Showing posts with label women. Show all posts
Showing posts with label women. Show all posts

Thursday, July 26, 2018

HCV antiviral drugs during pregnancy?

Perspective > Medscape Gastroenterology > DDW 2018

Antiviral Therapy for HCV During Pregnancy to Prevent Transmission: 6 Reasons in Favor of a Controversial Concept
July 23, 2018
Nancy Reau 
During this year's Digestive Disease Week in Washington, DC, I was asked to present an argument in favor of the controversial concept of giving antiviral therapy to pregnant patients with HCV to disrupt mother-to-child transmission (MTCT). I must clearly state that this concept is neither evidence-based nor is it recommended by any of the current treatment guidelines. Universally, national and societal guidelines, as well as experts and patient advocates, recommend viral eradication of HCV prior to conception—not during pregnancy. There are, however, several reasons that support the use of HCV antiviral drugs during pregnancy
Read the article:
HCV: 6 Reasons in Favor of Antiviral Therapy During Pregnancy 
Dr Nancy Reau discusses factors that could potentially support the use of antiviral therapy during pregnancy to prevent mother-to-child transmission of hepatitis C virus infection.
Medscape Gastroenterology, July 23, 2018 
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Monday, February 26, 2018

Podcast: What happens when a pregnant woman has hepatitis C

Host: Amber Smith

What happens when a pregnant woman has hepatitis C
Rates of hepatitis C infections are on the rise among adults in the United States, and some of those adults are pregnant women. Helene Bernstein, MD, PhD, explains how the disease can easily be diagnosed through a blood test and treated with medication. (Click here for a paper she published on this topic.) She’s an associate professor of obstetrics and gynecology and of microbiology and immunology at Upstate.

Listen here:
Podcast: Play in new window | Download
Thursday, February 22nd, 2018
Upstate University Hospital

Tuesday, January 9, 2018

Healio - Herbal, dietary supplement-induced liver injury more common in young women

Herbal, dietary supplement-induced liver injury more common in young women
Medina-Cáliz I, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.12.051.
January 9, 2018

Analysis of the Spanish Drug-Induced Liver Injury registry showed that cases of herbal and dietary supplement-induced liver injury were more common in young women than older patients or men and correlated with hepatocellular injury and high levels of transaminases.

“Herbal and dietary supplement-induced liver injury is an increasing healthcare problem,” Inmaculada Medina-Cáliz, PhD, from the University of Málaga, Spain, and colleagues wrote. “In contrast to medicinal products including Traditional Herbal Medicinal Products which are regulated in the European Union with regard to efficacy, safety and quality standards, the lack of regulation of ‘natural’ dietary supplemental products, together with the limited awareness of physicians and consumers about possible harmful effects of these supplements, reflect the need for research and reporting in this field.”

Monday, September 11, 2017

Women with HCV face low ovarian reserve, infertility, miscarriage

Women with HCV face low ovarian reserve, infertility, miscarriage
Karampatou A, et al. J Hepatol. 2017;doi:10.1016/j.jhep.2017.08.019.
September 11, 2017

Women of child-bearing age with hepatitis C showed early signs of menopause, putting them at greater risk for infertility, gestational diabetes and miscarriage, according to a recently published study. Sustained virologic response positively impacted these outcomes.

Read More

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Tuesday, September 5, 2017

Burden of HCV-induced cirrhosis expected to shift from men to women

Burden of HCV-induced cirrhosis expected to shift from men to women
Prevalence of hepatitis C virus (HCV) complications among women grew at a rate similar to that of men, while mortality among men was nearly double that of women, according to a study conducted through the Veterans Affairs office.

The retrospective cohort study analyzed 264,409 HCV-infected veterans, 7,162 of whom were women, between January 2000 and December 2013.
Continue reading....

Hepatitis C virus-related complications are increasing in women veterans: A national cohort study
Authors J. R. Kramer, H. B. El-Serag, T. J. Taylor, D. L. White, S. M. Asch, S. M. Frayne, Y. Cao, D. L. Smith, F. Kanwal First published: 16 August 2017

2017 Aug 16. doi: 10.1111/jvh.12728. [Epub ahead of print]

There are gender-specific variations in the epidemiology and clinical course of hepatitis C virus (HCV) infection. However, few long-term longitudinal studies have examined trends in the incidence and prevalence of serious liver complications among women compared with men with HCV infection.

We used the Veterans Administration Corporate Data Warehouse to identify all veterans with positive HCV viraemia from January 2000 to December 2013. We calculated gender-specific annual incidence and prevalence rates of cirrhosis, decompensated cirrhosis and hepatocellular cancer (HCC) adjusting for age, diabetes, HIV and alcohol use. We also calculated the average annual per cent change (AAPC) for each outcome by gender using piecewise linear regression in the Joinpoint software.

We identified 264 409 HCV-infected veterans during 2000-2013, of whom 7162 (2.7%) were women. There were statistically significant increases over time in the incidence rates of cirrhosis, decompensated cirrhosis and HCC for both men and women. The annual-adjusted incidence rates of cirrhosis, decompensated cirrhosis and HCC were higher in men than women for all study years. However, these complications increased at a similar rate in both groups. Specifically, the AAPC for cirrhosis was 13.1 and 15.2, while it was 15.6 and 16.9 for decompensated cirrhosis and 21.0 and 25.3 for HCC in men and women, respectively (all test of parallelism not significant). The results were similar in the prevalence analyses, although AAPCs were slightly smaller for each outcome.

In conclusion, we found an ongoing upward trend in the incidence and prevalence of HCV complications in this cohort of HCV-infected women. This increase in cirrhosis complications in women with active HCV infection is similar to those in men. With cure from HCV now becoming a reality, most of the projected burden of HCV is potentially preventable. However, benefits of HCV treatment will need to extend to all patients in order to stem the rising tide of HCV complications.

Monday, October 31, 2016

Two genes linked to postpartum immunity revival in women with persistent hepatitis C

Two genes linked to postpartum immunity revival in women with persistent hepatitis C
Research may provide a model for identifying immune factors needed to control chronic infections

Nationwide Children's Hospital

Alternative forms of two genes are associated with a boost in immunity to hepatitis C after childbirth, a study led by a Nationwide Children's Hospital physician-researcher shows.

At three months postpartum, the number of viruses circulating in the blood declined sharply in most women who carried particular versions of IFNL3 and HLA-DPB1 genes. Mothers lacking these gene variants experienced little change in viral levels after delivery.

The research is published in the Proceedings of the National Academy of Sciences. The study focused on hepatitis C, but it may serve as a model for identifying factors that restore immunity to other chronic infections, the researchers suggest.

"Immunity is normally exhausted in people who have chronic hepatitis C. The liver produces about a trillion viruses per day, and the T-cells that should attack the virus don't work," says Jonathan R. Honegger, MD, principal investigator at the Center for Vaccines and Immunity in The Research Institute at Nationwide Children's, and lead study author.

While studying hepatitis C transmission from mother to baby, he noticed that some mothers experienced unusual sharp declines (10-1000 fold) in blood viral levels after childbirth. Women with these viral load declines also had improved T-cell activity against hepatitis C after delivery.

"These initial observations really piqued our interest. There's a lot of effort underway to find ways to turn on exhausted T-cells, and the months following pregnancy appeared to provide a unique opportunity to study this," says Dr. Honegger, who is also assistant professor of clinical pediatrics at The Ohio State University College of Medicine.

Among 34 women in this study, five had consecutive pregnancies. "The postpartum viral load decline was very similar with each consecutive pregnancy, which made you think it wasn't just a random event--that some stable factor was controlling how viremia fell after delivery," Dr. Honegger says.

The team focused on genes.

Interferon lambda 3, a signaling protein that induces antiviral activity, is known to affect control hepatitis C in non-pregnant people. The researchers found that a common variant in the IFNL3 gene also increases the likelihood of controlling hepatitis C after pregnancy.

Human leukocyte antigen (HLA) molecules present small pieces of proteins to T-cells, enabling T-cells to recognize the presence of foreign pathogens such as viruses. The team found that women who possessed particular variants of HLA-DBP1 genes demonstrated greater T-cell recovery and virus control than women lacking these variants. HLA-DPB1 molecules present peptides to a type of T-cell called CD4+ "helper" T-cells. "This finding was important because helper T-cells are thought to be particularly dysfunctional in chronic hepatitis C. These findings suggest that HCV-specific helper T-cells may regain function after delivery. This is now an active line of investigation for us."

Reversal of T-cell exhaustion may also be relevant for controlling other persistent infections such as hepatitis B or HIV, the researchers say.

In another study to be published, the researchers examined effects of the IFNL3 genotype on immune gene signaling after childbirth in un-infected women.


Honegger JR, Tedesco D, Kohout JA, Prasad MR, Price AA, Lindquist T, Ohmer S, Moore-Clingenpeel M, Grakoui A, Walker CM. Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery. Proceedings of the National Academy of Sciences.

Monday, September 29, 2014

Review article: the management of cirrhosis in women

Alimentary Pharmacology & Therapeutics

Review article: the management of cirrhosis in women
  1. A. M. Allen and
  2. J. E. Hay*
Article first published online: 28 SEP 2014
DOI: 10.1111/apt.12974

View Full Text Article @ Alimentary Pharmacology & Therapeutics

There are differences in the predisposition, natural history of liver disease, complications and treatment response between men and women.

To review clinical differences in cirrhosis between men and women and to address unique management issues of fertility, pregnancy and contraception in this patient population.

PubMed and MEDLINE were searched using the terms ‘cirrhosis’ and ‘chronic liver disease’, each cross-referenced with specific liver diseases, as well as terms such as ‘cancer’, ‘hepatocellular carcinoma’, ‘smoking’, ‘liver transplantation’, ‘metabolic bone disease’, ‘fertility’,’ pregnancy’ and ‘contraception’.

Pre-menopausal status is protective in viral hepatitis C and non-alcoholic steatohepatitis. However, smoking, especially in combination with alcohol, is a stronger risk factor for cirrhosis and malignancies in women with chronic liver disease compared to men, although they are less likely than men to develop hepatocellular carcinoma. Women with cirrhosis have more osteopenic bone disease than men and require active management. Successful pregnancy is possible in well-compensated cirrhosis or with mild portal hypertension, although the maternal and foetal mortality and morbidity are higher than in the general population. The maternal risk correlates with liver disease severity and derives mostly from variceal bleeding. The choices for contraception in compensated cirrhosis are generally the same as for the general population. Women with cirrhosis are disadvantaged by the current MELD system of organ allocation, at least in part due to body size.

The management of women with chronic liver disease is unique in regards to counselling, screening for complications, fertility and pregnancy.

Differences in liver disease between men and women
Sex-based differences in gene expression and in a wide range of hepatocyte functions translate into differences in natural history of liver disease between men and women[4] affecting aetiology, clinical course, treatment response and complications. While men are most likely to have hepatitis C and alcoholic cirrhosis, women have predominantly autoimmune hepatitis and primary biliary cirrhosis (PBC).[1, 5] Although generally the management of cirrhosis is similar regardless of gender, some differences in natural history highlighted below may support a gender-based approach to counselling, treatment and follow-up.

Viral hepatitis
Women clear acute hepatitis C at a higher rate than men. In chronic hepatitis C, the female gender has long been associated with decreased progression to fibrosis,[6, 7] which is slower in pre-menopausal women than in men and post-menopausal women.[8] Most women with hepatitis C cirrhosis are post-menopausal. Women generally have a lower prevalence of additional risk factors for fibrosis – alcohol, smoking and iron overload. Furthermore, animal studies have shown that oestrogens protect hepatocytes from oxidative damage, inhibit secretion of pro-inflammatory cytokines (IL-1, IL-6 and TNFα) and suppress hepatic fibrosis in mice.[9] Hormone replacement therapy (HRT) is potentially beneficial in decreasing fibrosis progression.[10] Moreover, the likelihood of sustained virologic response (SVR) to interferon-based treatment is higher in pre-menopausal women than their post-menopausal counterparts and men.[11] It remains to be determined if the impact of hormonal status on SVR remains significant in the era of direct-acting antiviral agents. However, it is reasonable to conclude that the pre-menopausal status is prime time for initiating therapy while the rate of fibrosis progression is low.
Although sex-based differences in the natural course of chronic hepatitis B are less clear, female sex confers an advantage in some aspects of hepatitis B infection. As in hepatitis C, fibrosis progression is slower in women than men.[7] Women are more likely to clear hepatitis B surface antigen and to undergo e-antigen seroconversion.[12] Moreover, reactivation after e-antigen seroconversion is less likely in women.

Alcoholic liver disease
Women are at greater risk than men for developing alcoholic liver disease and cirrhosis. Unlike chronic viral hepatitis, women with alcoholic liver disease experience more rapid fibrosis progression than their male counterparts, even after abstinence.[7] The female susceptibility to alcoholic liver disease is increased for multiple reasons, including higher blood alcohol levels due to smaller volume of distribution and lower gastric metabolism. Increased gut permeability in female rats compared to male rats results in higher endotoxin levels to which female Kupffer cells have increased sensitivity, resulting in increased oxidative damage. Furthermore, female rats fed alcohol have differential gene expression from male rats and fail to upregulate hepato-protective genes of compensatory pathways involving oxidative stress and inflammation.[13] Chronic alcohol ingestion alters the hormone environment in blood and liver in both men and women, but the exact role of female hormones in the aetiology of alcoholic liver disease remains unknown.[13] Several other recent studies have suggested that smoking, especially combined with alcohol, is a stronger risk factor for fibrosis and cirrhosis in women with liver disease compared to men.[3, 14, 15]

Non-alcoholic fatty liver disease
As in chronic hepatitis, pre-menopausal status seems to be a protective factor in the rate of nonalcoholic steatohepatitis (NASH)-related fibrosis progression. Among NASH patients, men and post-menopausal women have a greater likelihood of fibrosis than women <50 years.[16] Therefore, reproductive age represents an opportune time for counselling and life style changes before the risk of fibrosis increases. Hormone replacement therapy has been found to be protective against non-alcoholic fatty liver disease (NAFLD) after menopause. In addition, of 4338 women in 3rd NHANES survey from 1988 to 1994, oral contraceptive users had less NAFLD than non-users.[17]

Sex-based differences in complications of cirrhosis
Cancer risk
It is known that male gender is a risk factor for hepatocellular carcinoma (HCC) in all populations.[18, 19] Men with cirrhosis have two to three times higher risk of HCC compared to women, with larger discrepancies found in medium-risk European populations. In USA, the incidence of HCC between 1992 and 2004 was 6.7 cases per 100 000 men and only 2 per 100 000 women.[20] Although the increased risk of male gender may be explained by higher exposure to risk factors, such as hepatitis B or C, there is some evidence that oestrogens may reduce the risk of carcinogenesis-induced inflammation and the subsequent development of HCC in women. The beneficial effects of female hormones is suggested by data from Taiwan showing that the risk of HCC was inversely related to the number of full-term pregnancies, age at natural menopause and use of hormone replacement therapy; the risk was increased in women who underwent oophorectomy during pre-menopausal years.[21] Despite this overall reduced risk of HCC, women have been shown to be as susceptible as men to the effects of alcohol as a risk factor for HCC.[22, 23] Therefore, women with cirrhosis, irrespective of the underlying liver disease, are at risk of developing hepatocellular cancer and should follow similar screening guidelines as men. Once HCC develops, the management strategies and survival rates between sexes are similar.[2, 24]

Women with cirrhosis are at least as susceptible as men to develop nonliver-related malignancies. In a Danish nationwide cohort study of 11 000 cirrhotics followed for 5–7 years, incidence of tobacco and alcohol-related cancers was higher in women than men.[25] A large Italian study of 1400 female cirrhotics with digestive tract cancers showed an increase in liver, oral and pharyngeal cancers, but not pancreas, colon or stomach.[26]

Early studies suggested that the risk of breast cancer may be increased in alcohol-related cirrhosis [25] and in PBC, but larger recent studies in patients with PBC have refuted this finding.[27-29] The risk of other gynaecologic cancers does not appear to be increased. Therefore, the recommendations for breast and gynaecologic health in women with cirrhosis follow the guidelines used in the general population.

Metabolic bone disease
Patients with cirrhosis of all aetiologies should be screened for osteoporosis irrespective of gender.[30] The major risks for bone loss are chronic cholestasis (commoner in women) and cirrhosis itself but additional, albeit lesser, risk factors for bone loss in women with cirrhosis are steroid therapy, female gender and post-menopausal status. In chronic cholestatic liver disease in particular, osteoporosis and fracturing are common. Thus, all female cirrhotics should undergo assessment of bone mineral density at the lumbar spine and hips. In addition to adequate calcium and vitamin D supplementation and weight-bearing exercise, correction of all reversible factors contributing to bone loss must be addressed. For the debilitated patient, appropriate physical therapy should be initiated.
Although there are no clinical trials in patients with cirrhosis, bisphosphonates are the preferred agents for the treatment of hepatic osteoporosis or advanced osteopenia. Therapy should be strongly considered prior to LT, to reduce the risk of bone loss and fracturing post-transplant. In patients with oesophageal varices, oral bisphosphonates are generally avoided. Intravenous pamidronate or zoledronic acid may be given every 3–12 months. Hormone replacement therapy remains an option for post-menopausal patients.

Portopulmonary hypertension
Portopulmonary hypertension (PPH) is an uncommon complication of cirrhosis which seems to occur more frequently in women.[31] Of 34 patients with PPH and 141 controls, the two identified independent risk factors for PPH were female gender and autoimmune hepatitis.[32] Therapy for PPH is the same for men and women.

Unique issues for women with cirrhosis
The unique issues for women with cirrhosis relate to reproduction and hormone therapy. The US prevalence of cirrhosis in women of reproductive age is only 0.045%,[33] which represents approximately 27 000 women. Autoimmune hepatitis is the most common underlying liver disease, while a few patients have primary sclerosing cholangitis (PSC), Wilson's disease, alpha 1- antitrypsin deficiency and chronic viral hepatitis. Pregnancy is rare in decompensated disease, but is increasingly encountered in patients with compensated disease and mild portal hypertension. Issues that concern women of reproductive age with cirrhosis or after LT include their fertility, maternal and foetal risks associated with pregnancy, and risks related to breastfeeding. Unfortunately the optimal management of cirrhotics in the modern era of obstetrics remains poorly defined, but some guidance can be provided.

The patient of child-bearing age with compensated cirrhosis and minimal portal hypertension commonly maintains regular menstrual periods and preserved fertility. If pregnancy is undesirable, then contraception must be offered. However, in decompensated cirrhosis, hypothalamic pituitary dysfunction leads to anovulation, amenorrhoea and infertility. Menstrual history is important, as conception is very unlikely with primary or secondary amenorrhoea. A high percentage of females listed for LT have amenorrhoea.[34] Assisted conception has been attempted [35] but with little success: three conceptions in two women with compensated autoimmune cirrhosis, resulted in two early miscarriages and one healthy baby whose mother died of hepatic decompensation 12 months after delivery. Similarly, assisted conceptions in pre-cirrhotic autoimmune hepatitis had complications; it is not recommended in decompensated disease.

Pregnancy in cirrhosis
Maternal outcomes
Pregnancy does not alter liver function in most patients with cirrhosis except in autoimmune hepatitis, where the course is unpredictable; flares can develop in about 50% of cases, either during pregnancy or in the post-partum period.[36, 37] In a study of 33 pregnancies in 21 women with cirrhosis due to autoimmune hepatitis, severe adverse maternal outcomes occurred in seven pregnancies, leading to two LTs, three deaths (two variceal bleeds and one decompensation) and two severe decompensations.[35] Risk factors for poor pregnancy-related outcomes in autoimmune hepatitis include persistent clinical disease or decompensated cirrhosis, poor compliance with therapy and relapse during a previous pregnancy.[34, 37]

The main maternal risk associated with pregnancy in cirrhosis is from portal hypertension. In a normal pregnancy, portal blood flow increases and drives more blood into the portosystemic collateral circulation.[33, 38] These changes exacerbate the pre-existing portal hypertension in cirrhosis and result in maternal complications in 30–50% of patients. There is a high risk of variceal bleeding in 20–45% of patients, especially in those with pre-existing varices; this risk is greatest in the second trimester and during delivery. Post-partum haemorrhage occurs in 7–10% of patients. Splenic artery aneurysm rupture can be a rare (2.6% of patients), but fatal complication. Occasionally, hepatic encephalopathy, ascites, spontaneous bacterial peritonitis and hepatic failure may occur.

Based on sparse data, maternal mortality is estimated at 10–18%. In a study of 33 pregnancies in patients with cirrhotic autoimmune hepatitis, three deaths occurred within 1 year of delivery.[35] Maternal prognosis correlates with severity of the liver disease. In 62 pregnancies in 29 cirrhotic patients, there were no complications in patients with preconception MELD score less than 6 but a MELD score of 10 or higher, was associated with liver-related complications in 10% of patients (3 variceal bleeds).[39]

Foetal outcomes
Cirrhosis in pregnancy is associated with worse foetal outcomes compared to the general population. There is a higher rate of prematurity (26–64%) and early spontaneous foetal loss (15–20% vs. 3–6% in the general population). Considering the additional foetal loss from maternal death, variceal haemorrhage and therapeutic abortion, the live birth rate is only 57–58%.[39] More recent data are shown in Table 1. A MELD score of 10 or higher predicts increased foetal prematurity and decreased live birth rate.[39]

Table 1. Foetal risk in cirrhosis
Cirrhotic AIH[35], N = 33Non-cirrhotic AIH[35], N = 48All cirrhotics[39], N = 62
  1. N, number of pregnancies
Live birth rate57%83%58%
Perinatal mortality0%0%0%
Congenital abnormalitiesPerthe's (1)Cerebral palsy (1)Cerebral palsy (2)
Learning difficulties(1)
General management of the cirrhotic pregnancy
Optimal management of the pregnant patient with cirrhosis requires coordinated care from the hepatologist, endoscopist and high-risk obstetrician. Preconception counselling about foetal and maternal risk is essential. In order to minimise the risks, the liver disease should be stable, compensated, and the portal hypertension optimally controlled. If LT is imminent, pregnancy should be postponed until 1 year post-transplant. Treatment of liver disease should be continued and tailored to minimise teratogenicity. Azathioprine and/or prednisone therapy for autoimmune hepatitis must be maintained throughout pregnancy; flares should be treated as in the non-pregnant patient. Chelating agents in Wilson disease must be maintained in pregnancy to avoid a flare of disease; foetal outcomes are satisfactory with zinc, trientine and D-penicillamine, although rare embryopathy may occur with the latter. Antiviral agents for hepatitis B (most commonly tenofovir or lamivudine) should be continued throughout the pregnancy. Treatment for hepatitis C is associated with high rate of teratogenicity and must be avoided during pregnancy. Ursodeoxycholic acid must be maintained during pregnancy in PBC[40] and can be used during the second and third trimesters to treat worsening cholestasis in PSC.

An ultrasound examination of the splenic artery should be performed in early pregnancy, to exclude pre-existing splenic artery aneurysm. Dietary sodium restriction to reduce fluid retention and portal pressure is recommended.

Management of portal hypertension
Preconception screening for varices is essential for optimal care. If no varices are identified, screening should be repeated in the second trimester. In the event that small varices have developed, beta blocker therapy should be started. Close foetal monitoring is important, as foetal bradycardia and intrauterine growth retardation may occur with beta blocker use. There are no studies comparing use of beta blockers vs. variceal band ligation in this setting.
Medium-large oesophageal varices noted before conception, without history of haemorrhage, can be controlled with either beta blockers or endoscopic therapy. As the varices will likely increase during pregnancy, it seems reasonable to proceed with variceal band ligation. Anecdotal data support prophylactic band ligation for high-risk varices as a safe and effective method before and during pregnancy.[38]

Large varices with previous gastrointestinal bleeding should be ligated to obliteration, preferably before conception, and treated during pregnancy as required. For failure of endoscopic therapy or for large varices with very well preserved hepatic function, a shunt may be considered before pregnancy. In the older literature, definitive surgical therapy for varices has been shown to improve foetal and maternal outcome.[41, 42] Although initially more risky, surgical shunts are less likely to occlude in pregnancy and any TIPSS intervention exposes the baby to significant radiation. However, more recently TIPSS has been used with success. Pregnancy is not advised prior to LT in patients with borderline liver function or with decompensated cirrhosis. If no preconception screening is performed, endoscopic evaluation is recommended in the second trimester. Thrombocytopenia (platelet count of <110 × 109 cells/L), but not MELD score, predicted the presence of varices on screening endoscopies during the second trimester.[39]

Management of the acute variceal bleed
Endoscopic management is similar to that of the non-pregnant patient. Serial endoscopies for variceal band ligation to obliteration should be performed. Use of adjunctive medications during the bleeding episode is limited. Vasopressin is contraindicated due to risk of placental ischaemia and potential teratogenicity. Octreotide use is controversial; although it is a category B drug, it causes splanchnic vasoconstriction and may precipitate placental ischaemia and abruption. Placement of TIPSS will expose the foetus to considerable radiation and its use must be weighed against the mother's status.[43]

Perinatal care
Recent data[44] on the impact of cirrhosis on maternal health during labour and delivery show a high rate of Caesarean section, preterm delivery, abruptio placentae and need for maternal blood transfusion compared to the general population (Table 2). During hospitalisation for delivery, 6.5% of patients experienced variceal bleeding, 10% ascites and 1.1% hepatic encephalopathy. In addition, there was a higher risk of venous thromboembolism, pregnancy-induced hypertension, peripartum haemorrhage and infection. Patients with cirrhosis have worse outcomes than liver transplant recipients.

Table 2. Impact of cirrhosis during labour and delivery[44]
Patients with cirrhosis (n = 187)General population
  1. a
     More in decompensated than compensated cirrhosis (also placenta previa).
  2. b
     Sepsis, pre-eclampsia with DIC.
Caesarean section ratea50%26%
Preterm laboura38%7%
Abruptio placentae5.6%1.1%
Maternal transfusiona12.8%0.6%
Maternal death rateb1%
Caesarean section is recommended in patients with large oesophageal or gastric varices, to decrease the risk of variceal rupture during vaginal delivery.[40] The risk of vaginal delivery in patients with small varices and a mature cervix is unknown. Assisted vaginal delivery can be employed to keep second stage short. Post-partum haemorrhage and bacterial infections can be reduced with correction of coagulopathy and prophylactic antibiotic use.

Few data exist on the effects of contraception in patients with cirrhosis.[45, 46] Although uncommon, unplanned or dangerous pregnancies may occur[39] and the safety of termination in cirrhosis is unknown. Tubal ligation is recommended after completion of child-bearing.
The choices for contraception are generally the same as those for the general population. Combined oral contraception (COC) has 99% efficacy, but has traditionally been discouraged in chronic liver disease due to concern about cholestasis and the risk of HCC. No link between oral contraception and HCC has been confirmed.[47, 48] A WHO study in 1989 found no association between HCC and COC. Widespread use of COC in women with hepatitis B and C in Asia has not led to an increase in HCC, perhaps even reduced its incidence. Indeed history of oral contraceptive use was an independent factor associated with survival in females treated for HCC in the setting of hepatitis B.[49]

In 2008, the WHO expert Working Group reviewed available data on hormonal contraceptive use and concluded that for women with mildly decompensated cirrhosis, there should be no restriction on use of any hormonal contraceptive methods, although in severe decompensated cirrhosis, hormonal contraception should not be used.[50] Present-day preparations, oral or transdermal, have even lower-dose oestrogen and are likely to be even safer. Progesterone-only preparations are safe in patients with liver disease with minimal hepatic effects. Depot medroxyprogesterone acetate is given once every 3 months with excellent efficacy.[51] Intrauterine contraceptive devices are the most effective form of birth control, without increase risk of infections in liver transplant recipients or HIV-infected patients. In patients with compensated disease without coagulopathy or significant thrombocytopenia, bleeding should not occur. Barrier methods (condoms and spermicidal preps) can be used safely but are less effective.

Hormone replacement therapy
Hormone replacement therapy has been used safely in PBC and chronic active hepatitis [52, 53] and may be protective against fibrosis in hepatitis C[8] and risk of HCC in viral hepatitis.[10] The presence of compensated cirrhosis is not a contraindication to HRT, but the same precautions and contraindications considered in the general population apply to patients with cirrhosis.

Access to and survival with LT
Women have less muscle mass and lower serum creatinine than men, thus may be disadvantaged for LT by the MELD system. The Organ Procurement and Transplantation Network (OPTN) database of the United Network of Organ Sharing (UNOS) shows that in 2013, 38% patients on the liver waiting list were female, consistent with the estimated prevalence of <40% cirrhosis in the USA occurring in women. Over the past 10 years, 34.5% liver allografts have been transplanted into female recipients, both before and after the introduction of the MELD system. In 2008, Moylan and colleagues published data showing that women were less likely to receive a LT within 3 years of listing both before and after MELD; in addition they were more likely to die or become too sick to transplant in the MELD era.[54] Several other studies have confirmed this gender-based disparity in LT.[55, 56] From the UNOS database of 2002–2007, 40 393 patients were listed for LT of which 36% were female; as expected, women had lower serum creatinine and lower MELD score than the men; they were also less likely to receive a LT within 90 days (22.7% vs. 27.5%) and had a higher 3 month mortality.[57] A further study expanded this Scientific Registry of Transplant Recipients (SRTR) data both pre- and post-MELD and showed that the disparity in LT rates between females and males has actually increased in the MELD era, especially for women with higher MELD scores, who are most likely to have a survival benefit; this disparity is geographically widespread but magnified in some areas.[58] Further analysis of wait-list mortality in the MELD era has shown that women have a 19% increased mortality compared to men with the same MELD scores, with at least some of this difference correlating with the shorter height of the women.[59] The reasons for gender disparity in access to LT from the waiting list are not entirely understood but may include deeming an organ too large for a small-size candidate.

Survival rates after LT at 1, 3 and 5 years are similar in men and women. While this may seem satisfactory, note should be made that the indications for LT in women are conditions which generally have an excellent outcome, such as autoimmune hepatitis and chronic cholestatic disease. This may be offset by the fact that more women undergo LT for fulminant hepatic failure. In addition, female survival is further reduced by the poorer outcomes of women transplanted for hepatitis C. In 2002, survival data of over 11 000 LT recipients transplanted from 1992 to 1998 showed that hepatitis C infection impairs both graft and patient survival and that this effect was greatest in female patients.[60] An extended study of this SRTR data (1999–2008) confirmed poorer survival of female recipients with hepatitis C, who have a 14% greater risk of death at 5 years than men with hepatitis C.[61] A more recent multicentre cohort study of 1264 HCV-infected patients (24% of which were women) showed that recipient female gender was associated with advanced recurrent hepatitis C, graft loss and mortality.[62] The reasons for worse HCV-disease progression after LT in women compared to men is not well understood and does not seem to be explained by age, increase in living donor LT, less HCC, more rejection or donor sex. The increased efficacy of the new antiviral agents will hopefully eliminate this disparity.

Although the current management of liver disease and associated complications is similar in men and women, there are significant sex-based differences in aetiology, natural progression and treatment response that deserve better understanding and may optimise future management of women. Female sex, and particularly the pre-menopausal status, is a protective factor in viral hepatitis and NASH, but a risk factor in alcoholic liver disease. Women with cirrhosis have more osteopenic bone disease and PPH than their male counterparts. Their risk of HCC is less than men but still occurs in all aetiologies of cirrhosis and requires screening. Smoking and alcohol use potentiates increasing fibrosis and cirrhosis in women with chronic liver disease, more so than in the male population, and also increases their risk of HCC and upper aerodigestive cancers. The mechanisms of this gender effect are unknown but demand further study, especially with regard to use of hormonal therapy in these women. Women with chronic liver disease must be strongly counselled against smoking and alcohol use.

Successful pregnancy is possible in inactive, compensated cirrhosis, but is still high risk and demands careful counselling about maternal and foetal risk. Active management of varices is essential before and during pregnancy. Contraception must be discussed with women of child-bearing age to avoid unwanted and potentially dangerous pregnancies.

Women listed for LT are disadvantaged by the present system of organ allocation. Lower muscle mass and subsequent lower creatinine does not entirely account for this disparity. Further study is needed and the necessary adjustments made to eliminate the preferential allocation of organs to men resulting in higher female mortality. Hopefully, the introduction of more effective antivirals for hepatitis C will greatly improve the transplant outcome for both men and women with hepatitis C. With their poor post-LT prognosis without treatment, antiviral therapy should be strongly considered for women with HCV-cirrhosis, before LT or in the early post-transplant period.

Guarantor of the article: J. Eileen Hay.
Author contributions: J.E.H designed the research study, A.M.A and J.E.H collected and analysed the data and wrote the manuscript. All authors approved the final version of the manuscript.

  • 1
    Kim WR, Brown RS Jr, Terrault NA, El-Serag H. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002; 36: 22742.
  • 2
    Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013; 58: 593608.
  • 3
    Liu B, Balkwill A, Roddam A, Brown A, Beral V. Separate and joint effects of alcohol and smoking on the risks of cirrhosis and gallbladder disease in middle-aged women. Am J Epidemiol 2009; 169: 15360.
  • 4
    Baik M, Yu JH, Hennighausen L. Growth hormone-STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism. Ann N Y Acad Sci 2011; 1229: 2937.
  • 5
    Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, Kim WR. Alcoholic liver disease-related mortality in the United States: 1980-2003. Am J Gastroenterol 2010; 105: 17827.
  • 6
    Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349: 82532.
  • 7
    Poynard T, Mathurin P, Lai CL, et al. A comparison of fibrosis progression in chronic liver diseases. J Hepatol 2003; 38: 25765.
  • 8
    Di Martino V, Lebray P, Myers RP, et al. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology 2004; 40: 142633.
  • 9
    Shimizu I. Impact of oestrogens on the progression of liver disease. Liver Int 2003; 23: 639.
  • 10
    Codes L, Asselah T, Cazals-Hatem D, et al. Liver fibrosis in women with chronic hepatitis C: evidence for the negative role of the menopause and steatosis and the potential benefit of hormone replacement therapy. Gut 2007; 56: 3905.
  • 11
    Villa E, Karampatou A, Cammà C, et al. Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology 2011; 140: 81829.
  • 12
    Zacharakis GH, Koskinas J, Kotsiou S, et al. Natural history of chronic HBV infection: a cohort study with up to 12 years follow-up in North Greece (part of the Interreg I-II/EC-project). J Med Virol 2005; 77: 1739.
  • 13
    Eagon PK. Alcoholic liver injury: influence of gender and hormones. World J Gastroenterol 2010; 16: 137784.
  • 14
    Corpechot C, Gaouar F, Chrétien Y, et al. Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis. J Hepatol 2012; 56: 21824.
  • 15
    Dam MK, Flensborg-Madsen T, Eliasen M, et al. Smoking and risk of liver cirrhosis: a population-based cohort study. Scand J Gastroenterol 2013; 48: 58591.
  • 16
    Yang JD, Abdelmalek MF, Pang H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014; 59: 140614.
  • 17
    Liu SH, Lazo M, Koteish A, et al. Oral contraceptive pill use is associated with reduced odds of nonalcoholic fatty liver disease in menstruating women: results from NHANES III. J Gastroenterol 2013; 48: 11519.
  • 18
    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 126473 e1.
  • 19
    Harada K, Hirohara J, Ueno Y, et al. Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology 2013; 57: 19429.
  • 20
    Wong R, Corley DA. Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med 2008; 121: 52531.
  • 21
    Yu MW, Chang HC, Chang SC, et al. Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk. Hepatology 2003; 38: 1393400.
  • 22
    Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002; 155: 32331.
  • 23
    Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology 2004; 127(5 Suppl. 1): S728.
  • 24
    El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology 2001; 33: 625.
  • 25
    Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998; 28: 9215.
  • 26
    Randi G, Altieri A, Gallus S, et al. History of cirrhosis and risk of digestive tract neoplasms. Ann Oncol 2005; 16: 15515.
  • 27
    Lööf L, Adami HO, Sparén P, et al. Cancer risk in primary biliary cirrhosis: a population-based study from Sweden. Hepatology 1994; 20: 1014.
  • 28
    Nijhawan PK, Therneau TM, Dickson ER, et al. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology 1999; 29: 13968.
  • 29
    Piscaglia F, Sagrini E. Malignancies in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2008; 20: 14.
  • 30
    Hay JE, Guichelaar MM. Evaluation and management of osteoporosis in liver disease. Clin Liver Dis 2005; 9: 74766, viii.
  • 31
    Krowka MJ. Portopulmonary hypertension. Semin Respir Crit Care Med 2012; 33: 1725.
  • 32
    Kawut SM, Krowka MJ, Trotter JF, et al. Clinical risk factors for portopulmonary hypertension. Hepatology 2008; 48: 196203.
  • 33
    Russell MA, Craigo SD. Cirrhosis and portal hypertension in pregnancy. Semin Perinatol 1998; 22: 15665.
  • 34
    Burra P, Senzolo M, Masier A, Prestele H, Jones R, Samuel D, Villamil F. Influence of age and gender before and after liver transplantation. Liver Transpl 2013; 19: 12234.
  • 35
    Westbrook RH, Yeoman AD, Kriese S, Heneghan MA. Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun 2012; 38: J23944.
  • 36
    Heneghan MA, Norris SM, O'Grady JG, Harrison PM, McFarlane IG. Management and outcome of pregnancy in autoimmune hepatitis. Gut 2001; 48: 97102.
  • 37
    Candia L, Marquez J, Espinoza LR. Autoimmune hepatitis and pregnancy: a rheumatologist's dilemma. Semin Arthritis Rheum 2005; 35: 4956.
  • 38
    Sandhu BS, Sanyal AJ. Pregnancy and liver disease. Gastroenterol Clin North Am 2003; 32: 40736, ix.
  • 39
    Westbrook RH, Yeoman AD, O'Grady JG, Harrison PM, Devlin J, Heneghan MA. Model for end-stage liver disease score predicts outcome in cirrhotic patients during pregnancy. Clin Gastroenterol Hepatol 2011; 9: 6949.
  • 40
    Ducarme G, Bernuau J, Luton D. Primary biliary cirrhosis and pregnancy. J Gynecol Obstet Biol Reprod 2014; 43: 33541.
  • 41
    Schreyer P, Caspi E, El-Hindi JM, Eshchar J. Cirrhosis–pregnancy and delivery: a review. Obstet Gynecol Surv 1982; 37: 30412.
  • 42
    Cheng YS. Pregnancy in liver cirrhosis and/or portal hypertension. Am J Obstet Gynecol 1977; 128: 81222.
  • 43
    Savage C, Patel J, Lepe MR, Lazarre CH, Rees CR. Transjugular intrahepatic portosystemic shunt creation for recurrent gastrointestinal bleeding during pregnancy. J Vasc Interv Radiol 2007; 18: 9024.
  • 44
    Murthy SK, Heathcote EJ, Nguyen GC. Impact of cirrhosis and liver transplant on maternal health during labor and delivery. Clin Gastroenterol Hepatol 2009; 7: 136772 e1.
  • 45
    Hannaford PC, Kay CR, Vessey MP, Painter R, Mant J. Combined oral contraceptives and liver disease. Contraception 1997; 55: 14551.
  • 46
    Connolly TJ, Zuckerman AL. Contraception in the patient with liver disease. Semin Perinatol 1998; 22: 17882.
  • 47
    Maheshwari S, Sarraj A, Kramer J, El-Serag HB. Oral contraception and the risk of hepatocellular carcinoma. J Hepatol 2007; 47: 50613.
  • 48
    Oral contraceptives and liver cancer. Results of the Multicentre International Liver Tumor Study (MILTS). Contraception 1997; 56: 27584.
  • 49
    Lam CM, Yong JL, Chan AO, et al. Better survival in female patients with hepatocellular carcinoma: oral contraceptive pills related? J Clin Gastroenterol 2005; 39: 5339.
  • 50
    Kapp N, Tilley IB, Curtis KM. The effects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver: a systematic review. Contraception 2009; 80: 3816.
  • 51
    Tagy AH, Saker ME, Moussa AA, Kolgah A. The effect of low-dose combined oral contraceptive pills versus injectable contraceptive (Depot Provera) on liver function tests of women with compensated bilharzial liver fibrosis. Contraception 2001; 64: 1736.
  • 52
    Menon KV, Angulo P, Boe GM, Lindor KD. Safety and efficacy of estrogen therapy in preventing bone loss in primary biliary cirrhosis. Am J Gastroenterol 2003; 98: 88992.
  • 53
    Guattery JM, Faloon WW, Biery DL. Effect of ethinyl estradiol on chronic active hepatitis. Ann Intern Med 1997; 126: 88.
  • 54
    Moylan CA, Brady CW, Johnson JL, Smith AD, Tuttle-Newhall JE, Muir AJ. Disparities in liver transplantation before and after introduction of the MELD score. JAMA 2008; 300: 23718.
  • 55
    Volk ML, Choi H, Warren GJ, Sonnenday CJ, Marrero JA, Heisler M. Geographic variation in organ availability is responsible for disparities in liver transplantation between Hispanics and Caucasians. Am J Transplant 2009; 9: 21138.
  • 56
    Bryce CL, Angus DC, Arnold RM, et al. Sociodemographic differences in early access to liver transplantation services. Am J Transplant 2009; 9: 2092101.
  • 57
    Myers RP, Shaheen AA, Aspinall AI, Quinn RR, Burak KW. Gender, renal function, and outcomes on the liver transplant waiting list: assessment of revised MELD including estimated glomerular filtration rate. J Hepatol 2011; 54: 46270.
  • 58
    Mathur AK, Schaubel DE, Gong Q, Guidinger MK, Merion RM. Sex-based disparities in liver transplant rates in the United States. Am J Transplant 2011; 11: 143543.
  • 59
    Lai JC, Terrault NA, Vittinghoff E, Biggins SW. Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system. Am J Transplant 2010; 10: 265864.
  • 60
    Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopicliver transplantation. Gastroenterology 2002; 122: 88996.
  • 61
    Thuluvath PJ, Guidinger MK, Fung JJ, Johnson LB, Rayhill SC, Pelletier SJ. Liver transplantation in the United States, 1999-2008. Am J Transplant 2010; 10: 100319.
  • 62
    Lai JC, Verna EC, Brown RS Jr, et al. Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men. Hepatology 2011; 54: 41824.