 6070 g initially;

2530 g by end
of year 3

Up to 3 yr

Variable; infrequent, prolonged, and frequent bleeding episodes are common

initially; 3 mo after insertion, 1420%
of users amenorrheic

Progestin only
Levonorgestrel-releasing intrauterine device (Mirena)

<1

Injectable DMPA
Depo-Provera

150 mg, intramuscular Every 3 mo

Initial unpredictable bleeding and spotting common; 12 mo after initiation,

50% of users amenorrheic

Depo-SubQ Provera

104 mg, subcutaneous Every 3 mo

Initial unpredictable bleeding and spotting common; 12 mo after initiation,

50% of users amenorrheic

<1

* Except for intramuscular Depo-Provera, all of these contraceptives are available only as branded formulas. DMPA denotes depot medroxyprogesterone acetate.
Pregnancy rates are expected to be lower among contraceptive users of older reproductive age. Data are from Trussell.8
Data are from Peterson and Curtis.7
Data are from Funk et al.10
Data are from Kaunitz.11

dromes, including carriers of the factor V Leiden

mutation, have a higher risk of venous thromboembolism with the use of combination oral contraceptives than women who do not have these
syndromes.13 Because screening costs would exceed benefits, routine screening for thrombophilic conditions before oral contraceptive use is
not recommended14,16,17; however, combination
oral contraceptives should be avoided in women
with a known thrombophilic condition.
Myocardial Infarction and Stroke

In women who use oral contraceptives, smoking

and hypertension are synergistic risk factors for
myocardial infarction and stroke. Thus, combination estrogenprogestin contraceptives should
not be used by women of older reproductive age
who smoke or who have hypertension.14
1264

Although some studies conducted abroad have

shown an increased risk of myocardial infarction
and stroke with oral-contraceptive use, the prevalence of smoking and untreated hypertension
was high among study participants. It is therefore uncertain whether findings from these studies are applicable to healthy women of older reproductive age who are nonsmokers.14,16 A large
casecontrol study that was based on data from
two health maintenance organizations (HMOs)
in the United States included few oral-contraceptive users older than 35 years of age who smoked
or had hypertension. This study reported no evidence of an increased risk of myocardial infarction or stroke among women of older reproductive
age who were current users of oral contraceptives containing less than 50 g of ethinyl estradiol.18,19 A recent large, prospective study involv-

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

clinical pr actice

ing Swedish women between 30 and 49 years of

age at enrollment, including 1761 current oralcontraceptive users between 40 and 49 years of
age, provided further reassurance regarding the
use of oral contraceptives containing an estrogen
dose of less than 50 g of ethinyl estradiol.20 As
compared with women who had never used oral
contraceptives, neither former nor current oralcontraceptive users had an increased risk of myocardial infarction over a mean period of 11 years
of follow-up. In addition, the initiation of oralcontraceptive use in women 30 years of age or
older was not associated with an elevated risk of
myocardial infarction, as compared with initiation at a younger age.20
On the basis of an increased risk of cardiovascular disease associated with diabetes among
both premenopausal and postmenopausal women,
it is prudent to limit the use of combination oral
contraceptives in women with diabetes to those
who are younger than 35 years of age and are
free of hypertension, other vascular diseases, and
nephropathy. Progestin-only and intrauterine contraceptives are reasonable choices in women who
are not good candidates for combination oral
contraceptives.14
Although controversial, some data suggest
that women with migraine headaches are at increased risk for stroke with the use of oral contraceptives.19 In a large HMO-based, casecontrol study in the United States, oral-contraceptive
use was associated with a risk of stroke that was
twice as high among women with migraines as
among women without a history of migraines.19
This study did not distinguish between migraines
with aura and those without aura. In another
study, women who had migraine headaches accompanied by aura, but not those who had migraine headaches without aura, had an increased
risk of stroke; among women who had migraine
headaches with aura, oral-contraceptive users
who smoked had a further increase in the risk of
stroke.21 Current guidelines from the American
College of Obstetricians and Gynecologists and
the World Health Organization (WHO) recommend progestin-only or intrauterine contraceptives in women of older reproductive age with
migraines.14,17

concern that the use of hormonal contraception

might increase the risk of breast cancer. However,
in a large British cohort study involving more
than 1 million person-years of follow-up, the use
of oral contraceptives (in most cases containing
50 g or more of ethinyl estradiol) was not associated with an increased risk of breast cancer, even
among women who used these contraceptives for
long periods of time. The risk was also not increased with current or recent oral-contraceptive
use or with use decades earlier. However, this
report did not provide information regarding the
age at which women in the cohort used oral contraceptives.22
The Womens Contraceptive and Reproductive
Experiences (CARE) Study, a population-based
casecontrol study, showed no increased risk of
invasive or in situ breast cancer among women
who were current or previous users of oral contraceptives as compared with women who had never
used them23,24; this study included an analysis
that was limited to women who had begun to use
oral contraceptives in their 40s. The CARE study
also showed no significant association between
the use of progestin-only injectable depot medroxy
progesterone acetate (DMPA) or implantable contraceptives and the risk of breast cancer.25
A recent large, population-based casecontrol
study in the United States similarly showed no
increase in the risk of death from breast cancer
among women who had previously used oral contraceptives, as compared with the risk among
those who had never used them; this study included a subgroup of women who had begun to
use oral contraceptives at 30 years of age or
older.26 Although the available data indicate that
the use of combination oral contraceptives or
progestin-only contraceptives does not affect the
risk of breast cancer, these reports have included
relatively few women older than 45 years of age.
A potential increase in the risk of breast cancer associated with the use of hormonal contraceptives is a particular concern for women at high
risk for breast cancer on the basis of family history. However, available data suggest that familial
risk should not be viewed as a contraindication
to the use of combination estrogenprogestin or
progestin-only contraception in women of older
reproductive age. In a large, Canadian prospecBreast Cancer
tive study involving women with a family history
The recognized association between long-term of breast cancer (mean age, 49 years), neither
estrogen exposure and breast cancer has raised former nor current oral-contraceptive use was
n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

1265

The

n e w e ng l a n d j o u r na l

associated with an increased risk of breast cancer27; information on BRCA mutation status was
not available.
Studies among known BRCA mutation carriers have yielded mixed results.28,29 In one study,28
the use of oral contraceptives was associated
with a modestly increased risk of breast cancer
among women with BRCA1 mutations (odds ratio,
1.20; 95% confidence interval, 1.02 to 1.40) but
not among women with BRCA2 mutations, whereas another study29 showed no significant increase
in risk among women in either group.
NONCONTRACEPTIVE BENEFITS

Irregular and Heavy Uterine Bleeding

In the United States, hysterectomy rates are highest among women between 40 and 44 years of
age.30 This surgery and endometrial ablation or resection are most commonly performed in women
in this age group for heavy menstrual bleeding,
which is often associated with uterine fibroids or
adenomyosis. The use of oral contraceptives can
restore cyclic, predictable bleeding in women of
older reproductive age with dysfunctional uterine
bleeding. In a trial involving women between 15
and 50 years of age with dysfunctional uterine
bleeding, more than 80% of those who were randomly assigned to receive an oral contraceptive
as compared with less than 50% of women in
the placebo group had improvement in their
bleeding patterns.31 In addition, significant reductions in menstrual blood loss associated with the
use of oral contraceptives have been reported in
women with menorrhagia as well as those with
normal menses.32
The use of the levonorgestrel intrauterine
device effectively treats menorrhagia, including
menorrhagia associated with fibroids and adenomyosis.33-35 Since long-term use of injectable
forms of contraception characteristically results
in amenorrhea, some clinicians recommend DMPA
injections to treat menorrhagia; however, data in
support of this approach are limited.11
Vasomotor Symptoms

Vasomotor symptoms are common in perimenopausal women. Hormonal therapy is effective in

treating these symptoms, but doses of estrogen
that are typically used in postmenopausal women
(generally the equivalent of 5 to 10 g of ethinyl
estradiol) are inadequate to prevent ovulation.2
Clinical experience suggests that the use of oral
1266

of

m e dic i n e

contraceptives reduces vasomotor symptoms in

perimenopausal women, although this has not
been well studied. In one double-blind trial, the
number and severity of vasomotor symptoms appeared to be reduced by a factor of about two in
perimenopausal women who were randomly assigned to receive an oral contraceptive containing
20 g of estrogen, as compared with women who
received placebo, but the differences were not
statistically significant.36 In a prospective observational study, 90% of perimenopausal women
with vasomotor symptoms who used an oral contraceptive containing 30 g of ethinyl estradiol
had complete relief of symptoms 2 months or
more after the start of oral-contraceptive use,
whereas only 40% of nonusers reported improvement in their vasomotor symptoms.37
In a trial involving symptomatic perimenopausal women, the use of oral conjugated equine
estrogen (at a dose of 1.25 mg daily) and a levonorgestrel-releasing intrauterine device resulted
in substantial improvement in vasomotor symptoms; most participants became amenorrheic,
and endometrial hyperplasia did not develop in
any subject.38 In placebo-controlled trials, contraceptive doses of DMPA have been shown to
suppress vasomotor symptoms in menopausal
women.39
Vasomotor symptoms may occur in perimenopausal women using oral contraceptive formulations with 21 active tablets during the hormonefree days. Some clinicians prescribe extended or
continuous oral-contraceptive regimens to reduce
such symptoms, although this approach has not
been studied extensively.
Skeletal Health

Bone mineral density (BMD) decreases in women

of older reproductive age.40 Data from a randomized trial indicate that the use of oral contraceptives increases BMD in women in this age group.40
Furthermore, in a population-based, casecontrol
study of postmenopausal Swedish women, a history of oral-contraceptive use was associated with
a 25% reduction in the risk of hip fracture; greater
reductions were noted among women who had
used oral contraceptives in their 40s and among
those who had used oral contraceptives for extended periods of time.41 In contrast, an analysis
of data from the observational cohort study of the
Womens Health Initiative did not show a reduced
risk of fractures among postmenopausal women

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

clinical pr actice

who were previous users of oral contraceptives,

but the subjects were not stratified according to
the age at which oral contraceptives were used.42
Current use of intramuscular DMPA (at a dose
of 150 mg) or subcutaneous DMPA (at a dose of
104 mg) is associated with reductions in BMD.
However, in former users, including women who
began to use DMPA at 40 years of age or older,
BMD has been found to be similar to that in
women who never used DMPA.11,43 Data on the
risk of fracture among postmenopausal women
who previously used DMPA are lacking.
Cancer

Women who use low-estrogen oral contraceptive

formulations have at least a 50% lower risk of subsequent epithelial ovarian cancer than women
who have never used these formulations.16 A longer duration of use is associated with greater protection.22,44 Although the protection associated
with the use of oral contraceptives may decrease
over time, it appears to persist for at least three
decades after the last use.44 Since the incidence
of ovarian cancer increases with age, the protection associated with oral-contraceptive use may
be particularly relevant for women of older reproductive age. The use of oral contraceptives has
been associated with a reduced risk of ovarian
cancer among both BRCA mutation carriers and
noncarriers.45,46
Extensive observational data indicate that the
use of contraceptives containing 30 g or more
of estrogen is associated with a reduction of approximately 50% in the risk of endometrial
cancer,16 with protection increasing with a longer
duration of oral-contraceptive use and persisting
for at least two decades after the discontinuation
of oral contraceptives.32,47 The use of DMPA is
associated with an 80% reduction in the risk of
endometrial cancer.48
The use of oral contraceptives has been associated with an approximately 20% reduced risk of
colorectal cancer.22,49 In contrast to protection
against ovarian and endometrial cancer, the protection against colorectal cancer associated with
the use of oral contraceptives does not appear to
increase with the duration of use. The use of oral
contraceptives within the past 5 years may be associated with greater protection against colorectal cancer than more remote use.22,49

A r e a s of Uncer ta in t y
The use of oral contraceptives among women of
older reproductive age is increasing, with 11% of
women between 40 and 44 years of age in the
United States who used contraception reporting
oral-contraceptive use in 2002, as compared with
6% in 1995.50,51 Nonetheless, women of older reproductive age are underrepresented in studies of
oral-contraceptive use, and information on the
safety and noncontraceptive benefits of hormonal contraception in women in this age group is
limited.
Data on the noncontraceptive benefits and
risks of the contraceptive vaginal ring, which
releases estrogen and progestin, are also lacking. Although pharmacokinetic data regarding
the contraceptive patch indicate that it results in
more estrogen exposure than oral contraceptives
or the vaginal ring,52 the findings of studies
comparing the risk of venous thromboembolism
associated with use of the patch with the risk
associated with oral contraceptives are conflicting.53 Pending further data, contraindications to
the use of combination oral contraceptives
should also be considered to apply to the ring
and the patch.14,17
The optimal timing for discontinuation of the
use of oral contraceptives in women of older
reproductive age remains uncertain. The measurement of follicle-stimulating hormone (FSH)
levels has been suggested as a means of identifying women who are menopausal and thus no
longer need contraception, but this measurement may be misleading and is not recommended. Elevated FSH levels suggestive of menopause may occur in ovulatory women of older
reproductive age.2 Moreover, in one study, suppressed FSH levels suggesting premenopausal
status were reported in a majority of postmenopausal women evaluated 1 month after the discontinuation of oral contraceptives.54 A reasonable strategy for healthy women who are
nonsmokers and doing well using a combination
contraceptive is to discontinue this method of
contraception in their early to mid-50s, when the
likelihood of ovulation is low.14 Barrier contraception until 55 years of age is prudent for menstruating women who discontinue the use of
oral contraceptives closer to 50 years of age.

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

1267

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 3. Guidelines Regarding the Use of Combination EstrogenProgestin Contraceptives in Women 35 Years of Age,
According to Risk Factors.*
Risk Factor

Guidelines
ACOG

WHO

Obesity

Progestin-only or intrauterine contraception may be safer than combination estrogenprogestin contraception

Benefit usually outweighs risks

Smoking

Progestin-only or intrauterine contraception should be used

Risk unacceptable

Hypertension

Progestin-only or intrauterine contraception should be used

Risk unacceptable

Diabetes

Progestin-only or intrauterine contraception should be used

Risk unacceptable

Migraine

Progestin-only or intrauterine contraception should be used

Risk unacceptable

None of the above

Healthy women who are nonsmokers

doing well with the use of a combination contraceptive can continue
this method until 5055 yr, after
weighing the risks and benefits

For women 40 yr, the risk of cardiovascular disease

increases with age and may also increase with combined hormonal contraceptive use; in the absence
of other adverse clinical conditions, combined hormonal contraceptives can be used until menopause

* Recommendations are from the American College of Obstetricians and Gynecologists (ACOG)14 and the World Health
Organization (WHO).17
This category includes progestin-only oral contraceptives, depot medroxyprogesterone acetate, contraceptive implants,
and copper and progestin-releasing intrauterine devices.
Obesity in women 35 years of age and older is not specifically addressed.

Guidel ine s from

Profe s siona l S o cie t ie s
The WHO and the American College of Obstetricians and Gynecologists have developed similar
guidelines addressing the use of combination
estrogenprogestin hormonal contraception in
women of older reproductive age (Table 3).

C onclusions
a nd R ec om mendat ions
Healthy, lean women of older reproductive age
who are nonsmokers, like the woman in the vignette, can safely use combination estrogenprogestin contraceptives. Benefits include effective
contraception and reductions in irregular bleeding and vasomotor symptoms associated with the
perimenopausal transition. Available epidemiologic data also suggest potential long-term benefits, including reductions in the risks of fractures
References
1. Bastian LA, Smith CM, Nanda K. Is
this woman perimenopausal? JAMA 2003;
289:895-902.
2. Gebbie AE, Glasier A, Sweeting V. In-

1268

among postmenopausal women and of ovarian,

endometrial, and colorectal cancer. However, for
women of older reproductive age who are obese,
smoke cigarettes, or have hypertension, diabetes,
or migraine headaches, the cardiovascular risks
associated with combination oral contraceptives
are considered to outweigh the benefits. For these
women, reasonable options include progestin-only
and intrauterine contraceptive methods14 as well
as barrier contraceptives and sterilization (in
women who have completed childbearing or do
not want to have children).7 Regardless of other
contraceptive use, consistent use of condoms
should be encouraged for all women at risk for
sexually transmitted infections.
Dr. Kaunitz reports receiving consulting fees or lecture fees
and grant support (to the University of Florida Research Foundation) from Bayer, Barr Pharmaceuticals, Johnson & Johnson,
Organon, and Warner Chilcott. No other potential conflict of
interest relevant to this article was reported.
I thank Karen Koppel Kaunitz, Esq., for invaluable editorial
support with an earlier version of the manuscript.

cidence of ovulation in perimenopausal

women before and during hormone replacement therapy. Contraception 1995;52:
221-2.

3. Kang BM, Wu TC. Effect of age on in-

trauterine insemination with frozen donor sperm. Obstet Gynecol 1996;88:93-8.

4. Callaghan WM, Berg CJ. Pregnancy-

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

clinical pr actice
related mortality among women aged 35
years and older, United States, 1991-1997.
Obstet Gynecol 2003;102:1015-21.
5. Viegas OA, Leong WP, Ahmed S, Ratnam SS. Obstetrical outcome with increas
ing maternal age. J Biosoc Sci 1994;26:
261-7.
6. Strauss LT, Herndon J, Chang J, et al.
Abortion surveillance United States,
2001. MMWR Surveill Summ 2004;53
(SS-9):1-32.
7. Peterson HB, Curtis KM. Long-acting
methods of contraception. N Engl J Med
2005;353:2169-75.
8. Trussell J. Contraceptive failure in the
United States. Contraception 2004;70:8996.
9. Gallo MF, Nanda K, Grimes DA, Schulz
KF. Twenty micrograms vs. >20 microg
estrogen oral contraceptives for contraception: systematic review of randomized
controlled trials. Contraception 2005;71:
162-9.
10. Funk S, Miller MM, Mishell DR Jr, et al.
Safety and efficacy of Implanon, a singlerod implantable contraceptive containing
etonogestrel. Contraception 2005;71:31926.
11. Kaunitz AM. Depot medroxyprogesterone acetate for contraception. In: Rose BD,
ed. UpToDate. Wellesley, MA: UpToDate,
2008.
12. Nightingale AL, Lawrenson RA, Simpson EL, Williams TJ, MacRae KD, Farmer
RDT. The effects of age, body mass index,
smoking and general health on the risk of
venous thromboembolism in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000;5:265-74.
13. Sidney S, Petitti DB, Soff GA, Cundiff
DL, Tolan KK, Quesenberry CP Jr. Venous
thromboembolic disease in users of lowestrogen combined estrogen-progestin
oral contraceptives. Contraception 2004;
70:3-10.
14. ACOG practice bulletin. No. 73: use
of hormonal contraception in women
with coexisting medical conditions. Obstet
Gynecol 2006;107:1453-72.
15. Jick SS, Kaye JA, Russman S, Jick H.
Risk of nonfatal venous thromboembolism
with oral contraceptives containing nor
gestimate or desogestrel compared with
oral contraceptives containing levonor
gestrel. Contraception 2006;73:566-70.
16. Petitti DB. Combination estrogen
progestin oral contraceptives. N Engl J
Med 2003;349:1443-50. [Erratum, N Engl
J Med 2004;350:92.]
17. Medical eligibility criteria for contraceptive use. 3rd ed. Geneva: World Health
Organization, 2004.
18. Sidney S, Siscovick DS, Petitti DB, et al.
Myocardial infarction and use of low-dose
oral contraceptives: a pooled analysis of 2
US studies. Circulation 1998;98:1058-63.
19. Schwartz SM, Petitti DB, Siscovick DS,
et al. Stroke and use of low-dose oral contraceptives in young women: a pooled

analysis of two US studies. Stroke 1998;29:

2277-84.
20. Margolis KL, Adami H-O, Luo J, Ye W,
Weiderpass E. A prospective study of oral
contraceptive use and risk of myocardial
infarction among Swedish women. Fertil
Steril 2007;88:310-6.
21. MacClellan LR, Giles W, Cole J, et al.
Probable migraine with visual aura and
risk of ischemic stroke: the stroke prevention in young women study. Stroke 2007;
38:2438-45.
22. Hannaford PC, Selvaraj S, Elliott AM,
Angus V, Iversen L, Lee AJ. Cancer risk
among users of oral contraceptives: cohort
data from the Royal College of General
Practitioners oral contraception study.
BMJ 2007;335:651.
23. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the
risk of breast cancer. N Engl J Med 2002;
346:2025-32.
24. Gill JK, Press MF, Patel AV, Bernstein
L. Oral contraceptive use and risk of breast
carcinoma in situ (United States). Cancer
Causes Control 2006;17:1155-62.
25. Strom BL, Berlin JA, Weber AL, et al.
Absence of an effect of injectable and implantable progestin-only contraceptives on
subsequent risk of breast cancer. Contraception 2004;69:353-60.
26. Wingo PA, Austin A, Marchbanks PA,
et al. Oral contraceptives and the risk of
death from breast cancer. Obstet Gynecol
2007;110:793-800.
27. Silvera SA, Miller AB, Rohan TE. Oral
contraceptive use and risk of breast cancer among women with a family history
of breast cancer: a prospective cohort
study. Cancer Causes Control 2005;16:
1059-63.
28. Narod SA, Dub MP, Klijn J, et al. Oral
contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2002;94:1773-9.
29. Haile RW, Thomas DC, McGuire V, et
al. BRCA1 and BRCA2 mutation carriers,
oral contraceptive use, and breast cancer
before age 50. Cancer Epidemiol Biomarkers Prev 2006;15:1863-70.
30. Keshavarz H, Hillis SD, Burney AK,
Marchbanks PA. Hysterectomy surveillance United States, 19941999.
MMWR Surveill Summ 2002;51(SS-5):1-8.
31. Davis A, Godwin A, Lippman J, Olson
W, Kafrissen M. Triphasic norgestimateethinyl estradiol for treating dysfunctional uterine bleeding. Obstet Gynecol 2000;
96:913-20.
32. Kaunitz AM. Noncontraceptive health
benefits of oral contraceptives. Rev Endocr
Metab Disord 2002;3:277-83.
33. Hurskainen R, Teperi J, Rissanen P, et
al. Clinical outcomes and costs with the
levonorgestrel-releasing intrauterine system or hysterectomy for treatment of
menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291:1456-63.
34. Kaunitz AM. Progestin-releasing intra-

uterine systems and leiomyoma. Contraception 2007;75:Suppl:S130-S133.

35. Bragheto AM, Caserta N, Bahamondes
L, Petta CA. Effectiveness of the levonor
gestrel-releasing intrauterine system in
the treatment of adenomyosis diagnosed
and monitored by magnetic resonance
imaging. Contraception 2007;76:195-9.
36. Casper RF, Dodin S, Reid RL. The effect of 20 g ethinyl estradiol/1 mg norethindrone acetate (Minestrin), a low-dose
oral contraceptive, on vaginal bleeding
patterns, hot flashes, and quality of life
in symptomatic perimenopausal women.
Menopause 1997;4:139-47.
37. Shargil AA. Hormone replacement
therapy in perimenopausal women with a
triphasic contraceptive compound: a threeyear prospective study. Int J Fertil 1985;
30:15, 18-28.
38. Hampton NRE, Rees MCP, Lowe DG,
Rauramo I, Barlow D, Guillebaud J. Levonorgestrel intrauterine system (LNG-IUS)
with conjugated equine estrogen: a success
ful regimen for HRT in perimenopausal
women. Hum Reprod 2005;20:2653-60.
39. North American Menopause Society.
Treatment of menopause-associated vasomotor symptoms: position statement of
the North American Menopause Society.
Menopause 2004;11:11-33.
40. Gambacciani M, Cappagli B, Lazzarini V, Ciaponi M, Fruzzetti F, Genazzani
AR. Longitudinal evaluation of perimenopausal bone loss: effects of different low
dose oral contraceptive preparations on
bone mineral density. Maturitas 2006;54:
176-80.
41. Michalsson K, Baron JA, Farahmand
BY, Persson I, Ljunghall S. Oral-contraceptive use and risk of hip fracture: a casecontrol study. Lancet 1999;353:1481-4.
42. Barad D, Kooperberg C, WactawskiWende J, Liu J, Hendrix SL, Watts NB.
Prior oral contraception and postmenopausal fracture: a Womens Health Initiative observational cohort study. Fertil Steril
2005;84:374-83.
43. Rosenberg L, Zhang Y, Constant D, et
al. Bone status after cessation of use of
injectable progestin contraceptives. Contraception 2007;76:425-31.
44. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian
cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women
with ovarian cancer and 87,303 controls.
Lancet 2008;371:303-14.
45. Narod SA, Risch H, Moslehi R, Dorum
A, Neuhausen S, Olsson H. Oral contraceptives and the risk of hereditary ovarian
cancer. N Engl J Med 1998;339:424-8.
46. Whittemore AS, Balise RR, Pharoah
PD, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1
or BRCA2 mutations. Br J Cancer 2004;
91:1911-5.
47. Schlesselman JJ. Risk of endometrial

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

1269

clinical pr actice
cancer in relation to use of combined oral
contraceptives: a practitioners guide to
meta-analysis. Hum Reprod 1997;12:185163.
48. Depot-medroxyprogesterone acetate
(DMPA) and risk of endometrial cancer:
the WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:186-90.
49. Fernandez E, La Vecchia C, Balducci A,
Chatenoud L, Franceschi S, Negri E. Oral
contraceptives and colorectal cancer risk:
a meta-analysis. Br J Cancer 2001;84:722-7.
50. Mosher WD, Martinez GM, Chandra A,
Abma JC, Willson SJ. Use of contraception
and use of family planning services in the

United States: 19822002. Advance data

from vital and health statistics. No. 350.
Hyattsville, MD: National Center for Health
Statistics, December 10, 2004.
51. Abma JC, Chandra A, Mosher WD,
Peterson LS, Piccinino LJ. Fertility, family
planning, and womens health: new data
from the 1995 National Survey of Family
Growth. Vital and health statistics. Series
23. No. 19. Hyattsville, MD: National Center for Health Statistics, May 1997:1-114.
(DHHS publication no. (PHS) 97-1995.)
52. van den Heuvel MW, van Bragt AJ,
Alnabawy AK, Kaptein MC. Comparison
of ethinylestradiol pharmacokinetics in
three hormonal contraceptive formula-

tions: the vaginal ring, the transdermal

patch and an oral contraceptive. Contraception 2005;72:168-74.
53. Jick S, Kaye JA, Li L, Jick H. Further
results on the risk of nonfatal venous
thromboembolism in users of the contraceptive transdermal patch compared to
users of oral contraceptives containing
norgestimate and 35 microg of ethinyl estradiol. Contraception 2007;76:4-7.
54. Creinin MD. Laboratory criteria for
menopause in women using oral contraceptives. Fertil Steril 1996;66:101-4.
Copyright 2008 Massachusetts Medical Society.

collections of articles on the journals web site

The Journals Web site (www.nejm.org) sorts published articles into

more than 50 distinct clinical collections, which can be used as convenient
entry points to clinical content. In each collection, articles are cited in reverse
chronologic order, with the most recent first.

1270

n engl j med 358;12 www.nejm.org march 20, 2008

Downloaded from www.nejm.org on December 11, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.