Menopause: The Journal of The North American Menopause Society

Vol. 25, No. 7, pp. 817-827

DOI: 10.1097/GME.0000000000001073
ß 2018 by The North American Menopause Society

INVITED REVIEW
Contraception for midlife women: a review
Taniqua A. Miller, MD,1 Rebecca H. Allen, MD, MPH,2 Andrew M. Kaunitz, MD,3
and Carrie A. Cwiak, MD, MPH 1

Abstract
Family planning represents a key component of reproductive health care. Accordingly, the provision of
contraception must span the reproductive age spectrum, including perimenopause. The risk of pregnancy is
decreased, but not trivial, among women over 40 years of age. Evidence-based guidelines for contraceptive use can
assist clinicians in counseling their patients in this population. Intrauterine contraception is one of the most effective
methods and is safe to use in midlife women with few exceptions. Progestin-only contraception is another safe
option for most midlife women because it is not associated with an increased risk of cardiovascular complications.
Combined (estrogen-containing) contraception can be safely used by midlife women who do not have cardiovas-
cular risk factors. Unique noncontraceptive benefits for this population include: improvement in abnormal uterine
bleeding, decreased hot flashes, and decreased cancer risk. Finally, guidelines state that contraception can be used by
midlife women without medical contraindications until the age of menopause, at which time they may consider
transition to systemic hormone therapy.
Key Words: Contraception – Hormone therapy – Midlife – Perimenopause – US Medical Eligibility Criteria
for Contraceptive Use.

F
amily planning represents a key component of repro-
ductive health care: since the average woman in North
America desires two children, she will spend about
3 years pregnant, postpartum, or attempting to become preg-
nant, and over 30 years trying to avoid pregnancy.1 Accord-
ingly, the provision of contraception must span the
reproductive age spectrum, including perimenopause. In this
article, we review the need for contraception among women
over 40 years of age and present evidence-based guidelines
for contraceptive use in this population. We detail the con-
traceptive options available to women over 40, and also the
unique contraceptive and noncontraceptive benefits and
health risks associated with contraceptive use in this popula-
tion. Finally, we assist clinicians as they provide guidance for
Received November 18, 2017; revised and accepted January 5, 2018.
From the 1Department of Gynecology and Obstetrics, Emory University
School of Medicine, Atlanta, GA; 2Department of Obstetrics and Gyne-
cology, Warren Alpert Medical School of Brown University, Providence,
RI; and 3Department of Obstetrics and Gynecology, University of Florida
College of Medicine, Jacksonville, FL.
Funding/support: None reported.
Financial disclosure/conflicts of interest: TAM—Emory University
receives research funding from Medicines360 and Contramed.
RHA—Nexplanon trainer for Merck; has also served as consultant for
Bayer. AMK—Consultant, Bayer, Medicines360, Merck, Mithra, Pfizer.
Research funds to University of Florida: Agile, Allergan, Bayer, Merck,
Mithra. CAC—Emory University receives research funding from Med-
icines360 and Contramed.
Address correspondence to: Taniqua A. Miller, MD, Emory University,
Department of Gynecology and Obstetrics, 1365 Clifton Road NE, 4th
Floor, Atlanta, GA 30322. E-mail: Taniqua.miller@emory.edu
women transitioning from contraception to their menopausal
years, including possible initiation of systemic hormone
therapy (HT).
RISK OF PREGNANCY
Likelihood of pregnancy declines with age.2 Women over
40 have lower fecundity (chance of a live birth per menstrual
cycle) compared with their younger cohort. The National
Survey of Family Growth observed that nulliparous women
aged 40 to 44 years were 2.5 times more likely to experience
impaired fecundity versus women aged 24 to 29 years.3 In a
study of women undergoing insemination with donor sperm,
fecundity was 0.2 for women less than 35 years of age versus
0.06 for women over the age of 40.4 Nonetheless, pregnancy is
not uncommon in older reproductive age women. The 2012
US census data reported approximately 26 births per 1,000
women 40 and older.5 Among pregnancies occurring in
women greater than age 40, roughly a third are unintended.6
Compared with younger women, pregnancies in older
reproductive age women carry a higher risk for significant
adverse events. The risk of spontaneous abortion and chro-
mosomal abnormalities increases markedly after the age of
40.7 In 2011, women aged 40 to 44 experienced spontaneous
abortion at a rate of 34% and women aged 45 and older at a
rate of 53%.8 Significant maternal morbidity is also more
likely, with increased risk of developing gestational diabetes
and hypertensive disorders of pregnancy, including pre-
eclampsia and renal failure.9 The incidence of perinatal
morbidity (including that associated with preterm delivery),

Menopause, Vol. 25, No. 7, 2018 817

Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
 MILLER ET AL
and also low birth weight, perinatal mortality, and cesarean
delivery are all elevated among women aged over 40.10
EVIDENCE-BASED GUIDELINES FOR
CONTRACEPTIVE CARE
In 2010, the Centers for Disease Control and Prevention
(CDC) published the first US Medical Eligibility for Con-
traceptive Use (MEC), which provides evidence-based rec-
ommendations for contraceptive options deemed safe to use
with a variety of medical comorbidities and patient character-
istics.11 Modeled after the World Health Organization (WHO)
MEC, the US MEC was developed as a joint venture of
systematic reviews of the medical literature with expert
opinion. In women with a variety of characteristics and
medical conditions, the MEC weighs risks and benefits
associated with the use of the various contraceptive methods
against the risks of unintended pregnancy. The US MEC was
updated in 2016.12
The US MEC is often used in conjunction with the US
Selected Practice Recommendations (SPR) for contraceptive
use. Similarly adapted from the WHO evidenced-based SPR,
the US SPR provides practical and evidence-based guidelines
to inform providers how to most effectively use and manage
the various contraceptive options (see When to Stop Contra-
ception).13 The US MEC and SPR are easy to access during
daily clinical care as they are available as a free USMEC/
USSPR app for smart phones and as free downloads from the
website for tablets and desktops (https://www.cdc.gov/repro-
ductivehealth/contraception/contraception_guidance.htm).
There is no single contraceptive choice contraindicated
based on age alone, because there is no evidence to suggest
that age itself is a risk factor for contraceptive-related com-
plications.12 However, with age comes increased risk of
medical conditions, including obesity, hypertension, diabetes,
and cancer. The US MEC provides guidance on which
contraceptive methods are safe to use given a particular
condition. Table 1 provides a summary of contraceptive
options and the corresponding US MEC recommendation
in regard to age.
In particular, the baseline rate of cardiovascular compli-
cations increases with age; therefore, age should be consid-
ered when assessing the safety of combined hormonal
contraceptive (ie, estrogen-containing) methods in patients
who have other pre-existing cardiovascular risk factors. For
example, the use of combined hormonal contraceptives
(CHCs) in patients 35 years of age or older is contraindicated
if they are heavy smokers (15 or more cigarettes/d) and
cautioned against if they are light smokers (less than 15
cigarettes /d). Furthermore, CHCs are contraindicated or
recommended with caution in older women with multiple
cardiovascular risks factors, including hypertension (con-
trolled and otherwise) and diabetes (see CHCs).12
INTRAUTERINE CONTRACEPTION
Because they provide highly effective, safe, long-term con-
traception, copper and progestin intrauterine devices (IUDs)
818 Menopause, Vol. 25, No. 7, 2018
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
TABLE 1. US medical eligibility criteria for contraceptive use
based on age
Method Age range, y US MEC category
Estrogen-containing 40 2
contraception
Progestin-only pill 40 1
Progestin implant 40 1
DMPA 40 to 45 1
>45 2
Cu-IUD 40 1
LNG-IUS 40 1
Adapted from US Medical Eligibility Criteria for Contraceptive Use,
2016.12
1, A condition for which there is no restriction for the use of the method;
2, a condition for which the advantages if using the method generally
outweigh the disadvantages of using the method; 3, a condition for which
the theoretical or proven risks usually outweigh the advantages of using
the method; 4, a condition that represents an unacceptable health risk if
the method is used.
Cu-IUD, copper intrauterine device; DMPA, depot-medroxyprogesterone
acetate; LNG-IUS, levonorgestrel intrauterine system; US MEC, US
Medical Eligibility for Contraceptive Use.
are considered ‘‘top-tier’’ by the WHO, CDC, and Society of
Obstetricians and Gynaecologists of Canada.13-15 IUDs act
locally within the uterus and cervix to prevent pregnancy.
Therefore, there are no known medication interactions that
compromise IUD effectiveness and few contraindications to
IUD use. Contraindications to IUD placement include the
following: known or suspected pregnancy, known or suspected
pelvic infection, known or suspected pelvic malignancy, or
anatomic conditions that prevent proper placement. IUDs can
easily be placed in the office or clinic setting, without the need
for anesthesia in most instances. The risk of complications with
placement is minimal and includes uterine perforation (0.1%)
and pelvic inflammatory disease (0%-2%).16,17 The cumulative
risk of IUD expulsion is 10% over 3 years of use.18 Satisfaction
and continuation rates associated with IUD use are significantly
higher than those associated with the use of shorter-acting
methods such as oral contraceptives.19
The copper IUD, available as ParaGard T 380A in the
United States, is approved for up to 10 years of contraceptive
use, but continues to be effective for at least 12 years.20 There
are multiple types of copper IUDs available in Canada, with
recommended duration of use ranging from 5 to 12 years of
use. The copper IUD is a nonhormone method; the copper
ions released in utero are spermicidal. The typical (real-life)
use failure (ie, pregnancy) rate is less than 1%.21 The copper
IUD may be the contraceptive of choice in women who should
avoid exposure to progestins (eg, breast cancer patients), and
also those who opt for a monthly menstrual flow or hormone-
free contraceptive. The copper IUD increases menstrual flow
in the first 3 to 6 months, but thereafter bleeding tends to be
normalized. Accordingly, it should be used with caution in
women with heavy menstrual bleeding. With its long duration
of effectiveness, the copper IUD may be used until it is certain
the user is menopausal.
Two 52-mg levonorgestrel-releasing intrauterine systems
(LNG-IUS), Mirena and Liletta, are approved in the United
ß 2018 The North American Menopause Society
 CONTRACEPTION IN MIDLIFE
States for 5 and 4 years of use, respectively, with effectiveness
likely extending to 7 years.22 The local release of levonor-
gestrel in utero thickens the cervical mucus, thereby prevent-
ing sperm entry into the uterus and potential for fertilization.
The typical use failure rate is less than 1%,21 with failure rates
likely lower in older reproductive-age women. The 52-mg
LNG-IUS has versatile appeal as not only a highly effective,
long-acting contraceptive but also for noncontraceptive ben-
efits, including treatment of heavy menstrual bleeding
(HMB). The progestin reservoir acts directly on the endome-
trial surface, causing endometrial thinning and glandular
atrophy. Therefore, bleeding is typically light, but unsched-
uled, and amenorrhea rates are high (up to 18% at 1 year of
use).23 Perimenopausal patients with HMB experience reduc-
tions in menstrual bleeding similar to endometrial ablation,
often precluding the need for surgery.24 Furthermore, for
patients opting to treat vasomotor symptoms with HT, the
LNG-IUS provides adequate suppression of endometrial pro-
liferation for women using estrogen therapy.25,26 The smaller,
13.5-mg LNG-IUS (Skyla) is approved in the United States
for up to 3 years for contraceptive use, and the 19.5-mg LNG-
IUS (Kyleena) is approved for up to 5 years of use. These two
smaller-frame LNG-IUS are associated with lower rates of
amenorrhea than the 52-mg LNG-IUS and may be better
suited for women with a smaller uterine cavity, including
some perimenopausal women.27
Studies exploring breast cancer risk and LNG-IUS use
suggest either no or minimal increased breast cancer risk
associated with use. Two large retrospective case-control
studies of European women showed no increased risk of
breast cancer in women using LNG-IUS for contracep-
tion.28,29 However, two analyses of a large Finnish cohort
suggest a small increased risk (up to 1.3 times) of breast
cancer, in particular, lobular and ductal cell cancers, in
women using LNG-IUS for HMB.30,31 LNG-IUS is currently
category 4 (unacceptable risk) for current/active breast can-
cers and category 3 (risks outweigh benefits) for personal
history of breast cancer in the past 5 years with no active
disease.12 There is no contraindication for patients considered
high-risk for breast cancer (eg, family history or breast cancer
[BRCA] 1/2 mutation carriers).
SYSTEMIC PROGESTIN-ONLY METHODS
Most perimenopausal patients with contraindications to
estrogen-containing options, including tobacco use, obesity,
migraines with aura, long-standing diabetes, hypertension, or
a history of venous thromboembolism (VTE), can safely use
progestin-only contraceptives. These methods include: the
etonogestrel implant, depot-medroxyprogesterone acetate
(DMPA) injection, and progestin-only pills.12 Bleeding is
typically light, but unscheduled, and amenorrhea rates can
be high depending on the method (up to 50% at 12 months of
DMPA use).32 The use of progestin-only methods of contra-
ception is generally not associated with an increased risk
of VTE, myocardial infarction (MI), or cerebrovascular
accident (CVA) in normotensive women.33,34 Therefore,
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
contraindications to progestin-only methods are limited to
a personal history of active or recent (within 5 years) breast
cancer.12
Like IUDs, the 68-mg etonogestrel single-rod subdermal
implant (Nexplanon) provides highly effective, convenient,
long-term contraception, with minimal side effects, compli-
cations, or contraindications. The implant is a 4 cm polymer
capsule that is inserted subdermally in the upper arm and
significantly inhibits ovulation in nearly 100% of cycles.35
The typical use failure rate is less than 1%.21 Originally
approved for 3 years of use, several postmarketing studies
have established efficacy for at least 5 years.36 The implant
can easily be placed in the office or clinic setting, using local
anesthesia. The risk of complications with placement is
minimal and includes localized bruising, infection, deep
placement, and damage to the arm. As with IUDs, satisfaction
and continuation rates associated with implant use are signif-
icantly higher than those of shorter-acting methods.19 How-
ever, menstrual irregularity and irregular spotting may occur
in more than 25% of implant users,37 sometimes leading to
discontinuation.38 Postmarketing research has demonstrated
the implant’s contraceptive efficacy in obese women.39
Depot-medroxyprogesterone acetate is administered intra-
muscularly (150 mg) or subcutaneously (104 mg) every
3 months and works to suppress luteinizing hormone (LH)
release, thus prohibiting ovulation. Typical use results in a
failure rate of 6%, due to the need for injection administration
every 3 months, to maintain effectiveness.21 The dose of
DMPA is relatively high compared with the progestin doses
in other progestin-only and estrogen-containing methods,
which has several unique implications for its use. Of benefit,
amenorrhea rates are higher than other methods—up to 50%
at 1 year of use, with the prevalence of amenorrhea further
increasing with ongoing use.31 The relatively higher dose of
progestin prevents clinically significant interactions with
medications that induce liver enzymes and can attenuate
the contraceptive efficacy of the implant and oral contra-
ceptives. However, return to fertility can be delayed up to an
average of 10 months after the last injection in patients who
desire pregnancy after use. Although randomized trials have
not observed weight gain with use of DMPA, this contracep-
tive is disproportionately chosen by populations at elevated
risk for weight gain.40 Accordingly, some observational
studies have observed weight gain with DMPA use.41,42
As a high-dose progestin contraceptive, DMPA suppresses
ovarian estradiol production.43 Accordingly, bone mineral
density (BMD) decreases during DMPA use. Overall, the
loss of BMD plateaus at 2 years of use and is reversible upon
discontinuation.43 This mirrors the limited and reversible
BMD loss women experience during pregnancy and lactation.
In 2004, concerns regarding lower circulating endogenous
estradiol and impact on BMD led the US Food and Drug
Administration (FDA) to add a black-box warning for DMPA
regarding the potential for increased fracture risk. However,
several studies have demonstrated that even with prolonged
use in perimenopausal women, bone mineral loss attributable
Menopause, Vol. 25, No. 7, 2018 819
 MILLER ET AL
to DMPA is highest in the first year of use and then plateaus,
with recovery after DMPA is discontinued.40
Whether or not the induced BMD loss from DMPA trans-
lates to an increased future fracture risk is controversial. Early
case-control studies demonstrated higher fracture risk in both
current and past DMPA users versus nonusers. The Danish
Vestergaard et al found an odds ratio (OR) of 1.44 (95%
confidence interval [CI] 1.01-2.04), but without adjustments
made for potential confounders such as smoking and body
mass index.44 Meier et al45 found that longer duration of
DMPA use (ie, 2-3 years) was associated with an OR of 1.54
(95% CI 1.33-1.78), but examined fractures typically related
to trauma rather than BMD loss. However, a subsequent
retrospective cohort, using the same database as Meier
et al, found that DMPA users at baseline had higher fracture
risk versus nonusers; DMPA users had incidence ratio of
fracture of 1.28 (95% CI 1.07-1.58) before the onset of DMPA
use.46 Moreover, the risk did not increase further after DMPA
use. Confounding variables not adjusted for, such as traumatic
injuries, may have accounted for the higher incidence of
fractures associated with use of DMPA noted in the two
earlier studies. Women who choose DMPA are different from
women who choose other methods of contraception,46,47 and
behavioral dissimilarities reflecting these differences may
account for women who choose DMPA for contraception,
having a higher fracture risk than women who choose other
contraceptives. For example, the authors of the Danish study
indicated that the prevalence of alcoholism (a condition
known to be associated with fractures from motor vehicle
and other accidents) in women using DMPA was 14%—
sevenfold higher than in women not using DMPA.44 Further-
more, the Danish investigators noted that cases with fractures
were some threefold more likely to be classified as alcoholics
as control women.
Most studies of DMPA and cancer risk suggest a protective
effect. A Thai case-control study found ever use of DMPA
was associated with an 80% decreased risk of endometrial
cancer that persisted for at least 8 years after last use.48 In the
largest case-control study of DMPA and ovarian cancer risk,
use of DMPA was associated with a 40% decreased risk of
epithelial ovarian cancer. This risk was further decreased after
at least 3 years of DMPA use.49 In a systematic review, five of
six studies examining the relationship between progestin use
and breast cancer (three case-control and two retrospective
cohort) found no statistically significant association. In the
remaining case-control study, the risk of breast cancer was
increased 2.3-fold (95% CI 1.3-4.1) in current DMPA users
aged 35 to 44 years versus never-users.50 These studies may
all be limited by small sample sizes, heterogeneity of study
site, and observational study design. Like other hormonal
contraceptive methods, use of DMPA is currently category 4
(unacceptable risk) for current/active breast cancers and
category 3 (risks outweigh benefits) for personal history of
breast cancer in the past 5 years with no active disease.12
A continuously administered progestin-only pill with
0.35 mg of norethindrone is also an effective form of
820 Menopause, Vol. 25, No. 7, 2018
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
contraception. It is recommended that the pill be taken at
the same time every day to maintain therapeutic levels in
cervical mucus to prevent pregnancy.13 Typical use failure
rate is 9% in reproductive age women overall, but may be
lower in women age 40 and older, because this latter popula-
tion has lower fecundity.21 This option may be appropriate for
women who desire a short-term, estrogen-free option. In
contrast with DMPA, progestin-only pills and the progestin
implant have no impact on BMD.43
COMBINED ESTROGEN-PROGESTIN METHODS
Women who desire combination hormonal contraception
(CHC) can choose combined oral contraceptives (COCs), the
transdermal patch, or the vaginal ring. CHCs contain an
estrogen component (typically ethinyl estradiol [EE]) and a
progestin component, and work primarily by inhibiting ovu-
lation. The annual failure rate with typical use of CHCs is 9%,
as individuals must adhere to daily (COC), weekly (patch), or
monthly (ring) administration to maintain effectiveness.21
CHCs are safe options for patients who desire lighter but
scheduled bleeding, and who have no contraindications to
using contraceptive doses of estrogen. Amenorrhea rates are
low with cyclic use. However, continuous use of CHCs (ie,
skipping the nonhormone tablets) eliminates withdrawal
bleeding and reduces menstrual-related side effects.51 With
continuous use, light but unscheduled bleeding may result.
Perimenopausal women may choose these options not only
for effective contraception but to also take advantage of the
noncontraceptive benefits, including bleeding regulation,
menstrual cycle suppression, or vasomotor symptom relief.
Table 2 illustrates the US MEC recommendations for CHCs.
Studies have consistently found an elevated risk of VTE
with CHC use. Among women of reproductive age, the risk is
doubled in CHC users versus nonusers (8-10 per 10,000
woman-years in CHC users vs 4-5 per 10,000 woman-years
in nonusers).52 The greatest risk occurs within the first
3 months of initiation (OR 12, 95% CI 7.1-22.4).53 A
dose-related response has also been observed, as VTE inci-
dence was higher with COCs formulated with 50 or more mcg
of EE.
While MI and stroke are rare in reproductive-age women,
long-term sequelae can be devastating. European studies have
found that use of CHCs increases these risks. Lidegaard et al
found that at baseline, risks of thrombotic stroke and MI were
20 and 100 times increased in an older (aged 45-49 years)
versus younger cohort (aged 15-19 years) of Danish women,
respectively.54 When CHC use was considered, the overall
risk of stroke increased 2.2 times and that of MI 2.3 times.
Furthermore, a dose-dependent relationship exists, with
higher EE formulations demonstrating the highest risks. A
meta-analysis demonstrated this dose relationship: with
50 mcg EE formulations having an OR of 3.62 (95% CI
2.22-5.90, P < 0.0005) for MI, 30 to 49 mcg EE formulations
having an OR of 1.97 (95% CI 1.43-2.71, P < 0.0005), and
20 mcg EE formulations having an OR of 0.92 (95% CI 0.21-
4.08, P ¼ 0.92) versus nonusers. Past users did not have an
ß 2018 The North American Menopause Society
 CONTRACEPTION IN MIDLIFE
TABLE 2. US medical eligibility criteria for contraceptive use for group had higher rates of continuation, shorter and lighter
the use of CHC
bleeding, and higher rates of satisfaction compared with the
Medical condition US MEC category progestin-only pill users.59 Several studies have shown that
Smoking age 35 y estradiol valerate also has less impact on hepatic metabolism,
<15 cigarettes/d 2 specifically hemostatic markers.58 Preliminary studies show
15 cigarettes/d 4
Obesity
either no difference or a decreased impact on VTE risk versus
BMI 30-34 2 EE-containing COCs.60 These findings could prove advanta-
BMI 35 2 geous for midlife patients in whom risk of VTE is increased
Hypertension by age alone. Further studies are needed to clarify whether the
Controlled hypertension 3
Elevated BP 3 safety profile of estradiol valerate/dienogest differs from that
Systolic >140-159 mm Hg or diastolic >90-94 mm Hg of EE formulations.
Systolic 160 mm Hg or diastolic 95 mm Hg 4
Controversy has surrounded the question of whether or not
Vascular disease 4
Diabetes the use of drospirenone-containing COCs increases the risk of
No vascular disease 2 VTE more than COCs with other progestins. The highest-
Vascular disease or >20 y duration 3, 4 (based on quality studies have concluded that any increased VTE risk
severity of
condition) associated with drospirenone-containing COC compared with
Stroke 4 levonorgestrel-containing COCs is negligible.61 However,
Current or history of ischemic heart disease 4
Multiple risk factors for cardiovascular 3, 4 (based on due to methodological limitations, an increased risk with
disease (older age, smoking, severity of drospirenone COC formulations compared with COCs for-
obesity, diabetes, hypertension) condition) mulated with older progestins such as levonorgestrel cannot
Adapted from US Medical Eligibility Criteria for Contraceptive Use, be entirely excluded. Women contemplating use of drospir-
2016.12 enone-containing COCs should be counseled accordingly.
1, A condition for which there is no restriction for the use of the method;
2, a condition for which the advantages if using the method generally While ample evidence has confirmed the relationship
outweigh the disadvantages of using the method; 3, a condition for which between CHC use and cardiovascular events, the absolute
the theoretical or proven risks usually outweigh the advantages of using numbers are relatively small as these events are rather uncom-
the method; 4, a condition that represents an unacceptable health risk if
the method is used. mon at baseline.62 Pregnant and postpartum patients have
BMI, body mass index; BP, blood pressure; CHC, combined hormonal higher risk of VTE than healthy CHC users.63 Considering the
contraceptive; US MEC, US Medical Eligibility for Contraceptive Use. elevated risk of VTE associated with an unplanned pregnancy,
providers may still offer CHC methods to perimenopausal
patients who do not have cardiovascular risk factors.12

elevated risk in this analysis.55 Similarly, a meta-analysis Nonoral options

concluded that the risk of ischemic stroke decreases with
decreasing EE dose: OR of 3.28 (95% CI 2.49-4.32) for
50 mcg EE formulations, an OR of 1.75 (95% CI 1.61-
1.89) for 30 to 40 mcg EE formulations, and an OR of 1.56
(95% CI 1.36-1.79) for 20 mcg EE formulations compared
with nonusers.56 Smoking and hypertension independently
elevate the risk of MI and stroke; therefore, CHC options
should thus be used with caution or not at all in women who
smoke or who have hypertension (Table 2).57
Ethinyl estradiol has traditionally been used as the estrogen
component in CHCs because of its bioavailability. However,
the development of estradiol valerate, an estradiol ester
subsequently metabolized to bioidentical 17b-estradiol, has
provided an alternative estrogen option. Available in the
United States (not in Canada), estradiol valerate/dienogest
(Natazia) is a four-phasic COC that is characterized by
varying levels of estradiol and progestin, providing effective
contraceptive similar to traditional COCs while minimizing
bleeding irregularity.58 With a hormone-free interval of 2
days, patients typically experience lighter and less painful
withdrawal bleeding than traditional 21-day COCs. Briggs
et al studied COC users who discontinued EE-containing
COCs and either switched to the estradiol valerate formula-
tion or a progestin-only pill. Women in the estradiol valerate
The transdermal patch (Xulane) is a 20 cm2 adhesive patch
that releases 35 mcg EE and 150 mcg norelgestromin (active
metabolite of norgestimate) per day. The patch provides the
convenience of once weekly application for 3 weeks, followed
by removal for 1 week for a withdrawal bleed. In clinical
trials, application site irritation of the transdermal contracep-
tive patch was noted by 20% of women using this method.64
The patch produces a 60% higher overall estrogen exposure
than with a typical 35 mcg EE COC.65 While earlier studies
did not find a statistically significant trend to higher rates of
nonfatal VTE,66,67 subsequent case-control studies demon-
strated a twofold increased risk of VTE in patch users versus
those using comparable COC formulations.68,69 In 2004 (and
reaffirmed in 2011), the US FDA placed a black box warning
on the transdermal patch package insert regarding these
findings. The contraceptive patch is formulated with EE. In
contrast, transdermal estrogen used for relief of menopausal
vasomotor symptoms employs 17-b estradiol at significantly
lower doses. Transdermal 17-b estradiol differs from oral
menopausal estrogen in that the former does not appear to
increase risk of VTE.70
The vaginal ring (Nuvaring) provides another nonoral CHC
that provides its users with 3 weeks of continuous use,
followed by removal for 1 week of withdrawal bleed. The

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 MILLER ET AL
ring releases 15 mcg EE and 120 mcg etonogestrel per day.71
Vaginal discharge, ring expulsion, and foreign body sensation
are unique reasons for ring discontinuation.72,73 The vaginal
ring is dispensed with 3 weeks in, 1 week off for monthly
withdrawal bleeding. Several studies have explored extended
cycles. Extended use of vaginal ring may initially present with
unscheduled bleeding, which typically normalizes within the
first year.74 Despite the unscheduled bleeding, Barreiros
et al75 found that few women discontinued use solely from
irregular spotting, indicating that the extended cycle is an
acceptable approach. Even though the vaginal ring has a lower
EE dose, the users of the vaginal ring have similar rates of
VTE as COC users.76
Effect on cancer risk
Use of COC substantially reduces risk of endometrial and
ovarian cancers. A large cohort study of women in the United
Kingdom found that women who had ever used COCs had a
significant 12% reduction in risk of any cancer and a 29% risk
reduction of gynecologic cancers.77 Reduction of risk for
endometrial and ovarian cancer persisted 15 years after
discontinuation. A meta-analysis found the risk for endome-
trial cancer was significantly decreased by 56% after only
4 years of use and by 72% after 12 years of use.78 A
collaborative meta-analysis of 45 studies found a relative
risk (RR) of 0.73 (95% CI 0.70-0.76) for ovarian cancer
for OC users versus nonusers.79 A second meta-analysis of
24 case-control and cohort studies not only confirmed the
above, but found that the greatest reduction in incidence
(>50%) was found in women who used COCs for more than
10 years.80 Furthermore, women whose last use was within
the past 20 years had a statistically significant reduction,
whereas any benefit after 20 years was not found to be
statistically significant.80 Women who rely on oral contra-
ceptives should consider use well into their 40s, if medically
appropriate, to maximize prevention of gynecologic can-
cers.81 COCs may also offer a modest colorectal cancer
protection. A meta-analysis of six studies revealed an 18%
risk reduction for colorectal cancer among COC users versus
nonusers.82 Current users received greatest benefit.
The impact of COCs on breast cancer risk is of clinical
importance for older reproductive-aged women. A case-con-
trol study funded by the National Institutes of Health and
conducted by the CDC, considered by some to be the best
quality analysis of this topic, found no statistically increased
risk of breast cancer in prior or ever COC users (RR of 0.9 and
0.9, respectively [95% CI 0.8-1.0 and 0.8-1.0, respectively])
regardless of EE dose, duration of use,83 or COC formula-
tion.84 In a recently published prospective cohort of 1.8
million Danish women aged 15 to 49 years, Mørch et al
found that current and recent users of any hormonal contra-
ception (with the vast majority utilizing COCs) had a RR of
1.20 (95% CI 1.14-1.26, P ¼ 0.002) for breast cancer com-
pared with never-users.85 This roughly translates to one
additional breast cancer per 7,690 women using hormonal
contraception per year. However, the cohort was limited to
822 Menopause, Vol. 25, No. 7, 2018
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
women no older than 49 years, though the vast majority of
breast cancer cases occur above this age. Furthermore, such a
small RR in an observational study should be read with
caution and not used to suggest causation.86 Patients should
ultimately be counseled on the data and be able to weigh the
risks and benefits that meet their contraceptive goals.
In a recent meta-analysis exploring oral contraceptive use
among BRCA1/2 carriers, the authors looked at breast cancer
risk associated with COC formulations pre and post-1975,
signifying the year of withdrawal of higher-dose EE formu-
lations from the market. Breast cancer risk was not signifi-
cantly increased by COC use with formulations containing
35 mcg or less EE.87 The same study found consistent evi-
dence that in both BRCA1 and BRCA2 carriers, use of COCs
is associated with protection against ovarian cancer (RR of
0.51 and 0.50, respectively [95% CI 0.40-0.65 and 0.29-0.89,
respectively]). Carriers of BRCA1/2 with no personal history
of breast cancer may reasonably use COCs for contraception
as well as protection from ovarian and endometrial cancer.88
A systemic review by Smith et al89 found an elevated risk of
invasive cervical cancer with long-term oral contraceptive
use (RR 1.6, 95% CI 1.4-1.7) and DMPA (RR 1.2, 95% CI
1.0-1.6) after 5 years of use. A later Lancet reanalysis of 24
similar studies reaffirmed this finding.90 The risk dissipated
with time since last use. Although the systematic review
controlled for human papilloma virus and cytology screening,
the screening technologies used in the individual studies
varied significantly, making it difficult to fully interpret
the results. As with all women, adherence to current cervical
cancer screening guidelines is appropriate for women using
hormonal contraception.
NONCONTRACEPTIVE BENEFITS
Hormonal contraceptives also confer many noncontracep-
tive benefits (Table 3). The noncontraceptive benefits detailed
in Table 3 may be of particular importance for midlife women
approaching menopause: treatment of abnormal uterine
bleeding (AUB), relief from vasomotor symptoms, and endo-
metrial protection in women using estrogen therapy.
Treatment of abnormal uterine bleeding
Over 90% of women will experience AUB in the 4 to
8 years, leading up to the final menstrual bleed.91 AUB may
include menstrual cycle irregularity (increased or decreased
frequency) or heavy menstrual bleeding. Several hormonal
TABLE 3. Noncontraceptive benefits of hormonal contraceptives
for perimenopausal women
Restoration of regular bleeding (CHC)
Decreased dysmenorrhea
Reduced heavy menstrual bleeding
Reduced pain associated with endometriosis
Suppression of vasomotor symptoms (CHC)
Enhanced bone mineral density and possible prevention of osteoporotic
fractures (CHC)
Decreased need for biopsies for benign breast disease (CHC)
Prevention of epithelial ovarian, and endometrial malignancies
Improvements in acne that may flare up with perimenopause (CHC)
CHC, combined hormonal contraception.
ß 2018 The North American Menopause Society
 CONTRACEPTION IN MIDLIFE
contraceptive methods are effective in overall reduction of
menstrual bleeding.
Combined hormonal contraceptive formulations may be
used cyclically or continuously, depending on a patient’s
individual goal for bleeding. Continuous usage is associated
with higher rates of amenorrhea and fewer opportunities for
vasomotor symptomatology. EE doses higher than 20 mcg
provide a more reliable bleeding pattern with less break-
through bleeding.92 Though light, unscheduled bleeding
may occur with progestin-only pills, the overall amount of
bleeding is reduced and may be adequate for perimenopausal
patients with AUB.
In 2009, the US FDA approved the 52-mg LNG-IUS for
treatment of heavy menstrual bleeding. The high concentra-
tion of progestin causes decidualization of the endometrium,
resulting in a reduced amount and duration of menstrual
bleeding.93 Menstrual blood loss reduction may be as high
as 79% to 97%.94 Compared with oral progestin therapies,
such as medroxyprogesterone acetate, the LNG-IUS was
superior in the reduction of menstrual blood loss.95 In a
randomized controlled trial of 571 women assigned to either
LNG-IUS or other medical treatments for heavy menstrual
bleeding (eg, tranexamic acid, mefenamic acid, CHCs, and
progesterone-only options), the LNG-IUS outperformed the
others on the Menorrhagia Multi-Attribute Scale and other
quality-of-life metrics.96 Furthermore, the women assigned
to the LNG-IUS were more likely to have continued the
LNG-IUS than those in the non-IUS medical therapy arm
(64% vs 38%, respectively; P < 0.001).96 The LNG-IUS is
also as effective in treating heavy menstrual bleeding as
endometrial ablation,24 providing patients with an alternative
to surgery. For patients with heavy menstrual bleeding related
to uterine leiomyomata, depending on the number, size, and
location of fibroids, the LNG-IUS can help with reduction of
menstrual bleeding.97 However, leiomyoma size remains
relatively unchanged and there may be incrementally
increased risk of IUS expulsion compared with women with-
out uterine fibroids.97 Likewise, although the LNG-IUS can
effectively treat heavy menstrual bleeding in women with
uterine adenomyosis, clinicians and women should be aware
that expulsion rates are increased in this clinical setting as
well.98
Relief from vasomotor symptoms
Approximately 75% of women will experience vasomotor
disturbances during the menopausal transition and beyond.99
CHC can provide the perimenopausal patient with vasomotor
symptom relief in addition to effective contraception, espe-
cially for severe symptoms.57 In one observational study, 40%
and 90% of perimenopausal women reported vasomotor
symptoms with use of COC versus nonuse, respectively.100
Continuous use regimens of CHCs are more likely to prevent
the recurrence of hot flushes and night sweats that can be
triggered by withdrawal of hormones.57
Hormone therapy traditionally used by menopausal patients
for the relief of vasomotor symptoms does not provide
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
contraceptive protection. Therefore, patients should be coun-
seled that HT is not synonymous with contraception. In fact,
current COCs contain EE doses substantially higher than seen
with HT. These high doses may be inappropriate for some
patients who would otherwise be candidates for HT, but no
longer candidates for COCs. Norethindrone acetate/ethinyl
estradiol with dosage of 1 mg/5 mcg is US FDA-approved for
treatment of vasomotor symptoms and osteoporosis prevention
in menopausal women. While not specifically labeled for
contraceptive use, the authors feel that the 1 mg of norethindrone
acetate (which represents the norethindrone dose used in many
COC formulations) is sufficient to provide ovulation inhibition.
Accordingly, this formulation may represent an appropriate off-
label choice for perimenopausal women, who, due to cardio-
vascular risk factors, may not be candidates for CHCs. The
lower formulation of 0.5 mg/2.5 mcg likely does not provide
contraception and should not be used for this purpose.
Endometrial protection during hormone therapy
Though an off-label use in the United States, the 52-mg
LNG-IUS is approved for endometrial protection for peri/
postmenopausal women receiving estrogen HT in many
countries.23 With its concentrated action of progestin on
the endometrial lining, patients using menopausal estrogen
therapy concomitantly with a 52-mg LNG-IUS have high
rates of amenorrhea and absence of endometrial hyperpla-
sia.101 This endometrial protection has been established for up
to 5 years of LNG-IUS use. Placement during the menopausal
transition provides midlife patients with highly effective
contraception, and provides an appealing segue to endome-
trial protection for patients who transition to menopausal
estrogen therapy. Limitations to use include possible patient
discomfort with placement, especially in women with a
smaller uterus. There are no data assessing the efficacy of
the 13.5 and 19.5 mg smaller-framed LNG-IUS for endome-
trial protection. Cost may also be an issue as this is not an US
FDA-approved method of uterine protection and may not be
covered by insurance. To improve placement success, use of
oral nonsteroidal anti-inflammatory medications and para-
cervical block may be used for pain control.93
OTHER OPTIONS FOR CONTRACEPTION
Permanent sterilization represents an effective option for
women who have concluded childbearing. Between 2006 and
2010, the National Survey of Family Growth reported that
50.6% of women aged 40 to 44 identified female sterilization
as their contraceptive method.102 The prevalence of female
sterilization for this cohort was two and a half times higher
than for male sterilization and 16 times higher for comparably
effective IUDs. Older women are less likely to express regret
from the procedure.103 Furthermore, hysteroscopic steriliza-
tion (Essure) can bypass transabdominal entry and be per-
formed in an office setting, which may be especially
beneficial for patients with obesity, medical comorbidities
for which anesthesia is risky, or significant intra-abdominal
adhesive disease.103
Menopause, Vol. 25, No. 7, 2018 823
 MILLER ET AL
Transabdominal tubal sterilization is associated with a
reduced risk of ovarian cancer. Green et al104 showed
a reduction of ovarian cancer at a RR of 0.61 (95% CI
0.46-0.85) for women with tubal sterilization versus those
without tubal sterilization, regardless of method of tubal
occlusion. With growing evidence suggesting that epithelial
ovarian cancers originate in the distal Fallopian tubes,
support for opportunistic salpingectomy (bilateral salpin-
gectomy performed in those electing sterilization for con-
traception) is growing.105 Bilateral salpingectomy in lieu of
traditional tubal sterilization appears safe, with no addi-
tional perioperative complications or adverse impact on
ovarian reserve compared with conventional methods of
tubal sterilization.106
Emergency contraception (EC) should be made available
when appropriate to perimenopausal patients regardless of
medical comorbidities since an unplanned pregnancy poses a
higher risk for these patients than use of EC. There are no
contraindications to EC apart from pregnancy.12 The most
effective form of EC is the copper-IUD with greater than 99%
effectiveness in pregnancy prevention when inserted within
5 days of unprotected sex.13 Patients who elect this option
have the added benefit of ongoing long-term contraceptive
with the IUD, if desired. Progestin EC pills provide a dose of
1.5 mg of levonorgestrel that must be taken within the first
72 hours of contraceptive failure or unprotected sex.107 They
are available in the United States and Canada without a
prescription. Ulipristal acetate, an antiprogestin, may be used
up to 5 days after unprotected sex. Ulipristal acetate has been
found to be more effective in pregnancy prevention than the
progestin options, but requires a prescription in both the
United States and Canada.107 It is important to note that
EC pills inhibit or delay ovulation and will not interfere with
a pregnancy that has already implanted.
WHEN TO STOP CONTRACEPTION/TRANSITION
TO HORMONE THERAPY
As previously mentioned, the US SPR provides guidance
on the appropriate time to stop contraception in perimen-
opausal patients. The Centers for Disease Control and
Prevention, American College of Obstetricians and Gyne-
cologists, and The North American Menopause Society
recommend that for patients who wish to avoid pregnancy,
use of contraception should continue until menopause is
reached.13
Nonhormone methods including the copper IUD can be
safely used until menopause is assured. For most perimen-
opausal women, menopause can be assumed after 1 year of
amenorrhea.108 With the use of progestin-only methods,
amenorrhea is a common occurrence; accordingly, the
absence of unscheduled bleeding may not accurately signal
the onset of menopause. Patients may continue their use until
55 years of age if they have no contraindications to progestin
use. With the continuous use of CHCs, amenorrhea is also a
common occurrence. With cyclic use of CHCs, the absence of
scheduled bleeding may not accurately signal the onset of
824 Menopause, Vol. 25, No. 7, 2018
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
menopause. Similarly, patients may continue to use CHCs
until 55 years of age if they have no contraindications to the
contraceptive doses of estrogen.13 As women near the age of
menopause, clinicians will need to reassess the safety of CHC
options if risks of cardiovascular disease change, and recom-
mend alternative options if indicated.12 At the time they
discontinue hormonal contraception when menopause is pre-
sumptively established (eg, age 55), some midlife women will
choose to initiate menopausal HT.
While the guidelines detailed above provide reasonable
endpoints for contraceptive use, some women may desire
discontinuation as soon as menopause is reached. Menopause
is a retrospective diagnosis based on cessation of menses for
12 months. For some patients, stopping their hormonal con-
traceptive method for a period of 1 or 2 months to allow the
resumption of menses may be a reasonable test of menopausal
status if an acceptable nonhormone contraceptive option is
available and used consistently.109 Follicle-stimulating hor-
mone (FSH) testing has also been utilized to assess meno-
pausal status in women who do not experience menstrual
bleeding. Expert opinion suggests contraception may not be
needed in patients of menopausal age who have FSH levels
greater than or equal to 30 IU/L on two occasions 6 to 8 weeks
apart over the age of 50.109 However, in perimenopausal
women, FSH levels can vary at any given moment and should
not be relied upon to diagnose menopause.
The FSH levels may be slightly elevated in LNG-IUS users,
a finding likely more influenced by older age rather than
LNG-IUS use itself.110,111 Etonogestrel implants have little
impact on FSH levels, even at 3 years of use.112 FSH levels are
not substantially suppressed by DMPA use.113-115 However,
FSH levels are significantly suppressed in CHC and proges-
tin-only pill users, and not a reliable source for determining
menopausal status.115,116 If using combined hormonal con-
traception, FSH testing to determine if menopause is present
should occur 14 days after last use of a CHC. DMPA users
may test on the first day of injection, with menopause
confirmed if FSH levels are consistently greater than
30 IU/L at intervals of at least 90 days.114
CONCLUSIONS
While the likelihood of pregnancy diminishes with age,
the risk is not trivial in older reproductive-age women.
Midlife women who do become pregnant face an increased
risk of medical morbidities, including VTE, hypertensive
disorders, and adverse neonatal outcomes. Many contracep-
tive options are compatible with the goals of providing safe
and effective pregnancy prevention, and also noncontracep-
tive benefits that may prove useful for midlife women. The
US MEC and SPR enable providers to use evidence-based
recommendations to counsel patients regarding the most
appropriate contraceptive options that fit their medical
circumstances and personal goals. Most patients can find
a contraceptive option that can be used until menopause
and perhaps beyond, bridging the transition to menopause
and possible use of HT.
ß 2018 The North American Menopause Society
 CONTRACEPTION IN MIDLIFE
REFERENCES
1. Sonfield AHK, Gold RB. Moving Forward: Family Planning in the Era
of Health Reform. Guttmacher Institute; 2014. Available at: https://
www.guttmacher.org/report/moving-forward-family-planning-era-
health-reform. Accessed October 31, 2017.
2. Menken J, Trussell J, Larsen U. Age and infertility. Science
1986;233:1389-1394.
3. Chandra A, Copen CE, Stephen EH. Infertility and impaired fecundity in
the United States, 1982-2010: data from the National Survey of Family
Growth. Natl Health Stat Report 2013;1-18; (1 p following 19).
4. Kang BM, Wu TC. Effect of age on intrauterine insemination with
frozen donor sperm. Obstet Gynecol 1996;88:93-98.
5. United States Census Bureau. Fertility of Women in the Unites States;
2012. Available at: https://www.census.gov/content/dam/Census/library/
publications/2014/demo/p20-575. Accessed September 12, 2017.
6. Finer LB, Zolna MR. Declines in unintended pregnancy in the United
States, 2008-2011. N Engl J Med 2016;374:843-852.
7. Cleary-Goldman J, Malone FD, Vidaver J, et al. Impact of maternal age
on obstetric outcome. Obstet Gynecol 2005;105:983-990.
8. American Congress of Obstetricians and Gynecologists. Women’s
Health Stats and Facts; 2011. Available at: https://www.acog.org/-/
media/NewsRoom/MediaKit.pdf. Accessed September 23, 2017.
9. Lisonkova S, Potts J, Muraca GM, et al. Maternal age and severe
maternal morbidity: a population-based retrospective cohort study.
PLoS Med 2017;14:e1002307.
10. Cavazos-Rehg PA, Krauss MJ, Spitznagel EL, et al. Maternal age and
risk of labor and delivery complications. Matern Child Health J
2015;19:1202-1211.
11. Centers for Disease Control and Prevention. U.S. medical eligibility
criteria for contraceptive use, 2010. MMWR Recomm Rep 2010;59:1-86.
12. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility
criteria for contraceptive use, 2016. MMWR Recomm Rep 2016;65:
1-103.
13. Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. selected practice
recommendations for contraceptive use, 2016. MMWR Recomm Rep
2016;65:1-66.
14. World Health Organization. Family planning: a global handbook for
providers. Available at: http://apps.who.int/iris/bitstream/10665/44028/
1/9780978856373_eng.pdf. Accessed September 12, 2017.
15. Black A, Guilbert E, Costescu D, et al. Canadian contraceptive consen-
sus (part 1 of 4). J Obstet Gynaceol Can 2015;37:936-942.
16. Mohllajee AP, Curtis KM, Peterson HB. Does insertion and use of an
intrauterine device increase the risk of pelvic inflammatory disease
among women with sexually transmitted infection? A systematic
review. Contraception 2006;73:145-153.
17. Heinemann K, Reed S, Moehner S, Minh TD. Risk of uterine perforation
with levonorgestrel-releasing and copper intrauterine devices in the
European Active Surveillance Study on Intrauterine Devices. Contra-
ception 2015;91:274-279.
18. Madden T, McNicholas C, Zhao Q, Secura GM, Eisenberg DL, Peipert
JF. Association of age and parity with intrauterine device expulsion.
Obstet Gynecol 2014;124:718-726.
19. Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of
reversible contraception. Obstet Gynecol 2011;117:1105-1113.
20. Wu JP, Pickle S. Extended use of the intrauterine device: a literature
review and recommendations for clinical practice. Contraception
2014;89:495-503.
21. Hatcher RATJ, Nelson AL, et al. Contraceptive Technology, 20th ed
New York: Ardent Media; 2011.
22. McNicholas C, Maddipati R, Zhao Q, Swor E, Peipert JF. Use of the
etonogestrel implant and levonorgestrel intrauterine device beyond the
U.S. Food and Drug Administration-approved duration. Obstet Gynecol
2015;125:599-604.
23. Bednarek PH, Jensen JT. Safety efficacy and patient acceptability of the
contraceptive and non-contraceptive uses of the LNG-IUS. Int J Wom-
ens Health 2010;1:45-58.
24. Kaunitz AM, Meredith S, Inki P, Kubba A, Sanchez-Ramos L. Levo-
norgestrel-releasing intrauterine system and endometrial ablation in
heavy menstrual bleeding: a systematic review and meta-analysis.
Obstet Gynecol 2009;113:1104-1116.
25. Sitruk-Ware R. The levonorgestrel intrauterine system for use in
peri- and postmenopausal women. Contraception 2007;75 (6 Suppl):
S155-160.
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
26. Sturdee D. Levonorgestrel intrauterine system for endometrial protec-
tion. J Br Menopause Soc 2006;12 (Suppl 1):1-3.
27. Allen RH, Cwiak CA. Contraception for midlife women. Menopause
2016;23:111-113.
28. Backman T, Rauramo I, Jaakkola K, et al. Use of the levonorgestrel-
releasing intrauterine system and breast cancer. Obstet Gynecol
2005;106:813-817.
29. Dinger J, Bardenheuer K, Minh TD. Levonorgestrel-releasing and
copper intrauterine devices and the risk of breast cancer. Contraception
2011;83:211-217.
30. Soini T, Hurskainen R, Grenman S, Maenpaa J, Paavonen J, Pukkala E.
Cancer risk in women using the levonorgestrel-releasing intrauterine
system in Finland. Obstet Gynecol 2014;124:292-299.
31. Soini T, Hurskainen R, Grenman S, et al. Levonorgestrel-releasing
intrauterine system and the risk of breast cancer: a nationwide cohort
study. Acta Oncol 2016;55:188-192.
32. Mishell DR Jr, Kletzky OA, Brenner PF, Roy S, Nicoloff J. The effect of
contraceptive steroids on hypothalamic-pituitary function. Am J Obstet
Gynecol 1977;128:60-74.
33. Chakhtoura Z, Canonico M, Gompel A, Thalabard JC, Scarabin PY, Plu-
Bureau G. Progestogen-only contraceptives and the risk of stroke: a
meta-analysis. Stroke 2009;40:1059-1062.
34. Chakhtoura Z, Canonico M, Gompel A, Scarabin PY, Plu-Bureau G.
Progestogen-only contraceptives and the risk of acute myocardial
infarction: a meta-analysis. J Clin Endocrinol Metab 2011;96:
1169-1174.
35. Makarainen L, van Beek A, Tuomivaara L, Asplund B, Coelingh
Bennink H. Ovarian function during the use of a single contraceptive
implant: Implanon compared with Norplant. Fertil Steril 1998;69:
714-721.
36. Ali M, Akin A, Bahamondes L, et al. Extended use up to 5 years of the
etonogestrel-releasing subdermal contraceptive implant: comparison to
levonorgestrel-releasing subdermal implant. Hum Reprod 2016;31:
2491-2498.
37. Merck. Nexplanon Prescribing Information. Available at: https://
www.merck.com/product/usa/pi_circulars/n/nexplanon/nexplanon_-
pi.pdf. Accessed September 24, 2017.
38. Casey PM, Long ME, Marnach ML, Bury JE. Bleeding related to
etonogestrel subdermal implant in a US population. Contraception
2011;83:426-430.
39. Xu H, Wade JA, Peipert JF, Zhao Q, Madden T, Secura GM. Con-
traceptive failure rates of etonogestrel subdermal implants in overweight
and obese women. Obstet Gynecol 2012;120:21-26.
40. Kaunitz AM, Peipert JF, Grimes DA. Injectable contraception: issues
and opportunities. Contraception 2014;89:331-334.
41. Kaunitz AM. Injectable contraception. New and existing options. Obstet
Gynecol Clin North Am 2000;27:741-780.
42. Curtis KM, Ravi A, Gaffield ML. Progestogen-only contraceptive use in
obese women. Contraception 2009;80:346-354.
43. Isley MM, Kaunitz AM. Update on hormonal contraception and bone
density. Rev Endocr Metab Disord 2011;12:93-106.
44. Vestergaard P, Rejnmark L, Mosekilde L. The effects of depot medrox-
yprogesterone acetate and intrauterine device use on fracture risk in
Danish women. Contraception 2008;78:459-464.
45. Meier C, Brauchli YB, Jick SS, Kraenzlin ME, Meiert CR. Use of depot
medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab
2010;95:4909-4916.
46. Lanza LL, McQuay LJ, Rothman KJ, et al. Use of depot medroxypro-
gesterone acetate contraception and incidence of bone fracture. Obstet
Gynecol 2013;121:593-600.
47. Winner B, Peipert J, Zhao Q, et al. Effectiveness of long-acting
reversible contraception. N Engl J Med 2012;386:1998-2007.
48. The World Health Organization. Depot-medroxyprogesterone acetate
(DMPA) and risk of endometrial cancer. The WHO Collaborative Study
of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:186-190.
49. Wilailak S, Vipupinyo C, Suraseranivong V, et al. Depot medroxypro-
gesterone acetate and epithelial ovarian cancer: a multicentre case-
control study. BJOG 2012;119:672-677.
50. Samson M, Porter N, Orekoya O, et al. Progestin and breast cancer risk: a
systematic review. Breast Cancer Res Treat 2016;155:3-12.
51. Edelman AB, Gallo MF, Jensen JT, Nichols MD, Schulz KF, Grimes
DA. Continuous or extended cycle vs. cyclic use of combined oral
contraceptives for contraception. Cochrane Database Syst Rev
2005;CD004695.
Menopause, Vol. 25, No. 7, 2018 825
 MILLER ET AL
52. Reid RL, Westhoff C, Mansour D, et al. Oral contraceptives and venous
thromboembolism consensus opinion from an international workshop
held in Berlin, Germany in December. J Fam Plann Reprod Health Care
2010;36:117-122.
53. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen
CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives,
effects of oestrogen dose and progestogen type: results of the MEGA
case-control study. BMJ 2009;339:b2921.
54. Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N.
Thrombotic stroke and myocardial infarction with hormonal contracep-
tion. N Engl J Med 2012;366:2257-2266.
55. Khader YS, Rice J, John L, Abueita O. Oral contraceptives use and the
risk of myocardial infarction: a meta-analysis. Contraception
2003;68:11-17.
56. Xu Z, Li Y, Tang S, Huang X, Chen T. Current use of oral contraceptives
and the risk of first-ever ischemic stroke: a meta-analysis of observa-
tional studies. Thromb Res 2015;136:52-60.
57. Kaunitz AM. Clinical practice. Hormonal contraception in women of
older reproductive age. N Engl J Med 2008;358:1262-1270.
58. Fruzzetti F, Tremollieres F, Bitzer J. An overview of the development of
combined oral contraceptives containing estradiol: focus on estradiol
valerate/dienogest. Gynecol Endocrinol 2012;28:400-408.
59. Briggs P, Serrani M, Vogtlander K, Parke S. Continuation rates,
bleeding profile acceptability, and satisfaction of women using an oral
contraceptive pill containing estradiol valerate and dienogest versus a
progestogen-only pill after switching from an ethinylestradiol-contain-
ing pill in a real-life setting: results of the CONTENT study. Int J
Womens Health 2016;8:477-487.
60. Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on
cardiovascular safety of combined oral contraceptives. Contraception
2016;94:328-339.
61. Larivee N, Suissa S, Khosrow-Khavar F, Tagalakis V, Filion KB.
Drospirenone-containing oral contraceptive pills and the risk of venous
thromboembolism: a systematic review of observational studies. BJOG
2017;124:1490-1499.
62. Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone
therapy: relative and attributable risks of cardiovascular disease, cancer,
and other health outcomes. Ann Epidemiol 2015;25:193-200.
63. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton
LJ 3rd. Trends in the incidence of venous thromboembolism during
pregnancy or postpartum: a 30-year population-based study. Ann Intern
Med 2005;143:697-706.
64. Sibai BM, Odlind V, Meador ML, Shangold GA, Fisher AC, Creasy
GW. A comparative and pooled analysis of the safety and tolerability of
the contraceptive patch (Ortho Evra/Evra). Fertil Steril 2002;77 (2 Suppl
2):S19-26.
65. Galzote RM, Rafie S, Teal R, Mody SK. Transdermal delivery of
combined hormonal contraception: a review of the current literature.
Int J Womens Health 2017;9:315-321.
66. Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous
thromboembolism in women using a contraceptive transdermal patch
and oral contraceptives containing norgestimate and 35 microg of
ethinyl estradiol. Contraception 2006;73:223-228.
67. Jick SS, Hagberg KW, Hernandez RK, Kaye JA. Postmarketing study of
ORTHO EVRA and levonorgestrel oral contraceptives containing hor-
monal contraceptives with 30 mcg of ethinyl estradiol in relation to
nonfatal venous thromboembolism. Contraception 2010;81:16-21.
68. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembo-
lism, myocardial infarction, and stroke among transdermal contraceptive
system users. Obstet Gynecol 2007;109 (2 Pt 1):339-346.
69. Dore DD, Norman H, Loughlin J, Seeger JD. Extended case-control
study results on thromboembolic outcomes among transdermal con-
traceptive users. Contraception 2010;81:408-413.
70. The NHTPSAP. The 2017 hormone therapy position statement of The
North American Menopause Society. Menopause 2017;24:728-753.
71. Brache V, Faundes A. Contraceptive vaginal rings: a review. Contra-
ception 2010;82:418-427.
72. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user
acceptability of a novel combined contraceptive vaginal ring. Obstet
Gynecol 2002;100:585-593.
73. Oddsson K, Leifels-Fischer B, de Melo NR, et al. Efficacy and safety of
a contraceptive vaginal ring (NuvaRing) compared with a combined oral
contraceptive: a 1-year randomized trial. Contraception 2005;71:176-
182.
826 Menopause, Vol. 25, No. 7, 2018
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
74. Guazzelli CA, Barreiros FA, Barbosa R, de Araujo FF, Moron AF.
Extended regimens of the vaginal contraceptive ring: cycle control.
Contraception 2009;80:430-435.
75. Barreiros FA, Guazzelli CA, de Araujo FF, Barbosa R. Bleeding patterns
of women using extended regimens of the contraceptive vaginal ring.
Contraception 2007;75:204-208.
76. Dinger J, Mohner S, Heinemann K. Cardiovascular risk associated with
the use of an etonogestrel-containing vaginal ring. Obstet Gynecol
2013;122:800-808.
77. 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 Practitioner’s oral contraception study. BMJ
2007;335:651.
78. Schlesselman JJ. Risk of endometrial cancer in relation to use of
combined oral contraceptives. A practitioner’s guide to meta-analysis.
Hum Reprod 1997;12:1851-1863.
79. Collaborative Group on Epidemiological Studies of Ovarian Cancer.
Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral
contraceptives: collaborative reanalysis of data from 45 epidemiological
studies including 23,257 women with ovarian cancer and 87,303 con-
trols. Lancet 2008;371:303-314.
80. Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive pills
as primary prevention for ovarian cancer: a systematic review and meta-
analysis. Obstet Gynecol 2013;122:139-147.
81. Kaunitz AM. Oral Contraceptives in the Prevention of Ovarian Cancer.
NEJM J Watch 2013; Available at: https://www.jwatch.org/na31600/
2013/07/19/oral-contraceptives-prevention-ovarian-cancer. Accessed
October 29. 2017.
82. 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;84:722-727.
83. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives
and the risk of breast cancer. N Engl J Med 2002;346:2025-2032.
84. Marchbanks PA, Curtis KM, Mandel MG, et al. Oral contraceptive
formulation and risk of breast cancer. Contraception 2012;85:
342-350.
85. Mørch L, Skovlund C, Hannaford P, et al. Contemporary contraception
and the risk of breast cancer. N Engl J Med 2017;377:2228-2239.
86. Grimes D, Schulz K. False alarms and pseudo-epidemics. The limita-
tions of observational epidemiology. Obstet Gynecol 2012;120:920-927.
87. Iodice S, Barile M, Rotmensz N, et al. Oral contraceptive use and breast
or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J
Cancer 2010;46:2275-2284.
88. American Congress of Obstetricians and Gynecologists. Committee
Opinion No. 634: hereditary cancer syndromes and risk assessment.
Obstet Gynecol 2015;125:1538-1543.
89. Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and
use of hormonal contraceptives: a systematic review. Lancet
2003;361:1159-1167.
90. International Collaboration of Epidemiological Studies of Cervical
Cancer. Appleby P, Beral V, Berrington de González A, et al. Cervical
cancer and hormonal contraceptives: collaborative reanalysis of indi-
vidual data for 16,573 women with cervical cancer and 35,509 women
without cervical cancer from 24 epidemiological studies. Lancet
2007;370: 1609-1621.
91. The North American Menopause Society. Menopause Practice: A
Clinician’s Guide. Mayfield Heights: North American Menopause
Society; 2014; 47-55.
92. Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF. 20 microg
versus >20 microg estrogen combined oral contraceptives for contra-
ception. Cochrane Database Syst Rev 2013;CD003989.
93. American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 121: long-acting reversible contraception: Implants and
intrauterine devices. Obstet Gynecol 2011;118:184-196.
94. Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-
releasing hormone system (LNG-IUS): a systematic enquiry and over-
view. Eur J Obstet Gynecol Reprod Biol 2006;125:9-28.
95. Kaunitz AM, Bissonnette F, Monteiro I, Lukkari-Lax E, Muysers C,
Jensen JT. Levonorgestrel-releasing intrauterine system or medroxy-
progesterone for heavy menstrual bleeding: a randomized controlled
trial. Obstet Gynecol 2010;116:625-632.
96. Gupta J, Kai J, Middleton L, et al. Levonorgestrel intrauterine system
versus medical therapy for menorrhagia. N Engl J Med 2013;368:
128-137.
ß 2018 The North American Menopause Society
 CONTRACEPTION IN MIDLIFE
97. Kaunitz AM. Progestin-releasing intrauterine systems and leiomyoma.
Contraception 2007;75 (6 Suppl):S130-S133.
98. Kaunitz AM, Inki P. The levonorgestrel-releasing intrauterine system in
heavy menstrual bleeding: a benefit-risk review. Drugs 2012;72:193-215.
99. Avis NE, Crawford SL, McKinlay SM. Psychosocial, behavioral, and
health factors related to menopause symptomatology. Womens Health
1997;3:103-120.
100. Shargil AA. Hormone replacement therapy in perimenopausal women
with a triphasic contraceptive compound: a three-year prospective study.
Int J Fertil 1985;30:1518-1528.
101. Depypere H, Inki P. The levonorgestrel-releasing intrauterine system for
endometrial protection during estrogen replacement therapy: a clinical
review. Climacteric 2015;18:470-482.
102. Jones J, Mosher W, Daniels K. Current contraceptive use in the United
States, 2006-2010, and changes in patterns of use since. Natl Health Stat
Report 1995;2012:1-25.
103. American Congress of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 133: benefits and risks of sterilization. Obstet Gynecol
2013;121 (2 Pt 1):392-404.
104. Green A, Purdie D, Bain C, et al. Tubal sterilisation, hysterectomy and
decreased risk of ovarian cancer. Survery of Women’s Health Study
Group. Int J Cancer 1997;71:948-951.
105. American Congress of Obstetricians and Gynecologists. Committee
Opinion No. 620: salpingectomy for ovarian cancer prevention. Obstet
Gynecol 2015;125:279-281.
106. Ely LK, Truong M. The role of opportunistic bilateral salpingectomy vs
tubal occlusion or ligation for ovarian cancer prophylaxis. J Minim
Invasive Gynecol 2017;24:371-378.
107. American Congress of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 152: emergency contraception. Obstet Gynecol 2015;126:
685-686.
Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
108. ESHRE Capri Workshop Group. Female contraception over 40. Hum
Reprod Update 2009;15:599-612.
109. Baldwin MK, Jensen JT. Contraception during the perimenopause.
Maturitas 2013;76:235-242.
110. Halmesmaki K, Hurskainen R, Tiitinen A, et al. A randomized con-
trolled trial of hysterectomy or levonorgestrel-releasing intrauterine
system in the treatment of menorrhagia-effect on FSH levels and
menopausal symptoms. Hum Reprod 2004;19:378-382.
111. Tasci Y, Caglar GS, Kayikcioglu F, Cengiz H, Yagci B, Gunes M.
Treatment of menorrhagia with the levonorgestrel releasing intrauterine
system: effects on ovarian function and uterus. Arch Gynecol Obstet
2009;280:39-42.
112. Inal MM, Yildirim Y, Ertopcu K, Avci ME, Ozelmas I, Tinar S. Effect of
the subdermal contraceptive etonogestrel implant (Implanon) on bio-
chemical and hormonal parameters (three years follow-up). Eur J
Contracept Reprod Health Care 2008;13:238-242.
113. Beksinska ME, Smit JA, Kleinschmidt I, Rees HV, Farley TM, Guidozzi
F. Detection of raised FSH levels among older women using depome-
droxyprogesterone acetate and norethisterone enanthate. Contraception
2003;68:339-343.
114. Juliato CT, Fernandes A, Marchi NM, Castro S, Olivotti B, Bahamondes
L. Usefulness of FSH measurements for determining menopause in long-
term users of depot medroxyprogesterone acetate over 40 years of age.
Contraception 2007;76:282-286.
115. Beksinska ME, Smit JA, Kleinschmidt I, Farley TM. Assessing meno-
pausal status in women aged 40-49 using depot-medroxyprogesterone
acetate, norethisterone enanthate or combined oral contraception. S Afr
Med J 2011;101:131-135.
116. Castracane VD, Gimpel T, Goldzieher JW. When is it safe to switch
from oral contraceptives to hormonal replacement therapy? Contracep-
tion 1995;52:371-376.
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