Adolescent Health Care: A Practical Guide

Chapter 43

Combination Hormonal Contraceptives

Anita L. Nelson

Lawrence S. Neinstein

Combination hormonal contraceptives are agents that include both estrogen and progestin. In general, the progestin component provides contraception (primarily by thickening cervical mucus and suppressing ovulation) and the estrogen component provides cycle control. Currently, several forms of combination hormonal contraception are available in the United States—oral contraceptive (OC) pills, contraceptive transdermal patches, and contraceptive vaginal rings. Progestin-only pills are also discussed in this chapter.

Oral Contraceptives

OCs are the most widely used method of reversible birth control in the United States. With>45 years of successful use, considerable professional confidence has developed in the safety and efficacy of OCs, and a growing appreciation is building among health care providers for the extensive noncontraceptive benefits that pills offer. However, public understanding of these issues lags considerably. Until recently, most Americans could not name a single noncontraceptive benefit of the pill. Today, many women are at least aware of the acne treatment and cycle control benefits, but many women remain concerned about the safety of the pill. These public (mis)perceptions directly influence patient compliance and continuation rates.

Efficacy

The first-year failure rate in typical use for combined OCs has been calculated to be 8%, which is virtually the same as the progestin-only OCs (Trussell, 2004). Because the failure rates observed in clinical trials are generally observed to be<1%, much of the real world failure has been attributed to incorrect pill-taking habits. The lack of daily use of pills has been substantiated by a telephone survey by Oakley et al. (1991), who found that among new start OC users, only 13% reported having taken the pill correctly for 9 months. Often, women are not even aware of their incorrect pill-taking habits. Potter et al. (1996) compared patients' diaries with records generated by computer chips built into the pill packaging, which recorded the time and date the pill was removed from its pack. In the first cycle, nearly 60% of patients' diaries reported that the patient had missed no pills at all, whereas the electronic device reported that only one third of women had reported perfect use. By the third cycle, the electronic device reported that>50% of women had missed more than two pills during that cycle.

Body Weight and Efficacy

Recent studies have suggested a connection between heavier body weight and increased failure rates with OCs. Comparing women in the highest quartile of weight (>70.5 kg) with the lower-weight women, Holt et al. (2002) found that the failure rates in heavier women were 1.2 to 4.5 times higher. In Holt's initial analysis, there was evidence that this increased pregnancy rate was even higher with lower-dose formulations. However, the author's later analysis did not report any dose-related pregnancy risk, although the second article confirmed the higher failure rates with greater body weight (Holt et al., 2005). It is not clear what the underlying cause of such a trend might be. Is it that taller women have a larger volume of distribution? Could it be that heavier women have more adipose tissue, which produces more estrogen to keep the cervical mucus favorable? Finally, are there other nonbiologic features that may explain the higher failure rates? A retrospective analysis of the 1997 National Health Interview Survey and the 1995 National Survey of Family Growth found that the increase in pregnancy rates seen in women with body mass indexes (BMIs)>30 was no longer statistically significant after adjustments were made for age, marital status, education, poverty, ethnic/race parity, and dual method use (Brunner and Hogue, 2005). More research is needed to answer this question. In the interim, clinicians may need to put this issue into perspective. Heavier women have a demonstrated increased risk for thrombotic complications with higher-dose pills. Their known risk for thrombosis outweighs the evidence currently available, suggesting the need for higher-dose pills to prevent pregnancy. However, it is appropriate to counsel heavier women that they may be at higher risk for pregnancy than are slender women to encourage more careful taking of pills and weight loss.

Changes in pill packets and new delivery systems have been designed to enhance successful use of hormonal contraception.

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Current Formulations

The doses of the sex steroids in OCs have been dramatically reduced since the 1960 introduction of norethynodrel (Enovid), which contained 9.85 mg of progestin and 150 µg of estrogen. All pills with>50 µg of estrogen have been removed from the U.S. market. The hormones used in combination birth control pills include an estrogen component and a progestin component:

  1. Estrogen component: All combination OCs contain one of two synthetic estrogens, mestranol or ethinyl estradiol (EE). These two estrogens differ by a methyl group at the C3 site. Mestranol is biologically inactive. It must be hepatically cleaved into EE; 50 µg of mestranol is approximately equivalent to 35 to 40 µg of EE. Most combination pills currently prescribed contain 30 to 35 µg of EE, although formulations with 20 or 25 µgof EE are increasing in popularity. Formulations with 50 µg of EE are reserved for use with other medications that induce hepatic enzymes.
  2. Progestin component: All pills in the United States currently have one of eight synthetic progestins. Seven (norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel, norgestimate, and desogestrel) are derived from an androgen precursor. Therefore, these progestins have both progestational and androgenic metabolic effects. In many instances, the latter can be interpreted as antiestrogenic. The eighth progestin, drosperinone, is a derivative of spironalactone and has progestational, antiandrogenic, and antimineralocorticoid properties.

An extensive array of formulations has evolved over the years in an attempt to meet the needs of women with individual sensitivities to particular sex hormone combinations and strengths. Table 43.1 lists the names, components, and doses of the branded pills currently available. Generic formulations of most of the branded pills are also used frequently to reduce contraceptive costs and are listed in Table 43.1.

Packaging

Most packs are for a single cycle. Some include only the active pills (generally 21), whereas others add additional (generally nonactive) pills to make a total of 28 pills in the pack. Active pills are packaged in one of three patterns:

  1. Monophasic packets: Each of the active pills has the same dose of estrogen and progestin.
  2. Multiphasic packets (biphasic or triphasic): The active pills vary the dose of the estrogen and progestin components throughout the active pill cycle. In most cases, the progestin progressively increases in dose; however, a few formulations hold the dose of progestin constant and increase the estrogen dose over the cycle. Some formulations vary both hormone doses.
  3. Progestin-only or minipill packets: Each pill contains a small dose of a progestin. No estrogen is included in the pills. There are no placebo pills.

Pill-Free Intervals

The placebo pills have been the focus of much recent innovation in pills. Some formulations add iron supplements to the placebo pills. The 7-day pill-free interval has been recognized to be excessively long with modern low-dose formulations (Mishell, 2005). The early, higher-dose pills required 5 days for serum hormone levels to drop low enough to permit the endometrium to start sloughing; with modern formulations endometrial support is lost within 2 days of taking the last active pill. Ovarian follicular recruitment with the low-dose formulations also begins much earlier during the pill-free week. As a result, breakthrough ovulation may be more likely with low-dose pills, especially if a woman misses any of the first pills in her next pill packet. In addition, patients have more time to develop estrogen-deficiency symptoms during the 7 days of placebo pills. To reduce the 7-day hormone-free interval, one formulation (Mircette) replaced the last five placebo pills with five pills containing 10 µg of EE. Two newer formulations (Yaz and Loestrin 24 Fe) include 24 active low-dose pills and either four placebo pills (Yaz) or four pills with ferrous sulfate (Loestrin 24 Fe) in their 28-day pill packet.

The most profound change in pill packaging and in pill-utilization patterns is the elimination or at least minimization of the number of withdrawal bleeding episodes a pill user experiences each year. Monthly withdrawal bleeding was critical to the acceptance of Enovid in 1960. Women wanted monthly reassurances that they were not pregnant. This was important because OCs were new and because the high-dose pills often caused symptoms that were suggestive of pregnancy, such as nausea, vomiting, and breast tenderness. In 1960, there were no rapid, early pregnancy tests, so the monthly withdrawal bleeding functioned as a home pregnancy test. The withdrawal bleed also signaled that “everything was still working” to women who might have been skeptical about how the pills might adversely impact their reproductive systems. When menstruation-like monthly withdrawal bleeding was built into the pill, it improved women's menses in two ways: OC withdrawal bleeding was generally shorter and lighter than the woman's usual spontaneous menstrual flow, and it was entirely predictable. For the first time, women could plan their lives and activities around their menses rather than having the menses interrupt their lives.

Extended Cycle Pills

Currently, we recognize that the placebo pill–induced withdrawal bleeding is not medically necessary and that it causes measurable suffering. Elimination of the pill-free interval also reduces breakthrough ovulation (Archer et al., 2005; Pierson et al., 2005). Extended cycle use of hormonal contraceptives is clearly the wave of the future for most women. Although extended cycle use of any monophasic formulation is possible, the available FDA-approved extended cycle OCs (EE and levonorgestrel [Seasonale and Seasonique]) allow easier patient education and utilization, which is very important for young women. Many insurance plans allow women only one pack of pills/month; extended cycle packages require fewer return trips for refills and less negotiation with pharmacists in months that last>28 days. Seasonale has 84 pills containing 30 µg EE with 0.15 mg levonorgestrel followed by 7 placebo pills. To reduce second cycle spotting, the seven placebo pills are replaced with 10 µg EE tablets in Seasonique. Lybrel was approved in May 2007 and includes 365 active pills per year. Other formulations with lower-dose pills (20 µg EE) in 84/7 configurations.

Drug Interactions

Drugs that induce hepatic enzymes can decrease serum concentrations of the estrogen or progestin components of

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combination hormonal contraceptives and increase failure rates (see Table 43.2).

TABLE 43.1
Estrogen-Containing Contraceptive Formulations Currently Available in the United States

O, Ortho-McNeil Pharm; B, Barr; W, Watson Labs; EE, ethinyl estradiol; S, GD Searle LLC; V, Warner-Chilcott; J, Johnson RW; A, Andrx Pharms; D, Duramed Pharms (Barr); C, Berlex; Z, Wyeth Pharms Inc.; N, Organon USA Inc; Y, Wyeth-Ayerst.
a Trademark abandoned.

Progestin-only pills

Major Brand Name

Companies

 

Progestin (21 pills)

Inactive Pills

Other Names

Companies

Ortho Micronor

O

 

Norethindrone 0.35 mg

7

Camila

B

         

Errin

B

         

Jolivette

W

         

Nor-QD

W

         

Nora-BE

W

Mestranol, 50 µg—Monophasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (21 pills)

Inactive Pills

Other Names

Companies

Norinyl 1 + 50 21-d

W

 

Norethindrone, 1 mg

0

Necon 1/50 21

W

         

Norethina1/50M-21

W

Ortho-Novum 1/50–28

O

 

Norethindrone, 1 mg

7

Necon 1/50 28

W

         

Norethina1/50M-28

W

         

Norinyl 1 + 50 28-d

W

EE, 50 µg—Monophasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (21 pills)

Inactive Pills

Other Names

Companies

Demulen 1/50–21

S

 

Ethynodiol diacetate, 1 mg

0

Zovia 1/50E-21

W

Demulen 1/50-28

S

 

Ethynodiol diacetate, 1 mg

7

Zovia 1/50E-28

W

Ogestrel 0.5/50–21

W

 

Norgestrel, 0.5 mg

0

 

Ogestrel 0.5/50–28

W

 

Norgestrel, 0.5 mg

7

 

Ovcon 50

V

 

Norethindrone, 1 mg

7

 

EE, 35 µg—Monophasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (21 pills)

Inactive Pills

Other Names

Companies

Balziva-21

B

 

Norethindrone, 0.4 mg

0

 

Demulen 1/35–21

S

 

Ethynodiol diacetate, 1 mg

0

Zovia 1/35E-21

W

Demulen 1/35–28

S

 

Ethynodiol diacetate, 1 mg

7

Kelnor

B

         

Zovia 1/35E-28

W

Modicon 28

O

 

Norethindrone, 0.5 mg

7

Brevicon

W

         

Necon 0.5/35 28

W

         

Nortrel 0.5/35-28

B

Norinyl 1 + 35 21-d

W

 

Norethindrone, 1 mg

0

Necon 1/35 21

W

         

Norethina1/35E-21

W

         

Nortrel 1/35-21

B

Nortrel 0.5/35–21

B

 

Norethindrone, 0.5 mg

0

Necon 0.5/35 21

W

Ortho-Cyclen–28

J

 

Norgestimate, 0.25 mg

7

MonoNessa

W

         

Previfem

A

         

Sprintec

B

Ortho-Novum 1/35–28

O

 

Norethindrone, 1 mg

7

Necon 1/35 28

W

         

Norethina1/35E-28

W

         

Norinyl 1 + 35 28-d

W

         

Nortrel 1/35–28

B

Ovcon 35

V

 

Norethindrone, 0.4 mg

7

Balziva-28

 
         

Ovcon 35 chewable

 

EE, 30 µg—Monophasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (21 pills)

Inactive Pills +

Other Names

Companies

Nordette

D

 

Levonorgestrel, 0.150 mg

7

Levlin 28

C

         

Levora 0.15/30–28

W

         

Portia

B

Loestrin 21 1.5/30

B

 

Norethindrone, 1.5 mg

0

Junel 1.5/30

B

         

Microgestin 1.5/30

W

Loestrin FE 1.5/30

B

 

Norethindrone, 1.5 mg

75-mg ferrous fumarate (7)

Junel FE 1.5/30

B

         

Microgestin Fe 1.5/30

W

Low-Ogestrel-21

W

 

Norgestrel, 0.300 mg

0

Cryselle

D

Lo/Ovral-28

Z

 

Norgestrel, 0.300 mg

7

Cryselle

D

         

Low-Ogestrel

W

Ortho-Cept

O

 

Desogestrel, 0.150 mg

7

Apri

B

         

Desogen

N

         

Reclipsen

W

Seasonale

D

 

Levonorgestrel, 0.150 mg (84 pills)

7

 

Seasonique

D

 

Levonorgestrel, 0.150 mg (84 pills)

7 EE,10 µg

 

Yasmin

   

Drospirenone, 3.0 mg

7

 

EE, 20 µg—Monophasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (21 pills)

Inactive Pills +

Other Names

Companies

Alesse

Z

 

Levonorgestrel, 0.1 mg

7

Aviane

D

         

Lessina

B

         

Levlite

C

         

Lutera

W

Loestrin 21 1/20

B

 

Norethindrone, 1 mg

0

Junel 1/20

B

         

Microgestin 1/20

W

Loestrin FE 1/20

B

 

Norethindrone, 1 mg

75-mg ferrous fumarate (7)

Junel FE 1/20

B

         

Microgestin Fe 1/20

W

Mircette

N

 

Desogestrel, 0.150 mg

2 + EE, 10 µg(5)

Kariva

B

Lybrel (taken continuously 365 days/year)

W

 

Levonorgestrel, 0.90 mg

None

None

 

EE, 20 µg—Monophasic Oral Contraceptives 24-d active pill formulation

Major Brand Name

Companies

 

Progestin (24 pills)

Inactive Pills +

Other Names

Companies

Yaz

C

 

Drospirenone 3 mg

4

   

Loestrin 24 Fe

V

 

Norethindrone 1 mg

75 mg ferrous fumarate (4)

   

EE, 35 µg—Biphasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (pills)

Inactive Pills

Other Names

Companies

Necon 10/11–21

W

 

Norethindrone, 0.5 (10)

0

Gencepta10/11–21

B

     

Norethindrone, 1.0 mg (11)

     

Ortho-Novum 10/11–28

O

 

Norethindrone, 0.5 (10)

7

Gencepta10/11–28

B

     

Norethindrone, 1.0 mg (11)

 

Necon 10/11–28

W

EE, 35 µg—Triphasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (pills)

Inactive Pills

Other Names

Companies

Ortho-Novum 7/7/7–28

O

 

Norethindrone, 0.50 mg (7)

7

Necon 7/7/7

W

     

0.75 mg (7)

 

Nortrel 7/7/7

B

     

1.00 mg (7)

     

Ortho Tri-Cyclen 28

J

 

Norgestimate, 0.180 mg (7)

7

Tri-Previfem

A

     

0.215 mg (7)

 

Tri-Sprintec

B

     

0.250 mg (7)

 

TriNessa

W

Tri-Norinyl-28

W

 

Norethindrone, 0.50 mg (7)

7

Aranelle

B

     

1.00 mg (9)

 

Leena

W

     

0.50 mg (5)

     

EE, 20/30/35 µg—Triphasic Oral Contraceptives

Brand name

Companies

Estrogen (pills)

Progestin (pills)

Inactive Pills +

Other Names

Companies

Estrostep 21

V

EE, 20 µg(5),30 µg(7), 35 µg(9)

Norethindrone, 1 mg(5)

0

   
     

1 mg(7)

     
     

1 mg(9)

     

Estrostep FE

V

EE, 20 µg(5),30 µg(7), 35 µg(9)

Norethindrone, 1 mg(5)

75-mg ferrous fumarate (7)

   
     

1 mg(7)

     
     

1 mg(9)

     

EE, 30/40/30 µg—Triphasic Oral Contraceptives

Brand name

Companies

Estrogen (pills)

Progestin (pills)

Inactive

Other Names

Companies

Triphasil-28

Z

EE, 30 µg(6),40 µg(5), 30 µg (10)

Levonorgestrel, 0.050 mg (6)

7

Enpresse

D

     

0.075 mg (5)

 

Tri-Levlen 28

C

     

0.125 mg (10)

 

Trivora-28

W

EE, 25 µg—Triphasic Oral Contraceptives

Major Brand Name

Companies

 

Progestin (pills)

Inactive Pills

Other Names

Companies

Cyclessa

N

 

Desogestrel, 0.100 mg (7)

7

Velivet

B

     

0.125 mg (7)

     
     

0.150 mg (7)

     

Ortho Tri-Cyclen Lo

O

 

Norgestimate, 0.180 mg (7)

7

   
     

0.215 mg (7)

     
     

0.250 mg (7)

     

Anticonvulsants

Anticonvulsants are the most common class of drugs known to have this effect. These drugs are of particular concern because they are also teratogens. The anticonvulsants that increase hepatic clearance include barbiturates (phenobarbitol and primidone), phenytoin, carbamazepine, felbamate, topiramate, and vigabatrin and are all known to decrease serum steroid levels in women taking OCs. Instead, women using these agents may be better served by using progestin injections or intrauterine contraceptives. If OCs are desired, low-dose formulations (<35 µg EE) or progestin-only pills should not be prescribed for women using these anticonvulsants. The 35-µgEE formulations should be used with caution. If a 3-month trial of 35-µg EE pills coupled with condoms yields continued breakthrough bleeding, a 50-µg EE formulation may be necessary. It should be recognized that no published data support the enhanced contraceptive efficacy of higher-dose (50 µg EE) pills (ACOG Committee on Practice Bulletins-Gynecology, 2006). Clinicians should avoid the use of 50-µg mestranol-containing pills in this situation, as 50 µg of mestranol converts to substantially lower levels (35–40 µg) of EE. There are also no data about the effectiveness of nonoral delivery systems of combination hormonal contraceptives used with these drugs. The transdermal method may be attractive, as the total estrogen delivery is higher than with 35 µg pills, but no specific studies of efficacy have been published. It is advisable to shorten or eliminate the hormone-free interval when any of the combination hormonal contraceptives are used in women taking any of these anticonvulsants. Not all anticonvulsants impact liver metabolism; valproic acid, gabapentin, lamotrigine, and tiagabim do not affect sex steroid levels.

Antibiotics

Contrary to popular belief and, in some cases, product labeling, there are only two anti-infective agents that decrease steroid levels in women taking combination OCs. These drugs are rifampin and griseofulvin. Isoniazid increases hepatic transaminase levels and may mask markers of an estrogen-induced hepatoma. Other more common anti-infective agents that do NOT decrease steroid levels in women taking combination OCs include tetracycline (Murphy et al., 1991), doxycycline (Neely et al., 1991), ampicillin (Joshi et al., 1980; Friedman et al., 1980), metronidazole (Joshi et al., 1980), and quinalones (Maggiolo et al., 1991; Back et al., 1991; Csemiczky et al., 1996). Routine use of backup methods with these antibiotics is not warranted (World Health Organization, Department of Reproductive Health and Research, 2005).

St. John's Wort

Studies have suggested that St. John's wort, which is sold over-the-counter to treat mild-to-moderate depression, may halve the circulating levels of sex steroids. One placebo-controlled study found that unscheduled bleeding was significantly higher in OC users who took St. John's wort; large follicles (≥30 mm) were seen at higher rates in St. John's wort users (40% versus 6%); and ovulation was detected in up to five times as many women if they used St. John's wort (Murphy et al., 2005).

Other Interactions

Some antiretroviral drugs induce hepatic enzymes and lower circulating steroid levels, whereas others decrease such activity and raise the steroid levels. Tobacco use also increases metabolism of sex steroids.

Mechanisms of Action

  1. Thickening of cervical mucus: The progestin component produces thick, viscous, scant cervical mucus that blocks sperm penetration into the upper genital tract. This is the single most important mechanism of action common to all hormonal methods of contraception.
  2. Inhibition of ovulation: The progestin-only pill contains such a low dose of progestin that ovulation is inhibited in only 40% to 60% of cycles. Combination pills, however, contain higher doses of progestin and suppress ovulation in 95% to 98% of cycles by inhibiting the surge in luteinizing hormone (LH). With combination pills, levels of follicle-stimulating hormone (FSH) are decreased by estrogen to 70% of normal; LH levels are only 20% of those found in women who are not taking OCs.
  3. Endometrial changes: The presence of a progestin early in the cycle induces a thin endometrium with atrophic glands and minimal glycogen stores, which is not conducive to implantation. However, the contribution these endometrial changes make to contraceptive efficacy is undoubtedly minimal, because fertilization is so profoundly prevented by ovulation suppression and impenetrable cervical mucus.
  4. Slowed tubal motility: The progestin in the pill slows tubal motility and disrupts the carefully orchestrated sequence of events necessary for successful fertilization and implantation. Again, the role that this theoretical mechanism plays in providing contraception is minor, because the ectopic pregnancy rates are significantly reduced by all combination hormonal methods.

Work-up Needed for Pill Initiation

A complete medical history is needed to identify any contraindications requiring further evaluation (see subsequent text). Blood pressure measurement is prudent before starting estrogen-containing contraceptives. Breast examination may also be needed. No other examinations are needed before initiating OCs (Stewart et al., 2001; World Health Organization, Department of Reproductive Health and Research, 2005). Having determined that the young woman wants to use birth control pills and is a good candidate, the next questions that arise are how to initiate the pills, how many packs to dispense, and when to schedule a return visit.

Pill Initiation

Quick Start/Same-Day Start

The quick start or same-day start of birth control pills is the most attractive protocol to use with adolescent women. Teens are often in acute need for immediate contraception. Studies have shown that up to 25% of teens given prescriptions to start their pills with their next menses never start them (Westhoff et al., 2003). The most common reasons for not starting pills include interval pregnancy, change in method, confusion about pill instructions, and fear about possible side effects. Virtually all of these barriers can be overcome by immediate initiation of the pills. If the clinician is reasonably certain that a woman is not pregnant, she should be told to

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start taking her pills the same day (starting with the first one in the pack) and to abstain from intercourse or to use condoms for the next 7 days. If she has had unprotected sexual intercourse within the previous 5 days, administer two levonorgestrel emergency contraceptive pills immediately and have her start the first pill in her pack the next day. Sensitive urine pregnancy testing may be performed if there is anything in her history that raises suspicion of an ongoing pregnancy. The patient should be advised that her next menses will be delayed and will start with the placebo pills. If she fails to have a withdrawal bleed or has any symptoms of pregnancy, she should have pregnancy testing done as soon as possible. There is no concern that birth control pills are teratogenic, but early diagnosis of pregnancy is always important (Ahn, 2005).

TABLE 43.2
Drug Interactions

Drugs that decrease contraceptive hormonal levels and/or efficacy

FFPRHC, Faculty of Family Planning and Reproductive Health Care
a Measuring serum levels after contraceptive initiation may be appropriate.
Adapted from ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. The use of hormonal contraception in women with coexisting medical conditions. Number 18, July 2000. Int J Gynaecol Obstet 2001;75(1):93.
Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit. FFPRHC Guidance (April 2005). Drug interactions with hormonal contraception. J Fam Plann Reprod Health Care 2005;31(2):139.

·         Anticonvulsants that decrease ethinyl estradiol (EE) and progestins

o    Barbiturates (including phenobarbital and primidone)

o    Carbamazepine

o    Felbamate

o    Oxcarbazepine

o    Phenytoin

o    Topiramate

o    Vigabatrin (Listed on ACOG Committee on Practice Bulletins-Gynecology, 2000, but research and FFPRHC find no impact)

·         Antibiotics/antifungals that reduce EE and progestins

o    Rifabutin

o    Rifampicin

o    Griseofulvin (pregnancies documented)

·         Antiretrovirals that reduce EE and progestins

o    Protease inhibitors

§  Amprenavir

§  Atazanavir

§  Nelfinavir

§  Lopanavir

§  Saquinavir

§  Ritonavir

o    Nonnucleoside reverse transcription inhibitors

§  Efavirenz

§  Nevirapine

·         Other agents that induce liver enzymes

o    Lansoprazole (no reduction in EE)

o    Tacrolimus (no published evidence of decreased efficacy)

o    Bosentan (no published evidence of decreased efficacy, but potent teratogen requiring monthly pregnancy testing)

o    Modafinil

Drugs whose effects may be altered by use of combination hormonal contraceptives

 

Decreased clinical effect

·         All antihypertensives

·         Antidiabetics

·         Anticoagulants:Phenidione, Warfarin

·         Tricyclic antidepressants

Hypotensive effect may be antagonized
Hypoglycemic effects maybe antagonized
Anticoagulant effect reduceda
Antidepressant effects of tricyclics may be reduced, but side effects may increase because serum concentration increased. No evidence identified
Increased clinical effect

·        Immunosuppressants:Cyclosporin

·         Corticosteroid

·         Bronchodilators:Theophylline

·         Dopaminergics:Ropinirole

·         Potassium-sparing diuretics

Serum levels increased; potential toxicity
Serum levels increased; no significant clinical effect
Serum levels increased; potential toxicity
Serum levels increased; no significant clinical effect
Drospirenone may lead to hyperkalemiaa

Reassuringly, clinical studies that compared women who used quick start with those who used conventional start of OCs found no increase in the number of days of unscheduled spotting, or bleeding. In fact, the only significant difference between the two groups was that many more of the quick start users (72%) were on the pill 3 months later than were the conventional start users (56%) (Lara-Torre and Schroeder, 2002; Westhoff et al., 2003).

Quick Start in Women with Irregular Menses

For women who do not have regular menses, the same quick start initiation rules apply. For example, if a woman is amenorrheic, she can start OCs at any time if it is reasonably certain that she is not pregnant. She will need to abstain or to use the backup method for 7 days. If a patient has just had an abortion (spontaneous or elective), she can start using OCs immediately; no backup method is necessary. If a woman is switching from another method, she can start pills immediately. There is no need to wait for menses. She will need to use a backup method for 7 days if there has been any interruption in her prior protection (e.g., >13 weeks since her last depot medroxyprogesterone acetate [DMPA] injection, late for restart of patches, etc.). In each of these circumstances, the need for emergency contraception (EC) should be evaluated.

First Day Start

If quick start of OCs is not possible, then the first day start is acceptable. With this protocol, the patient is given an interval method (condoms) to use until the first day of her next menses, when she should start her pills. No backup method is needed after a first day start. The patient may need to align the pills in her pack to correspond to her pill-taking day.

Sunday Start

The least attractive pill initiation protocol is the Sunday start. The most significant drawback for the Sunday start is that if a patient needs last-minute refills, she may have difficulty getting in touch with her provider during the weekend. Furthermore, as a Sunday start represents a start on cycle day 1 to 6, instructions for backup methods can be unduly complex, confusing, and are often ignored. However, sometimes the pill packets require a Sunday start.

Condoms

All teens should be given condoms and taught how to use them, even if they select OCs. This is important because teens need dual methods to help reduce the risk of sexually transmitted diseases. In addition, many will decide to discontinue the pill before they return for their scheduled follow-up visit (Rosenberg et al., 1995). If those young women are knowledgeable about condom use and have a supply of condoms available, they may be less likely to have unprotected intercourse. Because many women will forget to take all their pills, providing a prescription for EC in advance of need is an important part of OC initiation. At the time of pill initiation, be sure to review with the patient when she is to take her pills, where she plans to store them, what she should do about missed pills, and how she plans to remember to take her pills.

When OCs are initiated, two other practical and somewhat interrelated issues arise: How many cycles to dispense/prescribe, and how soon to see the patient in follow-up.

Prescription Length and Follow-up Appointments

For adult women, the World Health Organization (WHO) recommends that a year's requirement of OCs be given to reduce barriers to access (World Health Organization, Department of Reproductive Health and Research, 2005). However, adolescent women have relatively high rates of brand switching and method switching. Pills that are generously dispensed to a woman cannot be recalled and used by other patients if she changes methods or formulations. For that reason, clinics often limit initial users to three packs. Insurance companies may limit dispensing even more stringently for other reasons: To guarantee that a woman is still under their plan at the time she uses her pills, that she will not switch brands or methods, and that she pays a full co-pay for each pack of pills. In adolescents, the OC discontinuation rate is high and teenaged girls often think of new questions as they use their pills. For these reasons, the traditional 3-month follow-up visit is still important for new-start adolescents. In some situations, it may be advisable to see the teen in 1 month and again at 3 months after pill initiation.

Noncontraceptive Benefits Important to Adolescent Women

Decreased Menstrual Discomfort

Cyclically administered combination OCs significantly reduce monthly menstrual blood loss, the number of days of bleeding, and dysmenorrhea. Mittelschmerz is eliminated in most women because ovulation is inhibited in all but a very small percentage of cycles. Women with anovulatory cycles or dysfunctional uterine bleeding—common problems in adolescents—achieve predictable, controlled cycles with the use of OCs. Women who are taking medications that increase menstrual blood loss (e.g., anticonvulsants, anticoagulants) benefit from these impacts of OC use. Women who have bleeding disorders also benefit from suppression of ovulation, which reduces their risk of internal hemorrhage each month.

Dysmenorrhea is a particularly important problem faced by adolescent girls (see Chapter 50). Dysmenorrhea inflicts considerable suffering and compromises the young woman's productive potential. Painful menses is the single greatest reason why women younger than 25 years miss days at school and work (Davis et al., 2000). OCs significantly reduce dysmenorrhea, even when given in traditional cyclic manner. In a placebo-controlled study of teenaged girls with moderate-to-severe menorrhea, the mean overall pain scores decreased significantly in OC users by 3 months (Davis et al., 2005).

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Premenstrual tension syndrome may be reduced by the cyclic use of combination OCs. One formulation (Yaz) has been proved to be an effective treatment for premenstrual dysphoric disorder (Yonkers et al., 2005).

More creative applications of birth control pills, such as extended use of monophasic active pills (“bicycling,” “tricycling,” or continuous use), can provide even more benefits to women who have dysmenorrhea or exacerbations of their medical problems during menses. For example, women who have menstrual-related migraine headaches, catamenial seizures, or asthma exacerbations with menses can eliminate those problems by eliminating the placebo pills and avoiding hormone withdrawal. The first FDA-approved product for this was Seasonale. Other variations are expected soon. Flexibility in pill use can allow women to control more routinely when they have their menses. Health care providers frequently use OCs to avoid onset of menses while a patient is on her honeymoon; these same techniques can prevent menses from interfering with other important events in young women's lives.

Improvement in Acne, Hirsutism, and Other Androgen Excess Problems

The FDA has approved 3 brands of oral contraceptives for the treatment of mild-to-moderate cystic acne in women desiring to use oral contraceptives (Ortho Tri-Cyclen, Estrostep and Yaz). By reducing ovarian production of androgens and reducing circulating levels of free testosterone (through increased hepatic production of sex hormone–binding globulin [SHBG]), these OCs reduce the number of lesions and their intensity. Maximal beneficial effects in the clinical trials were seen at 6 months, which might encourage longer-term use. Hair shaft diameter is smaller in OC users, although this beneficial impact of OCs on hirsutism may take 12 months to become clinically apparent.

Treatment of Hypothalamic Hypoestrogenism

Many adolescents have eating disorders (e.g., anorexia nervosa, bulimia), excessive exercise programs, and/or stresses that suppress gonadotrophin production and create a hypoestrogenic state (see Chapters 33 and 52). The lack of estrogen in a teen can compromise bone mineral density accumulation and put her at risk for osteoporosis and fracture at an early age (Gordon and Nelson, 2003). Although it is important to deal with the underlying problems that cause hypoestrogenism, it may also be important to supply adequate estrogen to promote bone health. In most circumstances, the physiological doses of estrogen used to prevent bone loss in postmenopausal women are not adequate to build bone density in adolescent girls. Birth control pills have been the mainstay of therapy in treating women with the athletic triad (Hergenroeder et al., 1997). However, the skeletal benefits of estrogen continue to be debated among different patient groups (Liu and Lebrun, 2006). In addition, because menses may compromise athletic performance, many coaches oppose OC use unless the pills can be used in extended cyclic manner to maintain amenorrhea.

Reduce the Risk of Ovarian and Endometrial Carcinoma

OCs are the only medical intervention with strong evidence that they reduce the risk of developing ovarian cancer later in life. Women who have used OCs for at least 1 year reduce their risk of developing epithelial ovarian cancer by 40%. Long-term users (>10 years) enjoy an 80% reduction in risk. This effect endures for>15 years after the last pill. Ovarian cancer protection is most clearly demonstrated when the pill is taken by young women, just as childbearing and breast-feeding reduce ovarian cancer risk only if they occur before 30 years of age. A case–control study suggested that carriers of the BRCA1 genetic mutation also experience a reduction in ovarian cancer with OC use (Narod et al., 1998). Two mechanisms have been postulated to explain this risk reduction—the inhibition of “incessant ovulation” and increased follicular cell apoptosis.

OC use at any time during the reproductive years significantly reduces a woman's risk of developing any of the three major histological forms of endometrial carcinoma by providing progestin. This protection increases with longer duration of use; women who use OCs for 12 years reduce their risk of endometrial carcinoma by 72%. This protection endures 19 years beyond the last pill use (Schlesselman, 1995). Women with anovulatory cycles achieve the greatest risk reduction.

Other Health Benefits

Anemia is reduced because menstrual blood loss is diminished by OC use. This can benefit women with sickle cell disease and those with iron deficiency anemia. The thickened cervical mucus induced by OCs can block migration of bacteria into the upper genital tract, which reduces a woman's risk of acquiring gonococcal-related pelvic inflammatory disease. Long-term OC use has also been associated with a reduction in benign breast changes.

Metabolic Impacts

Both estrogen and progestin have important metabolic effects, with which clinicians should be familiar (Fig. 43.1). In many formulations, the estrogen-induced metabolic impacts may be partially cancelled by the androgenicity of the progestin acting as an antiestrogen. This is why different pills with the same dose of estrogen, but with different progestins or different doses of the same progestin, may have different estrogenic impacts. In general, the second-generation progestins (norgestrel and levonorgestrel) have greater androgenicity than do the first-generation progestins (norethindrone compounds) or the third-generation progestins (norgestimate and desogestrel). The newest progestin, drosperinone, hasantiandrogenic activity itself, and it allows full expression of the estrogen's impact. By the same logic, the androgen-induced metabolic impacts are partially canceled by the estrogen component of the pill. The net metabolic impact of each formulation differs. These differences may be helpful in selecting formulations for women with different medical problems or side effects.

Coagulation Factors

Factors associated with the extrinsic clotting pathway (fibrinogen and factors I, V, VII, VIII, and X) are uniformly increased by estrogen-containing birth control pills in proportion to their estrogen dose. The percutaneous delivery system may have different dose-dependent impacts on coagulation factors than seen with OCs. Most women balance their increases in clotting factors by inducing compensatory increases in their fibrinolytic and anticoagulation factors. However, some women are genetically unable to compensate. The clinical

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significance of these changes is discussed later in the section Thromboembolism.

 

FIGURE 43.1 Metabolic effects of oral contraceptives. HDL, high-density lipoprotein; LDL, low-density lipoprotein; Na, sodium.

Binding Globulins

Estrogen increases hepatic synthesis of carrier proteins such as albumin, SHBG, thyroxine-binding globulin (TBG), and corticosteroid-binding globulin (CBG). These increases can affect the interpretation of some laboratory tests (such as total thyroxine), but do not affect measures of unbound hormones (such as FT4). Increased levels of SHBG bind free testosterone and reduce androgen-induced changes such as hirsutism and acne (see earlier discussion).

Angiotensin

The estrogen component of the combination birth control pill increases angiotensin by increasing hepatic production of its precursor. Angiotensin can cause reversible hypertension in vulnerable patients. However, angiotensin sensitivity is difficult to predict. The pill also activates adrenal production of aldosterone, which causes fluid retention and contributes to higher blood pressure. A history of pregnancy-induced hypertension is not predictive nor is an increased risk for the development of increased blood pressure with OC use. However, women who have experienced hypertension with OC use in the past face at least a 10% risk of recurrence if rechallenged with estrogen-containing contraceptives.

Lipid Metabolism

Triglyceride levels are increased by approximately 20% to 30% with exogenous estrogen use. However, estrogen-induced triglycerides are composed of remnants that are not generally conducive to plaque formation. Triglycerides may pose a problem if a patient has baseline elevated triglyceride concentrations near a range predisposing to pancreatitis (>500). Estrogen also increases total cholesterol, high-density lipoprotein (HDL) cholesterol, while decreasing low-density lipoprotein (LDL) cholesterol. The androgenic component of the progestin has the opposite effect. The net impact on lipids, therefore, varies with different formulations. The third-generation progestins, designed to have greater selectivity for progestin receptors, have less androgenic impacts. In combination with estrogen they cause no significant changes in LDL. The drosperinone-containing pills have antiandrogenic effects and have the most notable impacts on reducing LDL and raising HDL. First-generation progestins at lower doses also have minimal impacts on lipid metabolism. The second-generation progestins and higher doses of the first-generation progestins have a slightly adverse impact on HDL/LDL ratio. The clinical significance of this impact has been questioned by experiments showing that OC usage in female monkeys was accompanied by a decrease in coronary artery plaque formation despite adverse lipid impacts (Clarkson et al., 1990). However, until human data are more firmly established, patients with dyslipidemia should be closely monitored when they use combination hormonal methods.

Glucose Metabolism

Both estrogen and progesterone have been implicated in influencing glucose metabolism—estrogen may suppress insulin production and progesterone can increase peripheral insulin resistance. With higher hormonal doses, older formulations of birth control pills were noted to cause deterioration in glucose tolerance. Most studies have found that modern pill formulations with lower hormonal doses cause no impairment in glucose tolerance in euglycemic women, but some minor impact of insulin resistance remains (Godsland and Crook, 1994). Even in high-risk patients, however, this is not clinically significant. In a prospective study of women with a history of gestational diabetes who used low-dose OC pills, Kjos et al. (1998) reported no acceleration in the development of glucose intolerance or overt diabetes compared with similar women using nonhormonal contraceptives. OC use in women with overt diabetes rarely changes insulin requirements and has been shown not to increase the risk of diabetic nephropathy or retinopathy.

Contraindications

Medical complications that are considered to be contraindications for estrogen-containing contraceptive use on the basis of current scientific evidence are listed in Table 43.3

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as WHO category 4. The contraindications from product labeling are also listed in that table. Apart from the different categories used for the major problems, there are some profound differences between the two lists. For example, endometrial cancer is listed as an absolute contraindication to OC use on product labeling, but is rated by WHO as category 1 (no restriction on use). Similarly, a history of cholestatic jaundice is a contraindication on the labeling, but has been found to be only a relative contraindication by recent scientific evidence (WHO category 2). These differences underscore the need to be familiar with more than product labeling when addressing an individual woman's contraceptive needs. The full WHO list is in Table 42.3.

TABLE 43.3
Absolute Contraindications to Estrogen-Containing Contraceptives

On Label

WHO Category 4

WHO, World Health Organization; DVT/PE, deep vein thrombosis/pulmonary embolism; CVA, cerebral vascular accident; BPS, systolic blood pressure; BPD, diastolic blood pressure.

Exclusive breast-feeding

Breast-feeding ≤6wk

History of thromboembolism

Current or history of DVT/PE

History of thrombophilia

Known thrombogenic mutation

Coronary artery disease

Current or history of ischemic heart disease

Cerebral vascular disease

Stroke (history of CVA)

Known or suspected cancer of the breast

Current breast cancer

Hepatic tumor (benign or malignant)

Liver tumors (benign or malignant)

History of cholestatic jaundice or jaundice with prior pill use

Known or suspected cancer of the endometrium or other estrogen-sensitive neoplasm

Unexplained abnormal vaginal bleeding

Known or suspected pregnancy

postpartum (<3wk)

 

Age ≥35 years and smoking ≥15 cigarettes/d

 

BPS>160 or BPD>100

 

Hypertension with vascular disease

 

Major surgery with prolonged immobilization

 

Complicated vascular heart disease

 

Migraine headaches with aura

 

Active viral hepatitis

 

Severe cirrhosis

Health Issues and Risks with Combination Hormonal Contraceptive Use

A summary of the serious side effects traditionally associated with combination hormonal contraceptive use is provided in Table 43.4, with estimates of both relative risk (RR) and absolute risk. These estimates are based on a mixture of newer and older formulations, as well as different age-groups. More specific information about selected issues is provided in the following paragraphs.

Thromboembolism

Estrogen-containing combination hormonal contraceptives increase hepatic production of extrinsic clotting factors. Some women, such as those with anticardiolipin antibodies or factor V Leiden mutation, are unable to compensate for this increase in clotting factors and may be subject to a substantially increased risk for thromboembolic events. The overall RR of thrombosis is between 2.6 and 4.0; the absolute incidence of venous thrombosis is 15 to 30 per 100,000 women-years for most of the low-dose OC formulations. The first-year RRs of venous thromboembolism are even higher, but these rates are still lower than the incidence of venous thromboembolism in healthy pregnant women (approximately 60 per 100,000).

Reports in the mid-1990s that third-generation progestins (desogestrel and gestodene) may have had more profound thrombotic impacts (three 1995 articles from the WHO [World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, 1995a, b, c]) were questioned by later analysis, which controlled for selection bias (Lewis, 1999). The fact that the rates of thromboembolism in the United Kingdom increased after the market share of the third-generation OC formulations decreased from 40% to 5%, suggests the lack of increased risk with third-generation progestins. Labeling reflects the uncertainty of the data.

However, the controversy highlighted the need to identify women at risk of venous thromboembolism when taking OCs, not only on the basis of a personal history of prior thromboembolic events but also by inquiring about family history. Suspect histories are those with multiple family members who experienced multiple unexplained clots, generally at an early age. Routine laboratory screening of all potential OC candidates for coagulopathies is inappropriate because it is clearly not cost effective and because

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current testing cannot identify all at-risk women. Screening of high-risk women should be considered. The recommendation to stop estrogen-containing contraceptives 1 month before scheduled surgery has been tempered to reflect modern surgical practices. OC use may not need to be interrupted if a low-risk patient is not expected to require prolonged postoperative bed rest; higher-risk women and low-risk women undergoing high-risk procedures should respect the 30-day rule before elective surgery.

TABLE 43.4
Serious Side Effects Associated with Oral Contraceptive Use

Adverse Effects

Relative Risk

Absolute Risk

Courtesy of Paul Brenner, M.D., University of Southern California.

Cholelithiasis

1:1,250

Myocardial infarction (smokers aged>35 yr)

1:5,000

Thrombophlebitis

1:10,000

Thromboembolism

1:30,000

Stroke

1:30,000

Hepatic adenoma

500×

1:50,000

Mild hypertension

2–3×

<1:20

Studies with low-dose formulations have detected no overall increased risk of hemorrhagic or ischemic stroke in healthy young women using OC, but one study did find that women who reported a history of migraine headaches doubled their risk of stroke with OC use (Schwartz et al., 1998). Analysis of the Transnational Research Group study concluded that the attributable risk of occlusive stroke for healthy OC users is very small and is overwhelmed by other risk factors, such as hypertension and smoking (Heinemann et al., 1998).

Cardiovascular Disease

Low-dose OCs (<50 µg EE) do not increase the risk of myocardial infarction (MI) in healthy, nonsmoking women. OCs do not increase plaque formation in adolescents; researchers reported a decrease in intima-media thickness in new-start OC users (Kapella et al., 2005). There are clearly identified groups of at-risk women. Smokers at all ages have increased risks for cardiovascular disease when they use OCs. In the study by Dunn et al. (1999), the adjusted odds ratio for MI in OC users who smoked 20 or more cigarettes/day was 12.5 (95% confidence interval [CI], 7.3 to 21.5). Schwingl et al. (1999) estimated that the attributable risk of death from cardiovascular disease resulting from OC use is 0.06 per 100,000 nonsmokers aged 15 to 34 years. In smokers, this risk rises to 1.73 per 100,000. However, the absolute risk of death with OC use in smokers is less than the risk of death during pregnancy until women are 35 to 40 years old. Smoking cessation should always be promoted in teens, but they do not need to avoid pill use if they continue to smoke. Selection of a low-androgenic formulation may be prudent for smokers (Straneva et al., 2000), as would shortening the pill-free interval, as smokers metabolize estrogen more rapidly.

Hypertension

Up to 3% of OC users experience increased blood pressure while using birth control pills. Estrogen is responsible for much of this risk. OCs also stimulate adrenal production of aldosterone, which can lead to rise in blood pressure induced by fluid retention. The increases in both diastolic and systolic measures are usually reversible within 3 months of pill cessation. If the hypertension does not spontaneously resolve, then other etiologies must be considered. The need for initial therapy depends on the severity of the hypertension.

Liver and Gallbladder Effects

A doubling of the risk of gallstones has been suggested by several prospective and retrospective studies. Although the increase in risk was more impressive with higher-dose pills, it may still be seen with the lower-dose formulations. Cholelithiasis is due to increased cholesterol saturation and biliary stasis. The risk appears to be concentrated in a few short-term users who may be prone to gallbladder disease.

Cholestatic jaundice is very rare, but it has been reported as a result of using estrogen-containing contraceptives.

Pruritus similar to that seen in pregnancy may develop with usage of estrogen-containing contraceptives.

Impact of Combination Hormonal Contraceptive Use on Neoplasia

The single largest concern women voice about OC use is the risk of cancer. Almost one third of all women believe that OCs cause cancer, but only a small minority is aware that OC use decreases the incidence of ovarian and endometrial cancer. A few of the more pertinent neoplasms in adolescents are discussed here.

Leiomyoma

Historically, there has been concern that OC use might stimulate growth of leiomyomas (fibroids), because they are known to be estrogen-sensitive tumors. Chiaffarino et al. (1999)found in a case–control study of 843 women with fibroids that the risk for current users of OCs was lower than for those who had never used OCs (RR, 0.3; 95% CI, 0.2 to 0.6). The risk of uterine fibroids decreases with duration of OC use. Marshall et al. (1998) also reported a reduction in risk of fibroids in current OC users; however, he noted a higher risk (RR, 1.26; 95% CI, 1.05 to 1.51) for development of clinically diagnosed fibroids in nurses who started using OCs at age 13 to 16 years, compared with never-users. This modest risk should not deter OC use by adolescents, because this association may reflect an earlier age of menarche, which is itself a risk factor for fibroids.

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Women who have existing fibroids are often successfully prescribed OCs to reduce their menorrhagia.

Cervical Cancer

OC use for>5 years causes a slight increase in the risk of cervical dysplasia. However, the risk for squamous cell carcinoma does not appear to be affected by OC use. The risk of adenocarcinoma of the cervix may be increased, although this has not yet been conclusively demonstrated. OC users do not require any more intensive or more frequent Pap smears than their relevant risk factors (e.g., age, number of sexual partners, exposure to human papillomavirus, smoking) would routinely dictate.

Breast Cancer

In contrast to the obvious benefits OCs have in reducing the risks of endometrial and ovarian cancer, the impact of OCs on breast cancer has been more controversial. In humans, there is no evidence that either estrogen or progestin can initiate the development of abnormal mitotic figures in normal breast cells. However, breast cancer cells do divide more rapidly in the presence of estrogen.

Epidemiological studies of present and past OC users have presented conflicting results, but virtually all the risk ratios for breast cancer calculated in these studies show either no increased risk or a small and temporary increased risk, especially with low-dose formulations.

The Cancer and Steroid Hormone (CASH) study of the Centers for Disease Control and Prevention (CDC) found no overall increase in breast cancer with OC use (Centers for Disease Control and Prevention, 1983), but in young women who used the pill, the risk of development of breast cancer by the age 35 years was raised by 2 to 3 cases per 100,000 women (Centers for Disease Control and Prevention, 1984). Importantly, these researchers investigated several high-risk groups and found that OC use was not associated with an increased incidence of breast cancer in the following important subgroups (a) women with a family history of breast cancer, (b) women with and without benign breast disease, and (c) women who started using OCs before their first pregnancy.

The Collaborative Group on Hormonal Factors in Breast Cancer (1996) meta-analysis of 54 studies from 23 countries reported that current users and women who had used OCs within the previous 10 years had a slightly increased risk of developing breast cancer (RR, 1.24; 95% CI, 1.15 to 1.33). Women who started OC use before 20 years of age had an even higher increase in risk when they were current or recent users. However, the magnitude of this increased risk was minimal; the estimated excess numbers of cancers diagnosed up to 10 years after stopping use was 0.5 per 10,000 women. The risk was reversible; no group displayed any increased risk 10 years after stopping OCs. No duration of usage effect was seen. More importantly, the increase in breast cancer was concentrated in the development of localized disease; in fact, the meta-analysis demonstrated that the risk of metastatic breast cancer with lower-dose pills was not increased among current or recent OC users.

Marchbanks et al. (2002) studied women aged 35 to 64 years and found no increased risk of breast cancer in current or past OC users. No increased risk was seen in women with family history of breast cancer or in women who used pills early in their reproductive lives. Norman et al. (2003) reported the results of a population-based case–control study of 1,847 postmenopausal women with invasive breast cancer and 1,932 normal controls and found that OC users were not at increased risk for invasive breast cancer. The risk of breast cancer was highest in women using postmenopausal hormone therapies, who had never used OCs.

On the basis of all these studies, it is not appropriate to deny any adolescent girl hormonal contraceptives even if she has fibrocystic breast changes or a family history of breast cancer. A strong family history of breast cancer, including (at a minimum) one affected first-degree relative is at most, a relative contraindication for the use of modern, low-dose pills. Only a personal history of breast cancer is a contraindication.

Side Effects

As described earlier, the sex hormones in OCs have various degrees of progestogenic, estrogenic, antiestrogenic, and androgenic activities. These differences are important to understand, especially when responding to a patient's concerns about side effects. The impacts of the relative potencies of different formulations vary from individual to individual.

Prospective, double-blind, placebo-controlled studies that were conducted to evaluate the role of the triphasic, norgestimate-containing birth control pills in treating acne provided a unique opportunity to evaluate the incidence of side effects with modern low-dose pills (Redmond et al., 1999). In the 6-month study period, the placebo group had the same incidence of headache, nausea, mastalgia, and other side effects, generally attributed to OCs, as the OC group did. Even the incidence of excessive weight gain was identical. The lack of attributable weight gain with OC use had earlier been demonstrated by Reubinoff et al. (1995), who also reported that users of low-dose OCs did not change body composition or fat distribution.

Some women have particular sensitivity to sex steroids. They may experience side effects either as a result of the pharmacological doses of hormone or because of hormonal imbalances. Many side effects are temporally self-limited and resolve spontaneously in the first few cycles, but sometimes women require a change of pill formulation. When these side effects arise, it is important to analyze them by their constituent hormonal effects (see Table 43.5) to select pills that meet the patient's needs.

Management of Common Side Effects

Breakthrough Bleeding

Typically, 20% to 25% of women experience unscheduled spotting or bleeding at some time during the first three cycles. The incidence of breakthrough bleeding with the more recent ultra–low-dose (20 µg) formulations containing levonorgestrel or desogestrel is roughly comparable to that of 30- to 35-µg pills, although an earlier 20-µg formulation containing low-dose norethindrone did have higher rates of unscheduled bleeding (DelConte et al., 1999; Rosenberg et al., 1999; Sulak et al., 1999). Other causes of vaginal spotting or bleeding must be considered in adolescent girls. Chlamydial cervicitis is a common cause of postcoital bleeding in teens. Inconsistent pill use also commonly causes breakthrough bleeding or spotting. Smokers have notably more challenges with breakthrough bleeding, especially with low-dose pills.

Treatment for persistent spotting or bleeding due to OCs in the face of appropriate pill use depends on the timing of those events within the woman's cycle. For women who have unscheduled spotting and/or bleeding at the

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end of their active pills, use a formulation with higher progesterone activity to support the endometrium during those days. Triphasic formulations, which progressively increase progestin dose, are particularly helpful in this situation. If the unscheduled spotting and/or bleeding occurs with the early pills, consider using formulations with higher doses of estrogen in the early pills, or those with lower progestin levels. This will allow the estrogen in the pills to induce endometrial proliferation and cover the denuded, bleeding areas left by menstrual shedding. Spotting and bleeding that occurs sporadically throughout the cycle is highly suspicious for inconsistent pill use, smoking, or drug–drug interactions. However, for women who do not have those problems but are still spotting, shortening the pill-free interval can reduce the frequency of that bleeding, especially if lower-dose formulations are being used.

TABLE 43.5
Impact of Hormones on Side Effects

 

Progestin-Related

Estrogen-Related

Progestogenic

Androgenic

Nausea and vomiting

Fatigue

Noncyclic weight gain

Edema, leg cramps

Depression

Oily skin

Bloating

Bloating

Hirsutism

Cervical ectropion

Mastalgia

Acne

Visual changes or vascular headaches

Increased breast size

Increased appetite

 

Venous dilation, pelvic congestion

Decrease in libido

Telangiectasia

 

Decreased breast size

Cyclic weight gain Irritability

Oligomenorrhea, amenorrhea, vaginal spotting

 

Clear vaginal discharge

   

Cystic breast changes

Cholestatic jaundice

 

Chloasma, hyperpigmentation

Pruritus

 

Hypermenorrhea (menorrhagia)

   

Acne and Hirsutism

These symptoms are caused by free androgens. In order to cope, switch to a formulation with a higher estrogen content, which will increase SHBG and reduce the level of unbound testosterone, and/or switch to a formulation with a less androgenic progestin.

Chloasma or Melasma

These symptoms are caused by estrogen stimulation of melanocytes. In this situation, it would be prudent to decrease (or eliminate) estrogen content and advise the use of sunscreen and hats.

Weight Gain

Explore other causes of weight gain before attributing it to pill use. If the weight gain is concentrated in a woman's breast, hips, and thighs, decrease the estrogen content of her pills. If the gain is accompanied by bloating and fluid retention, switch to a lower dose pill or to a drosperinone-containing formulation. If the weight gain is slowly progressive (and not due to other factors), change to a less androgenic formulation.

Headaches

Rule out serious problems, such as hypertension and new-onset or worsening migraines, which would require OC cessation. Reduce the dose of estrogen or change to a progestin-only method. If the headache occurs only before or during menses (menstrual or migraine), shorten or eliminate the pill-free interval.

Nausea

Have the patient take her pill at night. Reduce the estrogen dose if the first maneuver is not successful or if it will interfere with successful pill taking.

Mastalgia

Breast tenderness is usually self-limited, but if the problem persists, reduce the estrogen dose of the pill.

Coping with Missed Pills

The WHO has developed advice to be given to women when they miss OCs. The advice differs depending upon how many pills are missed, the strength of her formulation, and when in the cycle the pills are missed. The recommendations are summarized in Figure 43.2.

Because this may be somewhat complicated for a patient to remember, it may be prudent to simplify the instructions to cover two situations: One missed pill versus more than one missed pill. If one pill is missed, have her take it as soon as possible and take the current day's pill within 12 hours. If more than one pill is missed, then have her take two pills today, resume daily pill taking tomorrow, and use condoms for 7 days. If she has had intercourse in the 5 days before the missed pills, she should use EC in place of her two pills today (seeChapter 46).

Increasing Adolescent Compliance

Adolescent compliance with contraceptive methods is often suboptimal; however, adult compliance is also far from perfect. Studies of high-risk teenaged mothers found a 50% discontinuation rate by 12 months (Berenson and Wiemann, 1995). Many factors contribute to noncompliance. The desire of teens for independence and seeming invincibility decreases their motivation to use contraception. The unpredictability and frequent disruptions in their

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relationships often cause them to stop using contraception. Many adolescents receive incorrect information from sex education teachers in American schools (Davis, 1994); this misinformation about OCs affects the effectiveness of the method and also reduces compliance.

 

FIGURE 43.2 Handling missed oral contraceptive pills. (Adapted from Family Planning Association. How many Pills have you missed? Contraception and Sexual Health Guide. London: Family Planning Association.)

To enhance compliance, experts have suggested several measures:

  1. Emphasize the noncontraceptive benefits of OCs.Robinson et al. (1992) found that adolescent girls who experienced reduction in dysmenorrhea with OC use were eight times more likely to be consistent OC users.
  2. Demonstrate concretely how to use the pills.
  3. Have the patient discuss her concerns about pill use explicitly so that they can be addressed. Widespread myths about the dangers of OCs abound and can magnify the significance of a minor side effect in the mind of a young user.
  4. Help the teen plan for crucial logistics, such as where to store the pills (school lockers don't work on weekends!) and how to remember to take the pills each day (placing them next to makeup or an earring holder may work better in the real world than placing them near the tube of toothpaste).

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  1. Start the pills immediately if pregnancy can be ruled out, to simplify instructions, and use a barrier method as backup for first cycle.
  2. Shorten the pill-free interval. Start each new pack of pills on the first day of menses. Or eliminate the pill-free interval for several packs (“bicycling,” “recycling,” or “combination continuous use”).
  3. If the patient is unable to take daily pills use a longer-acting product, such as the contraceptive patch or vaginal ring (see subsequent text).

Special considerations in adolescents:

  1. When to start
  2. Young users: Ideally, a teen would have at least three to six regular periods after menarche before starting the pill. However, if a young menarchal teen is sexually active, the risks of pregnancy exceed those of taking hormonal contraceptives; there is no evidence that the early use of OCs leads to premature epiphyseal closure or to any disruption in the maturation of the hypothalamic-pituitary-ovarian axis.
  3. After pregnancy: After a first-trimester therapeutic abortion or miscarriage, the pill should be started immediately to prevent ovulation. After a pregnancy, a 3- to 4-week delay should be allowed before starting OCs, because of the risk of thromboembolism. However, progestin-only methods can be initiated immediately.
  4. If the teen has very irregular cycles, she should be informed that her cycles are likely to be regular while she is using the pills, but will return to their usual, irregular intervals when the pills are stopped. However, there is no evidence that the teen's fertility rate will be any lower after she discontinues the pills than if she had never used them.
  5. Initial examination
  6. History: Menstrual history, past history, risk factors for sexually transmitted diseases (STDs), history of problems that suggest any contraindications for use of the pill, and sexual and family histories.
  7. Physical examination: The optimal examination would include weight and blood pressure measurements, thyroid examination, breast examination, abdominal examination, and pelvic examination. However, only a blood pressure measurement and a breast examination are required to start hormonal contraceptives. The pelvic examination may be deferred for 3 to 6 months at least (Stewart et al., 2001). This is particularly the case for women who are being prescribed OCs for noncontraceptive benefits and who may not be sexually active.
  8. Laboratory tests: Screening for Chlamydiais recommended for every sexually active teen. This can be performed using a urine specimen. It is not needed before prescribing pills.
  9. Education: Counseling is the most critical component of the visit.
  10. Follow-up
  11. It is preferable to see the teenager at 1 month and again at 3 months after starting the pill, and then every 6 months. The visit after 1 month is important, especially in younger teens, because of their high rate of pill discontinuation during the first months.
  12. Check blood pressure at 3 months and then as indicated for well-adolescent care.
  13. Perform a breast and pelvic examination as indicated every 12 months for routine care. Pap smears should start 3 years after sexual debut. Screening for Chlamydiais required at least annually for sexually active women younger than 26 years.

Progestin-Only Pills

Progestin-only pills have traditionally been reserved for use by breast-feeding women. However, their potential is much greater than that niche. Virtually every woman may be a candidate from a medical standpoint for use of progestin-only pills. The only condition that the WHO rates as category 4 (do not use) for progestin-only pills is current breast cancer. Because the dose of progestin is significantly lower in progestin-only pills than it is in combination OCs, success requires consistent use. The progestin-only pill must be taken at the same time each day. The progestin-only pill works primarily by thickening cervical mucus to prevent sperm entry into the upper reproductive tract. Ovulation is suppressed in 40% to 60% of cycles. There are no placebo pills; a woman takes one active pill a day, even if she is menstruating. The most common side effect from progestin-only pills is unscheduled spotting and bleeding or amenorrhea, just as is seen with other progestin-only methods. Whenever estrogen is contraindicated or undesired (e.g., with melasma), the progestin-only pill is an excellent option. Table 43.1 lists the progestin-only pills available in the United States.

Transdermal Contraceptive Patch

The Ortho Evra transdermal contraceptive system is composed of a 20 cm2 tan-colored thin patch containing EE and 17-diacetyl norgestimate. This patch was very popular with adolescent girls because its once-a-week use is more convenient compared with the daily dosing requirement of OCs. The patch can be worn anywhere on the woman's trunk (except the breasts) or on her upper arms. Women should be cautioned to avoid placing it on areas subjected to friction from undergarments or waistbands. With current fashions, many women have abandoned the attempt to hide the patch and wear it as a fashion statement.

The efficacy of the patch is at least equivalent to that of standard birth control pills for women weighing<90 kg. For women weighing>90 kg, the risk of pregnancy is higher. In the clinical trials,>30% of the pregnancies occurred in the 3% of the study population who weighed>198 pounds (Zieman et al., 2002).

In clinical studies, it was shown that at every age-group, more patch users reported correct and consistent use of their method than did pill users. This difference was greatest among the adolescent girls in the study; 87.7% of 18- and 19-year-old girls in the patch arm used their patches correctly and consistently during the 1-year trial compared with 67.7% of the 18- and 19-year olds who used OCs (Creasy et al., 2000).

The first patch should be applied during the first 5 days of a woman's cycle. Each patch is to remain in place for 7 days, at which time another patch is applied at a different site. The third patch replaces the second patch at a different site 7 days later. After the last patch has been in

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place for 7 days, product labeling instructs the patient to remove it and use no patch for the following week, during which time she should start her withdrawal bleeding. It is important to give guidance to patients about what to do if things go wrong.

  • If the patch detaches, she should attempt to reattach it using its own adhesive; never anchor the patch in place with tape. If the patch will not reattach, have the patient place a new patch at a different site and replace that patch on her next regularly scheduled “change day” or modify her change day to the current day. If the patch was detached for<24 hours, no further action is needed. If it was detached for longer than 24 hours, she should use a backup method for 7 days and consider whether she needs EC (see Chapter 46).
  • If she is late in changing her patch, she should change it as soon as possible. If she is late by 2 days or less, no further action is necessary. If she is>2 days late, she should replace the patch and use a backup method for 7 days and consider whether she needs EC (see Chapter 46).

Patch initiation guidelines should also be flexible. Women switching from pills to patches should place their first patch on the first day of their withdrawal bleeding; they should not wait until they complete their pill pack. The patch should be started immediately after a first trimester pregnancy loss or after intrauterine contraception is removed or 13 weeks after the last DMPA injection. Remember, it takes 2 days to achieve therapeutic hormonal levels, so a backup method should be recommended if the patient is at risk.

The safety and efficacy of quick start of the contraceptive patch has been demonstrated. However, compared with quick start with OCs, quick start with the patch did not increase short-term continuation rates (Murthy et al., 2005). Extended cycle use of the patch has also been reported (Stewart et al., 2005 OBGYN 1389–96). Women using extended cycles had less frequent, but more prolonged, scheduled bleeding episodes than did women using the patch cyclically. There is a slight increase over time of serum levels of estrogen with extended cycle use of the contraceptive patch.

The patch has virtually the same contraindications, precautions, and side effects as combination OCs. One exception is that transdermal administration does not require gastrointestinal (GI) absorption, so that conditions which limit GI absorption, such as diarrhea associated with irritable bowel syndrome (IBS), do not present any problems with patch use. It is not known what the efficacy of the patch is when used by women taking anticonvulsants or other liver enzyme–inducing drugs. Patches cannot be applied to irritated skin surfaces. Women with sunburn, psoriasis, or rashes should not apply the contraceptive patch over affected areas. The patch will not attach or may detach if oils or moisturizers, sun tan lotions, or other skin products coat the area. However, baby oil is very helpful in removing the remnants of adhesive that may stick to the skin after the patch has been removed. Women using the patch are more likely to report first-cycle mastalgia than OC users, but by the second month the frequency of the problem drops to<10%, which is comparable to pill users.

The progestin in the patch is a derivative of norgestimate, which is the low androgen progestin in Ortho Tri-Cyclen. The peak levels of serum estrogen achieved with the patch are only two thirds as high as the daily peak of estrogen from 35-µg EE pills. However, because the patch maintains the same level of hormones in the bloodstream 24 hours/day, the total daily estrogen exposure is 60% higher than with a 35-µg EE pill and 3.4 times higher than the vaginal ring. Product labeling acknowledges the higher estrogen exposure, but it also states that the clinical significance of this higher dose is not known. The reason that higher doses of estrogen from the patch may not have the same thrombotic and other metabolic impacts as higher dose pills is that the percutaneous route of administration bypasses the pill's first pass effect. With the patch, the liver is not exposed to estrogen that does not appear in the bloodstream. With oral drugs, serum levels reflect only a fraction of the drug exposure of the liver, because much of the initial drug that is absorbed is conjugated in the liver and excreted back into the intestine by way of the gall-bladder. More than 5 million women in the United States have used the patch; to date, there has been no convincing evidence of any increased risk of thrombosis, but the U.S. Food and Drug Administration (FDA) now requires that Ortho Evra packaging contain a warning about this potential serious complication. Epidemiological studies focusing on the question of thrombosis have provided conflicting answers about the risk of thromboembolism with patch use.

Vaginal Contraceptive Rings

  1. Metabolism and efficacy: NuvaRing contraceptive vaginal ring is a soft, flexible ring with an outer diameter of 54 mm and a cross section diameter of 4 mm. The ring is impregnated with EE and etonogestrel (a metabolite of desogestrel). The ring produces total daily serum EE levels<50% of those seen with a 30-µg EE pill (van den Heuvel et al., 2005). The ring is placed in a woman's vagina, where it releases a constant amount of contraceptive hormones. The ring is placed inside the vaginal fornix within the first 5 cycle days and remains in place for 21 days, at which time it is removed and placed in its resealable pouch and discarded. The woman places a new ring 7 days later. Efficacy is at least comparable to that of OCs. Little data is available about efficacy in heavier women. In meta-analysis of existing clinical trials, which studied 3,259 women, none of the 41 ring users who weighed at least 89.9 kg became pregnant (Westhoff, 2005).
  2. Advantages: The ring has many features that are very attractive for adolescent women. It is a once-a-month, self-administered method with no telltale external evidence of its use. Cycle control is impressive; tested against the best modern pill for cycle control (Nordette), ring users had fewer days of unscheduled spotting and bleeding than pill users (Bjarnadottir et al., 2002). There are no published studies on the efficacy of the vaginal ring in women using hepatic enzyme–inducing medications, such as St. John's wort or anticonvulsants. Because the ring releases estrogen directly into the vagina, it increases vaginal lubrication and has been reported to reduce recurrences of bacterial vaginosis. Women who need vaginal therapies, such as antifungal agents or spermicides, may use them without fear of adversely affecting vaginal ring efficacy.
  3. Contraindications: The vaginal ring has the same contraindications as the transdermal patch except that there are no concerns about dermatologic conditions.

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Pelvic support is needed for the ring. The greatest barrier to acceptance of the vaginal ring is its placement and removal. Placement can be facilitated by loading the ring into an emptied tampon inserter with blunt opening. Have the woman place the tampon inserter into the vault and press the ring out. Once the ring is inside the vagina, it can rest against the vaginal wall in any location, and its movement within the vault causes no problems. In the clinical trials, the vast majority of male partners did not notice any adverse effects from the ring on their sexual satisfaction. If a woman's partner does complain, she can remove the ring and place it in its foil pouch until coitus is over. She must not leave the ring out of her vagina for>3 hours in any 24-hour period. Removal of the ring only requires that the woman introduce a finger into her vagina, locate the ring with her fingertip, and withdraw it from her vagina. If the ring is located high in the vault, it may help to have the woman squat slightly to remove it.

  1. Quick start and extended cycle use: Clinical trials have now been published validating the safety of quick start for the vaginal ring (Westhoff et al., 2005) and extended cycle use of NuvaRing (Miller et al., 2005). In the extended cycle study, some women changed rings every 3 weeks for up to a year without having a scheduled withdrawal bleed. Shorter interval cycles (2 and 4 months) were associated with less breakthrough bleeding. There is no evidence of accumulation of the contraceptive hormones with extended cycle use of the vaginal ring.
  2. Other formulations: Another estrogen-progestin ring that is to be used in 3-week cycles with 1 week out for up to 1 year is now undergoing clinical trials. Progestin-only vaginal rings are under development to provide the benefits of 1- to 3-month duration vaginal rings without estrogen's side effects or contraindications. At the time of this writing, none is available in the United States.

Web Sites

For Teenagers and Parents

http://www.advocatesforyouth.org/youth/health/contraceptives/pill.htm. Advocates for Youth information on OCs with links to other contraceptive choices.

http://www.sex-ed101.com/oral.html. Sex Education 101 Web site on OCs and other contraceptives.

http://www.teenwire.com/index.asp. Teenwire from Planned Parenthood with information about reproductive health including contraception.

http://www.fhi.org/en/RH/FAQs/COC_faq.htm. Frequently Asked Questions sheet on combined OCs from Family Health International.

http://www.orthowomenshealth.com/birthcontrol/options/pills.html. Information from the Ortho Women's Health Web site.

For Health Professionals

http://www.arhp.org/healthcareproviders/resources/contraceptionresources/. Association of Reproductive Health Professionals.

References and Additional Readings

ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol. 2006;107(6):1453.

Ahn HK. Poster presented at Teratology Society. Reported in www.obgynnews.com. Sept 15, 2005. Accessed 12/25/05 at http://download.journals.elsevierhealth.com/pdfs/journals/0029-7437/PIIS0029743705710090.pdf. 2005.

Archer DF, Kovalevsky G, Ballagh S, et al. Effect on ovarian activity of a continuous-use regimen of oral levonorgestrel/ethinyl estradiol. Abstract O-57. Fertil Steril 2005;84(Suppl 1):S24.

Back DJ, Tjia J, Martin C, et al. The lack of interaction between temafloxacin and combined oral contraceptive steroids. Contraception 1991;43(4):317.

Becker WJ. Use of oral contraceptives in patients with migraine. Neurology 1999;53(Suppl 1):S19.

Berenson AB, Wiemann CM. Use of levonorgestrel implants versus oral contraceptives in adolescence: a case-control study. Am J Obstet Gynecol 1995;172:1128.

Bjarnadottir RI, Tuppurainen M, Killick SR. Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol2002;186(3):389.

Brunner LR, Hogue CJ. The role of body weight in oral contraceptive failure: results from the 1995 national survey of family growth. Ann Epidemiol 2005;15(7):492.

Castelli WP. Cardiovascular disease: pathogenesis, epidemiology, and risk among users of oral contraceptives who smoke. Am J Obstet Gynecol 1999;180:S349.

Centers for Disease Control and Prevention. Cancer and steroid hormone study. Long-term oral contraceptive use and the risk of breast cancer. JAMA 1983;249:1591.

Centers for Disease Control and Prevention. OC use and the risk of breast cancer in young women. MMWR Morb Mortal Wkly Rep 1984;22:353.

Chiaffarino F, Parazzini F, La Vecchia C, et al. Use of oral contraceptives and uterine fibroids: results from a case-control study. Br J Obstet Gynaecol 1999;106:857.

Clarkson TB, Shively CA, Morgan TM, et al. Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys. Obstet Gynecol 1990;75:217.

The Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713.

Creasy G, Hall N, Shangold G. Patient adherence with the contraceptive patch dosing schedule versus oral contraceptives. Obstet Gynecol 2000;95(4 Suppl 1):S60.

Csemiczky G, Alvendal C, Landgren BM. Risk for ovulation in women taking a low-dose oral contraceptive (Microgynon) when receiving antibacterial treatment with a fluoroquinolone (ofloxacin). Adv Contracept 1996;12(2):101.

Davis AJ. The role of hormonal contraception in adolescents. Am J Obstet Gynecol 1994;170:1581.

Davis A, Lippman J, Godwin A, et al. Triphasic norgestimate/ethinyl estradiol oral contraceptive for the treatment of dysfunctional uterine bleeding. Obstet Gynecol 2000;95 (4 Suppl 1):S84.

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Davis AR, Westhoff C, O'Connell K, et al. Oral contraceptives for dysmenorrhea in adolescent girls: a randomized trial. Obstet Gynecol 2005;106(1):97.

DelConte A, Loffer F, Grubb GS, et al. Cycle control with oral contraceptives containing 20 micrograms of ethinyl estradiol: a multicenter, randomized comparison of levonorgestrel/ethinyl estradiol (100 micrograms/20 micrograms) and norethindrone/ethinyl estradiol (1,000 micrograms/20 micrograms). Contraception 1999;59:187.

Dunn N, Thorogood M, Faragher B, et al. Oral contraceptives and myocardial infarction: results of the MICA case-control study. BMJ 1999;318:1579.

Edelman A, Gallo MF, Nichols MD, et al. Continuous versus cyclic use of combined oral contraceptives for contraception: systematic Cochrane review of randomized controlled trials. Hum Reprod 2006;21(3):573.

Emans SJ, Grace E, Woods ER, et al. Adolescent compliance with the use of oral contraceptives. JAMA 1987;257:3377.

Friedman CI, Huneke AL, Kim MH, et al. The effect of ampicillin on oral contraceptive effectiveness. Obstet Gynecol 1980;55:33.

Godsland IF, Crook D. Update on the metabolic effects of steroidal contraceptives and their relationship to cardiovascular disease risk. Am J Obstet Gynecol 1994;170:1528.

Gordon CM, Nelson LM. Amenorrhea and bone health in adolescents and young women. Curr Opin Obstet Gynecol 2003;15:377.

Grabrick DM, Hartmann LC, Cerhan JR, et al. Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 2000;284:1791.

Halpern V, Grimes DA, Lopez L, et al. Strategies to improve adherence and acceptability of hormonal methods for contraception. Cochrane Database Syst Rev 2006;(1):CD004317.

Heinemann LA, Lewis MA, Spitzer WO, et al. Thromboembolic stroke in young women: a European case-control study on oral contraceptives. Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception 1998;57:29.

Hergenroeder AC, Smith EO, Shypailo R, et al. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol 1997;176:1017.

van den Heuvel MW, van Bragt AJ, Alnabawy AK, et al. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005;72(3):168.

Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol 2002;99(5 Pt 1):820.

Holt VL, Scholes D, Wicklund KG, et al. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol 2005;105(1):46.

Joshi JV, Joshi UM, Sankholi GM, et al. A study of interaction of low-dose combination oral contraceptive with Ampicillin and Metronidazole. Contraception 1980;22(6):643.

Kapella JG, Binder C, Shingler KC, et al. Hormonal contraceptives and intima-media thickness of common carotid artery in adolescent girls. Presented at Society for Adolescent Medicine Meeting. Century City, CA: April 1, 2005.

Kjos SL, Peters RK, Xiang A, et al. Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus. JAMA 1998;280:533.

Kripke C. Cyclic vs. continuous or extended-cycle combined contraceptives. Am Fam Phy 2006;73(5):804.

Lara-Torre E, Schroeder B. Adolescent compliance and side effects with Quick Start initiation of oral contraceptive pills. Contraception 2002;66(2):81.

Lewis MA. The transnational study on oral contraceptives and the health of young women: methods, results, new analyses and the healthy user effect. Hum Reprod Update1999;5:707.

Liu SL, Lebrun CM. Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review.Br J Sports Med 2006;40:11.

Maggiolo F, Puricelli G, Dottorini M, et al. The effect of ciprofloxacin on oral contraceptive steroid treatments. Drugs Exp Clin Res 1991;17(9):451.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002;346(26):2025.

Marshall LM, Spiegelman D, Goldman MB, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril1998;70:432.

Miller L, Verhoeven CH, Hout J. Extended regimens of the contraceptive vaginal ring: a randomized trial. Obstet Gynecol 2005;106(3):473.

Mishell DR Jr. Rationale for decreasing the number of days of the hormone-free interval with use of low-dose oral contraceptive formulations. Contraception 2005;71(4):304.

Murphy PA, Kern SE, Stanczyk FZ, et al. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 2005;71(6):402.

Murphy AA, Zacur HA, Charache P, et al. The effect of tetracycline on levels of oral contraceptives. Am J Obstet Gynecol 1991;164:28.

Murthy AS, Creinin MD, Harwood B, et al. Same-day initiation of the transdermal hormonal delivery system (contraceptive patch) versus traditional initiation methods.Contraception 2005;72(5):333.

Narod SA, Risch H, Moslehi R, et al. Hereditary Ovarian Cancer Clinical Study Group. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424.

Neely JL, Abate M, Swinker MR, et al. The effect of doxycycline on serum levels of ethinyl estradiol, norethindrone, and endogenous progesterone. Obstet Gynecol1991;77(3):416.

Norman SA, Berlin JA, Weber AL, et al. Combined effect of oral contraceptive use and hormone replacement therapy on breast cancer risk in postmenopausal women. Cancer Causes Control 2003;14(10):933.

Oakley D, Sereika S, Bogue EL. Oral contraceptive pill use after an initial visit to a family planning clinic. Fam Plann Perspect 1991;23:150.

Pierson RA, Birtch RL, Olatunbosun OA. Ovarian follicular dynamics during conventional versus continuous oral contraceptive use. Abstract O-58. Fertil Steril 2005;84(Suppl 1):S24.

Pons JE. Hormonal contraception compliance in teenagers. Pediatr Endo Rev 2006;(3 Suppl 1):164.

Potter L, Oakley D, de Leon-Wong E, et al. Measuring compliance among oral contraceptive users. Fam Plann Perspect 1996;28:154.

Redmond G, Godwin AJ, Olson W, et al. Use of placebo controls in an oral contraceptive trial: methodological issues and adverse event incidence. Contraception 1999;60:81.

P.615

 

Reubinoff BE, Gurbstein A, Meirow D, et al. Effects of low-dose estrogen oral contraceptives on weight, body composition, and fat distribution in young women. Fertil Steril1995;63:516.

Robinson JC, Plichta S, Weisman CS, et al. Dysmenorrhea and use of oral contraceptives in adolescent women attending a family planning clinic. Am J Obstet Gynecol1992;166:578.

Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception 1999;60:321.

Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med 1995;40(5):355.

Sarkar NN. The combined contraceptive vaginal device (NuvaRing): a comprehensive review. Eur J Contracept Reprod Health Care 2005;10(2):73.

Schlesselman JJ. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793.

Schwartz SM, Petitti DB, Siscovick DS, et al. Stroke and use of low-dose oral contraceptives in young women: a pooled analysis of two U.S. studies. Stroke 1998;29:2277.

Schwingl PJ, Ory HW, Visness CM. Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol1999;180:241.

Sidney S, Siscovick DS, Petitti DB, et al. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 U.S. studies. Circulation 1998;98:1058.

Stewart FH, Harper CC, Ellertson CE, et al. Clinical breast and pelvic examination requirements for hormonal contraception: current practice vs. evidence. JAMA 2001;285:2232.

Stewart FH, Kaunitz AM, Laguardia KD, et al. Extended use of transdermal norelgestromin/ethinyl estradiol: a randomized trial. Obstet Gynecol 2005;105(6):1389.

Straneva P, Hinderliter A, Wells E, et al. Smoking, oral contraceptives, and cardiovascular reactivity to stress. Obstet Gynecol 2000;95:78.

Sucato GS, Gerschultz KL. Extended cycle hormonal contraception in adolescents. Cur Opin Obstetr Gynecol 2005;17(5):461.

Sulak P, Lippman J, Siu C, et al. Clinical comparison of triphasic norgestimate/35 micrograms ethinyl estradiol and monophasic norethindrone acetate/20 micrograms ethinyl estradiol: cycle control, lipid effects, and user satisfaction. Contraception 1999;59:161.

Trussell J. The essentials of contraception: efficacy, safety, and personal considerations. In: Hatcher RA, Trussell J, Stewart F, et al. eds. Contraceptive technology, 18th ed. New York: Ardent Media, 2004:226.

Westhoff C. Higher body weight does not affect NuvaRing®'s. Poster Presented at the 53rd Annual Meeting of the American College of Obstetricians and Gynecologists. San Francisco, CA: May 7–11, 2005.

Westhoff C, Morroni C, Kerns J, et al. Bleeding patterns after immediate vs. conventional oral contraceptive initiation: a randomized, controlled trial. Fertil Steril2003;79(2):322.

Westhoff C, Osborne LM, Schafer JE, et al. Bleeding patterns after immediate initiation of an oral compared with a vaginal hormonal contraceptive. Obstet Gynecol2005;106(1):89.

World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995a;346:1575.

World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low-oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995b;346:1582.

World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995c;346:1589.

World Health Organization, Department of Reproductive Health and Research. Selected practice recommendations for contraceptive use, 2nd ed. Geneva, Switzerland: World Health Organization, Accessed 12/22/05 at http://www.who.int/reproductive-health/publications/spr/index.htm. 2005.

Yonkers KA, Brown C, Pearlstein TB, et al. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 2005;106(3):492.

Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril2002;77 (2 Suppl 2):S13.