Year : 2021 | Volume
: 11 | Issue : 4 | Page : 13--17
Contraception: What to use after a solid-organ transplant?
Kunur Nikhilesh Shah, Sumesh Divakant Choudhary, Vineet V Mishra, Rohina S Aggarwal
Department of Obstetrics and Gynecology, Institute of Kidney Diseases and Research Center-ITS, Ahmedabad, Gujarat, India
Kunur Nikhilesh Shah
Department of Obstetrics and Gynecology, Institute of Kidney Diseases and Research Center (IKDRC and ITS), B.J. Medical College, Civil Hospital, Ahmedabad - 380 016, Gujarat
Solid-organ transplant increases the physical and mental well-being of women suffering from chronic kidney diseases. It also improves the menstrual and reproductive function of the transplant recipient, putting a woman at risk of unplanned pregnancy. Various contraceptive options are available to such women. According to the World Health Organization Medical Eligibility Criteria, almost all contraceptive methods belong to Category 2 for uncomplicated post-transplant recipients. For complicated renal-transplant patients, intra-uterine devices are Category 3/2, and combined hormonal contraceptives are Category 4. It is of paramount importance to discuss the pros and cons of each method, and this counselling should be included routinely before undergoing transplant surgery.
|How to cite this article:|
Shah KN, Choudhary SD, Mishra VV, Aggarwal RS. Contraception: What to use after a solid-organ transplant?.Adv Hum Biol 2021;11:13-17
|How to cite this URL:|
Shah KN, Choudhary SD, Mishra VV, Aggarwal RS. Contraception: What to use after a solid-organ transplant?. Adv Hum Biol [serial online] 2021 [cited 2021 Dec 4 ];11:13-17
Available from: https://www.aihbonline.com/text.asp?2021/11/4/13/328401
End-stage renal disease is a chronic debilitating condition that affects the physical, emotional, psychological and economic well-being of an individual. Transplantation significantly improves the quality of lives of such women. Patients undergoing solid-organ transplantation have experienced increased graft survival rates over the past several decades. Before transplantation, a woman may find it difficult to conceive or avoids pregnancy due to multiple health risks, but restoration of fertility and subsequent successful pregnancies have been reported after solid-organ transplantation. These pregnancies are high-risk pregnancies, so it is advisable to avoid pregnancy till the patient's clinical condition stabilises.
There is a debate regarding the ideal time of conception following solid-organ transplant. The various guideline has variable opinions regarding the same. The American Society of Transplantation suggests an ideal time between 1- and 2-year post-renal transplant. According to the European best practice guideline, it is advisable to delay pregnancy for 2-year post-transplant. Recent studies reported higher chances of graft rejection if pregnancies occur in 1- or 2-year post-transplant. On the other hand, mortality and graft rejection were lower if pregnancies occur more than 2 years after transplant. This time is essential for stabilising the graft function, completion of viral prophylaxis and reduction of doses of immunosuppressive medications to the lowest level. As there is the return of menstruation and fertility potential after solid-organ transplant, contraception is required to delay pregnancies.
Guazzelli et al. reported that <50% (48.7%) women were given contraceptive advice, and only 72% of women were actually using one or the other method of contraception effectively. They also found a reduction (86% vs. 71%) in the use of contraception after the transplant as compared to pre-transplant. There is a paucity of data regarding the incidence of unplanned pregnancies among solid-organ transplant recipients in India, but the health risks of unplanned and high-risk pregnancy cannot be neglected. That is why it is advisable to have an obstetrician review to discuss contraception options before transplant and to start the same after transplantation.
Choice of Contraception
The choice of the best available contraceptive for solid-organ–transplant recipient is challenging due to the complex nature of transplant patients, where immunosuppressant and graft dysfunction create major concerns. The dilemma arises while treating these patients as most of the information are derived from observational and case–controlled studies, and there is a scarcity of good evidence. This review provides information regarding various methods of contraception available for post–solid-organ–transplant recipients along with evidence level.
Medical Eligibility Criteria
The World Health Organization (WHO) has classified contraceptive methods according to their risks and benefits in various health conditions. These are called medical eligibility criteria (MEC). There are four categories. Category 1: No restriction for the use of the contraceptive method, Category 2: A condition where the advantages of using the method generally outweigh the theoretical or proven risks, Category 3: A condition where the theoretical or proven risks usually outweigh the advantages of using the method, Category 4: A condition which represents an unacceptable health risk if the contraceptive method is used. Centers for Disease Control and Prevention (CDC) has given a list of conditions associated with an increased risk of adverse health events as a result of pregnancy, and solid-organ transplant within 2 years is one of them.
All contraceptive methods, including copper intra-uterine device (Cu IUD), levonorgestrel intra-uterine system (LNG-IUS), subdermal implant, depot medroxyprogesterone acetate (DMPA), Progestogen-only pills (POP) and combined hormonal contraception (CHC) methods, belong to Category 2 for an uncomplicated solid-organ transplant. For patients with complicated post-organ transplant (acute or chronic), e.g. graft rejection and cardiac allograft vasculopathy, initiation of Cu IUD and LNG-IUS is Category 3, while continuation is Category 2. CHC belongs to Category 4 in the case of complicated solid-organ–transplant recipients. Individualisation of the suitable contraceptive method as per the patient's own health risks should be done.
Male and female condoms can be used as a primary method of contraception or as an additional method, either short term (e.g. while starting hormonal contraception) or long term (to provide double protection). Consistent and correct use of condoms is the most efficient means of protecting against HIV and other sexually transmitted infections (STIs). Studies from the USA have concluded that with perfect (i.e., correct and consistent) use, there is a 5% failure rate with the female condom and a 2% failure rate with the male condom. With typical use (which includes incorrect and inconsistent use), the failure rates are 21% and 18%, respectively. Thus, condoms are simple, cheap, easy to use, without risk of drug interaction but with limited effectiveness in typical users, so this method of contraception should be combined with other more effective methods to provide protection against transmission of HIV and other STIs in already immunocompromised post-transplant recipients.
Combined Hormonal Contraception
Contraceptives containing a combination of oestrogen and progesterone comes in a variety of formulations, oral pills, vaginal ring and transdermal patches. Variation in oestrogen dose and progesterone types has been observed amongst different brands. Apart from higher effectiveness and lower failure rates, it has certain non-contraceptive benefits such as regularisation of the menstrual cycle, improvement in acne and hirsutism. A Cochrane review compared various types of CHC (pill, patch and ring) and concluded that all these methods have similar effectiveness. 0.3% of perfect (consistent and correct) users and 9% of typical (inconsistent and incorrect) users experienced unplanned pregnancy during the 1st year.
The oestrogen component is often contraindicated in comorbidities associated with post-transplant such as the history of thrombosis, severe uncontrolled hypertension, the recent history of myocardial infarction, migraine with aura and active liver disease. Specific to post-transplant recipients, CHC is contraindicated in women with cardiac allograft vasculopathy, acute or chronic graft rejection. A major concern associated with combined oral contraceptives (COCs) is a drug interaction with various immunosuppressors taken by post-transplant patients. Primarily, COCs are metabolised by the cytochrome P4503A4 system in the liver. Glucocorticoids, tacrolimus, sirolimus and azathioprine are metabolised by the liver and may interact with the metabolism and effectiveness of COCs. Although glucocorticoids are known to induce this enzyme, there is no clinical evidence that glucocorticoids impair the effectiveness of oral contraceptives. Seidegård et al. demonstrated that concentration and contraceptive efficacy are unchanged in the presence of glucocorticoids. The oestrogen component of COCs can lead to cholestasis, so patients should be monitored for the same. Pietrzak et al. studied the safety of COC use (for at least 18 months) in 26 post-renal–transplant recipients and reported no pregnancies in this cohort. They also concluded that COCs do not alter body mass index, mean blood pressure, serum creatinine and biochemical parameters (aspartate transaminase, alanine aminotransferase, total bilirubin, glucose and cholesterol). However, COCs had to be discontinued in two patients due to venous thrombosis in one and deterioration of liver function in the other. In their retrospective analysis of 15 post-liver–transplant recipients receiving low-dose COCs for at least 12 months, Jabiry-Zieniewicz et al. found no pregnancy, graft rejection or drug discontinuation. No significant changes in the liver enzymes and serum bilirubin levels were observed.
Transdermal contraceptive patch (TCP) is a novel delivery system that delivers oestrogen and progesterone transdermal through a patch placed on the maternal abdomen or inner aspect of the thigh. It requires only three applications a month (once a week), but it gives a higher circulating estrogen level as compared to COCs and vaginal ring. Jick et al., in their study, showed that the risk of non-fatal venous thromboembolism with transdermal patches is similar to that shown with combined hormonal contraceptives. Comparison of TCP versus COC use in post-renal–transplant patients concluded that transdermal mode of administration reduces chances of drug interaction and therefore safer for post-transplant patients.
Vaginal ring (NuvaRing®) is a Silastic ring impregnated with oetonogestrel (ENG) and ethinyl estradiol, requiring once a month application. Circulating levels of ethinyl estradiol are lower with the vaginal ring than those seen among COC users. Paternoster et al. studied the efficacy of vaginal rings among nine renal and eight liver-transplant patients who initiated the ring after 6 months of stable graft function and were followed up for 12 cycles. There were no unintended pregnancies and no intolerance issues. Hence, they concluded that vaginal rings are superior to oral and transdermal patches since they avoid the first-pass metabolism in the liver.
These methods are mainly useful in patients where oestrogen is contraindicated. There are three varieties available: Progestogen-only pills (POP), progestogen-only injectable and progestogen-only subdermal implant. Synthetic progestogen is used in various dosages and types in these contraceptives with more or less similar benefit and drawback profile.
Pearl index (PI) for levenorgesterol (LNG) containing POP was 1.41 as compared to 0.17 for desogestrel containing POPs. High hepatic first-pass metabolism makes it prone to efficacy reduction by cytochrome P450 enzyme inducers. POP has to be taken at the same time every day for maximum effect, along with lesser effective CHC. This makes it less popular among transplant recipients who are already on multiple medications. It has various side effects such as weight gain, amenorrhoea or irregular bleeding, drug interaction with calcineurin inhibitors and glucocorticoids and alteration in lipid metabolism.
Progestogen-only injectable includes DMPA. It is synthetic progesterone to be given intramuscularly at every 12 weeks interval. The failure rate of DMPA is 0.2% for perfect users and 6% for typical users. It has the advantage of bypassing the hepatic first-pass metabolism, so no major interactions with immunosuppressors are observed. It has several drawbacks. The most common one being amenorrhoea or irregular bleeding. Twenty-five percent of women receiving DMPA reported amenorrhea at 1 year, and 80% reported amenorrhea at 5 years. There is a delay in the return of fertility for 1 year after discontinuing DMPA. A systematic review undertaken by the NICE concluded that DMPA use is associated with a small loss of bone mineral density (BMD), which is largely recovered when DMPA is discontinued. The Medicines and Healthcare Products Regulatory Agency advises against using DMPA as a first-line drug in young women below 18 years and in women at high risk of osteoporosis (e.g. post-organ transplant and patients on steroids) where other options are available.
The progestogen-only implant is a single, non-biodegradable, subdermal rod licensed for up to 3 years of use., Each implant contains 68 mg ENG. The main difference between Nexplanon and Implanon is that barium sulphate has been added to nexplanon to enable detection by X-ray., The risk–benefit profile of Implanon is nearly similar to that of DMPA, except for reduction in BMD. There is a lack of data regarding the use of Implanon among organ-transplant recipients; however, owing to its similarity with other drugs having long safety data, its use among organ-transplant patients is likely to be safe.
Intra-Uterine Contraceptive Devices
They are a highly effective and reversible form of birth control. Intra-uterine contraceptive devicess are considered as long-acting reversible contraceptives (LARCs). They are more cost-effective for post-transplant patients than other short duration methods such as CHC., There are two subtypes: (1) Cu IUD nd (2) LNG-IUS. 52 mg LNG-IUS (Mirena) releases approximately 20 μg LNG per day, reducing to approximately 10 μg per day after 5 years. The 13.5 mg LNG-IUS (Jaydess) is licensed for contraception and has a release rate of approximately 14 μg per day for the first 24 days, decreasing to 5 μg per day after 3 years. the European Active Surveillance Study for IUDs found that PI (PI = pregnancies per 100 woman-years) of 0.06 for LNG-IUS and 0.52 for Cu IUD. Both devices have nearly similar effectiveness and safety profile. Cu IUD is effective for 3–10 years, while LNG-IUS is effective for 5 years.
In 2005, the American Society of Transplantation published a consensus statement and raised two major concerns associated with the use of IUD. The first is its reduced effectiveness due to chronic immunosuppression, and the second one is it increases the possibility of infection in already immunocompromised patients. This theoretical risk of reduced effectiveness is believed to be due to an IUD's mechanism of action is dependent on a local inflammatory response in the endometrium where macrophages play a major role in the destruction of ova and sperm. The immunosuppressive agents have minimal effects on the activation and function of macrophages. The mechanism of action of calcineurin inhibitors, antimetabolites, rapamycin, daclizumab and basiliximab is by preventing the activation of T-cells. Muromonab-CD3 (OKT-3) works by directly inactivating CD-3-positive T-cells. Corticosteroids may increase the activity of macrophages by activating macrophage migration inhibiting factor. In a Chinese study published in 2011, 178 amongst 647 post-renal–transplant recipients used IUDs, and none reported unwanted pregnancy. Many studies have proven the effectiveness of LNG-IUS in post-transplant patients.,, Thus, there is no reduction in the efficacy of IUC in immunocompromised patients or patients receiving immunosuppressive medications.
On addressing the second concern of increased risk of pelvic inflammatory disease (PID) in immunocompromised transplant recipients, the data can be extrapolated from the use of IUC in HIV-positive patients as there are limited studies available. Morrison et al. found no difference in the incidence of pelvic infection in HIV versus non-HIV patients. In small retrospective review and case series of LNG-IUS in post-renal–transplant and liver–transplant patients, no case of PID was reported., A large retrospective cohort study identifies no association between screening and reduction in the incidence of STI. It is advisable to take detailed sexual history before inserting IUC to identify patients at high risk of contracting STI who will require further STI testing. Cochrane Review examined the effectiveness of prophylactic antibiotic administration, before IUD insertion, in reducing IUD-related complications and discontinuations within 3 months of insertion. It concluded that the risk of IUD-related infections was low, with or without antibioticprophylaxis.
There are few additional advantages for LNG-IUS. The 52 mg LNG-IUS is very effective in reducing menstrual blood loss and more effective at improving quality of life than other medical treatments for heavy menstrual bleeding. Various studies have proven the efficacy of LNG-IUS in reducing severe pain due to primary dysmenorrhoea, endometriosis and adenomyosis.,, All these make IUC a suitable contraceptive for post-transplant recipients.
In case of unprotected sexual intercourse (UPSI) or failure of barrier or any other methods of contraception, a woman can use emergency contraception (EC) for up to 5 days. There are mainly three methods available: Cu IUD, LNG-EC, ulipristal acetate EC (UPA-EC). Later two methods act by interfering with ovulation, so not effective if ovulation has already taken place. Cu IUD is the most effective method and the only effective method if ovulation has already occurred. There is no restriction on the use of EC pills in post-transplant recipients, and both are included as MEC 1 Category. The use of IUD as a method of EC should only be avoided in cases of active or symptomatic STI to avoid a flare-up of infection. A Cochrane Review in 2010 and a systematic review in 2013 concluded that advance provision of oral EC did not reduce pregnancy rates when compared to conventional provision, although EC was taken more frequently and sooner after UPSI if supplied in advance. In view of comorbidities of post-transplant patients and risks involved in unplanned pregnancies, advance prevision of LNG-EC or UPA-EC is appropriate along with usage information, explaining the need for follow-up and risk of STI due to UPSI.
Menstruation, libido and fertility returns within few weeks to months after a solid-organ transplant. Therefore, contraceptive options should be discussed with the woman at multiple poin'ts of times, including during puberty, pre-transplant, at the time of discharge and during post-transplant OPD visits. WHO, CDC and FSRH have suggested multiple contraceptive options available for post-transplant patients. The preferred method should have a low failure rate, fewer side effects, minimal drug interactions and prompt reversal of fertility after stoppage of the use. LARC, including IUD and subdermal implant, fulfil the above-mentioned criteria. There should be a 'Cafeteria Approach', which means discussing all available contraceptive options with the patient along with their pros and cons and involving the patient herself in decision-making.
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Conflicts of interest
There are no conflicts of interest.
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