|Year : 2008 | Volume
| Issue : 2 | Page : 165-173
|Pregnancy and Contraceptive Issues in Renal Transplant Recipients
Kanoo Kidney Centre, Dammam Central Hospital, Dammam, Saudi Arabia
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| Abstract|| |
Fertility is improved within months and conception is achieved within one to six years after kidney transplantation. Pregnancy is safe and has little effect on long-term graft survival, but has increased maternal and fetal risks. Pregnancy is contraindicated in the first two years post-kidney transplantation due to increased risk of acute rejections and higher doses of immunosuppressive drugs. Poor renal function, uncontrolled diabetes mellitus and hypertension are other contraindications. Family planning and counseling, and consideration of a suitable contraceptive method are essential before transplantation. Tubal ligation and vasectomy are permanent contraceptives with the least failure results. Combined pills are highly effective and are among the lowest failure rate contraceptives, but they interact with cyclosporine, and are contraindicated in patients with thromboembolism and deep vein thrombosis. Progesterone-only minipill has the advantage of avoiding the risks associated with estrogen, but has a higher failure rate than the combined pills. The barrier methods (condom and diaphragm) are effective and safe contraceptives and can prevent sexually transmitted diseases, but require motivated couples. Intra uterine devices are convenient contraceptives, but have higher failure rate and are associated with increased incidence of pelvic infection. Pregnancy in renal transplant recipients should be managed by a multidisciplinary approach in a tertiary centre.
Keywords: Pregnancy, Contraception, Fertility, Renal recipient, Kidney transplantation
|How to cite this article:|
Karkar A. Pregnancy and Contraceptive Issues in Renal Transplant Recipients. Saudi J Kidney Dis Transpl 2008;19:165-73
| Pregnancy in renal transplant recipients|| |
It is always a dream for patients with chronic renal failure (CRF) on regular dialysis to get transplanted, not only to improve their health status and social conditions but also to enable them to have children. In fact, patients with CRF, and in particular those on dialysis for prolonged periods, suffer from many complications, which affect fertility and their ability to conceive. These include compromised immunity, psychological and social disturbance, nutritional deficiencies, anemia, secondary hyperparathyroidism and hypothalamicgonadal dysfunction with alterations in serum levels of reproductive hormones  such as follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone. Furthermore, patients with CRF suffer from ovarian dysfunction, anovulatory vaginal bleeding, amenorrhea, high prolactin (PRL) levels and loss of libido.  However, improvement in dialysis quality have lessened hormonal dysfunction, and unwanted or unexpected pregnancies may occur in women undergoing dialysis,  though most remain infertile. 
After renal transplantation, males achieve improvement in libido and an increase in sperm count and serum testosterone concentrations, whereas females attain similar concentrations of FSH, LH and PRL to that of healthy women. , In fact, females resume ovulatory cycles within 1-2 months and achieve fertility within an average of six months following kidney transplantation.  The mean interval between transplantation and conception is three years.  Therefore, renal transplantation offers the best hope for patients with end-stage renal disease, at least for those who wish to have children.
Although pregnancy after kidney transplantation is safe and has little, if any, effect on long-term graft survival, ,,,, it is associated with increased maternal and fetal morbidity. , Maternal risks include hypertension, ectopic pregnancy, pre-eclampsia, infection and the need for delivery by cesarean section, ,,,,, whereas fetal complications include abortion (spontaneous or therapeutic), intrauterine fetal death, pre-term delivery and low birth weight. ,, There is a 12% rate of spontaneous abortion among kidney transplant recipients, a rate similar to that in the general population.  The mean gestational age for infants born to kidney recipients is less than 37 weeks, with a mean birth weight of less than 2500 gm. 
The possible effects of post-renal transplant immunosuppressive medications on maternal and fetal outcome have not been fully investigated.  All medications used to prevent rejection of transplanted kidney cross the maternal-placental-fetal interface.  The varied structural defects of immunosuppressive drugs in animal models suggest that teratogenicity may be species-dependent and may not always be applicable in human beings.  Previous studies in humans have shown that pregnancies after renal transplantation are associated with an increased risk for both the mother and the fetus.  There is, however, very little information available on neonatal and long-term pediatric follow-up of babies born to mothers who have undergone renal transplantation and have been exposed to immunosuppressive medications.  Recent reports, with a reasonable period of experience, have shown that corticosteroids, cyclosporine, tacrolimus and azathioprine are, in general, safe drugs during pregnancy in renal transplant recipients. ,,,,, In comparison, mycophenolate mofetil and sirolimus may not be as safe as other conventional immunosuppressive drugs.  Pergola et al,  reported the first case of living relateddonor kidney transplantation who received mycophenolate mofetil, together with tacrolimus and prednisone, during the first trimester and throughout the entire pregnancy. The mother did well, except for mild preeclampsia and mild renal insufficiency at term. The baby girl was born prematurely at week 35. The only possible teratogenic effects detected included hypoplastic nails and short fifth fingers. No chromosomal abnormalities were found. The child has been growing and developing normally. In another study, no structural malformations were noted among offspring exposed to mycophenolate mofetil, although the exposure was limited (5 mothers, 29 fathers).  Recent reports indicate that mycophenolate mofetil and sirolimus may impose maternal and fetal risks. , In contrast, some longer term studies (2 months to 13 years) show that despite the increased incidence of spontaneous abortion, preterm delivery and low birth weight newborns in association with these immunosuppressive drugs, there were no congenital defects noted and their development was normal. , However, Sgro et al,  reported on a follow-up study (from 3 months to 11 years of age) that there was one child with insulindependent diabetes mellitus, two children with asthma and one child with recurrent otitis media. Developmental follow-up revealed one child with moderate to severe sensorineural hearing loss, one child with a learning disability and one child with pervasive developmental disorder. In none of these cases were there signs of perinatal asphyxia, and most pregnancies in the study group went well and their offspring had normal postnatal growth and development. In fact, the frequency of birth defects in infants born to women receiving immunosuppressive agents is not statistically different from that in general population. , The European Best Practice Guidelines for renal transplantation state that immunosuppressive therapy based on cyclosporine or tacrolimus with or without steroids and azathioprine may be continued in renal transplant women during pregnancy.  Other drugs, such as mycophenolate mofetil and sirolimus, are not recommended based on current information available  and these guidelines recommend that women receiving mycophenolate mofetil should be changed to another agent and then wait for six weeks before they attempt to conceive.  As there are significantly more stillbirths, preterm deliveries and increased incidence of low birth weight in the transplant group, further studies with long-term follow-up of the children are needed to delineate their outcome and rule out possible long-term effects of the immunosuppressive medication on their growth, development, reproduction and general health.
| Contraception in the general population|| |
In the general population, there has been a wide variation in the use of different types of contraceptive methods over the years. These include coitus interruptus, postcoital douching, postcoital estrogens, condom, spermicidal contraceptive agents, vaginal diaphragm, the rhythm method, oral contraceptives, intrauterine devices (IUDs), tubal ligation and vasectomy, induced abortion, immunization against human chorionic gonadotropin, pharmacologic suppression of the corpus luteum, long-acting injections of Depo-Provera (an injectable progesterone solution which works for up to three months), implantation of capsules containing norgestrel, the intravaginal ring, intracervical devices, release of contraceptive steroids through an arm bracelet, and male contraceptive agents. ,
Earlier studies in the 1980s showed that the most common methods of contraception were condoms (50%), coitus interruptus (17%), oral contraceptives (9%), IUDs (3%) and vasectomy (2%).  In the mid 1990s, an Italian survey on 500 women showed that the most common methods of contraception were coitus interruptus (61%), oral contraceptives (49%), condoms (45%) and, in 35% no method was used.  A life-history data was collected in 1986 on Australian women to derive the first national estimates of trends in contraception and sterilization from 1956-1986.  This 30year study, where 2,547 women aged 20-59 years were interviewed, showed that the use of traditional methods of contraception (coitus interruptus, periodic abstinence) was most common among the older women, whereas the use of modern methods, such as oral contraceptives and IUDs became the preferred methods after their introduction in 1961. It was also noted that the reliance on sterilization (tubal ligation and vasectomy), which began in the early 1970s, surpassed the use of oral contraceptives, while condoms and other coitus-related methods were not found to be very popular contraceptives. The Behavioral Risk Factor Surveillance System data, which represented the use of contraceptives in the 50 states in the United States (US),  showed variation of contraceptive use across states and territories and among men and women. Oral contraceptives, vasectomy, tubal ligation and condoms were the methods most frequently reported. Among female respondents using birth control, the oral contraceptive pill was the most common method reported, whereas vasectomy was the most commonly reported method among men. The prevalence of use for the four most commonly reported methods (pills, vasectomy, tubal ligation and condoms) varied as much as six-fold among states for vasectomy and three-to four-fold for condoms, pills, and tubal ligation.
| Contraception in renal transplant recipients|| |
It is advisable that women wishing to have children should avoid conceiving in the first two years following renal transplantation. , This is due to low incidence of acute rejection episodes, lower doses of immunosuppressive drugs, completion of viral prophylaxis and stabilized renal function after the first two years following transplantation. Presence of some degree of renal dysfunction, uncontrolled hypertension and diabetes mellitus are associated with increased risk of pregnancy complications, as some immunosuppressive medications, like calcineurin inhibitors, are associated with hypertension, diabetes mellitus and nephrotoxicity. ,,, In addition, contraception is indicated in couples who do not wish to have more children, and/or in those who wish to delay pregnancy in order to improve their health status or social conditions. However, if future fertility is not desired, it should be addressed and discussed with the patient prior to discharge from the hospital after renal transplantation. In fact, planning of pregnancy before kidney transplantation is very crucial in avoiding maternal and fetal risks, and deleterious effects on graft function and survival rate.
There have not been many reports in the literature studying the types of contraceptives used, their side effects as well as indications and success and failure rates in renal transplant recipients. However, some Iranian studies showed that coitus interruptus (56%) is the most common method of contraception in 126 kidney transplanted women, followed by tubal ligation (22%), condoms (14%), vasectomy (6%) and only 2% used oral contraceptives.  Another Iranian study that was conducted in 2005, showed that 92% of the unwanted pregnancies among 64 kidney transplanted recipients occurred in women using coitus interruptus as the only method of contraception.  Our own data show that oral combined pills, coitus interrupts and IUDs are the most popular forms of contraceptive methods (unpublished data).
| Types of contraceptives for renal transplant recipients|| |
There are many types of contraceptives available, which include the permanent and temporarily methods. Permanent contraceptives include tubal ligation and vasectomy. Temporarily contraceptive methods include barrier contraceptives, oral contraceptive pills, progesterone only minipill, IUD, coitus interruptus and the use of symptothermal method. However, the choice of contraceptive method is best determined by the efficacy of the method and the likelihood of patient adherence.
Tubal ligation and vasectomy
These are permanent methods of sterilization. The patient should be counseled before kidney transplantation, and tubal ligation or vasectomy should possibly be performed at the time of transplantation. These procedures have the least failure rates among all contraceptive methods. Vasectomy has the advantage of lacking the increased risk of ectopic pregnancy associated with tubal ligation.
Barrier methods (condom, diaphragm, sponge, spermicide, cervical cap) carry the lowest risk of side effects. Their bactericidal properties have the advantage of reducing transmission of sexually transmitted diseases, and condoms remain the only contraceptive method potentially reducing the transmission of HIV.  However, barrier methods may not provide a very reliable way for contraception, and require a highly motivated user.
Oral contraceptives are pills containing estrogen and progesterone, which are highly effective. Following their introduction in the early 1960s, their use has increased worldwide. However, they interact with cyclosporine and increase its serum concentration, and, therefore, require monitoring of liver and renal functions. Oral contraceptive pills are absolutely contraindicated in patients with thromboembolism, deep vein thrombosis, estrogen-dependent malignancy and severe liver disease  and are relatively contraindicated in patients with high blood pressure, uncontrolled diabetes mellitus, history of smoking, migraine headaches and depression. 
The progesterone-only minipill has the advantage of avoiding the risks associated with estrogen. However, this has to be taken at the same time daily, though the injection type can be given at 3-month intervals. In addition, they have a higher failure rate than combined pills. They may cause delay in ovulation after discontinuation, and could be a poor choice for re-planning of pregnancy. They have frequent side effects, which include interaction with cyclosporine metabolism, irregular bleeding or amenorrhea, weight gain, altered lipid metabolism, hair loss, vaginal atrophy and depression.
More recently, there have been new advances in the development of male contraceptive pills due to limitations to current methods of male contraception. It is known that administration of testosterone, which down regulates the secretion of LH and FSH in man, acts as a partial contraceptive by marked impairment of sperm production. Researchers have recently combined testosterone with progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Such combinations suppress spermatogenesis to zero without severe side effects in 8090% of men, with near-complete suppression in the remainder of individuals. 
Intrauterine devices (IUDs) are available in two types: a copper-containing device that may be left in place for 10 years and a progesteronecontaining device that is placed yearly. Placement of IUDs is usually associated with infection, and prophylactic antibiotics must be used. Also, tubal occlusions have been reported in previous IUD users.  Previous pelvic inflammation and ectopic pregnancy are contraindications to use of IUDs.  There are few published case reports of failure of IUDs in renal transplant patients, possibly due to immunosuppression effect; the efficacy of IUDs may be decreased by immunosuppressive medications and anti-inflammatory agents possibly because of modification of the leucocytic response. However, because of the increased risk of infection, IUDs are not a very popular contraceptive method for renal transplant patients.
| Failure rates of contraceptive methods|| |
Contraceptive failure, defined as use of contraceptive of any type at the time of intercourse when conception most likely occurred, has variably been reported in different studies. In a large study group (3520 pregnant women), 52% had induced abortions, 10% had spontaneous abortions and 3% had ectopic pregnancies. Women aged 15-24 years were more likely to have experienced contraceptive failure in relation to use of condom and oral contraception than women aged 25-34 years. In addition, contraceptive failure was found to be associated with being single, a student, and having given birth twice or more previously.  McLure  described the Pearl Index failure rates of contraceptives, where lactation for 12 months, coitus interruptus and symptothermal method carried the highest failure rates while tubal ligation, vasectomy, combined pill and condom had the least failure rates [Table - 1].
| Conclusions|| |
Fertility greatly improves in both sexes shortly after kidney transplantation. The mean interval between transplantation and conception is three years. Pregnancy is safe and has little effect on long-term graft survival, although there is increased maternal and fetal morbidity. Pregnancy is preferable after the first two years of transplantation, due to low risk of rejection, lower doses of immunosuppressive medications and stabilized renal function. Physicians should discuss fertility issues and counsel their patients regarding the time of pregnancy and the potential risks of pregnancy as well as the risks to the offsprings. Post-renal transplant immunosuppressive medications appear to be safe, but mycophenolate mofetil and sirolimus may impose maternal and fetal risks. Family planning and consideration of a suitable contraceptive method are quite essential before kidney transplantation. There are different types of contraceptive methods available with variable success and failure rates. The choice of contraceptive method is best determined by the efficacy of the method and the likelyhood of patient adherence. Finally, pregnancy in renal transplant recipients should be managed by a multidisciplinary approach (obstetrician, nephrologist and pediatrician) in a tertiary care centre.
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Department of Nephrology, Kanoo Kidney Centre, Dammam Central Hospital, P.O. Box 11825, Dammam 31463
[Table - 1]
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