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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- women transitioning from contraception to their menopausal
ductive health care: since the average woman in North years, including possible initiation of systemic hormone
America desires two children, she will spend about therapy (HT).
3 years pregnant, postpartum, or attempting to become preg-
nant, and over 30 years trying to avoid pregnancy.1 Accord- RISK OF PREGNANCY
ingly, the provision of contraception must span the Likelihood of pregnancy declines with age.2 Women over
reproductive age spectrum, including perimenopause. In this 40 have lower fecundity (chance of a live birth per menstrual
article, we review the need for contraception among women cycle) compared with their younger cohort. The National
over 40 years of age and present evidence-based guidelines Survey of Family Growth observed that nulliparous women
for contraceptive use in this population. We detail the con- aged 40 to 44 years were 2.5 times more likely to experience
traceptive options available to women over 40, and also the impaired fecundity versus women aged 24 to 29 years.3 In a
unique contraceptive and noncontraceptive benefits and study of women undergoing insemination with donor sperm,
health risks associated with contraceptive use in this popula- fecundity was 0.2 for women less than 35 years of age versus
tion. Finally, we assist clinicians as they provide guidance for 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
Received November 18, 2017; revised and accepted January 5, 2018.
women 40 and older.5 Among pregnancies occurring in
From the 1Department of Gynecology and Obstetrics, Emory University
School of Medicine, Atlanta, GA; 2Department of Obstetrics and Gyne- women greater than age 40, roughly a third are unintended.6
cology, Warren Alpert Medical School of Brown University, Providence, Compared with younger women, pregnancies in older
RI; and 3Department of Obstetrics and Gynecology, University of Florida reproductive age women carry a higher risk for significant
College of Medicine, Jacksonville, FL.
Funding/support: None reported. adverse events. The risk of spontaneous abortion and chro-
Financial disclosure/conflicts of interest: TAM—Emory University mosomal abnormalities increases markedly after the age of
receives research funding from Medicines360 and Contramed. 40.7 In 2011, women aged 40 to 44 experienced spontaneous
RHA—Nexplanon trainer for Merck; has also served as consultant for abortion at a rate of 34% and women aged 45 and older at a
Bayer. AMK—Consultant, Bayer, Medicines360, Merck, Mithra, Pfizer.
Research funds to University of Florida: Agile, Allergan, Bayer, Merck, rate of 53%.8 Significant maternal morbidity is also more
Mithra. CAC—Emory University receives research funding from Med- likely, with increased risk of developing gestational diabetes
icines360 and Contramed. and hypertensive disorders of pregnancy, including pre-
Address correspondence to: Taniqua A. Miller, MD, Emory University,
Department of Gynecology and Obstetrics, 1365 Clifton Road NE, 4th eclampsia and renal failure.9 The incidence of perinatal
Floor, Atlanta, GA 30322. E-mail: Taniqua.miller@emory.edu morbidity (including that associated with preterm delivery),

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MILLER ET AL

and also low birth weight, perinatal mortality, and cesarean TABLE 1. US medical eligibility criteria for contraceptive use
based on age
delivery are all elevated among women aged over 40.10
Method Age range, y US MEC category
EVIDENCE-BASED GUIDELINES FOR Estrogen-containing 40 2
CONTRACEPTIVE CARE contraception
Progestin-only pill 40 1
In 2010, the Centers for Disease Control and Prevention Progestin implant 40 1
(CDC) published the first US Medical Eligibility for Con- DMPA 40 to 45 1
traceptive Use (MEC), which provides evidence-based rec- >45 2
ommendations for contraceptive options deemed safe to use Cu-IUD 40 1
LNG-IUS 40 1
with a variety of medical comorbidities and patient character-
Adapted from US Medical Eligibility Criteria for Contraceptive Use,
istics.11 Modeled after the World Health Organization (WHO) 2016.12
MEC, the US MEC was developed as a joint venture of 1, A condition for which there is no restriction for the use of the method;
systematic reviews of the medical literature with expert 2, a condition for which the advantages if using the method generally
outweigh the disadvantages of using the method; 3, a condition for which
opinion. In women with a variety of characteristics and the theoretical or proven risks usually outweigh the advantages of using
medical conditions, the MEC weighs risks and benefits the method; 4, a condition that represents an unacceptable health risk if
associated with the use of the various contraceptive methods the method is used.
Cu-IUD, copper intrauterine device; DMPA, depot-medroxyprogesterone
against the risks of unintended pregnancy. The US MEC was acetate; LNG-IUS, levonorgestrel intrauterine system; US MEC, US
updated in 2016.12 Medical Eligibility for Contraceptive Use.
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, are considered ‘‘top-tier’’ by the WHO, CDC, and Society of
the US SPR provides practical and evidence-based guidelines Obstetricians and Gynaecologists of Canada.13-15 IUDs act
to inform providers how to most effectively use and manage locally within the uterus and cervix to prevent pregnancy.
the various contraceptive options (see When to Stop Contra- Therefore, there are no known medication interactions that
ception).13 The US MEC and SPR are easy to access during compromise IUD effectiveness and few contraindications to
daily clinical care as they are available as a free USMEC/ IUD use. Contraindications to IUD placement include the
USSPR app for smart phones and as free downloads from the following: known or suspected pregnancy, known or suspected
website for tablets and desktops (https://www.cdc.gov/repro- pelvic infection, known or suspected pelvic malignancy, or
ductivehealth/contraception/contraception_guidance.htm). anatomic conditions that prevent proper placement. IUDs can
There is no single contraceptive choice contraindicated easily be placed in the office or clinic setting, without the need
based on age alone, because there is no evidence to suggest for anesthesia in most instances. The risk of complications with
that age itself is a risk factor for contraceptive-related com- placement is minimal and includes uterine perforation (0.1%)
plications.12 However, with age comes increased risk of and pelvic inflammatory disease (0%-2%).16,17 The cumulative
medical conditions, including obesity, hypertension, diabetes, risk of IUD expulsion is 10% over 3 years of use.18 Satisfaction
and cancer. The US MEC provides guidance on which and continuation rates associated with IUD use are significantly
contraceptive methods are safe to use given a particular higher than those associated with the use of shorter-acting
condition. Table 1 provides a summary of contraceptive methods such as oral contraceptives.19
options and the corresponding US MEC recommendation The copper IUD, available as ParaGard T 380A in the
in regard to age. United States, is approved for up to 10 years of contraceptive
In particular, the baseline rate of cardiovascular compli- use, but continues to be effective for at least 12 years.20 There
cations increases with age; therefore, age should be consid- are multiple types of copper IUDs available in Canada, with
ered when assessing the safety of combined hormonal recommended duration of use ranging from 5 to 12 years of
contraceptive (ie, estrogen-containing) methods in patients use. The copper IUD is a nonhormone method; the copper
who have other pre-existing cardiovascular risk factors. For ions released in utero are spermicidal. The typical (real-life)
example, the use of combined hormonal contraceptives use failure (ie, pregnancy) rate is less than 1%.21 The copper
(CHCs) in patients 35 years of age or older is contraindicated IUD may be the contraceptive of choice in women who should
if they are heavy smokers (15 or more cigarettes/d) and avoid exposure to progestins (eg, breast cancer patients), and
cautioned against if they are light smokers (less than 15 also those who opt for a monthly menstrual flow or hormone-
cigarettes /d). Furthermore, CHCs are contraindicated or free contraceptive. The copper IUD increases menstrual flow
recommended with caution in older women with multiple in the first 3 to 6 months, but thereafter bleeding tends to be
cardiovascular risks factors, including hypertension (con- normalized. Accordingly, it should be used with caution in
trolled and otherwise) and diabetes (see CHCs).12 women with heavy menstrual bleeding. With its long duration
of effectiveness, the copper IUD may be used until it is certain
INTRAUTERINE CONTRACEPTION the user is menopausal.
Because they provide highly effective, safe, long-term con- Two 52-mg levonorgestrel-releasing intrauterine systems
traception, copper and progestin intrauterine devices (IUDs) (LNG-IUS), Mirena and Liletta, are approved in the United

818 Menopause, Vol. 25, No. 7, 2018 ß 2018 The North American Menopause Society

Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
CONTRACEPTION IN MIDLIFE

States for 5 and 4 years of use, respectively, with effectiveness contraindications to progestin-only methods are limited to
likely extending to 7 years.22 The local release of levonor- a personal history of active or recent (within 5 years) breast
gestrel in utero thickens the cervical mucus, thereby prevent- cancer.12
ing sperm entry into the uterus and potential for fertilization. Like IUDs, the 68-mg etonogestrel single-rod subdermal
The typical use failure rate is less than 1%,21 with failure rates implant (Nexplanon) provides highly effective, convenient,
likely lower in older reproductive-age women. The 52-mg long-term contraception, with minimal side effects, compli-
LNG-IUS has versatile appeal as not only a highly effective, cations, or contraindications. The implant is a 4 cm polymer
long-acting contraceptive but also for noncontraceptive ben- capsule that is inserted subdermally in the upper arm and
efits, including treatment of heavy menstrual bleeding significantly inhibits ovulation in nearly 100% of cycles.35
(HMB). The progestin reservoir acts directly on the endome- The typical use failure rate is less than 1%.21 Originally
trial surface, causing endometrial thinning and glandular approved for 3 years of use, several postmarketing studies
atrophy. Therefore, bleeding is typically light, but unsched- have established efficacy for at least 5 years.36 The implant
uled, and amenorrhea rates are high (up to 18% at 1 year of can easily be placed in the office or clinic setting, using local
use).23 Perimenopausal patients with HMB experience reduc- anesthesia. The risk of complications with placement is
tions in menstrual bleeding similar to endometrial ablation, minimal and includes localized bruising, infection, deep
often precluding the need for surgery.24 Furthermore, for placement, and damage to the arm. As with IUDs, satisfaction
patients opting to treat vasomotor symptoms with HT, the and continuation rates associated with implant use are signif-
LNG-IUS provides adequate suppression of endometrial pro- icantly higher than those of shorter-acting methods.19 How-
liferation for women using estrogen therapy.25,26 The smaller, ever, menstrual irregularity and irregular spotting may occur
13.5-mg LNG-IUS (Skyla) is approved in the United States in more than 25% of implant users,37 sometimes leading to
for up to 3 years for contraceptive use, and the 19.5-mg LNG- discontinuation.38 Postmarketing research has demonstrated
IUS (Kyleena) is approved for up to 5 years of use. These two the implant’s contraceptive efficacy in obese women.39
smaller-frame LNG-IUS are associated with lower rates of Depot-medroxyprogesterone acetate is administered intra-
amenorrhea than the 52-mg LNG-IUS and may be better muscularly (150 mg) or subcutaneously (104 mg) every
suited for women with a smaller uterine cavity, including 3 months and works to suppress luteinizing hormone (LH)
some perimenopausal women.27 release, thus prohibiting ovulation. Typical use results in a
Studies exploring breast cancer risk and LNG-IUS use failure rate of 6%, due to the need for injection administration
suggest either no or minimal increased breast cancer risk every 3 months, to maintain effectiveness.21 The dose of
associated with use. Two large retrospective case-control DMPA is relatively high compared with the progestin doses
studies of European women showed no increased risk of in other progestin-only and estrogen-containing methods,
breast cancer in women using LNG-IUS for contracep- which has several unique implications for its use. Of benefit,
tion.28,29 However, two analyses of a large Finnish cohort amenorrhea rates are higher than other methods—up to 50%
suggest a small increased risk (up to 1.3 times) of breast at 1 year of use, with the prevalence of amenorrhea further
cancer, in particular, lobular and ductal cell cancers, in increasing with ongoing use.31 The relatively higher dose of
women using LNG-IUS for HMB.30,31 LNG-IUS is currently progestin prevents clinically significant interactions with
category 4 (unacceptable risk) for current/active breast can- medications that induce liver enzymes and can attenuate
cers and category 3 (risks outweigh benefits) for personal the contraceptive efficacy of the implant and oral contra-
history of breast cancer in the past 5 years with no active ceptives. However, return to fertility can be delayed up to an
disease.12 There is no contraindication for patients considered average of 10 months after the last injection in patients who
high-risk for breast cancer (eg, family history or breast cancer desire pregnancy after use. Although randomized trials have
[BRCA] 1/2 mutation carriers). not observed weight gain with use of DMPA, this contracep-
tive is disproportionately chosen by populations at elevated
SYSTEMIC PROGESTIN-ONLY METHODS risk for weight gain.40 Accordingly, some observational
Most perimenopausal patients with contraindications to studies have observed weight gain with DMPA use.41,42
estrogen-containing options, including tobacco use, obesity, As a high-dose progestin contraceptive, DMPA suppresses
migraines with aura, long-standing diabetes, hypertension, or ovarian estradiol production.43 Accordingly, bone mineral
a history of venous thromboembolism (VTE), can safely use density (BMD) decreases during DMPA use. Overall, the
progestin-only contraceptives. These methods include: the loss of BMD plateaus at 2 years of use and is reversible upon
etonogestrel implant, depot-medroxyprogesterone acetate discontinuation.43 This mirrors the limited and reversible
(DMPA) injection, and progestin-only pills.12 Bleeding is BMD loss women experience during pregnancy and lactation.
typically light, but unscheduled, and amenorrhea rates can In 2004, concerns regarding lower circulating endogenous
be high depending on the method (up to 50% at 12 months of estradiol and impact on BMD led the US Food and Drug
DMPA use).32 The use of progestin-only methods of contra- Administration (FDA) to add a black-box warning for DMPA
ception is generally not associated with an increased risk regarding the potential for increased fracture risk. However,
of VTE, myocardial infarction (MI), or cerebrovascular several studies have demonstrated that even with prolonged
accident (CVA) in normotensive women.33,34 Therefore, use in perimenopausal women, bone mineral loss attributable

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MILLER ET AL

to DMPA is highest in the first year of use and then plateaus, contraception. It is recommended that the pill be taken at
with recovery after DMPA is discontinued.40 the same time every day to maintain therapeutic levels in
Whether or not the induced BMD loss from DMPA trans- cervical mucus to prevent pregnancy.13 Typical use failure
lates to an increased future fracture risk is controversial. Early rate is 9% in reproductive age women overall, but may be
case-control studies demonstrated higher fracture risk in both lower in women age 40 and older, because this latter popula-
current and past DMPA users versus nonusers. The Danish tion has lower fecundity.21 This option may be appropriate for
Vestergaard et al found an odds ratio (OR) of 1.44 (95% women who desire a short-term, estrogen-free option. In
confidence interval [CI] 1.01-2.04), but without adjustments contrast with DMPA, progestin-only pills and the progestin
made for potential confounders such as smoking and body implant have no impact on BMD.43
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 COMBINED ESTROGEN-PROGESTIN METHODS
(95% CI 1.33-1.78), but examined fractures typically related Women who desire combination hormonal contraception
to trauma rather than BMD loss. However, a subsequent (CHC) can choose combined oral contraceptives (COCs), the
retrospective cohort, using the same database as Meier transdermal patch, or the vaginal ring. CHCs contain an
et al, found that DMPA users at baseline had higher fracture estrogen component (typically ethinyl estradiol [EE]) and a
risk versus nonusers; DMPA users had incidence ratio of progestin component, and work primarily by inhibiting ovu-
fracture of 1.28 (95% CI 1.07-1.58) before the onset of DMPA lation. The annual failure rate with typical use of CHCs is 9%,
use.46 Moreover, the risk did not increase further after DMPA as individuals must adhere to daily (COC), weekly (patch), or
use. Confounding variables not adjusted for, such as traumatic monthly (ring) administration to maintain effectiveness.21
injuries, may have accounted for the higher incidence of CHCs are safe options for patients who desire lighter but
fractures associated with use of DMPA noted in the two scheduled bleeding, and who have no contraindications to
earlier studies. Women who choose DMPA are different from using contraceptive doses of estrogen. Amenorrhea rates are
women who choose other methods of contraception,46,47 and low with cyclic use. However, continuous use of CHCs (ie,
behavioral dissimilarities reflecting these differences may skipping the nonhormone tablets) eliminates withdrawal
account for women who choose DMPA for contraception, bleeding and reduces menstrual-related side effects.51 With
having a higher fracture risk than women who choose other continuous use, light but unscheduled bleeding may result.
contraceptives. For example, the authors of the Danish study Perimenopausal women may choose these options not only
indicated that the prevalence of alcoholism (a condition for effective contraception but to also take advantage of the
known to be associated with fractures from motor vehicle noncontraceptive benefits, including bleeding regulation,
and other accidents) in women using DMPA was 14%— menstrual cycle suppression, or vasomotor symptom relief.
sevenfold higher than in women not using DMPA.44 Further- Table 2 illustrates the US MEC recommendations for CHCs.
more, the Danish investigators noted that cases with fractures Studies have consistently found an elevated risk of VTE
were some threefold more likely to be classified as alcoholics with CHC use. Among women of reproductive age, the risk is
as control women. doubled in CHC users versus nonusers (8-10 per 10,000
Most studies of DMPA and cancer risk suggest a protective woman-years in CHC users vs 4-5 per 10,000 woman-years
effect. A Thai case-control study found ever use of DMPA in nonusers).52 The greatest risk occurs within the first
was associated with an 80% decreased risk of endometrial 3 months of initiation (OR 12, 95% CI 7.1-22.4).53 A
cancer that persisted for at least 8 years after last use.48 In the dose-related response has also been observed, as VTE inci-
largest case-control study of DMPA and ovarian cancer risk, dence was higher with COCs formulated with 50 or more mcg
use of DMPA was associated with a 40% decreased risk of of EE.
epithelial ovarian cancer. This risk was further decreased after While MI and stroke are rare in reproductive-age women,
at least 3 years of DMPA use.49 In a systematic review, five of long-term sequelae can be devastating. European studies have
six studies examining the relationship between progestin use found that use of CHCs increases these risks. Lidegaard et al
and breast cancer (three case-control and two retrospective found that at baseline, risks of thrombotic stroke and MI were
cohort) found no statistically significant association. In the 20 and 100 times increased in an older (aged 45-49 years)
remaining case-control study, the risk of breast cancer was versus younger cohort (aged 15-19 years) of Danish women,
increased 2.3-fold (95% CI 1.3-4.1) in current DMPA users respectively.54 When CHC use was considered, the overall
aged 35 to 44 years versus never-users.50 These studies may risk of stroke increased 2.2 times and that of MI 2.3 times.
all be limited by small sample sizes, heterogeneity of study Furthermore, a dose-dependent relationship exists, with
site, and observational study design. Like other hormonal higher EE formulations demonstrating the highest risks. A
contraceptive methods, use of DMPA is currently category 4 meta-analysis demonstrated this dose relationship: with
(unacceptable risk) for current/active breast cancers and 50 mcg EE formulations having an OR of 3.62 (95% CI
category 3 (risks outweigh benefits) for personal history of 2.22-5.90, P < 0.0005) for MI, 30 to 49 mcg EE formulations
breast cancer in the past 5 years with no active disease.12 having an OR of 1.97 (95% CI 1.43-2.71, P < 0.0005), and
A continuously administered progestin-only pill with 20 mcg EE formulations having an OR of 0.92 (95% CI 0.21-
0.35 mg of norethindrone is also an effective form of 4.08, P ¼ 0.92) versus nonusers. Past users did not have an

820 Menopause, Vol. 25, No. 7, 2018 ß 2018 The North American Menopause Society

Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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 The transdermal patch (Xulane) is a 20 cm2 adhesive patch
decreasing EE dose: OR of 3.28 (95% CI 2.49-4.32) for that releases 35 mcg EE and 150 mcg norelgestromin (active
50 mcg EE formulations, an OR of 1.75 (95% CI 1.61- metabolite of norgestimate) per day. The patch provides the
1.89) for 30 to 40 mcg EE formulations, and an OR of 1.56 convenience of once weekly application for 3 weeks, followed
(95% CI 1.36-1.79) for 20 mcg EE formulations compared by removal for 1 week for a withdrawal bleed. In clinical
with nonusers.56 Smoking and hypertension independently trials, application site irritation of the transdermal contracep-
elevate the risk of MI and stroke; therefore, CHC options tive patch was noted by 20% of women using this method.64
should thus be used with caution or not at all in women who The patch produces a 60% higher overall estrogen exposure
smoke or who have hypertension (Table 2).57 than with a typical 35 mcg EE COC.65 While earlier studies
Ethinyl estradiol has traditionally been used as the estrogen did not find a statistically significant trend to higher rates of
component in CHCs because of its bioavailability. However, nonfatal VTE,66,67 subsequent case-control studies demon-
the development of estradiol valerate, an estradiol ester strated a twofold increased risk of VTE in patch users versus
subsequently metabolized to bioidentical 17b-estradiol, has those using comparable COC formulations.68,69 In 2004 (and
provided an alternative estrogen option. Available in the reaffirmed in 2011), the US FDA placed a black box warning
United States (not in Canada), estradiol valerate/dienogest on the transdermal patch package insert regarding these
(Natazia) is a four-phasic COC that is characterized by findings. The contraceptive patch is formulated with EE. In
varying levels of estradiol and progestin, providing effective contrast, transdermal estrogen used for relief of menopausal
contraceptive similar to traditional COCs while minimizing vasomotor symptoms employs 17-b estradiol at significantly
bleeding irregularity.58 With a hormone-free interval of 2 lower doses. Transdermal 17-b estradiol differs from oral
days, patients typically experience lighter and less painful menopausal estrogen in that the former does not appear to
withdrawal bleeding than traditional 21-day COCs. Briggs increase risk of VTE.70
et al studied COC users who discontinued EE-containing The vaginal ring (Nuvaring) provides another nonoral CHC
COCs and either switched to the estradiol valerate formula- that provides its users with 3 weeks of continuous use,
tion or a progestin-only pill. Women in the estradiol valerate followed by removal for 1 week of withdrawal bleed. The

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Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
MILLER ET AL

ring releases 15 mcg EE and 120 mcg etonogestrel per day.71 women no older than 49 years, though the vast majority of
Vaginal discharge, ring expulsion, and foreign body sensation breast cancer cases occur above this age. Furthermore, such a
are unique reasons for ring discontinuation.72,73 The vaginal small RR in an observational study should be read with
ring is dispensed with 3 weeks in, 1 week off for monthly caution and not used to suggest causation.86 Patients should
withdrawal bleeding. Several studies have explored extended ultimately be counseled on the data and be able to weigh the
cycles. Extended use of vaginal ring may initially present with risks and benefits that meet their contraceptive goals.
unscheduled bleeding, which typically normalizes within the In a recent meta-analysis exploring oral contraceptive use
first year.74 Despite the unscheduled bleeding, Barreiros among BRCA1/2 carriers, the authors looked at breast cancer
et al75 found that few women discontinued use solely from risk associated with COC formulations pre and post-1975,
irregular spotting, indicating that the extended cycle is an signifying the year of withdrawal of higher-dose EE formu-
acceptable approach. Even though the vaginal ring has a lower lations from the market. Breast cancer risk was not signifi-
EE dose, the users of the vaginal ring have similar rates of cantly increased by COC use with formulations containing
VTE as COC users.76 35 mcg or less EE.87 The same study found consistent evi-
dence that in both BRCA1 and BRCA2 carriers, use of COCs
Effect on cancer risk is associated with protection against ovarian cancer (RR of
Use of COC substantially reduces risk of endometrial and 0.51 and 0.50, respectively [95% CI 0.40-0.65 and 0.29-0.89,
ovarian cancers. A large cohort study of women in the United respectively]). Carriers of BRCA1/2 with no personal history
Kingdom found that women who had ever used COCs had a of breast cancer may reasonably use COCs for contraception
significant 12% reduction in risk of any cancer and a 29% risk as well as protection from ovarian and endometrial cancer.88
reduction of gynecologic cancers.77 Reduction of risk for A systemic review by Smith et al89 found an elevated risk of
endometrial and ovarian cancer persisted 15 years after invasive cervical cancer with long-term oral contraceptive
discontinuation. A meta-analysis found the risk for endome- use (RR 1.6, 95% CI 1.4-1.7) and DMPA (RR 1.2, 95% CI
trial cancer was significantly decreased by 56% after only 1.0-1.6) after 5 years of use. A later Lancet reanalysis of 24
4 years of use and by 72% after 12 years of use.78 A similar studies reaffirmed this finding.90 The risk dissipated
collaborative meta-analysis of 45 studies found a relative with time since last use. Although the systematic review
risk (RR) of 0.73 (95% CI 0.70-0.76) for ovarian cancer controlled for human papilloma virus and cytology screening,
for OC users versus nonusers.79 A second meta-analysis of the screening technologies used in the individual studies
24 case-control and cohort studies not only confirmed the varied significantly, making it difficult to fully interpret
above, but found that the greatest reduction in incidence the results. As with all women, adherence to current cervical
(>50%) was found in women who used COCs for more than cancer screening guidelines is appropriate for women using
10 years.80 Furthermore, women whose last use was within hormonal contraception.
the past 20 years had a statistically significant reduction,
whereas any benefit after 20 years was not found to be NONCONTRACEPTIVE BENEFITS
statistically significant.80 Women who rely on oral contra- Hormonal contraceptives also confer many noncontracep-
ceptives should consider use well into their 40s, if medically tive benefits (Table 3). The noncontraceptive benefits detailed
appropriate, to maximize prevention of gynecologic can- in Table 3 may be of particular importance for midlife women
cers.81 COCs may also offer a modest colorectal cancer approaching menopause: treatment of abnormal uterine
protection. A meta-analysis of six studies revealed an 18% bleeding (AUB), relief from vasomotor symptoms, and endo-
risk reduction for colorectal cancer among COC users versus metrial protection in women using estrogen therapy.
nonusers.82 Current users received greatest benefit.
The impact of COCs on breast cancer risk is of clinical Treatment of abnormal uterine bleeding
importance for older reproductive-aged women. A case-con- Over 90% of women will experience AUB in the 4 to
trol study funded by the National Institutes of Health and 8 years, leading up to the final menstrual bleed.91 AUB may
conducted by the CDC, considered by some to be the best include menstrual cycle irregularity (increased or decreased
quality analysis of this topic, found no statistically increased frequency) or heavy menstrual bleeding. Several hormonal
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]) TABLE 3. Noncontraceptive benefits of hormonal contraceptives
regardless of EE dose, duration of use,83 or COC formula- for perimenopausal women
tion.84 In a recently published prospective cohort of 1.8 Restoration of regular bleeding (CHC)
Decreased dysmenorrhea
million Danish women aged 15 to 49 years, Mørch et al Reduced heavy menstrual bleeding
found that current and recent users of any hormonal contra- Reduced pain associated with endometriosis
Suppression of vasomotor symptoms (CHC)
ception (with the vast majority utilizing COCs) had a RR of Enhanced bone mineral density and possible prevention of osteoporotic
1.20 (95% CI 1.14-1.26, P ¼ 0.002) for breast cancer com- fractures (CHC)
Decreased need for biopsies for benign breast disease (CHC)
pared with never-users.85 This roughly translates to one Prevention of epithelial ovarian, and endometrial malignancies
additional breast cancer per 7,690 women using hormonal Improvements in acne that may flare up with perimenopause (CHC)
contraception per year. However, the cohort was limited to CHC, combined hormonal contraception.

822 Menopause, Vol. 25, No. 7, 2018 ß 2018 The North American Menopause Society

Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
CONTRACEPTION IN MIDLIFE

contraceptive methods are effective in overall reduction of contraceptive protection. Therefore, patients should be coun-
menstrual bleeding. seled that HT is not synonymous with contraception. In fact,
Combined hormonal contraceptive formulations may be current COCs contain EE doses substantially higher than seen
used cyclically or continuously, depending on a patient’s with HT. These high doses may be inappropriate for some
individual goal for bleeding. Continuous usage is associated patients who would otherwise be candidates for HT, but no
with higher rates of amenorrhea and fewer opportunities for longer candidates for COCs. Norethindrone acetate/ethinyl
vasomotor symptomatology. EE doses higher than 20 mcg estradiol with dosage of 1 mg/5 mcg is US FDA-approved for
provide a more reliable bleeding pattern with less break- treatment of vasomotor symptoms and osteoporosis prevention
through bleeding.92 Though light, unscheduled bleeding in menopausal women. While not specifically labeled for
may occur with progestin-only pills, the overall amount of contraceptive use, the authors feel that the 1 mg of norethindrone
bleeding is reduced and may be adequate for perimenopausal acetate (which represents the norethindrone dose used in many
patients with AUB. COC formulations) is sufficient to provide ovulation inhibition.
In 2009, the US FDA approved the 52-mg LNG-IUS for Accordingly, this formulation may represent an appropriate off-
treatment of heavy menstrual bleeding. The high concentra- label choice for perimenopausal women, who, due to cardio-
tion of progestin causes decidualization of the endometrium, vascular risk factors, may not be candidates for CHCs. The
resulting in a reduced amount and duration of menstrual lower formulation of 0.5 mg/2.5 mcg likely does not provide
bleeding.93 Menstrual blood loss reduction may be as high contraception and should not be used for this purpose.
as 79% to 97%.94 Compared with oral progestin therapies,
such as medroxyprogesterone acetate, the LNG-IUS was Endometrial protection during hormone therapy
superior in the reduction of menstrual blood loss.95 In a Though an off-label use in the United States, the 52-mg
randomized controlled trial of 571 women assigned to either LNG-IUS is approved for endometrial protection for peri/
LNG-IUS or other medical treatments for heavy menstrual postmenopausal women receiving estrogen HT in many
bleeding (eg, tranexamic acid, mefenamic acid, CHCs, and countries.23 With its concentrated action of progestin on
progesterone-only options), the LNG-IUS outperformed the the endometrial lining, patients using menopausal estrogen
others on the Menorrhagia Multi-Attribute Scale and other therapy concomitantly with a 52-mg LNG-IUS have high
quality-of-life metrics.96 Furthermore, the women assigned rates of amenorrhea and absence of endometrial hyperpla-
to the LNG-IUS were more likely to have continued the sia.101 This endometrial protection has been established for up
LNG-IUS than those in the non-IUS medical therapy arm to 5 years of LNG-IUS use. Placement during the menopausal
(64% vs 38%, respectively; P < 0.001).96 The LNG-IUS is transition provides midlife patients with highly effective
also as effective in treating heavy menstrual bleeding as contraception, and provides an appealing segue to endome-
endometrial ablation,24 providing patients with an alternative trial protection for patients who transition to menopausal
to surgery. For patients with heavy menstrual bleeding related estrogen therapy. Limitations to use include possible patient
to uterine leiomyomata, depending on the number, size, and discomfort with placement, especially in women with a
location of fibroids, the LNG-IUS can help with reduction of smaller uterus. There are no data assessing the efficacy of
menstrual bleeding.97 However, leiomyoma size remains the 13.5 and 19.5 mg smaller-framed LNG-IUS for endome-
relatively unchanged and there may be incrementally trial protection. Cost may also be an issue as this is not an US
increased risk of IUS expulsion compared with women with- FDA-approved method of uterine protection and may not be
out uterine fibroids.97 Likewise, although the LNG-IUS can covered by insurance. To improve placement success, use of
effectively treat heavy menstrual bleeding in women with oral nonsteroidal anti-inflammatory medications and para-
uterine adenomyosis, clinicians and women should be aware cervical block may be used for pain control.93
that expulsion rates are increased in this clinical setting as
well.98 OTHER OPTIONS FOR CONTRACEPTION
Permanent sterilization represents an effective option for
Relief from vasomotor symptoms women who have concluded childbearing. Between 2006 and
Approximately 75% of women will experience vasomotor 2010, the National Survey of Family Growth reported that
disturbances during the menopausal transition and beyond.99 50.6% of women aged 40 to 44 identified female sterilization
CHC can provide the perimenopausal patient with vasomotor as their contraceptive method.102 The prevalence of female
symptom relief in addition to effective contraception, espe- sterilization for this cohort was two and a half times higher
cially for severe symptoms.57 In one observational study, 40% than for male sterilization and 16 times higher for comparably
and 90% of perimenopausal women reported vasomotor effective IUDs. Older women are less likely to express regret
symptoms with use of COC versus nonuse, respectively.100 from the procedure.103 Furthermore, hysteroscopic steriliza-
Continuous use regimens of CHCs are more likely to prevent tion (Essure) can bypass transabdominal entry and be per-
the recurrence of hot flushes and night sweats that can be formed in an office setting, which may be especially
triggered by withdrawal of hormones.57 beneficial for patients with obesity, medical comorbidities
Hormone therapy traditionally used by menopausal patients for which anesthesia is risky, or significant intra-abdominal
for the relief of vasomotor symptoms does not provide adhesive disease.103

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Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
MILLER ET AL

Transabdominal tubal sterilization is associated with a menopause. Similarly, patients may continue to use CHCs
reduced risk of ovarian cancer. Green et al104 showed until 55 years of age if they have no contraindications to the
a reduction of ovarian cancer at a RR of 0.61 (95% CI contraceptive doses of estrogen.13 As women near the age of
0.46-0.85) for women with tubal sterilization versus those menopause, clinicians will need to reassess the safety of CHC
without tubal sterilization, regardless of method of tubal options if risks of cardiovascular disease change, and recom-
occlusion. With growing evidence suggesting that epithelial mend alternative options if indicated.12 At the time they
ovarian cancers originate in the distal Fallopian tubes, discontinue hormonal contraception when menopause is pre-
support for opportunistic salpingectomy (bilateral salpin- sumptively established (eg, age 55), some midlife women will
gectomy performed in those electing sterilization for con- choose to initiate menopausal HT.
traception) is growing.105 Bilateral salpingectomy in lieu of While the guidelines detailed above provide reasonable
traditional tubal sterilization appears safe, with no addi- endpoints for contraceptive use, some women may desire
tional perioperative complications or adverse impact on discontinuation as soon as menopause is reached. Menopause
ovarian reserve compared with conventional methods of is a retrospective diagnosis based on cessation of menses for
tubal sterilization.106 12 months. For some patients, stopping their hormonal con-
Emergency contraception (EC) should be made available traceptive method for a period of 1 or 2 months to allow the
when appropriate to perimenopausal patients regardless of resumption of menses may be a reasonable test of menopausal
medical comorbidities since an unplanned pregnancy poses a status if an acceptable nonhormone contraceptive option is
higher risk for these patients than use of EC. There are no available and used consistently.109 Follicle-stimulating hor-
contraindications to EC apart from pregnancy.12 The most mone (FSH) testing has also been utilized to assess meno-
effective form of EC is the copper-IUD with greater than 99% pausal status in women who do not experience menstrual
effectiveness in pregnancy prevention when inserted within bleeding. Expert opinion suggests contraception may not be
5 days of unprotected sex.13 Patients who elect this option needed in patients of menopausal age who have FSH levels
have the added benefit of ongoing long-term contraceptive greater than or equal to 30 IU/L on two occasions 6 to 8 weeks
with the IUD, if desired. Progestin EC pills provide a dose of apart over the age of 50.109 However, in perimenopausal
1.5 mg of levonorgestrel that must be taken within the first women, FSH levels can vary at any given moment and should
72 hours of contraceptive failure or unprotected sex.107 They not be relied upon to diagnose menopause.
are available in the United States and Canada without a The FSH levels may be slightly elevated in LNG-IUS users,
prescription. Ulipristal acetate, an antiprogestin, may be used a finding likely more influenced by older age rather than
up to 5 days after unprotected sex. Ulipristal acetate has been LNG-IUS use itself.110,111 Etonogestrel implants have little
found to be more effective in pregnancy prevention than the impact on FSH levels, even at 3 years of use.112 FSH levels are
progestin options, but requires a prescription in both the not substantially suppressed by DMPA use.113-115 However,
United States and Canada.107 It is important to note that FSH levels are significantly suppressed in CHC and proges-
EC pills inhibit or delay ovulation and will not interfere with tin-only pill users, and not a reliable source for determining
a pregnancy that has already implanted. menopausal status.115,116 If using combined hormonal con-
traception, FSH testing to determine if menopause is present
WHEN TO STOP CONTRACEPTION/TRANSITION should occur 14 days after last use of a CHC. DMPA users
TO HORMONE THERAPY may test on the first day of injection, with menopause
As previously mentioned, the US SPR provides guidance confirmed if FSH levels are consistently greater than
on the appropriate time to stop contraception in perimen- 30 IU/L at intervals of at least 90 days.114
opausal patients. The Centers for Disease Control and
Prevention, American College of Obstetricians and Gyne- CONCLUSIONS
cologists, and The North American Menopause Society While the likelihood of pregnancy diminishes with age,
recommend that for patients who wish to avoid pregnancy, the risk is not trivial in older reproductive-age women.
use of contraception should continue until menopause is Midlife women who do become pregnant face an increased
reached.13 risk of medical morbidities, including VTE, hypertensive
Nonhormone methods including the copper IUD can be disorders, and adverse neonatal outcomes. Many contracep-
safely used until menopause is assured. For most perimen- tive options are compatible with the goals of providing safe
opausal women, menopause can be assumed after 1 year of and effective pregnancy prevention, and also noncontracep-
amenorrhea.108 With the use of progestin-only methods, tive benefits that may prove useful for midlife women. The
amenorrhea is a common occurrence; accordingly, the US MEC and SPR enable providers to use evidence-based
absence of unscheduled bleeding may not accurately signal recommendations to counsel patients regarding the most
the onset of menopause. Patients may continue their use until appropriate contraceptive options that fit their medical
55 years of age if they have no contraindications to progestin circumstances and personal goals. Most patients can find
use. With the continuous use of CHCs, amenorrhea is also a a contraceptive option that can be used until menopause
common occurrence. With cyclic use of CHCs, the absence of and perhaps beyond, bridging the transition to menopause
scheduled bleeding may not accurately signal the onset of and possible use of HT.

824 Menopause, Vol. 25, No. 7, 2018 ß 2018 The North American Menopause Society

Copyright @ 2018 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
CONTRACEPTION IN MIDLIFE

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