CHAPTER 14
Family Planning
KEY POINTS
1 The most common methods of contraception used in the United States are
sterilization, oral contraceptives (OCs), and condoms, in that order.
2 Latex condoms and other barriers reduce the risk of sexually transmitted diseases
(STDs) and cervical cancer.
3 The intrauterine devices (IUDs) available in the United States are as effective as tubal
sterilization and confer no increased long-term risk of pelvic infection.
4 The combination estrogen–progestin OC, patch, and vaginal ring all provide excellent
contraception when used correctly but all can increase the risk of venous thrombosis
and thromboembolism.
5 Present low-dose estrogen–progestin combinations do not increase the risk of heart
attack among nonsmokers younger than age 35 years who have no other risks for
vascular disease.
6 The association between breast cancer and OC use remains controversial, but OCs do
not appear to substantially increase the risk of breast cancer. Furthermore, benefits
of OC use, particularly protection against pregnancy and other noncontraceptive
benefits, outweigh the risks for the majority of women.
7 Use of the progestin-only injectable or implant results in very low pregnancy rates
without the estrogen-associated risk of thrombosis.
8 Hormonal contraceptives provide extensive contraceptive and noncontraceptive
health benefits, including reduced risk for endometrial and ovarian cancer.
9 Levonorgestrel 1.5 mg and ulipristal acetate 30 mg are the most effective hormonal
means of emergency contraception in the United States. Efficacy is greatest within
24 hours of intercourse but remains high at 5 days. The copper T380A IUD within 5
days after unprotected intercourse is even more effective than hormonal methods.
10 Long-acting reversible contraceptive (LARC) methods include subdermal progestin
implants, and copper- or levonorgestrel-releasing IUDs. These offer pregnancy rates
comparable to sterilization and are among the safest methods.
11 Safe and permanent contraception is provided with laparoscopy or mini-laparotomy,
utilizing bipolar electrocautery, salpingectomy or partial salpingectomy, the Silastic
band, or the Filshie clip.
77012 Hysteroscopic sterilization techniques provide highly effective permanent
contraception for women without the use of general anesthesia or abdominal
incision. However, reports of adverse patient reactions have prompted the
manufacturer to remove the product from the market.
13 Vasectomy provides highly effective, low-cost sterilization for men and is not
associated with prostate cancer.
14 Abortion mortality rates fell rapidly with legalization; for safe abortions the overall
mortality risk is less than 1 per 100,000.
15 The risk of abortion mortality increases with gestational age. The mortality rate for
aspiration procedures was 0.3 per 100,000 at or before 8 weeks and increased to 6.7
per 100,000 at 18 weeks or greater.
The history of contraception is a long one, dating to ancient times. The voluntary
control of fertility is especially important in modern society (1). A woman who
expects to have no more than one or two children spends most of her reproductive
years trying to avoid pregnancy. Effective control of reproduction is essential to a
woman’s ability to accomplish her individual goals. From a larger perspective, the
rapid growth of the human population in modern times threatens the survival of
all. The world population is at 7.3 billion and is expected to reach 10 billion by
2056 (2). For both the individual and the planet, reproductive health requires
careful use of effective means to prevent pregnancy and sexually transmitted
infections (3).
From puberty until menopause, women are faced with challenges concerning
childbearing or its avoidance: the only options are sexual abstinence,
contraception, or pregnancy. The contraceptive choices made by couples in the
United States in 2013 are shown in Figure 14-1 (4). [1] Oral contraceptives
(OCs) were the first choice among women, used by 25.9%. Female sterilization
was the second choice, used by 25.1%. With the addition of the 8.2% of couples
relying on male sterilization, 33.3% of couples were relying on sterilization,
making this the first choice of couples. Condoms were third choice, used by
15.3%. OC use declines with age, and the rate of sterilization increases. Fortyseven percent of women under 25 who use contraceptives use OCs and only 1.6%
is sterilized. Of women aged 35 to 44 years using contraception 12.4% uses OCs
and 44.2% is sterilized, as is 17.9% of their consorts. About 10% of women use
more than one method of contraception. Although contraceptive prevalence is
high, a significant proportion of sexually active couples (6.9%) does not use
contraception, and each year, 1.46 of every 100 women aged 15 to 44 years have
an induced abortion (4,5). Abortion is an obvious indicator of unplanned
pregnancy. Abortion ratios by age group indicate that the use of abortion is
greatest for the youngest women and least for women in their late 20s and early
77130s who are most likely to continue pregnancies (Fig. 14-2) (6). The use of
abortion increases from the late 30s on. Young women are much more likely to
experience unplanned pregnancy because they are more fertile than older women
and because they are more likely to have unprotected intercourse.
FIGURE 14-1 Percent distribution of women aged 15 to 44 years who are currently using
contraception, by the type of contraceptive method used. United States, 2011 to 2013.
(From Daniels K, Daugherty J, Jones J, et al. Current contraceptive use and variation by
selected characteristics among women aged 15–44: United States, 2011–2013. Natl Health
Stat Report 2015;[86]:1–14; Figure 1.)
EFFICACY
Factors affecting the likelihood of pregnancy include the fecundity of both
partners, the timing of intercourse in relation to ovulation, the method of
contraception used, the intrinsic effectiveness of the contraceptive method, and
the correct use of the method. It is impossible to assess the effectiveness of a
contraceptive method in isolation from the other factors. The best way to assess
effectiveness is long-term evaluation of a group of sexually active women using a
particular method for a specified period to observe how frequently pregnancy
772occurs. A pregnancy rate per 100 women per year can be calculated using the
Pearl formula (dividing the number of pregnancies by the total number of months
contributed by all couples, and then multiplying the quotient by 1,200). With
most methods, pregnancy rates decrease with time as the more fertile or less
careful couples become pregnant and drop out of the calculations. More accurate
information is provided by the life-table method. This method calculates the
probability of pregnancy in successive months, which are then added over a given
interval. Problems relate to which pregnancies are counted: those occurring
among all couples or those in women the investigators deem to have used the
method correctly. Because of this complexity, rates of pregnancy with different
methods are best calculated by reporting two different rates derived from multiple
studies (i.e., the lowest rate and the usual rate), as shown in Table 14-1.
Medical Eligibility for Contraception
Since 1996, the World Health Organization (WHO) has regularly published
Medical Eligibility Criteria for Contraceptive Use (MEC). These
recommendations are based on the best evidence available supplemented by
expert opinion. The U.S. Centers for Disease Control undertook a formal process
to review and revise the WHO MEC and adapt it to US practice (7). These
eligibility criteria have become de facto US national (CDC) and international
(WHO) standards for contraceptive practice. All present methods of contraception
are assigned to one of four categories of suitability of use by women with more
than 60 characteristics or conditions. The categories are:
1. A condition for which there is no restriction for the use of the contraceptive
method;
2. A condition for which the advantages of using the method generally outweigh
the theoretical or proven risks;
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 contraceptive
method is used.
773FIGURE 14-2 Percentage of total abortions, abortion rate,* and abortion ratio† by age
group of women who obtained a legal abortion—selected reporting areas.§ United States,
2013. *Number of abortions per 1,000 women aged 15–44 years. †Number of abortions per
1,000 live births. §Data are for 47 areas; excludes five areas (California, Florida, Maryland,
New Hampshire, and Wyoming) that did not report, did not report by age, or did not meet
reporting standards. (From Jatlaoui TC, Ewing A, Mandel MG, et al. Abortion
surveillance—United States, 2013. MMWR Surveill Summ 2016;65[12]:1–44; Figure 2.)
Cost
Some methods, such as intrauterine devices (IUDs) and subdermal implants,
require an initial, “up-front” investment, which in some countries can be
substantial, but then provide prolonged protection for a low annual cost. A
complex cost analysis based on the cost of the method plus the cost of pregnancy
if the method fails concludes that sterilization and IUDs are the least expensive
over 5 years (Table 14-2) (8).
Long-Acting Reversible Contraceptives
[10] Several contraceptive methods are as effective as sterilization, but are
completely reversible. All have the important advantage of being “forgettable,”
774that is, little is required of the user after the method is begun, very much in
contrast to methods like the condom that must be used with each act of
intercourse, or the OC, which must be taken daily. [10] These “forgettable”
methods have typical-use pregnancy rates of less than 1%, are effective for at
least several years without attention from the user, and are among the safest
methods. They include the etonogestrel and levonorgestrel subdermal implants,
copper-bearing IUDs such as the copper T380A and levonorgestrel-releasing
intrauterine systems (9,10).
NONHORMONAL METHODS
Coitus Interruptus
Coitus interruptus is withdrawal of the penis from the vagina before ejaculation.
This method, along with induced abortion and late marriage, is believed to
account for most of the decline in fertility of preindustrial Europe (11). Coitus
interruptus remains a very important means of fertility control in many countries.
Eighty-five million couples are estimated to use the method worldwide, yet it has
received little formal study. This method has obvious advantages: immediate
availability and no cost. The penis must be completely withdrawn from the vagina
and the external genitalia. Pregnancy has occurred from ejaculation on the female
external genitalia without penetration. Efficacy is estimated to range from 4
pregnancies per 100 women in the first year with perfect use to 22 per 100 with
typical use (Table 14-1). Jones and colleagues offer a modern review of this
practice and conclude that it likely is as effective as the condom (12).
Breastfeeding
Breastfeeding can be used as a form of contraception and can be effective
depending on individual variables. The use of contraception during lactation
should take into consideration the women’s needs and the need to maintain
lactation. Ovulation is variably suppressed during lactation. The suckling of the
infant elevates prolactin levels and reduces gonadotropin-releasing hormone
(GnRH) from the hypothalamus, reducing luteinizing hormone (LH) release and
thus inhibiting follicular maturation (13). Even with continued nursing, ovulation
eventually returns but is unlikely before 6 months, especially if the woman is
amenorrheic and is fully breastfeeding with no supplemental foods given to the
infant (14). For maximum contraceptive reliability, feeding intervals should not
exceed 4 hours during the day and 6 hours at night, and supplemental feeding
should not exceed 5% to 10% of the total amount of feeding (15). Six-month
pregnancy rates of 0.45% to 2.45% are reported for couples relying solely on this
method (16). To prevent pregnancy, another method of contraception should be
775used from 6 months after birth or sooner if menstruation resumes. Breastfeeding
reduces the mother’s lifetime risk of breast cancer (17).
Table 14-1 Percentage of Women Experiencing an Unintended Pregnancy During the
First Year of Use of Contraception and the Percentage Continuing Use at
the End of the First Year
Contraception During Lactation (Lactation Amenorrhea)
Previously, the use of combination estrogen–progestin hormonal methods (OCs,
the patch, and the ring) was not advised during lactation because of concern about
reduction in the amount and quality of breast milk. However, clinical studies
demonstrate conflicting results regarding effects on breastfeeding continuation or
exclusivity in women exposed to COCs during lactation and the use of combined
estrogen–progestin hormonal methods are category 2 in breastfeeding women
776beyond 30 days of delivery (7). Progestin-only OCs, implants, and injectable
contraception do not affect milk quality or quantity (15). Barrier methods,
spermicides, and the copper T380A IUD (ParaGard) are excellent options for
nursing mothers. Few studies have specifically looked at the use of
levonorgestrel-IUDs (LNG-IUDs) on breastfeeding. One randomized controlled
trial (RCT) raised concerns that immediate insertion of the LNG-IUD postpartum
may be associated with poorer breastfeeding performance when compared with
delayed insertion (18). However, while more studies are needed before definitive
recommendations can be made, the safety and impact on breastfeeding with the
use of other contraceptives such as implants (which produce higher blood levels)
have been previously shown (19). Given the comparatively low level of
circulating hormone in LNG-IUDs, no adverse effect on breastfeeding is
anticipated.
Table 14-2 Cost Effectiveness (C/E) of Contraceptive Methods at 5 Years
Fertility Awareness
Periodic abstinence, described as “natural contraception” or “fertility
awareness,” requires avoiding intercourse during the fertile period around
777the time of ovulation. A variety of methods are used: the calendar method, the
mucous method (Billings or ovulation method), and the symptothermal method,
which is a combination of the first two methods. With the mucous method, the
woman attempts to predict the fertile period by feeling the cervical mucous with
her fingers. Under estrogen influence, the mucous increases in quantity and
becomes progressively more slippery and elastic until a peak day is reached. The
mucous becomes scant and dry under the influence of progesterone until the onset
of the next menses. Intercourse may be allowed during the “dry days”
immediately after menses until mucous is detected. Thereafter, the couple must
abstain until the fourth day after the “peak” day.
In the symptothermal method, the first day of abstinence is predicted either
from the calendar, by subtracting 21 from the length of the shortest menstrual
cycle in the preceding 6 months, or the first day mucous is detected, whichever
comes first. The end of the fertile period is predicted by the use of basal body
temperature. The woman takes her temperature every morning and resumes
intercourse 3 days after the thermal shift, the rise in body temperature that signals
that the corpus luteum is producing progesterone and that ovulation occurred. The
postovulatory method is a variation in which the couple has intercourse only after
ovulation is detected.
A system of hormone monitoring designed to better define the fertile period
involves placement of disposable test sticks in a small battery-powered device to
detect urinary estrone-3 glucuronide and LH. Changes in these hormones reliably
predict the fertile period. These devices (Persona and Clearblue Easy Fertility
Monitor [CEFM]) can serve as aids either to becoming pregnant or avoiding it
(20). Persona is marketed in Europe for contraception. It is reported to have a
correct-use effectiveness of 94% in avoiding pregnancy. CEFM is approved in the
United States as an aid to becoming pregnant but is used off label to avoid
pregnancy. Exact effectiveness rates are not known. The CEFM is used in the
Marquette method, which combines observation of cervical mucous changes with
the CEFM results. A correct-use pregnancy rate of 2% and a typical-use
pregnancy rate of 12% were reported (21).
Efficacy
The ovulation method was evaluated by the WHO in a five-country study.
Women who successfully completed three monthly cycles of teaching were
enrolled in a 13-cycle efficacy study. There was a 3.1% probability of pregnancy
in 1 year for the small proportion of couples who used the method perfectly and
86.4% probability of pregnancy for the rest (22). A review of 15 national surveys
from developing countries estimated a 12-month gross failure rate of 24
pregnancies per 100 (23). One systematic review of RCTs that examined fertility
778awareness-based methods found that most participants in trials discontinued
prematurely and thus comparative efficacy of these methods remains unknown
(24).
Risks
Conceptions resulting from intercourse remote from the time of ovulation
more often lead to a higher likelihood of spontaneous abortion than
conceptions from midcycle intercourse (25). Malformations are not more
common.
Condoms
In the 1700s, condoms made of animal intestine were used by the aristocracy of
Europe, but condoms were not widely available until the vulcanization of rubber
in the 1840s (1). Modern condoms usually are made of latex rubber, although
condoms made from animal intestine are still sold and are preferred by some who
feel they afford better sensation. New condoms made from nonlatex materials—
such as polyurethane or synthetic elastomers that are thin, odorless, transparent,
and transmit body heat—are available. Although the nonlatex condoms may
break more easily than the latex varieties, substantial numbers of study
participants preferred them and would recommend them to others (26).
The risk of condom breakage is about 3% and is related to friction (27). The
use of water-based lubricants may reduce the risk of breakage. Petroleum-based
products such as mineral oil must be avoided because even brief exposure to them
markedly reduces the strength of condoms (28).
Sexually Transmitted Diseases
Gonorrhea, ureaplasma, and pelvic inflammatory disease (PID) and its
sequel (tubal infertility) are reduced with consistent use of barrier methods
(29–31). [2] Tested in vitro, Chlamydia trachomatis, herpes virus type 2, HIV,
and hepatitis B did not penetrate latex condoms but did cross through condoms
made from animal intestine (32). Follow-up of sexual partners of HIV-infected
individuals showed that condom use provides considerable protection (33).
Consistent condom use provides more protection than inconsistent use (34). In
one study, couples who use condoms 0% to 50% of the time had an HIV
seroconversion rate of 20.8 per 100 couple years, whereas those who used
condoms 100% of the time had a conversion rate of only 2.3 per 100 couple years
(35). Nonoxynol-9 (N-9) should not be used with condoms for HIV protection
because it is associated with genital lesions. N-9 does not add to the protection
afforded by condoms alone (36).
779[2] Condoms offer protection from cervical neoplasia (37). The relative risk
(RR) for invasive cervical cancer was 0.4 when those who used condoms or
diaphragms were compared with those who never used them (38). The
presumed mechanism of protection is reduced transmission of human
papillomavirus (HPV).
Risks
Latex allergy could lead to life-threatening anaphylaxis in either partner from
latex condoms. Nonlatex condoms of polyurethane and Tactylon should be
offered to couples who have a history suggestive of latex allergy.
Female Condom
The original female condom introduced in 1992 was a polyurethane vaginal
pouch attached to a rim that partly covered the vulva. The FC2 female condom
was U.S. Food and Drug Administration (FDA) approved in 2009 and is an
improved version made from softer synthetic latex that does not require hand
assembly during manufacture and is therefore less expensive (39). It consists of a
loose-fitting nitrile sheath with two flexible rings. It is recommended for
prevention of pregnancy and STDs, including HIV. Although breakage may occur
less often with the female condom than the male condom, slippage appears to be
more common, especially for those new to its use (40). Male condoms should not
be used with female condoms as concurrent use increases the risk of breakage.
Exposure to seminal fluid is slightly higher than with the male condom (41).
Initial US trials showed a pregnancy rate of 15% in 6 months. Subsequent
analysis found that with perfect use, the pregnancy rate may be only 2.6%. This
rate is comparable to perfect use of the diaphragm and cervical cap, the other
female-controlled barrier methods (42). As with the male condom, failure rates
fall with increasing experience. Colposcopic studies of women using the female
condom demonstrate no signs of trauma or change in the bacterial flora (43).
Vaginal Spermicides
Vaginal spermicides combine a spermicidal chemical, either N-9 or octoxynol,
with a base of cream, jelly, aerosol foam, foaming tablet, film, suppository, or a
polyurethane sponge. N-9 is a nonionic surface-active detergent that immobilizes
sperm. N-9 spermicides alone appear considerably less effective in preventing
pregnancy than condoms or diaphragms. Women using N-9 spermicides
frequently have higher rates of genital lesions than women not using spermicides.
These lesions may increase their risk for STDs and HIV (44). In the same studies
of serodiscordant couples in which condoms were proven effective in preventing
transmission of HIV, N-9 spermicides alone were not effective (35).
780Concerns were raised about possible teratogenicity of spermicides. N-9 is not
absorbed from the human vagina (45). Several large studies found no greater risk
of miscarriage, birth defects, or low birth weight in spermicide users than in other
women (46,47).
N-9 is toxic to the lactobacilli that normally colonize the vagina. Women who
use spermicides regularly have increased vaginal colonization with the bacterium
Escherichia coli and may be predisposed to E. coli bacteriuria after intercourse
(48).
Vaginal Barriers
At the beginning of the 20th century, four types of vaginal barriers were used in
Europe: vaginal diaphragm, cervical cap, vault cap, and Vimule. Vaginal
diaphragms, new varieties of cervical caps, and the synthetic sponge are used in
the United States. When used consistently, vaginal barriers can be reasonably
effective. A recent search for alternatives to condoms for HIV prevention in highprevalence areas has rekindled interest in the other vaginal barriers (49).
Diaphragm
Traditional diaphragms consist of a circular dome covered with fine latex rubber
(Fig. 14-3). There are several types of diaphragms, as determined by the spring
rim: coil, flat, or arcing. Coil-spring and flat-spring diaphragms become a flat
oval when compressed for insertion. Arcing diaphragms form an arc or half-moon
when compressed; they are easiest to insert correctly. Traditionally, diaphragms
require fitting by practitioners. Spermicide is always prescribed for use with the
diaphragm; whether this practice is necessary is not well studied.
Fitting Diaphragms
Fitting a diaphragm should be performed as follows:
1. A vaginal examination should be performed. With the first and second
fingers in the posterior fornix, the thumb of the examining hand is placed
against the first finger to mark where the first finger touches the pubic bone.
The distance from the tip of the middle finger to the tip of the thumb is the
diameter of the first diaphragm that should be tried.
2. A set of test diaphragms of various sizes is used, and the test diaphragm is
inserted and checked by palpation. The diaphragm should open easily in the
vagina and fill the fornices without pressure. The largest diaphragm that fits
comfortably should be selected. A size 65, 70, or 75 diaphragm will fit most
women.
3. The patient should practice insertion and should be reexamined to
781confirm proper position of the device. About 1 teaspoon of water-soluble
spermicidal jelly or cream is placed in the cavity of the dome. The diaphragm
is inserted with the dome downward so that the cervix will sit in a pool of the
spermicide.
4. The diaphragm can be inserted several hours before intercourse. If
intercourse is repeated, additional spermicidal jelly should be inserted
into the vagina without removing the diaphragm. The diaphragm should
be left in place at least 6 hours after intercourse to allow for
immobilization of sperm. When removed, it is washed with soap and water,
allowed to dry, and stored away from heat. It should not be dusted with talc
because genital exposure to talc may increase the risk of ovarian cancer.
In 2014, the FDA approved the Caya contoured diaphragm for use in the
United States. It is a single-size reusable silicone diaphragm. Compared to
traditional diaphragms, this contoured diaphragm does not require fitting by a
practitioner to determine the size, which in low-resource settings may be
especially important for improving access. Caya should be used with a
spermicide. It should be kept in place for 6 hours after intercourse to ensure
sperm cells are no longer active, but removed within 24 hours to prevent toxic
shock syndrome.
Risks
Diaphragm use, especially prolonged use during multiple acts of intercourse,
appears to increase the risk of bladder infections. A smaller-sized, wide-seal
diaphragm or a cervical cap can be used if recurrent cystitis is a problem,
although the problem may relate not only to mechanical obstruction but also to
alterations in vaginal flora produced by the spermicide. An epidemiologic study
comparing cases of toxic shock with controls found no increased risk from
diaphragm use (50).
Other Barriers
FemCap
This version of the cervical cap made of silicone rubber was approved by the
FDA in 2003. It looks like a sailor’s hat with the dome covering the cervix and
the brim fitting into the vaginal fornices. It is made in three sizes—22-, 26-, and
30-mm diameter—and is expected to be reusable for 2 years. It is used with
spermicide and should be left in place for at least 6 hours after intercourse, but it
may be left in place as long as 48 hours at a time. Additional acts of intercourse
require insertion of more spermicide. FemCap requires a clinician’s fitting and
prescription for use. The only available efficacy study compared the FemCap to
782the vaginal diaphragm. The 6-month pregnancy rate for the FemCap was 13.5%,
substantially higher than the 7.9% rate for the diaphragm. Both groups used N-9
spermicide with the devices (52).
FIGURE 14-3 Wide-seal diaphragm. A: Outer caudal side. B: Inner cephalad side.
Future Development in Barrier Methods
The Ovaprene ring is a nonhormonal “one-size-fits-all” intravaginal organic
silicone ring that continuously releases spermiostatic and spermicidal agents over
a 4-week period. The phase I trial demonstrated patient acceptability and safety
(51). It is expected to undergo a postcoital test clinical trial in 2018.
Sponge
The Today sponge is a polyurethane dome-shaped device containing N-9. It is
moistened with water and then inserted high in the vagina to cover the cervix. It
combines the advantages of a disposable barrier with spermicide and provides
protection for 24 hours. The contraceptive efficacy appears to differ with parity.
Nulliparous women are reported to have a perfect use pregnancy rate of 9% per
year, whereas parous women have a pregnancy rate of 20% (Table 14-1). Rates
with typical use are estimated as 12% per year in nullipara and 24% in multipara
(52). A trial comparing the sponge with a vaginal spermicide preparation used
alone without barrier showed the sponge had a slightly lower pregnancy rate (53).
Intrauterine Contraception
Worldwide over 14% of married women use intrauterine contraception (54).
In the United States, usage is increasing, but the estimates are that only 6.4% of
women use intrauterine contraception (54). Candidacy includes nulliparous
women, adolescents, and immunocompromised women. Immediate use
postpartum or after a first- or second-trimester abortion broadened usage. Five
783IUDs are available in the United States: the copper T380A (ParaGard), two 52-
mg levonorgestrel-releasing IUDs (Mirena and Liletta), a 19.5-mg levonorgestrelreleasing IUD (Kyleena), and a 13.5-mg levonorgestrel-releasing IUD (Skyla).
The copper T380A has bands of copper on the cross arms of the T in addition to
the copper wire around the stem, providing a total surface area of 380 mm of
copper, almost double the surface area of copper in earlier copper devices (Fig.
14-4). It is approved for up to 10 years of continuous use. The Mirena (Fig. 14-5)
is approved in the United States for 5 years of use, although studies through 7
years of use show no loss of efficacy (55). The Kyleena is approved for 5 years of
use, while the Skyla is approved for 3 years. Liletta is manufactured by
Medicines360 and is approved for use up to 4 years, with eventual anticipated
approval for 7 years, and possibly 10 years (56). [3] All IUDs provide safe, longterm contraception with effectiveness equivalent to tubal sterilization.
FIGURE 14-4 Copper T380A (ParaGard) intrauterine device.
Mechanism of Action
IUDs cause the formation of “biologic foam” within the uterine cavity that
contains strands of fibrin, phagocytic cells, and proteolytic enzymes. All IUDs
stimulate the formation of prostaglandins within the uterus, consistent with both
smooth muscle contraction and inflammation. Copper IUDs continuously release
a small amount of the metal, producing an even greater inflammatory response.
Scanning electron microscopy studies of the endometrium of women wearing
nonmedicated IUDs show alterations in the surface morphology of cells,
especially of the microvilli of ciliated cells (57). There are major alterations in the
784composition of proteins within the uterine cavity and new proteins and proteinase
inhibitors are found in washings from the uterus (58). These altered intrauterine
environments interfere with sperm passage through the uterus, preventing
fertilization.
The levonorgestrel in IUDs is much more potent than natural progesterone and
has a profound effect on the endometrium. The hormone is released at an initial
rate of 20 μg daily, which declines to half this rate by 5 years. For the 52-mg
LNG-IUDs, blood hormone levels are significantly lower than with other
progesterone-only contraception and remain stable at approximately 130 to 200
pg/mL (59). About 85% of cycles are ovulatory. The contraceptive effect of the
LNG-IUD is a result of thickened and scant cervical mucous, endometrial
atrophy, and an intrauterine inflammatory response (56,59).
FIGURE 14-5 Levonorgestrel T (Mirena) intrauterine device.
The IUD is not an abortifacient. The contraceptive effectiveness does not
depend on interference with implantation, although this phenomenon can occur
and is, in part, the theoretical basis for using copper IUDs for emergency
contraception. Sperm can be obtained by laparoscopy in washings from the
fallopian tubes of control women at midcycle; fewer sperm are present in the
tubal washings from women wearing IUDs (60). Ova flushed from the tubes at
tubal sterilization showed no evidence of fertilization in women wearing IUDs
(61). Studies of serum β-human chorionic gonadotropin (β-hCG) levels in women
wearing IUDs do not indicate pregnancy (62).
Effectiveness
785The copper T380A and the 52-mg LNG-IUDs have remarkably low
pregnancy rates, less than 0.2 per 100 woman-years. Total pregnancies over a
7-year period were only 1.1 per 100 for the LNG-IUD and 1.4 for the copper
T380A (55). Twelve-year data on the copper T380A showed a cumulative
pregnancy rate of only 1.9 per 100 women and no pregnancies at all after year 8
(63).
Benefits
Modern IUDs provide excellent contraception without continued effort by the
user. The copper T380A and the LNG-IUDs protect against ectopic pregnancy.
The LNG-IUD, by releasing levonorgestrel, reduces menstrual bleeding and
cramping. It is used extensively to treat heavy menstrual bleeding and is used
in Europe and the United Kingdom as an alternative to hysterectomy for
menorrhagia (64). The LNG-IUD has a beneficial effect on menorrhagia from
uterine fibroids; the benefit may be diminished with distorting submucosal
fibroids (65,66). The LNG-IUD is an effective way to deliver the necessary
progestin therapy in postmenopausal women on estrogen therapy (67).
Additional noncontraceptive benefits include a reduced risk of endometrial cancer
and improvement in symptoms of endometriosis and adenomyosis (68–71).
Risks
Infection
The Women’s Health Study found the Dalkon Shield device (withdrawn from the
market since 1974) to increase the risk of PID eightfold when women hospitalized
for PID were compared with control women hospitalized for other illnesses (72).
In contrast, risk from the other IUDs was markedly lower. Increased risk was
detectable only within 4 months of insertion of the IUD. A prospective WHO
study revealed that PID increased only during the first 20 days after insertion.
Thereafter, the rate of diagnosis of PID was about 1.6 cases per 1,000 women per
year, the same as in the general population (73).
[3] Exposure to sexually transmitted pathogens is the more important determinant
of PID risk than IUD use. In the Women’s Health Study, women who were
married or cohabiting and who said they had only one sexual partner in the past 6
months had no increase in PID (72). In contrast, previously married or single
women had marginal increase in risk, even though they had only one partner in
the previous 6 months (74). The only pelvic infection that was unequivocally
related to IUD use is actinomycosis (75). It appears that PID with actinomycosis
was reported only in women wearing an IUD. Rates of colonization with
actinomycosis increase with duration of use for plastic devices but appear to be
much less for copper-releasing IUDs. Actinomyces may be found in cervical
786cytology of up to 7% of women with an IUD. Because of the low positive
predictive value and a lack of sensitivity and specificity of cervical cytology to
diagnose this organism, antibiotic treatment and IUD removal should be reserved
for symptomatic women (76).
When PID is suspected in a woman using an IUD, appropriate cultures should
be obtained, and antibiotic therapy should be administered. Removal of the IUD
is not necessary unless symptoms do not improve after 72 hours of treatment (77).
Pelvic abscess, if suspected, should be ruled out by ultrasound examination.
Ectopic Pregnancy
All contraceptive methods protect against ectopic pregnancy by preventing
pregnancy. But when the method fails and pregnancy occurs, the risk of ectopic
pregnancy is affected by the method of contraception. IUDs and tubal
sterilization increase the probability of the pregnancy being ectopic when
pregnancy occurs, but the rate of any pregnancy is so low that women using
either of these methods have much lower rates of ectopic pregnancy than
women not using contraception (78). Risk of any pregnancy with a LNG-IUD is
between 0.1 and 0.2 per 100 woman-years. The rate of an ectopic in users of this
device is reported as 0.02 per 100 woman-years (79). In a large study of the
copper T380A, the first-year pregnancy rate was 0.5 per 100 woman-years, and
the rate of ectopic was 0.1 per 100 woman-years (80). Ectopic is a very rare event
with either IUD, but should a woman wearing one present with pelvic pain and a
positive β-hCG, an ectopic must be ruled out.
Fertility
Tubal factor infertility is not increased among nulligravid women who used
copper IUDs, but exposure to sexually transmitted pathogens such as C.
trachomatis can increase the risk (81). The contraceptive actions of the LNG-IUD
reverse soon after removal of the device. One-year life-table pregnancy rates after
removal are 89 per 100 for women less than 30 years of age—rates are similar to
women who had not been using any form of birth control (82).
Expulsion and Perforation
The 36-month cumulative expulsion rate is 10.2 per 100 IUD users and did not
vary by IUD type (LNG-IUD 10.1 vs. copper IUD 10.7, p = 0.99) (83). The
cumulative rate of expulsion is lower in nulliparous women compared to parous
women and higher in females aged 14 to 19 years compared to older women. The
risk of uterine perforation associated with insertion is dependent on the inserter.
The risk in experienced hands is on the order of 1 per 1,000 insertions or less
(84). The risk of perforation is no different between the copper and the LNGIUDs (85). Multiparity decreases the risk of perforation (84). Breastfeeding and
787time since delivery are independently associated with uterine perforation risk. The
RR of perforation in lactating compared to nonlactating women at ≤36 weeks
since delivery was 4.7 (86).
Clinical Management
Conditions listed as a category 4 (unacceptable health risk) for IUDs by the WHO
include pregnancy, puerperal sepsis, PID, active purulent cervicitis, endometrial
or cervical cancer, undiagnosed genital bleeding, gestational trophoblastic disease
with persistent elevation in β-hCG, uterine anomalies, and fibroid tumors that
distort the endometrial cavity (87). Infection with HIV is not considered a
contraindication for IUD use. There are no differences in genital viral shedding,
HIV disease progression or disease transmission among IUD users compared to
users of other contraceptives (88). Copper allergy and Wilson disease are
contraindications to the use of copper IUDs.
Candidate Selection
IUDs are appropriate for long-term contraception in most women given their
ease of use, safety, high efficacy, and favorable side effect profile.
Nulliparous women, adolescents, women undergoing a first- or secondtrimester surgical abortion, women with a recent medical abortion, and
women immediately postpartum should all be considered candidates for
IUDs (89). There is renewed interest in postpartum and postabortal insertion of
IUDs. In both circumstances, the woman is clearly no longer pregnant, she may
be highly motivated to accept contraception, and the setting is convenient for the
woman and the provider (89). Postpartum and postabortal insertions are safe.
Complications are not increased by comparison to interval insertion. The only
disadvantage is that the expulsion rate is higher. Two recent RCTs, involving
LNG-IUDs, reported expulsion rates after vaginal postplacental insertion of 24%
and 27% (90,91). Postplacental expulsion rates after cesarean sections appear to
be lower (92). While comparing postpartum to interval insertion, all the women
requesting postpartum IUD received the device, but many women scheduled for
interval insertion did not return. When surveyed at 6 months postpartum, more
women who had immediate postpartum insertion were wearing IUDs than were
those who had scheduled for interval insertion (93,94). Expulsion by 6 months
was more likely following immediate insertion (odds ratio [OR], 4.89; 95%
confidence interval [CI], 1.47–16.32); however, IUD use at 6 months was more
likely with immediate insertion than with delayed insertion (OR, 2.04; 95% CI,
1.01–4.09) (95,96). Thus, in terms of actual continuation, overall, the benefits of
IUD insertion immediately postplacental far outweigh the higher expulsion rates
associated with such insertions (97). Goodman and colleagues found many fewer
788repeat abortions among women followed after postabortal IUD insertion
compared to a cohort of women choosing non-IUD methods of contraception
after an induced abortion (98).
Insertion
At the contraceptive visit, the patient’s history is obtained and a physical
examination, screening for Neisseria gonorrhoeae and chlamydia in high-risk
women, and detailed counseling regarding risks and alternatives are provided.
Clinicians have traditionally inserted IUDs at the time of menses to ensure the
patient is not pregnant, but it can be inserted at any time in the cycle if pregnancy
can be excluded (99). The copper T380A IUD can be inserted within 5 days of
unprotected intercourse for almost 100% effective emergency contraception.
There are limited data on effective treatment of pain during IUD insertion. One
randomized double-blind placebo-controlled study demonstrated that selfadministered vaginal 2% lidocaine gel did not reduce pain with IUD insertion but
did decrease pain with tenaculum placement (100). However, studies utilizing
lidocaine–prilocaine creams have demonstrated a reduction in pain during
tenaculum placement, sound insertion, and IUD insertion (101,102). Despite
some practitioners’ preference to premedicate with misoprostol or NSAIDs, these
interventions do not reduce pain with insertion (103).
Antibiotic prophylaxis is not beneficial, probably because the risk of pelvic
infection with IUD insertion is so low. A large randomized trial of 1,985
patients receiving either oral azithromycin or placebo found no difference in rates
of IUD removal during the first 90 days after insertion and no difference in rates
of salpingitis (104). A meta-analysis found that antibiotic prophylaxis at the time
of IUD insertion did not decrease the risk of PID nor did it reduce the likelihood
of removal within the first 3 months (105). For women at high risk of STIs (e.g.,
aged 25 years or younger or having multiple sex partners), it is reasonable to
screen for STIs and place the IUD on the same day. The International Planned
Parenthood Federation, in collaboration with WHO and other international
organizations, developed guidelines that include the restriction of IUD insertion
within 3 months of puerperal sepsis (106).
The technique of insertion is as follows:
1. The cervix is exposed with a speculum. The vaginal vault and cervix are
cleansed with a bactericidal solution, such as an iodine-containing
solution.
2. Traditionally, the next step is measurement of the uterine cavity with a
uterine sound. The depth of the cavity should measure at least 6 cm from
the external os. However, a pilot study assessing a simplified insertion
789technique without the use of uterine sound or bimanual examination was found
to be safe and effective (107).
3. The use of a tenaculum for insertion is mandatory to prevent perforation.
The cervix is grasped with a tenaculum and gently pulled downward to
straighten the angle between the cervical canal and the uterine cavity. The
IUD, previously loaded into its inserter, is gently introduced through the
cervical canal.
4. With the copper T380A, the outer sheath of the inserter is withdrawn a
short distance to release the arms of the T and is gently pushed inward
again to elevate the now-opened T against the fundus. The outer sheath
and the inner stylet of the inserter are withdrawn, and the strings are cut
to project about 2 cm from the external cervical os.
5. The Mirena 52-mg LNG-IUD is inserted somewhat differently from the
copper T380A. The inserter tube is introduced into the uterus until the
preset sliding flange on the inserter is 1.5 to 2 cm from the external os of
the cervix. The arms of the T device are released upward into the uterine
cavity, and the inserter is pushed up under them to elevate the IUD up
against the uterine fundus.
6. The Liletta 52-mg LNG-IUD can be inserted using a one-handed (United
States) or a two-handed inserter (international). In both cases, the
deployment mechanism is more similar to that for Mirena than for the copper
T380A.
In nulliparous women, insertion may be more challenging because of a
narrower cervical canal than in parous women. Mechanical dilation may be
necessary. While misoprostol was initially proposed to benefit some women
during IUD insertion, a systematic review found that routine pretreatment with
misoprostol did not lead to improved ease or success of IUD insertion and
resulted in more insertional discomfort (108).
Intrauterine Devices in Pregnancy
If an intrauterine pregnancy is diagnosed and the IUD strings are visible, the
IUD should be removed as soon as possible to prevent later septic abortion,
premature rupture of the membranes, and premature birth (109). When the
strings of the IUD are not visible, an ultrasound examination should be performed
to localize the IUD and determine whether expulsion has occurred. If the IUD is
present, there are three options for management:
1. Elective abortion
2. Ultrasound-guided intrauterine removal of the IUD
7903. Continuation of the pregnancy with the device left in place
If the patient wishes to continue the pregnancy, ultrasound evaluation of the
location of the IUD should be considered (110). If the IUD is not in a fundal
location, ultrasound-guided removal using small alligator forceps may be
successful. If the location is fundal, the IUD should be left in place. When
pregnancy continues with an IUD in place, the patient must be warned of the
symptoms of intrauterine infection and should be cautioned to seek care promptly
for fever or flulike symptoms, abdominal cramping, or bleeding. At the earliest
sign of infection, high-dose intravenous antibiotic therapy should be given and the
pregnancy evacuated promptly.
Duration of Use
Annual rates of pregnancy, expulsions, and medical removals decrease with each
year of use (111). Therefore, a woman who has no problem by year 5, for
example, is very unlikely to experience problems in the subsequent years. The
copper T380A is FDA approved for 10 years and the LNG-IUD for 5 years,
although good data support use of the copper T380A through 12 years and of the
LNG-IUD through 7 years (63,85). Newer data from a prospective cohort study
support the use of 52-mg LNG-IUD into year 6 and 7 (112,113).
Choice of Devices
All IUDs available in the United States, provide protection for many years,
have remarkably low pregnancy rates, and substantially reduce the risk of
ectopic pregnancy. The LNG-IUDs reduce the amount of menstrual bleeding and
dysmenorrhea. Amenorrhea rates are 19% to 20%, 12%, and 6% for the 52-, 19.5-
, and 13.5-mg LNG-IUDs at 1 year of insertion, respectively (56,59,114,115). The
copper T380A can be expected to initially increase menstrual bleeding. It is the
most effective means for emergency contraception.
Management of Bleeding and Cramping With Intrauterine Devices
The most important medical reason that women give for requesting removal
of an IUD is bleeding and pelvic pain. These symptoms are common in the first
few months, but diminish over time, in most cases in months. Nonsteroidal antiinflammatory drugs are usually helpful. When pain and bleeding occur later, the
patient should be examined for signs of PID, partial expulsion of the device, or an
intracavitary fibroid. Two ultrasonographic studies comparing women with these
symptoms after 6 months to women with no bleeding complaints show downward
displacement of the IUDs into the cervical canal in many symptomatic women
and in some cases, intracavitary fibroids (116,117). When the patient wishes to
791continue with an IUD, removal of the displaced device and insertion of a new one
is advisable. In situations where IUDs are inexpensive and ultrasound is
expensive or not available, the best course is to offer immediate removal and
replacement of the IUD without ultrasound proof of displacement.
Future of Intrauterine Devices
VeraCept
A novel nitinol-frame low-dose copper IUD, VeraCept (ContraMed, Campbell,
California), is under investigation in a phase II multicenter study in the United
States. Because of its thinner nitinol frame, the insertion tube has a small
diameter. In a randomized comparison against copper T380S, VeraCept was
associated with less pain with insertion, higher continuation rate at 12 months,
lower expulsion rate at 12 months, and fewer removals for pain/bleeding (118).
Despite containing less than half as much copper surface area (175 mm2) as the
T380S (380 mm2), the contraceptive efficacy is similar. However, long-term
efficacy has yet to be studied.
Intrauterine Ball With Copper Pearls
IUB (OCON Medical, Modiin, Israel) copper pearls are strung on a memory alloy
nitinol wire, and when inserted into the uterine cavity, take the shape of the
uterus. This device comes in three sizes, ranging from 12 to 18 mm in diameter
with copper ranging from 300 to 380 mm2. Preliminary results from a pilot study,
however, are concerning for high expulsion rates and low user satisfaction (119).
FibroPlant
The FibroPlant 14 LNG-IUS (Contrel Research, Ghent, Belgium) is a frameless
levonorgestrel-releasing IUD which contains a nonresorbable thread with a knot
that is implanted into the myometrium of the uterine fundus. The attached implant
delivers either 14 or 20 mcg of levonorgestrel each day and is approved for 5
years of use. The reported pregnancy rate at 5 years is 0.4%, with similarly low
expulsion and perforation rates (120).
HORMONAL CONTRACEPTION
Hormonal contraceptives are female sex steroids, synthetic estrogen and
synthetic progesterone (progestin), or progestin-only without estrogen. They
can be administered in the form of OCs, patches, implants, and injectables.
The most widely used hormonal contraceptive is the combination OC
containing estrogen and progestin. Combination OCs can be monophasic, with
792the same dose of estrogen and progestin administered each day, or multiphasic, in
which varying doses of steroids are given through a 21-day or 24-day cycle.
Combination OCs are packaged with 21 active tablets and 7 placebos, or 24 active
tablets and 4 placebo tablets. The inclusion of placebos allows the user to take
one pill every day without having to count. The medication-free interval while the
user takes the placebo tablets allows withdrawal bleeding that mimics a 28-day
menstrual cycle. To begin OC use, the user takes the first pill any time from the
first day of menses through the Sunday after menstruation begins and thereafter
starts a new pack as soon as the first pack is completed. The 7-day medicationfree interval was standard for years, but studies showed that a shorter medicationfree interval is adequate to trigger cyclic withdrawal bleeding and maintains better
suppression of ovulation. Ovarian follicles mature more during the 7-day
medication-free interval than during the 4-day interval. Hence the new 24/4
combination theoretically could be more effective in preventing pregnancy than
the 21/7 combination, but this has not been demonstrated. Other variations of OC
administration are the extended-cycle and the continuous-cycle methods. Users
take active pills containing an estrogen–progestin combination for 3 months at a
time (extended cycle) or indefinitely for a year or more (continuous cycle). Users
on these regimens have more unscheduled days of spotting or bleeding than those
on 28-day cycles in the beginning, but become amenorrheic. As a result, they
experience fewer cycle-triggered symptoms such as headache and menstrual pain.
Continuous combined regimens are preferred for women with chronic pelvic pain
or when dysmenorrhea is not relieved by OCs taken in 28-day cycles (121).
Progestin-only OCs are taken every day without interruption. Other forms of
hormonal contraception include transdermal administration with the patch,
injectable progestins, injectable estrogen–progestin combinations, subdermal
implants that release progestin, and vaginal rings that release either estrogen–
progestin or progestin alone (122).
Where modern hormonal contraception is concerned, it is important to note
that: (i) ALL hormonal contraceptives, even those containing estrogen are
progestin-dominant, meaning that progestin effects are the dominant ones and (ii)
the progestin is doing the real contraceptive “work” by either suppressing
ovulation or thickening the cervical mucous. The presence of the estrogen
component assists with cycle control and adds to the ovarian suppressive effect,
but overall the progestin component dominates.
Steroid Hormone Action
Sex steroids are characterized by their affinity for specific estrogen, progesterone,
or androgen receptors, and by their biologic effects in different systems (123).
Steroids are rapidly absorbed in the gut but go directly into the liver through the
793portal circulation, where they are rapidly metabolized and inactivated. Therefore,
large doses of steroids are required when they are administered orally. The
addition of the ethynyl group to carbon-17 of the steroid molecule hinders
degradation by the liver enzyme 17-hydroxysteroid dehydrogenase and allows
potent biologic activity after oral doses of only micrograms.
Progestins
Progestins are synthetic compounds that mimic the effect of natural progesterone
but differ from it structurally. The progestins differ from one another in their
affinities for estrogen, androgen, and progesterone receptors; their ability to
inhibit ovulation; and their ability to substitute for progesterone and to antagonize
estrogen. Some are directly bound to the receptor (levonorgestrel, norethindrone),
whereas others require bioactivation as, for example, desogestrel, which is
converted in the body to its active metabolite, etonogestrel. The 17-acetoxy
progestins (e.g., medroxyprogesterone acetate) are bound by the progesterone
receptor. Norgestrel exists as two stereoisomers, identified as dextronorgestrel
and levonorgestrel. Only levonorgestrel is biologically active. Three newer
progestins (norgestimate, desogestrel, and gestodene) are viewed as more
“selective” than the other 19-nor progestins, in that they have little or no
androgenic effect at doses that inhibit ovulation (124). The FDA-approved
norgestimate- and desogestrel-containing OCs, and gestodene are available in
Europe. Gestodene is a derivative of levonorgestrel that is more potent than the
other preparations (i.e., very little of it is required for antifertility effects).
Similarly, norelgestromin is an active metabolite of norgestimate and more potent
than the parent compound. It is used in the transdermal patch. Drospirenone, a
progestin introduced in the United States, is a derivative of the diuretic
spironolactone. It has a high affinity for progesterone receptors, mineralocorticoid
receptors, and androgen receptors. It acts as a progesterone agonist but is a
mineralocorticoid antagonist and androgen antagonist (125). Comparative studies
suggest a small decrease in body weight and in blood pressure, with equivalent
cycle control and contraceptive efficacy, in women taking an OC containing 3 mg
of drospirenone/30-μg ethinylestradiol (EE) versus women taking a 150-μg
levonorgestrel/30-μg EE preparation (126). Pilot studies among women with
polycystic ovary syndrome showed good cycle control and reduction in androgen
levels with no change in weight, blood pressure, or glucose metabolism (127).
The FDA approved the 20-μg EE/3-mg drospirenone OC for premenstrual
dysphoric disorder (PMDD) in women who chose OCs for contraception. When
compared to an OC with 30-μg EE/150-μg levonorgestrel, women taking the
drospirenone OC had better relief of menstrual symptoms, better improvement in
acne, reduction in negative affect during the menstrual phase, and a greater
794feeling of well-being (128). Dienogest, another progestin introduced in the United
States, is combined with estradiol valerate, not EE. Whether it offers any
advantage over already marketed OC combinations is not yet evident. The
dienogest/estradiol valerate combination is as effective as levonorgestrel/EE as a
contraceptive, and in treating abnormal uterine bleeding (129).
Estrogens
In the United States, most OCs contain EE. An older formulation OC contains
mestranol, which is EE with an extra methyl group. It requires bioactivation in
the liver, where the methyl group is cleaved, releasing the active agent, EE. OCs
with 35 μg of EE provide the same blood levels of hormone as do OCs containing
50 μg of mestranol (130). Other contraceptives contain 17 β-estradiol (Zoely) or
its ester, estradiol valerate (Qlaira) or estradiol cypionate (Cyclofem), an
injectable.
Antifertility Effects
Combination Estrogen–Progestin Contraceptives
Ovulation can be inhibited by estrogen or by progestin alone. Pharmacologic
synergism is exhibited when the two hormones are combined and ovulation is
suppressed at a much lower dose of each agent. Combination OCs, patches, and
the NuvaRing suppress basal follicle-stimulating hormone (FSH) and LH. They
diminish the ability of the pituitary gland to synthesize gonadotropins when it is
stimulated by hypothalamic GnRH (131). Ovarian follicles do not mature, little
estradiol is produced, and there is no midcycle LH surge. Ovulation does not
occur, the corpus luteum does not form, and progesterone is not produced. This
blockade of ovulation is dose related. Newer low-dose OCs do not provide as
dense a block and allow somewhat higher baseline FSH and LH levels than
higher-dose formulations (132). This makes ovulation somewhat more likely to
occur if pills are missed or if the patient takes another medication that reduces
blood levels of the contraceptive steroids.
Progestin-Only Preparations
Highly effective contraception can be provided by progestin alone, thus
avoiding the risks of estrogen. The mode of action of progestin-only
contraceptives is highly dependent on the dose of the compound (133). With low
levels of progestin in the blood, ovulation will occur part of the time. At moderate
levels of progestin in the blood, normal basal levels of FSH and LH are present,
and some follicle maturation may occur. At higher blood levels as seen with
DepoProvera, the basal FSH is reduced, and there is less follicular activity, less
795estradiol production, and no LH surge.
Transdermal Hormonal Contraception
The patch (Ortho Evra), which adheres to the user’s skin, and the vaginal
NuvaRing contain combinations of EE and a potent progestin. Both provide
sustained release of the steroids and result in relatively constant serum levels that
are less than the peak levels seen with OCs but sufficient to prevent ovulation.
Hormonal Implants
With the levonorgestrel subdermal implants there is some follicular maturation
and estrogen production, but LH peak levels are low and ovulation is often
inhibited. In the first year of use, ovulation is believed to occur in about 20% of
cycles. The proportion of ovulatory cycles increases with time, probably as a
result of the decline in hormone release. By the fourth year of use, 41% of cycles
are ovulatory. The more potent progestin released by the etonogestrel implant is
even more effective at preventing ovulation (134). The mechanisms of action of
low-dose progestins include effects on the cervical mucous, endometrium, and
tubal motility. The scant, dry cervical mucous that occurs in women using
implants inhibits sperm migration into the upper tract. Progestins decrease nuclear
estrogen receptor levels, decrease progesterone receptors, and induce activity of
the enzyme 17-hydroxysteroid dehydrogenase, which metabolizes natural 17 β-
estradiol (133).
The sustained release offered by contraceptive implants allows for highly
effective contraception at relatively low steroid blood levels. Figure 14-6 depicts
expected steroid blood levels with implants, injectables, and OCs. An additional
mechanism for contraception was discovered with the antiprogesterone
mifepristone (RU486). In the normal cycle, there is a small amount of
progesterone production from the follicle just before ovulation. This progesterone
appears essential to ovulation, because if mifepristone is given before ovulation
this can be delayed for several days (135,136).
796FIGURE 14-6 Schematic representation of the expected pharmacokinetic profiles of
progestogens administered in different formulations. (From Landgren BM. Mechanism of
action of gestagens. Int J Gynaecol Obstet 1990;32:95–110, with permission.)
Efficacy of Hormonal Contraception
[4] When used consistently, combination OCs have pregnancy rates as low as
2 to 3 per 100 women per year. Progestin-only OCs are less effective than
combination estrogen–progestin preparations, with best results of 3 to 4
pregnancies per 100 woman-years. All methods have the potential for user
error; therefore, there may be a 10-fold difference between the best results and
797results in typical users of OCs. Injectable progestins and implants are much less
subject to user error than OCs. The difference between the best results and results
in typical users is small and is comparable to pregnancy rates after tubal
sterilization (Table 14-1). Pregnancy rates with the Ortho Evra patch and the
NuvaRing were equivalent to those of OCs; however, because it is easier to use
these methods consistently, larger studies may well demonstrate better typical
user results than with OCs (137,138). Typical use pregnancy rates with
depomedroxyprogesterone acetate (DMPA) are lower. The subdermal implants
have the lowest failure rates of any hormonal contraceptive method.
Hormonal Contraception for Obese Women
The rate of obesity worldwide is increasing. Across the United States, more than
one in three adults are obese (139). Most studies of contraceptive efficacy
intentionally excluded obese women, so the available information is limited.
Obese women are no less likely than other women to become pregnant, but they
have an increased risk of pregnancy complications (140). A systematic review of
hormonal contraception for overweight and obese women focused on 12 relevant
studies (141). The data on the risk of pregnancy in overweight and obese women
using OCs was mixed, with one study showing increased risk while another
showing decreased risk. Analysis of data from other contraceptive methods
indicated no association of pregnancy with overweight or obesity. These included
depot medroxyprogesterone acetate (subcutaneous), LNG-IUD, the two-rod
levonorgestrel implant, and the etonogestrel implant. One study evaluated a
contraceptive patch containing EE and levonorgestrel, and found that obese
women in the “treatment-compliant” subgroup had a higher reported Pearl Index
than nonobese women.
Metabolic Effects and Safety
Venous Thrombosis
[4] Women who use estrogen-containing hormonal contraceptives are at
increased risk for venous thrombosis and thromboembolism. Normally the
coagulation system maintains a dynamic balance of procoagulant and
anticoagulant systems. Estrogens affect both systems in a dose-related fashion.
For most women, fibrinolysis (anticoagulation) is increased as much as
coagulation, maintaining the dynamic balance at increased levels of production
and destruction of fibrinogen (Fig. 14-7) (142). Older studies included women
with what are now considered contraindications to the use of estrogen-containing
hormonal contraceptives: previous thrombosis, preexisting vascular disease,
coronary artery disease, cancers, and serious trauma (142,143). Low-dose OCs
have a less measurable effect on the coagulation system, and fibrinolytic factors
798increase at the same rate as procoagulant factors. Lower estrogen–dose (30- to
35-lg EE) OCs reduce the risk of a thromboembolic event when compared
with higher-dose (50-lg estrogen) OCs (144). A very large Danish study showed
for the first time that combination OCs with 20 μg of EE have an 18% further
reduction in thrombosis risk compared with 30- to 40-μg OCs after adjustment for
duration of use (145). The progesterone-only OCs and the levonorgestrelreleasing IUD were not associated with venous thrombosis.
FIGURE 14-7 Dynamic balance of hemostasis. (From Winkler UH, Buhler K, Schlinder
AE. The dynamic balance of hemostasis: implications for the risk of oral contraceptive
use. In: Runnebaum B, Rabe T, Kissel L, eds. Female Contraception and Male Fertility
Regulation. Advances in Gynecological and Obstetric Research Series. Oxfordshire, UK:
CRC Press, 1991:85–92. Reproduced by permission of Taylor and Francis Group, LLC, a
division of Informa plc.)
The absolute risk of deep vein thrombosis was strongly influenced by age,
increasing from 1.84 per 10,000 women aged 15 to 19 years to 6.59 per 10,000
for women aged 45 to 49 years with current users, former users, and never users
combined. With all types of OCs combined, the overall absolute rate of deep vein
thrombosis was 6.29 per 10,000 woman-years for current OC users compared to
3.01 among nonusers, giving an adjusted rate ratio of 2.83 (95% CI, 2.65–3.01).
799This is a higher absolute risk than the 3 per 10,000 woman-years previously
estimated and may reflect, among other things, the use of better means for
diagnosis of deep vein thrombosis (145). This population-based study includes all
Danish women aged 15 to 49 years, excluding only women with a diagnosis of
cancer or of cardiovascular disease diagnosed before the study interval.
Thrombosis risk was highest during the first year of use and decreased thereafter.
Thrombophilia
Changes in the coagulation system are detectable in all women, including those
taking lower-dose OCs; some women are genetically predisposed to thrombosis
when challenged by pregnancy or administration of exogenous estrogen. Women
with inherited deficiencies of antithrombin III (ATIII), protein C, or protein
S are at very high risk for thrombosis with pregnancy or estrogen therapy,
but they make up a very small proportion of potential OC users. A much
more common variation, factor V Leiden exists in 3% to 5% of the Caucasian
population. It codes for a one amino acid mutation in the factor V protein,
inhibiting cleavage of the protein by activated protein C (APC), which is an
essential step in maintaining the balance between coagulation and fibrinolysis
(146). Risk for a first thromboembolic episode among women using OCs was 2.2
per 10,000 woman-years for women without the factor V mutation and 27.7 per
10,000 woman-years for women with the mutation (147). There are pronounced
ethnic differences in the presence of this mutation. The Leiden allele is found in
3% to 5% of Caucasians but is rare in Africans, Asians, Amerindians, Eskimos,
and Polynesians (148). A similar mutation is found in the prothrombin gene at
position 20,210 and is described as prothrombin G20210A. This mutation occurs
in 3% of the European population and is strongly associated with venous
thrombosis in women taking OCs (149). Many more genetic conditions
predisposing to thrombosis were described. Pregnancy is an even greater
challenge for women with inherited defects of anticoagulation (150). A woman
who sustains a venous event while using OCs should be evaluated thoroughly
after she has recovered. Assessment should include at minimum the measurement
of ATIII, protein C, and protein S levels, resistance to APC, serum homocysteine,
factor V Leiden mutation, the prothrombin G20210A mutation and testing for
antiphospholipid syndrome. It should not be assumed that hormonal contraception
was the unique cause of the thrombotic episode.
Routine screening for all women before prescribing hormonal
contraception is not justified because effective contraception would be denied
to 5% of Caucasian women, and only a small number of fatal pulmonary
emboli would be prevented (151,152). Screening women with a personal or
family history of deep vein thrombosis before starting estrogen-containing
800hormonal contraception or pregnancy is strongly recommended. Women already
diagnosed as having factor V Leiden should not receive estrogen-containing
contraceptives, that is, the pill, patch, or ring.
Thrombosis and the New Progestins
Several studies found increased risk of venous thrombosis when users of OCs
containing the newer progestins desogestrel or gestodene combined with 20 to 30
μg of EE were compared with users of levonorgestrel combined with the same
doses of estrogen (153,154). Subsequent studies showed mixed results. One study
found no difference in thrombosis risk in users of OCs containing desogestrel or
gestodene compared to users of OCs with other progestins in a large study of
cases occurring between 2002 and 2006 in Austria (155). In 2013, a systematic
review combining data from 26 studies (including the aforementioned ones)
demonstrated that the RR of venous thrombosis for OCs containing 30 to 35 μg of
EE and gestodene, desogestrel, cyproterone acetate or drospirenone were 50% to
80% higher than formulations containing levonorgestrel (Fig. 14-8). However,
this risk increase corresponds to approximately a difference of 3 cases per 10,000
women-years comparing second and third generation progestin users (in contrast
to a VTE incidence of 20 cases per 10,000 in pregnancy) (156).
FIGURE 14-8 Network meta-analysis, per contraceptive plotted on a logarithmic scale.
80120LNG, 20-μg ethinylestradiol with levonorgestrel; 30LNG, 30-μg ethinylestradiol with
levonorgestrel; 50LNG, 50-μg ethinylestradiol with levonorgestrel; 20GSD, 20-μg
ethinylestradiol with gestodene; 30GSD, 30-μg ethinylestradiol with gestodene; 20DSG,
20-μg ethinylestradiol with desogestrel; 30DSG, 30-μg ethinylestradiol with desogestrel;
35NRG, 35-μg ethinylestradiol with norgestimate; 35CPA, 35-μg ethinylestradiol with
cyproterone acetate; 30DRSP, 30-μg ethinylestradiol with drospirenone; overall relative
risk (95% confidence interval) of venous thrombosis (dots [lines]); non-use, reference
group.
Ischemic Heart Disease
Ischemic heart disease and stroke were the major causes of death attributed to OC
use in the past. It is known that the principal determinants of risk are advancing
age and cigarette smoking (157). With higher-dose OCs used in the 1980s,
smoking had a profound effect on risk. Women smoking 25 or more
cigarettes per day had a 30-fold increased risk for myocardial infarction if
they used OCs, compared with nonsmokers not using OCs (158). The use of
OCs became safer because most women are taking low-dose pills and
because physicians prescribe selectively, excluding women with major
cardiovascular risk factors. A very large study in the United States confirmed
the safety of OCs as currently prescribed. A total of 187 women aged 15 to 44
years with confirmed myocardial infarction were identified during 3.6 million
woman-years of observation in the Kaiser Permanente Medical Care Program in
California from 1991 to 1994. This is a rate of 3.2 per 100,000 woman-years
(159). Nearly all of the users took OCs with less than 50 μg of EE. After adjusting
for age, illness, smoking, ethnicity, and body mass index, risk for myocardial
infarction was not increased by OC use (OR, 1.14; 95% CI, 0.27–4.72). Of heart
attack victims, 61% smoked; only 7.7% were current users of OCs. In a later
study, the same investigators pooled results from the California study with a
similar study from the Washington State. The results were the same. [5] Current
users of low-dose OCs had no increased risk for myocardial infarction after
adjustment for major risk factors and sociodemographic factors (160). Past
use of OCs does not increase risk for subsequent myocardial infarction (161).
These observations are supported by another population-based prospective study.
OC use and myocardial infarction were studied prospectively among 48,321
randomly selected women aged 30 to 49 years in the Uppsala Health Care Region
of Sweden (162). There was no association between current or past OC use and
myocardial infarction. Most current users were taking low-dose estrogen pills
(defined as less than 50 μg of EE or less than 75 μg of mestranol) with second or
third generation progestins, more than half were aged 35 or older, and 26% were
current cigarette smokers.
802Oral Contraceptives and Stroke
In the 1970s, OC use appeared to be linked to the risk of hemorrhagic and
thrombotic stroke, but these studies failed to take into consideration preexisting
risk factors (163). A rare form of cerebrovascular insufficiency, the moyamoya
disease, is linked to OC use, especially among cigarette smokers (164). The
evidence shows no risk of stroke among women who are otherwise healthy
and who use low-dose pills. One study identified all Kaiser Permanente Medical
Care Program patients aged 15 to 44 years who sustained fatal or nonfatal stroke
in California from 1991 to 1994 (165). Hypertension, diabetes, obesity, current
cigarette smoking, and black ethnicity were strongly associated with stroke risk,
but neither current nor past OC use was associated with stroke. A WHO study of
cases from 1989 to 1993 from 17 countries in Europe and the developing world
included women taking higher-dose OCs and low-dose OCs. European women
using low-dose OCs had no increased risk for either type of stroke, thrombotic or
hemorrhagic. Those taking higher-dose OCs did have measurable risk (166,167).
Women in developing countries had an apparent modest increase in risk, but this
finding was attributed to undetected existing risk factors. Another study from
Europe found less stroke risk from low-dose pills than from older, higher-dose
pills, and that the risk was less if the patient’s blood pressure was checked before
starting OCs.
Women who smoke and those who have hypertension and diabetes are at
increased risk for cardiovascular disease regardless of whether they use OCs.
The important question is whether the risk is further increased if they use lowdose OCs, and if so, by how much. The WHO study provides some insight:
smokers taking OCs had seven times the risk of ischemic (thrombotic) stroke
when compared with smokers who did not use OCs, and hypertensive women had
10-fold increased risk if they took OCs, but a fivefold risk if they did not (166).
Similarly, a study from Denmark found that women with diabetes had a fivefold
increase risk for stroke, which increased to 10-fold if they took OCs (168). These
data were not limited to low-estrogen OCs. The data suggest that although the risk
is primarily determined by the predisposing condition—hypertension, diabetes, or
cigarette smoking—the risk can be magnified by OC use, even when the OCs are
low dose. These observations were confirmed in a systematic review (169).
Hypertensive women using combination estrogen– progestin oral contraceptives
(COCs) had higher risk for ischemic stroke and acute myocardial infarction than
hypertensive women not using COCs. The US practice of limiting hormonal
contraceptives containing estrogen by women older than 35 years of age to
nonsmokers without other vascular disease risk factors is prudent (7).
Blood Pressure
803OCs have a dose-related effect on blood pressure. With the older high-dose
pills, as many as 5% of patients could be expected to have blood pressure levels
greater than 140/90 mm Hg. The mechanism is believed to be an estrogeninduced increase in renin substrate in susceptible individuals. Low-dose pills
have minimal blood pressure effects, but surveillance of blood pressure is
advised to detect the occasional idiosyncratic response.
Glucose Metabolism
Oral estrogen alone has no adverse effect on glucose metabolism, but progestins
exhibit insulin antagonism (170). Older OC formulations with higher doses of
progestins produced abnormal glucose tolerance tests with elevated insulin levels
in the average patient. The effect on glucose metabolism, similar to the effect on
lipids, is related to androgenic potency of the progestin and to its dose.
Lipid Metabolism
Androgens and estrogens have competing effects on hepatic lipase, a liver
enzyme critical to lipid metabolism. Estrogens depress low-density lipoproteins
(LDL) and elevate high-density lipoproteins (HDL), changes that can be
expected to reduce the risk of atherosclerosis (171). Androgens and androgenic
progestins can antagonize these beneficial changes, reducing HDL and elevating
LDL levels. Estrogens elevate triglyceride levels. Low-dose formulations have
minimal adverse effect on lipids, and the newer formulations (with desogestrel
and norgestimate as the progestin) produce potentially beneficial changes by
elevating HDL and lowering LDL (172,173). Although average values of a large
group show only small lipid changes with the use of current OCs, an occasional
patient may have exaggerated effects. Women whose lipid values are higher than
the mean before treatment are more likely to experience abnormalities during
treatment (172).
Other Metabolic Effects
OCs can produce changes in a broad variety of proteins synthesized by the liver.
The estrogen in OCs increases circulating thyroid-binding globulin, thereby
affecting tests of thyroid function that are based on binding, increasing total
thyroxine (T4) levels, and decreasing triiodothyronine (T3) resin uptake. The
results of actual thyroid function tests, as measured by free T4 and radioiodine
tests, are normal (174).
Oral Contraceptives and Neoplasia
Endometrial and Ovarian Cancers
Combination OCs reduce the risk of subsequent endometrial cancer and
804ovarian cancer (175,176). [8] Two-year use of OCs reduces the risk of
endometrial cancer by 40%, and 4 or more years of use reduces the risk by
60%. The evidence for this benefit continues to accumulate (177). [8] A 50%
reduction in ovarian cancer risk for women who took OCs for 3 to 4 years
and an 80% reduction with 10 or more years of use were reported (178).
There was some benefit from as little as 3 to 11 months of use. A review of all
available studies in the world published in English through 2008 concluded
that ovarian cancer risk decreased by 20% for each 4 years of use and was
seen for carriers of the BRCA1 and BRCA2 mutations as well. The benefit
persisted for at least 30 years after last use (179). A similar reduction of risk of
ovarian epithelial cancer was found in a prospective study from Norway and
Sweden, with borderline tumor risk equally reduced. Combination OCs with less
than 50 μg of EE, or less than 100 μg of mestranol and reduced doses of
progestin, provided as much protection as higher-dose pills (180). Today’s lowerdose 20-μg EE pills were not separately studied. Whether or not they provide the
same benefit remains unproven; however, progestin-only contraceptives are
reported to provide risk reduction equivalent to that of combined OCs (181).
Colorectal Cancer
There is evidence that OC use is protective against colon cancer. A casecontrol study in Italy comparing women with colon cancer with controls found a
37% reduction in colon cancer and a 34% reduction in rectal cancer (colon cancer
OR, 0.63; 95% CI, 0.45–0.87 and rectal cancer OR, 0.66; 95% CI, 0.43–1.01).
Longer use produced more protection against colon cancer (182). Results of the
US Nurses’ Health Study disclosed some degree of protection. Women who used
OCs for 96 months or more had a 40% lower risk of colorectal cancer (RR, 0.60;
95% CI, 1.15–2.14) (183). A large case-control study from Wisconsin found most
of the benefit limited to women who were less than 14 years since discontinuing
OCs (184). The mechanism of protection has not been identified. A long-term
study that prospectively evaluated women for up to 44 years detected ever use of
OCs was associated with reduced colorectal cancer (IRR, 0.81; 99% CI, 0.66–
0.99) (185).
Cervical Cancer
There may be a weak association between OC use and cancer of the cervix. A
systematic review of 28 epidemiologic studies of cervical cancer in OC users
compared with those who never used OCs reported summary RRs of 1.1 (95% CI,
1.1–1.2) at less than 5 years of pill use, 1.6 (1.4–1.7) at 5 to 9 years, and 2.2 (1.9–
2.4) at 10 or more years (186). A 2007 update by these same authors reported a
pooled RR for all studies of 1.9 (95% CI, 1.69–2.13) for invasive cervical cancer
805or CIN3/carcinoma in situ (CIS) with 5 or more years of OC use. The risk
declined after use ceased and by 10 years returned to that of never users (187). In
a study that observed women for up to 44 years, an increased risk of cervical
cancer that was seen in current and recent users appeared to be lost within 5 years
of stopping oral contraception with no evidence of increased risk in ever users
with time (185). Critics of these studies argued that causation is not proven
because few adequately control for the key behavioral factors of partners, use of
barrier contraception, and adequacy of cervical cancer screening (188). Important
risk factors for cervical cancer are early sexual intercourse and exposure to HPV.
Women who used OCs typically started sexual relations at younger ages than
women who have not used OCs and, in some studies, report having had more
partners. These factors increase one’s chance of acquiring HPV, the most
important risk factor for cervical cancer. Because barrier contraceptives reduce
the risk of cervical cancer, the use of alternative choices for contraception
compounds the difficulty in establishing an association with OC use alone (189).
The presence of HPV types 16 or 18 is associated with a 50-fold increase in risk
for precancerous lesions of the cervix (190). Adenocarcinomas of the cervix are
rare, they are not as easily detected as other lesions by screening cervical
cytology, and the incidence appears to be increasing. One study found a doubling
of risk for adenocarcinoma with OC use that increased with the duration of use,
reaching an RR of 4.4 if the total use of OCs exceeded 12 years (191). The results
of this study were adjusted for history of genital warts, number of sexual partners,
and age at first intercourse. Another summary of case-control studies includes
testing for HPV. HPV types 16 or 18 were present in 82% of the patients, yielding
an RR of 81.3 (95% CI, 42.0–157.1) for the disease. Cofactors identified with
adenocarcinoma included longer-term use of hormonal contraception. The use of
hormonal contraception by women aged 20 to 30 years is estimated to increase
the incidence of cervical cancer (any cervical cancer, or CIN3/CIS) diagnosed by
age 50 from 7.3 to 8.3 per 1,000 women in lesser-developed countries and from
3.8 to 4.5 in developed countries (192). The use of OCs is, at most, a minor factor
in causation of cervical cancer; these findings emphasize the need to immunize
against HPV and to provide cervical cancer screening worldwide. To reduce the
risk, women who are not in mutually monogamous relationships should be
advised to use barrier methods in addition to hormonal contraception. A metaanalysis demonstrated that invasive cervical cancer may be approximately onethird less frequent in women who have used an IUD (193).
Breast Cancer
There is a large volume of conflicting literature on the relationship between
OC use and breast cancer (194). No increase in overall risk is found from OC
806use, but some studies found that risk may increase in women who used OCs
before their first term pregnancy, used OCs for many years, are nulligravid, are
young at the time of diagnosis, or continue using OCs in their 40s. [6] A metaanalysis of 54 studies of breast cancer and hormonal contraceptive use reanalyzed
data on 53,297 women with breast cancer and 100,239 controls from 25 countries,
representing about 90% of the epidemiologic data available worldwide (195).
Current use of OCs was associated with a very small, but statistically stable 24%
increased RR (1.24; 95% CI, 1.15–1.33). The risk fell rapidly after
discontinuation, to 16% 1 to 4 years after stopping and to 7% 5 to 9 years after
stopping. Risk disappeared 10 years after cessation (RR, 1.01; 95% CI, 0.96–
1.05). Results did not differ in any important way by ethnic group, reproductive
history, or family history. Since the meta-analysis was published, subsequent
studies found no increased risk. A case-control study of 4,575 women with breast
cancer and 4,682 controls aged 35 to 64 years living in five cities in the United
States concluded that breast cancer risk was not increased for current or past users
of OCs and did not increase with prolonged or with higher-estrogen OC use
(196). Neither family history of breast cancer nor beginning use at a young age
was associated with increased risk. A similar study in Sweden compared 3,016
women aged 50 to 74 years who had invasive breast cancer with 3,263 controls of
the same age. [6] No relation was found between the past use of OCs and breast
cancer (197). Effect of hormone dose was explored in a 2008 US study of 1,469
women with breast cancer who were matched by race, age, and neighborhood to
community controls. The investigators administered questionnaires and
performed BRCA1 and BRCA2 testing. Subjects who began OC use during or
after 1975 were considered to have used low-dose pills. “Low dose” was not
further defined. Neither OC use overall or “low-dose” OC use was associated
with breast cancer risk, among the total group, or within any subset. Women with
BRCA1 or BRCA2 did not have higher rates of cancer whether they were OC
users or nonusers (198). [6] A prospective cohort study evaluating very–longterm risks or benefits associated with the use of combined OCs found an
increased breast cancer risk in current and recent users that appeared to be lost
within 5 years of stopping (185). The controversy over the association between
breast cancer and OC use is likely to continue. While concerns about a
connection continue to circulate, the benefits of OC use, particularly
protection against pregnancy and the other noncontraceptive benefits,
outweigh the risks for the vast majority of women.
Liver Tumors
OCs were implicated as a cause of benign adenomas of the liver. These
hormonally responsive tumors can cause fatal hemorrhage. They usually regress
807when OC use is discontinued; the risk is related to prolonged use (199). The
tumors are rare; about 30 cases per 1 million users per year were predicted with
older formulations. Presumably, newer low-dose products pose less risk. A link to
hepatic carcinoma was proposed. This cancer is closely associated with chronic
hepatitis B and C infections and is usually seen in cirrhotic livers. There are case
reports of hepatocellular carcinoma in young women with no risk factors other
than long-term OC use (200). A large study from six countries in Europe found
no association between the use of OCs and subsequent liver cancer (201). A
systematic review looked for evidence of harm associated with hormonal
contraceptive use among women already at risk because of liver disease (202).
The authors concluded from the limited data available that OCs do not affect the
course of acute hepatitis or chronic hepatitis, and do not affect the rate of
progression or the severity of cirrhotic fibrosis, the risk of hepatocellular
carcinoma in women with chronic hepatitis, or the risk of liver dysfunction in
hepatitis B virus carriers.
Oral Contraceptives and Sexually Transmitted Infections
Chlamydial colonization of the cervix appears more likely in OC users than in
nonusers but, despite this finding, several case-control studies found a reduced
risk of acute PID among OC users (203,204). In contrast, a subsequent study
found no protection with OC use (205). Whether hormonal contraceptives
influence acquisition of HIV remains under debate. A recent systematic review
increased concern about a potential causal association between DMPA use and
HIV acquisition with hazard ratio (HR) estimated at 1.5 or less (206). In response
to these findings, the WHO convened and updated recommendations for the use
of progestogen-only injectables from category 1 to category 2. Women should not
be denied the use of progestogen-only injectables but should be advised about the
uncertainty over a causal relationship. There remains no suspected increased risk
of HIV acquisition with use of OCs or contraceptive implants.
Health Benefits of Oral Contraceptives
OCs have important health benefits (Table 14-3). These include contraceptive
and noncontraceptive benefits.
Contraceptive Benefits
OCs provide highly effective contraception and prevent unwanted
pregnancy, an important public health problem. Combination and progestinonly contraceptives decrease the risk of pregnancy and therefore, decrease
the risk of ectopic pregnancy. Studies have reported an increased proportion of
pregnancies that are ectopic, in women who became pregnant while using
808progestin-only implants, IUDs, and OCs (207). A systematic review of progestinonly injectables and implants reported higher proportions of ectopic pregnancies
in the event that pregnancy occurs; however, the review confirmed that the
absolute risk of ectopic pregnancy is lower for women using these methods
compared with noncontraceptive users (208). Furthermore, the clinical and
epidemiologic evidence indicated that LNG-containing implants are more likely
to result in an ectopic pregnancy (or any pregnancy) than the etonogestrel implant
or progestin-only injectables.
Noncontraceptive Benefits
OC use produces strong and lasting reduced risk for endometrial and
ovarian cancer. In addition, protection was found for women with known
hereditary ovarian cancer. The use of OCs in BRCA mutation carriers was
associated with a significantly reduced risk of ovarian cancer (SRR, 0.50; 95%
CI, 0.33–0.75) (209). Protection increased with longer duration of use. The exact
mechanisms of action of OCs in the prevention of ovarian cancer is unknown, but
one leading mechanism stems from the “incessant ovulation” theory, according to
which chronic ovulation contributes to ovarian cancer by causing repeated trauma
of the ovarian surface epithelium (210). Therefore, OCs may decrease the risk of
ovarian cancer by suppressing ovulation.
Table 14-3 Established and Emerging Noncontraceptive Benefits of Oral
Contraceptives
Established Benefits
Menses-related
Increased menstrual cycle regularity
Reduced blood loss
Reduced iron-deficiency anemia
Reduced dysmenorrhea
Reduced symptoms of premenstrual dysphoric disordera
Inhibition of Ovulation
Fewer ovarian cysts
Fewer ectopic pregnancies
809Other
Reduced fibroadenomas/fibrocystic breast changes
Reduced acute pelvic inflammatory disease
Reduced endometrial cancer
Reduced ovarian cancer
Emerging Benefits
Increased bone mass
Reduced acne
Reduced colorectal cancer
Reduced uterine leiomyomata
Reduced rheumatoid arthritis
Treatment of bleeding disorders
Treatment of hyperandrogenic anovulation
Treatment of endometriosis
Treatment of perimenopausal changes
aOnly the low-dose EE/droperidol oral contraceptive has U.S. Food and Drug
Administration approval for premenstrual dysphoric disorder treatment.
From Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits
associated with oral contraception. Am J Obstet Gynecol 2004;190(Suppl):S12, with
permission.
Other documented benefits of OC use include reduction of benign breast
disease (211). The use of OCs helps relieve dysmenorrhea (212). OCs offer
effective therapy for women with menorrhagia and dysfunctional uterine
bleeding.
All combination OCs offer some protection from functional ovarian cysts,
but this is dose related (213). Although OCs may prevent cyst formation, they are
not helpful in treating large functional ovarian cysts and should not be used for
this purpose (214).
All combination OCs reduce circulating androgen levels and usually
810improve acne. Three OCs were specifically FDA approved for acne treatment:
the norgestimate/EE triphasic (Ortho Tri-Cyclen), the norethindrone/EE
multiphasic (Estrostep), and the 20-μg EE/3-mg drospirenone OC.
Fertility After Oral Contraceptive Use
After discontinuing OCs, the return of ovulatory cycles may be delayed for a few
months. Women who have amenorrhea more than 6 months after discontinuation
of OCs should undergo a full evaluation because of the risk for prolactinproducing pituitary tumors. This risk is not related to OC use but rather to the
probability that the slow-growing tumor was already present and produced
menstrual irregularity, prompting the patient to take OCs (215).
Sexuality
There is limited literature focusing on the topic of sexual function among OC
users. A 2003 Spanish study demonstrated that in a comparative cohort of women
using OCs and a cohort using IUDs, sexual desire decreased over time, but was
not affected by the contraceptive method (216). OCs containing the new progestin
drospirenone are reported to improve sexual functioning and feelings of wellbeing (217,218).
Teratogenicity
A meta-analysis of 12 prospective studies, including 6,102 women who used OCs
and 85,167 women who did not, revealed no increase in the overall risk for
malformation, congenital heart defects, or limb reduction defects with the use of
OCs (219). Progestins were used to prevent miscarriage. A large study compared
women showing signs of threatened abortion who were treated with progestins
(primarily oral medroxyprogesterone acetate) with women who were not treated.
The rate of malformation was the same among the 1,146 exposed infants as
among the 1,608 unexposed infants (220). Conversely, exposure in utero to
diethylstilbestrol, a nonsteroidal estrogen, can induce clear cell vaginal cancer and
congenital anomalies of the reproductive tract in the female offspring (221). A
literature search revealed no recent reports linking teratogenicity to hormonal
contraception.
Interaction of Oral Contraceptives With Other Drugs
Some drugs (e.g., rifampin) reduce the effectiveness of OCs; conversely, OCs
can augment or reduce the effectiveness of other drugs (e.g., benzodiazepines)
(222,223). Perhaps of greatest clinical significance are six antiepileptic drugs:
phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate, and
topiramate (224). These drugs and the antibiotic rifampin all induce synthesis of
811liver cytochrome P450 enzymes and reduce plasma levels of EE in women taking
OCs, increasing the likelihood of contraceptive failure. Some antiseizure agents
have no effect on the levels of contraceptive steroids in the blood. These include
valproic acid, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam,
zonisamide, ethosuximide, and benzodiazepines (224). St. John’s wort induces
cytochrome P450 and is reported to increase clearance of EE and norethindrone
(225). The antifungal agents griseofulvin, ketoconazole, and itraconazole induce
these hepatic enzymes and may reduce OC efficacy (225). Ampicillin and
tetracycline were implicated in numerous case reports of OC failure. They kill gut
bacteria (primarily clostridia) that are responsible for hydrolysis of steroid
glucuronides in the intestine, which allows reabsorption of the steroid through
enterohepatic circulation. It was not possible to demonstrate reduced plasma
levels of EE overall or differences in pregnancy rates (226). Certain drugs, such
as protease inhibitor atazanavir, appear to increase plasma levels of contraceptive
steroids but the clinical significance of such an interaction is unclear (227).
An example of OCs affecting the metabolism of other drugs is seen with
diazepam and related compounds. OC use reduces the metabolic clearance and
increases the half-life of those benzodiazepines that are metabolized primarily by
oxidation: chlordiazepoxide, alprazolam, diazepam, and nitrazepam. Caffeine and
theophylline are metabolized in the liver by two of the P450 isozymes, and their
clearance is reduced in OC users. Cyclosporine is hydroxylated by another of the
P450 isozymes, and its plasma concentrations are increased by OCs. Plasma
levels of some analgesic drugs are decreased in OC users. Salicylic acid and
morphine clearances are enhanced by OC use; therefore, higher doses could be
needed for adequate therapeutic effect. Clearance of ethanol may be reduced in
OC users.
The interactions of antiretroviral drugs with contraceptive steroids are complex.
Some of the drugs increase plasma steroid levels and some reduce them. A
complete list of interactions is available in the Centers for Disease Control and
Prevention’s “U.S. Medical Eligibility for Contraception” (7).
Oral Contraceptives and Clinical Chemistry Alterations
OCs have the potential to alter a number of clinical laboratory tests as a result of
estrogen-induced changes in hepatic synthesis; however, a large study comparing
OC users with pregnant and nonpregnant controls found minimal changes (228).
Hormone users took a variety of OCs containing 50 to 100 μg of estrogen, higher
doses than are used today. Compared with nonpregnant women who were not
using OCs, the OC users had an increase in T4 that is explained by increased
circulating thyroid-binding protein, no change in creatinine and globulin levels,
slight reduction in mean fasting glucose values and serum glutamic oxaloacetic
812transaminase, and a decrease in total bilirubin and alkaline phosphatase.
Choice of Oral Contraceptives
More recently introduced OCs include those containing drospirenone, more
preparations with only 20 μg of EE, new multiphasic preparations, cyclic OCs
with 24 days of active medication and 4 days of either placebo or 10 μg of EE,
and extended-cycle and continuous-cycle preparations plus branded generic
versions of most OCs. A combination OC containing estradiol valerate with a
new progestin, dienogest, was approved in 2010. There is new evidence that 20-
μg EE pills offer reduced risk for venous thrombosis (145). An approach to OC
selection for new patients is to begin with a 20-μg EE combination and then
adjust depending on the patient’s symptoms after the first 2 to 3 months. As
reported in a large systematic review of 20-μg EE OCs compared to 30- to 35-μg
EE pills, women taking the lower-dose OCs more often report changes in vaginal
bleeding, episodes of irregular bleeding and heavy bleeding, and more
amenorrhea (229). If a 20-μg pill is offered, the patient should understand that
bleeding may be a problem and that she should return if this persists and try a
different OC rather than stop the pill. The progestin component may become more
important in determining cycle control when 20-μg EE is used. A comparison of
20-μg EE OCs, one containing 100 μg of levonorgestrel, the other with 1 mg of
norethindrone acetate (NEA) found the NEA to have about twice as many days of
unscheduled vaginal bleeding during the first 3 months, a critical time period for
new users, which might be expected to lead to discontinuation (230). In a threeway trial, the 35-μg EE/norgestimate triphasic OC (Tri-Cyclen) was compared
with two 20-μg EE pills, one containing 100 μg of levonorgestrel (Alesse), the
other containing 150-μg desogestrel, followed by 2 hormone-free days and 5 days
of 10-μg EE per day (Mircette) (231). Contraceptive efficacy was not
significantly different. In the first two-pill cycles, more women taking Alesse had
breakthrough bleeding and bleeding in the second half of the cycle than those
taking the other two OCs in the first two cycles, but thereafter there was little
difference. Women taking the higher-estrogen Tri-Cyclen consistently
experienced more frequent estrogenic side effects—bloating, breast tenderness,
and nausea—than did women taking either 20-μg EE OC. These authors
concluded that for the specific OCs evaluated, changing to either one of the 20-μg
preparations would be beneficial.
For the average patient, the first choice of preparation for contraceptive
purposes is a very low estrogen OC (20-lg EE) unless there are other
considerations, for example, previous pregnancy while taking the pill.
Patients with persistent breakthrough spotting or bleeding could be offered a
pill with the same low estrogen dose, but a more potent progestin, for
813example levonorgestrel. Patients with apparent weight gain from fluid retention
while taking OCs, or with hirsutism or acne that did not respond to other OCs,
may benefit from a change to the drospirenone/EE pill. The lower-estrogen
drospirenone combination is FDA approved for treatment of PMDD and should
be considered for women with these symptoms who want hormonal
contraception. Women with acne often benefit from the reduction in
circulating testosterone that occurs with all combination OCs. Women who
experience continuing pelvic pain, dysmenorrhea, or other menstrualtriggered symptoms or who simply prefer fewer menstruations may be
offered an extended-cycle or continuous-cycle OC regimen.
Alternative Routes for Hormonal Contraception
The Ortho Evra patch and the NuvaRing provide combinations of ultrapotent
progestins with EE. Both patch and ring provide almost constant low levels of the
contraceptive steroids that are less than the peak levels seen with OCs. Both offer
greater convenience to the user, which improves compliance. The patch has a
surface area of 20 cm2. It delivers a daily dose of 150-μg norelgestromin, the
active metabolite of norgestimate, and 20 μg of EE. The patch is worn for 1 week
then replaced with a new patch for 7 days, continuing for 3 consecutive weeks
followed by a week with no patch. The patch was compared with a multiphasic
OC containing levonorgestrel 50 to 125 μg, and 30- to 40-μg EE (Triphasil) in a
randomized trial of 1,417 women (137). The overall and method failure Pearl
indices were 1.24 and 0.99 pregnancies per 100 woman-years in the patch group
and 2.18 and 1.23 in the OC group, respectively, numerically less in the patch
group but not statistically significant. Patch users had more breakthrough
bleeding or spotting in the first two cycles, but thereafter this did not differ from
OC users. Patch users reported more breast discomfort, dysmenorrhea, and
abdominal pain than the OC users, but other adverse events were uncommon and
did not differ. Perfect compliance was reported for 88.2% of patch users’ cycles
versus 77.7% of the pill users’ cycles (p <0.001). Pregnancy risk with the patch
appears to be higher for women weighing more than 90 kg.
The NuvaRing is 54 mm in the outer diameter and has a cross section of 4 mm.
It delivers daily doses of 120 μg of etonogestrel, the active metabolite of
desogestrel, with 15 μg of EE, and thus is the lowest estrogen combination
hormonal method available in the United States. The soft, flexible ring is worn in
the vagina for 3 weeks, and then removed for 1 week, after which time a new ring
is inserted. Alternatively, similar to OCs, women trying to avoid menstrual
bleeding can simply use the ring for an entire month and then change immediately
to a new ring. In a pharmacokinetic study comparing the ring with a combination
814OC containing 150 μg of desogestrel and 30 μg of EE, maximum blood levels of
EE with the ring were about one-third of those seen with the OC, and the
etonogestrel level was about 40% of that produced by the OC. Despite these
findings, ovulation was inhibited in all women studied (232). Women wearing the
ring are reported to have fewer days of irregular bleeding or spotting than women
taking an OC with 150 μg of levonorgestrel and 30 μg of EE (233). A large study
found a Pearl Index of 1.18 (95% CI, 0.73–1.80) for the vaginal ring (233). Some
women prefer to remove the ring for intercourse, although this is not necessary. It
should be reinserted within 3 hours to avoid loss of efficacy. If the ring is out of
the vagina for more than 3 consecutive hours, contraceptive efficacy may be
reduced and a barrier method should be used for 7 days.
Patch and Ring and Thrombosis
Since both methods provide constant low blood levels of EE, it was hoped that
this might reduce the risk for thrombosis. The FDA took the unusual step of
issuing a “black box warning” for the EE/norelgestromin patch after several
thrombosis cases were reported, and a small study of pharmacodynamics was
interpreted as showing higher mean EE blood levels for the patch than with the
oral route of administration. A small crossover study found increased APC
resistance when women were changed from a 30-μg EE/150-μg desogestrel pill to
either the patch or the EE/etonogestrel ring. This was interpreted as
prothrombotic (234). In another study, women on a variety of OCs had baseline
measurement of APC resistance, and protein S. Then the patients were switched
to either the patch or the ring. Those moving to the patch had changes in
laboratory parameters that could be interpreted as prothrombotic, while those
moved to the ring showed an improvement in the same studies, theoretically
reducing the risk of clotting (235). Three data-based epidemiologic studies looked
at thrombosis in patch users compared to oral contraception. The first found no
difference, but two subsequent studies did find increased risk. One study found an
overall doubling of the risk of deep vein thrombosis when patch users were
compared to users of an OC containing 30-μg EE/150-μg levonorgestrel, but the
risk estimate was of borderline statistical significance and disappeared when the
analysis was restricted to women aged 39 years or less (236). Following the
publication of these studies, the FDA convened in December 2011 to discuss the
possibly increased risk of blood clots in users of Ortho Evra compared to women
who use certain birth control pills. The Joint Advisory Committee recommended
that Ortho Evra remain in the market as an option for contraception but that the
label be revised to more clearly describe the risks and benefits associated with
Ortho Evra (237).
No similar FDA warnings were issued about the ring. There are two case
815reports in the world literature of venous thrombosis with the ring. Both were
women in their 30s who sustained cerebral venous thrombosis (238,239). It is best
to assume that the ring has the same risk for thrombosis as the other combination
hormonal contraceptives and to counsel women about risk in the same way.
Future of the Vaginal Ring
The Population Council has developed a one-year contraceptive vaginal ring that
releases 150-mcg Nestorone, a nonandrogenic progestin that is inactive orally,
and 15-mcg EE daily. It can be worn for 3 weeks, removed for 1 week, and then
reinserted for up to 13 cycles (240). Refrigeration is unnecessary, and this method
may be especially advantageous for women in low resource settings where access
to a pharmacy and electricity are unreliable. The Population Council will submit a
New Drug Application (NDA) to the U.S. FDA and pursue regulatory approval in
low- and middle-income countries.
Injectable Hormonal Contraceptives
Depot Medroxyprogesterone Acetate
DMPA, a suspension of microcrystals of a synthetic progestin, was approved for
contraception in 1992. A single 150-mg intramuscular dose will suppress
ovulation in most women for 14 weeks or longer (241). [7] The regimen of 150
mg every 3 months is highly effective, producing pregnancy rates of about 0.3 per
100 women per year. Probably because of the high blood levels of the progestin,
efficacy appears not to be reduced by administration of other drugs and is not
dependent on the patient’s weight. Women treated with DMPA experience
disruption of the menstrual cycle and have initial spotting and bleeding at
irregular intervals. Eventually, total amenorrhea develops in most women who
take DMPA; with continued administration, amenorrhea develops in 50% of
women by 1 year and in 80% by 3 years (Fig. 14-9).
The most important medical reason women discontinue the use of DMPA
and other progestin-only methods is persistent irregular vaginal bleeding. A
variety of medications are used to stop this bleeding. Many are effective in
terminating individual bleeding episodes, but a systematic review concluded that
none improved continuation rates long term (242). New approaches include
mifepristone and low-dose doxycycline. Mifepristone is of interest because
irregular bleeding with DMPA was related to the downregulation of endometrial
estrogen receptors. Treatment with 50 mg of mifepristone every 2 weeks increases
endometrial estrogen receptors and reduces breakthrough bleeding in new users of
both DMPA and the levonorgestrel progestin implant (243). Another line of
investigation concerns endometrial matrix metalloproteinase, which appears to
816play a regulatory role in the breakdown of the endometrium to produce normal
menstruation. Treatment with doxycycline inhibits matrix metalloproteinase
production in the endometrium in women after insertion of levonorgestrel
subdermal implants (244). Five-day courses of either mifepristone 25 mg twice a
day for 1 day, followed by EE 20 μg per day for 4 days, or doxycycline 20 mg
twice a day for 5 days, reduced bleeding days by about 50% when compared to
placebos during a 6-month randomized trial in women treated for prolonged or
frequent bleeding occurring with etonogestrel subdermal implants (245). Capsules
of 20-mg doxycycline are sold in the United States for treatment of periodontal
disease.
817FIGURE 14-9 Bleeding pattern and duration of use of depomedroxyprogesterone acetate
(DMPA): percentage of women who have bleeding, spotting, or amenorrhea while taking
DMPA 150 mg every 3 months. (From Schwallie PC, Assenzo JR. Contraceptive useefficacy study utilizing medroxyprogesterone acetate administered as an intramuscular
injection once every 90 days. Fertil Steril 1973;24:331–339, with permission.)
DMPA use is commonly associated with weight gain, and that is another
principal reason women discontinue use. A large study is representative of the
literature. Three cohorts of women who chose their method of contraception were
818followed for 36 months with measurements of weight and body fat. DMPA users
gained an average of 5.1 kg. The cohort using OCs over the same interval gained
only 1.47 kg, slightly less than the 2.05 kg gained by the cohort not using any
hormonal contraception. Total body fat increased 4.14 kg in the DMPA cohort,
while the increase in the OC users was 1.9 kg, only slightly more than the 1.17 kg
in the nonhormonal contraceptive cohort. Many women were followed for 2 years
after discontinuing DMPA. Those who chose nonhormonal methods after
discontinuing DMPA lost a mean of 0.42 kg each 6 months. Those who chose to
use OCs gained a mean of 0.43 kg each 6 months during the follow-up interval
(246).
Weight gain during the first 6 months and self-reporting of increased appetite
are strongly predictive of continued weight gain. Women who gained less than or
equal to 5% of body weight in the first 6 months gained a mean of 2.49 kg by 36
months, while those who gained more than 5% by 6 months gained a total mean
of 11.08 kg by 36 months (247). Studies are needed of interventions to prevent
the weight gain. At minimum, women considering DMPA need to know the
possibility of significant weight gain and be advised to avoid calorie-dense foods
and weigh themselves regularly. Ideally they should be weighed when they return
for subsequent injections so they can be counseled about the need for avoiding
further gain. Women who gain 5% of body weight by 6 months should consider
other contraceptive options.
DMPA persists in the body for several months in women who used it for longterm contraception, and return to fertility may be delayed. Studies of return to
ovulation indicated a wide variation in time to ovulation post injection with the
majority ranging from 15 to 49 weeks from the last injection for DMPA (248). In
a cohort of Thai women, 70% of former users desiring pregnancy conceive within
12 months, and 90% conceive within 24 months after terminating DMPA use
(249).
Safety
DMPA suppresses ovarian estrogen production. Prospective studies demonstrated
bone loss during DMPA therapy, with recovery of bone mass after DMPA use is
discontinued (250). Although bone loss was observed, it did not approach the
fracture threshold. Similar bone loss and then recovery occurs with lactation.
Adolescents are of special concern because they normally gain bone mass; most
of adult bone mass is attained by age 20. Estrogen injections prevent the bone loss
and allow adolescent women to gain bone density despite the use of DMPA (251).
A long-term study in adolescents documented bone density loss and confirmed
recovery of lumbosacral bone mineral density to baseline by 60 weeks after
discontinuation of DMPA and significant gain above baseline by 180 weeks.
819Recovery of density at the hip was slower, 240 weeks to significant gain (252). A
systematic review of DMPA clinical trials could find no studies where fracture
was an outcome, so whether long-term use leads to fractures is still not known
(253). The FDA black box warning added to DMPA labeling proposes that DMPA
treatment be limited to 2 years at a time, unless the patient has no other good
options for contraception. For many women, especially in developing countries,
DMPA is often the only option for highly effective contraception because it is
inexpensive and easy to administer. The issue should be discussed with women
who are considering DMPA, but DMPA should not be routinely discontinued after
2 years unless the patient wants to conceive or wants to change to another
contraceptive method for other reasons.
The effect of DMPA on plasma lipids is inconsistent; DMPA users appear to
have reduced total cholesterol and triglyceride levels, slight reduction in HDL
cholesterol, and no change or slight increase in LDL cholesterol, all of which are
consistent with a reduction in circulating estrogen levels. In some studies, the
decrease in HDL and increase in LDL are statistically significant, although the
values remain within normal ranges (254). DMPA is not associated with
myocardial infarction. Glucose tolerance tests disclose a small elevation of
glucose in DMPA users.
There is no change in hemostatic parameters, with the exception that ATIII
levels are sometimes reduced with chronic therapy (254). As noted earlier, large
epidemiologic studies have not found DMPA to be associated with thrombosis
(145). DMPA is not associated with teratogenicity (255). Nor is it associated with
affective disorders or mood changes (256).
DMPA and Lactation
There is widespread support for the use of DMPA during lactation when the
DMPA is initiated at or after 6 weeks postpartum. There is good evidence that
neither infant growth nor lactation is impaired by DMPA or progestin-only OCs
(257). There is continued controversy as to how early DMPA should be given
after delivery. Because lactation occurs in response to falling maternal estrogen
and progesterone levels after birth, administration of DMPA in the first few days
theoretically might interfere with the initiation of lactation. There is concern
about the possible neonatal effects of the progestin, but investigators were unable
to demonstrate the presence of DMPA or its metabolites in the urine of infants
whose mothers received DMPA or any other suppression of reproductive
hormones (257). In the United States, DMPA is commonly started at the time of
hospital discharge, 48 to 72 hours after delivery. In a systematic review, including
11 nonrandomized clinical trials and observational studies, progestogen-only
injectables were initiated in the first 6 weeks postpartum and most found either no
820effect on breastfeeding outcomes or improved outcomes among DMPA users
(19). The “U.S. Medical Eligibility Criteria for Contraceptive Use 2016”
considers DMPA use prior to 1 month postpartum as category 2: the benefit is
thought to exceed the theoretical risk (7).
DMPA and Neoplasia
The use of DMPA is not associated with cervical cancer (258). Neither is it
associated with ovarian cancer (259). The risk of endometrial cancer is
substantially reduced by past use of DMPA (260). A large study found no increase
in breast cancer risk among DMPA users (261).
Benefits
DMPA has many of the noncontraceptive benefits of combination OCs (262).
Decreases in anemia, PID, ectopic pregnancy, and endometrial cancer are
reported. DMPA is reported to benefit women with sickle cell disease (263).
Subcutaneous DMPA
Depo-subQ Provera 104, a lower-dose DMPA preparation for subcutaneous
administration, received FDA approval in 2005. The total dose is 30% less than
that of the DMPA intramuscular preparation. Because the dose is administered
subcutaneously, blood levels are adequate to completely suppress ovulation for
more than 13 weeks in all subjects tested, with a mean time of 30 weeks for return
to ovulatory function (264). Contraception efficacy is superb, with no pregnancies
in a total of 16,023 woman-cycles in the phase III studies done in the United
States (265). Blood levels were lower in very obese women but still sufficient to
completely suppress ovulation. The weight gain reported with the 150-mg DMPA
remains a problem with the lower-dose DMPA. Mean weight gain was 1.59 kg in
the first year of use. Loss of bone density was observed with this dosage of
DMPA, as with the larger intramuscular dose. In select countries, DMPA-SQ is
available in a single-use Uniject device and is sold under the name Sayana Press
(266). The Uniject is a small, prefilled, single-use injection device that any trained
person, including community health workers, pharmacists, and even women
themselves can administer. In an open-label observational study, current users of
DMPA IM found Sayana Press to be acceptable, with most users preferring
Sayana Press over DMPA IM, indicating promising uptake (267).
Once-a-Month Injectable
A once-a-month injectable contraception containing only 25 mg of DMPA in
combination with 5 mg of the long-acting estrogen estradiol cypionate was
briefly available in the United States, but was withdrawn by the manufacturer
821because of a packaging problem (268). Originally developed by the WHO, it is
described as Cyclofem or CycloProvera in the literature and was marketed in the
United States as Lunelle (269). Given once a month, this combination produces
excellent contraceptive effects. Monthly withdrawal bleeding is similar to a
normal menses, leading to high continuation rates despite the need for a monthly
injection. Monthly injectable combinations continue to be widely used outside the
United States.
Subdermal Implants
Three progestin-releasing subdermal implants systems are in use worldwide:
Jadelle (Bayer, Leverkusen, Germany), Sino-Implant II (Dahua, Shanghai,
China), and Nexplanon (Merck, Kenilworth, USA). All three offer long-acting
contraception that requires no continuing action by the user and are, hence,
forgettable. All are very highly effective and have no serious risk. Each can
produce irregular bleeding, which is the principal reason for discontinuation. The
mechanism of action is suppression of ovulation in the initial years of use, plus
thickening of the cervical mucous that prevents sperm penetration.
The original levonorgestrel implant (Norplant) six-rod system was replaced
with a two-rod version (Jadelle), which is identical in its release rate and clinical
activity to Norplant and is easier to insert and remove (270). Jadelle is widely
used around the world. It is approved by the FDA but not marketed in the United
States. It is approved for 5 years. The Sino-Implant II (Levoplant) is a less
expensive two-rod levonorgestrel system manufactured in China and available in
several countries. It is labeled for 3 years of use, with trials ongoing for a fourth
year (271). In June 2017, the product received WHO prequalification, which
recognizes that the product meets international quality standards for
manufacturing and clinical performance. This allows additional donors to
purchase the product for country programs. Thus, the availability of the SinoImplant II (Levoplant) is likely to increase. Nexplanon (or Implanon-NXT) is a
single-rod system containing etonogestrel, the active metabolite of desogestrel. It
was first approved in 2006 as Implanon. In 2011, Merck replaced Implanon with
Nexplanon, which contains 15 mg of barium sulfate to create a radiopaque quality
and utilizes a simpler applicator for easier, and potentially safer insertion. All
studies regarding safety and effectiveness of Implanon apply to Nexplanon.
A systematic review of 29,972 women and 28,108 woman-months of follow-up
with Norplant, Jadelle, or Implanon found no differences in pregnancies or
continuation rate over 4 years. No pregnancies occurred in any of the trials. There
were no differences in side effects or adverse events. The most common side
effect was unpredictable vaginal bleeding (272).
In 923 women followed for 20,648 treatment cycles in 11 studies, there were
822no pregnancies with the etonogestrel implant in place. Six pregnancies occurred
within 14 days of removal of the devices. [7] When these are included, as
required by the FDA, the cumulative Pearl Index was 0.38 pregnancies per 100
woman-years at 3 years (273). Irregular bleeding was a problem, but occurred
most frequently in the first 90 days of use and decreased over time. In a
randomized comparison with the six-rod Norplant, etonogestrel implant users had
less frequent vaginal bleeding, but more became amenorrheic (274). Other
commonly reported side effects are headache, weight gain, acne, breast
tenderness, and emotional lability (273). Only 2.3% of subjects discontinued
because of weight gain. Most women can use Nexplanon. The US MEC lists only
a small number of conditions as category 3, and these are based on theoretical
concerns without actual evidence of harm (7). Insertion in the postpartum period
appears to have no adverse effects on the mother or infant. Among women who
initiated the ETG implant or LNG-IUD 6 weeks postpartum, there was no
difference in the weight or height of their infants through 6 months (275). An
RCT found no difference in growth at 12 months among breastfed infants whose
mothers had etonogestrel implant inserted within 48 hours postpartum versus at 6
weeks postpartum (276). A study of etonogestrel implants compared with the
copper IUD placed 4 to 8 weeks postpartum found no differences in infant
growth, adverse events, respiratory or skin disorders, or developmental scores
(277). One population in which special considerations should be taken when
using progestin implants is HIV-positive women concurrently taking efavirenzbased antiretroviral therapy (ART), because efavirenz may reduce the
effectiveness of contraceptive implants. Pharmacokinetic studies have reported
reduced etonogestrel and levonorgestrel concentrations in implant users
concurrently using efavirenz-based ART, which raises concerns about potential
decreased contraceptive efficacy (278,279). In a retrospective cohort study of
HIV-positive women with contraceptive implants, the adjusted pregnancy rates in
efavirenz users were triple that of nevirapine users (280). Nevertheless, these
findings should not preclude women taking efavirenz from using implants
because even in this population, the implant remains more effective than nonLARC contraceptive methods.
Bone density is not affected by the etonogestrel implant, probably because
ovarian follicular activity is not totally suppressed and estradiol synthesis
continues (281). Enlarged follicular ovarian cysts are common during the first
year of use of Jadelle or etonogestrel implant and usually resolve spontaneously
(282).
[7] A comparative study of coagulation and fibrinolytic factors in users of
etonogestrel and levonorgestrel implants showed no significant changes from the
baseline, with the exception of a modest increase in ATIII and a small decrease in
823factor VII activity, changes that might reduce coagulability. Lipid levels and liver
function studies were not changed, with the exception of small elevations of
bilirubin, with somewhat more observed in levonorgestrel users than etonogestrel
users (283). Another study of hemostatic factors found modest decreases in many
measurements, within the range of normal, and a modest reduction in the
generation of thrombin in users of the etonogestrel implant (284). Taken together
these studies provide considerable reassurance that the progestin implants do not
increase thrombosis risk. With several million women now using the implants,
there are no published studies linking either implant to venous thrombosis or
myocardial infarction.
Emergency Contraception
Postcoital use of sex steroids to prevent pregnancy began in the 1960s with highdose estrogen taken daily for 5 days (285). This was replaced with the
combination OC containing EE and levonorgestrel for greater convenience (286).
[9] In the late 1990s, levonorgestrel alone became the method of choice after the
WHO showed its superiority in a large randomized trial with 1,998 women. The
pregnancy rate was 3.2% with the EE/levonorgestrel method and only 1.1% with
levonorgestrel alone (RR for pregnancy, 0.32; 95% CI, 0.18–0.70) for women
treated within 72 hours of intercourse. Nausea and vomiting occurred much less
frequently with levonorgestrel alone (23.1% vs. 50.5%, and 5.6% vs. 18.8%,
respectively) (287). The efficacy of both methods declined as the time after
intercourse increased. But even after 72 hours, the pregnancy rate with the
levonorgestrel treatment was only 2.7% (288). A single dose of 1.5-mg
levonorgestrel is just as effective as two doses of 0.75 mg, has no more side
effects, and is more convenient for the patient. Both dosing regimens are FDA
approved. While recognizing that levonorgestrel is more effective the sooner it is
taken, the WHO allows for the use of 1.5 mg of levonorgestrel as a single dose,
given up to 120 hours after intercourse (289). Research suggests that the main
mechanism of action is delay of ovulation. Noe et al. established that
levonorgestrel works only if it is administered prior to the day of ovulation (290).
No pregnancies occurred to 87 women who received levonorgestrel from 1 to 5
days prior to the day of ovulation. Seven pregnancies occurred to 35 women
treated on the day of ovulation or later. Postcoital levonorgestrel is not an
abortifacient because it is effective only when taken before ovulation.
Levonorgestrel alone is safer than the estrogen-containing preparations. There
were several case reports of thrombotic events after use of the
estrogen/levonorgestrel combination emergency contraception (291). No such
complications with levonorgestrel alone were published.
824Antiprogestins
The antiprogesterone mifepristone (RU486) is highly effective for postcoital
contraception. The usual abortifacient dose is 200 mg, but a dose of only 10 mg
is effective for emergency contraception. In one study, 2,065 women were
randomized to mifepristone, 10 mg, or levonorgestrel, two doses of 0.75 mg,
including women up to 120 hours after intercourse (292). The crude pregnancy
rate was 1.3% for mifepristone and 2.0% for levonorgestrel (p = 0.46). Side
effects were the same, and both methods were judged highly acceptable by the
patients. Mifepristone is not being developed for this use and is not available at
the appropriate dose.
[9] Ulipristal acetate, sold by the trade name of Ella, is a progesterone-receptor
modulator that was approved by the FDA and the European Union for emergency
contraception up to 120 hours after intercourse. It is a single 30-mg tablet,
available by prescription only, whereas levonorgestrel 1.5 mg has been available
without a prescription since 2013. When ovulation is imminent, ulipristal is more
effective than levonorgestrel in delaying ovulation. The odds of pregnancy for
ulipristal were 42% lower by 72 hours after intercourse and 65% lower in the first
24 hours (293). When ulipristal is administered prior to the LH peak, it delays the
rupture of the preovulatory follicle for 5 days or more, which may be its primary
mechanism of action (294). In women with BMI >30, the risk of pregnancy is
greater for those taking levonorgestrel (OR, 4.41) than for those taking ulipristal
(OR, 2.62) (295). Thus, for obese women, ulipristal is preferred over
levonorgestrel. Subsequent studies on EC and obesity have shown that the total
concentration of levonorgestrel for obese women with one dose of levonorgestrel
was significantly lower than the level observed in normal BMI women (296).
However, the concentration of ulipristal was similar between obese and normal
BMI women (297). Ulipristal is primarily metabolized by the CYP3A4 enzyme
system; hence, patients on drugs such as barbiturates, rifampin, and several of the
anticonvulsants may have reduced protection from pregnancy with it. With
regards to starting hormonal contraception following the use of emergency
contraceptive pills, hormonal contraception can be started immediately after
administration of levonorgestrel. However, in one study where women were given
either a placebo or a progestin-only pill, desogestrel, the day after ulipristal,
ovulation occurred in 45% of cycles in women receiving desogestrel compared to
3% in the placebo group (298). Therefore, in 2015, the Ella label was updated to
recommend that patients who use ulipristal wait 5 days before starting a hormonal
contraceptive method (299).
The Copper Intrauterine Device for Emergency Contraception
Postcoital insertion of a copper IUD was first reported by Lippes et al. in 1976
825(300). In initial trials, the copper IUD was inserted within 7 days of intercourse
and was more effective than steroids for emergency contraception. Subsequent
studies included women only within 5 days from intercourse. The multicenter trial
by Wu and colleagues is an example of the superb efficacy offered by the copper
T380A (301). Of 1,893 women who returned for a follow-up visit, there were no
pregnancies within 1 month of IUD insertion. [9] Efficacy for emergency
contraception is 100% when the device is inserted up to 5 days after
intercourse, and almost 100% up to 7 days after intercourse (301). An added
benefit was that 94% of the patients were continuing with the IUD at the 12-
month follow-up. There were no uterine perforations. Zhou and colleagues
reported similar excellent results in a large study with a different copper device,
the Multiload Cu-375 IUD (302). In much of the world, copper IUDs are very
inexpensive. Even in the United States where IUDs are costly, the benefit to the
patient of extremely effective emergency contraception, and long-term
contraception with one intervention, makes emergency IUDs cost effective.
Whether the LNG-IUD would work for emergency contraception is being studied.
Hormonal Contraception for Men
The same negative feedback of sex steroids that blocks ovulation in women
suppresses spermatogenesis in men, but it will produce loss of libido and
potentially extinguish sexual performance. The principle was first demonstrated
in 1974 using oral estrogen and methyl testosterone (303). Testosterone given
alone can suppress sperm production to very low levels while maintaining normal
libido and sexual performance. Over many years investigators have studied longacting testosterone salts for male contraception (304). Ethnicity is an important
predictor of efficacy of sperm suppression with testosterone therapy. Asian men
virtually always achieve azoospermia or oligospermia when treated with
testosterone undecanoate (TU) monthly injections, whereas only 86% of
Caucasian men achieved azoospermia or oligospermia or with similar testosterone
regimens (305). In a Chinese trial, 1,045 men were treated with monthly TU 500
mg. Only 4.8% failed to suppress to a sperm count less than 1 × 106 per mL. The
cumulative pregnancy rate was only 1.1 per 100 men at 30 months (306). In
Caucasian populations, testosterone was combined with progestins to further
suppress gonadotropin and improve efficacy. In an important trial with Caucasian
men, etonogestrel subdermal implants and TU injections were compared to
placebo implants and injections. Only 3% failed to suppress to a sperm count of
less than 1 × 106 (307). Side effects that were more common in the medicated
group than placebo included acne, night sweats, libido changes (usually
increased), and weight gain. In a study using Nestorone (progestin) and
826testosterone transdermal gels, 89% of men achieved suppression of their sperm
concentrations to ≤1 × 106 per mL, with minimal side effects (308).
Nonhormonal male methods are being investigated. One product called
reversible inhibition of sperm under guidance (RISUG) has been studied in both
preclinical and human research in India (309). It consists of styrene maleic
anhydride which when injected into the vasa differentia creates an incompatible
pH level for sperm and blocks transport. Vasalgel involves a similar approach but
uses a different formulation and is being developed in the United States. It is a
high–molecular-weight polymer consisting of styrene-alt-maleic acid dissolved in
dimethyl sulfoxide, which is injected into the vasa deferentia, where it remains as
a soft gel-like state that allows water-soluble substances to pass but not sperm. It
is meant to be reversible and in rabbit studies shows rapid restoration of sperm
flow after an injection of sodium bicarbonate (310). Thus far, Vasalgel has been
studied only in animal models (311). Vasalgel is expected to begin enrollment of
men in clinical trials in the United States.
STERILIZATION
Surgical sterilization is the most common method of fertility control used by
couples worldwide, with more than 250 million women and men relying on
female sterilization or vasectomy for contraception (312). Laparoscopic and
hysteroscopic techniques for women and vasectomy for men are safe and readily
available throughout the United States. The mean age at sterilization is 30 years.
Age younger than 30 years when sterilized, conflict within the marriage, and
divorce and remarriage are predictors of sterilization regret, which may lead to a
request for reversal of sterilization (313).
Female Sterilization
Hysterectomy is no longer considered for sterilization because morbidity and
mortality are too high in comparison with tubal sterilization. Vaginal tubal
sterilization, which was associated with occasional pelvic abscess, is rarely
performed in the United States. [11] Five procedures are used in the United
States.
1. Tubal sterilization at the time of laparotomy for a cesarean delivery or
other abdominal operation
2. Postpartum minilaparotomy soon after vaginal delivery
3. Interval minilaparotomy
4. Laparoscopy
5. Hysteroscopy
827Postpartum tubal sterilization at the time of cesarean delivery adds no risk
other than a slight prolongation of operating time; cesarean birth poses more
risk than vaginal birth, and planned sterilization should not influence the decision
to perform a cesarean delivery. Minilaparotomy can be performed in the
immediate postpartum state. The uterus is enlarged, and the fallopian tubes
lie in the midabdomen, easily accessible through a small, 3- to 4-cm
subumbilical incision.
Interval minilaparotomy, first described by Uchida, was rediscovered and
popularized in the early 1970s in response to an increased demand for sterilization
procedures and a simpler alternative to laparoscopy (314). Still widely practiced
in lower resource settings, it is uncommon in the United States because of
widespread availability of the endoscopic techniques.
Surgical Technique
The procedure usually elected for tubal sterilization by laparotomy is the Pomeroy
or modified Pomeroy technique (Fig. 14-10). In the classic Pomeroy procedure, a
loop of tube is excised after ligating the base of the loop with a single absorbable
suture. A modification of the procedure is excision of the midportion of the tube
after ligation of the segment with two separate absorbable sutures. This modified
procedure has several names: partial salpingectomy, Parkland Hospital
technique, separate sutures technique, and modified Pomeroy. In the Madlener
technique, now abandoned because of too many failures, a loop of tube is crushed
by cross-clamping its base, ligated with permanent suture, and excised. Pomeroy
and partial salpingectomy procedures have failure rates of 1 to 4 per 1,000 cases
(313). In contrast, pregnancy is exceedingly rare after tubal sterilization by the
Irving or Uchida methods. In the Irving method, the midportion of the tube is
excised, and the proximal stump of each tube is turned back and led into a small
stab wound in the wall of the uterus and sutured in place, creating a blind loop.
With the Uchida method, a saline–epinephrine solution (1:1,000) is injected
beneath the mucosa of the midportion of the tube, separating the mucosa from the
underlying tube. The mucosa is incised along the antimesenteric border of the
tube, and a tubal segment is excised under traction so that the ligated proximal
stump will retract beneath the mucosa when released. The mucosa is closed with
sutures, burying the proximal stump and separating it from the distal stump. In
Uchida’s personal series of more than 20,000 cases, there were no pregnancies
(314).
828FIGURE 14-10 Pomeroy technique for tubal sterilization. A: Ligation of loop of fallopian
tube. B: Subsequent excision of loop.
Laparoscopy
Laparoscopy is the most common method of interval sterilization in the
United States. In the standard laparoscopy technique, after the abdomen is
inflated with a gas, the laparoscope is inserted into the abdominal cavity through a
trocar, usually at the lower margin of the umbilicus. Although single puncture
laparoscopic sterilization procedures can be performed with an “operating
laparoscope,” it is increasingly common for a second, and sometimes third, trocar
to be inserted in the suprapubic region or lateral lower quadrants to allow the
insertion of special grasping forceps. Laparoscopic sterilization is usually
performed in the hospital under general anesthesia but can be performed under
local anesthesia with conscious sedation. Overnight hospitalization for
laparoscopy is rarely needed.
Techniques for Tubal Occlusion at Laparoscopy
Laparoscopic tubal occlusion is accomplished by any of four techniques: bipolar
electrical coagulation, application of a small Silastic rubber band (Falope ring),
829the spring clip (Hulka clip), or the titanium clip (Filshie clip). The Filshie clip,
first introduced in the United States in 1996, is used extensively in the United
Kingdom and Canada (315). It is a hinged device made of titanium with a liner of
silicone rubber tubing. Because of its lower pregnancy rate, the Filshie clip has
largely supplanted the Hulka clip (316).
In the bipolar electrocoagulation technique, the midisthmic portion of the tube
and adjacent mesosalpinx are grasped with special bipolar forceps, and
radiofrequency electric current is applied to three adjacent areas, coagulating 3
cm of tube (Fig. 14-11). The tube alone is recoagulated in the same places. The
radiofrequency generator must deliver at least 25 W into a 100-Ω resistance at the
probe tips to ensure coagulation of the complete thickness of the fallopian tube
and not just the outer layer; otherwise, the sterilization will fail (317).
To apply the Falope ring, the midisthmic portion of the tube is grasped, with
tongs advanced through a cylindrical sleeve that has the ring stretched around it
(Fig. 14-12A). A loop of tube is pulled back into the sleeve, and the outer
cylinder is advanced (Fig. 14-12B), releasing the Silastic ring around the base of
the loop of the tube, producing ischemic necrosis over time (Fig. 14-12C). If the
tube cannot be pulled easily into the applicator, the operator should stop and
change to electrical coagulation rather than persist and risk lacerating the tube
with the Falope ring applicator. The banded tube must be inspected at close range
through the laparoscope to demonstrate that the full thickness of the tube was
pulled through the Falope ring.
The Hulka clip is placed across the midisthmus, ensuring that the applicator is
at right angles to the tube and that the tube is completely contained within the clip
before the clip is closed. The Filshie clip is placed at right angles across the
midisthmus, taking care that the anvil of the posterior jaw can be visualized
through the mesosalpinx beyond the tube to ensure that the complete thickness of
the tube is completely within the jaws of the clip before it is closed (Fig. 14-13).
The cautery band or clip techniques each have advantages and disadvantages.
Bipolar coagulation can be used with any fallopian tube. The Falope ring and
Hulka and Filshie clips cannot be applied if the tube is thickened from previous
salpingitis. There is more pain during the first several hours after Falope ring
application. This can be prevented by bathing the tubes with a few milliliters of
0.5% bupivacaine just before ring placement (318). Failure of the Falope ring or
the clips generally results from misapplication, and pregnancy, if it occurs, is
usually intrauterine. After bipolar sterilization, pregnancy may result from
tuboperitoneal fistula and is ectopic in more than 50% of cases. If inadequate
electrical energy is used, a thin band of fallopian tube remains that contains the
intact lumen and allows intrauterine pregnancy to occur. Thermocoagulation, the
use of heat probes rather than electrical current, is employed extensively in
830Germany for laparoscopic tubal sterilization but is little used in the United States.
FIGURE 14-11 Technique for bipolar electrocoagulation tubal sterilization.
831832FIGURE 14-12 Placement of the Falope ring for tubal sterilization.
Laparoscopic Salpingectomy
Salpingectomy, either partial or complete, has not been traditionally used for
sterilization because of perceived comparative ease and safety of occlusion
methods. However, a large observational study compared salpingectomy with
other methods and found no increase in complication rates but an increase in
operative time of approximately 10 minutes (319). A recent study including
salpingectomies and tubal occlusion cases showed comparable immediate and
short-term complications rates across sterilization methods and an average
increase of 6 minutes of operative time for salpingectomy (320). Prophylactic
salpingectomy may reduce the risk of ovarian/ fallopian tube cancer because
most epithelial ovarian cancers arise in the distal fallopian tube, and is now
recommended when women are undergoing gynecologic surgeries for other
benign indications.
Noncontraceptive Benefits of Tubal Sterilization
In addition to providing excellent contraception, tubal ligation is associated
with reduced risk for ovarian cancer. Among the largest studies to illustrate the
relationship between tubal ligation and ovarian cancer were the Nurses’ Health
Study and Nurses’ Health Study II. These two prospective cohort studies included
29,340 women who had tubal ligation and found that tubal ligation overall was
associated with a decreased risk of ovarian cancer (HR, 0.76; 95% CI, 0.64–0.90)
(321). In a large prospective cohort study in the United Kingdom, the association
of tubal ligation with decreased risk varied by histology, with a significant
decrease in the risk of high-grade serous carcinomas (RR, 0.77; 95% CI, 0.67–
0.89), endometrioid (RR, 0.54; 95% CI, 0.43–0.69), and clear cell tumors (RR,
0.55; 95% CI, 0.39–0.77) (322).
833FIGURE 14-13 Filshie clip for tubal sterilization. (Courtesy of Femcare Ltd, Romsey,
UK.)
Furthermore, studies have explored the risks and benefits of opportunistic
salpingectomy compared to tubal ligation with regards to ovarian cancer risk
reduction. One study concluded that opportunistic salpingectomy at the time of
sterilization is cost effective with an incremental cost effectiveness ratio of
$31,432 per quality-adjusted life year (323). Another study comparing partial
salpingectomy (modified Pomeroy method) to complete salpingectomy (use of
LigaSure) at the time of cesarean delivery found no significant differences in
short-term complications (postpartum fever, wound infection, relaparotomy,
834estimated blood loss) (324). In addition, one trial which aimed to evaluate shortterm ovarian reserve by measuring antimüllerian hormone levels, detected no
significant difference between the groups, with an average increase of 0.58 ± 0.98
versus 0.39 ± 0.41 ng/mL in the salpingectomy and tubal ligation groups,
respectively (p = 0.45). Surgeries including salpingectomy were longer by an
average 13 minutes (66.0 ± 20.5 vs. 52.3 ± 15.8 minutes, p = 0.01) (325). A trend
may develop that favors salpingectomy over tubal occlusion or ligation for
sterilization.
Risks of Tubal Sterilization
Tubal sterilization is remarkably safe. The Collaborative Review of
Sterilization (CREST) study, a 1983 review of 9,475 interval sterilizations from
multiple centers in the United States, reported a total complication rate of 1.7 per
100 procedures (313). Complications were increased by the use of general
anesthesia, previous pelvic or abdominal surgery, history of PID, obesity, and
diabetes mellitus. The most common significant complication was unintended
laparotomy for sterilization after intra-abdominal adhesions were found. In
another series, 2,827 laparoscopic sterilizations were performed with the Silastic
band using local anesthesia and intravenous sedation (326). Only four cases could
not be completed (a technical failure rate of 0.14%), and laparotomy was never
needed. Rarely, salpingitis can occur as a complication of the surgery. This occurs
more often with electric coagulation than nonelectric techniques. The risk of
death with female sterilization was 1 to 2 per 100,000 sterilizations in a national
study based on data from 1979 to 1980 (313). Almost half of the deaths were
from complications of general anesthesia, usually related to the use of mask
ventilation. When general anesthesia is used for laparoscopy, endotracheal
intubation is mandatory because the pneumoperitoneum increases the risk of
aspiration. International data from the Association for Voluntary Surgical
Contraception show a similar record of safety from third-world programs: 4.7
deaths per 100,000 female sterilizations and 0.5 deaths per 100,000 vasectomies
(327).
Sterilization Failure
Many “failures” occur during the first month after surgery and are the
result of a pregnancy already begun when the sterilization was performed.
Contraception should be continued until the day of surgery, and a sensitive
pregnancy test should be routinely performed on the day of surgery. Because
implantation does not occur until 6 days after conception, a woman could
conceive just before the procedure and there would be no way to detect it.
Scheduling sterilization early in the menstrual cycle obviates the problem but
835adds to the logistic difficulty. Another cause of failure is the presence of anatomic
abnormalities, usually adhesions surrounding and obscuring one or both tubes. An
experienced laparoscopic surgeon with appropriate instruments usually can lyse
the adhesions, restore normal anatomic relations, and positively identify the tube.
In some circumstances, successful sterilization will not be possible by
laparoscopy, and the surgeon must know before surgery whether the patient is
prepared to undergo laparotomy, if necessary, to accomplish sterilization. The
CREST study reported on a cohort of 10,685 women sterilized from 1978 to 1986
at any of 16 participating centers in the United States who were followed from 8
to 14 years (313). The true failure rates for 10 years obtained by the life-table
method are given in Table 14-4. Pregnancies resulting from sterilization during
the luteal phase of the cycle in which the surgery was performed were excluded.
Of all remaining pregnancies, 33% were ectopic. The most effective methods at
10 years were unipolar coagulation at laparoscopy and postpartum partial
salpingectomy, generally a modified Pomeroy procedure. Bipolar tubal
coagulation and the Hulka-Clemens clip were least effective. The Filshie clip was
not evaluated because it was not in use in the United States. Younger women had
higher risk for failure, as would be expected because of their greater fecundity.
Table 14-4 Ten-Year Life-Table Cumulative Probability of Pregnancy per 1,000
Procedures With Different Methods of Tubal Sterilization, United States,
1978–1986
Unipolar coagulation 7.5
Postpartum partial salpingectomy 7.5
Silastic band (Falope or Yoon) 17.7
Interval partial salpingectomy 20.1
Bipolar coagulation 24.8
Hulka-Clemens clip 36.5
Total: all methods 18.5
From Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal
sterilization: findings from the U.S. Collaborative Review of Sterilization. Am J Obstet
Gynecol 1996;174:1164; Table 2, with permission.
Since the CREST study began, sterilization by unipolar electrosurgery was
abandoned because of the risk of bowel burns and was replaced with bipolar
836electrosurgery or the nonelectric methods (tubal ring, Hulka-Clemens clip, and
the Filshie clip). An analysis of the CREST data found that bipolar
sterilization can have a very low long-term failure rate if an adequate portion
of the tube is coagulated. CREST study participants who were sterilized with
bipolar electrosurgery from 1985 to 1987 had lower failure rates than those
sterilized earlier (1978–1985). The important difference was in the application
technique of the electric energy to the tubes. Women whose bipolar procedure
involved coagulation at three sites or more had low 5-year failure rates (3.2 per
1,000 procedures), whereas women who had fewer than three sites of tubal
coagulation had a 5-year failure rate of 12.9 per 1,000 (p = 0.01) (328).
Family Health International reported large randomized multicenter trials of the
different means of tubal sterilization. The Filshie and Hulka clips were compared
in two trials. A total of 2,126 women were studied, of which 878 had either clip
placed by minilaparotomy and 1,248 had either clip placed by laparoscopy. The
women were evaluated at up to 24 months (329). Pregnancy rates were 1.1 per
1,000 women with the Filshie clip and 6.9 per 1,000 with the Hulka clip at 12
months, a difference in rates that approached statistical significance (p = 0.06).
This same group compared the Filshie clip with the Silastic tubal ring in a similar
study with a total of 2,746 women, of which 915 had the devices placed at
minilaparotomy and 1,831 at laparoscopy (330). Pregnancy rates at 12 months
were the same for the Filshie clip and the tubal ring: 1.7 per 1,000 women. The
ring was judged more difficult to apply. The Filshie clip was expelled
spontaneously from the vagina by three women during the 12 months of followup.
Hysteroscopy
In 2002, the FDA approved Essure, a hysteroscopic method of permanent birth
control. It can be provided in an office setting, with only local anesthesia or
conscious sedation and both offer the prospect of greater safety, lower cost, and
greater long-term effectiveness than the best laparoscopy [12] methods. Essure is
a microinsert consisting of a soft stainless steel inner coil and a dynamic
nickel titanium alloy outer coil (Fig. 14-14). Soft fibers of polyethylene
terephthalate run along and through the inner coil. To insert the device, a
hysteroscope is introduced into the uterine cavity, which is distended with saline.
The tubal ostia are visualized. The Essure device is inserted through the operating
channel of the hysteroscope on the end of a slender delivery wire, guided into the
tubal opening and advanced into the tube under direct vision (Fig. 14-15). Once
in place, an outer sheath is retracted, releasing the outer coils, which expand to
anchor the device in the interstitial portion of the tube. The delivery wire is
detached and removed and the procedure repeated for the other tube. When
837properly placed, three to eight of the end coils of the microinsert are visible inside
the uterine cavity. The rest are inside the fallopian tube (331,332).
[12] Essure can be installed under local anesthesia in an outpatient setting.
No incision is needed. Over time fibrous tissue grows, occluding the tubes
permanently. The Essure Confirmation Test using either a transvaginal ultrasound
(TVUS) or modified hysterosalpingogram (HSG) is required. The FDA approved
the TVUS as an alternative confirmation test in July 2015. Patients must meet all
criteria at the time of placement to be eligible for TVUS. Otherwise, they must
undergo confirmation with modified HSG. A few notable criteria include
certainty about bilateral placement, procedure time ≤15 minutes, and one to eight
trailing coils bilaterally (333). Patients who are on active immunosuppressive
therapy (systemic corticosteroids or chemotherapy) are not eligible for TVUS as a
result of concern for failure of tissue ingrowth. The modified HSG for Essure
should document bilateral placement of the devices at the uterotubal junction and
a lack of peritoneal spillage of dye. The patient with transcervical sterilization
should continue to use a reliable method of contraception until successful
occlusion is documented.
838FIGURE 14-14 Essure device for hysteroscopic sterilization. (Courtesy of Conceptus,
Inc.)
839FIGURE 14-15 Essure device with guide wire and handle. (Courtesy of Conceptus, Inc.)
Risks of Hysteroscopy
Adverse events or side effects were reported on the day of procedure in 3% of the
initial Essure patients. These consisted of vasovagal responses, cramping, nausea,
and vaginal spotting (334). Possible but uncommon risks of the hysteroscopic
tubal sterilization methods include perforation by the device at insertion and
expulsion of the device. Tubal and uterine perforation was reported to range from
0% to 1.8% (335). Other potential combinations with transcervical sterilization
are related to the hysteroscopy procedure, not the tubal occlusion process. These
include hypervolemia, injury to surrounding organs, bleeding, and infection and
occur in less than 1% of cases.
840[12] Between November 2002 and May 2015, the FDA received a total of 5,093
reports related to Essure, prompting it to convene a panel to review the safety and
effectiveness of Essure sterilization. In 2016, the FDA ordered the manufacturer
to conduct a postmarket surveillance study to determine heightened risks for
particular women, and issue a black box warning about risk of perforation,
persistent pain and suspected allergic or hypersensitivity reactions (336).
Subsequently, in July 2018, due to a decline in sales, the manufacturer removed
the device from the market.
Sterilization Failure With Essure
A meta-analysis of 31 studies including more than 12,000 procedures reported
bilateral placement rates of 81% to 98% with higher success rates reported from
studies published since 2007 (337). Reasons for failure of insertion were tubal
obstruction, stenosis, or difficulty in accessing the tubal ostia. In a review of over
66,000 Essure placements, there were 102 pregnancies (1.5 per 1,000). Seventysix percent occurred in women who did not have postprocedure imaging to
confirm tubal occlusion, did not have reliable contraception prior to confirmation
imaging or had misread imaging (338). Other studies report similar rates of
pregnancy, ranging from 1.2 to 1.5 per 1,000 (339).
Reversal of Sterilization
Reversal of sterilization is more successful after mechanical occlusion than
after electrocoagulation, because the latter method destroys much more of
the tube. With modern microsurgical techniques and an isthmus-to-isthmus
anastomosis, the first-year pregnancy rate is about 44% (340). A retrospective
review comparing microsurgical reanastomosis to in vitro fertilization (IVF)
found similar total pregnancy rates, but a higher live birthrate with IVF because
10% of the pregnancies after microsurgery were ectopic (340). Hysteroscopic
sterilization by Essure should be considered irreversible. However, reversal
following hysteroscopic sterilization has been reported using tubouterine
implantation. Thirty-six percent of those undergoing surgery subsequently
conceived naturally (341).
Late Sequelae of Tubal Sterilization
Increased menstrual irregularity and pain are attributed to previous tubal
sterilization. Study of the problem is complicated by the fact that many women
develop these symptoms as they age, even though they did not have tubal surgery,
and are treated with OCs that reduce pain and create an artificially normal
menstrual cycle. Women who discontinue OC use after tubal sterilization will
experience more dysmenorrhea and menstrual irregularity, which is unrelated to
841the sterilization. The best answer available comes from the CREST study (342). A
total of 9,514 women who underwent tubal sterilization were compared with 573
women whose partners had undergone vasectomy. Both groups were followed up
to 5 years with annual standardized telephone interviews. Women who underwent
tubal sterilization were no more likely to report persistent changes in
intermenstrual bleeding or length of the menstrual cycle than women whose
partners had vasectomy. The sterilized women reported decreases in the days of
bleeding, amount of bleeding, and menstrual pain but were slightly more likely to
report cycle irregularity (OR, 1.6; 95% CI, 1.1–2.3). In summary, the CREST
study provided good evidence that there is no “posttubal ligation syndrome.”
Vasectomy
About 500,000 vasectomies are performed each year in the United States (313).
Vasectomy is a highly effective method. The literature on efficacy is often
difficult to interpret because most studies report failure as failure to achieve
azoospermia, rather than long-term pregnancy rates among the relevant women.
Vasectomy is not effective until all sperm are cleared by the reproductive
tract, which can take up to 20 ejaculations or 3 months. It is estimated that
up to half of pregnancies after vasectomy occur during the interval between
the surgery and the clearance of all sperm (343). Not all pregnancies after
vasectomy can be attributed to the men who had the operation. [13] The best
long-term information comes from the CREST study. The cumulative probability
of failure was 7.4 per 1,000 procedures at 1 year and 11.3 at year 5, and
comparable to the failure rate of tubal sterilization (313).
[13] Vasectomy is usually performed under local anesthesia. The basic technique
is to palpate the vas through the scrotum, grasp it with fingers or atraumatic
forceps, make a small incision over the vas, and pull a loop of the vas into the
incision. A small segment is removed, and a needle electrode is used to coagulate
the lumen of both ends. Improved techniques include the no-scalpel vasectomy, in
which the pointed end of the forceps is used to puncture the skin over the vas.
This technique reduces the risk of hematoma (344). Another variation is the openended vasectomy, in which only the abdominal end of the severed vas is
coagulated while the testicular end is left open. This is believed to prevent
congestive epididymitis and sperm granuloma (345). Fascial interposition creates
a tissue barrier between the vasal ends and reduces vasectomy failure (346).
Reversibility
Vasectomy must be regarded as a permanent means of sterilization. However,
among men undergoing surgical reanastomosis (vasovasostomy), subsequent
842patency has been reported in over 90% of cases when current microsurgical
techniques are employed (347). Nevertheless, the longer the interval since
vasectomy, the poorer is the chance of reversal (348).
Safety
Operative complications include scrotal hematomas, wound infection, and
epididymitis, but serious sequelae are rare. There were no reports of deaths from
vasectomy in the United States in many years, and the death rate in a large thirdworld series was only 0.5 per 100,000. Concerns about long-term safety recurred
with the report of a possible association between prostate cancer and vasectomy
(349). [13] Large studies present the very clear conclusion that vasectomy is
not associated with prostate cancer (350–352).
843ABORTION
It is extremely likely that couples will experience at least one unwanted
pregnancy at some time during their reproductive years. In developing
countries, desired family size is larger (although decreasing), but access to
effective contraception is limited. As a result, abortion, often unsafe, is common.
Because of population growth, the absolute number of abortions increased by 5.9
million, from 50.4 million per year from 1990 to 1994 to 56.3 million per year
from 2010 to 2014 (353). Globally, 25% of pregnancies ended in abortion from
2010 to 2014. In the developed world, the percent of pregnancies ending in
abortion declined by 11 points from 39% to 28%, whereas in the developing
world, it increased significantly by 3 points from 21% to 24% (353). It is
estimated that 25 million, or nearly half of all abortions are “unsafe” where either
the persons terminating the pregnancy lack the necessary skills or the
environment in which it is performed does not conform to minimal medical
standards, or both (354).
As shown in Figure 14-16, there are large discrepancies in the rate of safe
abortions compared with unsafe abortions worldwide. In the developed countries
where there is access to legal abortion, unsafe abortions are rare. In developing
countries, where abortion is often highly restricted or completely illegal, they are
very common. The highest proportion of unsafe abortions are found in Middle
and Western Africa, where mortality rates from abortion are highest. The
subregions with the highest proportions of safe abortions (northern Europe and
northern America) include countries with less restrictive laws on abortion, high
contraceptive use, high economic development, high levels of gender equality,
and well-developed health infrastructures (354). [14] Where abortion is legal, it
is generally safe; where it is illegal, complications are common. Forty-seven
thousand women die every year from complications of unsafe abortion (355).
Societies cannot prevent abortion, but they can determine whether it will be
illegal and dangerous or legal and safe. [14] Death from illegal abortion was once
common in the United States. In the 1940s, more than 1,000 women died each
year of complications from abortion (356). In 1972, 24 women died of
complications of legal abortion and 39 died from known illegal abortions. In
2012, the most recent year for which complete data are available, there were four
deaths from legally induced abortion and no deaths from illegal abortion (abortion
induced by a nonprofessional) in the entire United States (6). The American
Medical Association’s Council on Scientific Affairs reviewed the impact of legal
abortion and attributes the decline in deaths during this century to the introduction
of antibiotics to treat sepsis; the widespread use of effective contraception
844beginning in the 1960s, which reduced the number of unwanted pregnancies; and
the shift from illegal to legal abortion (357).
The number of abortions reported each year in the United States—926,000 in
2014—has been declining since the peak level of 1.61 million in 1990 (5). In
2014, the national abortion ratio was 18.8 abortions for every 100 pregnancies,
and the national abortion rate was 14.6 per 1,000 women aged 15 to 44 years (5).
While abortion rates for all racial and ethnic groups have declined, they are
significantly higher for non-Hispanic black women. Non-Hispanic white women
have 37.5% of all abortions, non-Hispanic black women have 35.6%, and
Hispanic women 19%. Most women who obtain abortions are unmarried, 85.2%
in 2013 (6). The use of abortion varies markedly with age. In 2013, 11.3% of
women obtaining abortions were between 15 and 19 years of age, and 44.7%
were 24 years of age or younger. In 2013, the abortion ratio for women younger
than 15 years of age was 789 per 1,000 live births (Fig. 14-2) (6). The lowest
abortion ratio, 121 per 1,000 live births, is for women aged 30 to 34 years.
845FIGURE 14-16 Distribution of abortion safety categories worldwide and by region. Bars
and dots show the point estimates of the proportion of abortions in each category and
horizontal lines are 90% uncertainty intervals. (From Ganatra B, Gerdts C, Rossier C, et
al. Global, regional, and subregional classification of abortions by safety, 2010–14:
estimates from a Bayesian hierarchical model. Lancet 2017;390[10110]:2372–2381.)
Regardless of personal feelings about the ethics of interrupting pregnancy,
health professionals have a duty to know the medical facts about abortion and to
share them with their patients (358). Providers are not required to perform
abortions against their ethical principles, but they have a duty to help patients
assess pregnancy risks and to make appropriate referrals.
846Safety
[15] The overall annual risk of death with legal abortion decreased markedly,
from 4.1 per 100,000 in 1972 to 1.8 in 1976, and remained less than 1 per
100,000 since 1987. Today, legal abortion remains an extremely safe procedure,
with a mortality rate of 0.7 per 100,000 procedures (359). [15] Risk increases
exponentially with gestational age. Pregnancy-associated mortality rate with
aspiration procedures was 0.3 per 100,000 at or before 8 weeks and increased to
6.7 per 100,000 at 18 weeks or greater (359). Nevertheless, in comparison to a
maternal mortality rate of 8.8 deaths per 100,000 live births, abortion by dilation
and evacuation (D&E) beyond 18 weeks’ gestation is safer than continuing
pregnancy (360). It was estimated that 87% of the legal abortion deaths occurring
after 8 weeks would have been prevented had the woman been able get abortion
services by 8 weeks (361).
For individual women with high-risk conditions (e.g., cyanotic heart disease),
even late abortion is a safer alternative to birth. Because of the availability of lowcost, out-of-hospital, first-trimester abortion, 88% of legal abortions are
performed during the first trimester (before 13 weeks of amenorrhea), when
abortion is the safest.
Techniques for First-Trimester Abortion
Vacuum Curettage
Most first-trimester abortions are performed by vacuum curettage. Most are
performed with local anesthesia with or without moderate sedation, and usually
on an outpatient basis in a freestanding specialty clinic or doctor’s office (362).
Cervical dilation is accomplished with metal or plastic dilators, or by osmotic
cervical dilators or misoprostol 400 μg, given vaginally or by the buccal route 3 to
4 hours before the procedure (363). A plastic vacuum cannula of 5- to 12-mm
diameter is used with a manual vacuum source or an electric vacuum pump.
Manual vacuum provided by a modified 50-mL syringe is as effective as the
electric pump through 10 menstrual weeks (364). The Society of Family Planning
recommends a short course of antibiotics preoperatively to lower the risk of
infection following surgical abortion (365). A single dose of doxycycline is a safe
and effective prophylactic antibiotic and can be taken with dinner the night
preceding a procedure. A large retrospective study of women’s health care visits
within 6 weeks after an abortion using California Medicaid data estimated
abortion-related complication rates (366). Complications following first-trimester
aspiration procedures are presented in Table 14-5. Major complications, defined
as requiring hospital admission, surgery or blood transfusion, occurred in 0.16%
847of first-trimester aspiration abortions. The most common complications were
other or undetermined diagnoses, most of which led to repeat abortions. More
extensive descriptions of the management of complications are published
elsewhere (367).
Table 14-5 Distribution of Abortion-Related Complication Diagnoses Among 34,755
First-Trimester Aspiration Procedures
Complication Diagnosis
Incomplete abortion 116 (0.33)
Failed abortion 14 (0.04)
Hemorrhage 44 (0.13)
Infection 94 (0.27)
Uterine perforation 2 (0.01)
Anesthesia-related 2 (0.01)
Other or undetermineda 166 (0.48)
Total 438 (1.26)
aFor major complications, this diagnosis includes undetermined diagnoses that required
blood transfusions and surgery. For minor complications, the majority of this diagnosis
consisted of cases treated with repeat abortion, but the exact diagnosis could not be
determined. This category also includes diagnoses such as nonanesthesia-related allergic
reactions and seizures.
Data are n (%).
Adapted from Upadhyay UD, Desai S, Zlidar V, et al. Incidence of emergency
department visits and complications after abortion. Obstet Gynecol 2015;125(1):175–183.
Medical Abortion in the First Trimester
Mifepristone (RU486), an analog of the progestin norethindrone, has a strong
affinity for the progesterone receptor but acts as an antagonist, blocking the effect
of natural progesterone. Given alone, the drug was moderately effective in
causing abortion of early pregnancy; the combination of mifepristone with a low
dose of prostaglandin proved very effective, producing complete abortion in 96%
to 99% of cases (368). In 2016, the FDA approved updated labeling for
mifepristone. Changes included expansion of its use to 70 days from the start of
848the last menstrual period and a decrease in dose from 600 to 200 mg.
Furthermore, misoprostol dose was increased from 400 mcg orally to 800 mcg
buccally and home administration was allowed. Lastly, a posttreatment
examination visit to the clinic was no longer required. These label changes were
adopted because 200 mg of mifepristone was as effective as 600 mg, 800-mcg
misoprostol by vaginal or buccal routes provide higher efficacy than 400-mcg
oral dose, misoprostol can be taken at 24, 48, or 72 hours after mifepristone with
equal efficacy, and women may safely self-administer misoprostol at home (369–
373). Misoprostol can be taken by buccal or vaginal routes with similar blood
levels and similar areas under the plasma concentration curve (AUC) (374,375).
After case reports of death from Clostridium sordellii, a large cohort study was
published by Planned Parenthood describing the use of prophylactic doxycycline
100 mg twice a day for 1 week, and buccal rather than vaginal administration of
misoprostol (376). No additional cases of C. sordellii have been recently reported.
While individuals practitioners may decide to use antibiotics, the Society of
Family Planning does not believe universal antibiotics are required for all women
having a medical abortion.
Contraindications to medical abortion with mifepristone/ misoprostol include
ectopic pregnancy; an IUD in place (remove IUD first); chronic adrenal failure;
concurrent long-term corticosteroid therapy; history of allergy to mifepristone,
misoprostol, or other prostaglandins; hemorrhagic disorder; and inherited
porphyrias (377).
Methotrexate/Misoprostol and Misoprostol Alone
Alternatives to medical abortion when mifepristone is not available include
regimens with methotrexate/misoprostol and misoprostol alone. The antifolate
methotrexate provides another medical approach to pregnancy termination, but
takes longer than the technique using mifepristone/misoprostol (378). Medical
abortion can be induced with misoprostol alone, although it is less effective than
the mifepristone/misoprostol combination. Vaginal misoprostol, 800 μg, repeated
in 24 hours if fetal expulsion has not occurred, produces a complete abortion in
91% of pregnancies up to 56 days of amenorrhea (379).
Complications of Medical Abortion
Heavy or prolonged bleeding is the principal complication, with up to 8% of
women experiencing some bleeding for as long as 30 days. Need for surgical
curettage is predicted by the gestational age when the mifepristone is
administered. Two percent of women treated at 49 days or less, 3% of those
treated at 50 to 56 days, and 5% of those treated at 57 to 63 days needed curettage
for bleeding or failed abortion in a large study with 200 mg of mifepristone and
849800 μg of vaginal misoprostol (380). Late bleeding, at 3 to 5 weeks after
expulsion of the pregnancy, accounted for more than half of the curettages. Under
the updated protocol, serious complications requiring hospitalization for infection
treatment or transfusion occur in fewer than 0.4% of patients (381). The updated
regimen has been shown to cause fewer gastrointestinal side effects, such as
nausea, vomiting, and diarrhea (382).
Medication Abortion and Telemedicine
With the 2016 mifepristone FDA label update excluding the requirement of inclinic follow-up, telemedicine can facilitate the provision of medication abortions.
Removing barriers to clinic access for rural women or mitigating the need for
travel could reduce delays in receiving care and enable women to obtain an
abortion at the earliest stages of pregnancy when it is safest (383). In one study,
there were no differences in adverse events between in-person and telemedicine
patients seeking medication abortion, and telemedicine patients were more likely
to recommend the service to a friend (384).
Second-Trimester Abortion
Abortions performed after 13 weeks include those done for fetal anomalies,
medical illness, or delays resulting from pregnancy denial or difficulties making
arrangements. Young maternal age is the single greatest factor determining the
need for late abortion (6).
Dilation and Evacuation
D&E is the most commonly used method of midtrimester abortion in the United
States. Prior to surgery, it is essential to prepare the cervix (to make it soft and
pliable). There are a number of approaches to cervical ripening in this setting:
1. The cervix can be prepared by insertion of hygroscopic dilators, stems of the
seaweed Laminaria japonica (laminaria), or Dilapan-S hydrophilic polymer
rods. Placed in the cervical canal as small rods, these devices take up water
from the cervix and swell, producing mechanical dilation, and induce
endogenous prostaglandin synthesis, which aids in cervical softening. When
the dilators are removed the following day, sufficient cervical dilation is
accomplished to allow insertion of specialized forceps and a large-bore
vacuum cannula to extract the fetus and placenta (385,386). Ultrasound
guidance during the procedure is helpful (387). At the end of the midtrimester,
procedures that combine serial insertion of two or more sets of laminaria or
Dilapan-S for increased cervical dilation with a feticidal injection, or a
combination of dilators with misoprostol to induce labor, followed by assisted
850expulsion of the fetus are possible (388).
2. Misoprostol can also be used for cervical preparation prior to midtrimester
abortion. Osmotic dilator placement more effectively dilates and prepares the
cervix before D&E than misoprostol alone (389,390). However, misoprostol in
lieu of osmotic dilators has not been shown to increase the rate of serious
complications. A large case series of D&Es between 17 and 23 weeks
performed by highly experienced providers in women who received multidose
misoprostol regimen as an alternative to overnight dilation reported a major
complication rate less than 2% (391). However, the average dose of
misoprostol used was 1,200 mcg.
3. Mifepristone is another option. A recent study comparing mifepristone as an
adjunct or replacement for osmotic dilators in women undergoing D&E
between 19 and 23 weeks found that, while median total procedure time was
slightly longer for the mifepristone group compared to women who received
mifepristone and osmotic dilators or only osmotic dilators, there were no
differences in complications between the three groups (392). While some
providers insert osmotic dilators sequentially over the course of 2 days, an
RCT of D&Es from 19 to 23 weeks showed that there were no differences in
procedure times, initial cervical dilation, ease of procedure, or complications
in women who received overnight synthetic osmotic dilators with mifepristone
and misoprostol compared to women who received 2 days of dilators and
misoprostol (393).
Intact D&E is another modification useful for procedures at the end of the
midtrimester. After wide cervical dilation is achieved with serial placement of
cervical dilators, the membranes are ruptured and an assisted breech delivery is
performed, with decompression of the after-coming fetal head to allow delivery of
the fetus intact (394). In response to the federal abortion ban of 2003, an
increasing number of providers are using feticidal agents prior to late secondtrimester terminations (395). Intra-amniotic or intrafetal digoxin and intracardiac
potassium chloride are the two most common agents used for this purpose. Both
are efficacious with little maternal adverse effects (396,397). The clinical utility
of these agents is unproven. The only randomized controlled study looking at
clinical outcomes found no change in procedure time or blood loss with the use of
digoxin (398). Varying doses of digoxin were reported. In one study, 1.5-mg
intra-amniotic digoxin was always successful in inducing fetal demise within 24
hours (399).
Labor-Induction Methods
In Europe and the United Kingdom, labor induction is much more common than
851D&E for midtrimester abortion (400). Induction abortion with hypertonic saline
or urea was widely employed for labor induction abortion in the 1970s. These
were supplanted by the use of synthetic prostaglandins, and by regimens that
combine mifepristone and misoprostol.
Prostaglandins
Prostaglandins of the E and F series can cause uterine contraction at any stage of
gestation. The 15 methyl analogs of prostaglandin F2α (carboprost) and
prostaglandin E2 (dinoprostone) are highly effective for midtrimester abortion but
frequently produce side effects of vomiting, diarrhea, and with dinoprostone,
fever. Misoprostol, a 15 methyl analog of PGE1, is much less expensive than
other prostaglandins, stable at room temperature, and at doses effective for
abortion, produces fewer side effects (401). Transient fetal survival is not
infrequent after prostaglandin inductions. In the United States, it is common to
induce fetal demise before induction with regimens similar to those used in late
second-trimester D&E: intra-amniotic or intrafetal digoxin, 1 to 1.5 mg, or fetal
intracardiac potassium chloride (3 mL of a 2-mmol solution).
Midtrimester Mifepristone/Misoprostol
Mifepristone pretreatment markedly increases the abortifacient efficacy of
gemeprost and misoprostol. Mifepristone, 200 mg, is just as effective for this
purpose as 600 mg (402). A common protocol was developed using mifepristone
and misoprostol that is now recommended by the Royal College of Obstetricians
and Gynecologists (RCOG) and the WHO (403,404). Most women are cared for
as hospital day-patients without need for overnight admission, a marked
improvement over the labor induction methods of the past that often required 2 to
3 days of hospitalization. In the United States, ACOG recommends administering
mifepristone, 200 mg orally, followed in 24 to 48 hours by either 800-mcg
misoprostol vaginally followed by 400 mcg vaginally every 3 hours, or 400-mcg
misoprostol buccally every 3 hours (405). Earlier studies evaluated intervals of 24
to 48 hours between dosing mifepristone and misoprostol. A systematic review
including studies of 24- to 48-hour intervals calculated weighted median
induction times of 7.6 hours for 1-day interval and 6.8 hours for 2-day interval
(406). When comparing mifepristone–misoprostol intervals of 36 to 48 hours to
intervals of 24 hours or less, shorter intervals on average had only minimally
longer induction times (1 to 2 hours) but consistently much shorter overall total
procedure times (mifepristone to pregnancy expulsion).
Combination of Induction and Assisted Delivery
Hern developed a procedure that combines a feticidal injection of digoxin with
852serial insertion of multiple laminaria tents over 2 to 3 days, followed by
amniotomy, placement of misoprostol in the lower uterine segment, and
intravenous oxytocin to induce labor, and then an assisted delivery (407). The
procedure was successful in a large case series at 18 to 34 weeks with very few
complications.
Complications of Second-Trimester Abortion
Surgical Abortion Complications
Complications of second-trimester surgical abortion are uncommon, but risk
increases with gestational age. Complications and their frequency encountered in
almost 3,000 midtrimester abortions performed by laminaria followed by D&E on
a referral service are listed in Table 14-6. The gestational ages were 14 to 27
weeks and mean gestational age was 20.2 weeks. The most common complication
was a cervical laceration that required suturing. A major complication, defined as
one necessitating transfusion, disseminated intravascular coagulation,
reoperations with uterine artery embolization, laparoscopy, or laparotomy, was
encountered in 1.3% of patients. History of two or more cesareans, gestational
period of 20 weeks or more, and insufficient initial cervical dilation by laminaria
were independent risk factors for a major complication in a multivariate analysis
(408). The rates of complication in Table 14-6 cannot be directly compared to the
rates of complications with labor-induction abortion described below because half
of the D&E group were 20 weeks or more gestation, while only a few of the
induction patients were more than 20 weeks.
Table 14-6 Complications of 2,935 Midtrimester Dilation and Evacuation Abortion
and Intervention Rates on a Referral Service
Number
(%)
95% Confidence Interval
(%)
Complication
Cervical laceration 99 (3.3) 2.7–4.0
Atony 78 (2.6) 2.1–3.3
Hemorrhage 30 (1.0) 0.6–1.4
Other 15 (0.5) 0.3–0.8
853Disseminated intravascular
coagulation
7 (0.2) 0.1–0.4
Retained products 6 (0.2) 0.04–0.4
Perforation 6 (0.2) 0.04–0.4
Treatment of Complications
Reaspiration 46 (1.5) 1.1–2.0
Hospitalization 42 (1.4) 1.0–1.8
Transfusion 30 (1.0) 0.7–1.4
Uterine artery embolization 21 (0.7) 0.4–1.0
Laparoscopy or laparotomy 13 (0.4) 0.2–0.7
From Frick AC, Drey EA, Diedrich JT, et al. Effect of prior cesarean delivery on risk of
second-trimester surgical abortion complications. Obstet Gynecol 2010;115:762; Table 2,
with permission.
Induction Abortion Complications
The labor-induction methods share common hazards: failure of the primary
procedure to produce abortion within a reasonable time, incomplete abortion,
retained placenta, hemorrhage, infection, and embolic phenomena. With modern
protocols, these are rare. In a series of 1,002 women treated with mifepristone and
misoprostol at 13 to 21 weeks, 0.7% required a blood transfusion, 0.3% required
ergot treatment for hemorrhage, and one required laparotomy for otherwise
uncontrollable hemorrhage; 2.6% of patients received antibiotics for presumed
pelvic infection after hospital discharge and 7.9% complained of prolonged
bleeding (409). Uterine rupture has been reported in women with previous
cesarean delivery treated with misoprostol in the midtrimester. In a case series of
101 women with one or more previous cesarean births and three smaller case
series totaling 87 patients, no ruptures occurred (410). In another retrospective
study of women 14 to 26 weeks undergoing induction, there were 3 ruptures, all
in women who had 2 or more cesarean sections. These women had received 200
mcg vaginal misoprostol every 4 hours. The uterine rupture rate in these women
alone was 11.5% (411). The Society of Family Planning recommends
consideration of a 200 mcg or lower dose for women with a prior uterine scar, but
concludes that data are insufficient to advise a change in dosing interval (412).
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