Phillip G. Stubblefield
Danielle M. Roncari
• The most common methods of contraception used in the United States are sterilization, oral contraceptives, and condoms, in that order.
• Latex condoms and other barriers reduce the risk of sexually transmitted diseases (STDs) and cervical cancer.
• The two intrauterine devices (IUDs) available in the United States, the copper T380A (ParaGard) and the levonorgestrel T (Mirena), are as effective as tubal sterilization and are associated with a long-term risk of pelvic infection that is no greater than that in the general population.
• The combination estrogen–progestin oral contraceptive, patch, and vaginal ring all provide excellent contraception when used correctly but all increase the risk of venous thrombosis and thromboembolism.
• Present low-dose estrogen–progestin combinations do not increase the risk of heart attack among nonsmokers younger than age 35 years who have no other risks for vascular disease.
• Oral contraceptives do not increase the risk of breast cancer.
• Use of progestin-only injectable and implant hormonal contraceptives results in very low pregnancy rates without the estrogen-associated risk of thrombosis.
• Hormonal contraceptives provide extensive contraceptive and noncontraceptive health benefits, including reduced risk for endometrial and ovarian cancer.
• Levonorgestrel 1.5 mg (Plan B) and ulipristal acetate are the most effective hormonal means of emergency contraception. Efficacy is greatest within 24 hours of intercourse but remains high at 5 days. The copper T380AIUD inserted 5 days after intercourse is even more effective than hormonal methods.
Table 10.1 Number of Women Aged 15–44 Years, and Percentage Currently Using Contraception Methods According to Age at Interview, United States 2006–2008a
• Long-acting reversible contraceptive (LARC) methods include injectable progestins, subdermal progestin implants, and copper- or levonorgestrel-releasing intrauterine devices. These offer pregnancy rates comparable to sterilization and are among the safest methods.
• Safe, long-term contraception is provided with laparoscopy and bipolar electrocautery application to three adjacent sites on each tube, the Silastic band, or the Filshie clip.
• Hysteroscopic sterilization techniques provide highly effective permanent contraception for women without the use of general anesthesia or abdominal incision.
• Vasectomy provides highly effective, low-cost sterilization for men and is associated with neither heart disease nor prostate cancer.
• Abortion mortality rates fell rapidly with legalization; currently, the overall mortality risk is less than 1 per 100,000, well below the maternal mortality rate of 12.7 per 100,000 live births.
• The risk of abortion mortality increases with gestational age, from 0.1 per 100,000 at 8 weeks or less. Even at 16 to 20 weeks abortion is safer than continuing pregnancy.
The history of contraception is a long one, dating to ancient times. The voluntary control of fertility is especially important in modern society (1). A woman who expects to have no more than one or two children spends most of her reproductive years trying to avoid pregnancy. Effective control of reproduction is essential to a woman’s ability to accomplish her individual goals. From a larger perspective, the rapid growth of the human population in this century threatens the survival of all. At present rates, the population of the world will double in 66 years, and that of the United States will double in 75 years (2). For the individual and for the planet, reproductive health requires careful use of effective means to prevent both pregnancy and sexually transmitted disease (STD) (3).
Figure 10.1 Abortion rate*, ratio+, and percentage of total abortions by age group of women who obtained abortion, United States, 2006§. *Number of abortions per 1,000 women aged 15–44 years. +Number of abortions per 1,000 live births. §Data from 48 reporting areas, excludes California, Florida, Louisiana, and New Hampshire. (From Pazol K, Gamble SB, Parker WY, et al. Abortion surveillance—United States 2005. MMWR Surveil Sum 2009;58(SS08):35 [Figure 2].
Figure 10.2 Percentage of women experiencing an accidental pregnancy, in the first 2 years of use, according to method, combined 1988 and 1995 National Survey of Family Growth. (From Ranjit N, Bankole A, Forrest JD, et al. Contraception failure in the first two years of use: differences across socioeconomic subgroups. Fam Plann Perspect 2001;33:25 [Table 6.]).
From puberty until menopause, women are faced with concerns about childbearing or its avoidance: the only options are sexual abstinence, contraception, or pregnancy. The contraceptive choices made by couples in the United States in 2008 are shown in Table 10.1 (4). Oral contraceptives (OCs) were the first choice among women, used by 17.3%. Female sterilization was the second choice, used by 16.7%. With the addition of the 6.1% of couples relying on male sterilization, 22.8% of couples were relying on sterilization, making this the first choice of couples. Condoms were third choice, used by 10%. OC use declines with age, and the rate of sterilization increases. Twenty percent of women under 25 who use contraceptives use OCs and only 0.7% is sterilized. Of women aged 35 to 44 using contraception 17.3% uses OCs and 33.8% is sterilized, as is 13.9% of their consorts (Table 10.1). About 10% of women use more than one method of contraception. Although use of contraception is high, a significant proportion of sexually active couples (7.4%) does not use contraception, and each year, 2 of every 100 women aged 15 to 44 years have an induced abortion (4,5). Abortion is an obvious indicator of unplanned pregnancy. Abortion ratios by age group indicate that the use of abortion is greatest for the youngest women and least for women in their late 20s and early 30s who are most likely to continue pregnancies (Fig. 10.1). Use of abortion increases from the late 30s on. Young women are much more likely to experience unplanned pregnancy because they are more fertile than older women and because they are more likely to have intercourse without contraception. The effect of age on pregnancy rates with different contraceptive methods is shown in Figure 10.2.
Efficacy
Factors affecting whether pregnancy will occur include the fecundity of both partners, the timing of intercourse in relation to the time of ovulation, the method of contraception used, the intrinsic effectiveness of the contraceptive method, and the correct use of the method. It is impossible to assess the effectiveness of a contraceptive method in isolation from the other factors. The best way to assess effectiveness is long-term evaluation of a group of sexually active women using a particular method for a specified period to observe how frequently pregnancy occurs. A pregnancy rate per 100 women per year can be calculated using the Pearl formula (dividing the number of pregnancies by the total number of months contributed by all couples, and then multiplying the quotient by 1,200). With most methods, pregnancy rates decrease with time as the more fertile or less careful couples become pregnant and drop out of the calculations. More accurate information is provided by the life-table method. This method calculates the probability of pregnancy in successive months, which are then added over a given interval. Problems relate to which pregnancies are counted: those occurring among all couples or those in women the investigators deem to have used the method correctly. Because of this complexity, rates of pregnancy with different methods are best calculated by reporting two different rates derived from multiple studies (i.e., the lowest rate and the usual rate), as shown in Table 10.2.
Safety
Some contraceptive methods have associated health risks; areas of concern are listed in Table 10.3. All of the methods are safer than the alternative (pregnancy with birth), with the possible exception of estrogen-containing hormonal contraceptives (pills, patches and ring) used by women older than 35 years of age who smoke (6). Most methods provide noncontraceptive health benefits in addition to contraception. Oral contraceptives reduce the risk of ovarian and endometrial cancers and ectopic pregnancy. Barrier methods provide some protection against STDs including HIV, cervical cancer, and tubal infertility.
Table 10.2 Percentage of Women Experiencing a Contraceptive Failure During the First Year of Use and the Percentage Continuing Use at the End of the First Year
Table 10.3 Overview of Contraceptive Methods
Medical Eligibility for Contraception
Since 1996 the World Health Organization (WHO) has regularly published Medical Eligibility Criteria for Contraceptive Use (MEC). These recommendations are based on the best evidence available supplemented by expert opinion. The U.S. Centers for Disease Control undertook a formal process to review and revise the WHO MEC and adapt it to US practice (7). All present methods of contraception are assigned to one of four categories of suitability of use by women with more than 60 characteristics or conditions. The categories are:
1. A condition for which there is no restriction for the use of the contraceptive method;
2. A condition for which the advantages of using the method generally outweigh the theoretical or proven risks;
3. A condition for which the theoretical or proven risks usually outweigh the advantages of using method;
4. A condition that represents an unacceptable health risk if the contraceptive method is used.
Table 10.4 Cost per Patient per Year of Contraceptive Methods
|
Method |
Cost ($) |
Cost Multiple ($)a |
|
Vasectomy |
55 |
1.0 |
|
Tubal ligation |
118 |
2.14 |
|
Intrauterine device |
150 |
2.71 |
|
Norplant |
202 |
3.66 |
|
Depomedroxyprogesterone acetate |
396 |
7.19 |
|
Oral contraceptives |
456 |
8.27 |
|
Condoms |
776 |
14.08 |
|
Diaphragm |
1,147 |
20.81 |
|
aFor every $1.00 spent on vasectomy, the amount shown would be spent on the method indicated. |
||
|
From Ashraf T, Arnold SB, Maxfield M. Cost effectiveness of levonorgestrel subdermal implants: comparison with other contraceptive methods available in the United States. J Reprod Med 1994;39:791–798, with permission. |
||
Cost
Some methods, such as intrauterine devices (IUDs) and subdermal implants, require an initial high investment but provide prolonged protection for a low annual cost. A complex cost analysis based on the cost of the method plus the cost of pregnancy if the method fails concludes that sterilization and the long-acting methods are the least expensive over the long term (8) (Table 10.4).
Long-Acting Reversible Contraceptives
Several contraceptive methods are as effective as sterilization, but are completely reversible. All have the important advantage of being “forgettable,” that is, little is required of the user after the method is begun, very much in contrast to methods like the condom that must be used with each act of intercourse, or the OC, which must be taken daily. These forgettable methods have pregnancy rates in typical use of less than 2 per 100 woman-years, are effective for at least 3 months without attention from the user, and are among the safest methods. They include the injectable progestins, depomedroxyprogesterone acetate (DMPA) and norethindrone enanthate, the etonogestrel and levonorgestrel subdermal implants, copper-bearing intrauterine devices such as the copper T380A and the levonorgestrel-releasing intrauterine system (9,10).
Nonhormonal Methods
Coitus Interruptus
Coitus interruptus is withdrawal of the penis from the vagina before ejaculation. This method, along with induced abortion and late marriage, is believed to account for most of the decline in fertility of preindustrial Europe (11). Coitus interruptus remains a very important means of fertility control in many countries. Eighty-five million couples are estimated to use the method worldwide, yet it has received little recent formal study. This method has obvious advantages: immediate availability and no cost. The penis must be completely withdrawn both from the vagina and from the external genitalia. Pregnancy has occurred from ejaculation on the female external genitalia without penetration. Coitus interruptus reduces transmission of human immunodeficiency virus (HIV) in mutually monogamous couples (12). Theoretically, some reduction of risk from other STDs would be expected, but this phenomenon apparently was not studied. Efficacy is estimated to range from 4 pregnancies per 100 women in the first year with perfect use to 27 per 100 with typical use (Table 10.2). Jones and colleagues offer a modern review of this practice and conclude that it likely is as effective as the condom (13).
Breastfeeding
Breastfeeding can be used as a form of contraception and can be effective depending on individual variables. The use of contraception during lactation should take into consideration the women’s needs and the need to maintain lactation.
Ovulation is suppressed during lactation. The suckling of the infant elevates prolactin levels and reduces gonadotropin-releasing hormone (GnRH) from the hypothalamus, reducing luteinizing hormone (LH) release and thus inhibiting follicular maturation (14). Even with continued nursing, ovulation eventually returns but is unlikely before 6 months, especially if the woman is amenorrheic and is fully breastfeeding with no supplemental foods given to the infant (15). For maximum contraceptive reliability, feeding intervals should not exceed 4 hours during the day and 6 hours at night, and supplemental feeding should not exceed 5% to 10% of the total amount of feeding (16). Six-month pregnancy rates of 0.45% to 2.45% are reported for couples relying solely on this method (17). To prevent pregnancy, another method of contraception should be used from 6 months after birth or sooner if menstruation resumes. Breastfeeding reduces the mother’s lifetime risk of breast cancer (18).
Contraception during Lactation (Lactation amenorrhea)
Use of combination estrogen–progestin hormonal methods (OCs, the patch, and the ring) is generally not advised during lactation because they reduce the amount and quality of breast milk.Combination hormonal methods can be used after 6 weeks, once milk production is established. Progestin-only OCs, implants, and injectable contraception do not affect milk quality or quantity (16). Labeling of the U.S. Food and Drug Administration (FDA) and guidelines from the American College of Obstetricians and Gynecologists suggest that progestin-only OCs can be started 2 to 3 days postpartum, whereas depot medroxyprogesterone acetate (Depo Provera) injections or implants can begin at 6 weeks (19). These recommendations are not based on any observed adverse effect of early administration, and many maternity programs begin injectable contraception with progestin at the time of hospital discharge. Barrier methods, spermicides, and the copper T380A intrauterine device (IUD) (ParaGard) are good options for nursing mothers. Because levonorgestrel implants have no adverse effect on breastfeeding, none should be expected from the levonorgestrel T IUD, which releases levonorgestrel but produces lower blood levels than the implants.
Fertility Awareness
Periodic abstinence, described as “natural contraception” or “fertility awareness,” requires avoiding intercourse during the fertile period around the time of ovulation. A variety of methods are used: the calendar method, the mucous method (Billings or ovulation method), and the symptothermal method, which is a combination of the first two methods. With the mucous method, the woman attempts to predict the fertile period by feeling the cervical mucus with her fingers. Under estrogen influence, the mucus increases in quantity and becomes progressively more slippery and elastic until a peak day is reached. The mucus then becomes scant and dry under the influence of progesterone until onset of the next menses. Intercourse may be allowed during the “dry days” immediately after menses until mucus is detected. Thereafter, the couple must abstain until the fourth day after the “peak” day.
In the symptothermal method, the first day of abstinence is predicted either from the calendar, by subtracting 21 from the length of the shortest menstrual cycle in the preceding 6 months, or the first day mucus is detected, whichever comes first. The end of the fertile period is predicted by use of basal body temperature. The woman takes her temperature every morning and resumes intercourse 3 days after the thermal shift, the rise in body temperature that signals that the corpus luteum is producing progesterone and that ovulation occurred. The postovulatory method is a variation in which the couple has intercourse only after ovulation is detected.
A system of hormone monitoring designed to better define the fertile period involves placement of disposable test sticks in a small battery-powered device to detect urinary estrone-3 glucuronide and LH. Changes in these hormones reliably predict the fertile period. These devices (Persona™ and Clearblue Easy Fertility Monitor™) can serve as aids both to becoming pregnant and to avoiding it (20). Persona™ is marketed in Europe for contraception. It is reported to have a correct use effectiveness of 94% in avoiding pregnancy. Clearblue Easy™ (CEFM) is approved in the United States as an aid to becoming pregnant but is used off label to avoid pregnancy. Exact effectiveness rates are not known. The CEFM is used in the Marquette method, which combines observation of cervical mucus changes with the CEFM results. A correct use pregnancy rate of 2% and a typical use pregnancy rate of 12% were reported (21).
Efficacy
The ovulation method was evaluated by the World Health Organization in a five-country study. Women who successfully completed three monthly cycles of teaching were enrolled in a 13-cycle efficacy study. There was a 3.1% probability of pregnancy in 1 year for the small proportion of couples who used the method perfectly and 86.4% probability of pregnancy for the rest (22). A review of 15 national surveys from developing countries estimated a 12-month gross failure rate of 24 pregnancies per 100 (23).
Risks
Conceptions resulting from intercourse remote from the time of ovulation more often lead to spontaneous abortion than conceptions from midcycle intercourse (24). Malformations are not more common (18).
Condoms
In the 1700s, condoms made of animal intestine were used by the aristocracy of Europe, but condoms were not widely available until the vulcanization of rubber in the 1840s (1). Modern condoms usually are made of latex rubber, although condoms made from animal intestine are still sold and are preferred by some who feel they afford better sensation. New condoms made from nonlatex materials—such as polyurethane or synthetic elastomers that are thin, odorless, transparent, and transmit body heat—are available. Although the nonlatex condoms may break more easily than the latex varieties, substantial numbers of study participants preferred them and would recommend them to others (25).
The risk of condom breakage is about 3% and is related to friction (26). Use of water-based lubricants may reduce the risk of breakage. Petroleum-based products such as mineral oil must be avoided because even brief exposure to them markedly reduces the strength of condoms (27).
Sexually Transmitted Diseases
Gonorrhea, ureaplasma, and pelvic inflammatory disease (PID) and its sequel (tubal infertility) are reduced with consistent use of barrier methods (28–30). Tested in vitro, Chlamydia trachomatis, herpes virus type 2, HIV, and hepatitis B did not penetrate latex condoms but did cross through condoms made from animal intestine (31). Follow-up of sexual partners of HIV-infected individuals showed that condom use provides considerable protection (32). Consistent condom use provides more protection than inconsistent use (33). In one study, couples who use condoms 0% to 50% of the time had an HIV seroconversion rate of 20.8 per 100 couple years, whereas those who used condoms 100% of the time had a conversion rate of only 2.3 per 100 couple years (34). Nonoxynol-9 should not be used with condoms for HIV protection because it is associated with genital lesions. Nonoxynol-9 does not add to the protection afforded by condoms alone (35).
Condoms offer protection from cervical neoplasia (36). The relative risk for invasive cervical cancer was 0.4 when those who used condoms or diaphragms were compared with those who never used them (37). The presumed mechanism of protection is reduced transmission of human papillomavirus (HPV).
Risks
Latex allergy could lead to life-threatening anaphylaxis in either partner from latex condoms. Nonlatex condoms of polyurethane and Tactylon should be offered to couples who have a history suggestive of latex allergy.
Female Condom
The original female condom introduced in 1992 was a polyurethane vaginal pouch attached to a rim that partly covered the vulva. The recently FDA approved FC2 female condom is an improved version made from softer synthetic latex that does not require hand assembly during manufacture and is therefore less expensive (38). It is recommended for prevention of pregnancy and STDs, including HIV. Breakage may occur less often with the female condom than the male condom; slippage appears to be more common, especially for those new to its use (39). Exposure to seminal fluid is slightly higher than with the male condom (40). Initial US trials showed a pregnancy rate of 15% in 6 months. Subsequent analysis found that with perfect use, the pregnancy rate may be only 2.6%. This rate is comparable to perfect use of the diaphragm and cervical cap, the other female barrier methods (41). As with the male condom, failure rates fall with increasing experience. Colposcopic studies of women using the female condom demonstrate no signs of trauma or change in the bacterial flora (42).
Vaginal Spermicides
Currently available vaginal spermicides combine a spermicidal chemical, either nonoxynol-9 (N-9) or octoxynol, with a base of cream, jelly, aerosol foam, foaming tablet, film, suppository, or a polyurethane sponge. Nonoxynol-9 is a nonionic surface-active detergent that immobilizes sperm. Nonoxynol-9 spermicides alone appear considerably less effective in preventing pregnancy than condoms or diaphragms. Women using nonoxynol-9 spermicides frequently have higher rates of genital lesions than women not using spermicides. These lesions may increase their risk for STDs and HIV (43). In the same studies of serodiscordant couples in which condoms were proven effective in preventing transmission of HIV, nonoxynol-9 spermicides alone were not effective (34).
Concerns were raised about possible teratogenicity of spermicides. Nonoxynol-9 is not absorbed from the human vagina (44). Several large studies found no greater risk of miscarriage, birth defects, or low birth weight in spermicide users than in other women (45,46).
Nonoxynol-9 is toxic to the lactobacilli that normally colonize the vagina. Women who use spermicides regularly have increased vaginal colonization with the bacterium Escherichia coli and may be predisposed to E. coli bacteriuria after intercourse (47).
Vaginal Barriers
At the beginning of the 20th century, four types of vaginal barriers were used in Europe: vaginal diaphragm, cervical cap, vault cap, and Vimule. Vaginal diaphragms, new varieties of cervical caps and the synthetic sponge are used in the United States. When used consistently, vaginal barriers can be reasonably effective. They are safe, and, as with condoms, they have the noncontraceptive benefit of relative protection from STDs, tubal infertility, and cervical neoplasia. A recent search for alternatives to condoms for HIV prevention in high-prevalence areas has rekindled interest in the other vaginal barriers (48).
Figure 10.3 Wide-seal diaphragm. A: Outer caudal side. B: Inner cephalad side.
Diaphragm
The diaphragm consists of a circular spring covered with fine latex rubber (Fig. 10.3). There are several types of diaphragms, as determined by the spring rim: coil, flat, or arcing. Coil-spring and flat-spring diaphragms become a flat oval when compressed for insertion. Arcing diaphragms form an arc or half moon when compressed; they are easiest to insert correctly. The practitioner must fit the diaphragm for the patient, and instruct her in its insertion and verify by examination that she can insert it correctly to cover the cervix and upper vagina. Spermicide is always prescribed for use with the diaphragm; whether this practice is necessary is not well studied.
Fitting Diaphragms
Fitting a diaphragm should be performed as follows:
1. A vaginal examination should be performed. With the first and second fingers in the posterior fornix, the thumb of the examining hand is placed against the first finger to mark where the first finger touches the pubic bone. The distance from the tip of the middle finger to the tip of the thumb is the diameter of the first diaphragm that should be tried.
2. A set of test diaphragms of various sizes is used, and the test diaphragm is inserted and checked by palpation. The diaphragm should open easily in the vagina and fill the fornices without pressure. The largest diaphragm that fits comfortably should be selected. A size 65, 70, or 75 diaphragm will fit most women.
3. The patient should practice insertion and should be reexamined to confirm proper position of the device. About 1 teaspoon of water-soluble spermicidal jelly or cream is placed in the cavity of the dome. The diaphragm is inserted with the dome downward so that the cervix will sit in a pool of the spermicide.
4. The diaphragm can be inserted several hours before intercourse. If intercourse is repeated, additional spermicidal jelly should be inserted into the vagina without removing the diaphragm. The diaphragm should be left in place at least 6 hours after intercourse to allow for immobilization of sperm. When removed, it is washed with soap and water, allowed to dry, and stored away from heat. It should not be dusted with talc because genital exposure to talc may increase the risk of ovarian cancer.
Risks
Diaphragm use, especially prolonged use during multiple acts of intercourse, appears to increase the risk of bladder infections. The risk of cystitis increases with the numbers of days the diaphragm is used in a week (49). A smaller-sized, wide-seal diaphragm or a cervical cap can be used if recurrent cystitis is a problem, although the problem may relate not only to mechanical obstruction but also to alterations in vaginal flora produced by the spermicide. An epidemiologic study comparing cases of toxic shock with controls found no increased risk from diaphragm use (50).
Other Barriers
The Prentif cervical cap made of latex rubber is no longer available in the United States. It was in continuous use for most of the 20th century, but competition from other methods made its continued production impractical.
The FemCap
This new version of the cervical cap made of silicone rubber was approved by the FDA in 2003. It looks like a sailor’s hat with the dome covering the cervix and the brim fitting into the vaginal fornices (51). It is made in three sizes—22-, 26-, and 30-mm diameter—and is expected to be reusable for 2 years. It is used with spermicide and should be left in place for at least 6 hours after intercourse, but it may be left in place as long as 48 hours at a time. Additional acts of intercourse require insertion of more spermicide. Femcap requires a clinician’s fitting and prescription for use. The only available efficacy study compared the FemCap to the vaginal diaphragm. The 6-month pregnancy rate for the FemCap was 13.5%, substantially higher than the 7.9% rate for the diaphragm. Both groups used N-9 spermicide with the devices (52).
Lea's Shield
Lea’s Shield, approved by the FDA in 2002, is another vaginal barrier device made of silicone rubber. It is intended for use with a spermicide. It is shaped like an elliptical bowl with a central air valve approximately the size of a diaphragm, featuring an anterior loop to assist its removal. The posterior end is thicker and therefore less likely to rotate when in place. It comes in one size; proper fitting requires only that it cover the cervix, sit behind the symphysis, and be comfortable. The shield needs to be inserted prior to each act of intercourse and should not be left in the vagina for longer than 48 hours (53). A prescription is required. Approximately 87% of those responding to a question about their use of the shield stated that they would recommend its use to a friend (51). Of 59 women who used the device with N-9 spermicide, the 6-month pregnancy rate was 15% (54).
The Sponge
The Today sponge is a polyurethane dome-shaped device containing nonoxynol-9. It is moistened with water and then inserted high in the vagina to cover the cervix. It combines the advantages of a disposable barrier with spermicide and provides protection for 24 hours. The contraceptive efficacy appears to differ with parity. Nulliparous women are reported to have a perfect use pregnancy rate of 9% per year, whereas parous women have a pregnancy rate of 20% (Table 10.2). Rates with typical use are estimated as 16 per year in nullipara and 32% in multipara (55). A trial comparing the sponge with a vaginal spermicide preparation used alone without barrier showed the sponge had a slightly lower pregnancy rate (56).
Intrauterine Contraception
Worldwide over 15% of married women use intrauterine contraception (57). In the United States, usage is increasing, but the estimates are that only 3.4% of women and only 5.0% of married women use intrauterine contraception (4). Candidacy includes nulliparous women, adolescents, and immunocompromised women. Immediate use postpartum or after a first or second trimester abortion broadened usage. Two IUDs are in use in the United States: the copper T380A (ParaGard) and the levonorgestrel-releasing T (Mirena). The copper T380A has bands of copper on the cross arms of the T in addition to copper wire around the stem, providing a total surface area of 380 mm of copper, almost double the surface area of copper in earlier copper devices (Fig. 10.4). It is approved for up to 10 years of continuous use. The levonorgestrel T (Fig. 10.5) is approved in the United States for 5 years of use, although studies through 7 years of use show no loss of efficacy (58). Both provide safe, long-term contraception with effectiveness equivalent to tubal sterilization.
Figure 10.4 Copper T380A (ParaGard) intrauterine device.
Figure 10.5 Levonorgestrel T (Mirena™) intrauterine device.
Mechanism of Action
Intrauterine devices cause the formation of “biologic foam” within the uterine cavity that contains strands of fibrin, phagocytic cells, and proteolytic enzymes. All IUDs stimulate the formation of prostaglandins within the uterus, consistent with both smooth muscle contraction and inflammation. Copper IUDs continuously release a small amount of the metal, producing an even greater inflammatory response. Scanning electron microscopy studies of the endometrium of women wearing nonmedicated IUDs show alterations in the surface morphology of cells, especially of the microvilli of ciliated cells (59). There are major alterations in the composition of proteins within the uterine cavity and new proteins and proteinase inhibitors are found in washings from the uterus (60). The altered intrauterine environment interferes with sperm passage through the uterus, preventing fertilization.
The levonorgestrel in the T device is much more potent than natural progesterone and has a strong effect on the endometrium. The hormone is released at an initial rate of 20 μg daily, which declines to half this rate by 5 years. Blood hormone levels are significantly lower than with other progesterone-only contraception and remain stable at approximately 150 to 200 pg/mL (61). About 85% of cycles are ovulatory. The contraceptive effect of the levonorgestrel intrauterine device is a result of thickened and scant cervical mucus, endometrial atrophy, and an intrauterine inflammatory response (62).
The IUD is not an abortifacient. The contraceptive effectiveness does not depend on interference with implantation, although this phenomenon occurs and is the basis for using copper IUDs for emergency contraception. Sperm can be obtained by laparoscopy in washings from the fallopian tubes of control women at midcycle; fewer sperm are present in the tubal washings from women wearing IUDs (63). Ova flushed from the tubes at tubal sterilization showed no evidence of fertilization in women wearing IUDs (64). Studies of serum β-human chorionic gonadotropin (β-HCG) levels in women wearing IUDs do not indicate pregnancy (65).
Effectiveness
The copper T380A and the levonorgestrel T have remarkably low pregnancy rates, less than 0.2 per 100 woman-years. Total pregnancies over a 7-year period were only 1.1 per 100 for the levonorgestrel T and 1.4 for the copper T380A (58). Twelve-year data on the copper T380A showed a cumulative pregnancy rate of only 1.9 per 100 women and no pregnancies at all after year 8 (66).
Benefits
Modern IUDs provide excellent contraception without continued effort by the user. Both the copper T380A and the levonorgestrel T protect against ectopic pregnancy. The levonorgestrel T, by releasing levonorgestrel, reduces menstrual bleeding and cramping. It is used extensively to treat heavy menstrual bleeding and is used in Europe and the United Kingdom as an alternative to hysterectomy for menorrhagia (67). The levonorgestrel T also has a beneficial effect on menorrhagia from uterine fibroids; the benefit may be diminished with distorting submucosal fibroids (68,69). The levonorgestrel T is an effective way to deliver the necessary progestin therapy in postmenopausal women on estrogen therapy (70). Additional noncontraceptive benefits include a reduced risk of endometrial cancer and improvement in symptoms of endometriosis and adenomyosis (71–74).
Risks
Infection
The Women’s Health Study found the Dalkon Shield device (now withdrawn from the market) to increase the risk of PID eightfold when women hospitalized for PID were compared with control women hospitalized for other illnesses (75). In contrast, risk from the other IUDs was markedly less. Increased risk was detectable only within 4 months of insertion of the IUD. A prospective World Health Organization study revealed that PID increased only during the first 20 days after insertion. Thereafter, the rate of diagnosis of PID was about 1.6 cases per 1,000 women per year, the same as in the general population (76).
Exposure to sexually transmitted pathogens is the more important determinant of PID risk than is wearing an IUD. In the Women’s Health Study, women who were married or cohabiting and who said they had only one sexual partner in the past 6 months had no increase in PID (75). In contrast, previously married or single women had marginal increase in risk, even though they had only one partner in the previous 6 months (77). The only pelvic infection that was unequivocally related to IUD use is actinomycosis (78). It appears that PID with actinomycosis was reported only in women wearing an IUD. Rates of colonization with actinomycosis increase with duration of use for plastic devices but appear to be much less for copper-releasing IUDs. Actinomyces may be found in cervical cytology of up to 7% of women with an IUD. Because of the low positive predictive value and a lack of sensitivity and specificity of cervical cytology to diagnose this organism, antibiotic treatment and IUD removal should be reserved for symptomatic women (79).
When PID is suspected in a woman wearing an IUD, appropriate cultures should be obtained, and antibiotic therapy should be administered. Removal of the IUD is not necessary unless symptoms do not improve after 72 hours of treatment (80). Pelvic abscess, if suspected, should be ruled out by ultrasound examination.
Ectopic Pregnancy
All contraceptive methods protect against ectopic pregnancy by preventing pregnancy. But when the method fails and pregnancy occurs, risk of ectopic is affected by the method of contraception. IUDs and tubal sterilization increase the probability of the pregnancy being ectopic when pregnancy occurs, but the rate of any pregnancy is so low that women using either of these methods have much lower rates of ectopic pregnancy than women not using contraception (81). Risk of any pregnancy with a levonorgestrel IUD is between 0.1 and 0.2 per 100 woman-years. The rate of an ectopic in wearers of this device is reported as 0.02 per 100 woman-years (82). In a large study of the copper T380A, the first-year pregnancy rate was 0.5 per 100 woman-years, and the rate of ectopic was 0.1 per 100 woman-years (83). Ectopic is a very rare event with either IUD, but should a woman wearing one present with pelvic pain and a positive β-HCG, an ectopic must be ruled out. Increased risk of ectopic among past users of older IUDs was reported. The copper T380A and the levonorgestrel T were not included (81).
Fertility
Tubal factor infertility is not increased among nulligravid women who used copper IUDs, but exposure to sexually transmitted pathogens such as C. trachomatis does increase risk (84). The Oxford study found that women gave birth just as promptly after IUD removal as they did after discontinuing use of the diaphragm (85).
Expulsion and Perforation
The rate of expulsion with the copper T380A is reported to be 2.5 per 100 woman-years in the first year, and cumulates to 8 per 100 woman-years after 8 years (83). Expulsion rates with the levonorgestrel Twere reported at 4.2% in years 1 and 2, 1.3% in years 3 through 5, and 0% in years 6 and 7 (86). The risk of uterine perforation associated with insertion is dependent on the inserter. The risk in experienced hands is on the order of 1 per 1,000 insertions or less (87). There are no studies specifically addressing perforation in nulliparous as compared to parous women (88).
Clinical Management
Contraindications to IUD use listed by the World Health Organization include pregnancy, puerperal sepsis, PID, or STDs current or within the past 3 months, endometrial or cervical cancer, undiagnosed genital bleeding, uterine anomalies, and fibroid tumors that distort the endometrial cavity (87). Infection with HIV is not considered a contraindication for IUD use. No increase in pelvic infection, female-to-male transmission, or viral shedding was found among HIV-1 infected women (89,90). Copper allergy and Wilson’s disease are contraindications to the use of copper IUDs.
Candidate Selection
IUDs are appropriate for long-term contraception in most women given their ease of use, high efficacy, and favorable side effect profile. Nulliparous women, adolescents, women undergoing a first or second trimester surgical abortion, women with a recent medical abortion, and women immediately postpartum should all be considered candidates for IUDs (91). There is renewed interest in postpartum and postabortal insertion of IUDs. In both circumstances, the woman is clearly no longer pregnant, she may be highly motivated to accept contraception, and the setting is convenient for both the woman and the provider (92,93). Postpartum and postabortal insertions are safe. Complications are not increased by comparison to interval insertion. The only disadvantage is that the expulsion rate is higher. In comparing postpartum to interval insertion, all the women requesting postpartum IUD received the device, but many women scheduled for interval insertion did not return. When surveyed at 6 months postpartum, more women who had postpartum insertion were wearing IUDs than were those who had scheduled for interval insertion (94). Goodman and colleagues found many fewer repeat abortions among women followed after postabortal IUD insertion compared to a cohort of women choosing non-IUD methods of contraception after an induced abortion (94).
Insertion
At the contraceptive visit, the patient’s history is obtained and a physical examination, screening for Neisseria gonorrhoeae and chlamydia in high-risk women, and detailed counseling regarding risks and alternatives are provided. The IUD usually is inserted during menses to be sure the patient is not pregnant, but it can be inserted at any time in the cycle if pregnancy can be excluded(95). The copper-T380A IUD can be inserted within 5 days of unprotected intercourse for 100% effective emergency contraception.
There are limited data on effective treatment of pain during IUD insertion. One randomized nonblinded study suggested a benefit with 2% lidocaine gel applied to the cervical canal 5 minutes before insertion. Other techniques such as paracervical block were not evaluated. Premedication with oral prostaglandin inhibitors such as ibuprofen is strongly advised, although evidence of its benefit with modern IUDs is limited (96).
Antibiotic prophylaxis is not beneficial, probably because the risk of pelvic infection with IUD insertion is so low. A large randomized trial of 1,985 patients receiving either oral azithromycin or placebo found no difference in rates of IUD removal during the first 90 days after insertion and no difference in rates of salpingitis (97). These women were screened for STDs only by self-history. Screening for gonorrhea and chlamydia at the time of insertion is recommended for adolescents, but it is not necessary to wait for the results before insertion because patients with positive results have no adverse effects if treated promptly (98). PID, puerperal sepsis, or postabortion sepsis within the past 3 months are considered contraindications and patients with purulent cervicitis should be tested and treated before insertion.
The technique of insertion is as follows:
1. The cervix is exposed with a speculum. The vaginal vault and cervix are cleansed with a bacteriocidal solution, such as an iodine-containing solution.
2. The uterine cavity should be measured with a uterine sound. The depth of the cavity should measure at least 6 cm from the external os. A smaller uterus is not likely to tolerate currently available IUDs.
3. Use of a tenaculum for insertion is mandatory to prevent perforation. The cervix is grasped with a tenaculum and gently pulled downward to straighten the angle between the cervical canal and the uterine cavity. The IUD, previously loaded into its inserter, is then gently introduced through the cervical canal.
4. With the copper T380A, the outer sheath of the inserter is withdrawn a short distance to release the arms of the T and is gently pushed inward again to elevate the now-opened T against the fundus. The outer sheath and the inner stylet of the inserter are withdrawn, and the strings are cut to project about 2 cm from the external cervical os.
5. The levonorgestrel T IUD is inserted somewhat differently from the copper T380A. The inserter tube is introduced into the uterus until the preset sliding flange on the inserter is 1.5 to 2 cm from the external os of the cervix. The arms of the T device are released upward into the uterine cavity, and the inserter is pushed up under them to elevate the IUD up against the uterine fundus.
In nulliparous women, insertion may be more difficult because of a narrower cervical canal than in parous women. Mechanical dilation may be necessary. Pretreatment with misoprostol may be beneficial in difficult IUD insertions (99).
Intrauterine Devices in Pregnancy
If an intrauterine pregnancy is diagnosed and the IUD strings are visible, the IUD should be removed as soon as possible to prevent later septic abortion, premature rupture of the membranes, and premature birth (100). When the strings of the IUD are not visible, an ultrasound examination should be performed to localize the IUD and determine whether expulsion has occurred. If the IUD is present, there are three options for management:
1. Therapeutic abortion
2. Ultrasound-guided intrauterine removal of the IUD
3. Continuation of the pregnancy with the device left in place
If the patient wishes to continue the pregnancy, ultrasound evaluation of the location of the IUD should be considered (101). If the IUD is not in a fundal location, ultrasound-guided removal using small alligator forceps may be successful. If the location is fundal, the IUD should be left in place. When pregnancy continues with an IUD in place, the patient must be warned of the symptoms of intrauterine infection and should be cautioned to seek care promptly for fever or flulike symptoms, abdominal cramping, or bleeding. At the earliest sign of infection, high-dose intravenous antibiotic therapy should be given and the pregnancy evacuated promptly.
Duration of Use
Annual rates of pregnancy, expulsions, and medical removals decrease with each year of use (102,103). Therefore, a woman who has no problem by year 5, for example, is very unlikely to experience problems in the subsequent years. The copper T380A is FDA approved for 10 years and the levonorgestrel T for 5 years, though as previously noted, good data support use of the copper T380A through 12 years and of the levonorgestrel T through 7 years (66,86).
Choice of Devices
Both of the IUDs available in the United States, the copper T380A and the levonorgestrel T, provide protection for many years, have remarkably low pregnancy rates, and substantially reduce the risk of ectopic pregnancy. The levonorgestrel T reduces the amount of menstrual bleeding and dysmenorrhea. The copper T380A initially can be expected to increase menstrual bleeding. It is the most effective means for emergency contraception.
Management of Bleeding and Cramping with Intrauterine Devises
The most important medical reason that women give for requesting removal of an IUD is bleeding and pelvic pain. These symptoms are common in the first few months, but diminish. Nonsteroidal anti-inflammatory drugs are usually helpful. When pain and bleeding occur later, the patient should be examined for signs of PID, partial expulsion of the device, or an intracavitary fibroid. Two ultrasonographic studies comparing women with these symptoms after 6 months to women with no bleeding complaints show downward displacement of the IUDs into the cervical canal in many of the symptomatic women and in some cases, intracavitary fibroids (104,105). When the patient wishes to continue with an IUD, removal of the displaced device and insertion of a new one is advisable. In situations where IUDs are inexpensive and ultrasound is expensive or not available, the best course is to offer immediate removal and replacement of the IUD without ultrasound proof of displacement.
Hormonal Contraception
Hormonal contraceptives are female sex steroids, synthetic estrogen and synthetic progesterone (progestin), or progestin-only without estrogen. They can be administered in the form of OCs, patches, implants, and injectables. The most widely used hormonal contraceptive is the combination OC containing both estrogen and progestin. Combination OCs can be monophasic, with the same dose of estrogen and progestin administered each day, or multiphasic, in which varying doses of steroids are given through a 21-day or 24-day cycle. Combination OCs are packaged with 21 active tablets and 7 placebos, or 24 active tablets and 4 placebo tablets. The inclusion of placebos allows the user to take one pill every day without having to count. The medication-free interval while the user takes the placebo tablets allows withdrawal bleeding that mimics a 28-day menstrual cycle. To begin OC use, the user takes the first pill any time from the first day of menses through the Sunday after menstruation begins and thereafter starts a new pack as soon as the first pack is completed. The 7-day medication-free interval was standard for years, but studies showed that a shorter medication-free interval is adequate to trigger cyclic withdrawal bleeding and maintains better suppression of ovulation. Ovarian follicles mature more during the 7-day medication-free interval than during the 4-day interval. Hence the new 24/4 combination theoretically could be more effective in preventing pregnancy than the 21/7 combination, but this has not been demonstrated. Other variations of OC administration are the extended cycle and the continuous cycle methods. Users take active pills containing an estrogen–progestin combination for 3 months at a time (extended cycle) or indefinitely for a year or more (continuous cycle). Users on these regimens have more unscheduled days of spotting or bleeding than those on 28-day cycles in the beginning, but become amenorrheic. As a result they experience fewer cycle triggered symptoms such as headache and menstrual pain. Continuous-combined regimens are preferred for women with chronic pelvic pain or when dysmenorrhea is not relieved by OCs taken in 28-day cycles (106).
Progestin-only OCs are taken every day without interruption. Other forms of hormonal contraception include transdermal administration with the patch, injectable progestins, injectable estrogen–progestin combinations, subdermal implants that release progestin, and vaginal rings that release either estrogen–progestin or progestin alone (107).
Steroid Hormone Action
Sex steroids are characterized by their affinity for specific estrogen, progesterone, or androgen receptors, and by their biologic effects in different systems (108). Steroids are rapidly absorbed in the gut but go directly into the liver through the portal circulation, where they are rapidly metabolized and inactivated. Therefore, large doses of steroids are required when they are administered orally. The addition of the ethinyl group to carbon-17 of the steroid molecule hinders degradation by the liver enzyme 17-hydroxysteroid dehydrogenase and allows potent biological activity after oral doses of only micrograms.
Progestins
Progestins are synthetic compounds that mimic the effect of natural progesterone but differ from it structurally. The progestins differ from one another in their affinities for estrogen, androgen, and progesterone receptors; their ability to inhibit ovulation; and their ability to substitute for progesterone and to antagonize estrogen. Some are directly bound to the receptor (levonorgestrel, norethindrone), whereas others require bioactivation as, for example, desogestrel, which is converted in the body to its active metabolite, etonogestrel. The 17-acetoxy progestins (e.g., medroxyprogesterone acetate) are bound by the progesterone receptor. Norgestrel exists as two stereoisomers, identified as dextronorgestrel and levonorgestrel. Only levonorgestrel is biologically active. Three newer progestins (norgestimate, desogestrel, and gestodene) are viewed as more “selective” than the other 19-nor progestins, in that they have little or no androgenic effect at doses that inhibit ovulation (109). The FDA approved norgestimate- and desogestrel-containing OCs, and gestodene is available in Europe. Gestodene is a derivative of levonorgestrel that is more potent than the other preparations (i.e., very little of it is required for antifertility effects). Similarly, norelgestromin is an active metabolite of norgestimate and more potent than the parent compound. It is used in the transdermal patch. Drospirenone, a progestin introduced in the United States, is a derivative of the diuretic spironolactone. It has high affinity for progesterone receptors, mineralocorticoid receptors, and androgen receptors. It acts as a progesterone agonist but is a mineralocorticoid antagonist and androgen antagonist (110). Comparative studies suggest a small decrease in body weight and in blood pressure, with equivalent cycle control and contraceptive efficacy, in women taking an OC containing 3 mg of drospirenone/30 μg ethinyl estradiol versus women taking a 150 μg levonorgestrel/30 μg ethinyl estradiol (EE) preparation (111). Pilot studies of women with polycystic ovary syndrome showed good cycle control and reduction in androgen levels with no change in weight, blood pressure, or glucose metabolism (112). The FDA approved the 20 μg EE/3 mg drospirenone OC for premenstrual dysphoric disorder (PMDD) in women who choose OCs for contraception. When compared to an OC with 30 μg EE/150 μg levonorgestrel, women taking the drospirenoneOC had better relief of menstrual symptoms, better improvement in acne, reduction in negative affect during the menstrual phase, and a greater feeling of well-being (113). Dienogest, another progestin introduced in the United States, is combined with estradiol valerate, not ethinyl estradiol. Whether it offers any advantage over already marketed OC combinations is not yet evident. The dienogest/estradiol valerate combination is as effective as levonorgestrel/ethinyl estradiol as a contraceptive, and in treating abnormal uterine bleeding (114).
Estrogens
In the United States, most OCs contain either of two estrogens: mestranol or ethinyl estradiol (EE). Mestranol is EE with an extra methyl group. It requires bioactivation in the liver, where the methyl group is cleaved, releasing the active agent, EE. Oral contraceptives with 35 μg of EE provide the same blood levels of hormone as do OCs containing 50 μg of mestranol. (115). Estradiol cypionate and estradiol valerate are esters of natural 17 β-estradiol also in use for contraception.
Antifertility Effects
Combination Estrogen–Progestin Contraceptives
Ovulation can be inhibited by estrogen or by progestin alone. Pharmacologic synergism is exhibited when the two hormones are combined and ovulation is suppressed at a much lower dose of each agent. Combination OCs, patches, and the NuvaRing suppress basal follicle-stimulating hormone (FSH) and LH. They diminish the ability of the pituitary gland to synthesize gonadotropins when it is stimulated by hypothalamic GnRH (116). Ovarian follicles do not mature, little estradiol is produced, and there is no midcycle LH surge. Ovulation does not occur, the corpus luteum does not form, and progesterone is not produced. This blockade of ovulation is dose related. Newer low-dose OCs do not provide as dense a block and allow somewhat higher baseline FSH and LH levels than higher dose formulations (117). This makes ovulation somewhat more likely to occur if pills are missed or if the patient takes another medication that reduces blood levels of the contraceptive steroids.
Progestin-Only Preparations
Highly effective contraception can be provided by progestin alone, thus avoiding the risks of estrogen. The mode of action of progestin-only contraceptives is highly dependent on the dose of the compound (118). With low levels of progestin in the blood, ovulation will occur part of the time. At moderate levels of progestin in the blood, normal basal levels of FSH and LH are present, and some follicle maturation may occur. At higher blood levels as seen with DepoProvera, the basal FSH is reduced, and there is less follicular activity, less estradiol production, and no LH surge.
Transdermal Hormonal Contraception
The patch (OrthoEvra), which adheres to the user’s skin, and the vaginal NuvaRing both contain combinations of EE and a potent progestin. Both provide sustained release of the steroids and result in relatively constant serum levels that are less than the peak levels seen with OCs but sufficient to prevent ovulation.
Hormonal Implants
With the levonorgestrel subdermal implants there is some follicular maturation and estrogen production, but LH peak levels are low and ovulation is often inhibited. In the first year of use, ovulation is believed to occur in about 20% of cycles. The proportion of ovulatory cycles increases with time, probably as a result of the decline in hormone release. By the fourth year of use, 41% of cycles are ovulatory. The more potent progestin released by the etonogestrelimplant is even more effective at preventing ovulation (119). The mechanisms of action of low-dose progestins include effects on the cervical mucus, endometrium, and tubal motility. The scant, dry cervical mucus that occurs in women using implants inhibits sperm migration into the upper tract. Progestins decrease nuclear estrogen receptor levels, decrease progesterone receptors, and induce activity of the enzyme 17-hydroxysteroid dehydrogenase, which metabolizes natural 17 β-estradiol (118).
The sustained release offered by contraceptive implants allows for highly effective contraception at relatively low steroid blood levels. Figure 10.6 depicts expected steroid blood levels with implants, injectables, and oral contraceptives. An additional mechanism for contraception was discovered with the antiprogesterone mifepristone (RU486). In the normal cycle, there is a small amount of progesterone production from the follicle just before ovulation. This progesterone appears essential to ovulation, because if mifepristone is given before ovulation this can be delayed for several days (120,121).
Efficacy of Hormonal Contraception
When used consistently, combination OCs have pregnancy rates as low as 2 to 3 per 100 women per year. Progestin-only OCs are less effective than combination estrogen–progestin preparations, with best results of 3 to 4 pregnancies per 100 woman-years. All methods have the potential for user error; therefore, there may be a 10-fold difference between the best results and results in typical users of OCs. Injectable progestins and implants are much less subject to user error than are OCs. The difference between the best results and results in typical users is small and is comparable to pregnancy rates after tubal sterilization (Table 10.2). Pregnancy rates with the OrthoEvra patch and the NuvaRing were equivalent to those of OCs; however, because it is easier to use these methods consistently, larger studies may well demonstrate better typical user results than with OCs (122,123). Typical use pregnancy rates with DMPA are lower. The subdermal implants have the lowest rates of any hormonal contraceptive method.
Hormonal Contraception for Obese Women
The present rate of obesity in Europe and the United States is 30% and is increasing. Most studies of contraceptive efficacy intentionally excluded obese women, so the available information is limited. Obese women are no less likely than other women to become pregnant, but they do have an increased risk of pregnancy complications (124). A systematic review of hormonal contraception for overweight and obese women found only seven relevant studies (125). Overweight and obese women appear to be at a similar or slightly higher risk of pregnancy with oral contraceptives. The attributable risk is minimal (124). The efficacy of DMPA does not appear to be reduced in heavier women. A possible increase in pregnancies was reported for users of the contraceptive patch who weight more than 90 kg. Heavier women using the vaginal ring had no increase in pregnancies. Few heavy women were studied with the etonogestrel implant because the studies excluded women of body weight greater than 130% of ideal body weight. Pregnancy rate does appear to increase with weight in women using the levonorgestrel implants at weight 70 kg or more but it is still low. There were no pregnancies in any weight group during the first 3 years of use in a large study (125,126).
Metabolic Effects and Safety
Venous Thrombosis
Women who use estrogen containing hormonal contraceptives are at increased risk for venous thrombosis and thromboembolism. Normally the coagulation system maintains a dynamic balance of procoagulant and anticoagulant systems. Estrogens affect both systems in a dose-related fashion. For most women, fibrinolysis (anticoagulation) is increased as much as coagulation, maintaining the dynamic balance at increased levels of production and destruction of fibrinogen (127,128) (Fig. 10.7). Older studies included women with what are now considered contraindications to use of estrogen-containing hormonal contraceptives: previous thrombosis, preexisting vascular disease, coronary artery disease, cancers, and serious trauma (127,128). Current low-dose OCs have a less measurable effect on the coagulation system, and fibrinolytic factors increase at the same rate as procoagulant factors. Lower estrogen dose (30–35 μg EE) OCs reduce the risk of a thromboembolic event when compared with higher dose (50 μg estrogen) OCs (129) (Table 10.5). A very large Danish study showed for the first time that combination OCs with 20 μg of ethinyl estradiol have an 18% further reduction in thrombosis risk compared with 30 to 40 μg OCs after adjustment for duration of use (130). The progesterone-only OCs and the levonorgestrel-releasing intrauterine device were not associated with venous thrombosis.
Figure 10.6 Schematic representation of the expected pharmacokinetic profiles of progestogens administered in different formulations. (From Landgren BM. Mechanism of action of gestagens. Int J Gynaecol Obstet 1990;32:95–110, with permission.)
Figure 10.7 Dynamic balance of hemostasis. (From Winkler UH, Buhler K, Schlinder AE. The dynamic balance of hemostasis: implications for the risk of oral contraceptive use. In: Runnebaum B, Rabe T, Kissel L, eds. Female contraception and male fertility regulation. In Advances in Gynecological and Obstetric Research Series. Confort, England: Parthenon Publishing Group, 1991:85–92, with permission.)
Table 10.5 Oral Contraceptive Estrogen Dose and Risk for Deep Vein Thrombosis
The absolute risk of deep vein thrombosis was strongly influenced by age, increasing from 1.84 per 10,000 women aged 15 to 19 years to 6.59 per 10,000 for women aged 45 to 49 years with current users, former users, and never users combined. With all types of OCs combined, the overall absolute rate of deep vein thrombosis was 6.29 per 10,000 woman-years for current OC users compared to 3.01 among nonusers, giving an adjusted rate ratio of 2.83 (95% confidence interval [CI], 2.65–3.01) (Table 10.6). This is a higher absolute risk than the 3 per 10,000 woman-years previously estimated and may reflect, among other things, the use of better means for diagnosis of deep vein thrombosis (131). This population-based study includes all Danish women aged 15 to 49, excluding only women with a diagnosis of cancer or of cardiovascular disease diagnosed before the study interval. Thrombosis risk was highest during the first year of use and decreased thereafter (Table 10.6).
Table 10.6 Crude Incidence Rates and Adjusted Rate Ratios of Venous Thrombosis in Women Using Different Types of Hormonal Contraception
Thrombophilia
Changes in the coagulation system are detectable in all women, including those taking lower-dose OCs; some women are genetically predisposed to thrombosis when challenged by pregnancy or administration of exogenous estrogen. Women with inherited deficiencies of antithrombin III, protein C, or protein S are at very high risk for thrombosis with pregnancy or estrogen therapy, but they make up a very small proportion of potential OC users. A much more common variation, factor V Leiden exists in 3% to 5% of the Caucasian population. It codes for a one amino acid mutation in the factor V protein, inhibiting cleavage of the protein by activated protein C, which is an essential step in maintaining the balance between coagulation and fibrinolysis (109,132). Risk for a first thromboembolic episode among women using OCs was 2.2 per 10,000 woman-years for women without the factor V mutation and 27.7 per 10,000 woman-years for women with the mutation (133). Cigarette smoking did not affect this risk. There are pronounced ethnic differences in the presence of this mutation. The Leiden allele is found in 3% to 5% of whites but is rare in Africans, Asians, Amerindians, Eskimos, and Polynesians (134). A similar mutation is found in the prothrombin gene at position 20210 and is described as prothrombin G20210A. This mutation occurs in 3% of the European population and is strongly associated with venous thrombosis in women taking OCs (135). Many more genetic conditions predisposing to thrombosis were described. Pregnancy is an even greater challenge for women with inherited defects of anticoagulation (136). A woman who sustains a venous event while using OCs should be evaluated thoroughly after she has recovered. Assessment should include at minimum the measurement of antithrombin III, protein C, and protein S levels, resistance to activated protein C, serum homocysteine, factor V Leiden mutation, the prothrombin G20210A mutation and testing for antiphospholipid syndrome. It should not be assumed that hormonal contraception was the unique cause of the thrombotic episode.
Routine screening for all women before prescribing hormonal contraception is not justified because effective contraception would be denied to 5% of Caucasian women, and only a small number of fatal pulmonary emboli would be prevented (137,138). Screening women with a personal or family history of deep vein thrombosis before starting estrogen-containing hormonal contraception or pregnancy is strongly recommended. Women already diagnosed as having factor V Leiden should not receive estrogen-containing contraceptives, i.e., the pill, patch or ring.
Thrombosis and the New Progestins
Several studies found increased risk of venous thrombosis when users of OCs containing the newer progestins desogestrel or gestodene combined with 20 to 30 μg of EE were compared with users of levonorgestrel combined with the same doses of estrogen (115). A controversy resulted. It is likely that the biases “attrition of susceptibles,” “adverse selection,” and “healthy user bias” explain the apparent increase in thrombosis. Most cases of venous thrombosis attributable to OCs occur during the initial months of use (116). Comparing new users to women already taking OCs for some time without incident will demonstrate an apparent increase with the new product that is artificial. Physicians may presume that newer drugs are safer and prescribe them selectively for women with risk factors. Additional studies have not resolved this controversy. Heinemann and colleagues found no difference in thrombosis risk in users of OCs containing desogestrel or gestodene compared to users of OCs with other progestins in a large study of cases occurring between 2002 and 2006 in Austria (139). In contrast, both Lidegaard’s group in Sweden and van Hylckama Vlieg’s group in the Netherlands reported increased risk with the newer progestins (130,140).
Ischemic Heart Disease
Ischemic heart disease and stroke were the major causes of death attributed to OC use in the past. It is known that the principal determinants of risk are advancing age and cigarette smoking (141). With the higher-dose OCs used in the 1980s, smoking had a profound effect on risk. Women smoking 25 or more cigarettes per day had a 30-fold increased risk for myocardial infarction if they used OCs, compared with nonsmokers not using OCs (142). Use of OCs is became safer because most women are taking low-dose pills and because physicians prescribe selectively, excluding women with major cardiovascular risk factors. A very large study in the United States confirmed the safety of OCs as currently prescribed. A total of 187 women aged 15 to 44 years with confirmed myocardial infarction were identified during 3.6 million woman-years of observation in the Kaiser Permanente Medical Care Program in California from 1991 to 1994. This is a rate of 3.2 per 100,000 woman-years (143). Nearly all of the users took OCs with less than 50 μg of EE. After adjusting for age, illness, smoking, ethnicity, and body mass index, risk for myocardial infarction was not increased by OC use (odds ratio [OR], 1.14; 95% CI, 0.27–4.72). Of heart attack victims, 61% smoked; only 7.7% were current users of OCs. In a later study, the same investigators pooled results from the California study with a similar study from Washington State. The results were the same. Current users of low-dose OCs had no increased risk for myocardial infarction after adjustment for major risk factors and sociodemographic factors(144). Past use of OCs does not increase risk for subsequent myocardial infarction (145). These observations are supported by another population-based prospective study. OC use and myocardial infarction were studied prospectively among 48,321 randomly selected women aged 30 to 49 in the Uppsala Health Care Region of Sweden (146). There was no association between current or past OC use and myocardial infarction. Most current users were taking low-dose estrogen pills (defined as less than 50 μg of ethinyl estradiol or less than 75 μg of mestranol) with second or third generation progestins, more than half were aged 35 or older, and 26% were current cigarette smokers.
Oral Contraceptives and Stroke
In the 1970s, OC use appeared to be linked to risk of both hemorrhagic and thrombotic stroke, but these studies failed to take into consideration preexisting risk factors (147). A rare form of cerebrovascular insufficiency, moyamoya disease, is linked to OC use, especially among cigarette smokers (148). The present evidence shows no risk of stroke among women who are otherwise healthy and who use low-dose pills. One study identified all Kaiser Permanente Medical Care Program patients aged 15 to 44 years who sustained fatal or nonfatal stroke in California from 1991 to 1994 (149). Hypertension, diabetes, obesity, current cigarette smoking, and black ethnicity were strongly associated with stroke risk, but neither current nor past OC use was associated with stroke. A World Health Organization study of cases from 1989 to 1993 from 17 countries in Europe and the developing world included women taking higher-dose OCs and low-dose OCs. European women using low-dose OCs had no increased risk for either type of stroke, thrombotic or hemorrhagic. Those taking higher-dose OCs did have measurable risk (150,151). Women in developing countries had an apparent modest increase in risk, but this finding was attributed to undetected existing risk factors. Another study from Europe found less stroke risk from low-dose pills than from older, higher-dose pills, and that risk was less if the patient’s blood pressure was checked before starting OCs.
Women who smoke and those who have hypertension and diabetes are at increased risk for cardiovascular disease regardless of whether they use oral contraceptives. The important question is whether risk is further increased if they use low-dose OCs, and if so, by how much. The World Health Organization study described previously provides some insight: smokers taking OCs had seven times the risk of ischemic (thrombotic) stroke when compared with smokers who did not use OCs, and hypertensive women had 10-fold increased risk if they took OCs, but a fivefold risk if they did not (150). Similarly, a study from Denmark found that women with diabetes had a fivefold increase risk for stroke, which increased to 10-fold if they took OCs (152). These data were not limited to low-estrogen OCs. The data suggest that although risk is primarily determined by the predisposing condition—hypertension, diabetes, or cigarette smoking—the risk can be magnified by OC use, even when the OCs are low dose. These observations were confirmed in a recent systematic review (153). Hypertensive women using combination estrogen–progestin oral contraceptives (COCs) had higher risk for ischemic stroke and acute myocardial infarction than hypertensive women not using COCs. The current US practice of limiting hormonal contraceptives containing estrogen by women older than 35 years of age to nonsmokers without other vascular disease risk factors is prudent (7).
Blood Pressure
Oral contraceptives have a dose-related effect on blood pressure. With the older high-dose pills, as many as 5% of patients could be expected to have blood pressure levels greater than 140/90 mm Hg. The mechanism is believed to be an estrogen-induced increase in renin substrate in susceptible individuals. Low-dose pills have minimal blood pressure effects, but surveillance of blood pressure is advised to detect the occasional idiosyncratic response.
Glucose Metabolism
Oral estrogen alone has no adverse effect on glucose metabolism, but progestins exhibit insulin antagonism (154). Older OC formulations with higher doses of progestins produced abnormal glucose tolerance tests with elevated insulin levels in the average patient. The effect on glucose metabolism, similar to the effect on lipids, is related to androgenic potency of the progestin and to its dose.
Lipid Metabolism
Androgens and estrogens have competing effects on hepatic lipase, a liver enzyme critical to lipid metabolism. Estrogens depress low-density lipoproteins (LDL) and elevate high-density lipoproteins (HDL), changes that can be expected to reduce the risk of atherosclerosis (155). Androgens and androgenic progestins can antagonize these beneficial changes, reducing HDL and elevating LDL levels. Estrogens elevate triglyceride levels. Low-dose formulations have minimal adverse effect on lipids, and the newer formulations (with desogestrel and norgestimate as the progestin) produce potentially beneficial changes by elevating HDL and lowering LDL (156,157). Although average values of a large group show only small lipid changes with the use of current OCs, an occasional patient may have exaggerated effects. Women whose lipid values are higher than the mean before treatment are more likely to experience abnormalities during treatment (156).
Other Metabolic Effects
Oral contraceptives can produce changes in a broad variety of proteins synthesized by the liver. The estrogen in OCs increases circulating thyroid-binding globulin, thereby affecting tests of thyroid function that are based on binding, increasing total thyroxine (T4) levels, and decreasing triiodothyronine (T3) resin uptake. The results of actual thyroid function tests, as measured by free T4 and radioiodine tests, are normal (158).
Oral Contraceptives and Neoplasia
Endometrial Cancer and Ovarian Cancer
Combination OCs reduce the risk of subsequent endometrial cancer and ovarian cancer (159,160). Two-year use of OCs reduces the risk of endometrial cancer by 40%, and 4 or more years of use reduces the risk by 60%. The evidence for this benefit continues to accumulate (161). A 50% reduction in ovarian cancer risk for women who took OCs for 3 to 4 years and an 80% reduction with 10 or more years of use was reported (162). There was some benefit from as little as 3 to 11 months of use. A review of all available studies in the world published in English through 2008 concluded that ovarian cancer risk decreased by 20% for each 4 years of use and was seen for carriers of the BRCA1 and 2 mutations as well. The benefit persisted for at least 30 years after last use (163). A similar reduction of risk of ovarian epithelial cancer was found in a prospective study from Norway and Sweden, with borderline tumor risk equally reduced. Combination OCs with less than 50 μg of EE, or less than 100 μg of mestranol and reduced doses of progestin, provided as much protection as higher dose pills (164). Today’s lower-dose 20 μg EE pills were not separately studied. Whether or not they provide the same benefit remains unproven; however, progestin-only contraceptives are reported to provide risk reduction equivalent to that of combined OCs (165).
Cervical Cancer
There may be a weak association between OC use and cancer of the cervix. A systematic review of 28 epidemiologic studies of cervical cancer in OC users compared with those who never used OCs reported summary relative risks of 1.1 (95% CI, 1.1–1.2) at less than 5 years of pill use, 1.6 (1.4–1.7) at 5 to 9 years, and 2.2 (1.9–2.4) at 10 or more years (166). A 2007 update by these same authors reported a pooled relative risk for all studies of 1.9 (95% CI, 1.69–2.13) for invasive cervical cancer or CIN3/carcinoma in situ (CIS) with 5 or more years of OC use. Risk declined after use ceased and by 10 years returned to that of never users. Too few had used progestin-only pills to provide a conclusion as to their effect. For injectable progestins, the relative risk was very slightly increased to 1.22 (95% CI, 1.01–1.46), which was just statistically significant (167). Critics of these studies argued that causation is not proven because few adequately control for the key behavioral factors of partners, use of barrier contraception, and adequacy of cervical cancer screening (168). Important risk factors for cervical cancer are early sexual intercourse and exposure to HPV. Women who used OCs typically started sexual relations at younger ages than women who have not used OCs and, in some studies, report having had more partners. These factors increase one’s chance of acquiring HPV, the most important risk factor for cervical cancer. Because barrier contraceptives reduce the risk of cervical cancer, use of alternative choices for contraception compounds the difficulty in establishing an association with OC use alone (169). The presence of HPV types 16 or 18 is associated with a 50-fold increase in risk for preneoplastic lesions of the cervix (170). Adenocarcinomas of the cervix are rare, they are not as easily detected as other lesions by screening cervical cytology, and the incidence appears to be increasing. One study found a doubling of risk for adenocarcinoma with OC use that increased with duration of use, reaching a relative risk of 4.4 if total use of OCs exceeded 12 years (171). The results of this study were adjusted for history of genital warts, number of sexual partners, and age at first intercourse. Another summary of case-control studies that includes testing for HPV. HPV types 16 or 18 were present in 82% of the patients, yielding a relative risk of 81.3 (95% CI, 42.0–157.1) for the disease. Cofactors identified with adenocarcinoma included longer-term use of hormonal contraception. Intrauterine device use was associated with reduced relative risk of 0.41 (95% CI, 0.18–0.93) (172). Use of hormonal contraception by women from aged 20 to 30 years is estimated to increase the incidence of cervix cancer (any cervix cancer, or CIN3/CIS) diagnosed by age 50 from 7.3 to 8.3 per 1,000 women in lesser-developed countries and from 3.8 to 4.5 in developed countries (172). Use of OCs is, at most, a minor factor in causation of cervical cancer; these findings emphasize the need to immunize against HPV and to provide cervical cancer screening worldwide. To reduce risk, women who are not in mutually monogamous relationships should be advised to use barrier methods in addition to hormonal contraception.
Breast Cancer
There is a large volume of conflicting literature on the relationship between OC use and breast cancer (173). No increase in overall risk is found from OC use, but some studies found that risk may increase in women who used OCs before their first term pregnancy, used OCs for many years, are nulligravid, are young at the time of diagnosis, or continue using OCs in their 40s. A meta-analysis of 54 studies of breast cancer and hormonal contraceptive use reanalyzed data on 53,297 women with breast cancer and 100,239 controls from 25 countries, representing about 90% of the epidemiologic data available worldwide at that time (174). Current use of OCs was associated with a very small, but statistically stable 24% increased relative risk (1.24; 95% CI, 1.15–1.33). The risk fell rapidly after discontinuation, to 16% 1 to 4 years after stopping and to 7% 5 to 9 years after stopping. Risk disappeared 10 years after cessation (relative risk, 1.01; 95% CI, 0.96–1.05). Results did not differ in any important way by ethnic group, reproductive history, or family history. Since the meta-analysis was published, subsequent studies found no increased risk. A case-control study of 4,575 women with breast cancer and 4,682 controls aged 35 to 64 years living in five cities in the United States concluded that breast cancer risk was not increased for current or past users of OCs and did not increase with prolonged or with higher-estrogen OC use (175). Neither family history of breast cancer nor beginning use at a young age was associated with increased risk. A similar study in Sweden compared 3,016 women aged 50 to 74 years who had invasive breast cancer with 3,263 controls of the same age. No relation was found between past use of OCs and breast cancer (176). Effect of hormone dose was explored in a 2008 US study of 1,469 women with breast cancer who were matched by race, age, and neighborhood to community controls. The investigators then administered questionnaires and performed BRCA1 and 2 testing. Subjects who began OC use during or after 1975 were considered to have used low-dose pills. “Low-dose” was not further defined. Neither OC use overall or “low-dose” OC use was associated with breast cancer risk, among the total group, or within any subset. Women with BRCA1 or 2 did not have higher rates of cancer whether they were OC users or were nonusers (177). The controversy over the association between breast cancer and OC use is likely to continue. The best information available is that there is little or no connection.
Liver Tumors
Oral contraceptives were implicated as a cause of benign adenomas of the liver. These hormonally responsive tumors can cause fatal hemorrhage. They usually regress when OC use is discontinued; risk is related to prolonged use (178). The tumors are rare; about 30 cases per 1 million users per year were predicted with older formulations. Presumably, newer low-dose products pose less risk. A link to hepatic carcinoma was proposed. This cancer is closely associated with chronic hepatitis B and C infections and is usually seen in cirrhotic livers. There are case reports of hepatocellular carcinoma in young women with no risk factors other than long-term OC use (179). A large study from six countries in Europe found no association between use of OCs and subsequent liver cancer (180). A systematic review looked for evidence of harm associated with hormonal contraceptive use among women already at risk because of liver disease (181). The authors concluded from the limited data available that OCs do not affect the course of acute hepatitis or chronic hepatitis, and do not affect the rate of progression or severity of cirrhotic fibrosis, the risk of hepatocellular carcinoma in women with chronic hepatitis, or the risk of liver dysfunction in hepatitis B virus carriers.
Oral Contraceptives and Sexually Transmitted Infections
Chlamydial colonization of the cervix appears more likely in OC users than in nonusers but, despite this finding, several case-control studies found a reduced risk of acute PID among OC users (182,183). In contrast, a subsequent study found no protection with OC use (184).
Whether hormonal contraceptives influence acquisition of HIV remains uncertain. The largest study concluded that overall risk was not increased by oral combination OCs or injected DMPA (185).
Table 10.7 Established and Emerging Noncontraceptive Benefits of Oral Contraceptives
|
Established Benefits |
|
Menses-related |
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Increased menstrual cycle regularity |
|
Reduced blood loss |
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Reduced iron-deficiency anemia |
|
Reduced dysmenorrhea |
|
Reduced symptoms of premenstrual dysphoric disordera |
|
Inhibition of ovulation |
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Fewer ovarian cysts |
|
Fewer ectopic pregnancies |
|
Other |
|
Reduced fibroadenomas/fibrocystic breast changes |
|
Reduced acute pelvic inflammatory disease |
|
Reduced endometrial cancer |
|
Reduced ovarian cancer |
|
Emerging Benefits |
|
Increased bone mass |
|
Reduced acne |
|
Reduced colorectal cancer |
|
Reduced uterine leiomyomata |
|
Reduced rheumatoid arthritis |
|
Treatment of bleeding disorders |
|
Treatment of hyperandrogenic anovulation |
|
Treatment of endometriosis |
|
Treatment of perimenopausal changes |
|
aOnly the low-dose EE/droperidol oral contraceptive has U.S. Food and Drug Administration approval for premenstrual dysphoric disorder treatment. |
|
From Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190(Suppl):S12, with permission. |
Health Benefits of Oral Contraceptives
Oral contraceptives have important health benefits (Table 10.7). These include contraceptive and noncontraceptive benefits 182).
Contraceptive Benefits
Oral contraceptives provide highly effective contraception and prevent unwanted pregnancy, an important public health problem. Where safe abortion services are not available, women seek unsafe services and risk death from septic abortion. Combination OCs block ovulation and offer marked protection from ectopic pregnancy. Risk of ectopic pregnancy in a woman taking combination OCs is estimated to be 1/500 of the risk of women not using contraception; progestin-only OCs appear to increase risk of ectopic pregnancy (186).
Noncontraceptive Benefits
As noted earlier, OC use produces strong and lasting reduced risk for endometrial and ovarian cancer. In addition, protection was found for women with known hereditary ovarian cancer. Any past use of OCs conferred a 50% reduction in ovarian cancer risk when women with this history who took OCs were compared with their sisters as controls (OR, 0.5; 95% CI, 0.3–0.8). Protection increased with increasing duration of use (187). The mechanism of action of OCs in the prevention of ovarian cancer is unknown but may involve selective induction of apoptosis (programmed cell death). Macaques treated with EE plus levonorgestrel or levonorgestrel alone showed an increase in the proportion of ovarian epithelial cells in apoptosis in comparison with animals fed a diet containing no hormones (188).
Other documented benefits of OC use include reduction of benign breast disease (189). Use of OCs helps relieve dysmenorrhea (166). Oral contraceptives offer effective therapy for women with menorrhagia and dysfunctional uterine bleeding (163).
All combination OCs offer some protection from functional ovarian cysts, but this is dose related (190). Although OCs may prevent cyst formation, they are not helpful in treating large functional ovarian cysts and should not be used for this purpose (191). OCs appear to decrease the risk of developing leiomyomata (192).
All combination OCs reduce circulating androgen levels and usually improve acne. Three OCs were specifically FDA approved for acne treatment: the norgestimate/EE triphasic (TriCyclen), the norethindrone/EE multiphasic(Estrostep), and the 20 μg EE /3 mg droperidol OC.
There is some evidence that OC use is protective against colon cancer. A case-control study in Italy comparing women with colon cancer with controls found a 37% reduction in colon cancer and a 34% reduction in rectal cancer (colon cancer OR, 0.63; 95% CI, 0.45–0.87 and rectal cancer OR, 0.66; 95% CI, 0.43–1.01). Longer use produced more protection against colon cancer (193). Results of the U.S. Nurses Health Study disclosed some degree of protection. Women who used OCs for 96 months or more had a 40% lower risk of colorectal cancer (RR, 0.60; 95% CI, 1.15–2.14) (194). A large case-control study from Wisconsin found most of the benefit limited to women who were less than 14 years since discontinuing OCs (195). The mechanism of protection has not been identified.
Fertility after Oral Contraceptive Use
After discontinuing OCs, return of ovulatory cycles may be delayed for a few months. Women who have amenorrhea more than 6 months after discontinuation of OCs should undergo a full evaluation because of the risk for prolactin-producing pituitary tumors. This risk is not related to OC use but rather to the probability that the slow-growing tumor was already present and produced menstrual irregularity, prompting the patient to take OCs (196).
Sexuality
In a study that recorded all episodes of female-initiated sexual behavior throughout the menstrual cycle, an increase in sexual activity at the time of ovulation was noted. This increase was not present in women who were taking OCs (197). No other study appears to have addressed female initiated sexual activity and OC use. A 2003 study from Spain studied sexual desire in a comparative cohort of women using OCs and a cohort using IUDs. Sexual desire decreased over time, but was not affected by the contraceptive method (198). OCs containing the new progestin drospirenone are reported to improve sexual functioning and feelings of well-being (199,200).
Teratogenicity
A meta-analysis of 12 prospective studies, including 6,102 women who used OCs and 85,167 women who did not, revealed no increase in overall risk for malformation, congenital heart defects, or limb reduction defects with the use of OCs (201). Progestins were used to prevent miscarriage. A large study compared women showing signs of threatened abortion who were treated with progestins (primarily oral medroxyprogesterone acetate) with women who were not treated. The rate of malformation was the same among the 1,146 exposed infants as among the 1,608 unexposed infants (202). Conversely, estrogens taken in high doses in pregnancy can induce vaginal cancer in female offspring exposed in utero. A recent literature search revealed no recent reports linking teratogenicity to hormonal contraception.
Interaction of Oral Contraceptives with Other Drugs
Some drugs (e.g., rifampin) reduce the effectiveness of oral contraceptives; conversely, OCs can augment or reduce the effectiveness of other drugs (e.g., benzodiazepines) (203,204). Perhaps of greatest clinical significance are six antiepileptic drugs: phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate, and topiramate (205). These drugs and the antibiotic rifampin all induce synthesis of liver cytochrome P450 enzymes and reduce plasma levels of EE in women taking OCs, increasing the likelihood of contraceptive failure. Some antiseizure agents have no effect on the levels of contraceptive steroids in the blood. These include valproic acid, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide, ethosuximide, and the benzodiazepines (205). St. John’s wort induces cytochrome P450 and is reported to increase clearance of EE and norethindrone (206). The antifungal agents griseofulvin, ketoconazole, and itraconazole induce these hepatic enzymes and may reduce OC efficacy (204). Ampicillin and tetracycline were implicated in numerous case reports of OC failure. They kill gut bacteria (primarily clostridia) that are responsible for hydrolysis of steroid glucuronides in the intestine, which allows reabsorption of the steroid through the enterohepatic circulation. It was not possible to demonstrate reduced plasma levels of EEoverall or differences in pregnancy rates (207). Some individuals do experience reduced EE plasma levels when on tetracyclines or penicillins; it is best to advise women taking OCs who will be treated with antibiotics to use condoms as well (208). Certain drugs appear to increase plasma levels of contraceptive steroids. Ascorbic acid (vitamin C) and acetaminophen may elevate plasma EE, as do the antiretrovirals efavirenz and atazanavir/ritonavir (7).
An example of OCs affecting the metabolism of other drugs is seen with diazepam and related compounds. Oral contraceptive use reduces the metabolic clearance and increases the half-life of those benzodiazepines that are metabolized primarily by oxidation: chlordiazepoxide, alprazolam, diazepam, and nitrazepam. Caffeine and theophylline are metabolized in the liver by two of the P450 isozymes, and their clearance is reduced in OC users. Cyclosporine is hydroxylated by another of the P450 isozymes, and its plasma concentrations are increased by OCs. Plasma levels of some analgesic drugs are decreased in OC users. Salicylic acid and morphine clearances are enhanced by OC use; therefore, higher doses could be needed for adequate therapeutic effect. Clearance of ethanol may be reduced in OC users.
The interactions of antiretroviral drugs with contraceptive steroids are complex. Some of the drugs increase plasma steroid levels and some reduce them. A complete list of interactions is available in the Centers for Disease Control and Prevention’s “U.S. Medical Eligibility for Contraception” (7).
Oral Contraceptives and Clinical Chemistry Alterations
Oral contraceptives have the potential to alter a number of clinical laboratory tests as a result of estrogen-induced changes in hepatic synthesis; however, a large study comparing OC users with pregnant and nonpregnant controls found minimal changes (209). Hormone users took a variety of OCs containing 50 to 100 μg of estrogen, higher doses than are used today. Compared with nonpregnant women who were not using OCs, the OC users had an increase in T4 that is explained by increased circulating thyroid-binding protein, no change in creatinine and globulin levels, slight reduction in mean fasting glucose values and serum glutamic oxaloacetic transaminase, and a decrease in total bilirubin and alkaline phosphatase.
Choice of Oral Contraceptives
Recently introduced OCs include those containing drosperidol, more preparations with only 20 μg of EE, new multiphasic preparations, cyclic OCs with 24 days of active medication and 4 days of either placebo or 10 μg of EE, and extended-cycle and continuous cycle preparations plus branded generic versions of most OCs. A combination OC containing estradiol valerate with a new progestin, dienogest, was approved in 2010. There is new evidence that 20 μg EE pills offer reduced risk for venous thrombosis (130). An approach to OC selection for new patients is to begin with a 20 μg EE combination and then adjust depending on the patient’s symptoms after the first 2 to 3 months. As reported in a large systematic review of 20 μg EE OCs compared to 30 to 35 μg EE pills, women taking the lower dose OCs more often report changes in vaginal bleeding, episodes of irregular bleeding and heavy bleeding, and more amenorrhea (210). If a 20 μg pill is offered, the patient should understand that bleeding may be a problem and that she should return if this persists and try a different OC rather than stop the pill. The progestin component may become more important in determining cycle control when 20 μg EE is used. A comparison of 20 μg EE OCS, one containing 100 μg of levonorgestrel, the other with 1 mg of norethindrone acetate (NEA) found the NEA to have about twice as many days of unscheduled vaginal bleeding during the first 3 months, a critical time period for new users, which might be expected to lead to discontinuation (211). In a three-way trial, the 35-μg EE/norgestimatetriphasic OC (Tri-Cyclen) was compared with two 20-μg EE pills, one containing 100 μg of levonorgestrel (Alesse), the other containing 150 μg desogestrel, followed by 2 hormone-free days and 5 days of 10 μg EE per day (Mircette) (212). Contraceptive efficacy was not significantly different. In the first two pill cycles more women taking Alesse had breakthrough bleeding and bleeding in the second half of the cycle than those taking the other two OCs in the first two cycles, but thereafter there was little difference. Women taking the higher estrogen Tri-Cyclen consistently experienced more frequent estrogenic side effects—bloating, breast tenderness, and nausea—than did women taking either 20-μg EE OC. These authors concluded that for the specific OCs evaluated, changing to either one of the 20 μg preparations would be beneficial.
For the average patient, the first choice of preparation for contraceptive purposes is a very low estrogen OC (20 μg EE) unless there are other considerations, for example, previous pregnancy while taking the pill.Patients with persistent break-through spotting or bleeding could be offered a pill with the same low estrogen dose, but a more potent progestin, for example levonorgestrel.Patients with apparent weight gain from fluid retention while taking OCs, or with hirsutism or acne that did not respond to other OCs, may benefit from a change to the drospirenone/EE pill. The lower estrogen drospirenone combination is FDA approved for treatment of PMDD and should be considered for women with these symptoms who want hormonal contraception. Women with acne often benefit from the reduction in circulating testosterone that occurs with all combination OCs. Women who experience continuing pelvic pain, dysmenorrhea, or other menstrual triggered symptoms or who simply prefer fewer menstruations may be offered an extended-cycle or continuous cycle-OC regimen.
Alternative Routes for Hormonal Contraception
The OrthoEvra patch and the NuvaRing both provide combinations of ultrapotent progestins with EE. Both patch and ring provide almost constant low levels of the contraceptive steroids that are less than the peak levels seen with OCs. Both offer greater convenience to the user, which improves compliance. The patch has a surface area of 20 cm2. It delivers a daily dose of 150 μg norelgestromin, the active metabolite of norgestimate, and 20 μg of EE. The patch is worn for 1 week then replaced with a new patch for 7 days, continuing for 3 consecutive weeks followed by a week with no patch. The patch was compared with a multiphasic OC containing levonorgestrel 50 to 125 μg, and 30 to 40 μg EE (Triphasil) in a randomized trial of 1,417 women (122). The overall and method failure Pearl indices were 1.24 and 0.99 pregnancies per 100 woman-years in the patch group and 2.18 and 1.23 in the OC group, respectively, numerically less in the patch group but not statistically significant. Patch users had more breakthrough bleeding or spotting in the first two cycles, but thereafter this did not differ from OC users. Patch users reported more breast discomfort, dysmenorrhea, and abdominal pain than the OC users, but other adverse events were uncommon and did not differ. Perfect compliance was reported for 88.2% of patch users' cycles versus 77.7% of the pill users' cycles (p <.001). Pregnancy risk with the patch appears to be higher for women weighing more than 90 kg.
The NuvaRing is 54 mm in outer diameter and has a cross section of 4 mm. It delivers daily doses of 120 μg of etonogestrel, the active metabolite of desogestrel, with 15 μg of EE, and thus is the lowest estrogen combination hormonal method available in the United States. The soft, flexible ring is worn in the vagina for 3 weeks, and then removed for 1 week, after which time a new ring is inserted. If inserted on the first day of menstruation, no back up method of contraception is needed. It can be inserted on days 2 to 5 and used with a backup method such as condoms for the first week. In a pharmacokinetic study comparing the ring with a combination OC containing 150 μg of desogestrel and 30 μg of EE, maximum blood levels of EE with the ring were about one-third of those seen with the OC, and the etonogestrellevel was about 40% of that produced by the OC. Despite these findings, ovulation was inhibited in all women studied (213). Women wearing the ring are reported to have fewer days of irregular bleeding or spotting than women taking an OC with 150 μg of levonorgestrel and 30 μg of EE (214). A large study found a total pregnancy rate of 1.18 (95% CI, 0.73–1.80) per 100 woman-years and 0.77 (0.37–1.40) pregnancies per 100 woman-years with perfect use (214). Some women prefer to remove the ring for intercourse, although this is not necessary. It should be reinserted within 3 hours to avoid loss of efficacy.
Patch and Ring and Thrombosis
Since both methods provide constant low blood levels of EE, it was hoped that this might reduce risk for thrombosis. The FDA took the unusual step of issuing a “black box warning” for the EE/norelgestromin patch after several thrombosis cases were reported, and a small study of pharmacodynamics was interpreted as showing higher mean EE blood levels for the patch than with the oral route of administration. A small crossover study found increased activated protein C (APC) resistance when women were changed from a 30 μg EE/150 μg desogestrel pill to either the patch or the EE/etonogestrelring. This was interpreted as prothrombotic (215). In another study, women on a variety of OCs had baseline measurement of APC resistance, and protein S. The patients were then switched either to the patch or to the ring. Those moving to the patch had changes in laboratory parameters that could be interpreted as prothrombotic, while those moved to the ring showed an improvement in the same studies, theoretically reducing the risk of clotting (216).
Three databased epidemiologic studies looked at thrombosis in patch users compared to oral contraception. The first found no difference, but two subsequent studies did find risk. One study found an overall doubling of the risk of deep vein thrombosis when patch users were compared to users of an OC containing 30 μg EE/150 μg levonorgestrel, but the risk estimate was of borderline statistical significance and disappeared when the analysis was restricted to women aged 39 or less (217). After publication of this study the FDA issued a new document for consumers suggesting that women concerned about thrombosis and considering the patch discuss the issue with their physicians (218).
No similar FDA warnings were issued about the ring. There are two case reports in the world literature of venous thrombosis with the ring. Both were women in their 30s who sustained cerebral venous thrombosis (219,220). The authors of the fist report note that several other thrombosis cases in women using the ring were reported to Health Canada (220). It is best to assume that the ring has the same risk for thrombosis as the other combination hormonal contraceptives and to counsel women about risk in the same way.
Injectable Hormonal Contraceptives
Depomedroxyprogesterone Acetate
DMPA, a suspension of microcrystals of a synthetic progestin, was approved for contraception in 1992. A single 150-mg intramuscular dose will suppress ovulation in most women for 14 weeks or longer (221). The regimen of 150 mg every 3 months is highly effective, producing pregnancy rates of about 0.3 per 100 women per year. Probably because of the high blood levels of the progestin, efficacy appears not to be reduced by administration of other drugs and is not dependent on the patient’s weight. Women treated with DMPA experience disruption of the menstrual cycle and have initial spotting and bleeding at irregular intervals. Eventually, total amenorrhea develops in most women who take DMPA; with continued administration, amenorrhea develops in 50% of women by 1 year and in 80% by 3 years (Fig. 10.8).
Figure 10.8 Bleeding pattern and duration of use of depomedroxyprogesterone acetate (DMPA): percentage of women who have bleeding, spotting, or amenorrhea while taking DMPA 150 mg every 3 months. (From Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing medroxyprogesterone acetate administered as an intramuscular injection once every 90 days. Fertil Steril 1973;24:331–339, with permission.)
The most important medical reason women discontinue use of DMPA and other progestin-only methods is persistent irregular vaginal bleeding. A variety of medications are used to stop this bleeding. Many are effective in terminating individual bleeding episodes, but a systematic review concluded that none improved continuation rates long term (222). New approaches include mifepristone and low-dose doxycycline. Mifepristone is of interest because irregular bleeding with DMPA was related to the down-regulation of endometrial estrogen receptors. Treatment with 50 mg of mifepristone every 2 weeks increases endometrial estrogen receptors and reduces breakthrough bleeding in new users of both DMPA and the levonorgestrel progestin implant (223). Another line of investigation concerns endometrial matrix metalloproteinase, which appears to play a regulatory role in the breakdown of the endometrium to produce normal menstruation. Treatment with doxycycline inhibits matrix metalloproteinase production in the endometrium in women after insertion of levonorgestrel subdermal implants (224). Five-day courses of either mifepristone 25 mg twice a day for one day, followed by EE 20 μg per day for 4 days, or doxycycline 20 mg twice a day for 5 days, reduced bleeding days by about 50% when compared to placebos during a 6-month randomized trial in women treated for prolonged or frequent bleeding occurring with etonogestrel subdermal implants (225). Capsules of 20 mg doxycycline are sold in the United States for treatment of periodontal disease.
DMPA use is commonly associated with weight gain, and that is one of the principal reasons women discontinue use. A large study is representative of the literature. Three cohorts of women who chose their method of contraception were followed for 36 months with measurements of weight and body fat. DMPA users gained an average of 5.1 kg. The cohort using OCs over the same interval gained only 1.47 kg, slightly less than the 2.05 kg gained by the cohort not using any hormonal contraception. Total body fat increased 4.14 kg in the DMPA cohort, while the increase in the OC users was 1.9 kg, only slightly more than the 1.17 kg in the nonhormonal contraceptive cohort. Many women were followed for 2 years after discontinuing DMPA. Those who chose nonhormonal methods after discontinuing DMPA lost a mean of 0.42 kg each 6 months. Those who chose to use oral contraceptives gained a mean of 0.43 kg each 6 months during the follow-up interval (226).
Weight gain during the first 6 months and self-reporting of increased appetite are strongly predictive of continued weight gain. Women who gained less than or equal to 5% of body weight in the first 6 months gained a mean of 2.49 kg by 36 months, while those who gained more than 5% by 6 months gained a total mean of 11.08 kg by 36 months (227). Studies are needed of interventions to prevent the weight gain. At minimum, women considering DMPA need to know the possibility of significant weight gain and be advised to avoid calorie-dense foods and weigh themselves regularly. Ideally they should be weighed when they return for subsequent injections so they can be counseled about the need for avoiding further gain. Women who gain 5% of body weight by 6 months should consider other contraceptive options.
DMPA persists in the body for several months in women who used it for long-term contraception, and return to fertility may be delayed. It is reassuring that 70% of former users desiring pregnancy conceive within 12 months, and 90% conceive within 24 months after terminating DMPA use (228).
Safety
DMPA suppresses ovarian estrogen production. Prospective studies demonstrated bone loss during DMPA therapy, with recovery of bone mass after DMPA use is discontinued (229). Similar bone loss and then recovery occurs with lactation. Adolescents are of special concern because they normally gain bone mass; most of adult bone mass is attained by age 20. Estrogen injections prevent the bone loss and allow adolescent women to gain bone density despite use of DMPA (230). A long-term study in adolescents documented bone density loss and confirmed recovery of lumbosacral bone mineral density to baseline by 60 weeks after discontinuation of DMPA and significant gain above baseline by 180 weeks. Recovery of density at the hip was slower, 240 weeks to significant gain (231). A systematic review of DMPA clinical trials could find no studies where fracture was an outcome, so whether long-term use leads to fractures is still not known (232). The FDA black box warning added to DMPA labeling proposes that DMPA treatment be limited to 2 years at a time, unless the patient has no other good options for contraception. For many women, especially in third world countries, DMPA is often the only option for highly effective contraception because it is inexpensive and easy to administer. The issue should be discussed with women who are considering DMPA, but DMPA should not be routinely discontinued after 2 years unless the patient wants to conceive or wants to change to another contraceptive method for other reasons.
The effect of DMPA on plasma lipids is inconsistent; DMPA users appear to have reduced total cholesterol and triglyceride levels, slight reduction in HDL cholesterol, and no change or slight increase in LDL cholesterol, all of which are consistent with a reduction in circulating estrogen levels. In some studies, the decrease in HDL and increase in LDL are statistically significant, although the values remain within normal ranges (233). DMPA is not associated with myocardial infarction. Glucose tolerance tests disclose a small elevation of glucose in DMPA users.
There is no change in hemostatic parameters, with the exception that antithrombin III levels are sometimes reduced with chronic therapy (233). Venous thrombosis and thromboembolism have occurred in women on DMPA, but this is very rare (234). As noted earlier, large epidemiologic studies have not found DMPA to be associated with thrombosis (130). Thrombotic episodes occurred in elderly women with advanced cancer who were treated with a variety of agents, including DMPA and tamoxifen (235). Another episode occurred in a woman with a cerebral metastasis from breast cancer (236). Such patients are at high risk for thrombosis regardless of the use of DMPA. Two cases of retinal vein thrombosis were reported. Both women were hypertensive and one of them smoked cigarettes (237).
DMPA is not associated with teratogenesis (238). Nor is it associated with affective disorders or mood changes (239).
DMPA and Lactation
There is widespread support for use of DMPA during lactation when the DMPA is initiated at or after 6 weeks postpartum. There is good evidence that neither infant growth nor lactation is impaired by DMPA or progestin-only oral contraceptives (240). There is continued controversy as to how early DMPA should be given after delivery. Because lactation occurs in response to falling maternal estrogen and progesterone levels after birth, administration of DMPA in the first few days theoretically might interfere with the initiation of lactation. There is concern about the possible neonatal effects of the progestin, but investigators were unable to demonstrate the presence of DMPA or its metabolites in the urine of infants whose mothers received DMPA or any other suppression of reproductive hormones (240). In the United States, DMPA is commonly started at the time of hospital discharge, 48 to 72 hours after delivery. There is urgent need for controlled trials of immediate DMPA compared to other contraceptive options to determine whether this practice has an adverse effect on the initiation of lactation. The “U.S. Medical Eligibility Criteria for Contraceptive Use 2010” considers DMPA use prior to 1 month postpartum as category 2: the benefit is thought to exceed the theoretical risk (7).
DMPA and Neoplasia
Use of DMPA is not associated with cervical cancer (241). Neither is it associated with ovarian cancer (242). Risk of endometrial cancer is substantially reduced by past use of DMPA (243). A large study found no increase in breast cancer risk among DMPA users (244).
Benefits
DMPA has many of the noncontraceptive benefits of combination oral contraceptives (245). Decreases in anemia, PID, ectopic pregnancy, and endometrial cancer are reported. DMPA is reported to benefit women with sickle cell disease.
Subcutaneous DMPA
Depo-subQ Provera 104, a lower-dose DMPA preparation for subcutaneous administration, received FDA approval in 2005. The total dose is 30% less than that of the older DMPA intramuscular preparation. Because the dose is administered subcutaneously, blood levels are adequate to completely suppress ovulation for more than 13 weeks in all subjects tested, with a mean time of 30 weeks for return to ovulatory function (246). Contraception efficacy is superb, with no pregnancies in a total of 16,023 woman-cycles in the phase III studies done in the United States (247). Blood levels were lower in very obese women but still sufficient to completely suppress ovulation. The weight gain reported with the 150 mg DMPA remains a problem with the lower dose DMPA. Mean weight gain was 1.59 kg in the first year of use. Loss of bone density was observed with this dosage of DMPA, as with the larger intramuscular dose.
Once-a-Month Injectable
A once-a-month injectable contraception containing only 25 mg of DMPA in combination with 5 mg of the long-acting estrogen estradiol cypionate was briefly available in the United States, but was withdrawn by the manufacturer because of a packaging problem (248). Originally developed by the World Health Organization, it is described as CycloFem or CycloProvera in the literature and was marketed in the United States as Lunelle (249). Given once a month, this combination produces excellent contraceptive effects. Monthly withdrawal bleeding is similar to a normal menses, leading to high continuation rates despite the need for a monthly injection. Monthly injectable combinations continue to be widely used outside the United States.
Subdermal Implants
Three progestin-releasing subdermal implants systems are in use worldwide: Jadelle™, Sino-Implant II™, and Implanon™. All three offer long-acting contraception that requires no continuing action by the user and are, hence, forgettable. All are very highly effective and have no serious risk. Each can produce irregular bleeding, which is the principal reason for discontinuation. The mechanism of action is suppression of ovulation in the initial years of use, plus thickening of the cervical mucus that prevents sperm penetration.
The original levonorgestrel implant (Norplant™) six-rod system was replaced with a two-rod version (Jadelle™), which is identical in its release rate and clinical activity to Norplant™ and is easier to insert and remove (250). Jadelle™ is widely used around the world. It is approved by the FDA but is not marketed in the United States. It is approved for 5 years. The Sino-Implant II™ is a less expensive two-rod levonorgestrel system manufactured in China and available in several countries. It is effective for 4 years (251). Implanon™ is the only subdermal implant sold in the United States. It is a single rod system containing etonogestrel, the active metabolite of desogestrel.Because of the greater potency of etonogestrel, the single rod releases enough to completely inhibit ovulation for at least 3 years. The single-rod system is most easily inserted and removed. In a United States trial, mean time for insertion was only a half minute and removal required a mean time of 3.5 minutes (252).
A systematic review of 29,972 women and 28,108 woman-months of follow-up with Norplant™, Jadelle™, or Implanon™ found no differences in pregnancies or continuation rate over 4 years. No pregnancies occurred in any of the trials. There were no differences in side effects or adverse events. The most common side effect was unpredictable vaginal bleeding (253).
In 923 women followed for 20,648 treatment cycles in 11 studies there were no pregnancies with Implanon™ in place. Six pregnancies occurred within 14 days of removal of the devices. When these are included, as required by FDA, the cumulative Pearl index was 0.38 pregnancies per 100 woman-years at 3 years (254). Irregular bleeding was a problem, but occurred most frequently in the first 90 days of use and decreased over time. In a randomized comparison with the six-rod Norplant™, Implanon™ users had less frequent vaginal bleeding, but more became amenorrheic (255). Other commonly reported side effects are headache, weight gain, acne, breast tenderness, and emotional lability (254). Only 2.3% of subjects discontinued because of weight gain. Most women can use Implanon™. The US MEC lists only a small number of conditions as category 3, and these are based on theoretical concerns without actual evidence of harm (7). Insertion in the immediate postpartum period appears to have no adverse effects on mother or infant (256).
Bone density is not affected by Implanon™, probably because ovarian follicular activity is not totally suppressed and estradiol synthesis continues (257). Enlarged follicular ovarian cysts are common during the first year of use of Jadelle™ or Implanon™ and usually resolve spontaneously (258).
A comparative study of coagulation and fibrinolytic factors in users of etonogestrel and levonorgestrel implants showed no significant changes from baseline, with the exception of a modest increase in antithrombin III (ATIII)and a small decrease in factor VII activity, changes that might reduce coagulability. Lipid levels and liver function studies were not changed, with the exception of small elevations of bilirubin, with somewhat more observed in levonorgestrel users than etonogestrel users (259). Another study of hemostatic factors found modest decreases in many measurements, within the range of normal, and a modest reduction in the generation of thrombin in users of the etonogestrel implant (260). Taken together these studies provide considerable reassurance that the progestin implants do not increase thrombosis risk. With several million women now using the implants, there are no published studies linking either implant to venous thrombosis or myocardial infarction. Strokes were reported in users of Norplant™, but case reports do not allow calculation of whether risk is increased from baseline. Attempts to determine stroke risk of users compared to nonusers was inconclusive because so few stroke patients or controls were using the implant (261).
Figure 10.9 Emergency contraception: pregnancy rates by treatment group and time since unprotected coitus. LNG, levonorgestrel, 0.75 mg × 2. Yuzpe method is ethinyl estradiol, 0.100 mg plus levonorgestrel 0.50 mg × 2, 12 hours later. (From Randomized controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Task Force on Postovulatory Methods of Fertility Regulation. Lancet 1998;352:430 [modified from Table 3], with permission.)
Emergency Contraception
Postcoital use of sex steroids to prevent pregnancy began in the 1960s with high-dose estrogen taken daily for 5 days (262). This was replaced with the combination OC containing EE and levonorgestrel for greater convenience (263). More recently levonorgestrel alone became the method of choice after the World Health Organization showed its superiority in a large randomized trial with 1,998 women.The pregnancy rate was 3.2% with the EE/levonorgestrel method and only 1.1% with levonorgestrel alone (RR for pregnancy, 0.32; 95% CI, 0.18–0.70) for women treated within 72 hours of intercourse. Nausea and vomiting occurred much less frequently with levonorgestrel alone (23.1% vs. 50.5%, and 5.6% vs. 18.8%, respectively) (264). The efficacy of both methods declined as the time after intercourse increased. But even after 72 hours, the pregnancy rate with the levonorgestreltreatment was only 2.7% (Fig. 10.9) (265). A single dose of 1.5 mg levonorgestrel is just as effective as two doses of 0.75 mg, has no more side effects, and is more convenient for the patient. Both dosing regimens are FDA approved. Because levonorgestrel is almost as effective at 3 to 5 days after intercourse, the World Health Organization recommends 1.5 mg of levonorgestrel as a single dose, given up to 120 hours after intercourse (266). Research suggests that the main mechanism of action is delay of ovulation. Noe and colleagues established that levonorgestrel works only if it is administered prior to the day of ovulation (267). No pregnancies occurred to 87 women who received levonorgestrel from 1 to 5 days prior to the day of ovulation. Seven pregnancies occurred to 35 women treated on the day of ovulation or later. Postcoital levonorgestrel is not an abortifacient because it is effective only when taken before ovulation.
Levonorgestrel alone is safer than the estrogen-containing preparations. There were several case reports of thrombotic events after use of the estrogen/levonorgestrel combination emergency contraception (268). No such complications with levonorgestrel alone were published.
Antiprogestins
The antiprogesterone mifepristone (RU486) is highly effective for postcoital contraception. The usual abortifacient dose is 200 mg, but a dose of only 10 mg is effective for emergency contraception. In one study, 2,065 women were randomized to mifepristone, 10 mg, or levonorgestrel, two doses of 0.75 mg, including women up to 120 hours after intercourse (269). The crude pregnancy rate was 1.3% for mifepristone and 2.0% for levonorgestrel (p = .46). Side effects were the same, and both methods were judged highly acceptable by the patients. Mifepristone is not being developed for this use and is not available at the appropriate dose.
Ulipristal, a new progesterone-receptor modulator developed at the U.S. National Institutes of Health was approved by the FDA and the European Union for emergency contraception to 120 hours after intercourse. It is at least as effective as levonorgestrel 1.5 mg up to 72 hours, and may be superior between 72 and 120 hours (270). When Ulipristal is administered prior to the luteinizing hormone (LH) peak, it delays rupture of the preovulatory follicle for 5 days or more, which may be its primary mechanism of action (271). Ulipristal is primarily metabolized by the CYP3A4 enzyme system; hence, patients on drugs such as barbiturates, rifampin, and several of the anticonvulsants may have reduced protection from pregnancy with it. It is a prescription drug, while levonorgestrel 1.5 mg is available over the counter in the United States for women 18 years of age and over.
The Copper Intrauterine Device for Emergency Contraception
Postcoital insertion of a copper IUD was first reported by Lippes et al. in 1976 (272). In initial trials the device was inserted within 7 days of intercourse and was more effective than steroids for emergency contraception. Studies included women only within 5 days from intercourse. The multicenter trial by Wu and colleagues is an example of the superb efficacy offered by the copper T380A (273). Of 1,893 women who returned for a follow-up visit, there were no pregnancies within 1 month of IUD insertion. Efficacy for emergency contraception is 100% when the device is inserted up to 5 days after intercourse, and almost 100% up to 7 days after intercourse (273). An added benefit was that 94% of the patients were continuing with the IUD at the 12-month follow-up. There were no uterine perforations. Zhou and colleagues reported similar excellent results in a large study with a different copper device, the Multiload Cu-375 IUD (274). In much of the world, copper IUDs are very inexpensive. Even in the United States where IUDs are costly, the benefit to the patient of extremely effective emergency contraception, and long-term contraception with one intervention, makes emergency IUDs cost-effective. Whether the levonorgestrel IUD would work for emergency contraception is not known.
Hormonal Contraception for Men
The same negative feedback of sex steroids that blocks ovulation in women suppresses spermatogenesis in men, but it will produce loss of libido and potentially extinguish sexual performance. The principle was first demonstrated in 1974 using oral estrogen and methyl testosterone (275). Testosterone given alone can suppress sperm production to very low levels while maintaining normal libido and sexual performance. Over many years investigators have studied long-acting testosterone salts for male contraception (276). Ethnicity is an important predictor of efficacy of sperm suppression with testosterone therapy. Asian men virtually always achieve azoospermia or oligospermia when treated with testosterone undecanoate (TU) monthly injections, whereas only 86% of Caucasian men achieved azoospermia or oligospermia or with similar testosterone regimens (277). In a Chinese trial, 1,045 men were treated with monthly TU 500 mg. Only 4.8% failed to suppress to a sperm count less than 1 × 106 per mL. The cumulative pregnancy rate was only 1.1 per 100 men at 30 months (278). In Caucasian populations testosterone was combined with progestins to further suppress gonadotropin and improve efficacy. In an important trial with Caucasian men, etonogestrel subdermal implants and TU injections were compared to placebo implants and injections. Only 3% failed to suppress to a sperm count of less than 1 × 106 (279). Side effects that were more common in the medicated group than placebo included acne, night sweats, libido changes (usually increased), and weight gain. Theoretical risks include atherogenesis and prostate cancer but long-term trials will be needed to determine if risk is real. Liver cancer is a concern with long-term androgen therapy (280).
Sterilization
Surgical sterilization is the most common method of fertility control used by couples, with more than 180 million couples having tubal sterilization or vasectomy (4,281) Laparoscopic and hysteroscopic techniques for women and vasectomy for men are safe and readily available throughout the United States. The mean age at sterilization is 30 years. Age younger than 30 years when sterilized, conflict within the marriage, and divorce and remarriage are predictors of sterilization regret, which may lead to a request for reversal of sterilization (281).
Female Sterilization
Hysterectomy is no longer considered for sterilization because morbidity and mortality are too high in comparison with tubal sterilization. Vaginal tubal sterilization, which was associated with occasional pelvic abscess, is rarely performed in the United States. Five procedures are used in the United States.
1. Tubal sterilization at the time of laparotomy for a cesarean delivery or other abdominal operation
2. Postpartum minilaparotomy soon after vaginal delivery
3. Interval minilaparotomy
4. Laparoscopy
5. Hysteroscopy
Postpartum tubal sterilization at the time of cesarean delivery adds no risk other than a slight prolongation of operating time; cesarean birth poses more risk than vaginal birth, and planned sterilization should not influence the decision to perform a cesarean delivery. Minilaparotomy can be performed in the immediate postpartum state. The uterus is enlarged, and the fallopian tubes lie in the midabdomen, easily accessible through a small, 3- to 4-cm subumbilical incision.
Figure 10.10 Pomeroy technique for tubal sterilization.
Interval minilaparotomy, first described by Uchida, was rediscovered and popularized in the early 1970s in response to an increased demand for sterilization procedures and a simpler alternative to laparoscopy (282). Still widely practiced in lower resource settings, it is uncommon in the United States because of widespread availability of the endoscopic techniques.
Surgical Technique
The procedure usually elected for tubal sterilization by laparotomy is the Pomeroy or modified Pomeroy technique (Fig. 10.10). In the classic Pomeroy procedure, a loop of tube is excised after ligating the base of the loop with a single absorbable suture. A modification of the procedure is excision of the midportion of the tube after ligation of the segment with two separate absorbable sutures. This modified procedure has several names: partial salpingectomy, Parkland Hospital technique, separate sutures technique, and modified Pomeroy. In the Madlener technique, now abandoned because of too many failures, a loop of tube is crushed by cross-clamping its base, ligated with permanent suture, and then excised. Pomeroy and partial salpingectomy procedures have failure rates of 1 to 4 per 1,000 cases (281). In contrast, pregnancy is almost unheard of after tubal sterilization by the Irving or Uchida methods. In the Irving method, the midportion of the tube is excised, and the proximal stump of each tube is turned back and led into a small stab wound in the wall of the uterus and sutured in place, creating a blind loop. With the Uchida method, a saline-epinephrine solution (1:1,000) is injected beneath the mucosa of the midportion of the tube, separating the mucosa from the underlying tube. The mucosa is incised along the antimesenteric border of the tube, and a tubal segment is excised under traction so that the ligated proximal stump will retract beneath the mucosa when released. The mucosa is then closed with sutures, burying the proximal stump and separating it from the distal stump. In Uchida’s personal series of more than 20,000 cases, there were no pregnancies (282).
Laparoscopy
Laparoscopy is the most common method of interval sterilization in the United States. In the standard laparoscopy technique, the abdomen is inflated with a gas (carbon dioxide) through a special needle inserted at the lower margin of the umbilicus (281). A hollow sheath containing a pointed trocar is then pushed through the abdominal wall at the same location, the trocar is removed, and the laparoscope is inserted into the abdominal cavity through the sheath to visualize the pelvic organs. A second, smaller trocar is inserted in the suprapubic region to allow the insertion of special grasping forceps. Alternatively, an operating laparoscope that has a channel for the instruments can be used; thus, the procedure can be performed through a single small incision. Laparoscopic sterilization is usually performed in the hospital under general anesthesia but can be performed under local anesthesia with conscious sedation. Overnight hospitalization for laparoscopy is rarely needed.
Open Laparoscopy
Standard laparoscopy carries with it a small but definite risk for injury to major blood vessels with insertion of the sharp trocar. With the alternative technique of open laparoscopy, neither needle nor sharp trocar is used; instead, the peritoneal cavity is opened directly through an incision at the lower edge of the umbilicus. A special funnel-shaped sleeve, the Hassan cannula, is inserted, and the laparoscope is introduced through it.
Techniques for Tubal Closure at Laparoscopy
Sterilization is accomplished by any of four techniques: bipolar electrical coagulation, application of a small Silastic rubber band (Falope ring), the plastic and metal Hulka clip, or the Filshie clip. The Filshie clip, first introduced into the United States in 1996 is used extensively in the United Kingdom and Canada (283). It is a hinged device made of titanium with a liner of silicone rubber tubing. Because of its lower pregnancy rate, the Filshie clip has largely supplanted the Hulka clip (284).
Figure 10.11 Technique for bipolar electrocoagulation tubal sterilization.
In the bipolar electrocoagulation technique, the midisthmic portion of the tube and adjacent mesosalpinx are grasped with special bipolar forceps, and radiofrequency electric current is applied to three adjacent areas, coagulating 3 cm of tube (Fig. 10.11). The tube alone is then recoagulated in the same places. The radiofrequency generator must deliver at least 25 watts into a 100-ohm resistance at the probe tips to ensure coagulation of the complete thickness of the fallopian tube and not just the outer layer; otherwise, the sterilization will fail (285).
Figure 10.12 Placement of the Falope ring for tubal sterilization.
Figure 10.13 Filshie clip for tubal sterilization. (Courtesy of CooperSurgical, Inc., Trumbull, CT.)
To apply the Falope ring, the midisthmic portion of the tube is grasped, with tongs advanced through a cylindrical probe that has the ring stretched around it (Fig. 10.12A). A loop of tube is pulled back into the probe, and the outer cylinder is advanced (Fig. 10.12B), releasing the Silastic ring around the base of the loop of tube, producing ischemic necrosis (Fig. 10.12C). If the tube cannot be pulled easily into the applicator, the operator should stop and change to electrical coagulation rather than persist and risk lacerating the tube with the Falope ring applicator. The banded tube must be inspected at close range through the laparoscope to demonstrate that the full thickness of the tube was pulled through the Falope ring.
The Hulka clip is placed across the midisthmus, ensuring that the applicator is at right angles to the tube and that the tube is completely contained within the clip before the clip is closed. The Filshie clip is placed at right angles across the midisthmus, taking care that the anvil of the posterior jaw can be visualized through the mesosalpinx beyond the tube to ensure that the complete thickness of the tube is completely within the jaws of the clip before it is closed (Fig. 10.13).
The electric plus band or clip techniques each have advantages and disadvantages. Bipolar coagulation can be used with any fallopian tube. The Falope ring and Hulka and Filshie clips cannot be applied if the tube is thickened from previous salpingitis. There is more pain during the first several hours after Falope ring application. This can be prevented by bathing the tubes with a few milliliters of 2% lidocaine just before ring placement. Failures of the Falope ring or the clips generally result from misapplication, and pregnancy, if it occurs, is usually intrauterine. After bipolar sterilization, pregnancy may result from tuboperitoneal fistula and is ectopic in more than 50% of cases. If inadequate electrical energy is used, a thin band of fallopian tube remains that contains the intact lumen and allows intrauterine pregnancy to occur. Thermocoagulation, the use of heat probes rather than electrical current, is employed extensively in Germany for laparoscopic tubal sterilization but is little used in the United States.
Risks of Tubal Sterilization
Tubal sterilization is remarkably safe. The Collaborative Review of Sterilization (CREST) study, a 1983 review of 9,475 interval sterilizations from multiple centers in the United States, reported a total complication rate of 1.7 per 100 procedures (281). Complications were increased by use of general anesthesia, previous pelvic or abdominal surgery, history of PID, obesity, and diabetes mellitus. The most common significant complication was unintended laparotomy for sterilization after intra-abdominal adhesions were found. In another series, 2,827 laparoscopic sterilizations were performed with the Silastic band using local anesthesia and intravenous sedation (286). Only four cases could not be completed (a technical failure rate of 0.14%), and laparotomy was never needed. Rarely, salpingitis can occur as a complication of the surgery. This occurs more often with electric coagulation than nonelectric techniques. Risk of death with female sterilization was 1 to 2 per 100,000 sterilizations in the last national study that was based on data from 1979 to 1980 (281). Almost half of the deaths were from complications of general anesthesia, usually related to the use of mask ventilation. When general anesthesia is used for laparoscopy, endotracheal intubation is mandatory because the pneumoperitoneum increases the risk of aspiration. International data from the Association for Voluntary Surgical Contraception show a similar record of safety from third world programs: 4.7 deaths per 100,000 female sterilizations and 0.5 deaths per 100,000 vasectomies (287).
Table 10.8 Ten-Year Life-Table Cumulative Probability of Pregnancy per 1,000 Procedures with Different Methods of Tubal Sterilization, United States, 1978–1986
|
Unipolar coagulation |
7.5 |
|
Postpartum partial salpingectomy |
7.5 |
|
Silastic band (Falope or Yoon) |
17.7 |
|
Interval partial salpingectomy |
20.1 |
|
Bipolar coagulation |
24.8 |
|
Hulka-Clemens clip |
36.5 |
|
Total: all methods |
18.5 |
|
From Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. Am J Obstet Gynecol 1996;174:1164 [Table II], with permission. |
|
Sterilization Failure
Many “failures” occur during the first month after surgery and are the result of a pregnancy already begun when the sterilization was performed. Contraception should be continued until the day of surgery, and a sensitive pregnancy test should be routinely performed on the day of surgery. Because implantation does not occur until 6 days after conception, a woman could conceive just before the procedure and there would be no way to detect it. Scheduling sterilization early in the menstrual cycle obviates the problem but adds to the logistic difficulty. Another cause of failure is the presence of anatomic abnormalities, usually adhesions surrounding and obscuring one or both tubes. An experienced laparoscopic surgeon with appropriate instruments usually can lyse the adhesions, restore normal anatomic relations, and positively identify the tube. In some circumstances successful sterilization will not be possible by laparoscopy, and the surgeon must know before surgery whether the patient is prepared to undergo laparotomy, if necessary, to accomplish sterilization. The CREST study reported on a cohort of 10,685 women sterilized from 1978 to 1986 at any of 16 participating centers in the United States who were followed from 8 to 14 years (281). The true failure rates for 10 years obtained by the life-table method are given in Table 10.8. Pregnancies resulting from sterilization during the luteal phase of the cycle in which the surgery was performed were excluded. Of all remaining pregnancies, 33% were ectopic. The most effective methods at 10 years were unipolar coagulation at laparoscopy and postpartum partial salpingectomy, generally a modified Pomeroy procedure. Bipolar tubal coagulation and the Hulka-Clemens clip were least effective. The Filshie clip was not evaluated because it was not in use in the United States at the time. Younger women had higher risk for failure, as would be expected because of their greater fecundity.
Over the years since the CREST study began, sterilization by unipolar electrosurgery was abandoned because of the risk of bowel burns and was replaced with bipolar electrosurgery or the nonelectric methods (tubal ring, Hulka-Clemens clip, and the Filshie clip). An important later analysis of the CREST data found that bipolar sterilization can have a very low long-term failure rate if an adequate portion of the tube is coagulated.CREST study participants who were sterilized with bipolar electrosurgery from 1985 to 1987 had lower failure rates than those sterilized earlier (1978–1985). The important difference was in the application technique of the electric energy to the tubes. Women whose bipolar procedure involved coagulation at three sites or more had low 5-year failure rates (3.2 per 1,000 procedures), whereas women who had fewer than three sites of tubal coagulation had a 5-year failure rate of 12.9 per 1,000 (p = .01) (288).
Family Health International reported large randomized multicenter trials of the different means of tubal sterilization. The Filshie and Hulka clips were compared in two trials. A total of 2,126 women were studied, of which 878 had either clip placed by minilaparotomy and 1,248 had either clip placed by laparoscopy. The women were evaluated at up to 24 months (289). Pregnancy rates were 1.1 per 1,000 women with the Filshie clip and 6.9 per 1,000 with the Hulka clip at 12 months, a difference in rates that approached statistical significance (p = .06). This same group compared the Filshie clip with the Silastic tubal ring in a similar study with a total of 2,746 women, of which 915 had the devices placed at minilaparotomy and 1,831 at laparoscopy (290). Pregnancy rates at 12 months were the same for the Filshie clip and the tubal ring: 1.7 per 1,000 women. The ring was judged more difficult to apply. The Filshie clip was expelled spontaneously from the vagina by three women during the 12 months of follow-up.
Figure 10.14 Essure device for hysteroscopic sterilization. (Courtesy of Conceptus, Inc.)
Figure 10.15 Essure device with guide wire and handle. (Courtesy of Conceptus, Inc.)
Hysteroscopy
In 2002, the FDA approved Essure™, a hysteroscopic method of permanent birth control, and a second hysteroscopy method, Adiana™, was approved in 2009. Both methods can be provided in an office setting, with only local anesthesia or conscious sedation and both offer the prospect of greater safety, lower cost, and greater long-term effectiveness than the best laparoscopy methods. Essure™ is a microinsert consisting of a soft stainless steel inner coil and a dynamic nickel titanium alloy outer coil (Fig. 10.14). Soft fibers of polyethylene terephthalate run along and through the inner coil. To insert the device, a hysteroscope is introduced into the uterine cavity, which is distended with saline. The tubal ostia are visualized. The Essure™ device is inserted through the operating channel of the hysteroscope on the end of a slender delivery wire, guided into the tubal opening and advanced into the tube under direct vision (Fig. 10.15). Once in place, an outer sheath is retracted, releasing the outer coils, which expand to anchor the device in the interstitial portion of the tube. The delivery wire is detached and removed and the procedure repeated for the other tube. When properly placed, three to eight of the end coils of the microinsert are visible inside the uterine cavity. The rest are inside the fallopian tube (291,292).
The Adiana™ system consists of a catheter electrode that is guided into the interstitial portion of the fallopian tube via the operating channel of a 5-mm hysteroscope (Fig. 10.16). An array of bipolar electrodes on the catheter are used to apply radio frequency electric current for 60 seconds to achieve a temperature of 64°C, creating a superficial injury to the inner surface.
A 3.5-mm flexible cylindrical silicone matrix is deployed from the catheter into the tube at the site of the thermal lesion. The same process is repeated in the other tube. A nonionic medium such as 1.5% glycine is used to distend the uterus (293).
Essure™ and Adiana™ devices can be installed under local anesthesia in an outpatient setting. No incision is needed. A nonsteroidal anti-inflammatory drug is given 1 to 2 hours before the procedure to decrease tubal spasm. Over time fibrous tissue grows into both devices, occluding the tubes permanently. Because of this mechanism of action, these methods depend on scar formation, and women who are immunocompromised from HIV infection, medication, or chemotherapy should be advised that their success may be lower (293,294). The FDA requires a 3-month follow-up x-ray hysterosalpingography examination to document tubal occlusion for both methods. The hysterosalpingogram (HSG) for Essure™ should document bilateral placement of the devices at the uterotubal junction and a lack of peritoneal spillage of dye. Off-label and outside of the United States, plain x-ray, ultrasound, computerized x-ray tomography, and magnetic resonance imaging were used to confirm the presence and position of the Essure™ devices (295,296). The Adiana™ matrix is not radio opaque, so successful occlusion is documented only by lack of dye spillage. The patient with transcervical sterilization should continue to use a reliable method of contraception until successful occlusion is documented.
Figure 10.16 Adiana catheter as placed for tubal sterilization. (Courtesy of Hologic, Inc.)
Risks of Hysteroscopy
Adverse events or side effects were reported on the day of procedure in 3% of the initial Essure™ patients. These consisted of vasovagal responses, cramping, nausea, and vaginal spotting (297). Possible but uncommon risks of the hysteroscopic tubal sterilization methods include perforation by the device at insertion and expulsion of the device. In the initial clinical trials tubal perforation was reported in 1% of Essure™ placements. None were reported with Adiana™. There is theoretical risk of mutagenic or carcinogenic effect to the fetus from nickel alloy in Essure™ should pregnancy occur, although no such injury was reported (297). Other potential combinations with transcervical sterilization are related to the hysteroscopy procedure, not the tubal occlusion process. These include hypervolemia, injury to surrounding organs, bleeding, and infection and occur in less than 1% of cases. Excessive fluid absorbance leading to hypervolemia is more of a concern with Adiana™ and the nonionic solution that must be used to distend the uterine cavity because of the electrical energy applied. With Essure™ the distending medium is normal saline (293,294). An extensive 2009 review of the first 6 years of Essure™ use reported in publications, industry sources and the Manufacturer and User Facility Device Experience (MAUDE) database maintained by the FDA, found 20 reports of pelvic pain, which in some cases responded to hysteroscopy or laparoscopic removal of the device. An additional 20 women had second-look hysteroscopy because of persistent abnormal vaginal bleeding. During this time period more than 172,000 Essure™ devices were shipped, so such problems are quite rare (298).
Sterilization Failure with Hysteroscopic Methods
The Essure™ microinsert was successfully placed in 86% of patients after the first procedure, which increased to 90% after a second procedure using the initial insertion catheter. (298). Reasons for failure of insertion were tubal obstruction, stenosis, or difficulty in accessing the tubal ostia. Correct placement was confirmed at 3 months in 96%, and complete bilateral occlusion occurred in 92%. Of those patients with complete occlusion, there were no pregnancies in 5,305 woman-months of use. A subsequent study of an improved catheter design in 2004 reported a 98% successful placement rate (299). The Adiana™ trials reported a 94% successful placement rate with the first procedure, which increased to 95% after a second procedure (301).
As of October 2008, 258 Essure™-related pregnancies were reported to the manufacturer. Most can be attributed to patient or clinician noncompliance with the manufacturer’s instructions, failure to use contraception during the 3-month wait for a HSG, failure to return for the HSG, physician error in interpreting the HSG, and some luteal phase pregnancies. No known pregnancies occurred in the clinical trials when the subjects met the criteria to rely on Essure™ (297).
In patients with documented occlusion in the Adiana™ trials, a 1.1% failure rate was reported in the first year of use and a 1.8% failure rate at 2 years (297). Longer-term data are not yet available for Adiana™, but it appears that Essure™ will have a lower long-term pregnancy rate than Adiana™.
Reversal of Sterilization
Reversal of sterilization is more successful after mechanical occlusion than after electrocoagulation, because the latter method destroys much more of the tube. With modern microsurgical techniques and an isthmus-to-isthmus anastomosis, the first-year pregnancy rate is about 44% (301). A retrospective review comparing microsurgical reanastomosis to in vitro fertilization (IVF) found similar total pregnancy rates, but a higher live birthrate with IVF because 10% of the pregnancies after microsurgery were ectopic (301). Hysteroscopic sterilization by the Essure™ and Adiana™ procedures should be considered irreversible. Reversal was not reported and would have to involve cornual resection and reimplantation of the fallopian tubes, a procedure with a very low success rate. IVF appears to be the only alternative for these women.
Late Sequelae of Tubal Sterilization
Increased menstrual irregularity and pain are attributed to previous tubal sterilization. Study of the problem is complicated by the fact that many women develop these symptoms as they age, even though they did not have tubal surgery and are treated with OCs that reduce pain and create an artificially normal menstrual cycle. Women who discontinue OC use after tubal sterilization will experience more dysmenorrhea and menstrual irregularity, which is unrelated to the sterilization. The best answer available comes from the CREST study (302). A total of 9,514 women who underwent tubal sterilization were compared with 573 women whose partners had undergone vasectomy. Both groups were followed up to 5 years with annual standardized telephone interviews. Women who underwent tubal sterilization were no more likely to report persistent changes in intermenstrual bleeding or length of the menstrual cycle than women whose partners had vasectomy. The sterilized women reported decreases in days of bleeding, amount of bleeding, and menstrual pain but were slightly more likely to report cycle irregularity (OR, 1.6; 95% CI, 1.1–2.3). In summary, the CREST study provided good evidence that there is no posttubal ligation syndrome.
Noncontraceptive Benefits of Tubal Sterilization
In addition to providing excellent contraception, tubal ligation is associated with reduced risk for ovarian cancer that persists for as long as 20 years after surgery (303).
Vasectomy
About 500,000 vasectomies are performed each year in the United States (281). Vasectomy is a highly effective method. The literature on efficacy is often difficult to interpret because most studies report failure as failure to achieve azoospermia, rather than long-term pregnancy rates among the relevant women. Vasectomy is not effective until all sperm are cleared by the reproductive tract. It is estimated that up to half of pregnancies after vasectomy occur during this time (304). In addition, not all pregnancies after vasectomy can be attributed to the men who had the operation. The best long-term information comes from the CREST study. The cumulative probability of failure was 7.4 per 1,000 procedures at 1 year and 11.3 at year 5, and comparable to the failure rate of tubal sterilization (281).
Vasectomy is usually performed under local anesthesia. The basic technique is to palpate the vas through the scrotum, grasp it with fingers or atraumatic forceps, make a small incision over the vas, and pull a loop of the vas into the incision. A small segment is removed, and then a needle electrode is used to coagulate the lumen of both ends. Improved techniques include the no-scalpel vasectomy, in which the pointed end of the forceps is used to puncture the skin over the vas. This small variation reduces the chance of bleeding and avoids the need to suture the incision. Another variation is the open-ended vasectomy, in which only the abdominal end of the severed vas is coagulated while the testicular end is left open. This is believed to prevent congestive epididymitis (305). Fascial interposition can be used with any of the above techniques and is widely believed to reduce recanalization. This technique involves securing the thin layer of tissue that surrounds the vas over one of the cut ends (306).
Reversibility
Vasectomy must be regarded as a permanent means of sterilization; however, with microsurgical techniques, vasovasostomy will result in pregnancy about half of the time. The longer the interval since vasectomy, the poorer is the chance of reversal.
Safety
Operative complications include scrotal hematomas, wound infection, and epididymitis, but serious sequelae are rare. There were no reports of deaths from vasectomy in the United States in many years, and the death rate in a large third world series was only 0.5 per 100,000. Studies of vasectomized monkeys showed accelerated atherosclerosis, but several large-scale human studies found no connection between vasectomy and vascular disease (307). There is no evidence of cardiovascular risk even 20 years after the operation (308). Concerns about long-term safety recurred with the report of a possible association between prostate cancer and vasectomy (309). Recent large studies present the very clear conclusion that vasectomy is not associated with prostate cancer (310–312).
Table 10.9 Estimated Numbers and Rates of Safe and Unsafe Abortion Worldwide, by Region and Subregion, 2003
Abortion
It is extremely likely that normal couples will experience at least one unwanted pregnancy at some time during their reproductive years. In third world countries, desired family size is larger, but access to effective contraception is limited. As a result, abortion is common. While there was a decline in the overall number of abortions worldwide from 46 million in 1995 to 42 million in 2003, this decline was greater in developed than in developing countries. About half of induced abortions are illegal and considered “unsafe” by the World Health Organization definition: procedures carried out either by an unskilled person or in unsafe conditions or both (313,314).
As shown in Table 10.9 total abortion rates are quite similar over much of the world. What differs is the rate of safe abortions compared with unsafe abortions. In the developed countries, unsafe abortions are rare. In the developing countries they are very common. The highest rates of unsafe abortion are in Latin America and Africa, where abortion is generally illegal. North America, where abortion is legal and contraceptive use is high, has a lower abortion rate, 21 per 1000 women of reproductive age. Abortion rates are even lower in Western Europe, 12 per 1000 (314). Where abortion is legal, it is generally safe; where it is illegal, complications are common. Seventy thousand women die every year from complications of unsafe abortion. Societies cannot prevent abortion, but they can determine whether it will be illegal and dangerous or legal and safe. Death from illegal abortion was once common in the United States. In the 1940s, more than 1,000 women died each year of complications from abortion (315). In 1972, 24 women died of complications of legal abortion and 39 died from known illegal abortions. In 2005, the most recent year for which complete data are available, there were seven deaths from legally induced abortion and no deaths from illegal abortion (abortion induced by a nonprofessional) in the entire United States (316). The American Medical Association’s Council on Scientific Affairs reviewed the impact of legal abortion and attributes the decline in deaths during this century to the introduction of antibiotics to treat sepsis; the widespread use of effective contraception beginning in the 1960s, which reduced the number of unwanted pregnancies; and the shift from illegal to legal abortion (317). The United States has a serious problem with teenage pregnancy. Without legal abortion, there would be almost twice as many teenage births each year.
The number of abortions reported each year in the United States—1.2 million in 2006—has been declining since the peak level of 1.61 million in 1990. In 2006, the national abortion ratio was 22.4 abortions for every 1,000 live births, and the national abortion rate was 19.4 per 1,000 women aged 15 to 44 years (318). While abortion rates for all racial and ethnic groups have declined, they are significantly higher for black and Hispanic women. Non-Hispanic white women have 22% of all abortions, black women have 37%, and Hispanic women 22%. Most women who obtain abortions are unmarried, 83.5% in 2006 (316). Use of abortion varies markedly with age. In 2006, 16.9% of women obtaining abortions were between 15 and 19 years of age, and 49.6% were 24 years of age or younger. In 2006, the abortion ratio for women younger than 15 years of age was 759 per 1,000 live births, almost as many abortions as births (Fig. 10.1). The lowest abortion ratio, 141 per 1,000 live births, is for women aged 30 to 34 years.
Regardless of personal feelings about the ethics of interrupting pregnancy, health professionals have a duty to know the medical facts about abortion and to share them with their patients (319). Providers are not required to perform abortions against their ethical principles, but they have a duty to help patients assess pregnancy risks and to make appropriate referrals.
Safety
The overall annual risk of death with legal abortion decreased markedly, from 4.1 per 100,000 in 1972 to 1.8 in 1976, and remained less than 1 per 100,000 since 1987. Risk of death with vacuum curettage was 0.1 per 100,000 at or before 8 weeks in 1993 to 1997 and 0.2 per 100,000 at 9 to 10 weeks (320). Risk increases exponentially with gestational age, reaching 2.7 per 100,000 for dilatation evacuation abortion at 16 to 20 weeks and 7.2 per 100,000 at 21 weeks or more. The maternal mortality rate in the United States is 12.7 per 100,000 (321); hence, abortion by dilation and evacuation (D&E) through 20 weeks' gestation is safer than continuing pregnancy.It was estimated that 87% of the legal abortion deaths occurring after 8 weeks would have been prevented had the woman been able get abortion services by 8 weeks (322).
For individual women with high-risk conditions (e.g., cyanotic heart disease), even late abortion is a safer alternative to birth. Because of the availability of low-cost, out-of-hospital, first-trimester abortion, 88% of legal abortions are performed during the first trimester (before 13 weeks of amenorrhea), when abortion is the safest.
Table 10.10 Complications of 170,000 First-Trimester Abortions
|
Number of cases (%) |
Rate |
|
|
Minor complications |
||
|
Mild infection |
784 (0.46) |
1:216 |
|
Resuctioned day of surgery |
307 (0.18) |
1:553 |
|
Resuctioned subsequently |
285 (0.17) |
1:596 |
|
Cervical stenosisa |
28 (0.016) |
1:6,071 |
|
Cervical tear |
18 (0.01) |
1:9,444 |
|
Underestimation of gestational age |
11 (0.006) |
1:15,454 |
|
Convulsive seizureb |
5 (0.004) |
1:25,086 |
|
Total minor complications |
1,483 (0.846) |
1:118 |
|
Complications requiring hospitalization |
||
|
Incomplete abortionc |
47 (0.28) |
1:3,617 |
|
Sepsisd |
36 (0.021) |
1:4,722 |
|
Uterine perforation |
16 (0.009) |
1:10,625 |
|
Vaginal bleeding |
12 (0.007) |
1:14,166 |
|
Inability to complete abortion |
6 (0.003) |
1:28,333 |
|
Combined pregnancye |
4 (0.002) |
1:42,500 |
|
Total requiring hospitalization |
121 (0.071) |
1:1,405 |
|
aCausing amenorrhea. bAfter local anesthesia. cRequiring hospitalization. dTwo or more days of fever 40°C or higher. eIntrauterine and tubal pregnancy. |
||
|
Adapted from Hakim-Elahi E, Tovel HM, Burnhill HM, et al. Complications of first trimester abortion: a report of 170,000 cases. Obstet Gynecol 1990:76:129–135. |
||
Techniques for First- Trimester Abortion
Vacuum Curettage
Most first-trimester abortions are performed by vacuum curettage. Most are performed with local anesthesia with or without conscious sedation, and usually on an outpatient basis in a freestanding specialty clinic or doctor’s office (323). Cervical dilatation is accomplished with metal dilators, or by laminaria tents or misoprostol, 400 μg, given vaginally or by the buccal route 3 to 4 hours before the procedure (324). A plastic vacuum cannula of 5- to 12-mm diameter is used with a manual vacuum source or an electric vacuum pump. Manual vacuum provided by a modified 50-mL syringe is as effective as the electric pump through 10 menstrual weeks (325). Doxycycline is given to prevent infection and has proven effective (326). Complications of a large number of vacuum curettage procedures before 14 weeks of gestation from Planned Parenthood of New York City are presented in Table 10.10. Mild infection not requiring hospitalization and retained tissue or clot requiring resuctioning in the clinic were the most common complications. Somewhat less than 1% experienced any complications, and less than 1 per 1,000 were hospitalized (327). More extensive descriptions of the management of complications are published elsewhere (328,329).
Medical Means for First-Trimester Abortion
Mifepristone (RU486), an analogue of the progestin norethindrone, has strong affinity for the progesterone receptor but acts as an antagonist, blocking the effect of natural progesterone. Given alone, the drug was moderately effective in causing abortion of early pregnancy; the combination of mifepristone with a low dose of prostaglandin proved very effective, producing complete abortion in 96% to 99% of cases (330). The FDA approved a protocol of mifepristone, 600 mg orally, followed 2 days later by misoprostol, 400 mg, taken orally in women no more than 49 days from start of the last menstrual period. In the years before FDA approval, investigators established the superiority of the evidence-based protocols that are used. These protocols used 200 mg of mifepristone rather than 600 mg, because the lower dose is just as effective. Misoprostol, 800 μg is given by vaginal or buccal routes, which provides higher efficacy than the 400 μg oral dose (331–334). The misoprostol can be taken at 24, 48, or 72 hours after mifepristone with equal efficacy (333). Women may safely self-administer the misoprostol at home (334). It can be taken by buccal or vaginal routes with similar blood levels and similar areas under the plasma concentration curve (AUC) (335,336). After case reports of death from Clostridium sordelli, a large cohort study was published by Planned Parenthood describing use of prophylactic doxycycline 100 mg twice a day for one week, and buccal rather than vaginal administration of misoprostol (337).
Contraindications to medical abortion with mifepristone/misoprostol include ectopic pregnancy; an IUD in place (remove IUD first); chronic adrenal failure; concurrent long-term corticosteroid therapy; history of allergy to mifepristone, misoprostol, or other prostaglandin; and the inherited porphyrias (338). The mifepristone–misoprostol combination was studied for gestations at 9 to 13 weeks; although it is almost as effective as earlier in pregnancy, a larger proportion of patients will experience heavy bleeding and require vacuum curettage (339).
Methotrexate/Misoprostol and Misoprostol Alone
Alternatives to medical abortion when mifepristone is not available include regimens with methotrexate/misoprostol and misoprostol alone. The antifolate methotrexate provides another medical approach to pregnancy termination, but takes longer than the technique using mifepristone/misoprostol (340). Medical abortion can be induced with misoprostol alone, although it is less effective than the mifepristone/misoprostol combination. Vaginal misoprostol, 800 μg, repeated in 24 hours if fetal expulsion has not occurred, produces a complete abortion in 91% of pregnancies up to 56 days of amenorrhea (341).
Complications of Medical Abortion
Heavy or prolonged bleeding is the principal complication, with up to 8% of women experiencing some bleeding for as long as 30 days. Need for surgical curettage is predicted by the gestational age when the mifepristone is administered. Two percent of women treated at 49 days or less, 3% of those treated at 50 to 56 days, and 5% of those treated at 57 to 63 days needed curettage for bleeding or failed abortion in a large study with 200 mg of mifepristone and 800 μg of vaginal misoprostol (342). Late bleeding, at 3 to 5 weeks after expulsion of the pregnancy, accounted for more than half of the curettages. The complications reported to the manufacturer of mifepristonefrom the first 80,000 patients treated were published (343). One woman died of ectopic pregnancy after refusing care. Another patient survived severe sepsis, and another, a 21-year-old woman with no risk factors, survived an acute myocardial infarction. Other severe sepsis cases have since occurred. A 27-year-old woman participating in a clinical trial in Canada died of multiple organ system failure from Clostridium sordelli sepsis after complete expulsion of a 5.5-week pregnancy despite receiving excellent care (344). Five other similar sepsis deaths were reported in the popular press. The five deaths in the United States occurred among approximately 500,000 women treated with mifepristone/misoprostol, allowing estimation of a case fatality rate of 1 per 100,000, comparable to the rate of death with surgical abortion and much less than the risk of childbirth (345). There were no further cases of clostridial sepsis among the large number of women treated in the Planned Parenthood clinics when the new protocol of buccal misoprostol plus routine antibiotic prophylaxis was followed (337).
Second-Trimester Abortion
Abortions performed after 13 weeks include those done because of fetal defects, medical illness, or psychiatric problems that had not manifested earlier in pregnancy, and changed social circumstances, such as abandonment by the father. Young maternal age is the single greatest factor determining the need for late abortion (317).
Dilation and Evacuation
D&E is the most commonly used method of midtrimester abortion in the United States. Typically, the cervix is prepared by insertion of hygroscopic dilators, stems of the seaweed Laminaria japonicum(laminaria), or Dilapan-S hydrophilic polymer rods. Placed in the cervical canal as small sticks, these devices take up water from the cervix and swell, triggering dilation. Laminaria, in addition, induces endogenous prostaglandin synthesis, which aids in cervical softening. When the dilators are removed the following day, sufficient cervical dilation is accomplished to allow insertion of strong forceps and a large-bore vacuum cannula to extract the fetus and placenta (346,348). Ultrasound guidance during the procedure is helpful (348). For more advanced procedures, dilators are inserted sequentially over 2 or more days to achieve a greater degree of cervical dilation (349). At the end of the midtrimester, procedures that combine serial cervical dilation with feticidal injections, induction of labor, and assisted expulsion of the fetus are used (350). Pretreatment for a few hours with buccal or vaginal misoprostol provides sufficient cervical softening and dilatation for early midtrimester D&E, and there is considerable interest in using this as an alternative to overnight laminaria further into the midtrimester (351).
Intact D&E is another modification useful for procedures at the end of the midtrimester. After wide cervical dilatation is achieved with serial placement of cervical dilators, the membranes are ruptured and an assisted breech delivery is performed, with decompression of the after-coming fetal head to allow delivery of the fetus intact (352).
In response to the federal abortion ban of 2003, an increasing number of providers are using feticidal agents prior to late second trimester terminations (353). Intra-amniotic or intrafetal digoxin and intracardiac potassium chloride are the two most common agents used for this purpose. Both are efficacious with little maternal adverse effects (354,355). The clinical utility of these agents is unproven. The only randomized controlled study looking at clinical outcomes found no change in procedure time or blood loss with the use of digoxin (356). Varying doses of digoxin were reported. In one study, 1.5 mg intra-amniotic digoxin was always successful in inducing fetal demise within 24 hours (357).
Labor-Induction Methods
In Europe and the United Kingdom labor induction is much more common than D&E for midtrimester abortion (358). Induction abortion with hypertonic saline or urea was widely employed for labor induction abortion in the 1970s. These were supplanted by the use of synthetic prostaglandins, and by regimens that combine mifepristone and misoprostol.
Prostaglandins
Prostaglandins of the E and F series can cause uterine contraction at any stage of gestation. The 15 methyl analogues of prostaglandin F2α (carboprost) and prostaglandin E2 (dinoprostone) are highly effective for midtrimester abortion but frequently produce side effects of vomiting, diarrhea, and with dinoprostone, fever. Misoprostol a 15 methyl analogue of PGE1, is much less expensive than other prostaglandins, stable at room temperature, and at doses effective for abortion, produces many fewer side effects (359). Transient fetal survival is not infrequent after prostaglandin inductions. In the United States, it is common to produce fetal demise before induction with regimens similar to those used in late second trimester dilation and evacuation:. intra-amniotic or intrafetal digoxin, 1 to 1.5 mg, or fetal intracardiac potassium chloride (3 mL of a 2-mmol solution).
Midtrimester Mifepristone/Misoprostol
Mifepristone pretreatment markedly increases the abortifacient efficacy of gemeprost and misprostol. The mean interval from start of the prostaglandin to fetal expulsion is reduced to 6 to 9 hours, much shorter than with misoprostol alone (360). Mifepristone, 200 mg, is just as effective for this purpose as 600 mg (361). A common protocol was developed using mifepristone and misoprostol that is now recommended both by the Royal College of Obstetricians and Gynecologists (RCOG) and the World Health Organization (WHO) (358,362). Most women are cared for as hospital day-patients without need for overnight admission, a marked improvement over the labor induction methods of the past that often required 2 to 3 days of hospitalization. The protocol involves giving 200 mg of mifepristone orally on day 1. The patient returns 36 to 48 hours later for completion of the abortion with misoprostol. She is given 800 μg vaginally, and then 3 hours later, 400 μg is given orally and repeated at 3 hour intervals up to four doses. Efficacy is greater when the interval from mifepristone to starting misoprostol is at least 36 to 38 hours (363). Mean times from the start of misoprostol to fetal expulsion are 5.9 to 6.6 hours (358,360). The RCOG mandates that legal abortion must not be allowed to terminate in a live birth. Use of a feticide is required at 21 weeks (364). In the series by Ashok et al. of 1,002 women treated with the mifepristone/misoprostol protocol, described above, patients who had not expelled the fetus after 24 hours from start of the misoprostol were given an additional dose of 200 mg mifepristone at midnight, then started on another course of five doses of misoprostol the next morning, 800 μg initially, then 400 μg at 3 hour intervals, all given vaginally (360). About 8% needed a curettage procedure for retained placenta. Hemorrhage requiring transfusion occurred in about 1% of patients, usually from retained placenta.
Combination of Induction and Assisted Delivery
Hern developed a procedure that combines a feticidal injection of digoxin with serial insertion of multiple laminaria tents over 2 to 3 days, followed by amniotomy, placement of misoprostol in the lower uterine segment, and intravenous oxytocin to induce labor, and then an assisted delivery (365). The procedure was successful in a large case series at 18 to 34 weeks with very few complications.
High-Dose Oxytocin
Oxytocin in very high doses is as effective as dinoprostone at 17 to 24 weeks of pregnancy, but is not equal to the mifepristone/misoprostol regimen described above (365). Patients initially receive an infusion of 50 U of oxytocin in 500 mL of 5% dextrose and normal saline over 3 hours; 1 hour of no oxytocin, followed by a 100-U, 500-mL solution over 3 hours; another hour of rest; and then a 150-U, 500-mL solution over 3 hours, alternating 3 hours of oxytocin with 1 hour of rest. The oxytocin is increased by 50 U in each successive period, until a final concentration of 300 U in 500 mg.
Table 10.11 Complications of 2,935 Midtrimester Dilation and Evacuation Abortion and Intervention Rates on a Referral Service
|
95% Confidence |
||
|
Number (%) |
Interval (%) |
|
|
Complication |
||
|
Cervical Laceration |
99 (3.3) |
2.7–4.0 |
|
Atony |
78 (2.6) |
2.1–3.3 |
|
Hemorrhage |
30 (1.0) |
0.6–1.4 |
|
Other |
15 (0.5) |
0.3–0.8 |
|
Disseminated intravascular coagulation |
7 (0.2) |
0.1–0.4 |
|
Retained products |
6 (0.2) |
0.04–0.4 |
|
Perforation |
6 (0.2) |
0.04–0.4 |
|
Treatment of Complications |
||
|
Reaspiration |
46 (1.5) |
1.1–2.0 |
|
Hospitalization |
42 (1.4) |
1.0–1.8 |
|
Transfusion |
30 (1.0) |
0.7–1.4 |
|
Uterine artery embolization |
21 (0.7) |
0.4–1.0 |
|
Laparoscopy or laparotomy |
13 (0.4) |
0.2–0.7 |
|
From Frick AC, Drey EA, Diedrich JT, et al. Effect of prior cesarean delivery on risk of second-trimester surgical abortion complications. Obstet Gynecol 2010;115:762 [Table 2], with permission. |
||
Complications of Second Trimester Abortion
Surgical Abortion Complications
Complications of second trimester surgical abortion are uncommon, but risk increases with gestational age. Complications and their frequency encountered in almost 3,000 midtrimester abortions performed by laminaria followed by D&E on a referral service are listed in Table 10.11. The gestational ages were 14 to 27 weeks and mean gestational age was 20.2 weeks. The most common complication was a cervical laceration that required suturing. A major complication, defined as one necessitating transfusion, disseminated intravascular coagulation, reoperations with uterine artery embolization, laparoscopy, or laparotomy, was encountered in 1.3% of patients. History of two or more cesareans, gestational period of 20 weeks or more, and insufficient initial cervical dilation by laminaria were independent risk factors for a major complication in a multivariate analysis (366). The rates of complication in Table 10.11cannot be directly compared to the rates of complications with labor-induction abortion described below because half of the D&E group were 20 weeks or more gestation, while only a few of the induction patients were more than 20 weeks.
Induction Abortion Complications
The labor-induction methods share common hazards: failure of the primary procedure to produce abortion within a reasonable time, incomplete abortion, retained placenta, hemorrhage, infection, and embolic phenomena. With modern protocols, these are rare. In a series of 1,002 women treated with mifepristone and misoprostol at 13 to 21 weeks, 0.7% required a blood transfusion, 0.3% required ergot treatment for hemorrhage, and one required laparotomy for otherwise uncontrollable hemorrhage; 2.6% of patients received antibiotics for presumed pelvic infection after hospital discharge and 7.9% complained of prolonged bleeding (360). Uterine rupture was reported in women with previous cesarean delivery treated with misoprostol in the midtrimester, but in a case series of 101 women with one or more previous cesarean births and three smaller case series totaling 87 patients, no ruptures occurred (367). Larger series are needed to quantify the risk.
Selective Fetal Reduction
Multifetal pregnancies are at risk for extremely preterm birth and major neonatal complications. To prevent this, selective reduction of higher-order multiple gestations often is practiced. The largest series describes 3,513 pregnancies treated with ultrasound-guided fetal intracardiac injection of potassium chloride (0.2–0.4 mL of a 2-mmol solution in the first trimester, 0.5–3.0 mL in the second trimester). The rate of fetal loss fell as operators gained experience. Loss was greater with higher starting number of gestations (starting number greater than six, 15.4% loss, decreasing to 6.2% loss for starting number of two gestations), and greater if more fetuses were left intact (finishing number three, 18.4% loss, decreasing to 7.6% for finishing number of gestations of one) (368). Another indication for selective reduction is the presence of one anomalous fetus in a multifetal gestation. In a series of 402 patients treated for this indication, rates of pregnancy loss after the procedure by gestational age at the time of procedure were 5.4% at 9 to 12 weeks, 8.7% at 13 to 18 weeks, 6.8% at 19 to 24 weeks, and 9.1% at 25 weeks or more (369). No maternal coagulopathy occurred, and no ischemic damages or coagulopathies were seen in the surviving neonates. Maternal serum α-fetoprotein remains elevated into the second trimester after first-trimester procedures (370). Because of the possibility of embolic phenomena and infarction in the surviving twin, a different technique is needed for selective reduction of monoamniotic twins or with monochorionic twin–twin transfusion syndrome. He and colleagues describe ultrasound guided bipolar coagulation of the umbilical cord of the affected twin in such cases (371).
The Future
Spermicides
Research includes efforts to develop spermicides and microbicides that prevent pregnancy and are effective against HIV and STDs. Trials of microbicides such as cellulose sulphate and surfactant were disappointing and showed no efficacy against HIV (371,372). The most promising research includes development of antiretroviral microbicides with alternative delivery systems such as rings and gels. The antiretroviral tenofovir has good safety and efficacy in animals and human tissue models and is being evaluated in human effectiveness studies (373).
Intrauterine Devices
The GyneFix, a frameless copper IUD available in Europe, consists of a surgical suture with small copper cylinders crimped to it. The knot on the proximal end of the suture is pushed 1 cm into the uterine wall with a special inserter. Comparative trials found it more effective than the copper T380A and it requires fewer removals for pain and bleeding (374).
Other ongoing research of IUDs includes a smaller levonorgestrel IUD that may be more acceptable to nulliparous women and IUDs that are suitable for irregularly shaped uteri (38).
Vaginal Rings
Silastic vaginal rings releasing either progestin or progestin–estrogen combinations were studied for years. The NuvaRing contains both estrogen and progestin, must be changed monthly, and has the same safety concerns as the other estrogen-containing hormonal methods. A new reusable ring, Nestorone, contains a nonandrogenic progestin that is inactive orally, and ethinyl estradiol. It can be worn for 3 weeks, removed for 1 week, and then reinserted for a total of 13 months of use (375). The advantage of this method is the use of a less androgenic progestin and the elimination of regular trips to the pharmacy. Progering contains natural progesterone and no estrogen. It is approved in some countries in Latin America and Asia. It was developed for up to 3 months use by breastfeeding women (376).
Barrier Methods
The Ovaprene ring is a nonhormonal “one-size-fits-all” intravaginal organic silicone ring that continuously releases spermiostatic and spermicidal agents over a 4-week period. The phase I trial demonstrated patient acceptability and safety and the product is in phase II trials (377). Under investigation is the SILCS diaphragm, a single-size reusable device with a contoured rim. This device is nonlatex and is available over the counter with no requirement for a pelvic examination (378). Another potential new barrier method under development is a female condom with a dissolvable capsule to ease insertion, a polyurethane vaginal pouch, and a soft outer ring. Fit and concerns over slippage are improved by urethane foam that allows the condom to cling to the vaginal walls (38).
The Invisible Condom™ is a novel barrier/germicide/spermicide combination in human trials. It is a polymer gel that adheres to the vaginal and cervical mucosa when inserted into the vagina through a special applicator, forming a nondetectable physical barrier. One version has sodium laurel sulfate (SLS) incorporated in to the polymer film. The gel by itself blocks entry of HIV and of herpes virus into target cells in vitro. Daily vaginal application of the polymer plus SLS prevents pregnancy in rabbits (379).
Contraceptive Vaccines
Immunologic contraception–sterilization with vaccination against human chorionic gonadotropin was pursued for many years in India but appears to be abandoned (380). Zona pellucida glycoproteins are another target for a potential vaccine, but application in humans appears blocked by the ovarian dysfunction observed in animal studies (381). More promising are efforts that target sperm. Because of the large number of antigens associated with sperm, some of which are found on somatic cells, the challenge lies in choosing the correct antigen (382). The search continues for target proteins unique to reproduction to which a vaccine could be employed without adversely affecting other functions.
Male Contraception
As described earlier, considerable progress was made in hormonal contraception for men based on long-acting androgens in combination with progestins or GnRH antagonists. Nonhormonal male methods are being investigated. These include efforts to target and specifically interfere with spermatogenesis, epididymal sperm maturation, and sperm function (383). The majority of the targets being explored involve inhibiting sperm motility (384). Chinese researchers developed a method of percutaneous occlusion of the vas that was used in more than 100,000 men; it is effective and appears to be reversible. Polyurethane elastomer is injected into the vas, where it solidifies and forms a plug, providing an effective block to sperm. The plugs are removed using local anesthesia, and fertility returns in most cases after as long as 4 years with the plugs in situ (385).
Another potentially reversible method is the reversible inhibition of sperm under guidance (RISUG). This is a clear polymer gel mixed with dimethyl sulphoxide that solidifies, causing partial obstruction and the rupture of passing sperm membranes, when injected into the vas. Phase II trials demonstrated azoospermia for at least 1 year (38).
Simple Means for Female Sterilization
Another critical area for contraceptive development is nonsurgical means of sterilization of both men and women. Intrauterine quinacrine is the most promising method for nonsurgical female sterilization, but the method is embroiled in controversy because it was developed in the third world and moved quickly to widespread use without adequate proof of safety (386). Approximately 100,000 women were treated with it (387). The technique is very simple: pellets containing 252 mg of quinacrine are inserted into the uterus through an IUD inserter during the proliferative phase of the cycle and again 1 month later. Intrauterine quinacrine produces sclerosis of the proximal fallopian tube. In a large trial in Vietnam, the cumulative pregnancy rate for 1,335 women who received 2 doses was 3.3 at 1 year, 10.0 at 5 years, and 12.1 at 10 years (388). Another study of almost 25,000 women found the rate of ectopic pregnancy to be 0.26 per 1,000 women treated, which was similar to surgical sterilization and the IUD, OC pills, and condoms (0.42–0.45 per 1,000) and less than nonusers of contraception (1.18 per 1,000) (389). Concern was raised that quinacrine would lead to reproductive tract cancers. Two epidemiologic studies found no apparent increased risk for cancer from previous quinacrine sterilization in humans (390,391). A study of lifetime risk in rats sterilized with intrauterine quinacrine as young adults did find an increase in reproductive tract cancer in those rats treated with eight times the human dose, but not in the rats exposed to lower doses (392).
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