Pregnancy in Liver Transplant Recipients
1. What every clinician should know
Since 1988 over 42,000 liver transplants have been performed in women in the United States. The age distribution varies from children to adult women and as of 2006 there were over 3,000 female transplant recipients of childbearing age. The prognosis for these patients depends on the underlying disease, with best results for recipients who were transplanted for biliary atresia and other metabolic diseases. There are lower patient and graft survival rates for patients undergoing liver transplant for malignancy and noncholestatic cirrhosis usually due to Hepatitis C. (http://www.optn.org)
Since the first pregnancy in a liver transplant recipient reported in 1978, there have been several hundred reported in the literature. Data regarding pregnancy in liver transplant recipients is based on small case series and registries such as the National Transplantation Pregnancy Registry and the U.K. Transplant Registry. Although these case series and registries provide valuable information, they are limited by small sample size as well as various other biases. A recent case control analysis of the 1993-2005 U.S. Nationwide Inpatient Sample database attempts to compare 146 admission liver transplant deliveries with age-matched controls from the same hospitals.
In general, these case series and registries demonstrate that liver transplant recipients have fewer complications than kidney transplant recipients. Pregnancies in transplant recipients are associated with similar maternal mortality rates but higher fetal mortality rates than in the general population. Transplant recipients who become pregnant experience higher rates of preeclampsia, gestational hypertension, increased antepartum admissions, post-partum hemorrhage, blood transfusion and cesarean delivery.
Their pregnancies also are more likely to be complicated by fetal death/spontaneous abortion, preterm delivery and intrauterine growth restriction than the general population. These infants do not appear to experience a higher rate of malformation than the general population. However, some of the newer immunosuppressants, specifically mycofenolic acid products, have been associated with a specific pattern of abnormalities.
Preconception counseling and management
It is essential that pregnancies after transplantation be planned so as to optimize outcomes for mother and infant. Contraceptive planning should be discussed prior to transplant and at regular intervals after transplantation. The CDC Medical Eligibility Criteria published in 2010 have a category for Solid Organ Transplantation which may be used as a resource when counseling women about contraception. (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5909a1.htm)
Preconceptional care should be provided to the patient by a multidisciplinary team involving gynecology, maternal-fetal medicine, nurse coordinators, transplant surgeons and hepatologists. It is important to discuss ethical issues regarding maternal lifetime expectancy as well as possible risks of a pregnancy to the mother and infant during these discussions.
The clinician should evaluate a female transplant recipient seeking pregnancy with regard to her underlying ailment (e.g. chronic hepatitis, malignancy, hypercoagulable state) as well as other comorbidities (e.g. hypertension, diabetes, infections, impaired renal function). These disorders each impact pregnancy in addition to the liver transplant and the transplant recipient should be counseled regarding the impact of each one of these medical co-morbidities on the pregnancy.
Based on expert opinion the recommendation is to wait at least 1 year after liver transplantation prior to attempting pregnancy in a stable patient. This period of time allows for stabilization of graft function, minimization of immunosuppressant medications, as well as decreased risk of infectious morbidity such as cytomegalovirus reactivation. It is important to assess a woman’s overall health as well as whether she has had rejection or recurrent hepatitis when counseling about an attempt at pregnancy.
A summary of preconception management can be found in Table I.
|1. Effective contraception until stable graft function and no rejection. a. at least 1 year after transplant.|
|2. Assessment of renal and liver function. a. immunosupressant may cause renal insufficiency. b. ideally no signs of rejection and creatinine <1.5 ng/dl|
|3. Assess Hepatitis B and C.a. If active hepatitis B, discuss with transplant hepatoligist regarding possible treatment prior to pregnancy.b. Hepatitis C viremia is almost always present after transplant.c. Biopsy may be indicated as liver enzyme abnormalities may not correlate with disease and should be considered with the transplant team prior to pregnancy.|
|4. Assess for active CMV infection.a. If positive discuss management with transplant team.b. Management may include treatment with valganciclovir or ganciclovir, both FDA pregnancy category C, and if possible reduction in immunosupressant medications.c. Counsel patient regarding CMV effects on the fetus.|
|5. Assess for toxoplasmosis, varicella and herpes simplex virus, and counsel patient.|
|6. Review maintenance immunosuppression with the patient and the transplant team.a. Consider, with the transplant team, changing regimen if the woman is on mycophenolitic acid.|
|7. Review co-morbid conditions.a. Counsel patients regarding the effects of these.b. Optimize management.|
|8. Review the cause of the original disease.a. Review possible effects of pregnancy on the underlying condition b. Review possible genetic issues|
|9. Discuss the effects of pregnancy on allograft function, including risk of preeclampsia and HELLP syndrome.|
|10. Discuss increased chance of antepartum admission, preeclampsia and hypertension, post-partum hemorrhage, blood transfusion, cesarean delivery, fetal death/spontaneous abortion, preterm delivery, intrauterine growth restriction.|
|11. Assure adequate immunization.a. Live virus vaccines are generally contraindicated in transplant recipients.b. Transplant recipients may not mount a response to vaccines and vaccination is generally delayed until 6 months after transplant.|
The patient’s immunosuppressant regimen needs to be carefully considered. Most recipients with stable graft function after transplantation will require maintenance immunosuppression, usually consisting of double or triple therapy.
Corticosteroids may be used in maintenance immunosuppression. Most corticosteroids are classified as FDA pregnancy category B. Some of these agents, however, have been associated with an increase in cleft lip and palate as well as premature rupture of membranes and neonatal adrenal insufficiency.
Azathioprine (Imuran®), an antimetabolite that is converted into 6-mercaptopurine in the liver, was used before the introduction of cyclosporin in high doses with prednisone. Although listed as an FDA pregnancy category D drug, human studies have not found a predominant pattern of malformation. Hence it is often thought of as a possible alternative to mycophenolate mofetil.
Calcineurin inhibitors such as cyclosporin and tracrolimus are the mainstay of currently used maintenance immunosuppression. These agents act by blocking cytokine production needed for T-cell activation and proliferation. Cyclosporin (Sandimmune®, Neoral®, Gengraf®, others) the first calcineurin inhibitor, is listed as FDA pregnancy category C, and NTPR data reports an anomaly rate of 5% in kidney transplant recipients maintained on cyclosporin. Cyclosporin is associated with maternal hypertension, nephrotoxicity, tremor, hirsutism and hyperlipidemia.
Currently the most commonly used calcineurin inhibitor is tacrolimus (Prograf®, others) which is also FDA pregnancy category C. Tacrolimus can cause maternal nephrotoxicity, hypertension, neurotoxicity and diabetes. Neonates exposed to tacrolimus may exhibit hyperkalemia and cardiomyopathy. Pregnancy as well as medications and food may affect cyclosporin and tacrolimus blood levels and these levels should be monitored monthly during pregnancy. It is important to note that there may be wide variations in cyclosporin levels from commercially available assays.
Newer immunosuppressants include mycophenolic acid products (Mycophenolate Mofetil, MMF, Cellcept®, Mycophenolate Sodium, EC-MPS, Myfortic®, others) and sirolimus (Rapamune®). In 2007 mycophenolate mofetil (MMF) was changed from FDA Pregnancy Category C to D based on post-marketing data demonstrating a possible increase in miscarriage as well as structural malformations. Data from solid organ recipients from the NTPR and the Roche worldwide adverse reporting system revealed spontaneous abortion in 33-45% of reported cases and malformations in 18-22% of exposed infants.
The malformations include ear malformations, cleft lip and palate, micrognathia, hypertelorism and anomalies of the eyes, distal limbs, heart, esophagus and kidney. The concern for possible teratogenicity has prompted the recommendation that patients receiving MMF use two methods of contraception. Given the concern over structural abnormalities, many clinicians now advocate changing immunosuppressants in women who want to consider pregnancy.
There are not enough data to assess sirolimus safety in pregnancy but there are data suggesting that men treated with sirolimus have significantly lowered sperm counts. Both mycophenolate and sirolimus blood concentrations should be followed in pregnant women if they continue these agents.
It is important to stress to patients that stopping immunosuppressants will increase the likelihood of organ rejection, which will endanger her own life as well as that of her fetus. If a patient desires pregnancy, changing MMF to another immunosuppressant such as azathioprine prior to conception should be discussed with the transplant team. It important to assess that the transplanted organ is functioning well and that there is no evidence of rejection after the medication change prior to attempting pregnancy.
Antepartum care should be undertaken with collaboration between the obstetrics and transplant teams. As these pregnancies are at risk of maternal hypertensive disease, maternal infection, as well as growth restriction and premature delivery, patients should be closely monitored. (Table II)
|Table II. Prenatal Management|
|1. Early ultrasound for accurate dating, followed by ultrasounds every 4-6 weeks to asses growth.|
|2. Routine prenatal evaluation and counseling.|
|3. Counsel about pregnancy in liver transplant, risks and management.|
|4. Baseline 24-hour urine total protein and creatinine clearance at the initial evaluation.|
|5. Screen for gestational diabetes at the beginning of pregnancy and repeat at 24-28 weeks.|
|6. Initial visit assessment of complete metabolic panel, phosphorus, magnesium, CBC and PT and repeat every 2-4 weeks during pregnancy.|
|7. Monitor immunosuppressant levels at initial visit and every 2-4 weeks during pregnancy.|
|8. Infectious disease testing: hepatitis B and C, cytomegalovirus, toxoplasmosis, herpes simplex virus at initial evaluation or prior to pregnancy.|
|9. Monitor signs and symptoms of rejection (usually in advanced disease): jaundice, right upper quadrant pain, low grade temperature, malaise, etc.|
|10. Monthly urine culture.|
|11. Monitor for preeclampsia, hypertension and nephropathy.|
|13. Delivery planned for full term with cesarean for usual obstetric indications.|
Transplant recipients are at high risk for urinary tract infections. Cytomegalovirus (CMV) infection is common after solid organ transplantation and is associated with poorer outcomes in liver transplant recipients. It may be acquired from the transplanted organ or be reactivated due to the immunosuppression. Valganciclovir and ganciclovir are used for CMV infections, but their safety and efficacy in pregnancy is unknown. Herpes simplex virus and varicella may reactivate but generally do not cause severe disease in liver transplant recipients on maintenance immunosuppression. Treatment for these viruses should be guided by obstetrics considerations in consultation with the transplant team.
Hepatitis B may reactivate post-transplant and should be treated prior to pregnancy. Liver transplant for hepatitis C is associated with worse pregnancy prognosis. Most recipients continue to be viremic after transplant and may have an accelerated course of recurrent liver failure. Liver enzyme levels may not fully predict disease state and liver biopsy often is indicated to confirm stable graft function prior to pregnancy.
Hypertension and preeclampsia
Several immunosuppressants may affect renal function and cause hypertension. Chronic hypertension should be treated with medications appropriate to pregnancy in order to prevent organ damage. Transplant recipients are at increased risk of preeclampsia and its diagnosis may be unclear as immunosuppressants may cause proteinuria or thrombocytopenia. Acute rejection, drug toxicity or progressive underlying disease may be difficult to distinguish from hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome. If an organ biopsy is considered necessary for accurate diagnosis especially when remote from term, it should not be delayed until after pregnancy.
Organ rejection in liver recipients has been reported by the NTPR to occur in 7% of pregnancies. It is important to continue maintenance immunosuppression as rejection is associated with worse pregnancy outcomes. In addition, it is important to monitor immunosuppressant levels as nausea and vomiting in pregnancy as well as the increased volume of distribution may cause medication levels to fluctuate.
Fetal growth restriction and monitoring
The high incidence of low birth weight (less than 2,500 g) may be as a result of increased prematurity as well as growth restriction. The aforementioned case control study indicates that there is indeed an increased risk of growth restriction. This study also suggests an increased risk of fetal demise. In light of these risks an early ultrasound for accurate gestational dating is indicated followed by serial growth scans approximately every 4-6 weeks.
Pregnancies in transplant recipients should be delivered at term unless complications ensue, and cesarean sections should be reserved for usual obstetric indications. Liver transplant recipients generally have surgical scarring in the upper abdomen which does not interfere with cesarean section. Immunosuppressants should be continued during the labor and delivery process.
Changes in gastrointestinal motility during labor, as well fluid shifts and changes in renal glomerular filtration after delivery, may result in significant changes in immunosuppressant levels. It is well known that autoimmune diseases may reactivate after delivery and this may influence conditions such as autoimmune hepatitis. In general, graft function and immunosuppressant levels should be closely monitored in the 12 weeks following delivery.
Post-partum depression may be increased in transplant recipients and patients should be closely monitored.
Breastfeeding in the transplant recipient remains controversial as a small number of reports demonstrate a wide range of drug levels in the exposed infants. Correspondingly, the benefits and risks of breastfeeding should be considered based on the specific information available for the particular medications that are being used.
It is essential to offer a liver transplant recipient who has just given birth effective contraception. The recent CDC Medical Eligibility Guidelines for Contraception Use was published in May of 2010. (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a1.htm)
These criteria include a category for “Solid Organ Transplant.” This category is further subdivided into “complicated” and “uncomplicated.” For uncomplicated solid organ transplant emergency contraception is considered category 1: there are no restrictions to use of this method. Progesterone methods (progesterone only pill, depo-provera and progesterone implant), combined estrogen and progesterone methods (combined oral contraceptive, patch and vaginal ring) as well as intrauterine devices (IUDs) are classified as category 2: the benefits generally outweigh the risks.
For complicated solid organ transplant (acute or chronic graft failure, rejection, cardiac allograph vasculopathy), combined estrogen/progesterone methods are category 4: these methods pose unacceptable health risks, while progesterone-only methods are category 2. Risk of initiating IUD use in “complicated” solid organ transplant is deemed category 3: the risks may outweigh the benefits. These guidelines also offer guidance regarding contraceptive use and the other co-morbidities that liver transplant patients may have. Considerations regarding individual contraceptive methods in liver transplant recipients may be found in Table III.
|Method||Benefits||Problems||Issues related to Transplant||CDC Category (Uncomplicated)||CDC Category (Complicated)|
|Copper T IUD||*Most effective*Long Acting||*Heavy Menses||*Macrophages mediated action not affected by most immunosuppressants.||2||Initiation-2Continuation-3|
|Progestin IUD||*Most Effective*Long Acting*Decreased Anemia||*Irregular Bleeding||2||Initiation-2Continuation-3|
|DMPA||*Highly Effective*Decreased Anemia||*Decrease in BMD*Irregular Bleeding||*Possible cholestatic effect||2||2|
|Progestin Implant||*Most Effective*Long Acting*No Decrease in BMD||*Irregular Bleeding||2||2|
|Combined Oral Contraceptive (COC)||*Decreased anemia *Menstrual Regulation||*First-pass Liver Metabolism- *Metabolized in Liver- Levels May be Affected by Immunosuppressants. *Contraindicated in Uncontrolled Hypertension, active liver disease and personal history of myocardial infarction, stroke or deep venous thrombosis*May be used if stable organ function and no contraindication*Gastrointestinal Disturbance by Some Immunosuppressants May decrease Absorption*Possible Hyperkalemia caused by Some Immunosuppressant Precludes use of Drospirenone Containing COC||2 ( do not use in women with a history of Budd-Chiari syndrome)||4|
|Contraceptive Patch||*First-pass Liver Metabolism Avoided||*Higher Circulating Levels of Estrogen||*Contraindicated in Uncontrolled Hypertension, active liver disease and personal history of myocardial infarction, stroke or deep venous thrombosis*May be used if stable organ function and no contraindication||2 ( do not use in women with a history of Budd-Chiari syndrome)||4|
|Vaginal Ring||*Lower Circulating Estrogen*First-pass Liver Metabolism Avoided||*Contraindicated in Uncontrolled Hypertension, active liver disease and personal history of myocardial infarction, stroke or deep venous thrombosis*May be used if stable organ function and no contraindication||2 ( do not use in women with a history of Budd-Chiari syndrome)||4|
|Progestin Only Pill||*Less Effective Than COC||*First-pass Liver Metabolism||2||2|
|Condoms||*Protects from STI*No Drug Interactions||*Less Effective||1||1|
|Cervical Cap/Diaphragm||*No Drug Interactions||*Less Effective||1||1|
|Emergency Contraception||*Effective After Sexual Intercourse||*Not Effective as Ongoing Method||1||1|
|Withdrawal(coitus interruptus)||*No drug Interactions||* Least Effective||N/A||N/A|
3. What is the evidence for specific management and treatment recommendations
Mastrobattista, J, Gomez-Lobo, V. “for the Society for Maternal-Fetal Medicine: Pregnancy after Solid Organ Transplantation”. Obstet Gynecol. vol. 112. 2008. pp. 919-32. (Comprehensive review of pregnancy after solid organ transplants; includes all of the relevant literature up to this date.)
Coscia, LA, Constantinescu, S, Moritz, MJ. “Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation”. Clin Transpl . 2010. pp. 65-85. (Most recent report from the NTPR, the largest registry of pregnancy after solid organ transplant.)
Kociszewaska-Najman, B, Pietrzak, B, Cyganek. “Intrauterine hypotrophy and premature births in neonates delivered by female transplant recipients”. Transplant Proc. vol. 43. 2011. pp. 3038-51. (A case series which actually evaluates growth compared to gestational age. Registry data only reports birthweight.)
Coffin, CS, Shaheen, AA, Burak, KW, Myers, R. “Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis”. Liver Transplant. vol. 16. 2010. pp. 56-63. (Only case control study of pregnancy in liver transplant recipients; all other data is based on case series and registry data.)
Deshpande, NA, James, NJ, Kurcirka, LM. “Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis”. Liver Transpl. vol. 18. 2012. pp. 621-9. Meta-analysis of all previous reports.)
Armenti, VT. “Pregnancy after liver transplantation”. vol. 18. 2012. pp. 619-20. (Meta-analysis and review of pregnancy after transplantation.)
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