Chronic Liver Disease and Pregnancy

Rachel Westbrook

Consultant Hepatologist

Royal Free Hospital

Topics

• Cirrhosis

• Autoimmune liver disease

• Cholestatic liver disease

• Post Transplant

• 5 minutes for questions / discussion

Background

• Women with pre-existing liver disease often enquire about pregnancy• Safety for patient

• Outcomes for fetus

• Risk of medication

• Given that liver disease is a heterogenous group of conditions with spectrum of severity • Advice should be tailored to the individual; not generic

• Literature is extremely limited• Case reports

• Small case series

• No Meta-ananlysis / no RCT’s

Cirrhosis

• End stage of chronic liver disease

• Liver is irreversibly scared

• Can be due to a wide variety of conditions (AIH, Viral,)

• Blanket term – covering a wide spectrum of severity

• Effecting 30,000 within the UK, significant number of women

• Consequences• Encephalopathy; coagulopathy

• Portal Hypertension• Varices

• Ascites

Maternal Deaths and Liver Disease

• KNOWN

• Mortality:• 9/100,000 (240 women) died during or within 6 weeks of pregnancy (2011-

2013)

• 1-2 deaths / year cirrhosis / PHT

• KNOWN UNKNOWNS• Number of cirrhotic pregnancies / annum

• Morbidity from such pregnancies

• Spectrum of disease

• How to optimally manage such women

Fertility and Cirrhosis

• Pregnancy rare• Negative oestrogen feedback• Poor nutrition• Sexual dysfunction• Depression

• Incidence of amenorrhoea / oligomenorrhoea on LT w/l is 70%

• 70% women with cirrhosis have no or decreased sexual activity

• Degree of sexual dysfunction as been linked to severity of liver disease

Cundy TF; Amenorrhoea in women with non alcoholic CLD; GUT 1991Sorrell JH; Sexual function in patients with end-stage liver disease; Liver transplantation; 2008

Pregnancy and Cirrhosis

• Pregnancies do occur and can have successful outcomes

• But are associated with significant risk for mother and baby

When Pregnancies do occur….

• Pubmed “cirrhosis and pregnancy”• 45 citations from 1980 – present

• 37 case reports / reviews

Cirrhosis and Pregnancy

• 1968 Whelton and Sherlock: 1st case series

• 1994 Pajor: 2nd case series

• 1999 Aggarwal: 3rd case series

• Summary• 36 pregnancies

• Maternal mortality ~ 10%

• Variceal haemorrhage ~ 30%

• Decompensation ~ 50%

• LBR ~ 56%Pregnancy and cirrhosis of the liver. Aggarwal N, Sawnhey H, Suril V, Vasishta K, Jha M, Dhiman RK.Aust N Z J Obstet Gynaecol. 1999 Nov;39(4):503-6.

Significant morbidity and mortalitySuccessful outcomes can occur

Wrong to advise/deny all women with cirrhosis against pregnancy

Cirrhosis and Pregnancy – the 21st century

• Outcomes of pregnancy in patients with cirrhosis: a population based study. 2010

• Model for end stage liver disease score predicts outcome in cirrhotic patients during pregnancy 2011

• Prognosis and determinants of pregnancy outcome among patients with post hepatitis liver cirrhosis. 2013

• Pregnancy and childbirth in women with autoimmune hepatitis is safe even in compensated cirrhosis. 2016

Retrospective62 pregnancies in 29 womenPregnancy outcomes recorded and correlated Prognostic scores at conception

Live birth rate: 58%-2/3rd born premature-2/3rd low / very low birth weight-Need for SCBU in 30%

Prematurity and need for SCBU- ASSOCIATED with maternal MELD UKELD

1 - Specificity

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UKELD

MELD

ROC Curve

Maternal Decompensation – 10%Maternal Mortality – 1.6%

Decompensation in pregnancy associated with 50% mortality at 2 years

MELD / UKELD associated with decompensation

MELD score ≥ 10 points; UKELD >4783% sensitivity and specificity for decompensation

MELD score of 6 or a UKELD score of less than 42 no complications

Prospective study, 3 groups1- pregnant cirrhotic n=1292- Healthy pregnant control n=6473- cirrhotic, not pregnant n=853

Cirrhosis Vs. healthy pregnant women- prematurity, IUGR, LBW, neonatal

distress

Note – low number having VD (18%) Vs. C section (82%)

Hepatic Decompensation-VH in study grp vs. ascites and HEIn control grp

Variceal Bleeding

Mortality-90% was from VH – delivery

On multivariate logistic regression analysisVaginal delivery– associated with HD and VH

C section was not associated with increasedBleeding risk

Literature Summary:

• Spontaneous pregnancy loss 27% compared to 7% in gen population

• Foetal outcomes: LBR low with prematurity and high need for SCBU

• Hepatic decompensation 10-15%• 20% mortality; 50% over subsequent 2 years

• Events can be predicted by UKELD / MELD (decompensation, prematurity)

• Variceal haemorrhage leading cause of mortality;

• Vaginal delivery linked to HD and GOV haemorrhage – 1 study

DATA IS LIMITED BY RETROSPECTIVE NATURE, DATABASEINTERROGATION AND LACK OF CLINICAL INFORMATION,

NO UNIFIED MANAGAMENT STRATERGY AND PATIENT REPORTED EVENTS

Varices

• Optimal management undefined• Management extrapolated from non pregnant cohorts• Pre-conception eradication of varices seems appropriate• AASLD guidelines – screening endoscopy in 2nd trimester• Banding of large / at risk varices• Propanolol – use if concerned

• Treatment• Same as in non pregnant patients – resuscitation, antibiotics• Endoscopy and therapy: consider position and sedative drugs• Terlipressin – vasoconstriction => uterine ischaemia => risk stratification, case by case• Case reports of successful TIPSS

Savage C, Transjugular intrahepatic portosystemic shunt creation for recurrent gastrointestinal bleeding during pregnancy. Journal of vascular and interventional radiology : JVIR. 2007;18(7):902-4.Lodato F, Transjugular intrahepatic portosystemic shunt: a case report of rescue management of unrestrainable variceal bleeding in a pregnant woman. Digestive and liver disease :. 2008;40(5):387-90.

Varices - screening

• Preconception and 2nd trimester OGD

• Conception platelet count was predictive of varices on screening endoscopy (84 (28-225) vs. 184 (62-308), p<0.001).

• Platelets of < 110 x10^9cells/l gives an 89% specificity for the presence of OV on screening endoscopy

Westbrook RH,. Model for end-stage liver disease score predicts outcome in cirrhotic patients during pregnancy. Clinical gastroenterology and. 2011;9(8):694-9.

Ascites

• Rare during pregnancy due to raised intra abdominal pressure

• If occurs; USS to r/o PVT, or BCS

• Management as per non-pregnant patients

• Diuretics

• Caution with C section – wound healing, infection

Encephalopathy

• Rare

• PPt by intercurrent event, so screen

• Can use Lactulose / no data for rifaximin

• Possibly due to worsening PHT and formation / enlargement of portosystemic shunts

Delivery Planning / birth Plan

• Mode of delivery is dictated via MDT - largely obstetric / anaesthetic considerations

• From a hepatological perspective• No evidence that VD needs to be avoided

• Assisted delivery if large varices

• Abdominal wall varices – caution for C section

• If ascites / decompensates with C section – poor wound healing infection, mortality etc,

• No data exists comparing the benefits of one delivery mode over another in cirrhosis

Drugs and Cirrhosis

• B Blockers Not teratogenic; fetal bradycardia, IUGR and neonatal hypoglycaemia reported (FDA C)

• Spironalactone/ No large volume data available; adverse Furosemide outcomes in animal studies (FDA C)

• Lactulose Safe

• Rifaximin Limited data, likely safe

• Terlipressin Uterine ischaemia due to vasoconstrictive effects (FDA D)

• Octreotide Not Licenced in UK; No harmful effects in USA

Unmet need

• How many pregnancies are occurring in women with cirrhosis within the UK

• What is morbidity and mortality

• What are the outcomes

• 4 published studies in last 20 years!

• No defined evidence based management protocols (variceal haemorrhage / delivery / antenatal / postnatal)

• Cirrhosis spectrum of severity with many heterogenous aetiologies

• Does one strategy fit all?

• Falls between 2 specialities

Progress

• Pregnancy Champion in each hospital via BASL

• UKOSS study

• EASL Registry Grant

• BSG guidelines

Autoimmune hepatitis and Pregnancy

• Relatively common chronic hepatological condition in women of child bearing age

• Autoimmune condition

• Improves during pregnancy

• Flares in Post partum period when tolerance stops

• But unpredictable; and can present de novo in pregnancy

Autoimmune Hepatitis and Pregnancy

• 4 recent case series

• Data on 142 conceptions

• Live birth rate 71%-86%

• Comparable to other chronic AI conditions

Westbrook RH, Outcomes of pregnancy in women with autoimmune hepatitis. Journal of autoimmunity. 2012;38(2-3):J239-44.Terrabuio DR Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. Journal of clinical gastroenterology. 2009;43(4):350-6.Schramm C Pregnancy in autoimmune hepatitis: outcome and risk factors. The American journal of gastroenterology. 2006;101(3):556-60.Buchel E Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. The American journal of gastroenterology. 2002;97(12):3160-5.

Autoimmune Hepatitis and Pregnancy n=142

• AIH Flare; Gestation 7-21 (11)%, post partum 11-86 (33)%• Majority controlled by IS augmentation

• 3 hepatic decompensations, 3 deaths, 1 liver transplant

• Those that have a flare are more likely to have an adverse outcome

• Flares are more common in women who• Failed to achieve disease remission for >1-year and absence of IS therapy

Westbrook RH, Outcomes of pregnancy in women with autoimmune hepatitis. Journal of autoimmunity. 2012;38(2-3):J239-44.Terrabuio DR Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. Journal of clinical gastroenterology. 2009;43(4):350-6.Schramm C Pregnancy in autoimmune hepatitis: outcome and risk factors. The American journal of gastroenterology. 2006;101(3):556-60.Buchel E Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. The American journal of gastroenterology. 2002;97(12):3160-5.

Immunosuppressive drugs

• Corticosteroids: • Population-based study of >51,000 corticosteroid-exposed pregnancies

• no increase in orofacial cleft defects or other significant adverse events

• Azathioprine: • Concerns arose in animal studies using supratherapeutic doses

• no adverse events in AIH/pregnancy literature

• 3000 IBD patients – prematurity but no malformations

Hviid A , Mølgaard-Nielsen D . Corticosteroid use during pregnancy and risk of orofacial cleft s . CMAJ 2011 ; 183 : 796 – 804 Akbari M , Shah S , Velayos FS et al. Systematic review and meta-analysis on the eff ects of thiopurines on birth outcomes fromfemale and male patients with infl ammatory bowel disease . Infl amm Bowel Dis 2013 ; 19 : 15 – 22 .

Autoimmune hepatitis – practical tips

• Continuation of medication and maintenance of maternal health gives best outcome for pregnancy

• General advice is to continue IS

• Preconception counselling: disease control for >12 months

• Monitor LFT’s

• No role for pre-emptive post partum IS augmentation

• Bloods at GP / clinic 8-12 weeks post partum

Post Liver Transplant and Pregnancy

• Liver Transplant is life saving, excellent outcomes

• Want to give patients back a full holistic life

• For women of child bearing age becoming a mother is often important aspect

• Data on pregnancy following solid organ transplantation is growing

• Registry data and single centre reports

• Largely favourable outcomes

Deshpande NA , James NT , Kucirka LM et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis . Liver Transpl 2012 ; 18 : 621 – 9 .

Post Liver Transplant and Pregnancy

• Fertility can return as early as 1 month

• Can take up to a year before women start ovulating

• Fetal outcomes• LBR in 70%

• Prematurity (30%)

• Low birth weight (30%)

• Iatrogenic in part due to high occurrence of hypertension in mother.

Westbrook RH Outcomes of pregnancy following liver transplantation: The king's college hospital experience. Liver transplantation 2015.Deshpande NA , James NT , Kucirka LM et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis . Liver Transpl 2012 ; 18 : 621 – 9 .

Post Liver Transplant and pregnancy

• Maternal Complications• Acute cellular rejection

• Gestational (10-17%)

• Post LT (3-12%)

• Pre-eclampsia (14-23%)

• Infection (27%)

• Diabetes (5%)

• Instrumental delivery / C section

Westbrook RH Outcomes of pregnancy following liver transplantation: The king's college hospital experience. Liver transplantation 2015.Deshpande NA , James NT , Kucirka LM et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis . Liver Transpl 2012 ; 18 : 621 – 9 .

Post Liver Transplant and pregnancy

• ACR more common in women <1-year post LT• Delay pregnancy for 1-year

• Allows stable / reduced IS, potentially less infection

• Episode of ACR• Controlled by IS augmentation, (IV methylprednisolone)

• Graft loss reports are exceedingly rare

• 2 recent publications• Link between ACR in pregnancy and recurrent rejection and graft loss in long

term

• Raising question should women with ACR in pregnancy receive augmented IS

Westbrook RH Outcomes of pregnancy following liver transplantation: The king's college hospital experience. Liver transplantation 2015.Deshpande NA , James NT , Kucirka LM et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis . Liver Transpl 2012 ; 18 : 621 – 9 .

Immunosupressive Drugs

• Mycophenolate• Contraindicated

• Increased risk of congenital abnormalities

• Ear / cleft lip, palate

• Sirolimus• limited data in Liver transplant pregnancy

• Data from renal cohorts, appears safe, no increased risk on congenital abnormalities reported

• Poor wound healing (C Section)

• CNI• Teratogenic potential appears low

• Growing evidence for continuation during breast feeding

Post LT and Pregnancy – practical tips

• Contraception: fertility restored as early as one month

• Avoid pregnancy for 12 months – association with ACR

• IS safe and should be continued (exception MMF)

• Always liaise with patients transplant centre

• Delivery plan as per obstetric indications

PBC Pregnancy

• Numbers small / data sparse

• Difficult to draw robust conclusions from reports – continue urso

• Outcomes generally favourable in the absence of cirrhosis

• Pruritus may worsen or appear de novo

• Worsening of cholestasis post partum – return to base line at 1 year

Poupon R, Pregnancy in women with ursodeoxycholic acid-treated primary biliary cirrhosis. Journal of hepatology. 2005;42(3):418-Olsson R, Pregnancy in patients with primary biliary cirrhosis--a case for dissuasion? The Swedish Internal Medicine Liver Club. Liver. 1993;13(6):316-8.Trivedi PJ,l. Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis. Clinical gastroenterology and hepatology . 2014;12(7):1179-85 e1.

PSC Pregnancy

• Numbers small, data sparse

• Pruritus and cholestasis can worsen especially in the third trimester.

• Increased risk of preterm delivery(3.6 fold)

• Unclear if disease or iatrogenic

• Favourable outcomes in the absence of cirrhosis

Wellge BE, Pregnancy in primary sclerosing cholangitis. Gut. 2011;60(8):1117-21.

Ludvigsson JF,. A population-based cohort study of pregnancy outcomes among women with primary sclerosing cholangitis. Clinical gastroenterology and hepatology 2014;12(1):95-100 e1.

Further Reading