One of the perceived benefits of organ transplantation is restoration of fertility (1). Ovulatory cycles may begin as early as 1 month after transplantation (2). Pregnancy is not always contraindicated and has been reported after every type of solid-organ transplantation (3). United States registry data show that pregnancy complications are more common among transplant recipients (4), including Cesarean section, gestational diabetes, preeclampsia, and preterm delivery. This has been confirmed by metaanalysis of both kidney (5) and liver (6) transplantation studies and a case control analysis of liver transplantation patients (7). The teratogenicity of the Class D antirejection agent mycophenolate mofetil makes preconception medication an important consideration for both the mother and the fetus. Finally, transplant recipients may not desire pregnancy or pregnancy could present an unacceptable medical risk. Despite the need to consider contraception, the literature is scant regarding the use of hormonal methods, and highly effective methods have not been studied in a systematic fashion (8).
Our goal is to assist patients and providers in choosing a highly effective contraceptive method for solid-organ transplant recipients, regardless of whether pregnancy prevention is medically indicated or simply a patient’s choice.
Contraceptive choice balances the risk of using a contraceptive method with the risk of pregnancy, which includes the risk of both becoming and remaining pregnant. There are two national estimates of the live birth rate among female solid-organ transplant recipients: the National Transplantation Pregnancy Registry and Medicare data (7, 9). In the National Transplantation Pregnancy Registry, a voluntary registry, there is a live birth rate of 50% to 86% among all solid-organ transplant recipients. A review of Medicare data from 1990 to 2003 revealed a pregnancy rate of 33 per 1000 women with a kidney transplant and a live birth rate of 55%. Although both studies include patients with induced abortion, neither estimate can fully account for this. Induced abortion is stigmatized and systematically underreported (10–12), and Medicare does not cover induced abortion except in extenuating circumstances (13). Thus, we do not have a true estimate of the total pregnancy rate among transplant recipients in the United States.
The overall unplanned pregnancy rate is 50% in the United States, and approximately half of unplanned pregnancies result in abortion—one-third of U.S. women will have an abortion in their lifetime (14). There is no data regarding the prevalence of unplanned pregnancy among women with solid-organ transplant in the United States. However, survey studies from Brazil, Iran, and China report unplanned pregnancy rates of 92.9%, 48.5%, and 88%, respectively, in this population, with many of these pregnancies reported in the first 2 years after transplantation (15–17). We can conclude that there is a high risk of unintended pregnancy among transplant recipients, based on the overall unplanned pregnancy rate in the United States and the high rates reported among transplant recipients internationally. The risk of unplanned pregnancy combined with the high risk of pregnancy, if it occurs, can inform the risk/benefit balance of using contraceptive methods among women with solid-organ transplant.
Medical Eligibility Criteria
To clarify the risks and benefits of contraception for women with specific medical conditions, the World Health Organization has issued Medical Eligibility Criteria (MEC) for contraceptive use among women with specific medical conditions (18). There are four categories: Category 1, methods have no restriction for a specific condition; Category 2, methods can be used with careful follow-up; Category 3, methods are generally not recommended unless other methods are not available or acceptable; and Category 4, methods present an unacceptable risk. In 2010, the Centers for Disease Control (CDC) released an adaptation for the United States (19), which included high-risk medical conditions that are prevalent in this country, such as solid-organ transplantation.
For women with uncomplicated solid-organ transplantation, every method reviewed—combined hormonal methods, progestin-only pills (POP), depot medroxyprogesterone acetate (DMPA), subdermal implants, levonorgestrel intrauterine device (IUD), and copper IUD—is considered Category 2. In women with complicated solid-organ transplantation, defined as graft failure, rejection, or cardiac allograft vasculopathy, the only differences are that combined hormonal methods are Category 4 and that the initiation of IUDs are Category 3 (continuation is still Category 2). These recommendations support the conclusion that the risk of pregnancy outweighs the theoretical or actual risk of any contraceptive method among women with uncomplicated solid-organ transplantation. Contraceptive choice can be individualized for each patient to minimize the risk of both the method and unintended pregnancy.
Barrier methods, female and male condoms, prevent both pregnancy and infection. These methods are ideal for use in conjunction with another method, especially for women using teratogenic medications for immunosuppression. For example, the manufacturer of mycophenolate mofetil recommends a woman to use two methods of contraception 4 weeks before the initiation of therapy. Condoms are always recommended to prevent infection but have relatively low contraceptive efficacy when used alone among typical users (20). Their use should be advocated for the prevention of infection in conjunction with a second method that provides reliable pregnancy protection.
COMBINED HORMONAL CONTRACEPTION (ESTROGEN PLUS PROGESTIN)
Combined hormonal methods include the combined oral contraceptive (COC) pill, patch, and ring and contain a combination of estrogen and progestin. Among brands, there are variations in estrogen dosage and progestin type. Combined methods have noncontraceptive benefits such as improved menses, hirsutism, ovarian cysts, and acne. They are advertised as 99% effective; however, among typical users, efficacy is 92% (20). The estrogen component is contraindicated among women with the following conditions: personal history of thrombosis, hypertension, myocardial infarction, stroke, migraine with aura, smoking at an age of 35 years or older, active liver disease, or hepatic adenoma. Specific to transplantation patients, combined hormonal methods are contraindicated in women with cardiac allograft vasculopathy or active liver disease.
Combined hormonal methods have been studied in a series of transplantation patients with favorable results. In a prospective study of 26 renal transplant recipients, there were no significant changes in liver enzymes, cholesterol, creatinine, and glucose after 18 months of COC pill use. No pregnancies or ovarian cysts were reported, and the hematocrit improved (21). Several women in this series required modification of their antihypertensive medications. Furthermore, there was one case of profound thrombophlebitis and one case of deterioration of liver function in a patient approximately 10 years after transplantation. A retrospective study of 15 liver transplantation patients noted no changes in liver function, glucose metabolism, blood pressure, or body mass index associated with COC pill use. There were no cases of rejection, and no patients discontinued therapy for medical indications (22).
Novel formulations of combined hormonal methods have also been studied in small groups. A report of 10 renal transplantation patients using the transdermal patch showed similar results to the group of 26 COC pill users described above (23). The contraceptive vaginal ring has been described in a prospective group of 17 renal and liver transplantation patients during the course of several years (24). There were no cases of rejection or change in immunosuppressive medication, and patients demonstrated improved menstrual cycle control. The only estrogen-related events reported were nausea and breast tenderness, in two patients. The vaginal ring avoids a first-pass effect through the liver but has not been evaluated for improved safety as a result of this delivery mechanism.
As with any systemic medication, there is a concern that drug interaction through the cytochrome 450 system may decrease the efficacy of immunosuppressive medications or hormonal contraception. One crossover study demonstrated an increase in serum prednisolone but not serum budesonide in women taking COC pills (25). No matter the formulation, estrogen-related contraindications combined with the 8% failure rate with typical use make combined hormonal methods less than ideal in women with a history of transplantation.
Progestin-only systemic methods are effective options in women with contraindications to estrogen use. These methods include DMPA, POP, and the subdermal etonogestrel implant. These methods use varying types and dosages of synthetic progestins. The progestin-only pill requires strict compliance but may be acceptable to a patient accustomed to a daily medication regimen. In addition, POPs undergo first-pass effect in the liver.
Both DMPA and the subdermal implant have the advantage of no first-pass liver effect and longer duration of action. DMPA is administered intramuscularly every 12 weeks. It is highly effective, and the most common adverse effects are irregular bleeding and amenorrhea. DMPA is metabolized by the liver but is only contraindicated in the setting of active liver disease. In 2004, the Food and Drug Administration added a black box warning to DMPA regarding skeletal health. Mounting evidence has led family planning specialists to advocate for the removal of this warning (26); however, transplantation patients, specifically kidney transplantation patients, have long-term risk of osteoporosis. In the case of transplantation patients, the effect of DMPA on bone health is of greater concern than for the average woman; so, it should be used with caution.
The contraceptive subdermal implant is the longest acting systemic progestin-only method. It is placed under the skin of the arm, releases etonogestrel, and is effective for 3 years. Because it does not require daily dosing or frequent follow-up, the typical and perfect use failure rates for this method are identical. The adverse effects are similar to DMPA, with the notable differences of a less predictable bleeding pattern and lack of adverse effect on bone density. The use of the contraceptive subdermal implant has not been described in transplantation patients, but the progestin is similar to other methods.
There are two types of IUDs: copper and levonorgestrel, a progestin. They do not require motivation for adherence and long-term use and thus are highly effective. Historically, a case report of two copper IUD failures in 1981 has led to the theory that immunosuppressive medication would render an IUD inactive (27). There are two lines of evidence to refute this claim. First, large-scale IUD failure has not been reported in the modern literature, although no studies have been specifically designed to address this question. In the previously noted Chinese survey, none of the 178 women who used the IUD became pregnant (17). In addition, a study evaluating the ease of insertion in nulligravidas included 12 transplant recipients who received the levonorgestrel IUD (28). There were no pregnancies in this study after 1 year. Second, evidence suggests that macrophages play the most important role in the destruction of ova and sperm (29), and macrophage function is minimally affected by most currently used immunosuppressants. There is no biologic evidence for decreased IUD efficacy in transplantation patients.
Infection is another historic concern for IUD use in a transplantation population. In the 1980s, the poorly designed Dalkon shield caused pelvic infection in thousands of U.S. women, resulting in the removal of all IUDs from the market (30). The two modern IUDs do not increase the risk of pelvic infection or resulting tubal infertility (31), and although they have not been studied extensively in a transplantation population, they have been studied systematically in patients with human immunodeficiency virus (HIV). In a trial of 599 women randomized to copper IUD or oral contraceptive pills, IUD was found to be safe and effective, and women assigned to hormonal contraception were more likely to become pregnant (32). A prospective cohort study of 649 women with IUDs, including 156 with HIV, showed no association between HIV infection and risk of pelvic infection (33). In the absence of comparable studies in transplantation patients, these data showing safety of IUD use in women with HIV are reassuring. Lastly, a retrospective review of use of the levonorgestrel IUD in 11 transplant recipients from a single Irish center did not report any case of pelvic infection or unplanned pregnancies after a mean duration of use of 38 months (34).
The levonorgestrel IUD has noncontraceptive benefits, such as markedly decreased menses, with minimal systemic drug absorption. It is approved to treat menorrhagia, and there is one case report of the effective use of this device to treat menorrhagia in a transplantation patient with uterine fibroids (35). Modern IUDs represent an opportunity to provide women with a history of transplantation a highly effective contraceptive method without systemic medication or risk of infection.
When a method is not used, or when a barrier method fails, a woman has up to 5 days to use emergency contraception (EC). Available methods include the progestin levonorgestrel in a single or divided dose, a single dose of the antiprogestin ulipristal, and the copper IUD. EC pills should be prescribed in advance to increase use (36). EC pills are CDC Medical Eligibility Criteria Category 1 for women with a history of solid-organ transplantation, and there should be no restrictions for their use. In using the copper IUD for EC, providers should avoid insertion during active pelvic infection; otherwise, any patient who is a candidate for use of copper IUD is a candidate for its use for EC.
Protection from unplanned pregnancy is a measure of quality of life for all women (37), including those with received solid-organ transplant. CDC has confirmed that there are a wide range of contraceptive options available based on patient preference and efficacy. Long-acting reversible contraception, which includes IUDs and the subdermal implant, are optimal for use in a transplantation population because they have little to no drug interaction, minimal risk to a patient, high efficacy, and reversibility. Future study should focus on the use of highly effective long-acting methods because their theoretical risks are far outweighed by the benefits of reliable pregnancy prevention.
1. McKay DB, Josephson MA. Pregnancy
in recipients of solid organs: effects on mother and child. N Engl J Med
2006; 354: 1281.
2. Farber M. Pregnancy
and renal transplantation. Clin Obstet Gynecol
1978; 21: 931.
3. Mastrobattista JM, Gomez-Lobo V. Pregnancy
after solid organ transplantation. Obstet Gynecol
2008; 112: 919.
4. Coscia LA, Constantinescu S, Moritz MJ, et al. Report from the National Transplantation Pregnancy
Registry (NTPR): outcomes of pregnancy
after transplantation. Clin Transpl
5. Deshpande NA, James NT, Kucirka LM, et al. Pregnancy
outcomes in kidney transplant recipients: a systematic review and meta-analysis. Am J Transplant
2011; 11: 2388.
6. Deshpande NA, James NT, Kucirka LM, et al. Pregnancy
outcomes in liver transplant recipients: a systematic review and meta-analysis. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22344967
. Accessed March 11, 2012.
7. Coffin CS, Shaheen AAM, Burak KW, et al. Pregnancy
outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl
2010; 16: 56.
8. Paulen ME, Folger SG, Curtis KM, et al. Contraceptive use among solid organ transplant patients: a systematic review. Contraception
2010; 82: 102.
9. Gill JS, Zalunardo N, Rose C, et al. The pregnancy
rate and live birth rate in kidney transplant recipients. Am J Transplant
2009; 9: 1541.
10. Jones EF, Forrest JD. Underreporting of abortion in surveys of U.S. women: 1976 to 1988. Demography
1992; 29: 113.
11. Jones RK, Kost K. Underreporting of induced and spontaneous abortion in the United States: an analysis of the 2002 National Survey of Family Growth. Stud Fam Plann
2007; 38: 187.
12. Fu H, Darroch JE, Henshaw SK, et al. Measuring the extent of abortion underreporting in the 1995 National Survey of Family Growth. Fam Plann Perspect
1998; 30: 128.
13. National Coverage Determination (NCD) for Abortion (140.1). Centers for Medicare and Medicaid Services. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=127&ncdver=2&bc=AAAAgAAAAAAA&
. Accessed October 20, 2012.
14. Finer LB, Zolna MR. Unintended pregnancy
in the United States: incidence and disparities, 2006. Contraception
2011; 84: 478.
15. Guazzelli CAF, Torloni MR, Sanches TF, et al. Contraceptive counseling and use among 197 female kidney transplant recipients. Transplantation
2008; 86: 669.
16. Ghazizadeh S, Lessan-Pezeshki M, Khatami M, et al. Unwanted pregnancy
among kidney transplant recipients in Iran. Transplant Proc
2005; 37: 3085.
17. Xu L, Yang Y, Shi JG, et al. Unwanted pregnancy
among Chinese renal transplant recipients. Eur J Contracept Reprod Health Care
2011; 16: 270.
18. WHO. Medical eligibility criteria for contraceptive use. Available at: http://www.who.int/reproductivehealth/publications/family_planning/9789241563888/en/index.html
. Accessed January 17, 2012.
19. Curtis KM, Jamieson DJ, Peterson HB, Marchbanks PA. Adaptation of the World Health Organization’s medical eligibility criteria for contraceptive use for use in the United States. Contraception
2010; 82 (1): 3.
20. Hatcher R, Trussell J, Nelson A, et al. Contraceptive Technology, Revised 20th Edition
. 20th ed. New York: Ardent Media; 2011.
21. Pietrzak B, Kaminski P, Wielgos M, et al. Combined oral contraception in women after renal transplantation. Neuro Endocrinol Lett
2006; 27: 679.
22. Jabiry-Zieniewicz Z, Bobrowska K, Kaminski P, et al. Low-dose hormonal contraception after liver transplantation. Transplant Proc
2007; 39: 1530.
23. Pietrzak B, Bobrowska K, Jabiry-Zieniewicz Z, et al. Oral and transdermal hormonal contraception in women after kidney transplantation. Transplant Proc
2007; 39: 2759.
24. Paternoster DM, Riboni F, Bertolino M, et al. The contraceptive vaginal ring in women with renal and liver transplantation: analysis of preliminary results. Transplant Proc
2010; 42: 1162.
25. Seidegård J, Simonsson M, Edsbäcker S. Effect of an oral contraceptive on the plasma levels of budesonide and prednisolone and the influence on plasma cortisol. Clin Pharmacol Ther
2000; 67: 373.
26. Kaunitz AM, Grimes DA. Removing the black box warning for depot medroxyprogesterone acetate. Contraception
2011; 84: 212.
27. Zerner J, Doil KL, Drewry J, et al. Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med
1981; 26: 99.
28. Bahamondes MV, Hidalgo MM, Bahamondes L, et al. Ease of insertion and clinical performance of the levonorgestrel-releasing intrauterine system in nulligravidas. Contraception
2011; 84: e11.
29. Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception
2007; 75 (suppl 6): S16.
30. Cox ML. The Dalkon Shield saga. J Fam Plann Reprod Health Care
2003; 29: 8.
31. Hubacher D, Lara-Ricalde R, Taylor DJ, et al. Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med
2001; 345: 561.
32. Stringer EM, Kaseba C, Levy J, et al. A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol
2007; 197: 144.e1.
33. Morrison CS, Sekadde-Kigondu C, Sinei SK, et al. Is the intrauterine device appropriate contraception for HIV-1-infected women? BJOG
2001; 108: 784.
34. Ramhendar T, Byrne P. Use of the levonorgestrel-releasing intrauterine system in renal transplant recipients: a retrospective case review. Contraception. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22305914
. Accessed March 5, 2012.
35. Fong YF, Singh K. Effect of the levonorgestrel-releasing intrauterine system on uterine myomas in a renal transplant patient. Contraception
1999; 60: 51.
36. Jackson RA, Schwarz EB, Freedman L, et al. Advance supply of emergency contraception: effect on use and usual contraception—a randomized trial. Obstet Gynecol
2003; 102: 8.
37. Institute of Medicine of the National Academies. Clinical preventive services for women: closing the gaps. Report brief. Available at: http://www.iom.edu/Reports/2011/Clinical-Preventive-Services-for-Women-Closing-the-Gaps/Report-Brief.aspx?page=1
. Accessed January 16, 2012.