PROGESTIN-ONLY CONTRACEPTIVES GROUP
FERTILITY AWARENESS-BASED METHODS
Half of all pregnancies each year in the United States are unintended (Finer, 2011). These may follow contraceptive method failure or stem from lack of contraceptive use. Specifically, 10 percent of sexually active American women not pursuing pregnancy did not use any birth control method (Jones, 2012). And, for sexually active fertile women not using contraception, pregnancy rates approach 90 percent at 1 year.
For those seeking contraception, various effective contraceptive methods are available. Preferences of United States women are shown in Table 38-1. With these methods, wide variations are seen between estimated failure rates of perfect and typical use during the first year. Similarly, the World Health Organization (WHO) has grouped methods according to effectiveness tiers that reflect these failure rates (Table 38-2). Implants and intrauterine devices are found in the top tier. They are effective in lowering unintended pregnancy rates and are considered long-acting reversible contraception (LARC) (Winner, 2012). The American College of Obstetricians and Gynecologists (2013c) recognizes these efficacy tiers and the high unintended pregnancy rate. Thus, the College recommends that clinicians provide counseling on all options and encourages highly effective LARC for all appropriate candidates.
TABLE 38-1. Method Use among Women in the United States
TABLE 38-2. Contraceptive Failure Rates During the First Year of Method Use in Women in the United States
Unfortunately, no contraceptive method is completely without side effects. That said, an important tenet is that contraception usually poses less risk than pregnancy. During appropriate method selection, underlying patient health conditions should be known. Some disorders or the medications used for their treatment can increase the risk of some contraceptives. The WHO (2010) has provided evidence-based guidelines, termed Medical Eligibility Criteria, for the use of all highly effective reversible contraceptive methods by women with various health conditions. Individual countries have subsequently modified these. The United States Medical Eligibility Criteria (US MEC) was published in the United States by the Centers for Disease Control and Prevention (CDC) (2010b), and its use is encouraged by the American College of Obstetricians and Gynecologists (2011b). Shown on page 698, the CDC (2011, 2012) has since added updates to reflect changes for women at high risk for human immunodeficiency virus (HIV) infection and for women in the puerperium. The US MEC guidelines and these updates, as well as a free smart-phone application of the guidelines, are available at the CDC website: http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/USMEC.htm.
In the US MEC, reversible contraceptive methods are organized into six groups by their similarity: combination hormonal contraceptives (CHCs), progestin-only pills (POPs), depot medroxyprogesterone acetate (DMPA), implants, levonorgestrel-releasing intrauterine system (LNG-IUS), and copper intrauterine devices (Cu-IUDs). For a given health condition, each method is categorized 1 through 4. The score describes a method’s safety profile for a typical woman with that condition: (1) no restriction of method use, (2) method advantages outweigh risks, (3) method risks outweigh advantages, and (4) method poses an unacceptably high health risk.
Alternatively, depending on the underlying disorder or patient desire, male or female sterilization may be a preferred or recommended permanent contraceptive method. These options are fully discussed in Chapter 39 (p. 720).
LONG-ACTING REVERSIBLE CONTRACEPTION: INTRAUTERINE DEVICES
These are the most commonly used method of reversible contraception worldwide, and in the United States, nearly 4 percent of women select this method (d’Arcanques, 2007; Jones, 2012). Fortunately, contraindications to IUD use are few.
Intrauterine devices (IUDs) that are chemically inert are composed of nonabsorbable materials. The three IUDs currently approved for use in the United States are chemically active and have continuous elution of copper or a progestin. Of these, there are two different levonorgestrel-releasing intrauterine systems—Mirena and Skyla (Fig. 38-1). Each releases the progestin into the uterus at a relatively constant rate, which reduces systemic effects. Their T-shaped radiopaque frames have a stem wrapped with a cylinder reservoir that contains the levonorgestrel. There are two trailing brown strings attached to the stem (Bayer Healthcare Pharmaceuticals, 2013a,b). Mirena is currently approved for 5 years of use following insertion, however, some evidence supports its efficacy for 7 years (Thonneau, 2008). Skyla is approved for 3 years of use. It has slightly smaller overall dimensions than its counterpart and was sized to more appropriately fit a nulliparous uterus (Gemzell-Danielsson, 2012). It can also be differentiated from Mirena visually and sonographically by a silver ring near the junction of the device’s stem and arms.
FIGURE 38-1 Intrauterine devices (IUDs). A. ParaGard T 380A copper IUD. B. Mirena levonorgestrel-releasing intrauterine system.
The third device is the T 380A IUD, named ParaGard. It has a polyethylene and barium sulfate T-shaped frame wound with copper, and two strings extend from the stem base. Originally blue, the strings are now white. It is currently approved for 10 years of use following insertion (Teva Women’s Health, 2011).
In addition to these three currently marketed, women may retain discontinued brands of IUD. A Lippes Loop has two “S” shapes stacked one on the other. The Dalkon Shield has a crab form, whereas a Copper 7 mirrors that number. Progestasert is an early T-shaped progestin-releasing IUD. Last, various metal-eluting ring-shaped devices are common in Asia.
All these IUDs are effective. Failure rates are well below 1 percent and similar overall to those of tubal sterilization (American College of Obstetricians and Gynecologists, 2013a; Thonneau, 2008; Trussell, 2011b). Their mechanisms have not been precisely defined, but prevention of fertilization is now favored. Within the uterus, an intense local endometrial inflammatory response is induced, especially by copper-containing devices. Cellular and humoral components of this inflammation are expressed in endometrial tissue and in fluid filling the uterine cavity and fallopian tubes. These lead to decreased sperm and egg viability (Ortiz, 2007). Also, in the unlikely event that fertilization does occur, the same inflammatory actions are directed against the blastocyst. The endometrium is transformed into a hostile site for implantation. With the copper IUD specifically, copper levels increase in the cervical mucus of users and decrease sperm motility and viability (Jecht, 1973). With the LNG-IUS, in addition to an inflammatory reaction, long-term progestin release leads to endometrial atrophy, which hinders normal implantation. Moreover, progestins create scant viscous cervical mucus that obstructs sperm motility. The LNG-IUS may also inconsistently release sufficient progestin to inhibit ovulation, although this is a lesser effect than its local actions.
Method-Specific Adverse Effects
Several method-specific complications may follow IUD insertion and include uterine perforation, device expulsion, menstrual changes, infection, and miscarriage if pregnancy occurs. Also, in the past, IUDs were perceived to increase the risk of ectopic pregnancy. However, this has been clarified. Specifically, IUDs are so effective as contraceptives that they lower the absolute number of ectopic pregnancies by half compared with the rate in noncontracepting women (World Health Organization, 1985, 1987). But, the IUD mechanisms of action are more effective in preventing intrauterine implantation. Thus, if an IUD fails, a higher proportion of pregnancies are likely to be ectopic (Backman, 2004; Furlong, 2002).
During uterine sounding or IUD insertion, the uterus may be perforated, which is identified by the tool traveling further than the expected uterine length based on initial bimanual examination. Rates approximate 1 per 1000 insertions, and risks include puerperal insertion, lactation, provider inexperience, and extremes of uterine flexion (Harrison-Woolrych, 2003). Although devices may migrate spontaneously into and through the uterine wall, most perforations occur, or at least begin, at the time of insertion.
With the more common fundal perforation, bleeding typically is minimal due to myometrial contraction around the site. If no brisk or persistent bleeding is noted from the os following instrument removal, then patient observation alone is reasonable. Rarely, lateral perforations may lead to uterine artery laceration and brisk bleeding, which may prompt laparoscopy or laparotomy for control. Following any perforation, although this is not firmly evidence-based, a single dose of broad-spectrum antibiotic may mitigate infection.
Expulsion of an IUD from the uterus is most common during the first month. Thus, women should be examined approximately 1 month following IUD insertion, usually after menses, to identify the tails trailing from the cervix. Following this, a woman should be instructed to palpate the strings each month after menses.
If the tail of an IUD cannot be visualized, the device may have been expelled, may have perforated the uterus, or may be malpositioned. Some have found that IUD perforation, rotation, or embedding may cause pain or bleeding (Benacerraf, 2009; Moschos, 2011). Alternatively, the device may be normally positioned with its tail folded within the endocervical canal or uterine cavity. To investigate, after excluding pregnancy, a cytological brush can be twirled within the endocervical canal to entangle the strings and bring them gently into the vagina. If unsuccessful, the uterine cavity is probed gently with a Randall stone clamp or with a specialized rod with a terminal hook to retrieve the strings.
It should never be assumed that the device has been expelled unless it was seen. Thus, if tails are not visible and the device is not felt by gentle probing of the uterine cavity, transvaginal sonography can be used to ascertain if the device is within the uterus. Although traditional sonography will document IUD position adequately in most cases, three-dimensional sonography offers improved visualization, especially with the levonorgestrel-releasing IUD (Moschos, 2011). If sonography is inconclusive or if no device is seen, then a plain radiograph of the abdominopelvis is taken. Computed tomography (CT) scanning or less commonly, magnetic resonance (MR) imaging is an alternative (Boortz, 2012). It is safe to perform MR imaging at 1.5 and 3 Tesla (T) with an IUD in place (Pasquale, 1997; Zieman, 2007).
A device may penetrate the muscular uterine wall to varying degrees. Those with a predominantly intrauterine location are typically managed by hysteroscopic IUD removal. In contrast, devices that have nearly or completely perforated through the uterine wall are more easily removed laparoscopically. Chemically inert devices usually are removed easily from the peritoneal cavity. An extrauterine copper-bearing device, however, frequently induces an intense local inflammatory reaction and adhesions. Thus, copper IUDs may be more firmly adhered. Laparotomy may be necessary, and bowel preparation is considered. Perforations of large and small bowel and bladder and bowel fistulas have been reported remote from insertion (Lyon, 2012; Mascarenhas, 2012; Zeino, 2011).
Women who choose the copper IUD should be informed that dysmenorrhea and menorrhagia may develop. These are often treated with nonsteroidal antiinflammatory drugs (NSAIDs) (Grimes, 2006). Heavy bleeding may cause iron deficiency anemia, for which oral iron salts are given (Hassan, 1999).
With the LNG-IUS, women are counseled to expect irregular spotting for up to 6 months after placement, and thereafter to expect monthly menses to be lighter or even absent (Bayer HealthCare Pharmaceuticals, 2013a). Specifically, the Mirena device is associated with progressive amenorrhea, which is reported by 30 percent of women after 2 years and by 60 percent after 12 years (Ronnerdag, 1999). This is often associated with improved dysmenorrhea.
The device-related infection risk is increased only during the first 20 days following insertion (Farley, 1992). Of those who develop an infection during this time, most usually have an unrecognized coexistent cervical infection. Accordingly, women at risk for sexually transmitted diseases (STDs) should be screened either before or at the time of IUD insertion (Centers for Disease Control and Prevention, 2010a; Sufrin, 2012). That said, device insertion need not be delayed while awaiting Neisseria gonorrhoeae, Chlamydia trachomatis, or PAP screening results in asymptomatic women. If these bacteria are found and the patient is without symptoms, then the IUD may remain and treatment prescribed as detailed in Chapter 65 (p. 1269). Importantly, routine antimicrobial prophylaxis before insertion is not recommended (Grimes, 2001; Walsh, 1998). Moreover, the American Heart Association does not recommend infective endocarditis prophylaxis with insertion (Wilson, 2007).
After these first 3 weeks, infection risk is not increased in IUD users who would otherwise be at low risk of STDs. Correspondingly, IUDs appear to cause little, if any, increase in the risk of infertility in these low-risk patients (Hubacher, 2001). For these reasons, the American College of Obstetricians and Gynecologists (2011a, 2012a) recommends that women at low risk for STDs, including adolescents, are good candidates for IUDs (Table 38-3). The IUD is also safe and effective in HIV-infected women and may be used in others who are immunosuppressed (Centers for Disease Control and Prevention, 2012).
TABLE 38-3. Contraindications and Cautions with Specific Contraceptive Methods
If infection does develop, it may take several forms and typically requires broad-spectrum antimicrobials. Septic abortion mandates immediate uterine evacuation in addition to antimicrobials. Pelvic inflammatory disease (PID) without abscess is treated with systemic antibiotics. There are theoretical concerns that a coexistent IUD might worsen the infection or delay resolution. Although a provider may choose to remove an IUD in this setting, some evidence also supports allowing a device to remain during treatment in those hospitalized with mild or moderate PID (Centers for Disease Control and Prevention, 2010b; Tepper, 2013). Last, tuboovarian abscess may develop with PID and is treated aggressively with intravenous broad-spectrum antibiotics and IUD removal.
In addition to these infections, Actinomyces israelii is a gram-positive, slow-growing, anaerobic indigenous vaginal bacterium that rarely causes infection with abscess formation (Persson, 1984). Some have found it more frequently in the vaginal flora or on the Pap smears of IUD users (Curtis, 1981; Fiorino, 1996). Current recommendations advise that an asymptomatic woman may retain her IUD and does not require antibiotic treatment (American College of Obstetricians and Gynecologists, 2013c; Lippes, 1999; Westhoff, 2007a). However, if signs or symptoms of infection develop in women who harbor Actinomyces species, then the device should be removed and antimicrobial therapy instituted. Early findings with infection include fever, weight loss, abdominal pain, and abnormal vaginal bleeding or discharge. Actinomyces species are sensitive to antimicrobials with gram-positive coverage, notably the penicillins.
Pregnancy with an IUD
For women who become pregnant while using an IUD, ectopic pregnancy should be excluded (Chap. 19, p. 379). With intrauterine pregnancy, until approximately 14 weeks’ gestation, the tail may be visible through the cervix, and if seen, it should be grasped and the IUD removed by gentle outward traction. This action reduces complications such as subsequent abortion, chorioamnionitis, and preterm birth (Brahmi, 2012; Kim, 2010). Tatum and coworkers (1976) reported an abortion rate of 54 percent with the device left in place compared with a rate of 25 percent if it was promptly removed.
If the tail is not visible, attempts to locate and remove the device may result in abortion. However, some practitioners have successfully used sonography to assist in device removal in cases without visible strings (Schiesser, 2004). After fetal viability is reached, it is unclear whether it is better to remove an IUD whose string is visible and accessible or to leave it in place. There is no evidence that fetal malformations are increased with a device in place (Tatum, 1976).
Second-trimester miscarriage with an IUD in place is more likely to be infected (Vessey, 1974). Sepsis may be fulminant and fatal. Pregnant women with a device in utero who demonstrate any evidence of pelvic infection are treated with intensive antimicrobial therapy and prompt uterine evacuation. Because of these risks, a woman should be given the option of early pregnancy termination if the device cannot be removed early in pregnancy. Last, in women who give birth with a device in place, appropriate steps should be taken at delivery to identify and remove the IUD.
Immediately following miscarriage, surgical abortion, or delivery, an IUD may be inserted in the absence of infection. Also, Shimoni and colleagues (2011) describe “immediate” insertion 1 week after medical abortion. The risk of IUD expulsion is slightly higher if it is placed immediately following any of these recent pregnancies. That said, the advantages of preventing future unplanned pregnancies appear to outweigh this (Bednarek, 2011; Chen, 2010; Grimes, 2010a; Steenland, 2011).
Insertion techniques depend on uterine size. After first-trimester evacuation, the IUD can be placed using the manufacturer’s standard instructions. If the uterine cavity is larger, the IUD can be placed using ring forceps with sonographic guidance (Stuart, 2012). Immediately following vaginal or cesarean delivery, an IUD can be placed by hand or with an instrument (Grimes, 2010b). To reduce expulsion rates and to minimize the perforation risk, some may choose to wait for complete involution—at least 6 weeks after delivery. Women delivered at Parkland Hospital are seen 3 weeks postpartum, and IUDs are inserted 6 weeks postpartum or sooner if involution is complete.
For placement not related to pregnancy, insertion near the end of normal menstruation, when the cervix is usually softer and somewhat more dilated, may be easier and at the same time may exclude early pregnancy. But, insertion is not limited to this time. For the woman who is sure she is not pregnant and does not want to be pregnant, insertion is done at any time.
Before insertion, several procedural steps are carried out. Any contraindications are identified. If there are none, the woman is counseled and written consent obtained. An oral NSAID, with or without codeine, can be used to allay cramps (Karabayirli, 2012). Strong evidence does not support an advantage to supplemental misoprostol, intrauterine or cervical canal instillation of lidocaine, or paracervical blockade to lessen insertional pain (McNicholas, 2012; Nelson, 2013; Swenson, 2012). Bimanual pelvic examination is performed to identify uterine position and size. Abnormalities are evaluated, as they may contraindicate insertion. Mucopurulent cervicitis or significant vaginitis should be appropriately treated and resolved before IUD insertion.
The cervical surface is cleansed with an antiseptic solution, and sterile instruments and a sterile IUD should be used. A tenaculum is placed on the cervical lip, and the canal and uterine cavity are straightened by applying gentle traction. The uterus is then sounded to identify the direction and depth of the uterine cavity. Specific steps of ParaGard and Mirena insertion are shown in Figures 38-2 and 38-3 and outlined in their respective package inserts.
FIGURE 38-2 Insertion of the Mirena intrauterine system. Initially, threads from behind the slider are first released to hang freely. The slider found on the handle should be positioned at the top of the handle nearest the device. The IUD arms are oriented horizontally. A flange on the outside of the inserter tube is positioned from the IUD tip to reflect the depth found with uterine sounding. A. As both free threads are pulled, the Mirena IUD is drawn into the inserter tube. The threads are then tightly fixed from below into the handle’s cleft. In these depictions, the inserter tube has been foreshortened. The inserter tube is gently inserted into the uterus until the flange lies 1.5 to 2 cm from the external cervical os to allow the arms to open. B. While holding the inserter steady, the IUD arms are released by pulling the slider back to reach the raised horizontal mark on the handle, but no further. C. The inserter is then gently guided into the uterine cavity until its flange touches the cervix. D. The device is released by holding the inserter firmly in position and pulling the slider down all the way. The threads will be released automatically from the cleft. The inserter may then be removed, and IUD strings trimmed.
FIGURE 38-3 Insertion of ParaGard T 380A. The uterus is sounded, and the IUD is loaded into its inserter tube not more than 5 minutes before insertion. A blue plastic flange on the outside of the inserter tube is positioned from the IUD tip to reflect uterine depth. The IUD arms should lie in the same plane as the flat portion of the oblong blue flange. A. The inserter tube, with the IUD loaded, is passed into the endometrial cavity. A long, solid, white inserter rod abuts the base of the IUD. When the blue flange contacts the cervix, insertion stops. B. To release the IUD arms, the solid white rod within the inserter tube is held steady, while the inserter tube is withdrawn no more than 1 cm. C.The inserter tube, not the inserter rod, is then carefully moved upward toward the top of the uterus until slight resistance is felt. At no time during insertion is the inserter rod advanced forward. D. First, the solid white rod and then the inserter tube are withdrawn individually. At completion, only the threads should be visible protruding from the cervix. These are trimmed to allow 3 to 4 cm to extend into the vagina.
Following insertion, only the threads should be visible trailing from the cervix. These are trimmed to allow 3 to 4 cm to protrude into the vagina, and their length is recorded. If there is suspicion that the device is not positioned correctly, then placement should be confirmed, using sonography if necessary. If the IUD is not positioned completely within the uterus, it is removed and replaced with a new device. An expelled or partially expelled device should not be reinserted.
LONG-ACTING REVERSIBLE CONTRACEPTION: PROGESTIN IMPLANTS
Contraception can be provided by thin, pliable progestin-containing cylinders that are implanted subdermally and release hormone over many years. One of these, Implanon is a single-rod implant with 68 mg of etonogestrel covered by an ethylene vinyl acetate copolymer cover. The implant is placed subdermally on the medial surface of the upper arm 8 to 10 cm from the elbow in the biceps groove and is aligned with the long axis of the arm. It may be used as contraception for 3 years and then replaced at the same site or in the opposite arm (Merck, 2012a).
Implanon is not radiopaque, and a misplaced implant may be identified with sonography using a 10- to 15-MHz linear array transducer (Shulman, 2006). In some cases, MR imaging may be required if supplemental information is needed despite sonography (Correia, 2012). To improve radiologic detection, the manufacturer developed Nexplanon, which is similarly shaped and pharmacologically identical to Implanon but is radiopaque. Additionally, the Nexplanon inserter device is designed to assist with subdermal placement and avert deeper insertions. Both implants are highly effective, and the mechanism of action for progestin-only products is described on page 704 (Croxatto, 1998; Mommers, 2012). Although still approved by the Food and Drug Administration (FDA), Implanon is no longer distributed by the manufacturer.
The first progestin implants contained levonorgestrel, and systems are still available outside the United States. Jadelle, originally named Norplant-2, provides levonorgestrel and contraception for 5 years through two subdermally implanted Silastic rods. After this time, rods may be removed and if desired, new rods inserted at the same site (Bayer Schering Pharma Oy, 2010). Jadelle is approved by the FDA, however, it is not marketed or distributed in the United States (Population Council, 2013). Sino-implant II is a two-rod implant with the same amount (150 mg) of levonorgestrel and same mechanism of action as Jadelle but provides 4 years of contraception (Shanghai Dahua Pharmaceutical, 2012). Sino-implant II is manufactured in China and approved for use by several countries in Asia and Africa.
Both implant systems are highly effective, and the mechanism of action for progestin-only products is described on page 704. Like the etonogestrel implant, these systems are placed subdermally on the inner arm approximately 8 cm from the elbow and have similar removal steps. Implants vary regarding their insertion technique, and manufacturer instructions should be consulted.
The forerunner of these implants was the Norplant System, which provided levonorgestrel in six Silastic rods implanted subdermally. The manufacturer stopped distributing the system in 2002.
Method-Specific Adverse Effects
Risks that are specific to implants stem mainly from malpositioning. First, branches of the medial antebrachial cutaneous nerve can be injured if the implant or insertion needle is placed too deeply or if exploration for a lost implant is aggressive. Clinically, numbness and paresthesia over the anteromedial aspect of the forearm are noted (Brown, 2012; Wechselberger, 2006). Second, nonpalpable devices are not uncommon and may require radiological imaging for localization as described earlier. If imaging fails to locate an Implanon or Nexplanon implant, etonogestrel blood level determination can be used to verify that the implant is in situ.
For those not currently using hormonal contraception, the etonogestrel implant is ideally inserted within 5 days of menses onset. If inserted later in the cycle, then alternative contraception is recommended for 7 days following placement. With levonorgestrel-releasing implants, contraception is established within 24 hours if inserted within the first 7 days of the menstrual cycle (Sivin, 1997; Steiner, 2010). For transitioning methods, an implant is placed on the day of the first placebo COC pill; on the day that the next DMPA injection would be due; or within 24 hours of taking the last POP (Merck, 2012a). Related to pregnancy, an implant may be inserted before discharge following delivery, miscarriage, or abortion.
Nexplanon Insertion Technique
With the patient lying down, her nondominant arm, forearm, and hand are outstretched on the bed with the inner aspects of each exposed upward, and the elbow is flexed. The insertion site is marked with a sterile pen 8 to 10 cm proximal to the medial condyle of the humerus. A second mark is placed 4 centimeters proximally and delineates the final path of the implant. The Nexplanon is inserted using sterile technique. The area is cleaned aseptically, and a 1-percent lidocaine anesthetic track is injected beneath the skin along the planned insertion path. The implant is then placed as shown in Figure 38-4. After placement, both patient and provider should palpate and identify both ends of the 4-cm implant. To minimize bruising at the site, a pressure bandage is created around the arm and is removed the following day.
FIGURE 38-4 Nexplanon insertion. A sterile pen marks the insertion site, which is 8 to 10 cm proximal to the medial humeral condyle. A second mark is placed 4 cm proximally along the arm’s long axis. The area is cleaned aseptically, and a 1-percent lidocaine anesthetic track is injected along the planned insertion path. A. The insertion device is grasped at its gripper bubbles found on either side, and the needle cap is removed outward. The device can be seen within the needle bore. The needle bevel then pierces the skin at a 30-degree angle. B. Once the complete bevel is subcutaneous, the needle is quickly angled downward to lie horizontally. C. Importantly, the skin is tented upward by the needle as the needle is slowly advanced horizontally and subdermally. D. Once the needle is completely inserted, the lever on the top of the device is pulled backward toward the operator. This retracts the needle and thereby deposits the implant. The device is then lifted away from the skin. After placement, both patient and operator should palpate the 4-cm implant.
With sterile implant removal, the proximal end of the implant is depressed with a finger to allow the distal end to bulge toward the skin. After anesthetizing the skin over this bulge, the skin is incised 2 mm toward the elbow along the long axis of the arm. The proximal butt of the implant is then pushed toward this incision. Once visible, the distal implant is grasped with a hemostat and removed. If present, superficial adhesions surrounding an implant may be dissected away with hemostat tips placed into the incision.
PROGESTIN-ONLY CONTRACEPTIVE GROUP
Actions and Side Effects
Progestin-only contraceptives include the implants just described, pills, and injectables. As their primary contraceptive action, these progestins suppress luteinizing hormone (LH) and in turn block ovulation. As other effects, cervical mucus is thickened to retard sperm passage, and atrophy renders the endometrium unfavorable for implantation. Fertility is restored rapidly following cessation of progestin-only contraception, with the exception of DMPA as described on page 711 (Mansour, 2011).
For all progestin-only methods, irregular uterine bleeding is a distinct disadvantage. It may manifest as metrorrhagia or menorrhagia and is the most frequently reported adverse event leading to method discontinuation. Often, counseling and reassurance regarding this effect is sufficient. Particularly troublesome bleeding may be improved by one to two cycles of COCs, by a 1- to 3-week course of estrogen alone, or by a short course of NSAIDs combined with the established method. Fortunately, with prolonged use, progestins induce endometrial atrophy, which leads to sustained amenorrhea. And, for the well-counseled patient, this is often an advantage.
Most progestin-only contraceptive methods do not significantly affect lipid metabolism, glucose levels, hemostatic factors, liver function, thyroid function, and blood pressure (Dorflinger, 2002). Moreover, these have not been shown to increase the risk for thromboembolism, stroke, or cardiovascular disease (Mantha, 2012; World Health Organization, 1998). However, as described on page 711, the increased low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol levels seen with DMPA may be less desirable if there are cardiac or vascular risks.
Progestin-only methods do not impair milk production and are an excellent choice for lactating women. There are no increased risks of genital tract or breast neoplasia (Wilailak, 2012; World Health Organization, 1991a,b, 1992). Weight gain and bone mineral density loss are not prominent side effects of this contraceptive group, except for DMPA, as noted on page 711 (Funk, 2005; Lopez, 2011). Functional ovarian cysts develop with a greater frequency in women using progestin-only agents, although they do not usually necessitate intervention (Brache, 2002; European Society of Human Reproduction and Embryology, 2001). Last, an association between depression and DMPA or POPs is unclear (Civic, 2000; Svendal, 2012; Westhoff, 1995). Women with depression may be prescribed these methods, but surveillance following initiation is reasonable.
Contraindications to Progestin-Only Contraceptives
These methods are ideal for most women, but contraindications and cautions are associated with a few conditions. Current breast cancer and pregnancy are the only two absolute contraindications. However, conditions for which limited and cautious use should be considered are listed in Table 38-3.
There are a few instances in which manufacturer restrictions differ from the US MEC. First, manufacturer prescribing information lists thrombosis or thromboembolic disorders as contraindications (Merck, 2012a; Pfizer, 2012). However, for individuals with these disorders, US MEC considers progestin-containing methods category 2. Second, for many progestin products, manufacturers note prior ectopic pregnancy as a contraindication. This is secondary to progesterone’s effect to slow fallopian tube motility and thereby delay fertilized egg transport to the endometrial cavity. But again, US MEC considers progestin injectables and implants category 1, and progestin-only pills are category 2 for those with prior ectopic pregnancy.
VERY EFFECTIVE CONTRACEPTION: HORMONAL CONTRACEPTIVES
These currently are available in forms that contain both estrogen and progestin or contain only progestin. Progestin-only injectables and pills are considered very effective, yet second-tier agents, due to the need for increased patient compliance. Similarly, products containing both estrogen and progestin, often termed combination hormonal contraception (CHC), are considered in this tier. These may be supplied as pills, transvaginal rings, or transdermal patches.
Combination Hormonal Contraceptives Mechanism of Action
The contraceptive actions of CHCs are multiple, but the most important effect is suppression of hypothalamic gonadotropin-releasing factors. This in turn blocks pituitary secretion of follicle-stimulating hormone (FSH) and LH to inhibit ovulation. The progestin component provides ovulation prevention by suppressing LH; they thicken cervical mucus and thereby retard sperm passage; and they render the endometrium unfavorable for implantation. Estrogen blocks ovulation by suppressing FSH release. It also stabilizes the endometrium, which prevents intermenstrual bleeding—also known as breakthrough bleeding. The net effect is an extremely effective yet highly reversible method (Mansour, 2011).
Combination Oral Contraceptive Pills
Combination oral contraceptive pills are the most frequently used birth control method in the United States. In a 2006 to 2010 survey, 17 percent of US women were using these (Jones, 2012). COCs are marketed in an almost bewildering variety (Table 38-4). Most are also available as generics, and the FDA (2013) confirms the bioequivalence of COC generics. The American College of Obstetricians and Gynecologists (2013b) supports the use of either branded or generic preparations.
TABLE 38-4. Combination Oral Contraceptives Formulations
Pharmacologically, ethinyl estradiol is the most common estrogen present in COC formulations in the United States. Less frequently, mestranol or estradiol valerate is used. Unwanted effects most often attributed to the estrogen component include breast tenderness, fluid retention, weight gain, nausea, and headache.
COCs also contain one of several progestins that are structurally related to progesterone, testosterone, or spironolactone. Thus, these progestins bind variably to progesterone, androgen, estrogen, glucocorticoid, and mineralocorticoid receptors. These affinities explain many pill-related side effects and are often used to compare one progestin with another.
Most progestins used in COCs are related to testosterone and may impart androgenic side affects such as acne and adverse HDL and LDL levels. To avoid these effects, progestins more structurally similar to the progestone molecule have been developed. Medroxyprogesterone acetate is one example, but it is mainly used in a progestin-only injectable form. Another, nomegestrol acetate, is used in a COC approved outside the United States. Despite these pharmacological differences, the true advantage of one progestin over another is less apparent clinically (Lawrie, 2011; Moreau, 2007).
Another progestin, drospirenone, is structurally similar to spironolactone. The doses used in currently marketed COCs have effects similar to 25 mg of this diuretic hormone (Seeger, 2007). Drospirenone displays antiandrogenic activity, provides an antialdosterone action to minimize water retention, and has antimineralocorticoid properties that may, in theory, cause potassium retention and hyperkalemia (Krattenmacher, 2000). Thus, it is avoided in women with renal or adrenal insufficiency or with hepatic dysfunction. Moreover, serum potassium level monitoring is recommended in the first month for patients chronically treated concomitantly with any drug associated with potassium retention. These include NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, heparin, aldosterone antagonists, and potassium-sparing diuretics (Bayer HealthCare Pharmaceuticals, 2012).
Since the development of COCs, their estrogen and progestin content has dropped remarkably to minimize adverse effects. Currently, the lowest acceptable dose is limited by the ability to prevent pregnancy and to avoid unacceptable breakthrough bleeding. Thus, the daily estrogen content varies from 10 to 50 μg of ethinyl estradiol, and most contain 35 μg or less.
With COCs termed monophasic pills, the progestin dose remains constant throughout the cycle. In others, the dose frequently is varied, and terms biphasic, triphasic, or quadriphasic pill are used depending on the number of dose changes within the cycle. In some formulations, the estrogen dose also varies. In general, phasic pills were developed to reduce the total progestin content per cycle without sacrificing contraceptive efficacy or cycle control. The theoretical advantage of a lower total progesterone dose per cycle has not been borne out clinically (Moreau, 2007). Cycle control also appears to be comparable among mono- through triphasic pills (van Vliet, 2006, 2011a,b).
Hormones are taken daily for a specified time (21 to 81 days) and then replaced by placebo for a specified time (4 to 7 days), which is called the “pill-free interval.” During these pill-free days, withdrawal bleeding is expected.
With the trend to lower estrogen doses to minimize side effects, there is concern for follicular development and ovulation. To counter this, the active-pill duration in some formulations is extended to 24 days. And, these 24/4 regimens do appear to reduce ovulation and breakthrough bleeding rates (Fels, 2013).
Alternatively, longer durations of active hormone, designed to minimize the number of withdrawal episodes, have been introduced (Edelman, 2006). These extended-cycle products produce a 13-week cycle, that is, 12 weeks of hormone use, followed by a week for withdrawal menses. The product Amethyst provides continuous active hormone pills for 365 days each year. Such extended or continuous regimens may be especially suited for women with significant menstrual symptoms.
For general initiation, women should ideally begin COCs on the first day of a menstrual cycle. In such cases, a supplementary contraceptive method is unnecessary. With the more traditional “Sunday start,” women begin pills on the first Sunday that follows menses onset, and an additional method is needed for 1 week to prevent conception. If menses begin on a Sunday, then pills are begun that day and no supplementary method is required. Alternatively, with the “Quick Start” method, COCs are started on any day, commonly the day prescribed, regardless of cycle timing. An additional method is used during the first week. This latter approach improves short-term compliance (Westhoff, 2002, 2007b). If the woman is already pregnant during Quick Start initiation, COCs are not teratogenic (Lammer, 1986; Rothman, 1978; Savolainen, 1981). Similarly, same-day initiation can be implemented with the contraceptive vaginal ring or patch (Murthy, 2005; Schafer, 2006).
For maximum efficiency, pills should be taken at the same time each day. If one dose is missed, contraception is likely not diminished with higher-dose monophasic COCs. Doubling the next dose will minimize breakthrough bleeding and maintain the pill schedule. If several doses are missed or if lower-dose pills are used, the pill may be stopped, and an effective barrier technique used until menses. The pill may then be restarted. Alternatively, a new pack can be started immediately following identification of missed pills, and a barrier method used for 1 week. If there is no withdrawal bleeding, the woman should continue her pills but seek attention to exclude pregnancy.
With initiation of COCs, spotting or bleeding is common. It does not reflect contraceptive failure and typically resolves within one to three cycles. If unscheduled bleeding persists, those with bleeding during the first part of a pill pack may benefit from an increase in the pill’s estrogen dose, whereas those with bleeding during the second part may improve with a higher progestin dose (Nelson, 2011).
Altered Drug Efficacy
Combination oral contraceptives interfere with the actions of some drugs. In such cases, doses can be adjusted as shown in Table 38-5. Conversely, some drugs decrease the COC effectiveness. Three groups are notable: the antitubercular drugs rifampin and rifabutin; efavirenz and ritonavir-boosted protease inhibitors, which are used to treat HIV infection; and enzyme-inducing anticonvulsants, which include phenytoin (Dilantin), carbamazepine (Tegretol), oxcarbazepine (Trileptal), barbiturates, primidone (Mysoline), and topiramate (Topamax) (Gaffield, 2011; Panel on Antiretroviral Guidelines for Adults and Adolescents, 2013). With these, a method other than COCs is preferable. However, if a COC is selected for concurrent use with an agent from these three groups, then a preparation containing a minimum of 30 μg ethinyl estradiol should be chosen.
TABLE 38-5. Drugs Whose Effectiveness Is Influenced by Combination Oral Contraceptives
In obese women, COCs are highly effective (Lopez, 2010). That said, some but not all studies point to a potential increased pregnancy risk with COC use due to lowered hormone bioavailability (Brunner, 2005; Holt, 2002, 2005; Westhoff, 2010). With the transdermal patch method, however, there is stronger evidence that obesity may alter pharmacokinetics and lower efficacy (p. 701).
Although their effects on carbohydrate metabolism are considered clinically insignificant, COCs do have notable effects on lipid and protein synthesis. In general, COCs increase serum levels of triglycerides and total cholesterol. Estrogen decreases LDL cholesterol concentrations but increases HDL and very-low density (VLDL) cholesterol levels. Some progestins cause the reverse. Despite this, the clinical consequences of these perturbations have almost certainly been overstated. Oral contraceptives are not atherogenic, and their impact on lipids is inconsequential for most women (Wallach, 2000). But in women with dyslipidemias, the American College of Obstetricians and Gynecologists (2013e) recommends assessment of lipid levels following COC initiation. Moreover, for women with LDL cholesterol levels > 160 mg/dL or for those with multiple additional risk factors for cardiovascular disease, alternative contraceptive methods are recommended.
With COCs, protein metabolism is affected, and estrogens prompt increased hepatic production of various globulins. First, fibrinogen and many of the clotting factor levels are increased in direct proportion to estrogen dose and may lead to thrombosis (Comp, 1996). Angiotensinogen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with “pill-induced hypertension” discussed subsequently. Last, COCs increase sex-hormone binding globulin (SHBG) levels, which decrease bioavailable testosterone concentrations and improve androgenic side effects.
Regarding carbohydrate metabolism, there are fortunately limited effects with current low-dose formulations in women who do not have diabetes (Lopez, 2012a). And, the risk of developing diabetes is not increased (Kim, 2002). Moreover, COCs may be used in nonsmoking, diabetic women younger than 35 years who have no associated vascular disease (American College of Obstetricians and Gynecologists, 2013e). Last, studies have not supported a connection between COCs and weight gain (Gallo, 2011).
Other metabolic changes, often qualitatively similar to those of pregnancy, have been identified in women taking oral contraceptives. For example, total plasma thyroxine (T4) and thyroid-binding proteins are elevated. These pregnancy-like effects should be considered when evaluating laboratory tests in women using COCs.
Despite increased plasma angiotensinogen (renin substrate) levels, most women using low-dose COCs formulations rarely develop clinically significant hypertension (Chasan-Taber, 1996). However, it is common practice for patients to return 8 to 12 weeks after COC initiation for evaluation of blood pressure and other symptoms.
During initial contraception selection, a history of gestational hypertension does not preclude subsequent COC use. Also, COCs are permissible in women with well-controlled uncomplicated hypertension who are nonsmokers, otherwise healthy, and younger than 35 (American College of Obstetricians and Gynecologists, 2013e). In contrast, severe forms of hypertension, especially those with end-organ involvement, usually preclude COC use.
For women with prior stroke, COCs should not be considered due to risks for repeat events. The risk for a first stroke is substantially increased in women who have hypertension, who smoke, or who have migraine headaches with visual aura or other focal neurological changes and use oral contraceptives (MacClellan, 2007). However, for nonsmoking women younger than 35, the risk of ischemic and hemorrhagic strokes is extremely low, and method benefits considerably outweigh risks (World Health Organization, 1996, 1998). Moreover, because of this low risk, the American College of Obstetricians and Gynecologists (2013e) notes that COCs may be considered for women with migraines that lack focal neurological signs if they are otherwise healthy, normotensive nonsmokers younger than 35 years.
For women with prior myocardial infarction, COCs should not be considered. Also, in women with multiple cardiovascular risk factors, which include smoking, hypertension, older age, and diabetes, the risk for myocardial infarction outweighs the benefits of this method. However, for those without these risks, low-dose oral contraceptives are not associated with an increased risk of myocardial infarction (Margolis, 2007; World Health Organization, 1997).
It has long been known that the risk of deep-vein thrombosis and pulmonary embolism is increased in women who use COCs (Stadel, 1981). These clearly are estrogen-dose related, and rates have substantively decreased with lower-dose formulations containing 10 to 35 μg of ethinyl estradiol. The incidence of venous thromboembolism (VTE) with COC use is only 3 to 4 per 10,000 woman-years and is lower than the incidence of 5 to 6 per 10,000 woman-years estimated for pregnancy (Chap. 52, p. 1028) (Mishell, 2000). The enhanced risk of VTE appears to decrease rapidly once COCs are stopped. And because these complications are increased in women smokers older than 35 years, COCs are not recommended for this population (Craft, 1989).
Those most at risk for VTE include women with thrombophilias (Comp, 1996). Other clinical factors that increase the risk of VTE with COC use are hypertension, obesity, diabetes, smoking, and a sedentary lifestyle (Pomp, 2007, 2008). Moreover, COC use during the month before a major operative procedure appears to double the risk for postoperative VTE (Robinson, 1991). Thus, the American College of Obstetricians and Gynecologists (2013d) recommends balancing the risks of VTE with those of unintended pregnancy during the 4 to 6 weeks required to reverse the thrombogenic effects of COCs before surgery. In the early puerperium, VTE risks are also increased, and COCs are not recommended for women within the first 4 weeks after delivery. For all women, an increased VTE risk with drospirenone-containing COCs has been shown in two studies. Accordingly, the FDA has encouraged an assessment of benefits and VTE risks in users of these pills (Food and Drug Administration, 2011; Jick, 2011; Parkin, 2011).
Fortunately, most studies indicate that overall, COCs are not associated with an increased risk of cancer (Hannaford, 2007). In fact, a protective effect against ovarian and endometrial cancer has been shown (Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2008; Tsilidis, 2011). Protection from these cancers decreases, however, as time from pill use lengthens (Tworoger, 2007). In contrast, the relative risk of cervical dysplasia and cervical cancer is increased in current COC users, but this declines after use is discontinued. Following 10 or more years, risk returns to that of never users (International Collaboration of Epidemiological Studies of Cervical Cancer, 2007).
Although COC use in the past was linked to development of hepatic focal nodular hyperplasia and benign hepatic adenoma, large studies do not support this (Heinemann, 1998). Moreover, there is also no evidence for increased risk of hepatocellular cancer (Maheshwari, 2007). For women with known tumors, COCs may be used in those with focal nodular hyperplasia, but avoided in those with benign hepatic adenoma and hepatocellular carcinoma (Kapp, 2009b). Rates of colorectal cancer appear to be reduced in ever users (Bosetti, 2009; Kabat, 2008).
It is unclear whether COCs contribute to the development of breast cancer, and major studies show no risk or a small risk among current users, which drops with time following cessation (Collaborative Group on Hormonal Factors in Breast Cancer, 1996; Marchbanks, 2002). In women who are carriers of the BRCA1 or BRCA2 gene mutation, risks for breast cancer are not increased by COC use (Brohet, 2007; Iodice, 2010). With regard to benign breast disease, COCs appear to lower rates (Vessey, 2007).
As summarized in Table 38-6, many noncontraceptive benefits are associated with COC use (American College of Obstetricians and Gynecologists, 2012c). And indeed, COCs may be used for these effects, even in those without contraceptive needs.
TABLE 38-6. Some Benefits of Combined Estrogen Plus Progestin Oral Contraceptives
Increased bone density
Reduced menstrual blood loss and anemia
Decreased risk of ectopic pregnancy
Improved dysmenorrhea from endometriosis
Fewer premenstrual complaints
Decreased risk of endometrial and ovarian cancer
Reduction in various benign breast diseases
Inhibition of hirsutism progression
Improvement of acne
Prevention of atherogenesis
Decreased incidence and severity of acute salpingitis
Decreased activity of rheumatoid arthritis
Low-dose estrogen formulations are not associated with depression or premenstrual mood changes and may actually improve the latter (Joffe, 2007). This is especially true with the drospirenone-containing COCs. Several studies have shown symptom improvement in women with premenstrual dysphoric disorder (PMDD) who use the drospirenone-containing COC Yaz (Lopez, 2012b; Pearlstein, 2005; Yonkers, 2005). And, the FDA has approved indications for this pill to include treatment of PMDD and moderate acne vulgaris for women requesting oral contraception.
Cholestasis and cholestatic jaundice are uncommon, but they resolve when COCs are discontinued. For women who have active hepatitis, COCs should not be initiated, but these may be continued in women who experience a flare of their liver disease while already taking COCs. Use of progestin-only contraception in these women is not restricted. Moreover, there is no reason to withhold COCs from women who have recovered. With cirrhosis, mild compensated disease does not limit the use of COCs or progestin-only methods. However, in those with severe decompensated disease, all hormonal methods should be avoided (Kapp, 2009a).
The progestin component of COCs reduces serum free testosterone levels and inhibits 5α-reductase to limit conversion of testosterone to its active metabolite, dihydrotestosterone. The estrogen component increases SHBG production and also lowers circulating androgen levels. The expected results of these actions are to improve androgenic conditions such as acne and hirsutism.
Hyperpigmentation of the face and forehead—chloasma—is more likely in women who demonstrated such a change during pregnancy. This is less common with low-dose estrogen formulations. Cervical mucorrhea, likely due to cervical ectopy, is common in response to the estrogen component of COCs (Critchlow, 1995). Although previously used for treating functional ovarian cysts, low-dose COC formulations have no effects related to cyst resolution or prevention (European Society of Human Reproduction and Embryology, 2001; Grimes, 2011).
The Ortho Evra patch is another combination hormonal contraceptive formulation. It has an inner layer containing an adhesive and hormone matrix, and a water-resistant outer layer. Thus, women can wear the patch in bathtubs, showers, swimming pools, saunas, and whirlpools without decreased efficacy. The patch may be applied to buttocks, upper outer arm, lower abdomen, or upper torso, but the breasts are avoided. Because the hormones are combined with the adhesive, improper skin adherence will lower hormone absorption and efficacy. Therefore, if a patch is so poorly adhered that it requires reinforcement with tape, it should be replaced.
Initiation of the patch is the same as for COCs, and a new patch is applied weekly for 3 weeks, followed by a patch-free week to allow withdrawal bleeding. Although a patch is ideally worn no longer than 7 days, hormone levels remain in an effective range for up to 9 days. This affords a 2-day window for patch change delays (Abrams, 2001).
In general, the transdermal patch and vaginal ring produce metabolic changes, side effects, and efficacy rates comparable to those with COC pills. However, the patch has been associated with a higher VTE risk in some but not other studies (Cole, 2007; Jick, 2010; Lidegaard, 2012). And despite this lack of convincing association, the FDA (2008) ordered labeling for the patch to state that users may be at increased risk for developing VTE. Obesity—90 kg or greater—may be associated with an increased risk for patch contraceptive failure (Zieman, 2002). Last, application-site reaction and breast tenderness are more frequent during initial cycles in patch wearers (Urdl, 2005).
The NuvaRing is yet another form of combination hormonal contraception and is a flexible intravaginal ring. Constructed of ethinyl vinyl acetate, the ring measures 54 mm in diameter and 4 mm in cross section (Fig. 38-5). During insertion, the ring is compressed and threaded into the vagina, but no specific final intravaginal position is required. Its core releases ethinyl estradiol and the progestin etonogestrel, which are absorbed across the vaginal epithelium. Before being dispensed, the rings are refrigerated, and once dispensed, their shelf life is 4 months. The ring is placed within 5 days of menses onset and after 3 weeks of use, is removed for 1 week to allow withdrawal bleeding. Contraception will still be afforded if a ring is left in place for a fourth week (Merck, 2012b).
FIGURE 38-5 NuvaRing: estrogen-progestin—releasing vaginal contraceptive ring.
Patient satisfaction is high with this method, although vaginitis, ring-related events, and leukorrhea are more common (Oddsson, 2005). Despite this, no deleterious affect on vaginal flora or on lower reproductive-tract or endometrial epithelia has been found (Bulten, 2005; Veres, 2004). Approximately 70 percent of partners feel the ring during intercourse (Dieben, 2002). If this is bothersome, the ring may be removed for intercourse but should be replaced within 3 hours to maintain efficacy.
Injectable Progestin Contraceptives
Both intramuscular depot medroxyprogesterone acetate (Depo-Provera), 150 mg every 3 months, and norethisterone enanthate, 200 mg every 2 months, are injectable progestin contraceptives that have been effectively used worldwide for years. Available in the United States, DMPA is injected into the deltoid or gluteus muscle, but massage is avoided to ensure that the drug is released slowly. Alternatively, a subcutaneous version, depo-subQ provera 104, is also available and is injected into the subcutaneous tissue of the anterior thigh or abdomen every 3 months.
DMPA is an effective method, and as with other progestin-only methods, contraception is provided by ovulation inhibition, increased cervical mucus viscosity, and creation of an endometrium unfavorable for ovum implantation. Initial injection is given within the first 5 days following menses onset. Therapeutic serum levels sufficient to exert a consistent contraceptive effect are observed by 24 hours. Thus, no additional contraceptive method is required with initiation within this window. Alternatively, limited data support a “Quick Start” or initiation of DMPA regardless of cycle day. If so implemented, investigators recommend an initial negative pregnancy test result before injection, a supplemental contraceptive method during the 7 days following injection, and a second pregnancy test after 3 to 6 weeks to identify an early pregnancy (Rickert, 2007; Sneed, 2005). Fortunately, pregnancies conceived during DMPA use are not associated with an increased risk of fetal malformation (Katz, 1985). For women who present for intramuscular DMPA reinjection more than 13 weeks or subcutaneous DMPA reinjection more than 14 weeks after the prior dose, the manufacturer recommends exclusion of pregnancy before reinjection (Pfizer, 2010, 2012).
Actions and Side Effects
Injected progestins offer the convenience of a 3-month dosing schedule, contraceptive effectiveness comparable with or better than COCs, and minimal to no lactation impairment. Iron deficiency anemia is less likely in long-term users because of amenorrhea, which develops in up to 50 percent after 1 year and in 80 percent after 5 years.
Similar to other progestin-only contraceptive, irregular menstrual bleeding is common, and a fourth of women discontinued DMPA in the first year because of this (Cromer, 1994). Unique to DMPA, prolonged anovulation can follow discontinuation, which results in delayed fertility resumption. After injections are stopped, one fourth of patients do not resume regular menses for up to 1 year (Gardner, 1970). Accordingly, DMPA may not be ideal for women who plan to use birth control only briefly before attempting conception.
As with other progestins, DMPA has not been associated with cardiovascular events or stroke in otherwise healthy women. However, in those with severe hypertension, an increased risk of stroke has been found in DMPA users (World Health Organization, 1998). Moreover, the US MEC expresses concerns regarding hypoestrogenic effects and reduced HDL levels from DMPA in women with vascular disease or multiple risks for cardiovascular disease.
Weight gain is generally attributed to DMPA, and these increases are comparable between the two depot forms (Bahamondes, 2001; Nault, 2013; Westhoff, 2007c). In long-term users, loss of bone mineral density is also a potential problem (Petitti, 2000; Scholes, 1999). In 2004, the FDA added a black box warning to DMPA labeling, which notes that this concern is probably most relevant for adolescents, who are building bone mass, and perimenopausal women, who will soon have increased bone loss during menopause. That said, it is the opinion of the World Health Organization (1998) and American College of Obstetricians and Gynecologists (2008) that DMPA should not be restricted in those high-risk groups. And, it seems prudent to reevaluate overall risks and benefits during extended use (d’Arcangues, 2006).
It is somewhat reassuring that bone loss appears to be reversible after discontinuation of therapy but is still not complete after 18 to 24 months (Clark, 2006; Gai, 2011; Scholes, 2002).
So-called mini-pills are progestin-only contraceptives that are taken daily. These contraceptives have not achieved widespread popularity and are used by only 0.4 percent of American women (Hall, 2012). Unlike COCs, they do not reliably inhibit ovulation. Rather, their effectiveness depends more on cervical mucus thickening and endometrial atrophy. Because mucus changes are not sustained longer than 24 hours, mini-pills should be taken at the same time every day to be maximally effective. If a progestin-only pill is taken even 4 hours late, a supplemental form of contraception must be used for the next 48 hours. Progestin-only pills are contraindicated in women with known breast cancer or pregnancy. Other cautions are listed in Table 38-3.
EFFECTIVE CONTRACEPTION: BARRIER METHODS
For many years, male and female condoms, vaginal diaphragms, and periodic abstinence have been used for contraception with variable success (see Table 38-2). The contraceptive efficacy of the male condom is enhanced appreciably by a reservoir tip and probably by the addition of a spermicide. Such agents, as well as those used for lubrication, should be water-based because oil-based products destroy latex condoms and diaphragms.
When used properly, condoms provide considerable but not absolute protection against a broad range of STDs. These include gonorrhea, syphilis, trichomoniasis, and HIV, herpetic, and chlamydial infections.
For individuals sensitive to latex, condoms made from lamb intestines are effective, but they do not provide infection protection. Fortunately, nonallergenic condoms have been developed that are made of polyurethane or of synthetic elastomers. Polyurethane condoms are effective against STDs but have a higher breakage and slippage rate than latex condoms (Gallo, 2006).
The only female condom available is marketed as the FC2 Female Condom. It is a synthetic nitrile sheath with one flexible polyurethane ring at each end. Its open ring remains outside the vagina, whereas its closed internal ring is fitted under the symphysis like a diaphragm (Fig. 38-6). The female condom can be used with both water-based and oil-based lubricants. Male condoms should not be used concurrently because simultaneous use may cause friction that leads to condom slipping, tearing, and displacement. Following use, the female condom outer ring should be twisted to seal the condom so that no semen spills. As an added value, in vitro tests have shown the female condom to be impermeable to HIV and other STDs.
FIGURE 38-6 FC2 Female Condom insertion and positioning. A. The inner ring is squeezed for insertion. The sheath is inserted similarly to a diaphragm. B. The inner ring is pushed inward with an index finger.
Diaphragm Plus Spermicide
The diaphragm consists of a circular latex dome of various diameters supported by a circumferential latex-covered metal spring. It is effective when used in combination with spermicidal jelly or cream. The spermicide is applied into the dome cup and along the rim. The device is then positioned so that the cup faces the cervix and so that the cervix, vaginal fornices, and anterior vaginal wall are partitioned effectively from the remainder of the vagina and the penis. In this fashion, the centrally placed spermicide is held against the cervix. When appropriately positioned, one rim is lodged deep in the posterior vaginal fornix, and the opposite rim fits behind the inner surface of the symphysis and immediately below the urethra (Fig. 38-7). If a diaphragm is too small, it will not remain in place. If it is too large, it is uncomfortable when forced into position. A coexistent cystocele or uterine prolapse typically leads to instability and expulsion. Because size and spring flexibility must be individualized, the diaphragm is available only by prescription.
FIGURE 38-7 A diaphragm in place creates a physical barrier between the vagina and cervix.
With use, the diaphragm and spermicide can be inserted hours before intercourse, but if more than 6 hours elapse, additional spermicide should be placed in the upper vagina for maximum protection and be reapplied before each coital episode. The diaphragm should not be removed for at least 6 hours after intercourse. Because toxic shock syndrome has been described following its use, it may be worthwhile to remove the diaphragm at 6 hours, or at least the next morning, to minimize this rare event. Diaphragm use is associated with a slightly increased rate of urinary infections, presumably from urethral irritation by the ring under the symphysis.
FemCap is currently the only available cervical cap in the United States. Made of silicone rubber, it has a sailor-cap shape with a dome that covers the cervix and a flared brim, which allows the cap to be held in place by the muscular walls of the upper vagina. Available in 22-, 26-, and 30-mm sizes, it should be used with a spermicide applied once at insertion to both sides of the dome cup. For contraception, it should remain in place for 6 hours following coitus and may remain for up to 48 hours. Even with proper fitting and correct use, pregnancy rates with this method are higher that with the diaphragm (Gallo, 2002; Mauck, 1999).
Fertility Awareness-Based Methods
All of these family planning methods attempt to identify the fertile days each cycle and advise sexual abstinence during these days. However, their limited efficacy is shown in Table 38-2. Common forms of these fertility awareness-based (FAB) methods include Standard Days, Calendar Rhythm, Temperature Rhythm, Cervical Mucus, and Symptothermal Methods.
The Standard Days Method counsels women to avoid unprotected intercourse during cycle days 8 through 19. For successful use, women must have regular monthly cycles of 26 to 32 days. Those who use this method can mark a calendar or can use Cycle-Beads, which is a ring of counting beads, to keep track of their days.
The Calendar Rhythm Method requires counting the number of days in the shortest and longest menstrual cycle during a 6- to 12-month span. From the shortest cycle, 18 days are subtracted to calculate the first fertile day. From the longest cycle, 11 days are subtracted to identify the last fertile day. This is problematic because ovulation most often occurs 14 days before the onset of the next menses. Because this is not necessarily 14 days after the onset of the last menses, the calendar rhythm method is not reliable.
The Temperature Rhythm Method relies on slight changes—sustained 0.4°F increases—in the basal body temperature that usually occur just before ovulation. This method is much more likely to be successful if during each menstrual cycle, intercourse is avoided until well after the ovulatory temperature rise. For this method to be most effective, the woman must abstain from intercourse from the first day of menses through the third day after the temperature increase.
The Cervical Mucus Method, also called the Two-Day Method or Billings Method, relies on awareness of vaginal “dryness” and “wetness.” These reflect changes in the amount and quality of cervical mucus at different times in the menstrual cycle. With the Billings Method, abstinence is required from the beginning of menses until 4 days after slippery mucus is identified. With the Two-Day method, intercourse is considered safe if a woman did not note mucus on the day of planned intercourse or the day prior.
The Symptothermal Method combines changes in cervical mucus—onset of fertile period; changes in basal body temperature—end of fertile period; and calculations to estimate the time of ovulation. This method is more complex to learn and apply, but it does not appreciably improve efficacy.
LESS EFFECTIVE CONTRACEPTION: SPERMICIDES
These contraceptives are marketed variously as creams, jellies, suppositories, films, and aerosol foam. They are especially useful for women who need temporary protection, for example, during the first week after starting COCs. Most can be purchased without a prescription.
Typically, spermicides function by providing a physical barrier to sperm penetration and a chemical spermicidal action. The active ingredient is nonoxynol-9 or octoxynol-9. Although these are spermicidal, they do not provide STD protection. Ideally, spermicides must be deposited high in the vagina in contact with the cervix shortly before intercourse. Their duration of maximal effectiveness is usually no more than 1 hour, and thereafter, they must be reinserted before repeat intercourse. Douching should be avoided for at least 6 hours after coitus.
High pregnancy rates are primarily attributable to inconsistent use rather than to method failure. Even if inserted regularly and correctly, however, they are considered a less effective method (see Table 38-2). Fortunately, if pregnancy does occur, they are not considered teratogenic (Briggs, 2011).
The Today contraceptive sponge is an over-the-counter, one-size-fits-all device. The nonoxynol-9–impregnated polyurethane disc is 2.5 cm thick and 5.5 cm wide and has a dimple on one side and satin loop on the other (Fig. 38-8). The sponge can be inserted up to 24 hours prior to intercourse, and while in place, it provides contraception regardless of coital frequency. It should remain in place for 6 hours after intercourse. Pregnancy is prevented primarily by the spermicide nonoxynol-9 and to a lesser extent, by covering the cervix and absorbing semen.
FIGURE 38-8 Today sponges. The sponge is moistened with tap water and gently squeezed to create light suds. It is then positioned with the dimple directly against the cervix. The fabric loop trails within the vagina and can be hooked with a finger to later extract the sponge.
Although the sponge is possibly more convenient than the diaphragm or condom, it is less effective than either (Kuyoh, 2003). Most common causes for discontinuance are pregnancy, irritation, discomfort, or vaginitis (Beckman, 1989). Although toxic shock syndrome (TSS) has been reported with the contraceptive sponge, it is rare, and evidence suggests that the sponge may actually limit production of the responsible staphylococcal exotoxin (Remington, 1987). Still, it is recommended that the sponge not be used during menses or the puerperium.
Many women present for contraceptive care following unprotected sexual intercourse. In this situation, several emergency contraception (EC) regimens substantially decrease the likelihood of an unwanted pregnancy when used correctly. Current methods include COCs, POPs, progesterone antagonists, and copper-containing IUDs (Table 38-7). Patients can obtain information regarding emergency contraception by calling 1-888-NOT-2-LATE or accessing The Emergency Contraception Website: http://not-2-late.com.
TABLE 38-7. Methods Available for Use as Emergency Contraception
Hormonal Emergency Contraception
Also known as the Yuzpe method, one EC method provides a minimum of 100 μg of ethinyl estradiol and 0.5 mg of levonorgestrel in each of two doses. As shown in Table 38-7, a sufficient dose may be achieved by two or more pills. The first dose is taken ideally within 72 hours of intercourse but may be given up to 120 hours. The initial dose is followed 12 hours later by a second equivalent dose.
With progestin-only regimens, 1.5 mg of levonorgestrel is taken, either as a single, one-time 1.5-mg dose or as two tablets, each containing 0.75 mg levonorgestrel. With these regimens, the first dose is ideally taken within 72 hours of unprotected coitus but may be given up to 120 hours. With the two-pill regimen, the second dose follows 12 hours later, although a 24-hour interval between the doses is also effective (Ngai, 2005).
One progesterone-receptor modulator currently available for EC is ulipristal acetate and is marketed as Ella. It is taken as a single 30-mg tablet up to 120 hours after unprotected intercourse (Brache, 2010; Watson, 2010).
The major mechanism with all hormonal regimens is inhibition or delay of ovulation. Emergency hormonal contraceptive regimens are more effective the sooner they are taken and decrease the risk of pregnancy by up to 94 percent (American College of Obstetricians and Gynecologists, 2012b). Although highly effective, if EC fails to prevent pregnancy or is mistimed, no associations with major congenital malformation or pregnancy complications have been noted with estrogen- or progestin- containing regimens. Data regarding ulipristal acetate in this setting are limited.
With EC administration, nausea and vomiting can be a significant side effect (Gemzell-Danielsson, 2013). Accordingly, an oral antiemetic may be prescribed at least 1 hour before each dose. If a woman vomits within 2 hours of a dose, the dose must be repeated.
Copper-Containing Intrauterine Devices
For women who are candidates, copper IUD insertion is an effective EC method and provides an effective 10-year method of contraception (Cheng, 2012). If an IUD is placed up to 5 days after unprotected coitus, the failure rate approximates only 0.1 percent (Fasoli, 1989; Wu, 2010).
For mothers who are nursing exclusively, ovulation during the first 10 weeks after delivery is unlikely. Nursing, however, is not a reliable method of family planning for women whose infants are on a daytime-only feeding schedule. Moreover, waiting for first menses involves a risk of pregnancy, because ovulation usually antedates menstruation. Certainly, after the first menses, contraception is essential unless the woman desires pregnancy.
For nursing mothers, progestin-only contraceptives are the preferred choice in most cases. In addition, IUDs have been recommended for the lactating sexually active woman. Estrogen-progestin contraceptives may reduce both the rate and the duration of milk production, although data are limited (Truitt, 2010). Moreover, very small quantities of the hormones are excreted in breast milk, but no adverse effects on infants have been reported (World Health Organization, 1988). Thus, in many cases, the benefits from pregnancy prevention by the use of COCs after the first 4 puerperal weeks would appear to outweigh the risks in selected patients. Immediate postpartum COC initiation is avoided due to VTE risks (Centers for Disease Control and Prevention, 2011).
Abrams LS, Skee DM, Wong FA, et al: Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin Pharmacol 41:1232, 2001
American College of Obstetricians and Gynecologists: Depot medroxyprogesterone acetate and bone effects. Practice Bulletin No. 415, September 2008
American College of Obstetricians and Gynecologists: Increasing use of contraceptive implants and intrauterine devices to reduce unintended pregnancy. Committee Opinion No. 450, December 2009, Reaffirmed 2011a
American College of Obstetricians and Gynecologists: Understanding and using the U.S. Medical Eligibility Criteria for Contraceptive Use, 2010. Committee Opinion No. 505, September 2011b
American College of Obstetricians and Gynecologists: Adolescents and long- acting reversible contraception: implants and intrauterine devices. Committee Opinion No. 539, October 2012a
American College of Obstetricians and Gynecologists: Emergency contraception. Practice Bulletin No. 112, May 2010, Reaffirmed 2012b
American College of Obstetricians and Gynecologists: Noncontraceptive use of hormonal contraceptives. Practice Bulletin No. 110, January 2010, Reaffirmed 2012c
American College of Obstetricians and Gynecologists: Benefits and risks of sterilization. Practice Bulletin No. 133, February 2013a
American College of Obstetricians and Gynecologists: Brand versus generic oral contraceptives. Committee Opinion No. 375, August 2007, Reaffirmed 2013b
American College of Obstetricians and Gynecologists: Long-acting reversible contraception: implants and intrauterine devices. Practice Bulletin No. 121, July 2011, Reaffirmed 2013c
American College of Obstetricians and Gynecologists: Prevention of deep vein thrombosis and pulmonary embolism. Practice Bulletin No. 84, August 2007, Reaffirmed 2013d
American College of Obstetricians and Gynecologists: Use of hormonal contraception in women with coexisting medical conditions. Practice Bulletin No. 73, June 2006, Reaffirmed 2013e
Backman T, Rauramo I, Huhtala S, et al: Pregnancy during the use of levonorgestrel intrauterine system. Am J Obstet Gynecol 190(1):50, 2004
Bahamondes L, Del Castillo S, Tabares G: Comparison of weight increase in users of depot medroxyprogesterone acetate and copper IUD up to 5 years. Contraception 64(4):223, 2001
Bayer HealthCare Pharmaceuticals: Mirena (levonorgestrel-releasing intrauterine system): highlights of prescribing information. 2013a. Available at: http://labeling.bayerhealthcare.com/html/products/pi/Mirena_PI.pdf. Accessed February 17, 2013
Bayer HealthCare Pharmaceuticals: Skyla (levonorgestrel-releasing intrauterine system): highlights of prescribing information. 2013b. Available at: http:// labeling.bayerhealthcare.com/html/products/pi/Skyla_PI.pdf. Accessed March 2, 2013
Bayer HealthCare Pharmaceuticals: Yaz (drospirenone and ethinyl estradiol tablets): highlights of prescribing information. 2012. Available at: http://labeling.bayerhealthcare.com/html/products/pi/fhc/YAZ_PI.pdf?WT.mc_id=www.berlex.com. Accessed March 7, 2013
Bayer Shering Pharma Oy: Jadelle: data sheet. 2010. Available at: http://www.bayerresources.com.au/resources/uploads/DataSheet/file9537.pdf. Accessed February 16, 2013
Beckman LJ, Murray J, Harvey SM: The contraceptive sponge: factors in initiation and discontinuation of use. Contraception 40:481, 1989
Bednarek PH, Creinin MD, Reeves MF, et al: Immediate versus delayed IUD insertion after uterine aspiration. N Engl J Med 364(23):2208, 2011
Benacerraf BR, Shipp TD, Bromley B: Three-dimensional ultrasound detection of abnormally located intrauterine contraceptive devices which are a source of pelvic pain and abnormal bleeding. Ultrasound Obstet Gynecol 34(1):110, 2009
Boortz HE, Margolis DJ, Ragavendra N, et al: Migration of intrauterine devices: radiologic findings and implications for patient care. Radiographics 32(2):335, 2012
Bosetti C, Bravi F, Negri E, et al: Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis. Hum Reprod Update 15(5):489, 2009
Brache V, Cochon L, Jesam C, et al: Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum Reprod 25(9):2256, 2010
Brache V, Faundes A, Alvarez F, et al: Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials. Contraception 65(1):63, 2002
Brahmi D, Steenland MW, Renner RM, et al: Pregnancy outcomes with an IUD in situ: a systematic review. Contraception 85(2):131, 2012
Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation, 9th ed. Philadelphia, Lippincott Williams & Wilkins, 2011, p 1049
Brohet RM, Goldgar DE, Easton DF, et al: Oral contraceptives and breast cancer risk in the International BRCA 1/2 Carrier Cohort Study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25:5327, 2007
Brown M, Britton J: Neuropathy associated with etonogestrel implant insertion. Contraception 86(5):591, 2012
Brunner LR, Hogue CJ: The role of body weight in oral contraceptive failure: results from the 1995 national survey of family growth. Ann Epidemiol 15:492, 2005
Bulten J, Grefte J, Siebers B, et al: The combined contraceptive vaginal ring (NuvaRing) and endometrial histology. Contraception 72:362, 2005
Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2010. MMWR 59 (12):1, 2010a
Centers for Disease Control and Prevention: Update to CDC’s U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: revised recommendations for the use of contraceptive methods during the postpartum period. MMWR 60(26):878, 2011
Centers for Disease Control and Prevention: Update to CDC’s U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: revised recommendations for the use of hormonal contraception among women at high risk for HIV infection or infected with HIV. MMWR 61(24):449, 2012
Centers for Disease Control and Prevention: U.S. medical eligibility criteria for contraceptive use, 2010. MMWR 59(4):1, 2010b
Centers for Disease Control and Prevention: U.S. selected practice recommendations for contraceptive use, 2013. MMWR 62 (5):1, 2013
Chasan-Taber L, Willett WC, Manson JE, et al: Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 94:483, 1996
Chen BA, Reeves MF, Hayes JL, et al: Postplacental or delayed insertion of the levonorgestrel intrauterine device after vaginal delivery: a randomized controlled trial. Obstet Gynecol 116(5):1079, 2010
Cheng L, Che Y, Gulmezoglu AM: Interventions for emergency contraception. Cochrane Database Syst Rev 2:CD001324, 2012
Civic D, Scholes D, Ichikawa L, et al: Depressive symptoms in users and non-users of depot medroxyprogesterone acetate. Contraception 61(6):385, 2000
Clark MK, Sowers M, Levy B, et al: Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril 86:1466, 2006
Cole JA, Norman H, Doherty M, et al: Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 109:339, 2007
Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, et al: Ovarian cancer and oral contraceptives: collaborative reanalysis of data of 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371:303, 2008
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 347:1713, 1996
Comp PC: Coagulation and thrombosis with OC use: physiology and clinical relevance. Dialogues Contracept 5:1, 1996
Correia L, Ramos AB, Machado AI, et al: Magnetic resonance imaging and gynecological devices. Contraception 85(6):538, 2012
Craft P, Hannaford PC: Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ Oral Contraceptive Study. BMJ 298:165, 1989
Critchlow CW, Wölner-Hanssen P, Eschenback DA, et al: Determinants of cervical ectopia and of cervicitis: age, oral contraception, specific cervical infection, smoking, and douching. Am J Obstet Gynecol 173:534, 1995
Cromer BA, Smith RD, Blair JM, et al: A prospective study of adolescents who choose among levonorgestrel implant (Norplant), medroxyprogesterone acetate (Depo-Provera), or the combined oral contraceptive pill as contraception. Pediatrics 94:687, 1994
Croxatto HB, Mäkäräinen L: The pharmacodynamics and efficacy of Implanon. An overview of the data. Contraception 58:91S, 1998
Curtis EM, Pine L: Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Am J Obstet Gynecol 140:880, 1981
d’Arcangues C: WHO statement on hormonal contraception and bone health. Contraception 73(5):443, 2006
d’Arcangues C: Worldwide use of intrauterine devices for contraception. Contraception 75:S2, 2007
Dieben TO, Roumen FJ, Apter D: Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 100:585, 2002
Dorflinger LJ: Metabolic effects of implantable steroid contraceptives for women. Contraception 65(1):47, 2002
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 21:573, 2006
European Society of Human Reproduction and Embryology—ESHRE Capri Workshop Group: Ovarian and endometrial function during hormonal contraception. Hum Reprod 16(7):1527, 2001
Farley TMM, Rosenberg MJ, Rowe PJ, et al: Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 339:785, 1992
Fasoli M, Parazzini F, Cecchetti G, et al: Post-coital contraception: an overview of published studies. Contraception 39:459, 1989
Fels H, Steward R, Melamed A, et al: Comparison of serum and cervical mucus hormone levels during hormone-free interval of 24/4 vs. 21/7 combined oral contraceptives. Contraception 87(6):732, 2013
Finer LB, Zolna MR: Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception 84(5):478, 2011
Fiorino AS: Intrauterine contraceptive device–associated actinomycotic abscess and Actinomyces detection on cervical smear. Obstet Gynecol 87:142, 1996
Food and Drug Administration: Drug safety communication: safety review update on the possible increased risk of blood clots with birth control pills containing drospirenone. 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm273021.htm. Accessed March 7, 2013
Food and Drug Administration: Orange book: approved drug products with therapeutic equivalence evaluations. 2013. Available at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed February 20, 2013
Funk S, Miller MM, Mishell DR Jr, et al: Safety and efficacy of Implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception 71:319, 2005
Furlong LA: Ectopic pregnancy risk when contraception fails. J Reprod Med 47:881, 2002
Gaffield ME, Culwell KR, Lee CR: The use of hormonal contraception among women taking anticonvulsant therapy. Contraception 83(1):16, 2011
Gai L, Zhang J, Zhang H, et al: The effect of depot medroxyprogesterone acetate (DMPA) on bone mineral density (BMD) and evaluating changes in BMD after discontinuation of DMPA in Chinese women of reproductive age. Contraception 83(3):218, 2011
Gallo MF, Grimes DA, Lopez LM, et al: Non-latex versus latex male condoms for contraception. Cochrane Database Syst Rev 1:CD003550, 2006
Gallo MF, Grimes DA, Schulz KF: Cervical cap versus diaphragm for contraception. Cochrane Database Syst Rev 4:CD003551, 2002
Gallo MF, Lopez LM, Grimes DA, et al: Combination contraceptives: effects on weight. Cochrane Database Syst Rev 9:CD003987, 2011
Gardner JM, Mishell DR Jr: Analysis of bleeding patterns and resumption of fertility following discontinuation of a long-acting injectable contraceptive. Fertil Steril 21:286, 1970
Gemzell-Danielsson K, Berger C, Lalitkumar PG: Emergency contraception—mechanisms of action. Contraception 87(3):300, 2013
Gemzell-Danielsson K, Schellschmidt I, Apter D: A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 97(3):616, 2012
Grimes DA, Hubacher D, Lopez LM, et al: Non-steroidal anti-inflammatory drugs for heavy bleeding or pain associated with intrauterine-device use. Cochrane Database Syst Rev 4:CD006034, 2006
Grimes DA, Jones LB, Lopez LM, et al: Oral contraceptives for functional ovarian cysts. Cochrane Database Syst Rev 9:CD006134, 2011
Grimes DA, Lopez LM, Schulz KF, et al: Immediate postabortal insertion of intrauterine devices. Cochrane Database Syst Rev 6:CD001777, 2010a
Grimes DA, Lopez LM, Schulz KF, et al: Immediate post-partum insertion of intrauterine devices. Cochrane Database Syst Rev 5:CD003036, 2010b
Grimes DA, Schulz KF: Antibiotic prophylaxis for intrauterine contraceptive device insertion. Cochrane Database Syst Rev 2:CD001327, 2001
Hall KS, Trussell J, Schwarz EB: Progestin-only contraceptive pill use among women in the United States. Contraception 86(6):653, 2012
Hannaford PC, Selvaraj S, Elliott AM, et al: Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioners’ oral contraception study. BMJ 335:651, 2007
Harrison-Woolrych M, Ashton J, Coulter D: Uterine perforation on intrauterine device insertion: is the incidence higher than previously reported? Contraception 67:53, 2003
Hassan EO, el-Husseini M, el-Nahal N: The effect of 1-year use of the CuT 380A and oral contraceptive pills on hemoglobin and ferritin levels. Contraception 60(2):101, 1999
Heinemann LA, Weimann A, Gerken G, et al: Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case-Control Study. Eur J Contracept Reprod Health Care 3:194, 1998
Holt VL, Cushing-Haugen KL, Daling JR: Body weight and risk of oral contraceptive failure. Obstet Gynecol 99:820, 2002
Holt VL, Scholes D, Wicklund KG, et al: Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol 105:46, 2005
Hubacher D, Lara-Ricalde R, Taylor DJ, et al: Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 345:561, 2001
International Collaboration of Epidemiological Studies of Cervical Cancer: Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 370:1609, 2007
Iodice S, Barile M, Rotmensz N, et al: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46(12):2275, 2010
Jecht EW, Bernstein GS: The influence of copper on the motility of human spermatozoa. Contraception 7:381, 1973
Jick SS, Hagberg KW, Kaye JA: ORTHO EVRA and venous thromboembolism: an update. Contraception 81(5):452, 2010
Jick SS, Hernandez RK: Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 340:d2151, 2011
Joffe J, Petrillo LF, Viguera AC, et al: Treatment of premenstrual worsening depression with adjunctive oral contraceptive pills: a preliminary report. J Clin Psychiatry 68:1954, 2007
Jones J, Mosher W, Daniels K: Current contraceptive use in the United States, 2006–2010, and changes in patterns of use since 1995. Natl Health Stat Report 60:1, 2012
Kabat GC, Miller AB, Rohan TE: Oral contraceptive use, hormone replacement therapy, reproductive history and risk of colorectal cancer in women. Int J Cancer 122:643, 2008
Kapp N, Curtis KM: Hormonal contraceptive use among women with liver tumors: a systematic review. Contraception 80(4):387, 2009a
Kapp N, Tilley IB, Curtis KM: The effects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver: a systematic review. Contraception 80(4):381, 2009b
Karabayirli S, Ayrim AA, Muslu B: Comparison of the analgesic effects of oral tramadol and naproxen sodium on pain relief during IUD insertion. J Minim Invasive Gynecol 19(5):581, 2012
Katz Z, Lancet M, Skornik J, et al: Teratogenicity of progestogens given during the first trimester of pregnancy. Obstet Gynecol 65(6):775, 1985
Kim C, Siscovick DS, Sidney S, et al: Oral contraceptive use and association with glucose, insulin, and diabetes in young adult women: the CARDIA Study. Coronary Artery Risk Development in Young Adults. Diabetes Care 25:1027, 2002
Kim SK, Romero R, Kusanovic JP, et al: The prognosis of pregnancy conceived despite the presence of an intrauterine device (IUD). J Perinat Med 38(1):45, 2010
Krattenmacher R: Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 62:29, 2000
Kuyoh MA, Toroitich-Ruto C, Grimes DA, et al: Sponge versus diaphragm for contraception: a Cochrane review. Contraception 67:15, 2003
Lammer EJ, Cordero JF: Exogenous sex hormone exposure and the risk for major malformations. JAMA 255:3128, 1986
Lawrie TA, Helmerhorst FM, Maitra NK, et al: Types of progestogens in combined oral contraception: effectiveness and side-effects. Cochrane Database Syst Rev 5:CD004861, 2011
Lidegaard Ø, Nielsen LH, Skovlund CW, et al: Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ 343:d6423, 2011
Lippes J: Pelvic actinomycosis: a review and preliminary look at prevalence. Am J Obstet Gynecol 180:265, 1999
Lopez LM, Edelman A, Chen-Mok M, et al: Progestin-only contraceptives: effects on weight. Cochrane Database Syst Rev 4:CD008815, 2011
Lopez LM, Grimes DA, Chen-Mok M, et al: Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database Syst Rev 7:CD008452, 2010
Lopez LM, Grimes DA, Schulz KF: Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst 2:CD006133, 2012a
Lopez LM, Kaptein AA, Helmerhorst FM: Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database Syst Rev 2:CD006586, 2012b
Lyon A, Pandravada A, Leung E, et al: Emergency laparoscopic sigmoid colectomy for perforation secondary to intrauterine contraceptive device. J Obstet Gynaecol 32(4):402, 2012
MacClellan LR, Giles W, Cole J, et al: Probable migraine with visual aura and risk of ischemic stroke: the Stroke Prevention in Young Women Study. Stroke 38:2438, 2007
Maheshwari S, Sarraj A, Kramer J, et al: Oral contraception and the risk of hepatocellular carcinoma. J Hepatol 47:506, 2007
Mansour D, Gemzell-Danielsson K, Inki P, et al: Fertility after discontinuation of contraception: a comprehensive review of the literature. Contraception 84(5):465, 2011
Mantha S, Karp R, Raghavan V, et al: Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ 345:e4944, 2012
Marchbanks PA, McDonald JA, Wilson HG, et al: Oral contraceptives and the risk of breast cancer. N Engl J Med 346(26):2025, 2002
Margolis KL, Adami HO, Luo J, et al: A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women. Fertil Steril 88:310, 2007
Mascarenhas MP, Tiraboschi RB, Paschoalin VP, et al: Exercise-induced hematuria as the main manifestation of migration of intrauterine contraceptive device into the bladder. Case Rep Urol 2012:736426, 2012
Mauck C, Callahan M, Weiner DH, et al: A comparative study of the safety and efficacy of FemCap, a new vaginal barrier contraceptive, and the Ortho All-Flex diaphragm. The FemCap Investigators’ Group. Contraception 60(2):71, 1999
McNicholas CP, Madden T, Zhao Q, et al: Cervical lidocaine for IUD insertional pain: a randomized controlled trial. Am J Obstet Gynecol 207(5): 384.e1, 2012
Merck: Nexplanon: highlights of prescribing information. 2012a. Available at: http://www.nexplanon-usa.com/en/hcp/main/prescribing-information.asp. Accessed February 16, 2013
Merck: Nuvaring: prescribing information. 2012b. Available at: http://www.merck.com/product/usa/pi_circulars/n/nuvaring/nuvaring_pi.pdf. Accessed March 7, 2013
Mishell DR Jr: Oral contraceptives and cardiovascular events: summary and application of data. Int J Fertil 45:121, 2000
Mommers E, Blum GF, Gent TG, et al: Nexplanon, a radiopaque etonogestrel implant in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial. Am J Obstet Gynecol 207(5):388.e1, 2012
Moreau C, Trussell J, Gilbert F, et al: Oral contraceptive tolerance: does the type of pill matter? Obstet Gynecol 109:1277, 2007
Moschos E, Twickler DM: Does the type of intrauterine device affect conspicuity on 2D and 3D ultrasound? AJR Am J Roentgenol 196(6):1439, 2011
Murthy AS, Creinin MD, Harwood B, et al: Same-day initiation of the transdermal hormonal delivery system (contraceptive patch) versus traditional initiation methods. Contraception 72(5):333, 2005
Nault AM, Peipert JF, Zhao Q, et al: Validity of perceived weight gain in women using long-acting reversible contraception and depot medroxyprogesterone acetate. Am J Obstet Gynecol 208(1):48.e1, 2013
Nelson AL, Cwiak C: Combined oral contraceptives (COCs). In Hatcher RA, Trussell J, Nelson AL, et al (eds): Contraceptive Technology, 20th ed. New York, Ardent Media, 2011, p 313
Nelson AL, Fong JK: Intrauterine infusion of lidocaine does not reduce pain scores during IUD insertion. Contraception 88(1):37, 2013
Ngai SW, Fan S, Li S, et al: A randomized trial to compare 24 h versus 12 h double dose regimen of levonorgestrel for emergency contraception. Hum Reprod 20:307, 2005
Oddsson K, Leifels-Fischer B, Wiel-Masson D, et al: Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial. Hum Reprod 20:557, 2005
Ortiz ME, Croxatto HB: Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception 75:S16, 2007
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2013. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 3, 2013
Parkin L, Sharples K, Hernandez RK, et al: Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 340:d2139, 2011
Pasquale SA, Russer TJ, Foldes R, et al: Lack of interaction between magnetic resonance imaging and the copper-T380A IUD. Contraception 55(3):169, 1997
Pearlstein TB, Bachmann GA, Zacur HA, et al: Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation. Contraception 72:414, 2005
Persson E, Holmberg K: A longitudinal study of Actinomyces israelii in the female genital tract. Acta Obstet Gynecol Scand 63:207, 1984
Petitti DB, Piaggio G, Mehta S, et al: Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. The WHO Study of Hormonal Contraception and Bone Health. Obstet Gynecol 95(5):736, 2000
Pfizer: Depo-Provera (medroxyprogesterone acetate) injectable suspension: highlights of prescribing information. 2012. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=522. Accessed February 19, 2013
Pfizer: Depo-subQ Provera 104: physician information. 2010. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=549. Accessed February 19, 2013
Pomp ER, le Cessie S, Rosendaal FR, et al: Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 139(2):289, 2007
Pomp ER, Rosendaal FR, Doggen CJ: Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. Am J Hematol 83:97, 2008
Population Council: Jadelle. 2013. Available at: http://www.popcouncil.org/what/jadelle.asp. Accessed February 16, 2013
Remington KM, Buller RS, Kelly JR: Effect of the Today contraceptive sponge on growth and toxic shock syndrome toxin-1 production by Staphylococcus aureus. Obstet Gynecol 69:563, 1987
Rickert VI, Tiezzi L, Lipshutz J, et al: Depo Now: preventing unintended pregnancies among adolescents and young adults. J Adolesc Health 40(1):22, 2007
Robinson GE, Burren T, Mackie IJ, et al: Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery. BMJ 302:269, 1991
Ronnerdag M, Odlind V: Health effects of long-term use of the intrauterine levonorgestrel-releasing system. Acta Obstet Gynecol Scand 78:716, 1999
Rothman KJ, Louik C: Oral contraceptives and birth defects. N Engl J Med 299:522, 1978
Savolainen E, Saksela E, Saxen L: Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 140:521, 1981
Schafer JE, Osborne LM, Davis AR, et al: Acceptability and satisfaction using Quick Start with the contraceptive vaginal ring versus an oral contraceptive. Contraception 73(5):488, 2006
Schiesser M, Lapaire O, Tercanli S, et al: Lost intrauterine devices during pregnancy: maternal and fetal outcome after ultrasound-guided extraction. An analysis of 82 cases. Ultrasound Obstet Gynecol 23:486, 2004
Scholes D, LaCroix AS, Ichikawa LE, et al: Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 13:581, 2002
Scholes D, LaCroix AS, Ott SM, et al: Bone mineral density in women using depot medroxyprogesterone acetate for contraception. Obstet Gynecol 93:233, 1999
Seeger JD, Loughlin J, Eng PM, et al: Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 110:587, 2007
Shanghai Dahua Pharmaceutical: Sino-implant (II): questions and answers for clients. 2012. Available at: http://www.k4health.org/toolkits/implants/sino-implant-ii%C2%AE-implants. Accessed February 16, 2013
Shimoni N, Davis A, Ramos ME, et al: Timing of copper intrauterine device insertion after medical abortion: a randomized controlled trial. Obstet Gynecol 118(3):623, 2011
Shulman LP, Gabriel H: Management and localization strategies for the nonpalpable Implanon rod. Contraception 73:325, 2006
Sivin I, Viegas O, Campodonico I, et al: Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception 55(2):73, 1997
Sneed R, Westhoff C, Morroni C, et al: A prospective study of immediate initiation of depot medroxyprogesterone acetate contraceptive injection. Contraception 71(2):99, 2005
Stadel BV: Oral contraceptives and cardiovascular disease. N Engl J Med 305:612, 1981
Steenland MW, Tepper NK, Curtis KM, et al: Intrauterine contraceptive insertion postabortion: a systematic review. Contraception 84(5):447, 2011
Steiner M, Lopez M, Grimes D, et al: Sino-implant (II)—a levonorgestrel releasing two-rod implant: systematic review of the randomized controlled trials. Contraception 81(3)197, 2010
Stuart GS, Cunningham FG: Contraception and sterilization. In Hoffman BL, Schorge JO, Schaffer JI, et al: Williams Gynecology, 2nd ed. New York, McGraw-Hill, 2012, p 139
Sufrin CB, Postlethwaite D, Armstrong MA, et al: Neisseria gonorrhea and Chlamydia trachomatis screening at intrauterine device insertion and pelvic inflammatory disease. Obstet Gynecol 120(6):1314, 2012
Svendal G, Berk M, Pasco JA, et al: The use of hormonal contraceptive agents and mood disorders in women. J Affect Disord 140(1):92, 2012
Swenson C, Turok DK, Ward K, et al: Self-administered misoprostol or placebo before intrauterine device insertion in nulliparous women: a randomized controlled trial. Obstet Gynecol 120(2 Pt 1):341, 2012
Tatum HJ, Schmidt FH, Jain AK: Management and outcome of pregnancies associated with Copper-T intrauterine contraceptive device. Am J Obstet Gynecol 126:869, 1976
Tepper NK, Steenland MW, Gaffield ME, et al: Retention of intrauterine devices in women who acquire pelvic inflammatory disease: a systematic review. Contraception 87(5):655, 2013
Teva Women’s Health: ParaGard T 380A intrauterine copper contraceptive: prescribing information, 2011. Available at: http://hcp.paragard.com/images/ParaGard_info.pdf. Accessed February 17, 2013
Thonneau PF, Almont TE: Contraceptive efficacy of intrauterine devices. Am J Obstet Gynecol 198:248, 2008
Truitt ST, Fraser AB, Gallo MF, et al: Combined hormonal versus nonhormonal versus progestin-only contraception in lactation. Cochrane Database Syst Rev 2:CD003988, 2010
Trussell J: Contraceptive efficacy. In Hatcher RA, Trussell J, Nelson AL, et al (eds): Contraceptive Technology, 20th ed. New York, Ardent Media, 2011a, p 791
Trussell J: Contraceptive failure in the United States. Contraception 70:89, 2011b
Tsilidis KK, Allen NE, Key TJ, et al: Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 105(9):1436, 2011
Tworoger SS, Fairfield KM, Colditz GA, et al: Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk. Am J Epidemiol 166(8):894, 2007
Urdl W, Apter D, Alperstein A, et al: Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Biol 121:202, 2005
Van Vliet HA, Grimes DA, Helmerhorst FM, et al: Biphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 3:CD002032, 2006
Van Vliet HA, Grimes DA, Lopez LM, et al: Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 11: CD003553, 2011a
Van Vliet HA, Raps M, Lopez LM, et al: Quadriphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 11: CD009038, 2011b
Veres S, Miller L, Burington B: A comparison between the vaginal ring and oral contraceptives. Obstet Gynecol 104:555, 2004
Vessey M, Yeates D: Oral contraceptives and benign breast disease: an update of findings in a large cohort study. Contraception 76:418, 2007
Vessey MP, Johnson B, Doll R, et al: Outcome of pregnancy in women using intrauterine devices. Lancet 1:495, 1974
Wallach M, Grimes DA (eds): Modern Oral Contraception. Updates from The Contraception Report. Totowa, Emron, 2000, pp 26, 90, 194
Walsh T, Grimes D, Frezieres R, et al: Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. IUD Study Group. Lancet 351:1005, 1998
Watson: Ella prescribing information. 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf. Accessed March 5, 2013
Wechselberger G, Wolfram D, Pülzl P, et al: Nerve injury caused by removal of an implantable hormonal contraceptive. Am J Obstet Gynecol 195(1):323, 2006
Westhoff C: IUDs and colonization or infection with Actinomyces. Contraception 75:S48, 2007a
Westhoff C, Heartwell S, Edwards S, et al: Initiation of oral contraceptive using a quick start compared with a conventional start: a randomized controlled trial. Obstet Gynecol 109:1270, 2007b
Westhoff C, Jain JK, Milson, et al: Changes in weight with depot medroxyprogesterone acetate subcutaneous injection 104 mg/0.65 mL. Contraception 75:261, 2007c
Westhoff C, Kerns J, Morroni C, et al: Quick start: novel oral contraceptive initiation method. Contraception 66:141, 2002
Westhoff C, Wieland D, Tiezzi L: Depression in users of depo-medroxyprogesterone acetate. Contraception 51(6):351, 1995
Westhoff CL, Torgal AH, Mayeda ER, et al: Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women. Contraception 81(6):474, 2010
Wilailak S, Vipupinyo C, Suraseranivong V, et al: Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study. BJOG 119(6):672, 2012
Wilson W, Taubert KA, Gewitz M, et al: Prevention of infective endocarditis: Guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 116:1736, 2007
Winner B, Peipert JF, Zhao Q, et al: Effectiveness of long-acting reversible contraception. N Engl J Med 366(21):1998, 2012
World Health Organization: A multinational case-control study of ectopic pregnancy. Clin Reprod Fertil 3:131, 1985
World Health Organization: Acute myocardial infarction and combined oral contraceptives: results of an international multi-center case-control study. Lancet 349:1202, 1997
World Health Organization: Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. Contraception 57:315, 1998
World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer 49:186, 1991a
World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. Contraception 45(4): 299, 1992
World Health Organization: Depot-medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer 49(2):182, 1991b
World Health Organization: Effects of hormonal contraceptives on breast milk composition and infant growth. Stud Fam Plann 19/361, 1988
World Health Organization: Ischaemic stroke and combined oral contraceptives: results of an international, multi-center case-control study. Lancet 348:498, 1996
World Health Organization: Mechanism of action, safety and efficacy of intrauterine devices. Technical Report No. 753, Geneva, Switzerland, WHO, 1987
World Health Organization: Medical Eligibility for Contraceptive Use, 4th ed. 2009. Geneva, World Health Organization, 2010
World Health Organization/Department of Reproductive Health and Research (WHO/RHR), Johns Hopkins Bloomberg School of Public Health (SHSPH): Family Planning Handbook for Providers, Baltimore and Geneva, 2007
Wu S, Godfrey EM, Wojdyla D, et al: Copper T380A intrauterine device for emergency contraception: a prospective, multicentre, cohort clinical trial. BJOG 117(10):1205, 2010
Yonkers KA, Brown C, Pearlstein TB, et al: Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 106:492, 2005
Zeino MY, Wietfeldt ED, Advani V, et al: Laparoscopic removal of a copper intrauterine device from the sigmoid colon. JSLS 15(4):568, 2011
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 Steril 77:S13, 2002
Zieman M, Kanal E: Copper T 380A IUD and magnetic resonance imaging. Contraception 75:93, 2007