Introduction

Orthotopic liver transplantation (OLT) is the treatment of choice for end-stage liver diseases and for selected hepatocellular cancer patients. In the following decades after the first human OLT was performed by Thomas Starzl in 1963 , several major advances in transplant immunosuppression, organ preservation, and donor and recipient transplantation surgical techniques have significantly increased patient survival and improved the quality of life of recipients after OLT. Consequently, the recipients’ expectations for a normal life with the ability to enjoy normal sexual relations and to have children have also increased. Currently, women constitute >30% of patients who have had OLT. About 8% are women of reproductive age (18–49 years old), and another 5% are pediatric female patients who have >80% survival into adulthood and will consider the option of pregnancy . The first reported pregnancy after OLT was in 1978. Several concerns that were raised at that time included the potential adverse effects of OLT on the pregnancy, the effect of pregnancy on graft and patient survival, and the potential harmful effects of immunosuppressive drugs on fetal development. However, these were disproven when the mother, who was maintained on prednisone and azathioprine, gave birth to a 2400-g healthy boy after a gestational period of 40.5 weeks . Several hundred successful pregnancies after OLT have been reported worldwide in the next decades. The National Transplantation Pregnancy Registry (NTPR) has been established in 1991 to analyze pregnancy outcomes in solid-organ transplant recipients in North America . There are 357 pregnancies in 198 liver transplant recipients registered in the NTPR according to the 2012 NTPR annual report. Pregnancy outcome data continue to accrue in OLT recipients and additional studies are in progress.

Fertility and OLT

Women with chronic liver disease develop menstrual dysfunction due to malnutrition and hormonal abnormalities (elevated estradiol and testosterone levels) that affect the hypothalamic–pituitary–gonadal system, leading to decreased ovulation and amenorrhea . Amenorrhea occurs in about 50% of women with chronic liver disease, while males develop oligospermia or azoospermia, in addition to functional impotence . However, almost all female patients of reproductive age recover menstrual and reproductive function within 7 months after a successful OLT . Nonalcoholic recipients can have normal menstrual function at a median of 8 weeks post OLT . Therefore, this group of women should receive counseling on pregnancy and contraception before and after OLT to avoid unintended pregnancy.

Theoretical concerns exist for solid-organ transplant recipients regarding the contraceptive efficacy of combined oral contraceptives (COCs), progestin-only pills (POPs), and intrauterine devices (IUDs), and the safety of depot medroxyprogesterone acetate (DMPA). A systematic review of literature conducted by the Centers for Disease Control and Prevention on the outcome of contraceptive use identified six articles in kidney transplantation and only two articles in OLT that satisfied the inclusion criteria . In a retrospective study of 15 OLT recipients on hormonal contraception, Jabiry-Zieniewicz et al. did not observe any change in metabolic and cardiovascular (liver function, glucose metabolism, blood pressure, and body weight) values, thromboembolic complication, graft rejection, or drug discontinuation. Furthermore, there was no pregnancy reported during the 12-month follow-up period. One case report described a 20-year-old nulligravid OLT recipient who developed cholestasis associated with high-dose COC (ethinyl estradiol 50 mcg) for severe menorrhagia, which resolved after drug discontinuation .

As hormonal contraceptive drugs and many immunosuppressive drugs are metabolized by and may affect the cytochrome P-450 (CyP-450) in the liver, several safety and efficacy concerns related to drug interactions have been raised . Corticosteroids activate CyP-450 resulting in faster metabolism and decreased efficacy of oral contraceptives. On the other hand, oral contraceptives can cause calcineurin inhibitor (CNI) toxicity by CyP-450 inhibition and decreased CNI metabolism . Therefore, closer monitoring of immunosuppressive drug levels, particularly tacrolimus (Tac) and cyclosporine levels, and allograft function is very important in recipients who are on hormonal contraceptive drugs.

There are concerns that immunosuppressive drugs used among transplant patients can decrease the efficacy of IUDs through their anti-inflammatory effect. Furthermore, IUD use among immunosuppressed transplant patients is supposedly associated with an increased risk of infection. However, these theoretical concerns are not supported by any clinical evidence .

Fertility and OLT

Women with chronic liver disease develop menstrual dysfunction due to malnutrition and hormonal abnormalities (elevated estradiol and testosterone levels) that affect the hypothalamic–pituitary–gonadal system, leading to decreased ovulation and amenorrhea . Amenorrhea occurs in about 50% of women with chronic liver disease, while males develop oligospermia or azoospermia, in addition to functional impotence . However, almost all female patients of reproductive age recover menstrual and reproductive function within 7 months after a successful OLT . Nonalcoholic recipients can have normal menstrual function at a median of 8 weeks post OLT . Therefore, this group of women should receive counseling on pregnancy and contraception before and after OLT to avoid unintended pregnancy.

Theoretical concerns exist for solid-organ transplant recipients regarding the contraceptive efficacy of combined oral contraceptives (COCs), progestin-only pills (POPs), and intrauterine devices (IUDs), and the safety of depot medroxyprogesterone acetate (DMPA). A systematic review of literature conducted by the Centers for Disease Control and Prevention on the outcome of contraceptive use identified six articles in kidney transplantation and only two articles in OLT that satisfied the inclusion criteria . In a retrospective study of 15 OLT recipients on hormonal contraception, Jabiry-Zieniewicz et al. did not observe any change in metabolic and cardiovascular (liver function, glucose metabolism, blood pressure, and body weight) values, thromboembolic complication, graft rejection, or drug discontinuation. Furthermore, there was no pregnancy reported during the 12-month follow-up period. One case report described a 20-year-old nulligravid OLT recipient who developed cholestasis associated with high-dose COC (ethinyl estradiol 50 mcg) for severe menorrhagia, which resolved after drug discontinuation .

As hormonal contraceptive drugs and many immunosuppressive drugs are metabolized by and may affect the cytochrome P-450 (CyP-450) in the liver, several safety and efficacy concerns related to drug interactions have been raised . Corticosteroids activate CyP-450 resulting in faster metabolism and decreased efficacy of oral contraceptives. On the other hand, oral contraceptives can cause calcineurin inhibitor (CNI) toxicity by CyP-450 inhibition and decreased CNI metabolism . Therefore, closer monitoring of immunosuppressive drug levels, particularly tacrolimus (Tac) and cyclosporine levels, and allograft function is very important in recipients who are on hormonal contraceptive drugs.

There are concerns that immunosuppressive drugs used among transplant patients can decrease the efficacy of IUDs through their anti-inflammatory effect. Furthermore, IUD use among immunosuppressed transplant patients is supposedly associated with an increased risk of infection. However, these theoretical concerns are not supported by any clinical evidence .

Timing of pregnancy after OLT

Most transplant centers would recommend delaying conception for at least 1 year after transplantation when recipients have achieved optimal liver graft function and are on a stable immunosuppressive regimen. However, data on the optimal transplant to conception interval (TCI) vary from center to center. Nagy et al. advocated delaying conception for at least 24 months post OLT. This is based on their single-center series of 38 pregnancies in 29 post-OLT recipients, which showed one live term birth out of seven pregnancies conceived <1 year post OLT, while the remaining cases resulted in spontaneous abortion or elective termination. Another single-center study of 71 pregnancies in 45 OLT recipients reported no difference in the incidence of live births and abortions . However, they observed increased rates of prematurity, low birth weight, and acute rejection for pregnancies occurring within 1 year after OLT. Based on these findings, the authors recommended delaying pregnancy until after 1 year post OLT. A recent NTPR study, which analyzed 130 pregnancy outcomes in 128 OLT recipients by TCI (<1 year, 1–2 years, 3–5 years, and >5 years), noted a significantly higher incidence of very low-birth-weight newborns in patients with TCI <1 year and 1–2 years, and a higher rejection rate during pregnancy and graft loss within 2 years of pregnancy in patients with TCI 1–2 years. The authors suggested that while successful pregnancy outcomes were reported for all TCI groups, better outcomes were observed for the mother and newborn with TCI >2 years .

The outcomes of successive pregnancies in female OLT recipients were analyzed using NTPR data . There were 213 pregnancies (including twins) with 217 outcomes. Out of 125 female OLT recipients with a first pregnancy, there were 61 who had between one and four subsequent pregnancies. There was no significant difference in newborn outcomes, rejection during pregnancy, and graft loss within 2 years of delivery with subsequent deliveries. Based on these findings, they concluded that successive pregnancies in OLT recipients were not associated with adverse fetal outcomes and/or maternal graft loss. They suggested that female OLT recipients with excellent allograft function and without significant recurrent disease or chronic rejection who wish to have more than one pregnancy should not be discouraged from conceiving.

Immunosuppressive agents and teratology

The major considerations in the management of pregnant transplant patients are the potential effects of immunosuppressive drugs on the mother, the allograft, and the fetus. These drugs are known to be associated with an increased risk of maternal complications, particularly hypertension, diabetes, hyperlipidemia, anemia, preeclampsia, renal impairment, neurotoxicity, and infection. In the fetus, they may have potential fetal developmental effects, intrauterine growth retardation, low birth weight, prematurity, etc. Permissive reduction or withdrawal of immunosuppressive drugs to prevent these side effects during pregnancy may precipitate acute rejection and adversely affect graft function, which may eventually lead to graft loss. Therefore, one can only emphasize the significance of closer monitoring and maintenance of therapeutic immunosuppressive drug levels during pregnancy. The following are commonly used immunosuppressive drugs in liver transplantation:

Corticosteroids (prednisone and methylprednisolone) – Food and Drug Administration (FDA) category B (no fetal risk, no controlled studies). These agents are used for induction and treatment of rejection, and maintenance immunosuppression. They reduce macrophage activation, prevent T-cell proliferation, inhibit cytokine production (interleukin 1 (IL-1) and IL-2), decrease adhesion molecule expression, and alter lymphocyte trafficking .They have been found to induce cleft palate and low birth weight in mice, while in humans, they were found to increase the risk of premature rupture of the membranes and adrenal insufficiency in the newborn .

Azathioprine (Imuran®) – FDA category D (evidence of fetal risk). This group of drugs, which inhibits clonal proliferation of T lymphocytes by interfering with purine synthesis, used to be a primary agent before the introduction of cyclosporine (CsA). The evidence of embryotoxicity in rats and mice and the increase in the incidence of fetal death and fetal and neonatal growth retardation in Fischer rats have been shown at doses of 1–20 mg/kg body weight . Although teratogenicity has not been reported, it has been associated with preterm delivery, fetal growth retardation, neonatal bone marrow suppression, and transient chromosomal aberrations . This drug is now used rarely in OLT but considered a safe option for adjunctive maintenance immunosuppression.

CNIs (Tacrolimus or Tac, Cyclosporine or CsA) – animal studies have been conducted, FDA category C (fetal risk cannot be ruled out). CNIs are macrolide immunosuppressive drugs that have been the mainstay of immunosuppression to prevent rejection. They act by binding to intracellular immunophilins: cyclophilin (CsA) or FK-binding protein (Tac) forming CNI–immunophilin complexes that inhibit the phosphatase activity of calcineurin, consequently inhibiting regulatory enzymes that control IL-2 cytokine transcription and T-cell proliferation. CNIs are transmitted transplacentally and secreted in the breast milk; thus, mothers are advised not to breast-feed their babies.

Cyclosporine (CsA) has had a major impact in the advancement of clinical transplantation by improving graft and patient survival since its introduction in 1978. Maternal side effects of CsA, also attributed to CNIs in general, include hypertension, nephrotoxicity, neurotoxicity, hyperkalemia, hyperuricemia, hypomagnesemia, and hyperglycemia, while side effects unique to CsA include hypertrichosis and gingival hyperplasia.

Tac is a potent and currently the most widely used immunosuppressive drug in OLT. Its safety in pregnant solid-organ transplant recipients has been described in a single-center case series and registry data reports . Jain et al. reported a lower incidence of hypertension, preeclampsia, and maternal complications in 37 female OLT recipients on Tac-based immunosuppression compared to previous reports of OLT patients on cyclosporine-based immunosuppression. Preterm deliveries and low birth weight were common in Tac-based immunosuppression. However, pre- and postnatal growths were appropriate for gestational and postpartum age, respectively .

A 2011 NTPR data analysis comparing pregnancy outcomes in 182 OLT recipients with CNI (CsA, CsA-modified, and Tac) exposure during pregnancy reported a lower incidence of hypertension, higher incidence of diabetes during pregnancy, and lower infection rate in the Tac group versus both CsA groups. The incidence of rejection during pregnancy and the percentage of graft loss within 2 years of delivery were higher in the CsA group compared to the Tac and CsA-M groups.

Mycophenolic Acid Products (Mycophenolate mofetil and enteric-coated mycophenolic acid) – animal studies have been conducted, FDA category D (evidence of fetal risk) from category C based on registry and post-marketing data in October 2007 . Mycophenolic acid products (MPAs) are antimetabolites that inhibit purine synthesis and thus inhibit lymphocytic proliferation without influencing early activation of these cells. These agents have been approved for maintenance immunoprophylaxis in kidney and OLT recipients.

A 2010 NTPR data analysis of 97 pregnancies in 68 solid-organ transplant recipients showed a 23% incidence of structural birth defects in newborns of recipients exposed to MPA during pregnancy compared to newborns of recipients without MPA exposure . The incidence of birth defects in the newborn of transplant recipients before the advent of MPA use was about 4–5%. The birth defects included microtia, hypoplastic nails, cleft lip and palate, syndactyly, facial malformations, duodenal atresia, atrioventricular canal defect, tetralogy of Fallot, and total anomalous pulmonary venous return. Multiple anomalies were reported in one stillbirth. The analysis of available MPA dosing information showed a dose–effect relationship with pregnancies having nonviable outcomes noted to have higher MPA dose exposures . Based on a more recent NTPR study, the authors noted that the number of pregnancies with exposure to MPA may be falling with more recent entries, which may be reflective of recipient and physician awareness of concerns. Issues still remain as to management with MPA exposures in the setting of unplanned pregnancies or where MPA is felt to be the best agent for the recipient and her transplant .

Target of rapamycin inhibitors ( sirolimus and everolimus) – animal studies have been conducted, FDA category C (fetal risk cannot be ruled out). The target of rapamycin (TOR) inhibitors inhibit the TOR-mediated cell-cycle progression, influencing lymphocytic and mesenchymal cell proliferation.

There are limited data available for transplant recipients with sirolimus exposure. A 2011 NTPR data analysis of 21 female transplant (15 kidney, three liver, one pancreas–kidney, and two heart transplant) recipients reporting 23 pregnancies with sirolimus exposure resulted in 16 live births and one therapeutic abortion. Two of the three live births with birth defects also had MMF exposure. Birth defects included facial malformations (on CsA-M, MMF, and sirolimus at conception), cleft lip, cleft palate and microtia (MMF exposure with late pregnancy exposure to sirolimus), and tetralogy of Fallot. Among three liver recipients, three pregnancies were reported with two live births and one spontaneous abortion.

Basiliximab – animal studies conducted, FDA category B (no fetal risk, no controlled studies). Basiliximab is a chimeric (human/mouse) monoclonal antibody that competitively binds to IL-2 receptors on the surface of activated T lymphocytes, thereby effectively inhibiting IL-2 driven T-lymphocyte proliferation, a vital phase in the immune response involved in allograft rejection. Due to the lack of controlled studies in pregnant women, and no data on its effect on fertility or on the fetus, the FDA has assigned basiliximab to category B. As it is well known that immunoglobulin G (IgG) crosses the placenta, theoretically putting the fetus at risk, basiliximab should be avoided during pregnancy.