Journal of Hepatology
Volume 49, Issue 4 , Pages 507-519, October 2008

Pregnancy and sexual function in liver transplantation☆

  • Michael A. Heneghan

      Affiliations

    • Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom
    • Corresponding Author InformationCorresponding author. Tel.: +44 207 3464952; fax: +44 207 3463167.
    • ,
  • Markus Selzner

      Affiliations

    • Department of Surgery, Multi-Organ Transplantation Unit, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
    • ,
  • Eric M. Yoshida

      Affiliations

    • Division of Gastroenterology, Vancouver General Hospital, Diamond Health Care Centre, 5153-2775 Laurel Street, Vancouver, BC, Canada V5Z 1M9
    • ,
  • Beat Mullhaupt

      Affiliations

    • Swiss HPB (Hepato-Pancreato-Biliary) Center, University Hospital Zurich, Switzerland

published online 28 July 2008.

Article Outline

Abbreviations: orthotopic liver transplantation, OLT, acute fatty liver of pregnancy, AFLP, haemolysis, elevated liver enzymes, low platelet count, HELLP, intrauterine device, IUD, combined oral contraceptive, COC, depot medroxyprogesterone acetate, DMPA, cyclosporine A, (CyA), model for end-stage liver disease, MELD, mycophenolate mofetil, MMF, food and drug administration, FDA, National Transplant Pregnancy Registry, NTPR

 

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1. Introduction 

Over the past forty years, liver transplantation (OLT) has evolved from an experimental, surgical procedure with a low likelihood of success to a universally accepted multi-disciplinary endeavor for the treatment of both acute liver failure and end-stage liver disease. In 2008, the expectation of 1-year post-transplant survival is greater than 85% for most indications, and indeed, the majority of clinical challenges have been addressed [1], [2], [3]. In that context, the expectation for most liver graft recipients is one of achieving long-term survival in conjunction with significantly improved quality of life [4], [5], [6], [7], [8].

For younger patients, the expectation of contributing to society means considerably more than merely returning to the workforce or achieving specific goals. For younger patients, who have undergone successful OLT, the expectation in 2008 is one of a full and normal life, including the ability to have children, and enjoyment of normal sexual relations. In this, the 11th Forum on Liver Transplantation we examine a much neglected combination of topics reflecting the full tapestry of issues pertaining to sexual health and function, contraception and pregnancy in the OLT recipient. Additionally, we examine the rare indications for transplantation in patients who develop liver failure as a consequence of pregnancy.

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2. Pregnancy-related liver disease: is there ever an indication for liver transplantation? (Markus Selzner) 

Alteration in aspects of liver function is normal during pregnancy. Severe liver dysfunction is rare, but when it occurs, it can do so in a catastrophic fashion for both mother and infant. Liver disease in pregnancy can be considered in three separate categories. First, liver dysfunction specific to the pregnant state, i.e. conditions occurring only in the setting of pregnancy. Second, management of the pre-existing disorders that may be provoked by the pregnant state, i.e. pre-existing liver disease that must cope with the extra physiological demands of pregnancy. Finally, liver disease coincident with pregnancy, i.e. apparent concurrent liver conditions occurring in a pregnant woman that do not typically affect the pregnancy. In the context of liver transplantation, it is this first category that is most pertinent.

Liver failure in its broadest sense, occurring in the context of the pregnant state is rare, and is most often caused by acute fatty liver of pregnancy (AFLP), eclampsia-related liver disease, or the haemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome. Indeed, the distinction between eclampsia-related liver disease in pregnancy, HELLP syndrome and AFLP is blurred in many cases and it is often difficult to distinguish one from another. These specific conditions typically occur in the third trimester of pregnancy but may present at any time during pregnancy or even in the early post-partum period [9]. In considering a differential diagnosis in patients who may present with liver failure, it is important to reflect on conditions outwith those that occur only in the pregnant state. These are summarized in Table 1.

Table 1. Liver dysfunction in pregnancy in patients without pre-existing liver disease
Liver disease specific to pregnancy
Acute fatty liver of pregnancy
Hypertension-associated liver disease of pregnancy
Pre-eclampsia and eclampsia
Hepatic infarction, hematoma and rupture
HELLP syndrome

Liver disease coincident with pregnancy
Acute viral hepatitis Hepatitis A–E
Herpes simplex hepatitis
Drug toxicity
Acetaminophen toxicity
Budd-Chiari syndrome
Liver transplant recipients

Consideration should be given in differential diagnosis to each of these conditions. For patients with liver disease specific to pregnancy, it is pertinent to consider that it is frequently clinically difficult to differentiate between HELLP syndrome AFLP and eclampsia-related liver disease. In all such instances, early delivery and intensive supportive care may abrogate the need for liver transplant.

AFLP and HELLP syndromes are both infrequent with AFLP reported as occurring in 1/7000–15,000 pregnancies. First described in 1934 by Sheehan et al. as a yellow atrophy of the liver, the condition has been widely described and significant advances in the pathogenesis of the condition reported [10], [11], [12], [13]. Histological findings are those of severe microvesicular steatosis in association with minimal necrosis.

Acute fatty liver of pregnancy is regarded as one of the family of diseases characterised by a mitochondrial cytopathy, which also includes conditions such as Reye’s Syndrome, drug-related liver disease and other genetic defects in mitochondrial function. Ultimately, these conditions are characterised by vomiting, hypoglycaemia, lactic acidosis, hyperammonaemia and microvesicular fat in organs. Acidosis occurs as a result in defective energy supply within the mitochondria during oxidative phosphorylation. Hypoglycaemia in these disorders may relate to failure of mitochondrial tricarboxylic acid cycle enzymes [11], [12], [13].

The understanding of the pathogenesis of the condition has been greatly enhanced by the description of full term infants born to mothers with AFLP in whom hypoglycaemia, hepatic encephalopathy and steatosis developed. The infants were found to have a defect in fatty acid oxidation, and specifically were deficient in long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD)[13]. In a seminal investigation, this pattern was noted in 11 women whose pregnancies were complicated by acute fatty liver with features of HELLP syndrome. Six babies from this series were found to have LCHAD deficiency[13]. Heterozygosity for LCHAD in the mother appears to be responsible at least in part for the development of disease in the infant. The molecular basis has been identified as the substitution of guanosine to cytosine in the alpha-subunit that catalyses the last three steps of beta oxidation. Consistent with these findings is the fact that in murine models, pregnancy decreases fatty oxidation with the effect mediated by estrogens and progesterones.

Patients with AFLP present in the third trimester at a mean gestational age 34 weeks with non-specific symptoms, such as vomiting, malaise, fever, and abdominal pain [13]. In later stages, patients develop jaundice, coagulopathy, hypoglycaemia, and encephalopathy. Serum transaminases rarely exceed 1000IU/L, and usually ranges from 300 to 500IU/L [14]. Disseminated intravascular coagulation (DIC) may occur in up to 70% of cases. In severe cases, the clinical course may be complicated by hepatic necrosis and liver rupture. The differential diagnosis includes acute viral hepatitis and HELLP syndrome. Ultrasound imaging and viral serological assessment are required in all cases. Liver biopsy is not mandatory but may be necessary if the diagnosis is clinically unclear, the liver function tests do not normalise after delivery or, the diagnosis of ALFP is required as an indication for delivery [15]. The therapy of choice is rapid delivery, usually by caesarian section.

In the past, AFLP was considered to be universally fatal, but aggressive optimization in the peri-delivery period, has improved the prognosis with both maternal and foetal mortality rates ranging from 0% to 20% reported in the literature [16]. Although AFLP may progress to acute liver failure (ALF), liver transplantation is rarely indicated/required since the condition is typically reversible following delivery. Liver transplantation should be considered in cases with severe disseminated intravascular coagulation (DIC), rupture of the liver, or severe encephalopathy. Where present, the cardinal management paradigm is emergency delivery by caesarian section, with aggressive supportive care. OLT is performed only in the context of failure to recover liver function.

In the European Liver Transplantation Registry (ELTR) database (www.eltr.org) 75,530 liver transplantations have been recorded since 1968. OLT has been performed in only six instances for AFLP during this time, (René Adam, personal communication) demonstrating that transplantation is rarely required, and is only indicated in exceptional cases of advanced disease.

The second clinical scenario associated with liver failure during pregnancy is the HELLP syndrome, which was first described by Weinstein et al. in 1982 and usually occurs towards the end of pregnancy in young primagravidae [17]. The pathogenesis of HELLP syndrome is unclear but an imbalance of prostacyclin and thromboxane has been suggested [18], [19]. Patients with HELLP syndrome typically have evidence of pre-eclampsia as well as thrombocytopenia. The HELLP syndrome affects about 6/1000 pregnancies and manifests most frequently in the 34th gestational week. However, 10–30% of cases occur within the first six days post-partum [9]. The most common presenting symptom is abdominal pain but as many as 40% of all cases may be asymptomatic. The clinical course can be complicated by renal failure, pulmonary edema, cerebral hemorrhage, and seizures. Serum aspartate aminotransferase (AST) is usually elevated to a mean level of 250IU/L, but levels in excess of 7000IU/L have been reported. The condition may not meet criteria for ALF since the prothrombin time is typically normal, except in its most extreme form when DIC may exist. The severity of the histological changes are not usually reflected by the laboratory abnormalities, and biopsy of the liver is not mandatory for diagnosis. The most important differential diagnoses are acute viral hepatitis, idiopathic thrombocytopaenia purpura, and AFLP. The treatment of choice is early delivery. Once delivered, the infants have no liver involvement and an appropriate outcome for the gestational age may be anticipated. In most instances there are no long-term sequelae for the mother although the condition may recur in subsequent pregnancies.

In 2–3% of the cases, HELLP syndrome can lead to a variety of hepatic complications such as subcapsular liver hemorrhage and subsequent hepatic rupture, resulting in the death of either mother and/or foetus [20]. Such patients present in shock, with abdominal hemorrhage and require rapid laparotomy and surgical management with packing of the liver. In addition, HELLP syndrome can also lead to hepatic infarction with significant aminotransferase elevation. This is typically identified on axial imaging such as computed tomography and frequently is accompanied by coagulopathy and progressive encephalopathy, i.e. ALF. While the overall mortality of the HELLP syndrome is 2–3%, the presence of hepatic complications increases the maternal mortality to 50%, and in such cases, transplant should be considered [21].

Only case reports and one small series about liver transplantation for HELLP syndrome have been reported. Zarrinpar et al. reported the largest series of liver transplantation for HELLP syndrome [22]. A review of 3090 adult liver transplant operations performed at a single center revealed that eight patients were transplanted for this indication [22]. The most frequent clinical manifestations in this group were encephalopathy, renal failure, DIC, and respiratory failure. A mean model for end-stage liver disease (MELD) score of 40 at the time of OLT typifies the severity of liver disease. In the report, four patients developed primary non-function after transplantation resulting in one death. After three successful re-transplantations in the remaining patients, a 5-year patient survival of 88% was reported. In the European Liver Transplant Registry (www.eltr.org) only four of 75,530 liver transplantations were performed for liver involvement of HELLP syndrome (René Adam personal communication), suggesting that only selected cases with severe liver involvement require transplantation.

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3. When does sexual function become normal after liver transplantation? (Eric M. Yoshida) 

Despite the great wealth of accumulated post-transplant medical knowledge, sexuality or “sexual health” remains largely unexplored post-liver transplantation out-with questions and variables on generic quality of life instruments.

3.1. Challenges in exploring and investigating sexual health post-liver transplantation 

There are many possible reasons why sexual health has been poorly studied following OLT, despite its importance to recipients and their partners. In the highly specialized arena of the post-transplant clinic, physicians, surgeons and allied health care professionals may not feel comfortable dealing with questions regarding sexual health. Many healthcare providers feel that it is outside of their area of expertise and that they have too little to offer patients. Similarly, primary care physicians who are less familiar with liver transplantation often assume that post-transplant patients have more life-threatening transplant-related issues to contend with, and that a return to “normal” life after transplantation is unlikely.

From an academic perspective, the topic itself is, admittedly, a difficult one to study. Sexual attitudes and practices amongst patient populations are heterogeneous and vary from community to community and temporally from generational cohort to generational cohort. Even within individual patients, sexuality changes with time. The subject matter itself is also controversial, just as it is in the greater society.

Similar to contemporary society, some patients may perceive any enquiry or investigation of post-transplant sexuality to be “offensive” and a factor that will negatively affect participation rates in clinical studies. This in turn leads to questions regarding the internal validity of studies, since participation and non-participation may reflect systemic bias that skews the results. Lastly, the generalisability of study findings from one country to another and from one time-point to another becomes problematic.

3.2. Sexual health pre-liver transplantation 

End-stage liver disease is well recognised as altering the normal physiology of the hypothalamic–pituitary–gonadal axis, which in turn can affect sexual function in these patients. In male patients, cirrhosis is associated with decreased levels of serum testosterone [23], [24], [25], [26], [27], inappropriately low levels of the pituitary gonadal stimulating hormones, lutenizing hormone (LH) [23], [24], [25], [27] and follicular stimulating hormone (FSH) [23], [25], [26], [28] and possibly blunting of pituitary responses to gonadotrophic-releasing hormones [29] resulting in a hypogonadal state. In addition, serum levels of oestrogens [24], [28] and prolactin [26], [27] are elevated in cirrhotic men that may further contribute to sexual dysfunction. Although these endocrinologic effects affect patients with cirrhosis of any aetiology, it has also been suggested that ongoing alcohol consumption associated with end-stage alcoholic liver disease may have additional detrimental effects on the hypothalamic–pituitary–gonadal axis in men and women [25].

From a functional perspective, cirrhosis in men has been reported to be associated with decreased volume of ejaculatory fluid [27], and reduced libido/interest in sex [27], [29]. Erectile dysfunction including frank impotence, has been reported to some degree in anywhere from 60% to 90% of patients with cirrhosis [27], [29]. In women, one survey documented close to 60% of patients with chronic liver disease pre-transplant suffering menstrual irregularities: half of this group had amenorrhea compared to less than 20% of women classified as ALF pre-transplant experiencing menstrual problems [30]. Of some interest is a recent report that found 60% of women on a transplant waiting list suffered amenorrhea compared to 19% with cholestatic liver disease (p=0.0009) [31]. One of the difficulties in interpreting studies that report sexual function in patients with cirrhosis is that the severity of the end-stage disease may be either unclear or simply not stated. Although it would appear intuitive that patients with more severe cirrhotic decompensation would suffer worse sexual dysfunction, until recently, this has not been definitively correlated with any index of liver function. In an important paper, using MELD scores as an indicator of liver disease severity, Sorrell and Brown, from the University of Nebraska, correlated sexual activity pre-transplant with MELD scores [29] They found that patients with no reported sexual activity had the highest mean MELD scores of 15.18, whereas those patients that reported no change in sexual activity had the lowest MELD scores of 10.74. Those who were in-between the highest and lowest MELD scores (=13.88) also reported decreased sexual activity. These investigators also found a similar correlation between MELD score and erectile dysfunction [32], thereby scientifically and definitively confirming what clinicians have long-suspected.

3.3. Sexual health after liver transplantation 

Physiologically, the marked hypothalamic–pituitary–gonadal abnormalities of end-stage liver disease are reversed post-transplantation [24], [25], [27] although it has been suggested that some transplant recipients may have persisting abnormalities [27]. Functionally, the vast majority of women of child-bearing age will recover regular menstrual bleeding within one year post-transplant [30], [31] and a significant proportion will experience menses within the first month [30], [33]. Sexual health, which encompasses sexual function and satisfaction, however, is influenced by more than just hormonal and endocrinologic physiology. Concomitant health issues, medications, aging, as well as psychological and social issues may also affect post-transplant sexual health. The post-transplant literature on sexual health is mixed, reflecting the context of the study, the study population(s) and the specific questions asked. Post-transplant quality of life studies using standard but generic instruments tend to report improvements in sexual function as summarized in an excellent meta-analysis by Bravata and colleagues [4]. A large Spanish study however, reported that older recipients, women, and those who were unemployed long-term pre-transplant demonstrated worse adjustment in the sexual domains of a psychosocial adjustment scale [5].

Generic quality of life and psychosocial instruments, however, do not study specific issues concerning sexuality post-transplantation. In terms of specific questions regarding sexual activity, a Brazilian study [33] of relatively young post-transplant women (mean age 44 years) found that 75% reported weekly sexual intercourse with 70% experiencing orgasm and 70% experiencing satisfaction with their sexual health. The North American experience, however, is markedly less favourable. A survey of post-liver transplant recipients in British Columbia, Canada [34], reported that 32% of 150 respondents (median age=54 years, 93% were a minimum of one-year post-transplant) experienced de novo post-transplant sexual dysfunction (i.e. the recipients felt that the problems began after liver transplantation). Twenty-three percent and 26% of men and women, respectively, reported decreased libido and 33% of men and 26% of women reported difficulty with orgasm [34]. Thirty percent of men in the same study reported some degree of erectile dysfunction and 40% of females reported dysparenuia only after their liver transplant. Not surprisingly, 36% blamed their sexual dysfunction on their immunosuppressive medications (approximately 60% were on tacrolimus and 30% on cyclosporine). Overall, approximately 60% reported that, despite their problems, they were “moderately” to “very satisfied” with their sexual relationships suggesting that sexual function/performance itself is only a component of overall post-transplant sexual health. A recent American study of 39 post-transplant recipients surveyed by a telephone interviewer was less favourable than our own reported Canadian experience [29]. Overall, 44% reported a decreased satisfaction with sex, and only 24% of men reported “no problems” with erectile dysfunction, although 35% did report an increased “interest in sex” and 28% reported an increased frequency of intercourse.

If sexual dysfunction exists in a significant minority of post-transplant patients, can anything be done about it? Over a decade ago, it was reported that close to 70% of solid organ transplant recipients did not receive any form of education or counseling on the matter [35] and in liver transplantation, it is uncertain if this has changed significantly. Clearly referral and communication to those with expertise in the area would be appropriate if the transplant clinics did not feel comfortable with this area of healthcare. In terms of pharmacologic therapy for erectile dysfunction, our own study [34] discovered that, unknown to the transplant team, 19% of transplant respondents were using the phosphodiesterase-5 inhibitor sildenafil (Viagra; Pfizer Canada Inc., Kirkland, Que., Canada). Sildenafil or tadalafil (Eli Lilly, Indianapolis, USA) another longacting phosphodiesterase-5 inhibitor use have not been previously reported in the liver transplant setting, although its successful use has been reported in post-renal transplant recipients with erectile dysfunction [36], [37], [38]. Neither adverse effects nor interactions with cyclosporine or tacrolimus have been found in renal transplant clinics, although the elimination of sildenafil was prolonged [38]. In our liver transplant clinic, 65% of sildenafil users reported that they felt that the drug was beneficial, suggesting that sildenafil use post-transplant should be further studied.

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4. Contraception after liver transplantation: how and when? (Beat Mullhaupt) 

As discussed in the previous section, women with end-stage liver disease are often amenorrheic and have a significantly reduced fertility [33]. In parallel with an improvement in general well being, menstrual cycles will return in most women (>90%) of reproductive age within the first year after transplantation [33], [39] Together with menstruation, sexual function can return to normal and consequently women who have undergone successful OLT may conceive as early as one month following OLT [40] Although there is a clear need for contraception in fertile women after OLT, only a few studies have investigated the different contraceptive possibilities in this special population. The data on which to base these recommendations are therefore very limited and consequently opinion is derived largely from kidney transplant populations.

As such, the same contraceptive methods are available for women after liver transplantation as for the general population. However OLT recipients have some factors, which deserve special attention. These include an increased risk of infection and (some) cancer(s), increased prevalence of chronic renal insufficiency and systemic hypertension, increased cardiovascular risk, and greater potential for hepatotoxicity and drug interactions by virtue of lifelong requirement for immunosuppressive therapy. The available contraceptive methods will be reviewed in turn.

4.1. Interrupted intercourse and barrier methods 

Periodic abstinence and coitus interruptus are ineffective methods of contraception, but are not associated with side effects or drug interactions. Among 16 unintended/unplanned pregnancies in female kidney transplant recipients from Iran, 94% of patients used coitus interruptus as their only form of contraception [41]. Therefore, this method can not be recommended. Nevertheless, one quarter of US female kidney transplant recipients that participated in a survey on contraceptive practices reported using no contraception at all [42].

Barrier methods, such as diaphragms and condoms are widely used in the general population, are of low cost and drug interactions are avoided. However, the use of diaphragms increases the risk of urinary tract infections by a factor of two compared to women on oral contraceptives. This increased risk of infection can be especially problematic in the transplant population [43]. Regarding the use of condoms, these represent the only form of contraception that prevents transmission of (most) sexually transmitted disease(s), and should therefore be recommended for all patients without a stable sexual partner [44]. Most barrier methods should be combined with a spermicide to increase their efficacy. However, failure rates are reported to range between 15% and 32% [45]. Nevertheless, all barrier methods can be recommended for birth control in female transplant recipients [44].

4.2. Intrauterine contraceptive devices (IUD) 

Two types of intrauterine devices are currently available: The copper containing ParaGard and levonorgestrel-releasing Mirena coil [45]. Both are very effective at preventing unplanned/unintended conception with failure rates reported below 1% during the first-year of use, and they are effective over a period of 5 (Mirena) to 10 years (ParaGard). Two factors, which limit the use of IUD in post-transplant patients, are the fear of infectious complications upon insertion of a foreign body into the uterine cavity [46], and a reduced effectiveness in immunosuppressed patients [47]. The fear of infectious complications however, appear to be more theoretical than real. To date, there are no studies in cohorts of transplant patients that can confirm or refute this increased risk [46]. However, in a prospective cohort of 156 HIV-positive women, no increased rate of infectious complications was observed when compared to 493 HIV-negative women [48].

Based on such data, IUDs are classified as category two contraceptive devices for HIV-positive women receiving antiviral therapy. This indicates that the benefit exceeds the risk associated with use of IUDs [45]. The reduced effectiveness of IUD among transplant patients is based on failures in two kidney transplant patients and on the theoretical basis that immunosuppression reduces the local inflammatory response [47]. It is generally believed that the effectiveness of an IUD depends on local inflammatory processes. Macrophages are presumably the most important inflammatory cells responsible for the action of IUDs [49]. Most immunosuppressive drugs however, inhibit T cell activation and their effect on macrophages is limited. On the other hand, drug interactions are obviously only of minor importance, and therefore it has recently been suggested that IUDs maybe the ‘perfect’ option for transplant recipients [44].

4.3. Hormonal contraception 

A number of hormonal contraceptives administered in various ways are currently available to OLT recipients with a one-year failure rate that varies between 3% and 8% [45].

4.3.1. Combined oral or transdermal contraceptives 

Combined oral contraceptives (COCs) are the most commonly used type of contraceptive prescribed in many parts of the world. In patients who have undergone solid organ transplantation the same contraindications as in the general population have to be respected, such as a personal history of myocardial infarction, stroke or deep vein thrombosis, smokers over the age of 35 (>15 cigarettes/day), migraine with focal aura, uncontrolled systemic hypertension, marked unexplained liver test abnormalities and hepatic adenoma [45]. In addition, since COCs are metabolized by the hepatic cytochrome P4503A4 system, drug interactions are of at least theoretical concern.

The concentrations of cyclosporine and tacrolimus, which are both also metabolized by the cytochrome P4503A4 could be increased by the concurrent administration of COCs. However, in clinical practice these interactions are most likely of minor importance. Surprisingly, only few published data are available that have analysed the efficacy and safety in female liver transplant recipients. In one study of 15 female liver graft recipients, who used hormonal contraceptives after transplantation for at least 12 months, the authors could show, that COCs were effective, well tolerated and had no impact on graft function [50]. Finally COCs might increase the risk for cervical cancer, whilst at the same time reduce the risk for endometrial and ovarian cancer [46].

Therefore, COCs should be considered carefully after liver transplantation. It has recently been recommended that COCs should only be used in recipients with stable graft function for at least 6–8 months and without other contraindications to commencing therapy [51]. In addition, careful monitoring of liver enzymes should be performed. Far less experience is available for both the transdermal contraceptive patch and the vaginal ring, although one potential advantage of the vaginal ring relates to the absence of the first pass metabolism in the liver.

4.3.2. Progesterone only contraceptives 

An alternative, especially for women with contraindications to estrogens, is the progestin-only method of contraception. These agents can be delivered orally, as an intramuscular injection or as an implantable device. Progestins have a minimal effect on the liver and drug interactions are less common. Depot medroxyprogesterone acetate (DMPA) is a synthetic progestin, which is delivered as an injection every three months. It is highly effective with a failure rate of around 2% [45] Its side effect profile is associated with irregular menstrual bleeding, weight gain and decreased bone mineral density. These latter two issues are especially important in OLT populations, whereby patients have to deal with weight gain post-transplant in addition to the high likelihood of pre-existing osteoporosis in the context of cirrhosis and end-stage chronic liver disease. An etonorgestrel implant, which is implanted in the subcutaneous tissue, is an alternative to DMPA. It can provide protection for up to three years. Its side effect profile is similar to DMPA other than for the risk of reduced bone mineral density which is significantly less.

4.4. Surgical sterilization 

In studies of adult renal and liver transplant recipients 60% and 24%, respectively, choose surgical sterilization as the contraceptive method of choice [39], [52]. Surgical sterilization is very effective at preventing unwanted conception, and drug interactions can be avoided. Despite its efficacy, this method may not be a viable option for women who might wish to consider a pregnancy at a future time-point.

In summary, female patients after OLT need an effective, safe and reversible contraceptive method to avoid unwanted pregnancy. Table 2 summarizes the efficacy and limitations of these contraceptive options. In 2008, IUDs appear to be the method of choice. However, this is based on consensus opinion extrapolated predominantly from the non-transplant literature rather than firm data derived from transplant patients [44].

Table 2. Contraceptive methods available after liver transplantation
EffectivenessDrug interactionsReversibility
IUD++–++
COC+++++
Progestin-only pill++(−)++
DMPA++(−)++
Barrier method+−++
Surgical sterilisation++––

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5. What do we know about pregnancy after liver transplantation? (Michael A. Heneghan) 

Although the majority of OLT recipients are men or women of non-child-bearing age, as discussed previously, a significant proportion of recipients are pre-menopausal women and many of them are of child-bearing potential [53]. OLT reverses the biochemical imbalances associated with pre-transplant infertility [54], [55], [56], [57]. The first successful pregnancy following OLT occurred in 1978 and led to an excellent foetal outcome despite low birth weight [58]. Whilst subsequent decades have seen an expansion in our knowledge of pregnancy in the OLT recipient, much uncertainty remains regarding the absolute rate of conception amongst liver graft recipients and the success of subsequent pregnancies. Thus, the major questions regarding pregnancy post-transplantation are:

(1)What is the effect of immunosuppression on foetal development and outcomes ?

(2)How does OLT affect the foetal and maternal outcomes of pregnancy?

(3)What is the effect of pregnancy on the allograft?

5.1. Effect of immunosuppression on foetal outcomes 

5.1.1. In-utero effects of immunosuppression 

An increased risk of teratogenicity has been a concern regarding the use of immunosuppressive drug therapy during pregnancy. However, the absolute risk of teratogenicity and foetal loss with the commonly used immunosuppressive agents following OLT, appears low. Evidence has largely been gathered from experimental studies in animals or relatively small case series. Subsequently, such data have significant limitations in its ability to accurately predict outcomes. The most commonly used immunosuppressive drugs used post-OLT, in both Europe and the USA, are cyclosporine A (CyA), tacrolimus and prednisolone. The United States Food and Drug Administration (FDA) categorise the safety of drugs in pregnancy based on available evidence. These are presented in Table 3. In the early years of OLT, CyA was the mainstay of immunosuppressive therapy, in conjunction with prednisolone and/or azathioprine.

Table 3. United States of America Food and Drug Administration categories of the safety of drugs in pregnancy
Categories of drug safety in pregnancy
(A) Controlled studies show no risk: adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the foetus
(B) No evidence of risk in humans: either animal findings show risk (but human findings do not) or, if no adequate human studies have been done, animal findings are negative
(C) Risk cannot be ruled out: human studies are lacking and animal studies are either positive for foetal risk or lacking as well. However, potential benefits may justify the potential risk
(D) Positive evidence of risk: investigational or post-marketing data show risk to foetus. Nevertheless, potential benefits may outweigh the risk
(X) Contraindicated in pregnancy: studies in animals or humans, or investigational or post-marketing reports have shown foetal risk which clearly outweighs any possible benefit to the patient
5.1.2. Cyclosporine A and azathioprine 

Although controversy surrounds the trans-placental transfer of CyA, with some reports finding no significant placental levels and others demonstrating levels equivalent to those observed in maternal blood [58], [59], its teratogenic potential appears to be low. Premature labour, low birth weight as well as transient neonatal hyperkalaemia and elevated serum creatinine concentrations have, however, been reported [60], [61], [62], [63].

A meta-analysis of 15 studies of women who received CyA during pregnancy reported major malformations in 4.1% of live births, a rate not significantly higher than that noted in the general population [61]. A single center study of 154 pregnancy outcomes in 115 renal transplant recipients compared the effects of CyA immunosuppression with azathioprine and prednisone [64]. The CyA group had a lower rate of complications with no congenital malformations being noted, although CyA treated patients were more likely to have diabetes and systemic hypertension, and the child was more likely to have a low birth weight. CyA is considered a class C drug in terms of its risk for pregnancy by the United States Food and Drug Administration (FDA).

Azathioprine as an immunosuppressant has classically been prescribed in conjunction with CyA in transplant recipients and in the first two decades of solid organ transplant significant experience was obtained with the drug [39], [61]. In general, azathioprine is considered relatively safe during pregnancy in both non-transplant and transplant populations [39], [61], [64], although, it is considered a class D drug by the FDA as a consequence of reports of congenital malformation in some exposed infants.

5.1.3. Tacrolimus 

In the last decade, tacrolimus has supplanted CyA as the mainstay of immunosuppression post-OLT. Data on its safety in pregnancy are emerging. Among 100 pregnancies in 84 women treated with tacrolimus, 68 pregnancies progressed to live birth and 60% of these live births were premature [65]. The neonatal malformation rate was 4%, similar to the rate associated with CyA [61]. These outcomes have been similar across a range of reports [66], [67], [68], [69]. In common with CyA, tacrolimus is considered a class C drug in terms of its risk in pregnancy by the FDA.

5.1.4. Corticosteroids 

Whilst both prednisone and prednisolone cross the placenta, only small quantities appear in foetal cord blood [70]. Evidence suggests that the major foetal risks regarding steroids are cleft palate (particularly with high dose exposure in the first trimester), premature rupture of the membranes and intrauterine growth retardation [71], [72]. A systematic review of studies of women who took corticosteroids during pregnancy for non-transplant-related conditions, demonstrated a 3.4-fold increased risk of cleft palate [73]. Meanwhile, the increased risk of low birth weight in these studies is frequently confounded by the severity of underlying disease necessitating corticosteroid therapy. Foetal adrenal hypoplasia and suppression of the foetal pituitary gland have also been described though both of these are uncommon due to the rapid maternal metabolism, binding to plasma proteins and placental breakdown of corticosteroids. Prednisone is considered a class B drug in terms of its risk for pregnancy by the FDA.

5.1.5. Mycophenolate mofetil and sirolimus 

These two novel immunosuppressants have gained increased popularity either as add-on immunosuppression de novo following OLT as an alternative to azathioprine, or alternatively as steroid sparing agents. Mycophenolate mofetil (MMF), an inhibitor of purine biosynthesis, and sirolimus, an inhibitor of the mammalian target of rapamycin (MTOR), have been shown to cause abnormal ova development, and therefore, are both potentially teratogenic [74]. In a large report of registry data from all solid organ recipients, 18 kidney recipients reported 26 pregnancies with exposure to MMF. Of these, there were 15 live births, and 11 spontaneous abortions. Structural malformations were reported in four of the 15 children (26.7%) including hypoplastic nails and shortened fifth fingers, microtia with cleft lip and palate, microtia alone, and neonatal death with multiple malformations in one case [74]. One kidney/pancreas recipient reported one spontaneous abortion whereas, three liver recipients reported three pregnancies; two live births without malformations, and one second trimester spontaneous abortion. Two heart recipients reported one live birth without malformations and two spontaneous abortions. In another series, data from 119 human pregnancies with maternal exposure to MMF found outcome data for 65 and demonstrated a live birth rate of only 34% with miscarriage occurring in 31% and elective abortion in 20% [62]. The rate of congenital abnormalities, at 15%, was higher than that seen in the general United States population [75].

Sirolimus exposures during pregnancy was reported in seven recipients (four kidney, one kidney/pancreas and two liver) reporting four live births (one infant whose mother was switched from MMF to SRL during late pregnancy had cleft lip and palate and microtia) and three spontaneous abortions [74]. MMF is considered therefore by the FDA a class D drug in terms of the risks associated with its use in pregnancy, whereas, sirolimus has been designated as class C, albeit, with less data available to assess outcomes during pregnancy.

5.1.6. Other immunosuppressive agents 

Other immunosuppressive agents which pregnant OLT recipients may be exposed to include the monoclonal antibody muromonab and anti-thymocyte globulin (ATG). To date, no human studies regarding their safety in pregnancy exist. Consequently, all three are categorised as class C drugs in term of pregnancy risk by the FDA.

5.2. Breast feeding 

Most transplant physicians advise against breastfeeding due to concerns over the safety of neonatal exposure to immunosuppressants, with the optimal level above which complications occur being unknown. Corticosteroids, CyA and tacrolimus are all known to be excreted in breast milk whilst no data exist for sirolimus, muromonab or ATG. Corticosteroids, however, are excreted in extremely low concentrations and are felt to be safe during breastfeeding [76]. Meanwhile, both CyA and tacrolimus levels are excreted in breast milk and in some cases levels are equivalent to, or even exceed, that of maternal plasma and are therefore contraindicated [77], [78], [79].

In a seminal study from Jain et al., 15 pregnancies post-OLT were described under tacrolimus immunosuppression and all were followed prospectively. Maternal, cord and neonatal blood, as well as placental tissue was stored at, or shortly after, delivery for determination of tacrolimus levels. Mean tacrolimus concentrations were 4.3ng/mL in placenta versus 1.5, 0.7, and 0.5 in maternal, cord, and neonate plasma, and 0.6 in the initial breast milk, respectively [79]. These neonates, however were not subsequently breastfed and, as a consequence, little data have been accumulated on the safety or otherwise of neonatal exposure to the commonly used agents post-transplantation. What evidence exists is limited to small numbers collated by a national registry or in patients who have ignored physician advice not to breastfeed [67]. Such series have not demonstrated obvious concerns but are extremely limited by their size.

5.3. Foetal and maternal outcomes following liver transplantation 

Conception in the post-liver transplant recipient, although commonly resulting in live birth, does not always guarantee a successful outcome. The commonest encountered foetal problems are foetal loss, prematurity (defined as birth occurring prior to 37 weeks gestation) and low birth weight (<2500g), while maternal risks include systemic hypertension/pre-eclampsia, gestational diabetes, graft dysfunction and, in rare instances, maternal death. Therefore, it is preferable that post-transplant patients who conceive, are managed by centers who have easy access to the transplant team and multi-disciplinary care teams available to deal with the obstetric complications that arise.

5.3.1. Outcome studies of pregnancy post-liver transplantation 

National registries have been established to record foetal and maternal outcomes following any organ transplantation. The most comprehensive registry is the National Transplantation Pregnancy Registry (NTPR) maintained at Philadelphia in the United States. In 2004 the NTPR reported data regarding pregnancy following liver transplantation in 189 patients (these results are summarized in Table 4) [67]. Experience from our own center, has led to the report of the largest individual series of pregnancies in OLT recipients and demonstrated a live birth rate of 50/71 (70%) [68]. Although rejection episodes were noted in 17%, no patient lost their graft as a consequence of pregnancy and no maternal deaths were noted in this series. These data mirror UK registry data which are, to date, incomplete [80].

Table 4. National Transplantation Pregnancy Registry (NTPR) Report 2004: foetal and maternal outcomes in liver transplant recipients
Foetal outcomesMaternal outcomes
Live births73%Hypertension in pregnancy35%
Spontaneous abortion19%Pre-eclampsia23%
Therapeutic abortion6%Gestational diabetes5%
Premature birth30%Infection27%
Low birth weight30%Caesarean section rate35%
Stillbirth2%Graft rejection8%
Neonatal deaths0%Graft loss within 2 years7%
Mean gestation37 weeksMean OLT-conception4.3 years

Available evidence therefore suggests that there is an increased incidence of complications, including preterm delivery, foetal growth retardation, systemic hypertension/pre-eclampsia (PET), and gestational diabetes in pregnancy post-OLT. [66], [67], [68], [80], [81], [82], [83], [84]. Foetal and maternal complications reported in published, single center series are summarized in Table 5.

Table 5. Summary of important foetal and maternal outcomes of pregnancy in liver transplant recipients in single center series
Author [Reference]Live birth rate (%)Pre-term (%)Mean birth weight (g)HTN/PET (%)Graft dysfunction (%)CS rate (%)
Christopher et al., 2006 n=71 [68]70na266820/131740
Nagy et al., 2003 n=38 [75]6329276221/81746
Jain et al., 2003 n=49 [79]na49279711/225∧47
Rayes et al., 1998 n=19 [82]328265944/01154
Wu et al., 1998 n=22 [83]na14287614/14532
Ville et al., 1993 n=19 [81]3202990na/27545
Scantlebury et al., 1990 n=20 [69]8055294030/2030∗63

Key: ∧not biopsy proven; ∗ all abnormal LFTs; na, not available.

Abbreviations: HTN, hypertension; PET, pre-eclamptic toxaemia.

5.3.2. Low birth weight 

The prevalence of low birth weight is considerably higher than in the general population where, in the United Kingdom it is reported to occur in 5% [85]. Whilst the risk of preterm birth may be related to episodes of graft rejection and early onset pre-eclampsia [75], this has not been conclusively demonstrated.

5.3.3. Pregnancy loss 

Nagy et al. [75] reported that the interval between transplantation and conception was shorter in those who suffered abortions or miscarriages (mean 24.4±24.3 months versus 47.8±28.7 months p=0.02). They therefore suggested conception be delayed for up to two years post-OLT. Contrary to this recommendation, experience at our institution has not shown a significant association between conception in the first year post-OLT and increased foetal and maternal complications [78].

5.3.4. Maternal risks 

The most common maternal risks are systemic hypertension and/or pre-eclampsia, both of which occur at far higher frequency than in the general population. The cause of these complications is multi-factorial, but potential factors include the vasoconstrictive effects of calcineurin inhibitor therapy, chronic corticosteroid use and underlying renal dysfunction. These issues are not unique to OLT, with similar rates observed in renal transplant populations [82], [83]. Moreover, the risk of systemic hypertension, renal dysfunction and pre-eclampsia in pregnant patients treated with tacrolimus therapy appears to be lower than that seen with CyA [67], [79], [81], [84].

5.3.5. Mode of delivery 

The rate of caesarean section (CS) is considerably higher in patients post-OLT, with individual series quoting rates of 35–63% [66], [67], [75], [78], [79], in comparison to the general population rate of 23% recently reported from the UK [85]. Many authors report that the majority of CS are performed for standard obstetric indications and it is likely that prematurity and low birth weight predispose to foetal distress during childbirth thereby necessitating CS [66], [75].

The rate of CS is, however, variable and may relate to differing experience in OLT and subsequent experience in managing pregnancy post-OLT. A learning curve may therefore exist as evidenced by a reduction of CS rates series over time in one series [68].

5.4. Effect of pregnancy on allograft function 

Biopsy proven graft dysfunction in the form of acute cellular rejection occurs in approximately 10–20% of pregnant OLT recipients, but graft losses are rare [67], [68], [75]. Graft dysfunction, when present, generally responds either to augmentation of the baseline immunosuppression or may require additional therapy in the form of intravenous methylprednisolone or even ATG. Graft dysfunction is, however, associated with increased rates of miscarriage and lower birth weights. There is no evidence to date that it leads to increased maternal mortality [67], [75]. Available evidence suggests that, overall, episodes of rejection do not occur with any greater frequency than in non-pregnant individuals and that liver biopsy is safe in pregnancy [68], [75].

Regarding the timing of conception, most transplant centers advise that conception be delayed for at least 12 months after transplantation and this is supported by the NTPR [67]; although, some authors advocate waiting 24 months [75], [81]. This delay is to allow for stability of both graft function and immunosuppressive therapy, including possible withdrawal of corticosteroids. Moreover, opportunistic infections are less likely to occur after this period.

A further key issue for practitioners is that of whether immunosuppression should be reduced either prior to or during pregnancy. Our own experience having applied both strategies at different time-points over a 20 year period, is to maintain standard levels of immunosuppression during pregnancy appropriate for the time course, post-transplant [68]. This approach limits graft-related issues, whilst allowing the multi-disciplinary team to deal appropriately with the known complications associated with pregnancy.

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6. Summary 

In this the 11th Forum, we have reviewed many of the issues pertaining to sexuality and sexual function in the liver transplant recipient. It is disappointing that despite forty years of OLT, only a relatively small literature exists in relation to many of these topics, particularly the area of sexual health.

As hepatologists and transplant physicians, much is made of graft and patient survival and indeed it is correct to do so. However, it is clear that our patients wish to, and do form and maintain normal healthy sexual relationships. Yet, this area of transplantation has been largely neglected not just in OLT, but also across other organs. Indeed, despite the many successful pregnancies that do occur in our transplant recipients, the management of such patients has been derived from largely self-reported patient series, and the criticism of all such series is that there exists a reporting bias of predominantly successful outcomes. That said, the multi-disciplinary transplant team should not fear addressing issues of sexuality and sexual health, but rather encourage it. Indeed, all concerned, both patients and healthcare providers alike may be pleasantly surprised by the responses and the interest in the topic!

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Acknowledgements 

Prof. Rene Adam, European Liver Transplant Registry. Dr. Andrew Yeoman, King’s College Hospital, London, UK. Dr. Nilu Partovi, Vancouver General Hospital Department of Pharmacy.

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☆ The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.

PII: S0168-8278(08)00483-2

doi:10.1016/j.jhep.2008.07.011

Journal of Hepatology
Volume 49, Issue 4 , Pages 507-519, October 2008

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