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Pregnancy and vascular

liver diseases

J B Dilawari, Chandigarh, India

Pierre-Emmanuel Rautou, Clichy, France

Outline

• Introduction

• Is pregnancy a risk factor for vascular liver

disease?

• What are the outcomes of pregnancy in women

with vascular liver disorders ?

• Management of pregnancy and delivery

Pregnancy and liver disorders

1. Pre-existing chronic liver disease:

2. Unique to pregnancy:

3. Developing during with pregnancy:

Hyperemesis gravidarum

Acute fatty liver of pregnancy

HELLP, preeclampsia

Intrahepatic cholestasis of pregnancy

Viral hepatitis

Drug induced liver injury

Vascular liver disease

Cirrhosis

Viral hepatitis

Cholestastic liver disease

Benign liver nodules

Wilson’s disease

Vascular liver diseases

IVC

PV HA

HVHV

• Affect either IVC, HV, PV

• Frequent during pregnancy

Pregnancy and vascular liver disorders

Hemodynamic changes in pregnancy

- Vasodilatation, arterial BP

- Cardiac out put , Blood Volume

- Portal blood flow , P.V. diameter

- Venous return in IVC due to Gravid uterus

(blood flows from lower part to azygous system)

Changes reminiscent of those of cirrhosis

Munnell, JCI 1947. Mustafa, J Pregnancy 2012; Bissonnette, JCEH 2015

Procoagulant

state

Anticoagulant

state

Pregnancy

Von Willebrand factor

Fibrinogen

Factors II, VII, VIII and X

Protein S

Resistance to activated protein C

Plasminogen activator inhibitor-1

Pregnancy

-

Battaglioli, Curr Opin Hematol 2007; Marik, NEJM 2008

Coagulation changes in pregnancy

Outline

• Introduction


disease?




• A 29 year old female

• History of 2 miscarriages

• Day 10 post-partum (baby born at 32 weeks):

– Acute onset of right upper quadrant abdo. pain

– Ascites and jaundice

– T Bili: 5.6 mg/dL; AST/ALT: 205/418 IU/L; INR: 2.6

– Doppler U/S: localized thrombosis right HV, Coma

shaped collaterals

CASE 1

Is that a fortuitous association?

Is pregnancy a risk factor for Budd-Chiari

syndrome?

Mohanti, Hepatology 2001; Dilawari, Medicine 1994; Rautou, Gut 2009

• Temporal association between the 2 conditions

• Prevalence of pregnancy/postpartum in women

aged 15-45 in France between 1995 and 2005:

Yes(likely, and other risk factors frequently associated)

Among women

presenting with BCS:

16% (7/43)

In the general French

population:

7–8%

Pregnancy

Budd-Chiari syndrome Yes (likely)

Portal vein thrombosis Rare reports

Sinusoidal obstruction syndrome No report

Liver hemangioma Exceptional

Obliterative portal veinopathy No report

Is pregnancy a risk factor for vascular liver

diseases?

Bissonnette, JCEH 2015

Outline

• Introduction


disease?




CASE 2

• A 29 year old woman with BCS due to

myeloproliferative disease desires a pregnancy

• Treatment: vitamin K antagonists; hydroxyurea

• Physical examination: no symptom

• Blood test: INR 1,1; serum bilirubin normal

- Is pregnancy contraindicated?

- What is the expected risk for the baby, for her?

Pregnancy and BCS: Maternal outcome

0

10

20

30

40

50

60

% o

f m

ate

rnalde

ath

Khuroo

1963-78

Dilawari

1967-91

Rautou

1985-2005

N=16 N=38

Khan,

2001-15

N=16N=24

Shukla

2012-15

N=15Number of

pregnancies

No treatment

0% 0% 0%

Anticoagulation angioplasty/TIPS

56 pregnancies

GI Bleeding 0

Genital, parietal bleeding33 pts with anticoagulation

7

Thrombotic event 0

Liver relatedascites, pulmonary artery hypertension

4

Related to pregnancycholestasis, placenta praevia, preeclampsia

13

Rautou, J Hepatol 2009; Khan, World J Hepatol 2017;

Shukla, Liv Int 2017; Aggarwal Arch Gynecol Obstet 2013

Pregnancy and BCS: Maternal outcome

Pregnancy and BCS: Fetal outcome

Rautou, J Hepatol 2009; Khan, World J Hepatol 2017

Num

be

r o

f p

reg

na

ncie

s

13

3

16

8

0

2

4

6

8

10

12

14

16

18

< 20 20-31 32-36 > 36

Weeks of gestation

40 pregnancies

26 alive

No sequelae

1 stillbirth

Miscarriage/

ectopic

pregnancy

Early

preterm

Preterm

Term

CASE 3

• 34 year old female

• INCPH revealed 1 year ago:

• Splenomegaly, no varices

• Liver blood tests abnormalities

• Liver biopsy: no cirrhosis, nodular regenerative hyperplasia

• Sicca syndrome

• Desires pregnancy (1 daughter, 5 year-old)

- Is fertility preserved?

- Is pregnancy contraindicated?

- What is the expected risk for the baby, for her?

0,00%

0,05%

0,10%

0,15%

0,20%

0,25%

Kochhar R Dig Dis Sci. 1999

INCPH and fertility

Controls

(N=44)

Before diagnosis After diagnosis

Fe

rtili

tyra

te

of noncirrhotic portal hypertension (n=55)

No difference

INCPH and pregnancy24 pregnancies (16 women)

Diagnosis 1st pregnancy

controlled

Anticoagulation (n=6)

Antiplatelet (n=1)

No treatment (n=19)

• 7 w/o prophylaxis of GI bleeding

• 5 with portal vein thrombosis

• 4 TIPS

Median: 38 months

Andrade, revised

24 pregnancies

Maternal death 0

Esophageal varices1 w/o appropriate prophylaxis

2

Ascites 3

Porto-pulmonary hypertension 1

Genital-parietal bleeding 2

Thrombotic event 1

INCPH: maternal outcome

Andrade, revised

24 pregnancies in 16 women with INCPH

Num

ber

of pre

gnancie

s

5

2

8

9

0

2

4

6

8

10

< 20 20-31 32-36 > 36

Weeks of gestation

Miscarriage/

ectopic

pregnancy

18 alive

No sequelae

2 death

Andrade, revised; similar or better results in: Kochhar R Dig Dis Sci. 1999

INCPH: fetal outcome

• 27 yr-old female

• Acute portal vein thrombosis in 2009 – Superior mesenteric and splenic veins

– Mesenteric intestinal ischemia

• Associated conditions – Pernicious anemia (vit B12 supplementation)

– Hyperhomocysteinemia

CASE 3

• Anticoagulation therapy– By 3 months: portal cavernoma development

– Maintained long term

• Esophageal varices → Nonselective β-block.

• 2015: Routine work-up – Normal liver blood tests

– Unchanged esophageal varices

– Desire for pregnancy

CASE 3

What is your answer to patient’s

concern about pregnancy outcome?

1.The probability of a term birth of a healthy

child is below 50%.

2.The rate of miscarriage is increased.

3.The probability of preterm birth is

increased.

4.The probability of congenital malformation

is increased.

5.Perinatal mortality rate is about 25 %.

1.The probability of a term birth of a healthy

child is below 50%.

2.The rate of miscarriage is increased.

3.The probability of preterm birth is

increased.

4.The probability of congenital malformation

is increased.

5.Perinatal mortality rate is about 25 %.

What is your answer to patient’s

concern about pregnancy outcome?

PVT: fetal outcome

Mandal, Singapore Med J 2012. Hoekstra, J Hepatol 2012.

Aggarwal, J Obstet Gynaecol Res 2011

PVT General population

Miscarriages 14% 15%

Stillbirths 2% 0.5%

Live birth 83% 85%

Preterm births 14% 6-10%

Perinatal death 1% -

in 104 pregnancies with known PVT

Bissonnette et al., J Clin Exp Hepatol 2015

A gestation reaching the 20th week

is very likely to end with a live newborn

PVT: fetal outcome

1. Portal hypertension worsens

2. Risk of variceal bleeding is about 30%

3. Risk of deep vein thrombosis/pulmonary

embolism is about 30%

4. Risk of complications of anticoagulation

therapy is about 30%

5. Risk of maternal death is not increased

What is your answer to patient’s concern about maternal outcome?

PVT: Maternal outcome

PVTN = 104

CirrhosisN = 129

Maternal death 0% 8%

Variceal bleeding3 pts without adequate prophylaxis

5% 6%

Genital/parietal bleeding 1 pt on anticoagulation therapy

6% 16%

Thrombotic events 2% 1%

Mandal, Singapore Med J 2012. Hoekstra, J Hepatol 2012.

Aggarwal J Obstet Gynaecol Res 2011.

PVTN = 104

CirrhosisN = 129

Maternal death 0% 8%

Variceal bleeding3 pts without adequate prophylaxis

5% 6%

Genital/parietal bleeding 1 pt on anticoagulation therapy

6% 16%

Thrombotic events 2% 1%

Rasheed Int J Gynaecol Obstet 2013

PVT: Maternal outcome

Outline

• Introduction


disease?




• Routine screening - before conception?

- second trimester?

• Safety of nonselective beta-blockers

- small for gestational age, preterm birth and

perinatal mortality?

- risk of neonatal hypoglycemia

Pregnancy and management of portal hypertension

Bleeding occurred mostly in patients without adequate prophylaxis

Petersen, BMJ Open 2012. Cissoko, Arch Pediatrie 2005

→ No data

• Risk/benefit of pharmacologic therapy

→ Safe in selected case reports

• Endoscopic band ligation

• Sclerotherapy

• TIPS insertion *

Scarce data on acute variceal bleeding

* 3 pregnant patients with cirrhosis

Pregnancy and management of portal hypertension

March 2016: Pregnancy

Management of anticoagulation therapy?

CASE 3

What do you propose for

anticoagulation therapy?

1. No change of anticoagulation therapy

2. Increase anticoagulation intensity

3. Shift to LMWH

4. Add-on aspirin

5. Shift to direct oral anticoagulant agents

1. No change of anticoagulation therapy

2. Increase anticoagulation intensity

3. Shift to LMWH

4. Add-on aspirin

5. Shift to direct oral anticoagulant agents

What do you propose for

anticoagulation therapy?

Risk factor for DVT/PE in pregnancy

• Underlying Thrombophilia

• History of thrombosis

• APLS or lupus

• Age > 35 yr-old

• Obesity

• Smoking

James et al., Am J. Obstet. Gynecol. 2006

Anticoagulation therapy and pregnancy

Switch from VKA to LMWH

within 4 wks of conception

VKA LMWH

Teratogenic effects Yes No

Fetal anticoagulation Yes No

Recommendations for pregnant women with previous unprovoked VTE

American College of Chest Physicians. Chest 2012

Royal College of Obstetricians and Gynecologists. April 2015

Thromboprophylaxis

•Until delivery:

•Postpartum: - LMWH for 6 weeks dose 50-75% of therapeutic dose

- or Vitamin K antagonists targeted at INR 2 to 3

- LMWHdose 50-75% of therapeutic dose

Safety of LMWH in pregnancy

• 2777 pregnancies (a systematic review)

• No maternal deaths

• Adverse effects:– Significant bleeding: 1.98%

– Allergic skin reactions: 1.80%

– Heparin-induced thrombocytopenia: 0%

– Thrombocytopenia (unrelated to LMWH): 0.11%

– Osteoporotic fracture: 0.04%

• Live births: 94.7%

Greer et al, Blood. 2005

Anticoagulation therapy: our proposal

Already on

Anticoagulation?

Consider switching

to therapeutic dose

of LMWH

preconception

Consider

Prophylactic dose of

LMWH during

pregnancy

YES NO

March 2016 : Pregnancy

Management of anticoagulation therapy?

3-week gestation

Tinzaparin 0.6 ml S/C

(12,000 anti Xa Units)

CASE 3

• Acute abdominal pain and vomiting

• No evidence of infection

• Normal LFTs - Anti Xa 0.6 Units/ml

• Doppler-US: recent thrombosis of a collateral of the right gastric vein

• Shift tinzaparin q.d. to enoxaparin b.i.d.

• Uneventful pregnancy

9-wk gestation

CASE 3

Vaginal or caesarean delivery?

Sultan, Blood 2013; Aggarwal, Int J Gynaecol Obstet 2001

• Vaginal delivery

– Variceal bleeding during active phase of

labor uncommon (selected case reports)

– Impact of labor on portal pressure?

• Caesarean section

– Injury to collateral veins, ascites

– Postpartum thromboembolism

Sultan, Blood 2013; Aggarwal, Int J Gynaecol Obstet 2001

• Vaginal delivery as a preferred option

(assisted phase of active labour)

• Caesarean section for obstetrical

reasons

Vaginal or caesarean delivery?

• 37-wk gestation:

–Induced labor

–Vaginal delivery

• No bleeding during labor or post-partum

• Apgar score 10/10

• Birth weight 2.800 kg

CASE 3

Delivery: our proposal of management of anticoagulation

• Stop LMWH 24 hrs before delivery

• Resume LMWH early after uneventful vaginal delivery if the thrombotic risk is judged to be very high.

• Resume LMWH 24 hrs after the procedure when bleeding risk is considered low

Safe platelet count for delivery

• > 50 000/mL for caesarean section

• > 20 000/mL for vaginal delivery

• > 75,000/mL for epidural anesthesia

• > 50,000/mL for spinal anesthesia

Bissonnette et al, JCEH 2015

• Can be used:

Warfarin (not excreted in breast milk)

Propanolol

• Do not use:

Hydroxyurea

Breastfeeding

Elective termination of pregnancy

• Delicate issue

• Discuss risks perceived to be too high for the

mother and/or the fetus.

• With high-risk thrombophilia and/or previous

major complications of pregnancy

Bissonnette et al, JCEH 2015

Conclusion

1. Preconception counseling

• Preterm birth and stillbirth increased

• Portal hypertension manageable

• Prothrombotic disorder manageable

• Pregnancy is not contraindicated

2. Multidisciplinary team

3. Antenatal management

• Variceal bleeding prophylaxis

• Shift to/prefer LMWH anticoagulation

4. Delivery and Postpartum

• Prefer vaginal delivery

• Anticoagulation therapy not a risk

factor for bleeding

Conclusion