After organ transplantation, patients are prone to unwanted pregnancies as hypothalamic-gonadal axis function improves and sexual function and fertility gradually return. This can pose a risk to the transplant recipient, the graft, and the next generation. Therefore, it is important to use contraception for transplant recipients of childbearing age. Transplant recipients who wish to become pregnant must also use contraception until they reach the desired state of pregnancy. The question of what type of contraception is more reasonable and how to properly use it after transplantation is an important issue for transplant recipients and must be actively addressed by medical professionals and transplant recipients. Improper choice of post-transplant contraceptive methods can have serious consequences. Currently, there is not much information on post-transplantation contraception. This article reviews the current status of international research on post-transplantation contraception.
I. Organ transplantation and changes in fertility
Hypothalamic-pituitary-gonadal axis dysfunction and impaired follicle or sperm formation are common in patients with end-stage cardiac, pulmonary, hepatic, renal and other vital organ insufficiency, which can manifest as various forms of menstrual disorders, hypogonadism, infertility and other complications. After organ transplantation, the patient’s hypothalamic-gonadal axis function gradually improves. After kidney transplantation some recipients resume menstruation 1 month after transplantation, most recipients return to normal gonadal function 6 months after transplantation, and ovulation resumes in fertile women, while a few transplanted women may also experience menstrual disorders. The first menstruation in fertile women with liver transplantation occurs 1-8 months after surgery, and pregnancy is possible within 1 month after surgery. 97% of menstruation returns to normal within 1 year after surgery. Other organ transplants have a similar recovery process .
Lessan-Pezeshki et al. reported that 16 of 33 post-transplant pregnancies were unwanted, accounting for 48.5% of unwanted pregnancies. Recently Guazzelli et al. reported a group of post-transplant pregnancies in which 13 out of 14 pregnancies were unwanted, accounting for 93% of unwanted pregnancies. Unwanted pregnancy poses many risks to the transplant recipient, the graft and the fetus. Therefore, to prevent unwanted pregnancies after transplantation, the issue of contraception in patients of childbearing age should be emphasized before transplantation. Most authors recommend the use of contraception before discharge from the hospital after transplantation.
II. Choice of contraceptive methods after organ transplantation
1. Barrier contraception (BARR): BARR includes condoms, vaginal diaphragm and cervical cap, etc. Condoms are also available for men and women. WHO reported that the contraceptive failure rate (use failure rate) of male condoms in the first year of usual use (typically use) is 15%, and the contraceptive failure rate (method failure rate) under continuous and correct use is 2% respectively. The use of BARR in transplant recipients is controversial because of its high failure rate if not used consistently and correctly. It is generally accepted that BARR is suitable for use in the early post-transplant period for a short period of time or for the prevention of sexually transmitted diseases.
2.Estrogen and progestin combination preparation
(1) Combination oral contraceptives (COC): COC contains both estrogen (e.g. ethinyl estradiol, EE) and progestin (e.g. norethindrone). At present, the use rate of COC is about 50% in developed countries in Europe and America, and 2% in China. 8% failure rate in the first year of use of COC, and 0.3% failure rate in the method. the contraceptive effect of COC is reliable, and it does not affect the pregnancy again after stopping, so it has become a widely used contraceptive method in the world, and post-transplant contraception is also widely used. The COC used in the early years contained more than 50ug of EE per tablet and was prone to estrogen-related tumors (e.g., breast cancer, cervical cancer) and vascular embolic diseases (e.g., venous thrombosis, myocardial infarction). The COCs used now contain 30-35 μg of EE or even 20 μg or 15 μg of EE, and with the continuous improvement of progestin types, side effects are significantly reduced.
The effects of COC on transplanted and non-transplanted organs are similar and not specific. COC acts mainly by affecting the metabolism of immunosuppressants and affecting the concentration of immunosuppressants, which can manifest as side effects such as rejection reactions or drug toxicity of immunosuppressants. 3A4 enzymes, thus increasing the concentration of the corresponding drug. For example, COC increases the concentrations of calcium-modulated neurophosphatase inhibitors (cyclosporine, tacrolimus) and sirolimus, which are also substrates of P-450 3A4 enzymes. COC concentrations vary due to differences in metabolism among individuals. COC concentrations may decrease with the use of mycophenolate esters and other GI symptoms such as diarrhea, etc. COC also decreases clearance of certain corticosteroids and can increase plasma concentrations of prednisone by up to 30%. Therefore, immunosuppressive blood concentrations should be closely monitored when using COC.
Under routine COC usage, elevated immunosuppressive concentrations may occur on the 21 days of contraceptive hormone use, while immunosuppressive concentrations may decrease on the 7 days of contraceptive discontinuation. Therefore, switching to a long-cycle COC can reduce the number of periodic discontinuations of COC, reduce the number of fluctuations in immunosuppressant concentrations, and reduce the risk of rejection reactions and drug toxicities. To avoid fluctuations in immunosuppressive drug concentrations, an uninterrupted COC regimen was recently proposed by Sucato et al. and Waite et al.
COC also interacts with other drugs used by transplant recipients. The use of hepatic enzyme P-450 3A4 inhibitors such as the antifungals ketoconazole, fluconazole, itraconazole, or their substrates such as statin lipid-lowering drugs can increase the concentration of steroidal contraceptives and increase side effects, and if necessary, the dose of contraceptives can be appropriately reduced or switched to a very low dose of COC (containing 15-20 μg EE). In contrast, the use of hepatic enzyme P-450 3A4 inducers, such as the anti-tuberculosis drugs rifampin and rifapentine, and the anti-epileptic drugs phenytoin sodium, carbamazepine and topiramate, can accelerate the clearance of EE and/or progesterone and reduce the contraceptive efficiency of the contraceptive pill. This can be done by switching to a low dose of COC (containing 30-35 μg EE) or increasing the amount of COC taken appropriately, and adding other remedies (e.g. condoms) if necessary. At this time, cyclosporine, tacrolimus and sirolimus concentrations will also increase or decrease accordingly, and the dose should also be adjusted according to the concentration.
Estrogen is a prothrombotic factor or hypercoagulable factor (prothrombotic factor) that increases the synthesis of certain coagulation factors (especially coagulation factors VII and X and fibrinogen) by the liver and has a procoagulant effect. The annual incidence of venous thrombosis in the currently used low-dose COC is about 2/10,000, which is about twice as high as in the general population. Some patients on COC may also develop hypertension, hyperlipidemia and hyperglycemia. Therefore, COC should not be used in patients with a hypercoagulable state or thrombotic tendency after transplantation, and in patients with uncontrollable hypertension. heart transplantation patients with a 40% incidence of coronary artery disease 2-5 years after transplantation should also be contraindicated in patients who develop these coronary artery diseases. transplant recipients are prone to hypertension. The WHO considers hypertension with systolic blood pressure ≥ 160 mmHg, or diastolic blood pressure ≥ 100 mmHg to be a contraindication to the application of COC. However, in patients with well-controlled hypertension, the advantages of using COC outweigh the disadvantages.
There is little literature related to the use of COC in transplant recipients. Recently Pietrzak et al. reported 26 female renal transplant cases on a low-dose estrogen (20-35 μg of EE) COC regimen for contraception and none of them became pregnant. Jabiry-Zieniewicz et al. recently reported 9 cases of women with liver transplants on a very low-dose estrogen (20 μg EE) COC regimen without any pregnancies and without any side effects such as cardiovascular events, deep vein thrombosis, or severe headaches. Also, all of the above studies showed good improvement in menstrual disorders and a significant improvement in quality of life in the recipients.
In conclusion, as noted by McKay et al. at the 2005 American Society for Transplantation (AST) Consensus Conference on Reproductive Issues and Transplantation, despite limited data, there is no reason to believe that the use of low-dose CO The use of low-dose COCs in the setting of well-controlled blood pressure after transplantation has been shown to have adverse consequences. With attention to complications, drug interactions, and the exclusion of contraindications to estrogen application, low-dose COC can be considered 6-8 months after graft function returns to normal after transplantation.
(2) Compounded contraceptive patch (CP) and compounded vaginal ring (CR): the failure rate and method failure rate of these two methods in the first year of use are the same as COC. CR (Nuva ring) is a monthly ring. The ring releases 15ug of EE and 120ug of etonogestrel per day. Both methods are not administered orally, thus bypassing the first-pass metabolic pathways in the intestinal wall and liver. According to the available data, the indications for their use should be the same as for COC. in transplant recipients, Pietrzak et al [2] recently reported that 10 renal transplant women of childbearing age used CP for 18 months without any pregnancy, without any complications such as venous thrombosis or cardiovascular events, with stable renal function and no changes in liver function, lipids, or glucose. jabiry-Zieniewicz et al [3] also recently reported 6 cases of liver transplant women using CP without a single pregnancy or complications.
3. Progestin-only preparations
Patients with contraindications to estrogen use can use progestin-only contraceptive methods.Waite et al. concluded that progestin contraception should be the preferred choice for pharmacological contraception in transplant recipients. There are currently several delivery methods for progestin contraception such as oral pills, injectables, dermal (subcutaneous) implants, and IUD release systems. Progestin has a low impact on the liver and rarely affects the metabolism of other drugs. However, it also inhibits hepatic P-450 3A4 enzymes to some extent, so it is still necessary to pay attention to changes in drug concentrations of immunosuppressive drugs.
(1) Progestin-only pill: Its contraceptive efficiency is the same as that of COC; this contraceptive method needs to be taken regularly every day, and if it is not taken in time, contraceptive failure may easily occur. Irregular vaginal bleeding can occur with this contraceptive method. For transplant recipients, it is not a bad choice because it does not contain estrogen and has less effect on immunosuppression.
(2) Medroxyprogesterone acetate injection (DMPA): DMPA is effective in contraception, with a failure rate of 3% in the first year of use and a method failure rate of 0.3%. It is a slow-release, long-acting preparation, which is given once every 11 to 13 weeks and is popular among women of childbearing age. DMPA is metabolized in the liver. In liver disease, the indication for safe use was considered to be limited to hepatitis virus carriers, and in 2008 the WHO revised the indication based on evidence-based medical data, stating that DMPA or other progestin preparations are safe for use in patients with liver disease, including hepatitis virus carriers, acute or chronic hepatitis, and compensated cirrhosis [19]. There are no reports on the use of DMPA in transplant recipients. Based on its good safety record, the use of DMPA should not be contraindicated after liver transplantation with normal liver function.Scholes et al. reported in recent years that the use of this drug is also associated with reduced bone mineral density and many transplant recipients have osteoporosis before and after transplantation, therefore, its use requires additional attention and should be accompanied by more exercise and maintenance of adequate calcium and vitamin D intake.DMPA during the initial period of use (first 8 months) Irregular vaginal bleeding is likely to occur, and amenorrhea is likely to occur with long-term use. Therefore, it should not be used for those who want to get pregnant in the near future.
(3) Progestin dermal implant: At present, the main methods used internationally are levonorgestrel dermal implant (Norplant) and etopregnant dermal implant (Implanon). The contraceptive effect of this method is exact, and the failure rate of the first year of use and method failure rate of both methods are 0.05%. Contraceptive validity is 3-5 years. Their safety profile is similar to that of DMPA, and neither causes bone mineral loss. There are no reports on the use of progestin dermal implants in organ transplantation, and based on their long-term record of safe use, they may also be safe for use in transplant recipients.
(4) Progestin IUD release system: Currently, the main use is the levonorgestrel IUD release system (LNG-IUS). LNG-IUS combines the characteristics of both progestin and intrauterine device (IUD) with reliable contraceptive effect (see below).
4. IUD: IUD is a long-term, safe, efficient, easy, economical and reversible contraceptive measure. The most representative ones recommended by WHO are TCu-380A and LNG-IUS. the failure rate of the two methods in the first year of use is 0.8% and 0.1% respectively, and the method failure rate is 0.6% and 0.1% respectively. The two methods are valid for 10 years and 5 years, respectively. IUD is currently used by about 150 million people worldwide and about 100 million people in China, accounting for 2/3 of the world. recently, IUD contraception has received renewed attention from developed countries such as Europe and the United States [24].
For transplant recipients, IUD use was generally not advocated in the past [2]. This was mainly based on two reasons. One is the belief that IUDs exert their contraceptive effect through their local inflammatory response in the uterus. After organ transplantation, the local inflammatory response decreases and the efficiency of contraception decreases due to the long-term application of immunosuppressive drugs in the transplant recipient. The second is the belief that the use of IUDs is prone to infectious complications. However, recently Estes et al. of Columbia University, USA, suggested that this view is wrong [25].
Studying the mechanism of IUD contraception, it is now certain that the local foreign body reaction in the uterus plays a major role in IUD contraception, and there is evidence that IUD affects sperm function and sperm movement in the uterine cavity and fallopian tubes, affecting fertilized egg implantation [23]. In addition, copper ions from copper-containing IUDs have toxic effects on sperm and fertilized eggs; progesterone from the progestogen-releasing system of IUDs can thicken cervical mucus and thin the endometrium, which is detrimental to sperm motility and fertilized egg implantation [23].
Ortiz et al [26] recently reported evidence that destruction of sperm and fertilized eggs by macrophages plays the most important role in IUD contraception. In contrast, immunosuppressive agents used in transplant recipients have less impact on macrophage activation and their function. For example, calcium-regulated neurophosphatase inhibitors, antimetabolites, rapamycin, dalizumab, and baliximab all act by blocking the proliferation and activation of T cells. Rabbit anti-human thymoglobulin works by destroying host T cells, and CD3 monoclonal antibody (OKT3) works by directly inactivating CD3-positive T cells. In contrast, corticosteroids regulate the immune response by decreasing the production of inflammatory mediators and reducing the production of intracellular transcription factors that can upregulate the activity of immune cells. Moreover, corticosteroids also activate a pro-inflammatory mediator, macrophage movement inhibitory factor (MIF), which actually increases macrophage activity [27]. Therefore, there is no reason to assume that the efficiency of contraception in transplant recipients with an IUD would be reduced. Although Zerner et al. had reported 2 cases of contraceptive failure using IUD in kidney transplant recipients in 1981, there have been no similar reports since then.
There have been no reports of increased pelvic and cervical infections in transplant recipients with IUD use. A recent study of IUD use in HIV-infected women in Africa may provide insight into this study.Morrison et al [28] conducted a prospective study of 156 HIV-positive and 493 HIV-negative women in Kenya using copper IUD for contraception with a follow-up of 24 months, 16/150 (10.7%) HIV-positive women and 43/486 (8.8 %) HIV-negative women developed complications of infection. There was no significant difference in the incidence of infection between the two groups by COX regression analysis. The incidence of pelvic infections was low in both groups, with three cases in the HIV-positive group and two cases in the HIV-negative group, all of which were cured in the outpatient setting.The WHO medical criteria for contraceptive method selection have changed the use of IUD for HIV-infected patients from a category 3 method (application of more harm than benefit) to a category 2 (application of more benefit than harm) [10]. Although immunosuppression in HIV infection cannot be exactly equated with medically induced immunosuppression in transplant recipients, they are very similar in that both can cause immunodeficiency, mainly T-cell immune deficiency.
Accordingly, Estes et al. concluded that IUD is one of the most effective contraceptive methods for transplant recipients [25]. Of course, the effectiveness of IUD use in the transplant population and the complications of infection need to be further studied.
IUD hardly affects other drug treatments. Copper IUD has no interaction with other drugs and does not affect immunosuppressive concentrations. With LNG-IUS, blood concentrations of levonorgestrel are very low, only 375 pg/L at 6 months of use [29], and are also unlikely to affect anti-rejection drug concentrations.WHO does not require routine screening for gonorrhea and chlamydia prior to IUD placement [10], but screening and treatment of positive cases should be beneficial in transplant recipients using immunosuppressive drugs.
5. emergency contraception: emergency contraception can prevent pregnancy within 3-5 days after unprotected intercourse. This can be done with oral high-dose progestin, or high-dose estrogen-progestin combination, or progestin antagonists [30], or with the placement of a copper-containing intrauterine device, TCu380A [31]. Emergency contraception can prevent 75-85% of pregnancies [7,10]. Progestin emergency contraception is safe and effective and is often used in preference. Levonorgestrel can be administered as a single dose (1.5 mg) or as two doses (0.75 mg for the first dose, followed by 0.75 mg 12 hours later). There are no reports on the use of emergency contraception in organ transplantation. Given that transplant recipients account for more than half of unwanted pregnancies, all sexually active transplant recipients should know about emergency contraception [7,16].
6. in vitro fertilization: the failure rate of this method is 27% in the first year of use,and the method failure rate is 4% [10]. According to Lessan-Pezeshki et al [5] reported that 16 out of 33 cases of post-transplant pregnancy were unwanted pregnancies, 15 of which (92%) were caused by the use of in vitro fertilization method of contraception. Therefore the method has a high failure rate and should not be used [2].
7, sterilization: the failure rate of male and female sterilization in the first year of use was 0.15% and 0.5%, respectively, and the method failure rate was 0.1% and 0.5%, respectively [10]. If fertility is not intended after transplantation, sterilization is feasible for the patient himself or his spouse [2].
III. Summary
Due to the rapid recovery of fertility after transplantation, active attention must be paid to post-transplantation contraception. The choice of post-transplantation contraceptive methods depends mainly on the transplant recipient’s own status, the characteristics and side effects of the various contraceptive methods themselves, the cost of their use, and local religious culture, laws and regulations [2-4,7,9-12]. The choice of contraceptive methods is often complex and should be decided by transplantation specialists, family planning specialists and transplant recipients based on a comprehensive analysis of the pros and cons of each case [6]. The ideal contraceptive method should not only be a comprehensive measure of the possible advantages and disadvantages of the method for the transplant recipient, but also its cost and the patient’s wishes [12]. The choice of post-transplant contraceptive method needs further research and continuous improvement in practice.