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The ART of medicine: Counselling women with liver disease about assisted reproductive technology

  • Jennifer A. Flemming
    Correspondence
    Corresponding author. Address: Medicine and Public Health Sciences, Queen’s University, Kingston Health Sciences Centre – HDH Site S4-012, 166 Brock Street, Kingston ON Canada K7L 5M2; Tel.: 613-544-3400 x 2483, fax: 613-544-3114.
    Affiliations
    Department of Medicine, Queen’s University, Kingston, Ontario, Canada

    Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada
    Search for articles by this author
  • Maria P. Velez
    Affiliations
    Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada

    Department of Obstetrics and Gynecology, Queen’s University, Kingston, Ontario, Canada
    Search for articles by this author
Published:March 30, 2021DOI:https://doi.org/10.1016/j.jhep.2021.03.007

      Linked Article

      See Article, pages 1407–1415
      The number of women of reproductive age living with chronic liver disease (CLD), cirrhosis, and post liver-transplantation (LT) is growing along with rising rates of childbirth in women with liver disease documented in Europe,
      • Hagström H.
      • Höijer J.
      • Marschall H.-U.
      • Williamson C.
      • Heneghan M.A.
      • Westbrook R.H.
      • et al.
      Outcomes of pregnancy in mothers with cirrhosis: a national population-based cohort study of 1.3 million pregnancies.
      Canada,
      • Flemming J.A.
      • Mullin M.
      • Lu J.
      • Sarkar M.
      • Djerboua M.
      • Velex M.P.
      • et al.
      Outcomes of pregnant women with cirrhosis and their infants in a population-based study.
      and the United States.
      • Sarkar M.
      • Grab J.
      • Dodge J.L.
      • Gunderson E.P.
      • Rubin J.
      • Irani R.A.
      • et al.
      Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.
      As chronic medical conditions can result in both a delay in conception and infertility, counselling women with liver disease and post-LT regarding the success and safety of assisted reproductive technology (ART) is becoming more frequent. The most common form of ART is in vitro fertilization (IVF), where ovarian stimulation occurs via injectable gonadotropins followed by egg retrieval, fertilization of the egg (either conventional in vitro insemination or intracytoplasmic sperm injection), and embryo transfer. In the United States in 2017,
      • Sunderam S.
      • Kissin D.M.
      • Zhang Y.
      • Jewett A.
      • Boulet S.L.
      • Warner L.
      • et al.
      Assisted reproductive technology surveillance — United States, 2017.
      IVF achieved a clinical pregnancy (ultrasound confirmation as opposed to positive pregnancy test) in 57% of embryo transfers while the live birth rate was 43% with success dependant on patient and treatment-related factors. Safety concerns are of particular importance in women considering IVF. Ovarian stimulation is associated with a risk of ovarian hyperstimulation syndrome (OHSS) occurring in 3–6% of women, with severe OHSS (ascites, elevated liver enzymes, thromboses etc.) developing in <2%.
      • Corbett S.
      • Shmorgun D.
      • Claman P.
      The prevention of ovarian hyperstimulation syndrome.
      Additionally, the risk of perinatal events including multiple births, premature birth, need for caesarian section, and low birth weight are higher in IVF pregnancies compared to spontaneous conception.
      • Nassar A.H.
      • Usta I.M.
      • Rechdan J.B.
      • Harb T.S.
      • Adra A.M.
      • Abu-Musa A.A.
      Pregnancy outcome in spontaneous twins versus twins who were conceived through in vitro fertilization.
      As pregnant women with CLD, cirrhosis, and post-LT have higher risks of adverse pregnancy outcomes compared to the general population,
      • Flemming J.A.
      • Mullin M.
      • Lu J.
      • Sarkar M.
      • Djerboua M.
      • Velex M.P.
      • et al.
      Outcomes of pregnant women with cirrhosis and their infants in a population-based study.
      ,
      • Sarkar M.
      • Grab J.
      • Dodge J.L.
      • Gunderson E.P.
      • Rubin J.
      • Irani R.A.
      • et al.
      Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.
      ,
      • Rahim M.N.
      • Long L.
      • Penna L.
      • Williamson C.
      • Kametras N.A.
      • Nicolaides K.H.
      • et al.
      Pregnancy in liver transplantation.
      and knowing hepatocytes express sex hormone receptors which may respond to stimulation by gonadotropins,
      • Kur P.
      • Kolasa-Wołosiuk A.
      • Misiakiewicz-Has K.
      • Wiszniewska B.
      Sex hormone-dependent physiology and diseases of liver.
      there is concern that these risks are higher if conception in liver disease is facilitated by ART. To date, outcomes of ART in women with liver disease and post-LT have been limited to case reports, forcing patients and care providers to make decisions regarding fertility treatment in the absence of adequate data.
      In this issue of the Journal of Hepatology,
      • Rahim M.N.
      • Theocharidou E.
      • Yen Lau K.G.
      • Ahmed R.
      • Marattukalam F.
      • Long L.
      • et al.
      Safety and efficacy of in vitro fertilisation in patients with chronic liver disease and liver transplantation recipients.
      Rahim et al. describe the first case series outlining outcomes of IVF in women with liver disease and post-LT. This was a retrospective analysis of data from King’s College Hospital in the United Kingdom and the EASL Registry for Liver Disease in Pregnancy between 1990-2019. A total of 42 women (25 with CLD, 6 with cirrhosis, and 11 post-LT) who received 57 IVF cycles were evaluated. The median age at first IVF cycle was 33 years and included women from diverse ethnic backgrounds, with the main causes of liver disease being autoimmune conditions and viral hepatitis. New liver enzyme derangement occurred in 9/57 (16%) cycles and all improved within 1 month. Clinical pregnancy (defined by the authors as successful implantation) was seen in 43/57 cycles (75%) with live birth occurring in 32/57 cycles (56%). These rates are higher than typically quoted in the literature,
      • Sunderam S.
      • Kissin D.M.
      • Zhang Y.
      • Jewett A.
      • Boulet S.L.
      • Warner L.
      • et al.
      Assisted reproductive technology surveillance — United States, 2017.
      however, when restricted to only women in whom the total number of IVF cycles was known (n = 32), rates of clinical pregnancy and live birth per cycle were 61% and 40% respectively, more consistent with known success in the general population. OHSS occurred in 3/42 women (7%) but details required to define the severity of OHSS were not described. Review of peripartum complications showed hypertensive complications in 3/42 (7%), intrahepatic cholestasis of pregnancy (ICP) in 6/42 (14%), caesarian section in 22/32 (69%), with 16/32 (50%) of infants born premature. Although limited by the small number of women, heterogenous patient population, lack of comparator groups, and long study duration during which ART has evolved, this is the first data able to enhance evidence-based discussions regarding ART in women with liver disease and post-LT.
      It is important to recognize the data used were obtained from liver disease patient registries as opposed to IVF registries. Therefore, key aspects important to the success and safety of IVF therapy (type of IVF regimen, total cycle numbers, dose of gonadotropins, number of oocytes retrieved, number of embryos transferred, type of embryo transfer [fresh vs. frozen/thaw]) were not known. Further, the study time frame spanned 30 years during which IVF protocols have evolved considerably to improve safety and pregnancy rates in addition to changes in the techniques for embryo vitrification, especially with respect to strategies to prevent OHSS.
      • Corbett S.
      • Shmorgun D.
      • Claman P.
      The prevention of ovarian hyperstimulation syndrome.
      In this study, OHSS occurred in 7% of women which is somewhat higher than would be expected,
      • Corbett S.
      • Shmorgun D.
      • Claman P.
      The prevention of ovarian hyperstimulation syndrome.
      therefore evaluation of modern cohorts of women with liver disease receiving ART may show the risk of OHSS to be lower. Investigators were unable to assemble comparator groups of women without liver disease receiving IVF, nor groups of pregnant women with liver disease or post-LT who conceived with spontaneous conception. Thus, it remains unclear if the adverse perinatal events described in this study are a result of IVF therapy itself as opposed to the expected natural history of pregnancy in CLD, cirrhosis, and post-LT. Studies have consistently shown these women have a higher risk of premature delivery
      • Hagström H.
      • Höijer J.
      • Marschall H.-U.
      • Williamson C.
      • Heneghan M.A.
      • Westbrook R.H.
      • et al.
      Outcomes of pregnancy in mothers with cirrhosis: a national population-based cohort study of 1.3 million pregnancies.
      ,
      • Flemming J.A.
      • Mullin M.
      • Lu J.
      • Sarkar M.
      • Djerboua M.
      • Velex M.P.
      • et al.
      Outcomes of pregnant women with cirrhosis and their infants in a population-based study.
      ,
      • Rahim M.N.
      • Long L.
      • Penna L.
      • Williamson C.
      • Kametras N.A.
      • Nicolaides K.H.
      • et al.
      Pregnancy in liver transplantation.
      and ICP
      • Flemming J.A.
      • Mullin M.
      • Lu J.
      • Sarkar M.
      • Djerboua M.
      • Velex M.P.
      • et al.
      Outcomes of pregnant women with cirrhosis and their infants in a population-based study.
      ,
      • Marschall H.U.
      • Wikström Shemer E.
      • Ludvigsson J.F.
      • Stephansson O.
      Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study.
      compared to women without liver disease, with recent data suggesting women with non-alcoholic fatty liver disease (NAFLD) are at higher risk of hypertensive complications.
      • Sarkar M.
      • Grab J.
      • Dodge J.L.
      • Gunderson E.P.
      • Rubin J.
      • Irani R.A.
      • et al.
      Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.
      Multiple pregnancy (twin or higher order) is the main complication of ART and occurred in 14% of pregnancies; yet, the investigators did not evaluate if perinatal events were higher in those with multiple pregnancy. Given elective single embryo transfer is the best strategy to decrease multiple pregnancy,
      • Vélez M.P.
      • Connolly M.P.
      • Kadoch I.J.
      • Phillips S.
      • Bissonnette F.
      Universal coverage of IVF pays off.
      this could be considered to reduce adverse outcomes in the setting of CLD, cirrhosis, and post-LT. Although only 6 women in this cohort had cirrhosis, 2/6 (22%) decompensated during IVF/pregnancy with 1 death 12 months post-partum, much higher than would be expected based on data from recent contemporary cohorts.
      • Hagström H.
      • Höijer J.
      • Marschall H.-U.
      • Williamson C.
      • Heneghan M.A.
      • Westbrook R.H.
      • et al.
      Outcomes of pregnancy in mothers with cirrhosis: a national population-based cohort study of 1.3 million pregnancies.
      ,
      • Flemming J.A.
      • Mullin M.
      • Lu J.
      • Sarkar M.
      • Djerboua M.
      • Velex M.P.
      • et al.
      Outcomes of pregnant women with cirrhosis and their infants in a population-based study.
      The majority of women with cirrhosis in this study (4/6, 67%) had preconception model for end-stage liver disease scores >10, which have been suggested to identify women at high risk of liver-related events during pregnancy.
      • Westbrook R.H.
      • Yeoman A.D.
      • O’Grady J.G.
      • Harrison P.M.
      • Devlin J.
      • Heneghan M.A.
      Model for end-stage liver disease score predicts outcome in cirrhotic patients during pregnancy.
      Therefore, the risk of decompensation in women with early/compensated cirrhosis receiving IVF is unknown. In order to address some of these limitations, linkage of both liver disease patient databases with IVF registries will be a key strategy to enhance our understanding of the success and risks of ART in women with liver disease.
      The results of this study are important for women who are considering pregnancy facilitated by IVF after LT, as implantation (71%/cycle) and live birth rates (50%/cycle) were similar to known rates in the general population. Although women post-LT had a higher proportion of liver enzyme derangement (37%/cycle) compared to those with CLD (26%/cycle) or cirrhosis (22%/cycle), no evidence of graft dysfunction or loss was reported. Prematurity, hypertensive complications, and post-partum hemorrhage were most frequent in women post-LT; this has also been shown after spontaneous conception.
      • Rahim M.N.
      • Long L.
      • Penna L.
      • Williamson C.
      • Kametras N.A.
      • Nicolaides K.H.
      • et al.
      Pregnancy in liver transplantation.
      Therefore, whether IVF is independently associated with these outcomes has yet to be determined.
      It is worth highlighting that the majority of women in this study had liver disease from either autoimmune causes or viral hepatitis (32/42, 76%). Over the past several decades, data from both North America
      • Flemming J.A.
      • Dewit Y.
      • Mah J.M.
      • Saperia J.
      • Groome P.A.
      • Booth C.M.
      Incidence of cirrhosis in young birth cohorts in Canada from 1997 to 2016: a retrospective population-based study.
      ,
      • Doycheva I.
      • Watt K.D.
      • Alkhouri N.
      Nonalcoholic fatty liver disease in adolescents and young adults: the next frontier in the epidemic.
      and Europe
      • Abeysekera K.W.M.
      • Fernandes G.S.
      • Hammerton G.
      • Portal A.J.
      • Gordon F.H.
      • Heron J.
      • et al.
      Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.
      have documented the growing burden of NAFLD in adolescents and young adults, with recent data from Canada suggesting that in a contemporary era, NAFLD is the most common etiology of CLD in pregnant women with cirrhosis.
      • Sarkar M.
      • Djerboua M.
      • Flemming J.A.
      NAFLD cirrhosis is rising among childbearing women and is the most common cause of cirrhosis in pregnancy.
      Further, as polycystic ovarian syndrome (PCOS) is associated with both NAFLD and infertility,
      • McCartney C.R.
      • Marshall J.C.
      Clinical practice. Polycystic ovary syndrome.
      we anticipate that the number of women with NAFLD considering ART will grow over the next several decades. Only 1 woman in this study had liver disease from NAFLD. This is an important group to study as women with NAFLD have a high prevalence of obesity and type 2 diabetes, both of which have been associated with lower rates of live birth in women undergoing IVF,
      • Kouhkan A.
      • Khamseh M.E.
      • Pirjani R.
      • Moini A.
      • Arabipoor A.
      • Maroufizadeh
      • et al.
      Obstetric and perinatal outcomes of singleton pregnancies conceived via assisted reproductive technology complicated by gestational diabetes mellitus: a prospective cohort study.
      ,
      • Sermondade N.
      • Huberlant S.
      • Bourhis-Lefebvre V.
      • Arbo E.
      • Gallot V.
      • Colombani M.
      • et al.
      Female obesity is negatively associated with live birth rate following IVF: a systematic review and meta-analysis.
      especially in the setting of co-morbid PCOS.
      • Sha T.
      • Wang X.
      • Cheng W.
      • Yan Y.
      A meta-analysis of pregnancy-related outcomes and complications in women with polycystic ovary syndrome undergoing IVF.
      Further, pregnant women with NAFLD have been shown to have higher risks of adverse peripartum outcomes compared to women without NAFLD;
      • Sarkar M.
      • Grab J.
      • Dodge J.L.
      • Gunderson E.P.
      • Rubin J.
      • Irani R.A.
      • et al.
      Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.
      therefore, understanding if ART further adds to these risks is important. Finally, alcohol-related liver disease (ALD) is also rising in young women, yet no women in this cohort had ALD. Hence, future studies able to evaluate outcomes in women with NAFLD and ALD will be important contributions to the literature.
      In summary, this study is the first to suggest that the success rate of IVF in terms of clinical pregnancy and live birth rates in women with liver disease and post-LT may be comparable to known rates in the general population. However, the ideal IVF regimen remains to be defined as are success rates in women with NAFLD and ALD. Further, the independent risk of IVF on maternal, infant, and liver-related outcomes in women with liver disease remains unclear. Given this study spanned 30 years to identify 42 women, investigators will need to consider either the use of large population-based data with the ability to link clinical liver data to IVF registries or developing large international prospective cohorts able to accurately define both liver and IVF exposures and outcomes. In the meantime, this study further emphasizes the importance of routinely discussing issues related to conception and fertility in women with liver disease.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Concept: JAF and MPV; first draft of the manuscript: JAF; editing for content: MPV.

      Conflicts of interest

      The authors have no conflicts of interest to declare.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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