Pregnancy and contraception in the post-liver transplant patient

Abstract

INTRODUCTION

Due to altered estrogen metabolism and dysregulation of various hormonal pathways, women with chronic liver disease often suffer from anovulation, amenorrhea, and infertility. However, following liver transplantation (LT) most recipients will regain fertility within a year.¹ Pregnancy in the LT population is generally considered to be a higher risk compared to the general population. Despite this, studies show that there is a void in reproductive health counseling in LT recipients both pre- and post-LTs, which could result in suboptimal pregnancy planning and contraceptive utilization.^1,2 Therefore, for these reasons, it is increasingly important that transplant clinicians need to be knowledgeable regarding the management of pregnancy and contraception in this unique population.

PREGNANCY

General considerations

Based on the 2018 Transplant Pregnancy Registry International Annual Report, almost 40% of pregnancies in LT recipients are reported to be unplanned.³ Many of these occur early in the posttransplant period, and both unplanned pregnancy and pregnancy within the first year have been associated with increased risks of maternal and fetal complications in transplant recipients.^4,5 As such, it is vital that reproductive planning and consideration of the appropriate timing for pregnancy occur early after the transplant. Clinicians providing guidance to patients need to consider numerous patient-specific factors, including stability of the liver allograft, immunosuppression regimen, recent postoperative complications, and risk of infections and/or rejection. In 2005, the Women’s Health Committee of the American Society of Transplantation met to establish evidence-based guidelines regarding pregnancy in transplant recipients, which included a recommendation to wait at least 1 year after a liver transplant to conceive. In addition, it was also recommended that patients should be on a stable maintenance dosage of nonteratogenic immunosuppression with no rejection within the past year and without any evidence of acute infections that may harm the fetus (such as cytomegalovirus).⁶

Maternal/fetal outcomes

Although there is no difference in maternal or fetal mortality in pregnancy between LT recipients and the general population, rates of maternal and fetal complications are higher. Reported maternal complications include hypertensive diseases, gestational diabetes, placental abruption, postpartum hemorrhage, cesarean delivery, preterm labor, and coagulopathy.⁷ Many LT recipients have metabolic complications prior to conception, highlighting the importance of awareness of gestational diabetes and hypertensive disease in pregnant transplant recipients. For instance, transplant recipients have a twofold increase in gestational diabetes compared with the general population, while 7%–26% may develop preeclampsia. Hypertensive complications appear in a variable manner depending on the specifics of the immunosuppressive regimen.^8,9 Cholestasis of pregnancy has also been reported to be higher in post-LT patients than in the general population.³ Fetal complications predominantly include preterm birth and low-birth weight although outcomes are overall favorable.⁸ There is no indication for cesarean section in LT recipients outside of standard obstetrical indications.¹⁰ Ideally, potential maternal/fetal risks of pregnancy are reviewed with LT recipients in the preconception phase.

Rates of acute cellular rejection (ACR) in pregnant transplant recipients reported in the literature are variable although, fortunately, graft loss as a result appears to be rare.^3,9 Higher rates of ACR have been observed in those who become pregnant within the first year of transplant, likely reflective of the overall higher rate of ACR episodes in the early post-LT period regardless of pregnancy. However, this highlights the importance of contraception and graft stability prior to conception.^11,12 Most experts recommend frequent monitoring of graft function every 2 to 4 weeks in pregnant LT patients^8,10 although it is important to take into account normal physiologic changes expected in pregnancy such as increasing alkaline phosphatase and hypoalbuminemia when interpreting results. A broad differential should be considered in the pregnant LT recipient with new liver enzyme derangements, including both transplant-related issues (ie, acute cellular rejection (ACR) or recurrent primary liver disease) but also viral etiologies and pregnancy-specific diseases, such as HELLP syndrome or hyperemesis gravidarum. These can be in some cases difficult to distinguish from rejection although liver biopsy can be safely performed for clarification even in a pregnant patient. Steroids can be safely used for the treatment of rejection or maintenance immunosuppressive agents may be titrated, but the safety of therapies for more refractory ACR, such as antilymphocyte globulin, has not been established.⁶

Given patient complexity and the potential for complications, both maternal and fetal, pregnant transplant recipients should be managed through a multidisciplinary approach with the involvement of both transplant clinicians and a maternal-fetal medicine specialist.

Immunosuppression

Adequate immunosuppression is vital to maintaining graft function during pregnancy and must be maintained. However, although the continuation of preconception immunosuppression is ideal, this may not be possible depending on the agents in use. Mycophenolic acid (MPA) products, common immunosuppressive agents utilized in LT recipients, are known to be teratogenic and should not be used in pregnancy. An increased risk of spontaneous abortions and congenital malformations has been reported, including orofacial, esophageal, cardiac, and renal abnormalities.^2,4 Expert opinion recommends female LT patients on MPAs to be on reliable contraception for at least 4 weeks prior to initiation of MPA and at least 6 weeks after discontinuation.^8,9 Barrier protection is also recommended as a second form of contraception if a highly reliable method, such as an intrauterine device (IUD) or implant, is not in use. Patients on MPAs who desire pregnancy can be safely switched to azathioprine at least 6 months prior to planned conception,⁴ as the enzyme required to convert azathioprine to its active metabolites is not present in fetal livers.⁹

Calcineurin inhibitors (CNIs), such as cyclosporine and tacrolimus, make up the backbone of immunosuppression after LT. Overall, these agents are considered safe to use in pregnancy although there are some reports of intrauterine growth restriction (IUGR) with cyclosporine and hypertension with both agents.⁴ There is no established dosage for CNIs during pregnancy although changes in metabolism, GFR, body weight, and hemoglobin concentration can affect trough levels. Current guidelines recommend frequent monitoring of CNI troughs every 2–4 weeks.⁸ There is no indication for an immediate change in CNI dosing based on an LT patient becoming pregnant but patient-specific history (ie, prior rejection, complications of pregnancy, etc.) should be taken into account when determining goal trough levels.

Maintenance doses of prednisone are generally safe to continue during pregnancy. However, prolonged exposure to high doses of corticosteroids has been shown to be associated with IUGR, so maintaining the lowest effective dose in the pregnant LT recipient is prudent. Mammalian target rapamycin (mTOR) inhibitors, such as sirolimus or everolimus, are not recommended during pregnancy due to limited safety data.^8,9 These agents should be discontinued prior to conception if pregnancy is desired and an alternative immunosuppressive regimen pursued.

The use of immunosuppression in LT patients should not be considered an absolute contraindication to breastfeeding although patients should be counseled regarding potential risks. Recent practice guidelines from the American Association for the Study of Liver Disease (AASLD) consider the ongoing use of tacrolimus, cyclosporine, corticosteroids, and azathioprine to be safe while breastfeeding. Conversely, the lack of sufficient safety data limits the use of MPAs, sirolimus, and everolimus while breastfeeding.⁸ There are no studies to support the theoretical risk of immunosuppression rendering the infant susceptible to infections.⁴

CONTRACEPTION

As part of a broader discussion regarding reproductive health goals, contraception should specifically be discussed with any reproductive-aged post-LT recipient who either wishes to defer pregnancy or in whom pregnancy should be delayed from a medical standpoint. Patient lifestyle, reproductive goals, and graft function should be considered in the discussion of contraceptive options. The 2020 AASLD guidance recommendations and the Centers for Disease Control and Prevention (CDC) offer similar recommendations for the use of various forms of contraception in transplant recipients.⁸

Intrauterine devices (IUDs) are often preferred for contraception because of their low failure rates with efficacy that is not dependent on patient adherence. There has previously been some controversy regarding the use of IUDs in LT recipients because of the theoretical risk of pelvic inflammatory disease and the risk of contraceptive failure from a diminished inflammatory response in the setting of immunosuppression. However, these concerns have not been validated in the more recent literature.¹² Current guidelines by the AASLD support the use of both copper and levonorgestrel IUDs after liver transplantation, even in patients who have developed graft failure.⁸ IUDs have few side effects and provide prolonged contraception although notably copper IUDs have been associated with heavier menstrual bleeding and may be a less ideal option for contraception in patients with ongoing anemia and/or coagulopathy post-LT.⁴

Combined hormonal contraceptives (CHCs) contain both estrogen and progestin in the form of oral contraceptive pills, transdermal patches, or vaginal rings and are generally considered to be safe after transplant. However, they should be avoided in post-LT recipients who have developed evidence of graft failure, as there are concerns for increased risk of estrogen-associated complications, such as venous thromboembolism in this patient population. In contrast, progestin-only oral contraceptive pills, depot medroxyprogesterone acetate (DMPA) injections, and subcutaneous implants are acceptable alternatives in transplant recipients even in the setting of graft failure as they do not carry the risks associated with estrogen therapy. In addition, CHCs have been reported to worsen hypertension and can alter cytochrome P450 metabolism, so a review of potential drug interactions and cardiovascular risk is warranted prior to initiation.^4,8 Due to an overall failure rate of ~10%, as noted earlier, patients on MPA products who use either CHC or progestin-only contraceptives should utilize a second method of contraception to prevent pregnancy.

CONCLUSIONS

Patients who have undergone LT can have successful pregnancies and should not be discouraged from achieving their reproductive goals solely on the basis of their transplant status. However, due to the complexities and risks involved in pregnancy and contraception in the posttransplant setting, it is vital that transplant clinicians be able and willing to discuss reproductive goals with their patients prior to and after transplantation to allow for appropriate planning with expert counterparts in maternal-fetal medicine. Effective contraception, graft monitoring, optimizing comorbidities, and careful management of immunosuppression are fundamental to achieving a successful outcome.

KEY POINTS

• Most patients regain fertility within 1 year after liver transplantation (LT), making early discussions regarding reproductive goals and contraception crucial.

• There is a higher risk of maternal and fetal complications in LT recipients compared with the general population, including gestational diabetes, hypertensive complications, and preterm birth.

• Expert consensus recommends pregnancy should be delayed at least 1 year after LT, with patients having stable graft function on a maintenance dosage of immunosuppression, no evidence of active infections, and no rejection within the past year.

• Mycophenolic acid (MPA) products are contraindicated during pregnancy due to teratogenicity. Reliable contraceptive strategies are necessary for reproductive-aged female LT recipients who must remain on these agents.

• Intrauterine devices (IUD) are an acceptable form of contraception in post-LT recipients, while combined hormonal contraceptives (CHCs) should be avoided in patients who have developed graft failure.

• Given patient complexity and the potential for complications, pregnant transplant recipients should be managed via a multidisciplinary approach with the involvement of transplant clinicians and a maternal-fetal medicine specialist.