EXPERIMENTAL AND CLINICAL TRANSPLANTATION

There is a misconception among transplant clinicians that contraception after a successful renal transplant is challenging. This is partly due to the complex nature of transplant patients, where immunosuppression and graft dysfunction create major concerns. In addition, good evidence regarding contraception and transplant is scarce, with most of the evidence extrapolated from observational and case-controlled studies, thus adding to the dilemma of treating these patients. In this review, we closely analyzed the different methods of contraception and critically evaluated the efficacy of the different options for contraception after kidney transplant.

We conclude that contraception after renal transplant is successful with acceptable risk. A multidisciplinary team approach involving obstetricians and transplant clinicians to decide the appropriate timing for conception is recommended. Early counseling on contraception is important to reduce the risk of unplanned pregnancies, improve pregnancy outcomes, and reduce maternal complications in patients after kidney transplant. To ascertain appropriate advice on the method of contraception, individualizing the method of contraception according to a patient’s individual risks and expectations is essential.

Key words : Intrauterine device, Pregnancy, Contraception, Transplantation

The first successful pregnancy in a kidney transplant recipient was reported in 1967.¹ Since then, pregnancy after kidney transplant has become increasingly common.^2,3 In 2006, Josephson and McKay reported greater than 14 000 births after successful pregnancies in women with transplanted organs worldwide.⁴ The risk of rejection with the invention of modern immunosuppression has been reduced significantly, resulting in an increasing number of women of reproductive age with good functioning grafts.^5,6 Ovulation may start as soon as 1 month after transplant; therefore, it is crucial to plan for a timely, safe conception and effective maternity care.^6-8

In 2010, the National Transplantation Pregnancy Registry, founded in 1991 in the United States, reported a 52.4-month mean time from transplant to conception.⁹ However, a meta-analysis of 50 studies reported a shorter time of 38.4 months.¹⁰ Evidence suggests that a period of 1 year after transplant appears to be sufficient to minimize the risk of adverse events due to pregnancy,^11,12 as possible risks of acute rejection and graft loss^3,6,13 and prematurity will be less after this time.^14,15 Adequate graft function before conception (no proteinuria and well-controlled blood pressure) is the key factor toward a safe pregnancy because these 2 conditions are associated with poor outcomes to fetus and pregnant mothers after kidney transplant.^16,17 Major complications to the fetus in pregnant transplant recipients include prematurity, intrauterine growth retardation, and low birth weight.^18-20 The preterm delivery rate is 40% to 60% (whereas it is 5%-15% in the general population).^21,22 Registry data have described pregnancy outcomes and maternal complications after kidney transplant (Table 1).^9,13 Preeclampsia develops in 30% of pregnant kidney transplant patients,²³ with additional risks that include hypertension and poor graft function. In a 2015 retrospective cohort study, Chakhtoura and associates retrospectively followed 129 women on dialysis and after kidney transplant.²⁴ They showed a higher rate of obstetric complications and abnormal smear tests after transplant than before dialysis. Consequently, this study suggested that, after kidney transplant, patients must be closely followed to identify and treat gynecologic issues before and after conception.24 A systematic review and meta-analysis of 1343 studies published between 2000 and 2010 (National Transplantation Pregnancy Registry) reporting data on pregnancy outcomes after kidney transplant were reviewed, with 50 studies selected based on inclusion criteria, representing 4706 pregnancies in 3570 kidney recipients. The overall live birth rate was higher in the kidney recipients than in the general population (73.5% vs 66.7%), with lower rate of miscarriage (14.0% vs 17.1%). However, preeclampsia (27.0% vs 3.8%), gestational diabetes (8.0% vs 3.9%), cesarean delivery (56.9% vs 31.9%), and preterm delivery (45.6% vs 12.5%) were significantly higher in the kidney recipients than in the general population.¹⁰ In 2011, Xu and associates surveyed 647 female kidney recipients and found 133 unplanned pregnancies in 98 recipients. They concluded that education of patients during work-up for kidney transplant with their partners about the risks regarding unplanned pregnancy is important, since both are involved in the decision of choosing the method of contraception that is appropriate for them and the timing of pregnancy. The treating physician and the transplant nurse are the most suitable to provide initial counseling and to reinforce this advice in the outpatient setting.²⁵

Contraception After Kidney Transplantation: Facts and Concerns
Given the pregnancy-associated risks described and the fact that fertility can be efficiently reverted within 1 to 6 months after kidney transplant; it is essential that methods of contraception are discussed before and initiated soon after transplant surgery to prevent premature, unplanned, and unadvised pregnancies.²⁶ These measures would reduce the possible complications and adverse events that might occur during pregnancy after kidney transplant. Other concerns include optimization of immunosuppressive agents (Table 2)²⁷ and antihypertensive medications, since not all medications are safe during pregnancy.^28-30 Methyldopa and labetalol are safe during pregnancy, but others drugs, such as hydralazine and calcium channel blockers, can be used. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists are contraindicated for their teratogenicity.

Methods of Contraception After Kidney Transplantation
There are 2 principal methods of permanent contraception and several temporary methods (Table 3). Permanent methods include female tubal ligation and male vasectomy. Vasectomy has the advantage of having less associated risks of ectopic pregnancy than tubal ligation, but it is a nonreversible and invasive procedure. Temporary methods involve the use of combined hormonal oral contraception, intrauterine devices, vaginal rings, subcutaneous implants, barriers, and natural methods like coitus interruptus.

Combined hormonal contraceptives
The US Centers for Disease Control drafted guidelines for different methods of contraception, including recommendations after solid-organ transplant.³¹ Combined hormonal contraceptives are classified as category 4 in complicated transplant.³¹ Contraceptives containing estrogen and progestin are commonly used in daily practice as they are highly effective and with minimal failure rate (Pearl index, 0.1). In 1981, McLure³² described the failure rates of different contraceptive methods (Table 4) using the Pearl index. The risks with combined hormonal contraceptives are attributed to the estrogen component of these formulations, including exacerbation of migraine headaches, the risk of thromboembolism, and worsening hypertension control.^33,34 In a study of 26 women who used combined low-dose oral contraceptives after renal transplant for at least 18 months, no pregnancy was reported. Combined hormonal contraceptives were prescribed as the main contraceptive method in 58% of women in the study population. In 42% of women, combined hormonal contraceptives were additionally used for reducing the development of ovarian cysts and menorrhagia. These drugs were found to regulate menstrual bleeding patterns and may protect from ovarian cysts.³⁵Contraceptive therapy was stopped in only 2 patients (0.52%): for profound venous thrombosis in 1 patient and deterioration of liver function in the other patient. Combined hormonal contraceptives are primarily metabolized by the cytochrome P4503A4 system; hence, careful attention regarding the drugs’ interactions with calcineurin inhibitors is important in female kidney transplant recipients.³⁶ Patients who have a history of myocardial infarction, stroke, deep venous thrombosis, migraine, and uncontrolled hypertension and patients who have active liver disease or hepatic adenoma are advised not to use combined hormonal contraceptives, as they may aggravate these conditions.²⁶

Depot medroxyprogesterone acetate
Depot medroxyprogesterone acetate (DMPA; Depo-Provera, Pfizer, New York, NY, USA) is a synthetic progestin with slow release over 3 months. It is a highly effective and safe contraceptive method. The failure rate is only 2% due to delay in repeat injections. The reversible decrease in bone density is a concern that normalizes on DMPA cessation.³⁶ The major concern of DMPA is the thromboembolic risk.^37,38 Depot medroxyprogesterone acetate has the advantage of no drug interactions with immunosuppressive medications of transplant patients and is a good choice as long as patients are motivated to adhere to the injection schedule. The metabolism of DMPA is through the liver; therefore, it is not recommended for those with active liver disease.^39-41

Etonogestrel implant
The etonogestrel implant is a single silastic rod (Figure 1) implanted subcutaneously in the upper arm.⁴¹ The effectiveness is > 99%, and the protection lasts for 3 years. On removal, the etonogestrel drops rapidly, with most patients ovulating after 3 weeks. The adverse effect of this method is the bleeding irregularity encountered in a minority of patients.⁴¹ Etonogestrel implant has risk-benefit features similar to DMPA but has been shown to cause fewer decreases in bone mineral density, a concern that is also commonly encountered after transplant due to the effect of steroids on bones.⁴⁴ Etonogestrel implant, a new method of contraception for female kidney recipients, can be safely advised, is highly effective, and is rapidly reversible.⁴⁵

Transdermal contraceptive patch
This system delivers estrogen and progesterone through the transdermal route using a patch placed on the abdomen. The circulating levels of estrogen are substantially higher than with combined hormonal contraceptives. In 2007, Jick and associates showed that the risk with this method is similar to that shown with combined hormonal contraceptives. They evaluated an additional 17 months of data concerning nonfatal venous thromboembolism events for the contraceptive patch, documenting a risk similar to combined hormonal contraceptives.^36,46Some studies have shown more than 2-fold increase in the risk of venous thromboembolism associated with this method.⁴⁷

Progestin-only pills
The advantage of progestin-only pills is the avoidance of estrogen-related risks.⁴⁸ The significant incidence of amenorrhea and the 5% failure rate during the first year are the major concerns; this rate drops to < 0.5% if used correctly and constantly. Progestin-only pills require ensured compliance to reduce failure rates.⁴⁹ Progestin-only pills are orally administered, and, unlike DMPA and etonogestrel implant, they undergo the first-pass metabolism through the liver. Interactions with medications that are metabolized by the liver can occur with progestin-only pills, and they should be avoided in patients with liver disease. Their interaction with calcineurin inhibitors requires proper calcineurin inhibitor monitoring posttransplant. Progestin-only pills increase the risk of weight gain, and both progestin-only pills and calcineurin inhibitors alter the metabolism of lipids in female kidney recipients. Female kidney recipients who smoke or are at risk for cardiovascular problems such as high blood pressure may be able to use progestin-only pills since combined hormonal contraceptives are usually contraindicated for them.

Intrauterine devices
Intrauterine devices (IUDs) are classified as category 2 compared with combined pills, which are classified as category 4 in complicated transplants.³1 Currently available data suggest that immunocompromised women are not at greater risk of developing pelvic infections.^41,50,51 Sinei and associates studied the complications of IUDs among 649 women with human immunodeficiency virus infection and confirmed no increased risk of infection versus patients without human immunodeficiency virus infection.⁵⁰ However, many studies indicated that the risk of infection is significantly increased immediately after IUD insertion in immunocompromised patients.⁵¹ Grimes and associates studied the use of antibiotic prophylaxis for IUD insertion but found this conferred little benefit.⁵¹ The advantages of the IUD include easy insertion, long lasting, and low failure rate (Pearl index, 1-3).⁵² The major advantage of using IUDs is that the effect is reversible after IUD removal, and immunosuppression drug interaction is not a concern in women with kidney transplants. In addition, it is not associated with increased risk of thromboembolism. A prospective study (n = 649) showed no increase in overall complications in women regardless of immune status.⁵⁰ A more recent randomization study (2007) with 599 participants showed no differences in infectious morbidity.51 The levonorgestrel-releasing intrauterine system was shown to reduce menstrual blood loss.^54,55 Many of the studies did not control for potential confounders such as prior pelvic inflammatory disease, sexual behavior, and the presence of sexually transmitted diseases.56 Previous ectopic pregnancy and history of pelvic inflammation are contraindications to the use of IUDs.^57,58 Copper IUD (ParaGard, Teva Women’s Health, North Wales, PA, USA) and the levonorgestrel-releasing intrauterine system (Mirena, Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA) (Figure 2) are both effective and safe to use after kidney transplant.⁵⁹ Copper IUD has an effective duration of 10 years, and the levonorgestrel-releasing intrauterine system lasts for 5 years, rendering these cost-effective and long-lasting methods of contraception for women with kidney transplants.60 Theoretically, posttransplant immunosuppressive medications may decrease the efficacy of IUDs, possibly because they modify the leucocyte response. However, there is no solid evidence suggesting that the safety and effectiveness of the IUD would be compromised in the transplant patient.

The vaginal ring
The vaginal ring (NuvaRing; Organon, Oss, The Netherlands, a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA) is a silastic ring (Figure 3) that is impregnated with etonogestrel and ethinyl estradiol.⁶⁰ It is effective (Pearl index, 1-3),⁶² controls the menstrual cycles,⁶³ and has the advantage of a lower concentration of ethinyl estradiol compared with combined hormonal contraceptives, thus minimizing the adverse events related to ethinyl estradiol.^62,64,65 In a randomized trial, the vaginal ring group showed that exposure to ethinyl estradiol was significantly 3.4 times lower than in the patch group and 2.1 times lower than in the combined hormonal contraception group. Serum ethinyl estradiol levels of patients showed much lower variations with the vaginal ring than with the patch or combined hormonal contraceptives.⁶⁴

Barrier methods of contraception
Barriers (condoms, spermicides, diaphragm, cervical cap, sponges) are less effective contraceptive methods for organ transplant recipients due to the relatively high failure rate (Pearl index, 0.4-1.6) and the difficulty in achieving compliance.^26,32 Barrier success rate can reach 97% if used correctly and consistently. They have the advantage of being a convenient and easy to use method of contraception while also avoiding potential drug interactions, especially with immunosuppressive medications. All of these barrier methods can be used posttransplant but are best when combined with another method of birth control to reduce their potential failure rate.²⁶ Education of couples regarding this method of contraception encourages awareness and compliance and may reduce the failure rate of this method.⁶⁶

Pregnancy after kidney transplant is normal and commonly encountered,^67,68 although the risk of maternal and fetal complications is higher than in the general population.^16,21,69 Early counseling, ideally before transplant, to discuss the methods of contraception and to allow women to make an informed choice regarding contraception and subsequent pregnancy is of paramount importance. It sounds logical that patients must be made aware of the benefits and risks of each method used after transplant by proper education. An effective and suitable contraception is important to reduce the risk of unplanned pregnancy.^70-73 Women must be aware of the effects of pregnancy on graft function, fetal well-being, and maternal complications. These risks associated with pregnancy after kidney transplant may encourage some patients to select a permanent method of contraception if they do not want children.

Kidney transplant recipients are advised to delay pregnancy for a minimum of 1 year after transplant to reduce potential neonatal and maternal complications.⁷⁴ Different methods of contraception can be used after kidney transplant. Combined hormonal contraceptives are commonly used for their effectiveness. The benefits of estrogen-based contraceptives in an uncomplicated stable transplant recipient who have no contraindication to use combined hormonal contraceptives likely outweigh the potential for harm. Intrauterine devices are an effective method of contraception and should be considered as a safe and an effective method after transplant with no evidence to suggest increased infection rate in kidney transplant recipients.⁷⁵ Permanent methods of contraception are valid options for couples who decide not to have children. A multidisciplinary team approach involving obstetricians and nephrologists should be adopted to decide the appropriate timing for conception, ascertain appropriate follow-up, and advise on methods of contraception that suit the patient. There is no ideal contraceptive method; the best is to individualize the method of contraception according to a patient’s individual risk.

Volume: 14 Issue: 3 June 2016

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