Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases

Abstract

This first Practice Guidance on Reproductive Health from the American Association for the Study of Liver Diseases (AASLD) is intended to be a comprehensive reference on adolescents and adults with chronic liver disease. The Guidance specifically (1) addresses management of reproductive health in women and men from puberty to senescence and (2) summarizes the natural history, risk factors, evaluation, and optimal management of liver diseases during pregnancy and after delivery. Intended for use by health care providers, this Guidance identifies preferred approaches to diagnostic, therapeutic, and preventive aspects of reproductive health. It should not replace clinical judgment for a unique patient, but instead provide general guidance to optimize the care of most patients. A critical aspect of reproductive care in patients with liver disease is the need for close collaboration among hepatologists, maternal-fetal medicine (MFM) specialists, and pediatricians. Whether for preconception counseling, assisted reproduction, pregnancy, or postpartum care, a multidisciplinary approach is advised to help yield the best outcomes. This AASLD Guidance provides a data-supported approach to the management of reproductive health in patients with liver disease. It differs from AASLD Guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence and strength of the recommendations, and, if appropriate, meta-analysis of results using the Grading of Recommendations Assessment, Development, and Evaluation system. In contrast, this Guidance was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee at all stages of Guidance development. The Committee chose to perform a Guidance on this topic because a sufficient number of randomized controlled trials were not available to support the development of a meaningful Guideline. In women with advanced liver disease, altered estrogen metabolism and disruption of the hypothalamic-pituitary axis with low follicle-stimulating hormone and luteinizing hormone can lead to anovulation, amenorrhea, and infertility.(1, 2) Amenorrhea or oligomenorrhea are seen in more than 25% of women with advanced liver disease(3, 4) and nearly three quarters of premenopausal women awaiting liver transplant (LT).(5) Excess alcohol intake can also affect the hypothalamic-pituitary axis or more directly affect ovarian function.(6-8) Although menstrual irregularities are common in cirrhosis,(9) pregnancies occur even in those with decompensated disease, underscoring the need for contraception in women with cirrhosis who wish to avoid pregnancy. In men with advanced liver disease, low testosterone levels result from hypogonadotropic hypogonadism,(10) with an additional contribution of increased peripheral conversion of androgens to estrogen.(11, 12) Free testosterone also declines in part from observed rise in sex hormone–binding globulin (SHBG), although the reasons for SHBG rise in chronic liver disease remain unclear.(13-15) Produced in the liver, SHBG synthesis is stimulated by estrogens, although with further progression from compensated to decompensated cirrhosis, SHBG levels ultimately decline.(16, 17) Estrogen levels are also elevated in the setting of portosystemic shunting,(10, 18) and increased circulating levels suppress the hypothalamic-pituitary axis,(19) contributing to erectile dysfunction, oligospermia, testicular atrophy, and feminization.(20) Sexual dysfunction is common in chronic liver disease and may present with erectile dysfunction, dyspareunia, or impaired arousal, lubrication, orgasm or satisfaction.(21, 22) Libido can be decreased in the context of chronic illness and hormonal abnormalities.(10, 19, 23) The differential diagnosis of sexual dysfunction includes psychogenic causes, alcohol use, medication effects (e.g., spironolactone or beta-blockers), hypogonadism (including as seen in hemochromatosis), and autonomic dysfunction (as seen in diabetes).(19) Open and directed inquiry in clinic provides an opportunity for patients to identify and disclose sexual dysfunction. A careful history also assesses menstrual patterns and psychosocial health. Laboratory workup may include sex hormone levels and thyroid function, although patients should generally be referred to appropriate specialists for evaluation and management. Women with chronic liver disease or prior transplant have potential for unique risks in pregnancy, including worsening of underlying liver disease during pregnancy and/or the postpartum period, increased obstetric and/or perinatal complications, as well as potential exposure to liver-related medications that may not be safe for pregnancy or breastfeeding.(24, 25) Moreover, because many women with chronic liver disease have impaired fertility,(2, 3) the potential for pregnancy may not come to mind for sexually active patients or their clinicians. Thus, reproductive health counseling is critical in this population to ensure the use of safe and effective contraception in those wishing to avoid pregnancy, while ensuring appropriate planning to minimize pregnancy-associated risks in mothers and infants. Clinicians should routinely inquire about family planning, including sexual activity, contraception use, and pregnancy intentions, in all reproductive-aged patients. Pregnancy planning allows clinicians to perform necessary liver-related evaluation before conception, transition the patient from teratogenic medications to regimens that are compatible with pregnancy, and ensure liver disease stability on modified drug regimens. Moreover, pregnancy planning also ensures that patients are informed of the specific risks related to their disease etiology and degree of liver dysfunction, to help guide their decisions on whether to pursue pregnancy. Adolescents with chronic illness may struggle with self-management, including acceptance and understanding of their liver disease.(26) Scaffolding support—which may include temporary financial, housing, and emotional support or guidance, with the goal of gradually increasing autonomy of the teenager—is typically provided by family or friends.(27) For those with limited support, health services, including transition coordinators and public health teams, may help with the transition from adolescent to adult care. Approximately 75% of pregnancies among adolescents are unplanned.(28) Long-acting reversible contraception (LARC) has advantages in this setting.(29) Depending on jurisdiction, legal consent for reproductive medical care can vary by age and whether an adolescent is pregnant.(30) Collaboration between pediatric and adult hepatology and MFM specialists is needed to manage pregnant adolescents.(31) Adult providers must recognize the distinct psychosocial needs of most adolescents with chronic liver disease.(32) Contraceptive discussions should incorporate shared decision making with patients to maximize their adherence and satisfaction with selected methods.(33) A common reference for contraceptive safety in women with medical conditions is the Centers for Disease Control and Prevention (CDC) U.S. Medical Eligibility Criteria (MEC).(34) Here we provide recommendations for contraception use in female patients with medical conditions, including those with cirrhosis, hepatocellular adenomas (HCAs), and solid-organ transplant, and note instances in which the AASLD guidance recommendations may differ from the MEC (Table 1). Combined hormonal contraception (CHC) medications contain estrogen and progestin. Typical failure rates are approximately 9%.(34, 35) General safety concerns include venous thromboembolism (VTE), hypertension, and rarely stroke, although data in chronic liver disease are limited.(36) CHCs are not advised in Budd-Chiari syndrome (BCS).(34, 37-40) Higher-dose CHCs increased the risk of liver enzyme elevations, although current regimens carry no greater risk than placebo.(41-43) Rare cholestatic liver injury has been reported, particularly with higher-dose estrogens.(42, 44) CHCs are considered safe in women with compensated cirrhosis but should be avoided in decompensated cirrhosis due to concerns of impaired estrogen metabolism.(34) Although controlled studies are lacking, these agents are considered acceptable in LT recipients(45) but not in those with graft failure, because of the potential for increased estrogen-associated risks such as VTE. Women with HCAs should also avoid CHCs, as estrogens promote adenoma growth. CHCs affect P450 metabolism; thus, a review for potential drug interactions is warranted. CHCs should be avoided in women with multiple cardiovascular risk factors(34); therefore, women with nonalcoholic fatty liver disease (NAFLD), in particular, warrant careful review of metabolic profiles. CHCs are acceptable with other chronic liver diseases and are not known to increase liver enzymes or fibrosis progression.(46) Progestin-only pills, depot medroxyprogesterone acetate (DMPA) injections, and the subcutaneous implants do not have estrogen-associated risks.(34) Failure rates with progestin-only pills are approximately 9% and require strict adherence to timing of daily dosing.(34, 35) DMPA injections, administered every 12 weeks, have a typical failure rate of approximately 6%(34, 35) and delay return to fertility up to 18 months.(47) DMPA has a black box warning for decreased bone density, which normalizes with cessation of use.(48) The subcutaneous implant is considered a LARC agent and has the lowest failure rate (0.05%).(34, 35) It is associated with minimal to no bone loss(49) and may be used for up to 3 years. No prospective studies have evaluated HCA growth with progestin-only agents.(50-52) Intrauterine devices (IUDs), also considered a form of LARC, have failure rates of less than 1%.(34, 35) Effective for at least 10 years, copper IUDs are hormone-free. Progestin-only levonorgestrel IUDs are effective for at least 3 to 5 years. The levonorgestrel IUD lightens or eliminates menstrual bleeding,(53) whereas the copper IUD often increases menstrual bleeding. Data on liver-related risks of levonorgestrel IUD with either decompensated cirrhosis or HCAs are lacking, though none are anticipated given the lack of estrogen.(34) LARC is also favored by adolescents given their convenience and high efficacy, which does not rely on patient adherence.(54) IUD use in solid-organ transplant recipients has been controversial, largely due to early case reports of unplanned pregnancies with older, less effective IUDs. The hypothesis that IUD failures were due to a dampened inflammatory response with immunosuppression(55) has not been substantiated.(56) Initial concern for pelvic inflammatory disease in immunocompromised women using IUDs(55) has been dispelled.(57-60) Thus, IUDs are considered acceptable for use in LT recipients, including those with graft failure. Contraceptive risk in the perioperative setting is not well studied, although the American College of Obstetricians and Gynecologists does not recommend discontinuation of estrogen-containing contraception following major surgeries in the absence of prolonged immobility and advises that all other agents be continued regardless of postsurgical mobility status.(34, 61) This contraceptive strategy is reasonable for LT recipients and living donors. Emergency contraception can reduce the likelihood of pregnancy in the first 5 days following sexual intercourse. Options include the copper IUD and hormonal contraceptive pills. The copper IUD has the highest efficacy (<1% failure rate).(34) Progestin-only emergency contraception pills should be avoided if body mass index (BMI) is greater than 30 mg/kg2.(34) There are no data on estrogen-containing emergency contraception in specific liver conditions. Given the short duration of use, these are unlikely to pose harm, although non-estrogen-containing options are preferable in patients with HCAs, BCS, decompensated cirrhosis, or graft failure. Although liver disease may be associated with impaired fertility,(62, 63) assisted conception in this population is understudied. Infertility is defined as the failure to achieve pregnancy within 12 months of unprotected intercourse or donor insemination in women younger than 35 years of age or within 6 months in women older than 35 years of age.(64) Fertility rates are similar in patients with compensated cirrhosis and the general population but are 40% lower in women with a history of decompensation.(65) Hypothalamic–pituitary dysfunction is associated with an inadequate response to gonadotropic-releasing hormone agonists and clomiphene citrate as well as diminished gonadotrophin release relative to the reduced levels of circulating sex steroids.(7) In the post-LT literature, several case reports describe pregnancies with successful births after assisted reproduction.(66-68) One retrospective review included 18 women with liver disease: 7 who were post-LT patients, 6 with autoimmune hepatitis (AIH), 2 with primary biliary cholangitis (PBC), 1 with hepatitis B, 1 with BCS, and 1 with noncirrhotic portal hypertension (PHT).(69) Of the 18 women, 7 had cirrhosis, and 16 underwent in vitro fertilization, of which 3 (18%) failed to conceive after three cycles. In addition, 2 women experienced no liver-related adverse events, and 1 (after LT) developed severe worsening of graft function with hormonal treatment, with improvement in liver graft function with administration of steroids. The remaining 13 women had 16 conceptions. The live birth rate was 50% in patients with cirrhosis and 67% in patients with noncirrhotic liver disease. Data informing the risk of hepatic decompensation are lacking. Menopause is the process of reproductive aging, characterized by ovarian senescence, hormonal changes, and cessation of menses.(70) Estrogen levels begin to fluctuate during perimenopause, with irregularity of menses. Age-related biochemical and immunologic transitions in combination with hormonal changes influence liver-related health. The benefits of estrogen include inhibition of hepatic stellate cell activity and fibrogenesis(71-73) as well as broader benefits on metabolic health. Hormonal therapy is effective for menopausal symptoms and prevention of bone loss and fractures.(74, 75) Patients with advanced liver disease have decreased bone synthesis; increased bone resorption, poor nutritional status, and reduced muscle mass and immobility further increase this risk.(76-80) Hormone replacement therapy is used in the management of menopausal symptoms and bone health. There is concern about cholestatic effects of estrogens, particularly in women with existing cholestatic liver disease. However, topical, oral, and parenteral forms of estrogen-containing hormone therapy appear to be safe in women with PBC.(81, 82) Estrogen-containing menopausal hormone therapy can promote HCA growth.(42) Non-liver-related considerations include risk of VTE, ischemic stroke, and potentially breast cancer,(74, 75) and treatment decisions must consider personalized risk-benefit ratios. In men, testosterone levels gradually decline but may remain within age-appropriate normal range.(83) If testosterone declines below normal levels, symptoms consistent with hypogonadism ensue, an age-related clinical presentation referred to as andropause, late-onset hypogonadism, or testosterone deficiency syndrome. Clinical signs and symptoms of andropause include sexual dysfunction, mood changes, fatigue, and loss of bone mass that warrant treatment with testosterone replacement therapy.(84) Low testosterone levels are also observed in men with advanced liver disease and are associated with sarcopenia, which is a predictor of mortality in patients with cirrhosis.(85, 86) Benefits of testosterone therapy in men with cirrhosis, including those with decompensated disease, include significant increases in muscle and bone mass, with a trend toward lowering mortality.(87) However, testosterone repletion may be associated with myocardial infarction or stroke,(88) and testosterone levels that prompt replacement vary by clinical symptoms.(89, 90) Testosterone replacement therapy may be associated with transient elevations in liver enzymes that are usually self-limited.(42) An emerging area of clinical importance is transgender health, including the interplay of sex hormones and liver disease in this population. Clinicians should be prepared to support or refer transgender patients and to eliminate barriers to care. Limited data suggest effects of hormonal alterations on risk of hepatic steatosis and metabolic health in transgender patients.(91, 92) Female-to-male transgender patients should be screened for liver abnormalities and polycythemia before initiation of high-dose androgen therapy.(93) Male-to-female transgender patients receiving estrogen therapy should work in coordination with their hepatologist during transition. A welcoming and supportive environment for transsexual individuals seeking hepatology care is important.(94) Many physiological and hormonal changes occur in pregnancy, and these changes can mimic those seen in chronic liver disease. Pregnancy is associated with increased circulating plasma volume, heart rate, and cardiac output as well as decreased systemic and splanchnic vascular resistance (Fig. 1). Blood volume and red blood cell mass increase gradually during pregnancy. Cardiac output increases up to 50% in the third trimester,(95) although absolute hepatic blood flow remains unchanged, as the liver receives a lower percentage of the cardiac output.(96) This resultant hyperdynamic state is similar to the systemic changes seen in decompensated cirrhosis. These physiological changes may impair clearance of substances with hepatic metabolism(97, 98) and lead to decreased gallbladder motility with an increased risk of developing gallstones.(99) In pregnant women without underlying liver disease, clinically insignificant esophageal varices can occur in the latter part of pregnancy due to compression of the inferior vena cava by the gravid uterus and a reduction in venous return.(100) Spider angiomas and palmar erythema, presumably related to the hyperestrogenic state, can also develop.(101) The liver is generally not palpable but can be displaced upward as the gravid uterus enlarges. Normal changes include an increase in alkaline phosphatase of placental origin and an increase in alpha-fetoprotein of fetal liver origin (Table 2). Albumin levels decrease during the second half of pregnancy due to hemodilution. However, serum aminotransferases, bilirubin level, prothrombin time (PT), gamma-glutamyltransferase, and total bile acid levels remain normal throughout pregnancy, and any elevation should be evaluated. Clotting factors II, V, VII, X, XII, and fibrinogen are increased, increasing hypercoagulability. Liver dysfunction in pregnancy is best categorized as diseases unique to pregnancy, exacerbated by pregnancy, or coincidental to pregnancy. Diseases unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy (ICP), acute fatty liver of pregnancy (AFLP), and the spectrum of hypertensive disorders, including preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (Fig. 2). Each disorder typically occurs within a specific trimester, but overlap does occur.(102) Diseases exacerbated by pregnancy include gallstones, vascular diseases, and cirrhosis. Additionally, the natural history of chronic liver diseases may be affected by pregnancy or require unique management during pregnancy or lactation, as discussed in subsequent sections. Evaluation is similar to nonpregnant patients (Fig. 3) and must include a thorough history (including travel, environmental, and drug exposures), physical examination, and focused serologic testing. 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