Contraception

C H A P T E R

15 Contraception Donna Shoupe and Daniel R. Mishell Jr. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

CONTRACEPTIVE USE IN THE UNITED STATES Data accumulated from national surveys conducted from 1982 through 2006 2008 provide useful information about the contraceptive choices of American women (Table 15.1).1 It is encouraging to observe that over this period of time, the percentage of sexually active women, 15 44 years old, in the US who reported ever use of a contraceptive method rose from 94.8% to 99.1%. Of concern, however, is the fact that in the 2006 2008 survey, 10% of sexually active women at risk of pregnancy reported that they were not currently using any contraceptive method (Table 15.2).1 Also of concern is that 22.8% of the sexually active contraceptive users at risk of pregnancy in this survey had selected methods with high typical failure rates. Added together these 2 groups account for nearly one-third of the sexually active women at risk of pregnancy in the US. These groups also contribute heavily to the unacceptably high unintended pregnancy rate in the US which now stands at 50% unintended vs. 50% intended pregnancies. Data published in 2006 indicate that the unintended pregnancy rate is 98 per 1,000 black women, 78 per 1,000 Hispanic women, and 35 per 1,000 white women per year.2 The most popular method of contraception in the US during 2006 2008 was the oral contraceptive pill (OC, 10.7 million women). OC users account for 28% of contraceptive users, a number that has been relatively steady since 1982 (Table 15.3). The second most popular method was female sterilization at 27% (10.3 million women), a proportion that has also remained stable since 1995. One change in contraceptive use over the last 20 to 30 years has been a dramatic drop in the use of the diaphragm; from 8% in 1982 down to nearly zero. The use of intrauterine devices (IUD) is

Women and Health. DOI: http://dx.doi.org/10.1016/B978-0-12-384978-6.00015-7

again increasing, and has risen from 2% in 2002 to a current 5.5% (2.1 million women). The use of condoms has declined slightly from a high of 20.4% in 1995 to 16.1% in 2006 8.1 Some other trends in contraceptive use are:1 • Women with a college education are more likely to choose OCs (35% in college educated compared to 10% in the lowest education group) and less likely to choose female sterilization. • IUD use has increased from 2% to 6 7% among the top 2 education and income groups. • Female sterilization was the leading method in women ages 40 44 years, currently or formerly married, and with 3 or more children.

Contraceptive Effectiveness Extended use effectiveness reflects the effectiveness of a method over extended periods of time, using actuarial statistical techniques including life table analysis. Most contraceptive studies are performed in controlled clinical trials where frequent contact with supportive clinic personnel may result in lower failure rates and higher continuation rates than may actually occur in field use. Contraceptive failure occurs more often in couples seeking to delay a wanted birth compared to those seeking to prevent any more births. The woman’s age has a strong negative correlation with failure, as does socioeconomic status and level of education. Failure rates are lower among married women than unmarried women, and are usually higher during the first year of use than in subsequent years. Table 15.4 lists typical use and perfect use failure rates within the first year of use for various contraceptive methods.3 The actual use failure rate for 5 years of use for certain methods of long acting contraceptives has been

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15. CONTRACEPTION

TABLE 15.1 Number of Women Aged 15 44 Years Who Have Ever Had Sexual Intercourse and Percentage Who Have Ever Used the Specified Contraceptive Method: US, 1982, 1995, 2002, and 2006 20081 Method

1982

1995

2002

2006 2008

Number in thousands All women

46,684

53,800

54,190

53,240

PERCENT (STANDARD ERROR) WHO HAVE EVER USED SPECIFIED METHOD Any method

94.8 (0.4)

98.2 (0.2)

98.2 (0.2)

99.1 (0.2)

Female sterilization

22.3 (0.8)

23.4 (0.5)

20.7 (0.7)

19.9 (1.1)

Male sterilization

10.1 (0.6)

14.6 (0.4)

13.0 (0.7)

13.4 (0.8)

Pill

76.3 (0.8)

82.2 (0.5)

82.3 (0.6)

82.3 (1.1)

2.1 (0.2)

2.1 (0.2)

1.4 (0.3)

0.9 (0.1)

1.9 (0.5)

Norplantt or Implanont implant 1-month injectable (Lunellet)

–

–

3-month injectable (Depo-Proverat)

–

4.5 (0.2)

16.8 (0.8)

22.2 (1.1)

Emergency contraception

–

0.8 (0.1)

4.2 (0.3)

9.7 (0.7)

Contraceptive patch

–

–

0.9 (0.1)

10.0 (0.7)

Contraceptive ring

–

–

Todayt sponge

–

12.0 (0.4)

7.3 (0.4)

4.7 (0.5)

Intrauterine device (IUD)

18.4 (0.8)

10.0 (0.4)

5.8 (0.4)

7.4 (0.7)

Diaphragm

17.1 (0.8)

15.2 (0.5)

8.5 (0.5)

3.1 (0.4)

Condom

51.8 (1.0)

82.0 (0.5)

89.7 (0.6)

93.0 (0.6)

Female condom

–

1.2 (0.1)

1.9 (0.2)

1.9 (0.3)

Periodic abstinence — calendar rhythm

17.0 (0.8)

24.3 (0.5)

16.2 (0.6)

19.4 (1.1)

2.3 (0.3)

4.2 (0.3)

3.5 (0.3)

4.6 (0.5)

Withdrawal

24.5 (0.8)

40.6 (0.6)

56.1 (1.0)

58.8 (1.4)

Foam alone

24.9 (0.8)

18.3 (0.5)

12.1 (0.4)

6.6 (0.5)

Jelly or cream alone

5.8 (0.4)

9.1 (0.3)

7.3 (0.4)

4.7 (0.6)

Suppository or insert

9.7 (0.6)

10.6 (0.3)

7.5 (0.5)

3.4 (0.4)

9.3 (0.6)

0.3 (0.1)

1.0 (0.1)

0.8 (0.2)

Periodic abstinence — natural family planning

1

Other methods

reported.4 6 The cumulative failure rate for 5 years use of Norplants in clinical trials is 1.1%.4 In a large World Health Organization (WHO) study, the cumulative failure rates of the Copper T 380 IUD were 1.0, 1.4, and 1.6% after 3, 5, and 7 years of use.5 The percentages are comparable to those for tubal sterilization, which are reported as 1.3% after 5 years and 1.9% 10 years after the procedure.6

–

6.3 (0.6)

failures and side effects.7 Due to the high costs of unintended pregnancies, use of any of the 15 methods studied was less costly than use of no method. The most cost effective methods were the IUD, vasectomy, and progestin implant or injection. The more a method is used correctly, the more cost effective it becomes (Table 15.1).

CONTRACEPTIVE COST

CONTRACEPTIVE USE: MEDICAL ELIGIBILITY GUIDELINES

All contraceptive methods reduce health care costs. An economic model to compare costs projected the 5-year cost of using each method by adding the direct cost of each method with costs associated with method

There are now evidence-based guidelines regarding appropriate selection and use of various contraceptive options. WHO evidence-based guidelines on contraceptive use (WHO-MEC)8 are used around the world and

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CONTRACEPTIVE USE: MEDICAL ELIGIBILITY GUIDELINES

TABLE 15.2 Number of Women Aged 15 44 Years, Number at Risk of Unintended Pregnancy, and Percentage of Women Currently Using a Method of Contraception, by Selected Characteristics: US, 2006 2008 Women at Risk of Unintended Pregnancy1

All Women Characteristic

Percent Number Currently in Using a Thousands Method

(Standard Error)

Number in Thousands

Currently Using a Method

(Standard Error)

Not Currently Using a Method

(Standard Error)

61,864

61.8

(1.21)

42,756

89.4

(0.76)

10.6

(0.76)

15 19 years

10,431

28.2

(1.91)

3,618

81.3

(2.18)

18.7

(2.18)

20 24 years

10,140

54.7

(2.81)

6,475

85.7

(1.93)

14.3

(1.93)

25 29 years

10,250

64.2

(1.85)

7,468

88.2

(1.65)

11.9

(1.65)

30 34 years

9,587

70.3

(2.32)

7,245

93.0

(1.07)

7.0

(1.07)

35 39 years

10,475

75.0

(2.23)

8,701

90.3

(1.63)

9.7

(1.63)

40 44 years

10,982

77.8

(1.75)

9,251

92.4

(1.45)

7.6

(1.45)

All women2 AGE

MARITAL OR COHABITING STATUS Currently married

27,006

78.6

(1.25)

22,730

93.4

(0.76)

6.6

(0.76)

Currently cohabiting

6,821

71.2

(2.07)

5,329

91.1

(1.55)

8.9

(1.55)

Formerly married, not cohabiting

5,190

60.6

(2.80)

3,730

84.3

(3.40)

15.7

(3.40)

Never married, not cohabiting

22,847

39.3

(2.31)

10,967

81.9

(1.71)

18.1

(1.71)

0 births

26,882

44.3

(1.95)

13,860

86.0

(1.36)

14.0

(1.36)

1 birth

10,350

59.5

(2.26)

7,305

84.4

(2.14)

15.6

(2.14)

2 births

12,843

81.7

(1.20)

11,287

92.9

(0.99)

7.1

(0.99)

11,789

81.8

(1.79)

10,305

93.6

(1.26)

6.4

(1.26)

No high school diploma or GED

6,210

67.1

(2.44)

4,731

89.1

(1.89)

11.9

(1.89)

High school diploma or GED

11,793

73.5

(1.80)

9,557

90.7

(1.36)

9.3

(1.36)

Some college, no bachelor’s degree 13,537

68.9

(2.21)

10,260

90.9

(1.50)

9.1

(1.50)

Bachelor’s degree or higher

15,543

70.5

(1.80)

11,942

91.8

(1.13)

8.2

(1.13)

0% 149%

16,109

61.7

(1.65)

11,331

87.7

(1.56)

12.3

(1.56)

0% 99%

10,407

59.5

(2.26)

7,084

87.4

(1.78)

12.6

(1.78)

150% 299%

15,360

70.3

(2.21)

12,035

89.7

(1.27)

10.3

(1.27)

300% or more

19,965

72.8

(1.51)

15,773

92.1

(0.88)

7.9

(0.88)

PARITY

3 or more births EDUCATION

3

POVERTY LEVEL INCOME

4

INTENT TO HAVE MORE CHILDREN Intends more

30,148

47.3

(1.68)

16,697

85.4

(1.39)

14.6

(1.39)

Intends no more

30,866

75.8

(1.08)

25,462

91.8

(0.83)

8.2

(0.83)

10,377

58.5

(1.90)

6,669

91.1

(1.24)

9.0

(1.24)

White, single race

37,660

64.7

(1.59)

26,889

90.6

(0.92)

9.4

(0.92)

Black, single race

8,452

54.5

(2.54)

5,504

83.7

(1.86)

16.3

(1.86)

RACE AND HISPANIC ORIGIN Hispanic NON-HISPANIC

(Continued)

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15. CONTRACEPTION

TABLE 15.2

(Continued) Women at Risk of Unintended Pregnancy1

All Women Characteristic

Percent Number Currently in Using a Thousands Method

(Standard Error)

Number in Thousands

Currently Using a Method

(Standard Error)

Not Currently Using a Method

(Standard Error)

All other single race and multiple race

5,375

59.2

(3.00)

3,694

86.2

(2.39)

13.8

(2.39)

Asian, single race

2,493

63.9

(4.67)

1,739

91.5

(3.85)

8.5

(3.85)

TABLE 15.3 Number of Women Aged 15 44 Years Currently Using Contraception, and Percent Distribution By Current Contraceptive Method: US, 2006 2008

contraceptive method is assigned a number between 1 and 4 depending on the safety of using it with that condition (Table 15.5).

Contraceptive Method Choice Method use Among US Women Who Practice Contraception, 2006 2008

CONTRACEPTIVE METHODS

Method

No. of Users (in 000s)

% of Users

Spermicides: Foams, Creams, Suppositories, Films, Jelly, Tablets

Pill

10,700

28.0

Tubal sterilization

10,400

27.1

Male condom

6,200

16.1

Vasectomy

3,800

9.9

IUD

2,100

5.5

Withdrawal

2,000

5.2

3-month injectable (Depo-Provera)

1,200

3.2

Vaginal ring (NuvaRing)

900

2.4

Implant (Implanon or Norplant), 1-month injectable (Lunelle) or patch (Evra)

400

1.1

Periodic abstinence (calendar)

300

0.9

Other

200

0.4

Periodic abstinence (natural family planning)

100

0.2

Diaphragm

†

†

TOTAL

38,214

100.0

All spermicidal products contain a surfactant, usually nonoxynol-9, which immobilizes or kills sperm on contact. The typical use failure rate is 29%, although consistent and proper use of these products will reduce that rate substantially. The failure rate of spermicides decreases with increasing age of the woman, and is lowest among highly motivated users. A few studies linked the use of spermicides at the time of conception to an increased risk of congenital malformations, but several well-performed studies showed no increased risk of either congenital malformations10,11 or karyotypic abnormalities12 in pregnancies of women who conceived while using spermicides. Spermicides are clear, unscented, unflavored, nonstaining, and lubricative. The suppositories, tablets, and films need to be in place for 10 15 minutes prior to sexual activity. Although spermicides are toxic to viruses and bacteria, they are not considered to offer protection against sexually transmitted diseases (STD). Spermicides may cause genital irritation and may increase the risk of human immunodeficiency virus (HIV) infection due to damage and openings in the genital tissue. For this reason, WHO does not recommend the use of spermicides for persons outside monogamous relationships. The WHO-MEC classifies HIV and AIDS as Category 3 for spermicides (Table 15.5).8





Includes emergency contraception, female condom or vaginal pouch, foam, cervical cap, Today sponge, suppository or insert, jelly or cream (without diaphragm) and other methods. † Figure does not meet standards of reliability or precision.

were adapted for use in the US by the Centers for Disease Control and Prevention (US-MEC).9 The vast majority of the US-MEC guidelines are identical to the WHO-MEC guidelines, although some changes were made to more closely address the issues and contraceptive options used in the US. The WHOMEC addresses 18 contraceptive methods and over 160 medical conditions. For each medical condition, each

Barrier Techniques Male Condom The condom is one of the oldest and most widely used forms of contraception, and was used as early as

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CONTRACEPTIVE METHODS

TABLE 15.4 Percentage of Women Experiencing An Unintended Pregnancy During the First Year of Typical and Perfect Use of Contraception

TABLE 15.5 WHO and US Medical Eligibility Criteria for contraceptive Use Classifications Medical Eligibility Criteria for Contraceptive use, 20108,10

First Year Perfect and Typical Contraceptive Failure Rates

Classification Definition

Method

Perfect Use

Typical Use

1

No restriction for use the method

Combination pill

0.3

8.7

2

Tubal sterilization

0.5

0.7

The advantages of using the method generally outweigh the theoretical or proven risks

Male condom

2.0

17.4

3

The theoretical or proven risks generally outweigh the advantages of using the method

Vasectomy

0.1

0.2

4

3-month injectable

0.3

6.7

An unacceptable health risk if the contraceptive method is used

Withdrawal

4.0

18.4

Cu-IUD (Paragard)

0.6

1.0

LVG-IUS (Mirena)

0.1

0.1

Periodic abstinence

25.3

Calendar

9.0

Ovulation method

3.0

Symptothermal

2.0

Post-ovulation

1.0

1-month injectable

0.05

3.0

Implant

0.05

1.0

Patch

0.3

8.0

Diaphragm

6.0

16.0

Sponge Women

had a child

20.0

32.0

Sponge Women

never had a child

9.0

16.0

Cervical Cap

women had a child

26.0

32.0

Cervical Cap

never had a child

9.0

16.0

Female condom

5.0

27.0

Spermicides

18.0

29.0

No method

85.0

85.0

Adapted from: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Nelson AL, Cates W, Stewart FH, Kowal D. Contraceptive Technology: Nineteenth Revised Edition. New York NY: Ardent Media, 2007 and Kost K, et al., Estimates of contraceptive failure from the 2002 National Survey of Family Growth, Contraception, 2007, 77(1):10 21 Hatcher RA et al., eds., Contraceptive technology, 18th ed., New York: Ardent Media, 2004, Table 15 2. Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth, Family Planning Perspectives, 1999, 31(2):56 63; Hatcher RA et al., eds., Contraceptive technology, 18th ed., New York: Ardent Media, 2004.

the 1500s for protection against the spread of venereal infection. The United Nations Population Fund (UNFPA; www.unfpa.org) estimated that 10.4 billion male condoms were used worldwide in 2005. Until recently, most condoms were made from latex, but now the market offers condoms made from materials such as polyurethane, polyisoprene, and lamb intestines. Polyurethane is superior to latex in several ways

as it is not sensitive to temperature, has fewer storage requirements, has a longer shelf-life, can be used with oil-based lubricants, and is less allergenic than latex. However, since polyurethane condoms are less elastic, they have a greater chance of slippage. Male condoms come in a great variety of shapes, sizes, textures, and colors. Because of vast improvements in quality control, product defects of present-day condoms that could lead to failure are rare. First-year failure rates range between 0.4 and 6% in motivated populations, and between 8 and 31.9% in young, inexperienced, or inconsistent users.3,13,14 The male condom (made of latex or polyurethane) is currently considered to be the most effective method of contraception to prevent transmission of STDs in both men15 and women.16 Importantly, epidemiological evidence reports that use of condoms reduces the risk of HIV transmission.17,18 While not 100% effective, the condom also reduces the risk of transmission of genital herpes, chlamydia, gonorrhea, syphilis, and human papilloma virus,19 and reduces the incidence of pelvic inflammatory disease (PID).20 In 1 study, after 10 or more years of condom or diaphragm use, the relative risk (RR) of women developing severe cervical dysplasia was statistically significantly reduced (RR 5 0.2).21 The WHO-MEC lists allergy to latex as a Category 3 classification (risks outweigh advantages) to use of a latex male condom.8 Female Condom A new female condom (FC2), made with nitrile instead of polyethylene, replaced the original female condom in 2007. The FC2 is a soft, thin sheath that comes in various sizes housing a flexible ring at each end. The closed end of the sheath with the smaller ring is placed inside the vagina while the larger ring, located at the open end of the sheath, holds the condom in place at the entrance of the vagina. There is no spermicide used, but the inside of the condom contains a silicone-based lubricant. These new nitrile condoms

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214

15. CONTRACEPTION

$5,730 $5,700

Unintended pregnancy

$6,000

Side effects Method

$4,872

$5,000

$4,102

Total costs

$4,000

$3,666 $3,450 $3,278

$3,000 $2,584 $2,424 $2,042 $1,784

$2,000

$1,290 $1,000

$850

$764 $540

$0 ap lc ca vi er C ge om on nd Sp co e al m es Fe id ic m er Sp ce gn ra en in ph st ia D ab c di rio al Pe aw dr n ith io W at ig ll ba om D Tu nd IU co -T e es tiv al

M

ep

ne

ro

te

c ra

nt

co

es

og

Pr

t

le ab

ct

je

an

pl

l ra

O

In

Im

D

IU

y m

to

r-T

pe

ec

s Va

op

C

FIGURE 15.1 Five-year costs associated with contraceptive methods in the managed payment model. From Trussell, J, Leveque, JA, Koenig JD. Am J Public Health 85(49):494; 19956

provide the same efficacy and safety as the original condom, but at a lower price. In comparison with the male condom, the female condom may be inserted any time prior to sexual activity and can be left in place longer. Similar to the male condom, FC2 does not allow viral or bacterial transmission, and it is hoped that the large outer ring may provide the female with even greater protection against STD transmission than the male condom. In a multicenter clinical trial, the pregnancy rate after 6 months of use was 12.4%, although it was only 2.6% in those with perfect use.22 At the end of 6 months, about one-third of the women had discontinued use of the method. Diaphragm A diaphragm must be fitted by a health professional. The largest size diaphragm that does not cause discomfort should be used. For the most effective protection, the diaphragm should be left in place for 8 hours after intercourse. If repeated intercourse occurs, additional spermicide (foam) should be used. The number of urinary tract infections is higher in women who use diaphragms than in nonusers, probably because pressure of the diaphragm on the urethra may

result in partial obstruction of urinary outflow.23 The diaphragm should not be left in place for more than 24 hours, as ulceration of the vaginal epithelium may occur with prolonged use. HIV infection, AIDS, and a history of toxic shock syndrome are Category 3 classifications for diaphragm use. High risk for acquiring AIDS is a Category 4 classification (unacceptable health risk) for diaphragm use.8 Cervical Cap The cervical cap (FemCap) is a cup-shaped silicone device used with a spermicide that is designed to fit over the cervix. It has been used for decades in Europe, especially in Britain, but was only approved for use in the US in 1988. The cervical cap is manufactured in 3 sizes and can be left in the vagina for up to 48 hours. Spermicide should always be placed inside the cap before use. The cap requires more training than the diaphragm, both for the provider in order to fit the cap correctly and for the user to place it correctly. In a large clinical trial, 1-year pregnancy rates were 17% for the cap and diaphragm.22 Because of concern about a possible adverse effect on cervical tissue, the cervical cap should be used only in women with normal cervical

III. SEXUAL AND REPRODUCTIVE HEALTH

CONTRACEPTIVE METHODS

cytology. History of toxic shock syndrome is a Category 3 classification for the cervical cap.8 Intravaginal Sponge There are 3 marketed intravaginal sponges, but only 1 of them, the Today sponge, is available in the US. The Today sponge contains 1,000 mg of nonoxynol-9 that must be activated by running the sponge under water until fully wet prior to use. Following activation of the spermicide, the sponge is inserted vaginally and placed directly over the cervix to serve as a barrier against sperm penetration. The sponge can be inserted up to 24 hours before intercourse, and it must be left in place for at least 6 hours after intercourse. It should not be worn for more than 30 hours at a time, and should be discarded after a single use. Sponges provide no protection from STDs. Side effects of the sponge include local irritation, yeast infection, and urinary tract infection. Improper use may result in toxic shock syndrome. The same WHO-MEC guidelines as for spermicides apply to use of the sponge.8

Periodic Abstinence/Natural Family Planning As defined by WHO, natural methods of family planning include methods for planning or avoiding pregnancy by observing the natural signs and symptoms of the fertile and infertile phases of the menstrual cycle. Many couples are motivated to use these methods in order to avoid technology, to allow them to take autonomous control of their fertility, and for religious or cultural reasons. There are several techniques used to identify the female fertile period. The oldest is the calendar rhythm method which relies on 3 assumptions: 1. Human ova are capable of being fertilized for only 10 24 hours after ovulation; 2. Spermatozoa retain their fertilizing ability for only 48 hours; and 3. Ovulation occurs 12 16 days prior to the onset of the next menses. The first day of the fertile period is established by subtracting 18 20 days from the length of the shortest cycle, while the last day of the fertile phase is determined by subtracting 11 days from the longest cycle. This method often results in long periods of abstinence. In the temperature method, couples must refrain from intercourse from the onset of the menstrual cycle until the morning of the third day of a sustained elevated basal body temperature. In the cervical-mucus method, the first fertile day of the cycle is the first day when either the sensation of moistness or mucus occurs. The last fertile day is the fourth day after peak symptoms.

215

Changes in the cervical opening (softening or shift upward in the pelvis) before ovulation are also used to indicate the start of the fertile period. Symptothermal methods use changes in cervical mucus or calendar calculations to determine the onset of the fertile period and changes in mucus or basal temperature to estimate the end. Simple, self-administered tests that measure urinary estrogen and pregnanediol glucuronide are now available. Such tests are performed for about 12 days each month and can usually reduce the days of abstinence required to about 7. These techniques are used alone or in combination. Method-related failures are usually low and range from 1 to 7%.24 26 However, as with many other contraceptives, the user failure rates are substantially higher than the method-related failure rates, and range from 6.6 to 39%.27,28 Generally, the many varieties of the symptothermal method are the most commonly used and are associated with the lowest failure rates.29

Combination Oral Contraceptive (COC) and Progestin Only Oral Contraceptive (POP) Pills Combination oral contraceptives (COC) are reliable, reversible, and have been the subject of much research. Initially marketed in the US in 1960, COCs quickly became the most widely used method of contraception. COC formulations combine a balanced combination of an estrogen and a progestin. The major action of the progestin component is to inhibit ovulation and produce other contraceptive actions such as thickening of the cervical mucus. The major effect of the estrogen component is to maintain the endometrium and prevent unscheduled bleeding. Initially marketed OC formulations contained 150 μg of estrogen (mestranol) and 9.85 mg of progestin (norethynodrel). Formulations now contain progestin doses as low as 100 to 150 μg, and a recently introduced COC contains only 10 μg of estrogen. Pharmacology/Selectivity There are 2 major types of COC formulation: combination phasic and fixed-dose combination. The COC phasic formulations were designed to lower the total monthly steroid dose. The POPs are packaged only as a daily progestin with no pill free days (minipill). All but 1 of the currently marketed formulations are made from synthetic steroids and contain no natural estrogen or progestin. Most formulations of COCs and POPs contain a derivative of 19-nortestosterone in either the estrane or gonane group. The 19-nortestosterone progestins are of 2 major types: estranes (Figure 15.2) and gonanes (Figure 15.3). The gonanes have greater progestational activity per unit weight than the estranes, and thus a smaller

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15. CONTRACEPTION

H3C

OH

H3C

C ≡ CH

Norethindrone O

C ≡ CH

Norethynodrel O O

O

H3C OCCH3 C ≡ CH

H3C OCCH3 C ≡ CH

O

OH

Norethindrone acetate

O

Ethynodiol diacetate

H3CCO

FIGURE 15.2 Chemical structure of the estrane progestins used in oral contraceptives. OH C ≡ CH

OH C ≡ CH

Levonorgestrel O

Gestodene O

OCOCH2 C ≡ CH

Norgestimate

OH H2C

C ≡ CH

Desogestrel

HON

FIGURE 15.3 Chemical structure of the gonane progestins used in oral contraceptives.

amount of gonane is used in OC formulations. The parent compound of the gonanes is DL-norgestrel, which consists of 2 isomers, dextro and levo. Only the levo form is biologically active. Levonorgestrel is 10 20 times more potent per unit weight than the estrane progestin norethinedrone.30 31 The less androgenic derivatives of levonorgestrel, namely desogestrel, norgestimate, gestodene, and dienogest have been marketed in Europe for many years. COCs with desogestrel and norgestimate, but not gestodene, have been marketed in the US since 1992. Drosperinone is the unique progestin used in COCs as it is a derivative of spironolactone. Drosperinone has antiandrogenic and antimineralocorticoid activity, and is marketed as a COC with and without the supplement folic acid (levomefolate). A new 4-phase COC (Natazia), approved in May 2010, contains estradiol valerate and the gonane dienogest. All but 1 (Natazia) of the currently marketed COC formulations contain ethinyl estradiol (EE). Older formulations of COCs containing $ 50 μg of estrogen contain either EE or mestranol as shown in Figure 15.4, and are termed first-generation COCs. Those with 20 35 μg of EE are second-

generation COCs, unless they contain any of the 3 newest progestins. The progestins in third-generation COCs, desogestrel, norgestimate, or gestodene, have similar or greater progestogenic potency compared to other gonane progestins, but less androgenic activity per unit weight. Selectivity is the comparison of a progestin’s progestational potency to its androgenic potency. Ethinyl estradiol is about 1.7 times as potent as mestranol and 100 times more potent than an equivalent weight of conjugated estrogen.32 Mechanism of Action The COCs owe much of their contraceptive efficacy to consistent inhibition of the midcycle gonadotropin surge and ovulation. Several studies report that most women on COCs have a marked suppression of the release of luteinizing hormone (LH) and folliclestimulating hormone (FSH) after infusion of gonadotropin releasing hormone (GnRH), indicating a direct inhibitory effect on the pituitary, as well as on the hypothalamus. The amount of suppression is unrelated to the age of the woman or the duration of steroid use, but is related to the potency of the COC formulation.33 In comparison, POPs have a lower dose of progestin and do not consistently inhibit ovulation.34 Both COCs and POPs act on many other aspects of the reproductive process including: 1. Altering the cervical mucus, making it viscid and thick, thus retarding sperm penetration; 2. Decreasing motility of the oviduct and uterus, impairing ova and sperm transport; 3. Suppressing the endometrium so that glandular production of glycogen is decreased, therefore allowing less available energy for the blastocyst to survive in the uterine cavity; and 4. Altering ovarian responsiveness to gonadotropin stimulation. With current OCs, neither ovarian steroidogenesis nor gonadotropin secretion is completely abolished. Women on OCs have circulating levels of endogenous estradiol similar to those found in the early follicular phase of a normal cycle.35 Effectiveness No significant differences in clinical effectiveness have been demonstrated among the various COCs. As long as no tablets are omitted (perfect use), the annual pregnancy rate for COCs is less than 0.2 0.3%. Among COC users in the US, rates of users as low as 3% become pregnant during the first year of typical use.36 Failure rates in COCs occur more frequently when 1 to 2 pills are missed following the end of the pill-free period compared to cycles where pills are missed during other parts

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CONTRACEPTIVE METHODS

OH C ≡ CH

OH C ≡ CH

SHBG

240

5

CH3O

HO Mestranol

Ethinylestradiol

FIGURE 15.4 Structures of the 2 estrogens used in combination oral contraceptives.

of the cycle. The requirement that the POP must be taken at the same time of day (within 3 hours) to maintain effectiveness may have a negative impact on pill typical use effectiveness. During the first year of typical use of the minipill, the percentage of women becoming pregnant ranges from 1.1 to 13.2%.37 In lactating women the minipill is nearly 100% effective.38 Side Effects Most women taking new lower dose formulation COCs do not experience estrogen-mediated side effects such as nausea (a central nervous system effect), breast tenderness, fluid retention, melasma, or leukorrhea. COCs may cause minor, clinically insignificant changes in circulating vitamin levels, such as decreases in B complex and ascorbic acid,39 and increases in vitamin A.40 Older, high dose COCs are reported to accelerate the appearance of symptoms of gallbladder disease, related to an estrogenic effect on the gallbladder whereby cholesterol concentration is increased.41 43 While all new low-dose pills tend to have a beneficial impact on acne and oily skin, some progestins may have androgenic side effects. These androgenic side effects include increased appetite and weight gain, acne, oily skin, adverse effect on lipids, diabetogenic effect, pruritis, depression, mood changes, nervousness, and fatigue.44 The new progestins, as well as use of combination pills with a low dose of progestin, generally minimize these androgenic effects. Both the estrogen and progestin component of the pill may contribute to problems such as hypertension, headaches, and breast tenderness. Failure to have withdrawal bleeding or amenorrhea is due to a progestin dominant pill and can be alleviated by switching to a more estrogenic or lower progestogenic formulation. LIVER PROTEIN EFFECTS: SHBG AND CLOTTING CHANGES

A major hepatic effect of androgenic progestins is a dose-dependent suppression of sex hormone-binding globulin (SHBG). Because estrogens increase SHBG, measurement of SHBG is a good way to determine the relative estrogen/androgenic balance of different formulations (Figure 15.5). The greatest increases in SHBG occur after ingestion of combination pills

ADJ(G Mean NMOL/L)

200

160

3 7 6

120

4 2

80

1 40

A 1

2

3 Cycle

4

5

6

FIGURE 15.5 Effects of monophasic levonorgestrel (1), monophasic cyproterone acetate (2), monophasic desogestrel (3), triphasic levonorgestrel (4), monophasic cyproterone acetate (5), triphasic gestodene (6), and biphasic desogestrel (7) on plasma levels of SHBG in 70 healthy women. From van der Vange MA, Blankenstein MA, Klooster-boer HJ, et al. Contraception 41:345, 1990.42

with desogestrel, gestodene, cyproterone acetate,45 and norgestimate, suggesting that these formulations, in addition to drosperinone and dienogest that have antiandrogenic activity are most useful for treating women with symptoms of hyperandrogenism such as acne, hirsutism, or android obesity. Orally ingested synthetic estrogens in COCs cause a dose-related increase in hepatic protein production. The increases in proteins leading to increased clotting activity (Factor V, VIII, X, and fibrinogen) are countered by changes in factors that increase antithrombosis action (Figure 15.6).46 Another globulin that is increased is angiotensinogen, which when converted to angiotensin may increase blood pressure.46 While angiotensinogen levels in users taking COCs that contain 30 35 μg of ethinyl estradiol are lower than those in users who ingest higher dose pills, a slight but significant increase in mean blood pressure may occur.47 The circulating levels of these globulins are directly correlated with the amount of estrogen in the pill, and lower-dose pills appear to have fewer deleterious effects. The most serious complications associated with COC use are related to circulatory diseases due to coagulation changes. Cardiovascular disease is most likely to occur in pill users who smoke or who are overweight, diabetic, hypertensive, or over age 50. Epidemiological studies have shown that the incidence of both arterial and venous thrombosis is directly related to the dose of estrogen (Table 15.6). The risk of serious cardiovascular disease attributable to the use of new low-dose pills is low, and much lower than the

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15. CONTRACEPTION

Four observational studies reported that the risk of VTE in users of third-generation COCs was higher than that of second-generation COCs.51 54 While these studies raised concern, the results relating to duration of use were inconsistent, and the odds ratio for MI was significantly lower in women using thirdgeneration products compared to those using secondgeneration pills. In a reanalysis of the Transnational Study,55 after the data were analyzed according to duration of COC use, the risk of VTE for first-time users was dependent on duration of prior COC use and essentially identical for second- and thirdgeneration pills (Table 15.7).

Activation Fibrinogen Factors V, VII, VIII, X, VwF

Plasminogen

Coagulation

Fibrinolysis α 2 antiplasmin PAI-1

Antithrombin III Protein C Protein S Activated Protein C

Inhibition

FIGURE 15.6 Factors involved in coagulation and fibrinolysis. TABLE 15.6 Ratio of Observed to Expected Embolism and Thrombosis in Relation to type and Dose of Estrogen in Combined Oral Contraceptives Estrogen

Mestranol Dose (µg)

Ethinyl Estradiol Dose (µg)

150

100

75 80

50

100

50

Fatal pulmonary embolisma

2.8

1.5

0.9

0.6

1.0

0.5

Nonfatal pulmonary embolismb

2.3

1.2

0.9

1.0

1.8

0.7

3.2

1.2

0.7

0.5

—

0.8

2.6

1.2

0.3

1.1

1.8

0.9

Cerebral thrombosisc a

Coronary thrombosis

Modified from Mann J I. Am J Obstet Gynecol 142:752,1982. a Linear trend test: P , 0.05. b Linear trend test: P , 0.01. c Linear trend test: P , 0.001.

incidence associated with pregnancy. The incidence of hospitalizations for serious cardiovascular complications associated with, or not avoided by, use of lowdose combination COCs is one myocardial infarction (MI), 3 strokes, and 11 venous thromboses/emboli per 100,000 COC users.48 The background rate of venous thrombosis/embolism (VTE, DVT) in non-pregnant women of reproductive age (not using COCs) is about 0.8 per 10,000 woman-years. A large observational study found that the incidence of VTE among users of COCs with 20 50 μg ethinyl estradiol was 3 per 10,000 woman-years. While this was about 4 times the background rate, it was still one-half the rate of 6 per 10,000 woman-years associated with pregnancy.49 Women with an inherited coagulation disorder (such as protein C, S, Leiden factor, antithrombin III deficiency, or activated Protein C resistance) are at higher risk. In one study, the overall risk of developing thrombosis increased from a baseline rate of 6 to 30 per 10,000 woman-years in COC users.50 Screening for these coagulation deficiencies is recommended in women with a strong family or personal history of thrombotic events.

CARBOHYDRATE METABOLISM

Carbohydrate metabolism is not clinically affected in women on current low-dose COCs, although older high-dose pills had a profound effect on glucose and insulin levels. Conflicting data exist on the effect of the estrogen component; however, it probably acts synergistically with progestin to impair glucose tolerance.56 Generally, the higher the dose and potency of the progestin, the greater the impairment of glucose metabolism. Due to the minor effects on glucose, insulin, and glucagon levels, low-dose pills are safe to use in women with a history of gestational diabetes57 and in many insulin-dependent diabetics. In the Nurses’ Health Study, although type 2 diabetes developed in more than 2,000 women, the risk was not increased among current OC users (RR 5 0.86, 95% confidence interval (CI) 0.46 1.61).58 LIPIDS AND LONG-TERM RISK OF ATHEROSCLEROSIS

Estrogens in COCs increase high-density lipoprotein (HDL)-cholesterol, total cholesterol, and triglyceride levels, and decrease low-density lipoprotein (LDL)-cholesterol levels. The progestin component causes decreases in HDL, total cholesterol, and triglyceride levels and increases LDL-cholesterol. While older formulations with progestin-dominant formulations had an overall adverse lipid effect, current low-dose formulations report little change in HDL- and LDL- or total cholesterol, although triglyceride levels are increased. Formulations with a high estrogen to progestin ratio (i.e., those containing # 0.5 mg norethindrone or new progestins) increase HDL- and triglycerides and decrease LDL-cholesterol (Figure 15.7).59 61 In spite of any changes in lipids, there is no increased risk of atherosclerosis in former users of old or new formulation COCs.62,63 In fact, data continue to accumulate showing that COCs have a long-term protective effect on vascular disease,64 although there is an increased short-term risk of thrombosis associated with current COC use. Evidence that MI in current pill

III. SEXUAL AND REPRODUCTIVE HEALTH

CONTRACEPTIVE METHODS

TABLE 15.7

NEOPLASTIC EFFECTS

Risk of Idiopathic DVT and OC use

Study

Comparison

RR(CI)

WHO

LNG: DSG, GTD

2.6 (1.4 2.8)

UKR

LNG: DSG, GTD

2.2 (1.1 4.0)

Transnational

LNG: DSG, GTD

1.5 (1.1 2.2)

Leiden

LNG: DSG

2.2 (0.9 5.4)

Transnational Reanalysis

LNG: DSG, GTD

1.0

Odds Ratio of MI Transnational Study 3rd generation OCs versus no use

0.8 CI (.3 2.3)

3rd generation OCs versus 2nd generation OCs

0.3 CI (0.1 0.9)

Note. LNG, levonorgestrel; DSG, desogestrel; GTD, gestodene.

Difference in LDL cholesterol (%)

4 0 –4 –8 –12 –16

*

*

Difference in HDL cholesterol (%)

15

*

*

10 5 0 –5 –10 –15 –20

219

*

E

0E

/3

G

0D

15 EE

35

E/

EE

EE

35

E/

N

00

10

0-

EE

40

0-

E

/3

35

LG

E

0E

E/

N

0N

50

50

00

10 25

-1

50 /3

G 0E

/3

G

0L

15

0L

25

FIGURE 15.7 Percent differences in HDL and LDL cholesterol levels and in the incremental area for insulin in response to the OGTT between women taking 1 of 7 combination oral contraceptives and those not taking oral contraceptives. The T bars indicate 1 SD. The asterisk (p , 0.001) and dagger (p , 0.01) indicate significant differences between users and nonusers in the mean values for the principal metabolic variables. Modified from Godsland IF, Crook D, Simpson R, et al. N Engl J Med 323:1375, 1990 [53a].

users is due to thrombosis and not atherosclerosis is supported by an angiographic study of young women diagnosed with an MI, where evidence of coronary atherosclerosis was present in 79% of non-COC-users, but only 36% of COC users.65 Data support a longterm protective effect rather than an increase in risk.

Breast cancer risk. Because estrogen stimulates the growth of breast tissue, there are concerns that COCs may either initiate or promote breast cancer among users. In 1991, a comprehensive meta-analysis of all published epidemiological studies reported that a summary, relative risk in COCs users was 1.0 (95% CI 1.0 1.1) (Table 15.8).66 Eight case-control studies and one cohort study investigated the relative risk of breast cancer in COC users who did and did not have a family history of breast cancer. None of the studies showed a significant difference in either group.39 In 1996, an international group reanalyzed the entire worldwide epidemiological data on COCs and breast cancer.67 Analysis was performed on data from 54 studies representing 25 countries and more than 53,000 women with breast cancer and over 100,000 controls. Women who used COCs had a slightly increased risk of developing breast cancer (RR 5 1.24, 95% CI 1.15 1.33).68 The risk declined steadily after stopping use of COCs so that 10 years after use, the relative risk was 1.01 (95% CI 0.96 1.05). It is of interest that the breast cancers diagnosed in women taking COCs were less advanced clinically. The risk of having breast cancer that had spread beyond the breast compared to a localized tumor was significantly reduced (RR 5 0.88, 95% CI 0.81 0.95) in current OC users compared to nonusers. Overall, the vast body of data concerning COCs is reassuring. It is likely that contraceptive steroids promote the growth and increase the chance of early diagnosis of existing cancers, thus avoiding the usual pattern where it takes many years before breast cancer is clinically detected. Use of the lowest dose COC is advocated. Cervical cancer. The epidemiological data regarding the risk of invasive cervical cancer in COC users are conflicting. Confounding factors such as the number of sexual partners, age at first intercourse, exposure to human papillomavirus (HPV), use of barrier contraceptives and spermicides, cigarette smoking, and cytological screening frequency may account for the results in some studies. Schlesselman’s review of 14 studies of over 3,800 women with invasive cervical cancer reported a significantly increased risk with increased duration of use (Figure 15.8).68 Other studies reported that long-term use increased the risk 1.5- to 2.5-fold.69,70 In contrast to these findings, other wellcontrolled studies indicated no change in the risk of cervical intraepithelial neoplasia (CIN) with COC use.69,71 A population-based case-control study reported that COC use and cigarette smoking influenced the ability of HPV infection to cause invasive

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15. CONTRACEPTION

TABLE 15.8 Relative Risks of Breast Cancer in Women in Developed Countries Who Ever Used Oral Contraceptives: Case-Control Studies of Women of All Ages at Risk of Exposure Source, Year

Upper Age Limit of Cases

Cases/Controls Users

Nonusers

RR Estimate (95% CI)a

Henderson et al, 1974

64

59/69

248/238

0.7 [0.5 1.2]

Pallenbarger et al, 1977

50

226/398

226/474

1.1 [0.9 1.4]

Sartwell et al, 1977

74

22/34

262/333

0.9 (0.5 1.5)

Awnihar et al, 1979

64

30/65

160/315

0.9 [0.6 1.5]

Vessey et al, 1981

74

30/141

300/1207

0.9 (0.6 1.3)

Harris et al, 1982

54

36/189

73/279

1.0 (0.6 1.4)

Vessey et al, 1983

50

537/554

639/622

1.0 (0.8 1.2)

Rosenberg et al, 1984

59

397/2558

794/2468

0.9 (0.8 1.1)

Paganini et al, 1985

79

15/23

353/351

0.7 (0.4 1.4)

CASH 1986

54

2743/2802

1870/1774

1.0 (0.9 1.1)

Paul et al, 1986

54

310/708

123/189

0.9 (0.7 1.3)

La Vecchia et al, 1986

60

104/178

672/1104

1.1 (0.8 1.5)

Awnihar et al, 1988

54

162/467

372/1522

1.6 (1.3 2.1)

Stanford et al, 1989

.60

481/515

1541/1668

1.0 (0.9 1.2)

WHO 1990

62

438/1496

716/1888

1.1 (0.9 1.3)

—

—

—

1.0 [1.0 1.1]

b

Summary RR

From Thomas, D. B. Contraception 43:597, 1991.58 a Indicates confidence intervals estimated from published data. b P-value of chi-square test for heterogeneity 5 0.08.

Relative risk

10

1

0.1 0

2

4

6 8 10 12 14 Total years of OC use

16

18

20

FIGURE 15.8 Relative risk of cervical cancer by total years of oral contraceptive use. From Schlesselman JJ Obstet Gynecol 85: 793, 1995.60

cervical cancer.72 The authors suggested that COC use may only be important in the etiology of invasive squamous cell cervical tumors if the use occurs at a critical time in the development of a woman’s reproductive tract, that is, at ages #17 years.

Endometrial cancer. Thirteen of 15 case-control and cohort studies reported that COCs protect against endometrial cancer, the fourth most common cancer among US women after breast, lung, and colon and rectum.73,74 Women who used COCs for at least 1 year had a 50% lower risk of developing endometrial cancer between ages 40 and 55 compared to nonusers. A significant trend of decreasing risk with increasing duration of combined COC use has been observed (Figure 15.9).68 The protective effect is highest in nulliparous women and occurs with combination formulations with both high and low doses of progestins.75 Ovarian cancer. Eighteen of 20 published reports found a reduction in the risk of ovarian cancer among COC users, specifically the most common type, epithelial ovarian cancer (Figure 15.10).76 The summary relative risk for development of ovarian cancer among ever users of COCs was 0.64, a 36% reduction. COCs reduce the risk of the 4 major histological types of epithelial ovarian cancer (serous, mucinous, endometrioid, and clear-cell), and the risk of both invasive ovarian cancers and those with low malignant potential. The magnitude of the decrease in risk is directly

III. SEXUAL AND REPRODUCTIVE HEALTH

CONTRACEPTIVE METHODS

Contraindications for Use of OCs

10

Relative risk

221

1

0.1

0.01 0

2

4

6 8 10 12 14 Total years of OC use

16

18

20

FIGURE 15.9 Relative risks of endometrial cancer by total years of oral contraceptive use. From Schlesselman JJ. Obstet Gynecol 85: 793, 1995.60

related to the duration of use, ranging from a 40% reduction with 4 years of use to a 53% reduction after 8 years and a 60% reduction after 12 years. The protective effect begins within 10 years of first use and continues for at least 20 years after COC use ends. There is a similar level of protection with low-dose monophasic formulations as well as higher dose agents.77 As with endometrial cancer, the protective effect occurs only in women of low parity (#4 births) who are at greatest risk for this type of cancer. Liver adenoma and cancer. The development of benign hepatocellular adenoma is a rare occurrence associated with prolonged use of high-dose COC formulations, particularly those containing mestranol. Although 2 British studies reported an increased risk of liver cancer among users, the number of patients was small and there were many confounding factors.78 Data from a large multicenter epidemiological study coordinated by WHO found no increased risk of liver cancer in COC users, even with increasing duration of use.79 Pituitary adenoma. COCs mask the symptoms of a prolactinoma, namely amenorrhea and galactorrhea. When COC use is discontinued, these symptoms appear, suggesting a causal relationship. However, data from 3 studies indicate that the incidence of pituitary adenoma is not higher in pill users compared to matched controls.80 Malignant melanoma. Several epidemiological studies assessing the relationship between COC use and the development of malignant melanoma reported ambiguous results. A report from the Royal College of General Practitioners’ Oral Contraceptive Study and the Oxford Family Planning Association Study, involving over 450,000 woman-years of observation, concluded that oral contraceptive use is probably not associated with an increased risk of melanoma.81

Although it is safe to prescribe COCs and POPs to the majority of reproductive aged women, health care providers who are making clinical decisions regarding contraceptive options for women with medical conditions can rely on the WHO-MEC or US-MEC recommendations to provide evidence-based guidelines.8 Contraindications to COCs include a history of thromboembolism, atherosclerosis, stroke, or any systemic disease with associated vascular disease (such as lupus or diabetes with retinopathy or nephropathy). Cigarette smoking, migraines, or hypertension in women over age 35, uncontrolled hypertension, pregnancy, pituitary macroadenoma, migraine headaches (at any age) with localizing signs or aura, acute liver disease, and cancer of the breast or endometrium are also contraindications. The following are not contraindications for pill use: asymptomatic mitral valve prolapse; age over 40; past history of liver disease; family history of breast cancer; controlled diabetes; and prolactin secreting pituitary microadenoma. COCs should be stopped in women who develop more severe migraine headaches, fainting, temporary loss of vision or speech, or paresthesias while taking COCs. Drug Interactions Some drugs interfere with the action of COCs by inducing liver enzymes that convert the steroids to more polar and less biologically active metabolites. These drugs include barbiturates, sulfonamides, cyclophosphamide, and rifampin. There may be a higher incidence of COC failure in women using these drugs. The clinical data concerning failures during treatment with certain antibiotics (e.g., penicillin, ampicillin, sulfonamides, and tetracycline), analgesics and barbiturates (e.g., phenytoin) are less clear. Use of lamotrigine is considered a Category 3 classification for COC use due to the fact that pharmacokinetic studies report that during COC use, lamotrigine levels decrease significantly and increase during the pill-free days. In 1 trial, women on both COCs and lamotrigine experienced an increase in seizure activity.8 Non-Contraceptive Health Benefits In addition to being one of the most effective methods of contraception, COCs provide many health benefits. REPRODUCTIVE EFFECTS

COC use appears to have a long-term beneficial effect on fertility due to a decreased risk of salpingitis, ectopic pregnancy, and ovarian cyst formation. However, there is a short-term negative impact due to a variable delay in the return of ovulation after

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15. CONTRACEPTION

FIGURE 15.10 Relative risk of ovarian cancer associated with different durations of oral contraceptive use; findings of 15 studies. The overall summary relative risk of 0.64 (95% confidence interval 0.57 0.73) was associated with ever-use of OC, indicating a 36% reduction in ovarian cancer risk. The risk of ovarian cancer decreased with increasing duration of OC use; there was a 10 12% decrease in risk with 1 year of use and appropriately a 50% decrease after 5 years of use. From Hankinson SE, Colditz GA, Hunter DJ, Rosner B. Obstet Gynecol 80:708, 1992.67

4.4

Relative risk

1

0.5

0.1 0

2

4

6 8 Duration (years)

10

12

14

stopping COCs. For 2 years after stopping pill use, fertility is lower than in women discontinuing barrier methods (Figure 15.11).82,83

have an 85% reduction in fibroadenomas, and a 50% reduction in chronic cystic disease and nonbiopsied breast lumps compared with nonusers.84

BENEFITS FROM ANTIESTROGENIC ACTION OF PROGESTINS

BENEFITS FROM INHIBITION OF OVULATION

Both natural and synthetic progestins inhibit the proliferative effect of estrogen, the so-called antiestrogenic effect. Progestins decrease the number of estrogen receptors and also stimulate the activity of the enzyme estradiol 17-β-dehydrogenase within the endometrial cell. This enzyme converts the more potent estradiol to the less potent estrone, reducing estrogenic action within the cell. The progestin action limits the height of the endometrium compared to an ovulatory cycle, resulting in a reduction in the amount of blood loss at the time of endometrial shedding. In a normal ovulatory cycle the mean blood loss is about 35 ml compared to 20 25 ml for COC users. As a result, COC users are about half as likely to develop iron deficiency anemia, and are less likely to suffer menorrhagia, irregular menstruation, or intermenstrual bleeding. Because these disorders are frequently treated by curettage or hysterectomy, users require these procedures less frequently. Additionally, adenocarcinoma of the endometrium is significantly less likely in COC users.73 Estrogen exerts a proliferative effect on breast tissue, which contains estrogen receptors. Progestins probably inhibit the synthesis of estrogen receptors in the breast, thus exerting an antiestrogenic action on the breast. Several studies have shown that COCs reduce the incidence of benign breast disease, indicating that this reduction is directly related to the amount of progestin. Studies report that current COC users

Disorders such as dysmenorrhea and premenstrual tension occur less frequently in anovulatory cycles. Only about 30% of users previously suffering from dysmenorrhea report no improvement after starting COCs.85 Low-dose, combined COCs virtually eliminate cyclic PMS symptoms for most women.86 When ovulation is inhibited, functional cysts are less likely to develop (Table 15.9).87 The incidence of functional cysts is reduced by 80 90% in women using COCs.84 Users of multiphasic COCs also have protection from cysts, although to a lesser extent. Another disorder linked to incessant ovulation, ovarian cancer, is significantly reduced in users (see above). OTHER BENEFITS

Several European studies reported that the risk of development of rheumatoid arthritis in COC users was only half that of controls,88 while other studies have not found this protection.89 Another benefit is protection against salpingitis, commonly referred to as PID. The risk is reduced by 50% and may be related to a decreased duration of menstrual flow, or to thickened cervical mucus preventing bacteria from ascending to the upper genital tract. COCs reduce the risk of ectopic pregnancy by more than 90% in current users.44 There are several studies indicating that COCs reduce bone loss in perimenopausal women,90 particularly those with oligomenorrhea, reduce the risk of fibroids,91 and improve bleeding control.92

III. SEXUAL AND REPRODUCTIVE HEALTH

CONTRACEPTIVE METHODS

effects associated with the CVR are related to its placement in the vagina and include leukorrhea, vaginal discomfort, and vaginitis. The contraceptive patch, OrthoEvra, is a transdermal patch that delivers 150 μg of the progestin norelgestromin (a derivative of norgestimate) and 20 μg EE. The mechanism of action, effectiveness,93 side effects profile, and contraindications are similar to those associated with COCs as discussed above. In the North American trial where the patch was compared to a COC, skin site reactions to the local application of the skin patch were reported by 20.2% of patch users, and 2.6% discontinued use as a result of these problems. Patch users also complained of more breast tenderness and more dysmenorrhea than did pill users.94 According to the manufacturer, the patch results in 60% higher levels of EE compared to levels in women using a daily COC containing 35 μg of EE. There are conflicting data regarding the thromboembolic risk of the patch compared to COCs.95 Lower-dose EE patches are available in other countries.

Other (n = 1400)

100 90 80

OC (n = 281)

Cumulative percent

70 60 50 40 30 20 10 0 0

5

10 15 Months

223

20

25

FIGURE 15.11

Cumulative conception rates for former oral contraceptive and other contraceptive users, Yale-New Haven Hospital 1980 to 1982. From Bracken MB, Hellenbrand KG, Holford TR. Fertil Steril 53:21, 1990.74

TABLE 15.9 Rate Ratio Estimates for Functional Ovarian Cysts Comparing Each Oral Contraceptive Category with No Oral Contraception Rate Ratioa

95% Confidence Interval

No prescription

1.00

Reference category

Active prescription Multiphasic

0.91

0.30 2.31

35 μg estrogen

0.52

0.17 1.33

.35 μg estrogen

0.24

0.01 1.34

From Lanes AF, Birmann B, Walter AM, Singer S. Am J Obstet Gynecol 166:956, 1992.79 a Rate ratios standardized to age distribution of index (i.e., exposed) category.

Contraceptive Ring and Patch The contraceptive vaginal ring (CVR), NuvaRing, is a soft, transparent, pliable plastic ring-shaped device. The ring is made of the copolymer ethylene vinylacetate in which ethinyl estradiol (2.7 mg) and etonogestrel (11.7 mg) are embedded. The CVR is inserted into the vagina once a month for 3 weeks and then removed for 1 week. The efficacy, safety, and noncontraceptive benefits are basically the same as those associated with COCs as described above. Specific side

Long-Acting Injectable Contraceptives Because most of the long-acting steroid formulations contain only a progestin without an estrogen, the endometrium, particularly during early use, may not be maintained and uterine bleeding may occur at irregular and unpredictable intervals. The 3 types of injectable steroid formulations include depo-medroxyprogesterone acetate (DMPA), norethindrone enanthate, and several once-a-month injections of combinations of progestins and estrogens. Injectable contraceptives are a popular method of contraception worldwide, although only DMPA is approved for use in the US. Depot Formulations of MPA DMPA is a 17-acetoxy progesterone and is 1 of only 2 progestins used for contraception that is not a 19nortestosterone derivative. The acetoxyprogesterones, including medroxyprogesterone acetate and megestrol acetate, are not used in current COCs. The acetoxyprogestins are structurally related to progesterone and do not have androgenic activity. MPA was commonly used in OC formulations until US regulatory approval ended in response to studies reporting that MPA increased the risk of mammary cancer in beagle dogs. It was later learned that beagles uniquely metabolize 17-acetoxy progestins to estrogen, thus stimulating mammary hyperplasia. In humans DMPA is not metabolized to estrogen. In 1992, after epidemiological studies reported that DMPA does not increase the risk of breast cancer in humans, the Food and Drug Administration (FDA) approved DMPA 150 mg

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15. CONTRACEPTION

intramuscularly (IM) as a contraceptive agent. In 2004, Depo-SubQ provera 104 containing 104 mg DMPA was introduced as a contraceptive option, and later approved as a treatment for pain related to endometriosis. In a large WHO trial, the pregnancy rate at 1 year was only 0.1% and the cumulative rate at 2 years was 0.4%. Inhibition of ovulation is the primary mechanism of action, although DMPA also causes the endometrium to become thin, thus preventing implantation. In addition, DMPA makes the cervical mucus thick and viscous, making it unlikely that sperm are able to reach the oviduct.

100 90 80 Cumulative conception rate, %

224

Depo-Provera, 150 mg/90 days

70 60 50

IUCD - Tietze IUCD - Wajntraub Diaphragm, condom, other

40 30 20

PHARMACOKINETICS

DMPA can be detected in the systemic circulation 30 minutes after injection, and levels rise steadily to effective blood levels (.0.5 ng/ml) within 24 hours. MPA levels plateau at 1.0 1.5 ng/ml for about 3 months, decline to about 0.2 ng/ml during the fifth month, and are often detectable for up to 7 9 months. Estradiol levels remain below 100 pg/ml during the first 4 months. Return of follicular activity precedes the return of luteal activity by 2 3 months. Return of ovulation may not occur in some users for 7 9 months when MPA levels fall to ,0.01 ng/ml.96 OVULATORY SUPPRESSION

During the first 2 months after injection, although the midcycle LH/FSH peak is suppressed, LH and FSH are still secreted in a pulsatile manner.96 Estradiol levels varied from 5 to 100 pg/ml (mean 42 pg/ml) among women who used DMPA for 4 5 years, although none had hypoestrogenic complaints. RETURN OF FERTILITY

Because of the lag time in clearing DMPA from the circulation, resumption of ovulation may be delayed for as long as 1 year after the last injection. After this delay, there is normal fecundability (Figure 15.12).97,98 The delay in return to fertility is not related to the number of injections but increases with increasing weight, most likely because the drug is absorbed into adipose tissue and is not rapidly cleared. ENDOMETRIAL CHANGES

Endometrial biopsies taken at intervals of 1.5, 3, 6, 9, and 12 months after the first DMPA injection in a group of women receiving DMPA every 3 months showed about half the biopsies were proliferative at 6 weeks. After the second injection, ,10% of the biopsies were proliferative. The majority of specimens showed a quiescent type of endometrium, but after 1 year of DMPA, about 40% were characterized as atrophic.

10 95% C.I. 0 0

5 10 15 20 25 30 Months after removal or since last injection

35

FIGURE 15.12 Cumulative conception rates of women who discontinued a contraceptive method to become pregnant. From Schwallie PC, Assenzo JR. Contraception 10(2):181, 1974.85

ADVERSE EFFECTS

Clinical. The major side effect of DMPA is complete disruption of the menstrual cycle. In the 3 months after the first injection, about 30% of women are amenorrheic and another 30% have irregular bleeding and spotting occurring more than 11 days per month. The bleeding is usually light and does not cause anemia. By the end of 2 years, about 70% of women treated with DMPA are amenorrheic.98 After discontinuation of DMPA, about half resume regular cycles within 6 months and three-fourths have regular menses within 1 year. In 5 cross-sectional studies, users of DMPA weighed more than women not using hormonal contraceptives.39 Several longitudinal studies have indicated that DMPA users gain between 1.5 and 4 kg per year,99 which is higher than the typical weight gain of about 1 kg per year. The product labeling lists depression and mood changes as side effects of DMPA. Several studies, however, indicate that the incidence of depression and mood change is less than 5%. No clinical trials with a comparison group have been performed to determine whether a causal relation between use of DMPA and development of depression exists. Although development of headaches is the most frequent medical event reported by DMPA users and is a common reason for discontinuation, there are no comparative studies indicating that DMPA increases the incidence or severity of either tension or migraine headaches.

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Metabolic. DMPA does not increase liver globulin production; therefore, there are no alterations in blood clotting factors or angiotensinogen levels associated with its use. DMPA is not associated with an increased incidence of hypertension or thromboembolism. A WHO study reported that blood pressure measurements were unchanged in DMPA users after 2 years of injections.100 There is little or no change in mean triglyceride and total cholesterol levels with DMPA use. In all 7 studies in which HDL cholesterol level was measured, levels were lower among DMPA users. Of 5 studies measuring LDL cholesterol, 3 noted an increase among users.39 There are no studies reporting an increased incidence of cardiovascular events among current or former long-term DMPA users, and there is no evidence that DMPA is associated with an acceleration of atherosclerosis. Bone loss. In one cross-sectional study using DEXA bone scanning, 30 long-term DMPA users had a reduction in lumbar spine and femoral bone mineral density (BMD) compared to 30 nonusers. A follow-up report indicated that after stopping DMPA, there was normalization of BMD.101 Data suggest that loss of BMD with DMPA can be minimized or avoided with adequate calcium intake among users. Other long-term studies have not shown a decrease in BMD with DMPA use and, to date, no studies have been able to demonstrate an increased risk of fracture in current or former users.39 Cancer risk. Approval of DMPA for contraceptive use in the US was delayed for many years due to a concern about increased risks of cervical, breast, and endometrial cancer. Two large case-control studies indicated that the relative risk of developing breast cancer among DMPA users was not increased.102,103 In those who had used the drug for more than 5 years or more than 14 years earlier, the risk of developing breast cancer was also not increased (RR 5 1.0, 95% CI 0.7 1.5 and RR 5 0.89, 95% CI 0.63 1.3, respectively). However, among women under age 35 who had started use within the last 5 years, there was a significantly increased risk of breast cancer (RR 5 2.0, 95% CI 1.5 2.8), similar to that found with use of OCs. Overall, DMPA does not appear to change the incidence of developing breast cancer. A WHO case-control study found the risk of developing endometrial cancer to be significantly reduced among DMPA users (RR 5 0.21, 95% CI 0.06 0.79). This reduction in risk persisted for at least 8 years after stopping use.104 In a WHO case-control study, the risk of developing ovarian cancer among DMPA users was unchanged (RR 5 1.1, 95% CI 0.6 1.8).105 These findings do not demonstrate a protective effect similar to that observed with OCs despite inhibition of ovulation with both

225

agents. The lack of a protective effect observed with DMPA was probably due to the fact that in the countries studied, DMPA was given only to multiparous women (women at low risk of developing epithelial ovarian cancer). In several large case-control studies, the risk of developing invasive cancer of the cervix was not significantly increased (RR 5 1.1, 95% CI 1.0 1.3) with either short- or long-term use. The overall risk of developing cancer in situ was slightly increased in the WHO study (RR 5 1.4, 95% CI 1.2 1.7), but not in the Costa Rica study site (RR 5 1.0, 95% CI 0.6 1.8)106 or in 2 New Zealand studies.107,108 CONTRACEPTIVE HEALTH BENEFITS

There is good epidemiological evidence that use of DMPA reduces the risk of developing iron deficiency anemia, PID, and endometrial cancer, and has a beneficial effect in women with sickle cell disease (Table 15.10). DMPA also reduces seizure frequency in women with epilepsy and probably reduces the incidence of primary dysmenorrhea, ovulation pain, and functional ovarian cysts. DMPA reduces the symptoms of endometriosis, and in 2 small studies it reduced the incidence of vaginal candidiasis.39 WHO-MEC and US-MEC guidelines include Category 3 (theoretical or proven risks usually outweigh the advantages of using the method) for multiple cardiovascular risk factors, blood pressure .160/ 100 mm Hg, acute DVT, stroke, positive antiphospholipid antibodies, severe thrombocytopenia, severe vascular disease, severe cirrhosis, hepatoma. Breast cancer is a Category 4 (A condition which represents an unacceptable health risk if the contraceptive method is used).8 TABLE 15.10 Noncontraceptive Health Benefits of Contraceptive Use of DMPA Definite Salpingitis Endometrial cancer Iron deficiency anemia Sickle cell problems Probable Ovarian cysts Dysmenorrhea Endometriosis Epileptic seizure Vaginal candidiasis Premenstrual syndrome

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15. CONTRACEPTION

Norethindrone Enanthate (NET-EN) NET-EN is an injectable progestin that is approved for contraceptive use in more than 40 countries, but not in the US. Because of a shorter duration of action, it is recommended that NET-EN (200 mg in an oily suspension) be given every 60 days for at least the first 6 months of use and not less often than every 12 weeks thereafter. Progestin-Estrogen (Monthly) Injectable Formulations Because of the bleeding problems associated with progestin-only formulations, several combined progestinestradiol ester injectables have been developed. They are designed for once-a-month administration and are often associated with regular withdrawal bleeding. Four formulations are currently the most popular. A formulation containing 17α-hydroxyprogesterone caproate 250 mg and estradiol valerate 5 mg is used in China. A combination of dihydroxyprogesterone acetophenide 150 mg plus estradiol enanthate 10 mg is widely used in Mexico and Latin America. The WHO has developed 2 new formulations that are used by several national family planning programs. A combination of MPA 25 mg and estradiol cypionate is marketed as Cyclofem (or Cycloprovera), and a combination containing NET-EN 50 mg and estradiol valerate 5 mg is marketed as Mesigyna. These preparations offer better bleeding control than progestinonly products. About 85% of cycles are regular and amenorrhea rates are low. The results of 5 clinical trials with Mesigyna and Cyclofem demonstrate 12 month pregnancy rates of # 0.4% and 0.2%, respectively.109 None of these products are marketed in the US.

Subdermal Implants Implanon and Nexplanon are almost identical onerod etonogestrel (ENG) contraceptive implants that are placed just under the skin in the upper inner arm. These implants require a minor surgical procedure for placement and removal, and health care providers are required to attend special training sessions. Disturbances of menstrual bleeding patterns are frequent and counseling regarding these changes is important. These implants offer 3 years of very effective contraception. Mechanism of Action The progestin ENG diffuses from the implant into the surrounding tissues resulting in low circulating levels of the progestin. The ENG implant initially releases around 60 μg of etonorgestrel and around 30 μg after 2 years of use. The low levels of circulating progestin suppresses ovulation for at least 21/2 years

and thicken and decrease the amount of cervical mucus, forming a barrier to sperm.110 Effectiveness The ENG implant is one of the most effective forms of contraception available. In 11 international clinical trials there were no pregnancies in 942 women. Most of the failures reported with the ENG implant are due to incorrect insertion or insertion after pregnancy had already occurred.111 One of the reasons that the method is so successful is that its use requires very little effort on the part of the users after insertion. Side Effects Irregular bleeding. Unlike injectable contraceptives, fertility returns immediately following removal of the ENG implants. The low levels of circulating progestins cause few side effects, which generally decrease over time. Irregular bleeding is the most common reason for discontinuation (10%). Although endogenous estrogen production is relatively normal, the progestin effect is not withdrawn at regular intervals, resulting in unpredictable shedding and bleeding patterns. The majority of users have decreased bleeding after insertion (Table 15.11).112,113 Ovarian cysts. Regression of follicles is sometimes delayed in users and the follicle can continue to grow. Generally, these follicles will eventually disappear and rarely require surgery. Other side effects. Other adverse experiences include emotional lability (6.1%), weight increase (3.3%), depression (2.4%), and acne (1.5%). The link of the implant to a variety of reported problems including headache, weight changes, breast pain, and thrombosis needs further evaluation.112,113 Insertion/removal problems. Although these problems are not common, the implant can be broken or damaged, undergo slight migration, be unable to be palpated, or fibrosis can develop around the implant. Localization of the implant can be done with ultrasound and MRI for Implanon. Nexplanon has a radioopaque stripe and can also be visualized with x-ray or CT scan. TABLE 15.11 Pattern of Bleeding Episodes In Implanon/ Nexplanon Users106 107 Bleeding Pattern

Pattern of Bleeding Episodes in 90 Day Periods

% Implanon/ Nexplanon Users

Amenorrhea No bleeding

22.2

Infrequent

,3 episodes

33.6

Prolonged

Any episode lasting .14 days

17.7

Frequent

.5 episodes

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6.7

227

CONTRACEPTIVE METHODS

Medical Eligibility Criteria ENG implant is not recommended for women with a past history of thromboembolic disorders, hepatic tumors, active liver disease, or breast cancer. Although the manufacturer recommends that the implant not be used in women who take anti-epileptic medications, the WHO-MEC lists this condition as a 2 (advantages generally outweigh the risks).8

Emergency Contraception Although use of these products has been disappointing, it is estimated that appropriate use of emergency contraception could reduce the number of unintended pregnancies each year by 1.7 million and the number of abortions by 800,000.112 Use of emergency contraception pills reduces the risk of pregnancy after unprotected intercourse by at least 74% (Table 15.12).114 117 Plan B One-Steps, Next Choice, and Plan B are levonorgestrel only, FDA-approved emergency contraception pills that can be taken up to 72 hours after unprotected intercourse or contraceptive failure. These products are not effective if the user is already pregnant. The common side effects include changes in menses, nausea, lower abdominal pain, headache, fatigue, and dizziness. Emergency contraceptives are designed to prevent ovulation. In August, 2010, the FDA approved ellaTM for emergency contraception. Ella contains ulipristal acetate, a progesterone agonist/antagonist, whose mechanism of action is inhibition of ovulation. Dosing and side effect profile are the same as the levonorgestrel emergency contraceptives discussed above. Another post-coital option is insertion of a copper 380 T IUD for up to 7 10 days after unprotected sex. TABLE 15.12 Observed and Expected Pregnancies According to Various Methods of Postcoital Contraception Treatment

Number of Studies

Ethinyl estradiol — high dosage

4

Other estrogens — high dosage

2

Total Number of Patients Considered

Number of Observed Pregnancies

3168

19

975

Pregnancy Rate (%)

This is used in women who are candidates for an IUD and plan to continue its use. The originally-used emergency contraceptive pills are ordinary COCs (2 4 pills in 1 dose) taken within 72 hours of unprotected coitus. A second dose is taken 12 hours later. The FDA has approved specific protocols using Lo/Ovral, Levlen, Nordette, Triphasil, and Trilevelen for use as emergency contraceptive pills. The side effects, including nausea, vomiting, breast soreness, and menstrual irregularities, are generally much higher than the more recently introduced progestin-only alternatives.

Intrauterine Devices (IUDs) The main benefits of IUDs are a high level of effectiveness, a lack of associated systemic metabolic changes, and the need for a single visit for insertion. There are two IUDs available in the US. The copper T380 A (ParaGards, Cu-T) is one of the most effective and low cost contraceptive methods available. The levonorgestrel-releasing intrauterine system (Mirenas, LNG-IUS) also offers effective contraception and has the added benefit of reducing heavy periods. Effectiveness First-year failure rates with the Cu-T and the LNGIUS are less than 1%. The cumulative pregnancy rate after 10 years of use of the Cu-T 380A is only 2.1%.118,119 The incidence of all major adverse events with IUDs, including pregnancy, expulsion, or removal for bleeding and/or pain, steadily decreases with increasing age (Table 15.13). The Cu-T 380A is currently approved for 10 years of use and the LNG-IUS is approved for 5 years of use. A large comparative trial of the Cu-T 380A and the levonorgestrel releasing-IUD reported similar effectiveness and continuation rates.120 The LNG-IUS has a duration of action of at least 5 years. This IUD reduces menstrual TABLE 15.13 380A IUD

Cumulative Discontinuation Rate for Copper T

Event

11

69

3

0.6

1.1

Ethinyl 11 estradiol plus dl/-norgestrel

3802

1.8

Danazol

3

998

20

2.0

IUD

9

879

1

0.1

Years Since Insertion 5

7

Pregnancies

1.0

1.4

1.6

Expulsions

7.0

8.2

8.6

Medical removals

14.6

20.8

25.8

Nonmedical removals

13.8

25.6

34.4

Loss to follow-up

10.2

15.5

22.1

All discontinuations

32.2

46.7

56.3

Woman-months

38,571

56,010

67,885

Modified from World Health Organization (WHO): Contraception 42:141. 1990.4

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15. CONTRACEPTION

blood loss and can be used therapeutically. The FDA approval for this indication is restricted to women choosing IUDs as a method of contraception. Types of IUD The IUDs of the 1960s were made of polyethylene impregnated with barium sulfate to make them radiographic. In order to diminish the frequency of side effects, including bleeding and pain, smaller plastic devices covered with copper were developed. In the 1980s, devices bearing a larger amount of copper, including sleeves on the horizontal arm, such as the Cu-T 380 A, the Cu-T 220 C, and the multiload Cu 250 and Cu 375, were introduced. The multiload Cu 375 is widely used in Europe. Adding a reservoir of progesterone to the vertical arm also increases the effectiveness of the T-shaped devices. The LNG-IUS contains a reservoir of 52 mg levonorgestrel in the vertical arm releasing 20 μg/day after placement. The rate of release falls to 10 μg/day after 5 years. Mechanisms of Action The IUDs main mechanism of contraceptive action is spermicidal, causing a local sterile inflammatory reaction produced by the presence of a foreign body in the uterus. There is a 1,000% increase in the number of leukocytes in washings of the human endometrial cavity after insertion of an IUD.121 Leukocytes cause phagocytosis of sperm, and the tissue breakdown products of leukocytes are toxic to both sperm and blastocyst. The amount of inflammatory reaction and thus contraceptive effectiveness is directly related to the size and composition of the IUD. Copper markedly increases the extent of the inflammatory reaction and also impedes sperm transport and viability. Additionally, copper impedes sperm transport through and viability in the cervical mucus. Very few, if any, sperm reach the oviducts and the ovum usually does not become fertilized. Sperm transport from the cervix to the oviduct in the first 24 hours after coitus is markedly impaired in women wearing IUDs. Additionally, in a study where women had unprotected sexual intercourse shortly before ovulation, normally cleaving fertilized ova were found in the tubal flushings in about half the women not wearing IUDs, whereas none were found in users.122 Further evidence that the IUD acts as a spermicide rather than an abortifacient are data showing that while intrauterine pregnancy rates gradually increase with duration of use, the ectopic rates remain low and constant. There are several mechanisms of action thought to inhibit pregnancy with use of the LNG-IUS. The local progestogenic effects on the endometrium induce stromal pseudodecidualization, glandular atrophy, a leukocytic infiltraton, and a decrease in glandular and stromal mitoses. Ovulation is inhibited in 25 45% of

cycles in users. The action of progestin also causes thickening of the cervical mucus preventing sperm capacitation and passage. Fertility After Removal Upon removal of the IUD, the inflammatory reaction rapidly disappears. Resumption of fertility is prompt and occurs at the same rate as resumption of fertility following discontinuation of barrier methods (see Figure 15.12).123 Adverse Effects The most common adverse side effects of the LNGIUS are bleeding alterations (51%), amenorrhea (23%), intermenstrual bleeding and spotting (23.4%), abdominal/pelvic pain (12.8%), ovarian cysts (12%), headache/migraine (7.7%), acne (7.2%), depressed/altered mood (6.4%), menorrhagia (6.3%), breast tenderness/ pain (4.9%), vaginal discharge (4.9%), and IUD expulsion (4.9%). In a large study, the cumulative termination rates in LNG-IUS users were 0.1, 7.4, and 3.4 per 100 women years at the end of 1 year, and 0, 3, 15.1, and 4.9 per 100 women respectively after 5 years.120 A common reason for removal of the Cu-T involves prolonged menses or intermenstrual bleeding (Table 15.14).124 This heavy bleeding may be due to an increased local release of prostaglandins in response to the presence of a foreign body. The deposition of calcium salts on IUDs is irritating to the endometrium and can cause excessive bleeding. Prostaglandins stimulate uterine contractions and these may prolong the duration of bleeding and cramps. The amount of blood loss each month is significantly increased in women wearing inert and copper IUDs (50 ml) compared to nonusers (35 ml). With use of the progestin-containing IUDs, the amount of blood loss is significantly reduced to ,25 ml/cycle.125 A sensitive indicator of iron stores is the serum ferritin level, and levels less than 4 μg/l require oral iron TABLE 15.14 T 380A

First-Year Event Rates per 100 Women for Copper

Event

1 Year Parous

Pregnancy

0.5

Expulsion

2.3

Bleeding/pain

3.4

Infection

0.3

Other medical

0.5

Planning pregnancy

0.6

Other personal

0.7

From Rosenberg MJ, Foldesy R, Mishell DR, Jr. et al. Contraception 53:197, 1996.13

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CONTRACEPTIVE METHODS

supplementation to prevent anemia. In a study, women wearing the Cu-T IUD had no significant change in serum ferritin levels after 3, 6, and 12 months.126 Excessive bleeding that continues can be treated with prostaglandin synthetase inhibitors. Mefenamic acid (500 mg 3 times/day) significantly reduces blood loss in IUD users.127 A WHO study of the Cu-IUD reported event rates of 1.7% for pregnancy, 35.3% for bleeding, and 12.5% for expulsion at the end of 12 years.128 Perforation Although uncommon, one potentially serious complication is perforation of the uterine fundus. Perforation occurs at the time of insertion, although a partial perforation can turn into a full perforation if uterine contractions push the IUD through the wall into the peritoneal cavity. The incidence of perforation is generally related to the shape of the device as well as to the experience of the inserter, and is best prevented by straightening the uterine axis with a tenaculum and probing the cavity with a uterine sound prior to insertion. Complications Related to Pregnancy If pregnancy occurs with an IUD in place, implantation takes place at a site distant from the device itself, so the device is always extra-amniotic. Although there is a paucity of published data, there is no increased incidence of congenital anomalies. In studies of all types of IUDs left in situ during pregnancy, the frequency of spontaneous abortion was about 55%, approximately 3 times greater than would occur normally.129 However, the frequency of spontaneous abortion was only 20% if the device was removed or spontaneously expelled. Thus, the IUD should be removed if the appendage is visible. Several reports indicate that during early gestation, it is possible to safely remove an IUD without a visible appendage using sonographic guidance.130 If the IUD is not removed during early gestation, the risk of septic abortion is also increased. This is due, at least in part, to the fact that IUDs increase the risk of spontaneous abortion (50%) and 2% of all spontaneous abortions are septic. Ectopic Pregnancies Users of IUDs are 90% less likely to have an ectopic pregnancy than sexually active non-contraceptors, but if a pregnancy occurs, it is more likely to be a tubal pregnancy.131 Therefore, it is important to evaluate women for an ectopic pregnancy if pregnancy occurs during IUD use. Up to half of pregnancies that occur with LNG-IUS in place are ectopic. Women with a previous history of ectopic pregnancy, tubal surgery, or PID carry an increased risk of ectopic pregnancy.

229

The ratio of ectopic pregnancies to total pregnancies in women wearing the Cu-T IUD is 39 per 1,000 pregnancies, which is 3 times greater than the 14.1 per 1,000 pregnancies in the general population. However, because the Cu-T so effectively prevents all pregnancies, the estimated ectopic pregnancy rate is only 0.2 0.4 per 1,000 woman-years.132 The estimated ectopic pregnancy rate among sexually active US women using no contraceptive has been estimated to be 1.5 4.5 per 1,000 woman-years, thus women using a Cu-T have a substantially reduced risk of having an ectopic pregnancy.132,133 Prematurity The rate of prematurity is reported to be 4 times greater when the Cu-T is left in place during pregnancy compared to when it is removed. A higher incidence of prematurity was also noted in a British study which reported that 13.6% of infants conceived during IUD use weighed less than 2800 g at birth compared to 3% of infants conceived during use of other methods.134 It is recommended that if a pregnancy occurs, an attempt should be made to remove the IUD. Pelvic Inflammatory Disease (PID) A large WHO multicenter study on nearly 23,000 IUD users reported the highest PID rate was in the first 3 weeks after insertion, and then remained low and constant at 90.5 per 10,000 woman-years during the next 8 years.135 Several other studies have reported no increased rate of tubal infertility in either nulliparous or multiparous IUD users. IUDs do not protect against STDs and the risk of PID is greater for women who have multiple sexual partners. Placement of an IUD is contraindicated in the presence of PID. There were many studies published in the 1970s that suggested that IUD use increased the risk of PID. In 1966, a study was published where cultures were made of endometrial tissue obtained at various intervals after insertion of a loop IUD. During the first 24 hours, the normally sterile endometrial cavity was infected with bacteria. After 24 hours, however, 80% of the cavities were sterile.136 These findings indicate that development of PID more than 1 month after insertion of the IUD is due to infection with a sexually transmitted pathogen, and not to the presence of the device. In a Centers for Disease Control and Prevention study of a group of IUD users with only 1 sexual partner during the last 6 months, the only increased risk of PID was in previously married or never married women. The authors postulated that the partners of such women had an increased risk of transmitting a pathogen responsible for PID. In married or cohabiting women who had used an IUD for more than 4 months,

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15. CONTRACEPTION

the risk of developing PID was not significantly elevated (RR 5 1.2, 95% CI 0.7 1.9 for married and RR 5 1.0, 95% CI 0.4 2.4 for cohabiting women).137 There is evidence that IUD users may have an increased risk for colonizing Actinomyces in the upper genital tract. If Actinomyces are identified on a routine Pap smear, appropriate antimicrobial therapy should be started. The IUD does not have to be removed in asymptomatic users. The levonorgestrel-IUD is reported to reduce the risk of pelvic infections.138 Infertility The use of the Dalkon shield and possibly older plastic IUDs not containing copper, can lead to infertility in nulligravid women.139,140 The risk of primary tubal infertility in women who had ever used 1 of these IUDs was reported to be 3.7 times higher compared to women who had never used 1 (95% CI 2.2 6.1). The increased relative risk associated with use was highest for the Dalkon Shield (RR 5 6.0, 95% CI 2.7 13.3). Such IUDs are no longer available. In a similar study, the adjusted risk of primary tubal infertility associated with any IUD use before a first live birth was 2.0 (95% CI 1.5 2.6), relative to nonuse. Users of copper-containing IUDs had a relative risk of 1.6 (95% CI 1.1 2.4). Women who reported having only 1 sexual partner had no increased risk of primary tubal infertility associated with IUD use. The adjusted risk of secondary tubal infertility associated with use of a copper IUD after a first live birth was not statistically significant.140 Contraindications Absolute contraindications for IUD insertion include: 1. Pregnancy or suspicion of pregnancy; 2. Acute PID; 3. Postpartum endometritis or infected abortion within 3 months; 4. Known or suspected uterine or cervical malignancy; 5. Genital bleeding of unknown etiology; 6. Untreated acute cervicitis; and 7. A previously inserted IUD that has not been removed. There are few data available to support the assertions that Wilson’s disease (allergy to copper in potential Cu-IUD users) and genital actinomycosis are contraindications. Relative contraindications are: 1. Distortion of the uterine cavity; and 2. At increased risk of STDs (WHO-MED lists this as Categories 2/3). Breast cancer is Category 4 for use of the LNG-IUS system, while active liver disease is a Category 3.8

Overall Safety The IUD is not associated with an increased incidence of endometrial or cervical carcinoma. The modern IUD is a particularly useful method of contraception for women who have completed their families and do not wish to have permanent sterilization.

Sterilization In 1995, sterilization of 1 member of a couple was the most widely used method of preventing pregnancy in the US, with the exception of OCs. The rates of tubal sterilization have recently been declining, perhaps due to the increasing variety of highly effective reversible methods now available. Sterilization should be considered permanent, although reanastomosis after tubal ligation or vasectomy is possible. The decision for sterilization should be made solely by the patient in consultation with her physician. More than 1 counselor is useful if the woman seeking the procedure is younger than 25 years of age. The rationale for such careful scrutiny is that younger candidates tend to change their minds more often, their attitudes are less fixed, and they face a longer period of reproductive life during which divorce, remarriage, or death among their children can occur. In the US, approximately 7,000 women request reversal each year. About 2 per 1,000 sterilized women will eventually have a reversal.141 The most effective, least destructive method of tubal occlusion is the most desirable in younger patients, because ovarian dysfunction and adhesion formation are diminished. The effective laparoscopic band techniques or the modified Pomeroy technique (also called partial salpingectomy) should be used in women younger than 25 years old. Reversal of these procedures is followed by pregnancy rates of around 75%. Female Sterilization Techniques Postpartum sterilization can be done at the time of cesarean section or in the immediate postpartum period through a minilaparotomy. Local anesthesia can be used while making a small 3 5 cm incision. The simple Pomeroy-type tubal ligation is the most commonly used method. Laparoscopic sterilization can be achieved with unipolar and bipolar electrosurgery, ultrasound destruction, or by using mechanical means (clips, silastic rings, sutures). Discomfort is minimal and a return to full activity in 1 to 2 days is common. Transcervical approach sterilization has recently become more popular in the US. The Essure microinsert is inserted with hysteroscopic guidance into both fallopian tubes, either as an outpatient or in-office

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REFERENCES

procedure. For 3 months, a back-up system is used until confirmation of tubal occlusion is made by hysterosalpingogram (HSG). In July 2009, the FDA approved the Adiana system that relies on a hysteroscopic guided electrode to deliver a low level radiofrequency energy to the fallopian tubes. After the lesion has been created, a medical-grade silicone is placed into the area. Proper placement is immediately confirmed using ultrasound. An HSG and follow-up ultrasound are performed 3 months later. Effectiveness Female sterilization by surgical removal of a portion of the oviduct, or mechanically occluding a portion of the lumen by clips, bands, or electrocoagulation, was previously reported to be the most effective form of pregnancy prevention.142 However, the results of a long-term study indicate that pregnancies continue to occur for many years after the sterilization procedure. The failure rate increased from 0.55 per 100 women at 1 year to 1.31 at 5 years and 1.85 at 10 years after sterilization.143 For women 18 27 years of age, 2.8% became pregnant 5 10 years after bipolar coagulation of the fallopian tubes. There are several reversible methods of contraception with a failure rate similar to those of tubal sterilization. For example, cumulative 5-year failure rates with Norplant are 1.1%, and with the Cu-T 380 IUD are 1.2%, compared to 1.3% with female sterilization. Among women who become pregnant after female sterilization, about one-third have ectopic pregnancies compared with one-fourth with Norplant and 5% with the Cu-T 380 IUD. Because the Cu-T 380 IUD has an effective lifespan of 10 years with a failure rate comparable to female sterilization and a lower ectopic pregnancy rate, as well as being less expensive, it should be considered as an alternative to tubal sterilization.

References [1] Mosher WD, Jones J. Use of contraception in the United States: 1982 2008, Division of Vital Statistics. Data from the National Survey of Family Growth US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Hyattsville, Maryland. August 2010. DHHS Publication No. (PHS) 2010 1981.Vital health statistics. Series 23, Number 29. [2] Finer L, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sexual Reprod Health 2006;38:90 6. [3] Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Stewart FH, Kowal D, editors. Contraceptive technology: nineteenth revised edition. New York, NY: Ardent Media; 2007. [4] Sivin I. Contraception with Norplants implants. Hum Reprod 1994;9:1818 26.

231

[5] WHO Special Programme of Research, Development and Research Training in Human Reproduction. The TCU220, multiload 250 and Nova T IUDs at 3, 5 and 7 years of use. Results from three randomized multicenter trials. Contraception 1990;42:141 58. [6] Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: findings from the US Collaborative Review of Sterilization. Am J Obstet Gynecol 1996;174:1161 8. [7] Trussell J, Leveque JA, Koenig JD. The economic value of contraception: a comparison of 15 methods. Am J Public Health 1995;85(4):494 503. [8] WHO. Medical eligibility criteria for contraceptive use. 4th ed. Geneva: WHO; 2009. Available at ,http://www.who.int/reproductive health/publications/family_planning/9789241563888/ en/index.html.; [accessed 21.09.2012]. [9] US Medical eligibility criteria for contraceptive use 2010. Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed. Available at ,http://www.cdc.gov/mmwr/preview/mmwrhtml/rr59e0528a1. htm.; [accessed 21.09.2012]. [10] Bracken MB, Vita K. Frequency of non-hormonal contraception around conception and association with congenital malformations in offspring. Am J Epidemiol 1983;117:281. [11] Louik C, Mitchell AA, Werler MM, et al. Maternal exposure to spermicides in relation to certain birth defects. N Engl J Med 1987;317:474. [12] Strobino B, Kline J, Lai A, et al. Vaginal spermicides and spontaneous abortion of known karyotype. Am J Epidemiol 1986; 123:432. [13] Vessey M, Lawless M, Yeates D. Efficacy of different contraceptive methods. Lancet 1982;1:841. [14] John APK. Contraception in a practice community. J R Coll Gen Practitioners 1973;23:665. [15] Barlow D. The condom and gonorrhoea. Lancet 1977;2:811. [16] Kelaghan J, Rubin GL, Ory HW, Layde PM. Barrier-method contraceptives and pelvic inflammatory disease. J Am Med Assoc 1982;248:184. [17] Conant M, Hardy D, Sernatinger J, et al. Condoms prevent transmission of AIDS-associated retrovirus. J Am Med Assoc 1986;255:1706. [18] Fischl M, Dickinson GM, Scott GB, et al. Evaluation of heterosexual partners, children and household contacts of adults with AIDs. J Am Med Assoc 1987;257:640. [19] Richardson AC, Lyon JB. The effect of condom use on squamous cell cervical intraepithelial neoplasia. Am J Obstet Gynecol 1981;140:909. [20] Ness RB, Randall H, Richter HE, et al. Condom use and the risk of recurrent pelvic inflammatory disease, chronic pelvic pain, or infertility following an episode of pelvic inflammatory disease. Am J Public Health 2004;94(8):1327 9. [21] Harris RWC, Brinton LA, Cowdell RH, et al. Characteristics of women with dysplasia or carcinoma in situ of the cervix uteri. Br J Cancer 1980;42:359 69. [22] Trussel J, Sturgen K, Stricker J, Dominik R. Comparative contraceptive efficacy of the female condom and other barrier methods. Fam Plann Perspect 1994;26:66 72. [23] Fihn SD, Latham RH, Roberts P, et al. Association between diaphragm use and urinary tract infection. J Am Med Assoc 1986;254:240. [24] Marshall J. A field trial of the basal body temperature method of regulating births. Lancet 1968;2:8 10. [25] World Health Organization. Task force on methods for the determination of the fertile period. Special program of research, development and research training in human reproduction. A prospective multi-center trial of the ovulation method of

III. SEXUAL AND REPRODUCTIVE HEALTH

232

[26]

[27]

[28]

[29] [30]

[31] [32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40] [41]

[42]

[43]

[44] [45]

[46] [47]

15. CONTRACEPTION

natural family planning. 2. Effectiveness phase. Fertil Steril 1981;36:591 8. Perez A, Zabala A, Larrain A, et al. Clinical effectiveness of the ovulation method (Billings). Rev Chil Obstet Ginecol 1983;48 (2):97 107. Rice FJ, Lanctot CA, Garcia-Devesa C. Effectiveness of the sympto-thermal method of natural family planning: an international study. Int J Fertil 1981;26:222 30. Wade ME, McCarthy P, Abernathy JR, et al. A randomized prospective study of the use effectiveness of two methods of natural family planning: an interim report. Am J Obstet Gynecol 1979;134:628 31. Marshall J. A prospective trial of the mucothermic method of natural family planning. Int Rev Nat Fam Plann 1985;9: 139 43. Ferin J. Orally active progestational compounds. Human studies: effects on the utero-vaginal tract. International encyclopedia of pharmacology and therapeutics, vol. 2. Oxford: Pergamon; 1972. Dorlinger L. Relative potency of progestins used in oral contraceptives. Contraception 1985;31:557. Goldqieher JW, Tazewell S, de la Pean D. Plasma levels and pharmacokinetics of ethinyl estrogens in various populations. Contraception 1980;21:17. Scott JA, Letzky OA, Brenner PF, et al. Comparison of the effects of contraceptive steroid formulations containing two doses of estrogen on pituitary function. Fertil Steril 1978;30:141. Mishell Jr DR, Kletzky OA, Brenner PF, et al. The effect of contraceptive steroids on hypothalamic pituitary function 1978; 130:817. Mishell Jr DR, Thorneycroft IH, Nakamura RM, et al. Serum estradiol in women ingesting combination oral contraceptive steroids. Am J Obstet Gynecol 1972;114:923. Trussell J, Hatcher RA, Cates W, Stewart FH, Kost K. Contraceptive failure in the United States: an update. Stud Fam Plann 1990;21(1):51 4. Sheth A, Jain U, Sharma S, et al. A randomized double-blind study of two combined and two progestogen-only oral contraceptives. Contraception 1982;25(3):243 52. Shaaban MM. Contraception with progestogens and progesterone during lactation. J Steroid Biochem Mol Biol 1991;40(4 6): 705 10. Mishell DR. Family planning. In: Mishell, Herbst, Stenchever, Droegemueller, editors. Comprehensive gynecology. 3rd ed. St. Louis, MO: Mosby; 1997. Gal I, Parkinson C, Craft I. Effect of oral contraceptives on human plasma vitamin A levels. Br Med J 1971;2:436. Drife J. Complications of combined oral contraception. In: Filshie M, Guillebaud J, editors. Contraception science and practice. London: Butterworth; 1989. Layde PM, Vessey MP, Yeates D. Risk factors for gall-bladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Commun Health 1982;36:274. Boston Collaborative Drug Surveillance Project. Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease and breast tumors. Lancet 1973;1:1399. Kols A, Rinehart W, Piotrow P, et al. Oral contraceptives in the 1980s. Popul Rep 1982;10:A191 222. Van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 1990;41:345. Meade TW. Oral contraceptives, clotting factors, and thrombosis. Am J Obstet Gynecol 1982;142:758. Wilson ES, Cruickshank J, McMaster M, et al. A prospective controlled study of the effect on blood pressure of contraceptive

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56] [57] [58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

preparations containing different types of dosages and progestogen. Br J Obstet Gynaecol 1984;91:1254. Harlap S, Kost K, Forrest JD. Preventing pregnancy, protecting health: a new look at birth control choices in the United States. New York and Washington, DC: The Alan Guttmacher Institute; 1991. Farmer RD, Preston T. The risk of venous thrombosis associated with low oestrogen oral contraceptives. J Obstet Gynecol 1995;15:195. Vandenbroucke JP, Koster T, Briet E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344:1453. World Health Organization. Collaborative study of cardiovascular disease and steroid hormone contraception venous thromboembolic disease and combined oral contraceptives: results of international multicenter case-control study. Lancet 1995;346: 1572 82. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestogen components. Lancet 1995;346:1589 93. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation and risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestogen. Lancet 1995;346:1593 6. Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83 8. Lewis MA. Transnational study on oral contraceptives and the health of young women. Methods, results, new analyses and the healthy user effect. Human Reprod Update 1999;5: 707 20. Wynn V, Goldsland IF. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986;31(Suppl. 9): 892 7. Shoupe D, Bopp B. Contraceptive options for the gestational diabetic woman. Int J Fertil Suppl 1991;2:80 6. Rimm EB, Manson JE, Stampfer MJ, et al. Oral contraceptive use and the risk of type 2 (non-insulin-dependent) diabetes mellitus in a large prospective study of women. Diabetologia 1992;35:967 72. Petersen Skouby SO, Pedersen RG. Desogestrel and gestodene in oral contraceptives: 12 months’ assessment of carbohydrate and lipoprotein metabolism. Obstet Gynecol 1991;78:666. Speroff L, DeCherney A. The advisory board for the new progestins evaluation of a new generation of oral contraceptives. Obstet Gynecol 1993;81:1034. Godsland IF, Crook D, Simpson R, et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990;323:1375 81. Layde PM, Ory HW, Schlesselman JJ. The risk of myocardial infarction in former users of oral contraceptives. Fam Planning Perspect 1982;14:78. Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl J Med 1988;319:1313. Adams MR, Clarkson TB, Kortinik DR, et al. Contraceptive steroids and coronary artery atherosclerosis in cynomologus macaques. Fertil Steril 1987;47:1010. Engel H-J, Engel E, Lichtlen PR. Coronary atherosclerosis and myocardial infarction in young women role of oral contraceptives. Eur Heart J 1983;4:1. Thomas DB. Oral contraceptives and breast cancer. Review of the epidemiological literature. Contraception 1991;43:597 642.

III. SEXUAL AND REPRODUCTIVE HEALTH

REFERENCES

[67] Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and hormonal contraceptives: collaborative reanalyzes of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 347:1996;1713 1727. [68] Schlesselman JJ. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793 801. [69] Kjaer SK, Engholm G, Dahl C, et al. Case-control study of risk factors for cervical squamous-cell neoplasia in Denmark. III. Role of oral contraceptive use. Cancer Causes Control 1993;4:513 19. [70] Ursin G, Peters RK, Henderson BE, et al. Oral contraceptive use and adenocarcinoma of cervix. Lancet 1994;334:1390. [71] Coker AL, McCann MF, Hulka BS, Walter LA. Oral contraceptive use and cervical intraepilelial neoplasia. J Clin Epidemiol 1992;45:1111. [72] Daling JR, Madeleine MM, McKnight Carter JJ, Wipf GC, Ashley R, Schwartz, et al. The relationship of human papillomavirus-related cervical tumors to cigarette smoking, oral contraceptive use, and prior herpes simples virus type 2 infection. Cancer Epidemiol Biomarkers Prev 1996;5:541 8. [73] Centers for Disease Control. Combination oral contraceptives use and risk of endometrial cancer. J Am Med Assoc 1987; 257:976. [74] American Cancer Society. Cancer facts and figures 2012. Atlanta: American Cancer Society; 2012. [75] Voigt LF, Deng O, Weiss NS. Recency, duration, and progestin content of oral contraceptives in relation to the incidence of endometrial cancer. Cancer Causes Control 1994;5:227 33. [76] Hankinson SE, Colditz GA, Hunter DJ, et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol 1992;80:708. [77] Rosenberg L, Palmer JR, Lesko SM, et al. Oral contraceptive use and the risk of myocardial infarction. Am J Epidemiol 1990;131:1009. [78] Forman D, Vincent TJ, Doll R. Cancer of the liver and the use of oral contraceptives. Br Med J 1986;292:1357. [79] World Health Organization. Combined oral contraceptives and liver cancer. Int J Cancer 1989;43:254. [80] Pituitary Adenoma Study Group. Pituitary adenomas and oral contraceptives: a multicenter case-control study. Fertil Steril 1983;39:753. [81] Hannaford PC, Villard-Mackintosh L, Vessey MP, Kay CR. Oral contraceptives and malignant melanoma. Br J Cancer 1991;63:430. [82] Vessey MP, Wright NH, McPherson K, et al. Fertility after stopping different methods of contraception. Br Med J 1978;1: 265. [83] Bracken MB, Hellenbrand KG, Holford TR. Conception delay after oral contraceptive use: the effect of estrogen dose. Fertil Steril 1990;53:21 7. [84] Ory HW, Forrest JD, Lincoln R. Making choices: evaluating the health risks and benefits of birth control methods. New York: The Allan Guttmacher Institute; 1983. [85] Robinson JC, Plichta BA, Weismann CS, Nathanson CA, Ensminger M. Dysmenorrhea and use of oral contraceptives in adolescent women attending a family planning clinic. Am J Obstet Gynecol 1992;166(2):578 83. [86] Menstrual problems and common gynecologic concerns. In: Hatcher RA, Trussell T, Steward FH, Stewart D, Kowal F, Guest W. editors. Contraceptive technology: 16th rev ed. Irvington Publishers; New York: 1994. [87] Lanes AF, Birmann B, Walter AM, Singer S. Oral contraceptive type and functional ovarian cysts. Am J Obstet Gynecol 1992;166:956.

233

[88] Hazes JMW, Dijkmans BAC, Vanderbroucke JP, et al. Reduction of the risk of rheumatoid arthritis among women who take oral contraceptives. Arthritis Rheum 1990; 33:173. [89] Del Junco DJ, Annegers JF, Luthra HS, et al. Do oral contraceptives prevent rheumatoid arthritis? J Am Med Assoc 1985;254:1938 41. [90] Gambacciani M, Spinetti A, Toponeco F, et al. Longitudinal evaluation of perimenopausal vertebral bone loss: effects of a low-dose oral contraceptive preparation on bone mineral density and metabolism. Obstet Gynecol 1993;83:392 6. [91] Ross RK, Pike MC, Vessey MP, et al. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J 1986;293:359 62. [92] Guillebaud J. The pill and other hormones for contraception. 4th ed. Oxford: Oxford University Press; 1991. [93] Gallo MF, Grimes DA, Schultz KF. Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 2008;(1):CD003552. [94] Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs. an oral contraceptive: a randomized controlled trial. J Am Med Assoc 2001;285(18):2347 54. [95] Jick S, Kaye JA, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception 2007;76(1):4 7. [96] Mishell DR, Kharma KM, Thorneycroft IH, Nakamura RM. Estrogenic activity in women receiving an injectable progestogen for contraception. Am J Obstet Gynecol 1972;113:372. [97] Schwallie PC, Assenzo JR. Contraceptive use efficacy study utilizing medroxyprogesterone acetate administered as an intramuscular injection once every 90 days. Contraception 1974;10(2):181. [98] Schwallie PC, Assenzo JR. The effect of depomedroxyprogesterone acetate on pituitary and ovarian function, and the return of fertility following its discontinuation: a review. Fertil Steril 1973;24:331. [99] Moore LL, Valuck R, McDougall C, et al. A comparative study of one-year weight gain among users of medroxyprogesterone acetate, levonorgestrel implants, and oral contraceptives. Contraception 1995;52:215 20. [100] World Health Organization. Expanded program of research, development and research training in human reproduction task force on long-acting system agents for the regulation of fertility multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids, norethisterone enanthate and medroxyprogesterone acetate. Final report. Contraception 1983;18:1. [101] Cundy T, Cornish J, Evans MC, et al. Recovery of bone density in women who stop using medroxyprogesterone acetate. Br Med J 1994;308:247 8. [102] Skegg DC, Noonan EA, Paul C, et al. Depot medroxyprogesterone acetate and breast cancer: a pooled analysis of the World Health Organization and New Zealand studies. J Am Med Assoc 1995;273:799 804. [103] WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprogesterone acetate: a multinational study. Lancet 1991;338:833 8. [104] WHO Collaborative Study of Neoplasia and Steroid Contraceptive. DMPA and risk of endometrial cancer. Int J Cancer 1991;49:186 90. [105] WHO Collaborative Study of Neoplasia and Steroid Contraceptives. DMPA and risk of epithlelial ovarian cancer. Int J Cancer 1991;49:191 5.

III. SEXUAL AND REPRODUCTIVE HEALTH

234

15. CONTRACEPTION

[106] Thomas DB, Ray RM. Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. Contraception 1995;52:307 12. [107] New Zealand Contraception and Health Study Group. Risk of cervical dysplasia in users of oral contraceptives, intrauterine devices or depot medroxyprogesterone acetate. Contraception 1994;50:431. [108] New Zealand Contraception and Health Study Group. History of long-term use of depot-medroxyprogesterone acetate in patients with cervical dysplasia: case-control analysis nested in a cohort study. Contraception 1994;50:443 9. [109] World Health Organization. Task force of long-acting systemic agents for fertility regulation. Special Program of Research, Development and Research Training in Human Reproduction; a multicenter Phase III comparative study of two-hormonal contraceptive preparations given once-a-month by intramuscular injection: II. The comparison of bleeding patterns. Contraception 1989;40:531. [110] Brache V, Faundes A, Johansson E, et al. Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants. Contraception 1985;31:261. [111] Darney P, Patel A, Rosen K, et al. Safety and efficacy of a single-rod etonorgestrel implant: results from 11 international clinical trials. Fertil Steril 2009;91(65):47 63. [112] Implanon Official FDA information, accessed at: ,www. Drugs.com/pro/implanon.html.; [accessed 21.09.2012]. [113] Davies GC, Li XF, Newton JR. Release characteristics, ovarian activity and menstrual bleeding pattern with a single contraceptive implant releasing 3-keodesogestrel. Contraception 1993;47:251 61. [114] Van Look Paul FA, Stewart F. Emergency contraception. In: Hatcher RA, Trussell J, Stewart FH, Cates W, Stewart GK, Guest F, Kowal D, editors. Contraceptive technology. New York: Ardent Media; 1998. [115] Fasoli M, Parazzini F, Cecchetti G, LaVecchia C. Post-coital contraception: an overview of published studies. Contraception 1989;39:459 68 [Erratum in Contraception 1989; 39:699.] [116] Glasier A, Thong KJ, Dewar M, Mackie M, Baird DT. Mifepristone compared with high-dose estrogen and progestogen for emergency postcoital contraception. N Engl J Med 1992;327:1041 4. [117] Hatcher RA, Trussell J, Stewart F, et al. Contraceptive technology. 16th ed. New York: Irvington Publishers; 1994. [118] World Health Organization. Long-term reversible contraception. Twelve years experience with the TCU 380A and TCu220C. Contraception 1997;56:341 52. [119] Rowe PJ. Research on intrauterine devices. In: World Health Organization. Special program of research. Development and research training in human reproduction. Annual technical report. Geneva: WHO; 1993. P. 289. 1992. [120] Andersson K, Odlin V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova-T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49: 56 72. [121] Moyer DL, Mishell Jr. DR. Reactions of human endometrium to the intrauterine foreign day. II. Long term effects on the endometrial histology and cytology. Am J Obstet Gynecol 1971;111:66. [122] Tredway DR, Umezaki CU, Mishell Jr DR. Effect of intrauterine devices on sperm transport in the human being. Am J Obstet Gynecol 1975;123:734.

[123] Vessey MP, Lawless M, McPherson K , et al. Fertility after stopping use of intrauterine contraceptive device. Br Med J 1983;286:106. [124] Rosenberg MJ, Foldesy R, Mishell Jr DR, et al. Performance of the TCu380A and Cu-Fix IUDs in an international randomized trial. Contraception 1996;53:197 203. [125] Rybo G. The IUD and endometrial bleeding. J Reprod Med 1977;20:715. [126] Milsom I, Andersson K, Jonasson K, et al. The influence of the Gyne-T 380S IUD on menstrual blood loss and iron status. Contraception 1995;52:175 9. [127] Anderson ABM, Haynes PJ, Guillebaud J, et al. Reduction of menstrual blood loss by prostaglandin synthetase inhibitor. Lancet 1976;1:774. [128] Sivin I, Stern J. Long-acting more effective copper T IUDs: a summary of US experience, 1970 75. Stud Fam Plann 1979;10:276 81. [129] Tatum HJ, Schmidt FH, Jain AK. Management and outcome of pregnancies associated with the copper T intrauterine contraceptive device. Am J Obstet Gynecol 1976;126:869. [130] Shalev E, Edelstein S, Engelhard J, et al. Ultrasonically controlled retrieval of an intrauterine contraceptive device in early pregnancy. J Clin Ultrasound 1987;15:525. [131] Rossing MA, Daling JR, Weiss NS. Past use of an intrauterine device and risk of tubal pregnancy. Epidemiology 1993;4: 245 51. [132] Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet Gynecol 1991;78:291 8. [133] Rossing MA, Daling JR, Voigt LF. Current use of an intrauterine device and risk of tubal pregnancy. Epidemiology 1993;4:252 8. [134] Vessey MP, Johnson B, Doll R, et al. Outcome of pregnancy in women using an intrauterine device. Lancet 1984;1:495. [135] Farley TM, Rosenberg MJ, Rowe PJ, et al. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992;339(8796):785 8. [136] Mishell Jr DR, Bell JH, Good RG, et al. The intrauterine device: a bacteriologic study of the endometrial cavity. Am J Obstet Gynecol 1996;96:119. [137] Lee NC, Rubin GL, Borucki R. The intrauterine device and pelvic inflammatory disease revisited: new results from the women’s health study. Obstet Gynecol 1988;72(1):1 6. [138] Toivonen J, Luukkainen T, Alloven H. Protective effect of intrauterine release of levonorgestrel on pelvic infection: three years comparative experience of levonorgestrel and copper-releasing intrauterine devices. Obstet Gynecol 1991; 77:261. [139] Daling JR, Weiss NS, Voigt LF, McKnight B, Moore DE. The intrauterine device and primary tubal infertility. N Engl J Med 1992;326:203 4. [140] Cramer DW, Schiff I, Schoenbaum SC, et al. Tubal infertility and the intrauterine device. N Engl J Med 1985;312:914 7. [141] Wilcox LS, Chu SY, Peterson HB. Characteristics of women who considered or obtained tubal reanastomosis: results from a prospective study of tubal sterilization. Obstet Gynecol 1990;75:661. [142] Trussel J, Hatcher RA, Cates WJR, Stewart FH, Kost K. Contraceptive failure in the United States: an update. Study Fam Planning 1990;21:51. [143] Peterson HB, Zia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: findings from the US collaborative review of sterilization. Am J Obstet Gynecol 1996;174:1161 70.

III. SEXUAL AND REPRODUCTIVE HEALTH