LNG IUS initiation
Solid organ transplantation
Many patients with a transplant have medical comorbidities such as hypertension or complicated diabetes that may preclude the use of estrogen-containing methods of birth control. The most effective, reversible methods of contraception are the hormonal and nonhormonal IUDs and the subdermal implant, for which there are few contraindications. The failure rates for these devices are less than 1% . As shown by the CHOICE study in which over 9,000 women were provided with no-cost contraception, overall satisfaction and continuation rates were higher with these devices than with other methods [30, 31].
For a patient with a complicated transplant, i.e., abnormal renal function in the setting of acute kidney injury, chronic allograft nephropathy, or rejection, estrogen-containing methods are considered to be Category 4, and the initiation of an IUD is Category 3. In this Category 3 setting, the risks generally outweigh the benefits, and the IUD would be safer than pregnancy. A conversation regarding risks and benefits between the patient and clinician would be warranted.
Implications of Immunosuppressive Medications
Transplant recipients are started on several classes of medications to prevent rejection of the allograft. Medication awareness is critical when discussing contraception as interactions may occur with the use of certain drugs. The first class of drugs are induction therapy agents, which are a group of medications initiated prior to or during transplant surgery. They include rabbit antithymocyte globulin (ATG), horse antithymocyte globulin (ATGAM), monoclonal antibodies (basiliximab and alemtuzumab), and corticosteroids . Maintenance immunosuppression has historically consisted of azathioprine (an antimetabolic agent) and then azathioprine combined with corticosteroids. In the 1980s, cyclosporine, a calcineurin inhibitor (CNI), was introduced. A second CNI, tacrolimus, and mycophenolate mofetil (an antimetabolic agent) followed a decade later. CNIs are metabolized through the hepatic cytochrome P450 3A4 pathway. This enzymatic system also metabolizes estrogen and progesterone, common components in hormonal contraceptives. The most recent class of agents introduced were the mammalian TOR (mTOR) inhibitors, sirolimus and everolimus. According to the 2016 Annual Report of the Scientific Registry of Transplant Recipients, 72% of patients are now managed with corticosteroids, and roughly 95% of kidney transplant patients are maintained on a mycophenolate acid derivative . These medications have the potential to interact with other contraceptive medications that are metabolized along similar pathways, but no direct studies have been performed examining drug levels.
Long-Acting Reversible Contraceptives (LARC)
Intrauterine Device (IUD)
The IUD is an ideal contraceptive method for many women due to its high efficacy and low maintenance. Studies evaluating the use of IUD in the transplant population are limited; however, the available data show that IUDs are safe and well tolerated in this group of patients [34–36]. Additionally, we have good information on the safety of IUDs in a similarly immunosuppressed cohort in women with HIV/AIDS. A systematic review of eight articles showed no difference in infectious complications in women with HIV who had IUDs . Accordingly, the CDC classifies IUDs in women with HIV as a Category 2 .
To examine whether IUD insertion caused infection in stable transplant patients, a pilot study employing uterine lavage, endometrial biopsy, and serum examination of cytokines and receptor levels in patients pre- and post-LNG-IUS insertion was performed. Investigators examined the immunologic response to the LNG-IUS in healthy women versus patients with stable solid organ transplants. In both healthy controls and organ transplant recipients, no increase in serum cytokines or soluble receptor levels were noted after the LNG-IUS was inserted. After IUD insertion, uterine lavage cytokine levels were increased in both groups. Macrophage activity was also increased in endometrial biopsy samples for both groups. These results indicate that both patients with transplants and healthy women are able to mount a local (but not systemic) inflammatory response, indicating the IUD is a safe and feasible option in transplant patients . Additionally, a recent case series of 23 women with solid organ transplant who received the LNG-IUS showed no cases of pelvic infection or pregnancy, with a medican follow up of 49.3 months .
There are two types of IUDs currently on the market, the nonhormonal copper-containing IUD (copper IUD ) ParaGard® and the LNG-IUS. The hormone-containing intrauterine system releases levonorgestrel, which is a type of progesterone. There are currently four hormonal IUDs, two high-dose: (52 mg) Liletta® (Allergan) and Mirena® (Bayer), and two low-dose: (19.5 mg) Kyleena® and (13.5 mg) Skyla® (Bayer).
The copper IUD causes a local inflammatory response in the uterus. This mechanism of action has been raised as a concern for contraceptive failure for women on immunosuppressive medications. A case report from 1981 of two women with solid organ transplants who had pregnancies using the copper 7 IUD contributed to these worries . However, immunosuppressive medicines are not thought to alter the effectiveness of the IUD. The copper IUD works by inciting a foreign body response and increasing the number of plasma cells, neutrophils, and mononuclear cells . Immunosuppressive drugs (calcineurin inhibitors [CNIs], purine synthesis inhibitors [PNIs]) and steroids do not interfere with this response, as they primarily work through the tumor necrosis factor (TNF)-alpha system . It has also been reported that steroids increase macrophage activity thereby enhancing the copper IUD’s effectiveness .
Some clinicians are concerned about the possible increased risk of pelvic inflammatory disease (PID) in transplant patients using IUDs. There is evidence that the LNG-IUS may actually reduce the risk of PID as one of its mechanisms of action is to thicken cervical mucus, thus providing a barrier to semen and ascending infection . The risk of PID can be increased in the first 20 days following insertion, after which the risk returns to baseline . Regarding risk of infertility, IUDs themselves are not associated with an increased risk of tubal scarring, but prior infections with chlamydia are, and all patients at risk should be instructed to use condoms to avoid sexually transmitted infections [45, 46].
The copper IUD is FDA approved for 10 years and the LNG-IUS for 5 years. The copper IUD has been shown to be effective for up to 12 years . The 52 mg LNG-IUS has been shown to be effective for up to 7 years [48, 49]. The LNG-IUS causes shorter, lighter menses. This may be specifically beneficial in women on anticoagulation and those with menorrhagia, underlying PCOS, or endometriosis. The American College of Obstetricians and Gynecologists (ACOG) considers IUDs to be safe for nulliparous women and adolescents and women with a history of sexually transmitted infections (STIs) and/or ectopic pregnancies .
Subdermal Etonogestrel Implant
The etonogestrel implant (ENG-implant) Nexplanon® (Merck) is a single 4 cm x 2 mm radiopaque rod that contains 68 mm of etonogestrel and is approved for 3 years of use. It has been shown to be effective for up to 5 years . The ENG-implant has a very low failure rate (less than 1%). It is inserted subdermally in the upper arm, and the main side effects are irregular bleeding. Irregular bleeding can be managed using either high-dose cyclical progesterone for up to 3 months (medroxyprogesterone acetate 10 mg orally twice per day or oral progestin-only pills taken daily for up to 3 months . There are few data on the ENG-implant in transplant patients, but it is considered safe in these patients and is CDC MMWR Category 2 .
Depot Medroxyprogesterone Acetate
Depot medroxyprogesterone acetate (DMPA) is a progesterone-only intramuscular injection given every 12 weeks. The typical failure rate is 6% . Approximately 40–50% of users will become amenorrheic after 1 year of use . DMPA for patients with uncomplicated solid organ transplants is Category 2. DMPA inhibits bone resorption and can cause a reversible decrease in bone mineral density (BMD) . BMD loss in the non-transplant population is reversible, but women who have received solid organ transplants are often on steroids for extended periods of time, which can cause secondary osteoporosis . The risks to bone health need to be reviewed prior to initiation of DMPA.
Combined Hormonal Contraception
Combined hormonal contraception is the most familiar method as it is the mostly used reversible method in the United States. Nearly one-third of American women currently employ this method . However, this method has a failure rate of 9% and a high rate of discontinuation. In the CHOICE Project, only 31% of women continued using a combined method at 3 years compared to 67% of IUD and implant users .
There are multiple forms of delivery for combined hormonal contraception and include the combined oral contraceptive pill (COC), the contraceptive patch, and the vaginal ring. The last two delivery systems avoid first-pass hepatic metabolism, and their efficacy is unaffected by medications that may increase hepatic enzyme activation. Specific to transplant patients, there is uncertainty regarding the concomitant metabolism of oral estrogen, progesterone, and immunosuppressants as they are processed by the cytochrome P450 3A4 system.
In comparison with other contraceptive methods, however, there are relatively more data for COCs and transplant patients. A prospective cohort analysis examining the use of low-dose COCs in 26 stable renal transplant patients revealed major adverse events in two patients. Therapy was discontinued in two patients, one developed a severe deep venous thrombosis, and the other had deterioration of hepatic function . In a second prospective cohort study, 17 women with the vaginal contraceptive ring were studied over a 12-month period. One participant experienced significant bleeding due to thrombocytopenia, but the remainder of the participants tolerated the ring . In a retrospective analysis, 15 liver transplant recipients were given the contraceptive patch or COCs. Over the ensuing 12 months, no transplant rejections or pregnancies occurred .
While some patients may tolerate COCs, physicians should approach this method with caution. COCs may be contraindicated in this population due to the presence of medical comorbidities (i.e., hypertension, coagulopathies, and lupus), and they also have a 9% failure rate .
There are no studies of the progestin-only pill (POP) in transplant patients. The POP is less effective than the combined birth control pill, with a failure rate of up to 13% . One of the reasons for the higher failure rate is that the user must take the pill at the same time every day.
The external condom is the most familiar barrier method. It has contraceptive failure rate of 18% . It is a commonly used method in the transplant population as there are no medical contraindications to its use. Condoms should always be worn to prevent sexually transmitted infections.
The internal condom is a loose, soft polyurethane sheath that contains two flexible polyurethane rings. The smaller inner ring is placed at the top of the inside of the vagina, and the larger outer ring forms the external opening outside the vagina. It is not reusable. The failure rate for the internal condom is 21% . It can be used in those with latex allergies.
The failure rate for the diaphragm is 12% . The use of the diaphragm has decreased due to fewer manufacturers and a decreasing number of providers who are able to fit the patient. A newer, latex-free, one-size-fits-most diaphragm is available, called Caya® (HPSRx). The diaphragm must remain in place in the vagina for at least 6 h after intercourse, and patients must use spermicidal gel with each act of intercourse.
Fertility Awareness Methods
Fertility awareness methods or “natural family planning” requires regular, monthly menstrual cycles. Given that patients with CKD and patients on dialysis often have irregular menses, referral to an obstetrician g ynecologist is important for counseling if this is the desired method of contraception.
Emergency contraception (EC) is used when a woman has unprotected or underprotected intercourse. There are three options. The copper IUD is the most effective form of emergency contraception (pregnancy rates between 0% and 2%) and can be placed within 5 days of unprotected intercourse . Ulipristal acetate (Ella®) can be taken up to 5 days from intercourse. Pregnancy rates with ulipristal acetate range from 1.4% to 1.9% [59, 60]. Levonorgestrel (Plan B®) can be taken up to 5 days post-intercourse, but it is most effective within 72 hours. It has the highest failure rate (10–40%). Both oral methods of emergency contraception are safe (Category 1) for women after a solid organ transplant. The copper IUD is safe for women with an uncomplicated transplant (Category 2), but if the transplant is complicated (i.e., abnormal renal function), the IUD is considered Category 3, meaning the risks may outweigh the benefits . Of note, levonorgestrel emergency contraception is less effective in women who have a BMI greater than 25 . Ulipristal acetate is not affected by BMI to the degree that levonorgestrel is; however, it becomes less effective when BMI exceeds 30 . Currently, levonorgestrel EC is the only method available in the United States without a prescription.
As discussed previously, nearly half of all pregnancies in the United States are unintended, and almost half of these pregnancies will end in abortion . For the medically complicated patient, pregnancy termination is an important and often life-saving option, particularly in the presence of coexisting medical comorbidities.
One should consider inpatient care in the high-risk patient with impaired renal function (serum creatinine >2.5 mg/dL), uncontrolled blood pressure (systolic BP >160 or diastolic blood pressure >105 mmHg), uncontrolled diabetes, underlying coronary artery disease (prior myocardial infarction, angina, cardiomyopathy, cyanotic heart disease, uncontrolled tachyarrhythmia), rheumatologic concern (lupus flare, lupus requiring anticoagulation), or transplant concern (impaired renal function, recent organ rejection, or poorly functioning transplanted organ). This allows the procedure to be performed in a monitored surgical setting . Women without these high-risk comorbidities can be candidates for outpatient procedures.
Medical abortion, using a combination of mifepristone (an anti-progesterone) and misoprostol (a prostaglandin), is used to induce abortion at home for up to 10 weeks of gestational age. Patients with severe renal disease (creatinine >2.5 mg/dL), hypertension (blood pressure >160/110 mmHg), and anemia (Hb < 9.5 g/dL) or on anticoagulation are not appropriate candidates for this procedure. Mifepristone may not be used in patients who are on chronic steroids as it may precipitate Addisonian crisis. Since many CKD patients or posttransplant patients will have one or several of these conditions, many may not be appropriate medical abortion candidates .
Abnormal Uterine Bleeding
Abnormal uterine bleeding (AUB) can be diagnostically challenging in women with renal disease. AUB is defined as menstrual flow outside of normal volume, duration, regularity, or frequency . It is a common complaint, accounting for up to one-third of visits to gynecologists. Because the most common causes of abnormal uterine bleeding in reproductive-aged women with renal disease or transplantation are uterine pathologies such as sexually transmitted infection, myomas, polyps, endometriosis, and adenomyosis, the evaluation of these women should include routine testing for these conditions. However, special attention must be paid to abnormal renal function as a potential cause of AUB.