This document provides an outline and overview of liver diseases in pregnancy. It begins by discussing normal liver changes during pregnancy, such as increases in plasma volume and coagulation factors. It then covers approaches to evaluating liver disease in pregnancy and classifying diseases by trimester and etiology. Specific conditions discussed in detail include intrahepatic cholestasis of pregnancy (ICP), including risk factors, pathophysiology, diagnosis, complications, and treatment with ursodeoxycholic acid. Other conditions mentioned more briefly include hyperemesis gravidarum, HELLP syndrome, acute fatty liver of pregnancy, and viral or autoimmune hepatitis.

1. 31.07.2017
Liver Diseases in
Pregnancy
Candidate: Dr Amenda Davis
Consultant: Dr Reeta Mahey
SR: Dr Varnit

2. Outline
• Liver changes in normal pregnancy
• Approach to liver disease
• Intrahepatic cholestasis of pregnancy
• Hyperemesis gravidarum
• HELLP Syndrome
• Acute fatty liver of pregnancy
• Viral hepatitis
• Auto-immune hepatitis
• Cirrhosis

3. Liver Changes in Normal
Pregnancy

4. Hematological Changes
• Plasma Volume (50%)
• RBC Volume (20%)
• Cardiac Output
• Fibrinogen
• Coagulation factors (II, VIII, IX and XII)
• Cholesterol and Triglyceride
• Hematocrit
• Concentration of Albumin
• Protein S
• Plasma volume increases from the 6th to the 36th week of gestation
by 50%.
• Red cell volume also increases but only by 20% and delayed.
• The hematocrit decreases by the 24th week and becomes stable.
Hemodilution should be kept in mind during interpretation of all
serum concentrations.
Lee, Brady, World J Gastroenterol 2009 February 28; 15(8): 897-906
• Pregnancy- procoagulant state.
• Limits bleeding during delivery
• Increased risk of thromboembolism during pregnancy and the
post-partum period.
ANY derangement in PT-INR - pathologic.
(Hellgren M et. al, Semin Thromb Hemost. 2003; 9(2):125–130)

5. • ALT and AST - most useful tests for the
routine diagnosis of liver diseases.
Any change is pathological.
• ALP increase in third trimester is due to
increase in placental and bone isoenzyme.
• Gammaglutamyl transferase or 5’
nucleotidase can be used to confirm
hepatic origin of raised ALP.
(Hellgren M et. al, Semin Thromb Hemost. 2003; 9(2):
125–130)
• Bilirubin may decrease due to
hemodilution.
William's 24th Ed.

6. (Williams, 24th Edition)

7. Physical Examination
Spider Angioma Palmar Erythema
Expanding uterus —>
pushes liver upwards —>
cannot be palpated.
Hyperestrogenemia - these changes usually seen in
liver disease may be normal findings in pregnancy.

8. Ultrasound Examination
• No dilatation of the biliary tract.
• Fasting gallbladder volume and
residual volume after contraction
are increased.
• Biliary sludge - up to one third of
pregnancies.
• Asymptomatic, spontaneously resolves.
• Gallstones - 2 to 12 % of pregnant women.
• Silent gallstones require no treatment.
Lee, Brady, World J Gastroenterol 2009 February 28; 15(8): 897-906

9. Trimester Pre- existing underlying
liver diseases
Liver diseases related to
pregnancy
Coincidental liver
diseases
First • Chronic hepatitis B, C
• Autoimmune hepatitis
• Wilson’s disease
• Primary biliary cirrhosis
• Primary sclerosing
cholangitis
• Cirrhosis of any cause
(ANY TRIMESTER)
• Hyperemesis, may
persist in 2nd, 3rd
• Acute viral hepatitis
(HEV, HAV)
• Gallstones
• Budd-Chiari syndrome
• Drug induced
hepatotoxicity
• Sepsis
(ANY TRIMESTER)
Second • ICP
• Preeclampsia
Third • ICP
• Acute fatty liver
• Pre-eclampsia,
eclampsia, HELLP
syndrome
Classification of Liver Diseases in Pregnancy

10. Approach to Liver Disease

11. ACG Practice Guidelines - 2016• A complete history, physical exam, and standard serological
workup should be performed as indicated by the clinical
presentation.
• Ascertain whether the disease is pre existing, related to
pregnancy, or coincident.
Pregnant woman:
initial workup of
abnormal liver tests
Hepatocellular profile?
AST/ ALT
Rule out:
Viral hepatitis
Herpes
Medications
Others: AIH, Wilson’s
Anti – HAV IgM
HbsAg
Hepatitis E IgM
HSV PCR
Bilirubin +/- ALP ALP only
No further workup
Biliary imaging
No evidence of
obstruction
Pregnancy Related Workup
Rule
out hepatitis
Rule
out gallstones/ extra hepatic
cholestasis
Biliary profile?
Elevated Bilirubin /
ALP

12. Recommendations:
A pregnant patient presenting with abnormal liver tests
should undergo standard workup as with any non-
pregnant individual.
(Strong Recommendation, Level IV Evidence)
ACG Practice Guidelines - 2016

13. Recommendations
Ultrasound - SAFE
Strong recommendation, Level
3 Evidence
MRI: can be used in the second and third trimester
Conditional recommendation,
Level 4 Evidence
CT- risk of teratogenesis and childhood hematologic
malignancies.
May be used with minimized radiation protocols (2–5
rads)
Conditional recommendation,
Level 4 Evidence
ACG Practice Guidelines - 2016

14. Intrahepatic Cholestasis of
Pregnancy

15. Pruritis
Adverse
fetal
outcomes
Deranged
LFTs
ICP
• Most common pregnancy specific liver disease (0.2-2%).
• 80% of cases occur after 30 weeks POG.
Geenes V et. al, Hepatology 2014;59:1482–91
• Isolated case reports exist of ICP as early as 7 weeks.
Pruritis of ICP
• Itching which occurs more on soles and palms.
• Worsens at night.
• May occur before or after LFT derangement.
Kenyon AP et. al, BJOG 2001;108:1190–2
• Incidence of pruritis in pregnancy : 20%
• Incidence of ICP : 0.2 to 2 %
Provisional diagnosis of ICP cannot be
made based on pruritis alone.
Williamson/ Geenes, Obstet Gynecol 2014;124:120–33

16. Multiple
pregnancies
?Conception
after IVF
Progesterone/
Estrogen
H/O ICP in
previous
pregnancy
Hepatitis C
? Deficiency of
Vit D/ Selenium
ICPEpidemiology of
Family history
Up to 14% of women with ICP in the U.K. report a
positive family history for the condition in sisters.
Williamson C et. al, BJOG 2004;111:676–81
The relative risk for the sisters of affected women is
reported to be 12.
Eloranta ML et. al, Clin Genet 2001;60:42–5
Reported pedigrees suggest an autosomal dominant,
sex limited pattern of inheritance.
RCOG 2011 - Jacquemin E et al, Lancet 1999;353:210–1
M/C mutation: ABCA4 gene encoding for Multidrug
resistance protein 3 (MDR3). Also causes oestrogen
induced cholestasis.
Dixon PH et. al, Obstet Med 2009;2009:65–71

17. Large sulphated progesterone metabolites may
saturate the hepatic transport system in
predisposed women. ICP peaks in 3rd trimester
when estrogen peaks, and more common in twin
In a study of 50 women with ICP in France, 64% had been
treated with progesterone.
Glantz A, Hepatology 2008; 47: 544–51.
Stop progesterone if ICP develops and avoid in
patients with h/o ICP in prior pregnancy.
Swedish study - 10,067 cholestasis cases and
94,863 women with uncomplicated pregnancy—>
Higher incidence of seropositivity for hepatitis C
(0.7% vs 0.2%) in women with ICP.
. Marschall HU et al, Hepatology 2013; 58:1385–91.
ICP is more common during winter in Scandinavian countries
when the levels of Vitamin D and Selenium are lower.
Wikström Shemer E et al, Acta Obstet Gynecol Scand 2010;89:1420–3.
There is up to 90% recurrence rate of ICP in future
pregnancies.
. Scheider G. et. al, Hepatology 2007;45: 150–58.
A study in Finland showed the rate of ICP 2.7% in patients
who conceived after IVF vs 2% in spontaneous pregnancy.
Koivurova S et. al, Hum Reprod 2002;17:2897–903

18. ICPPathophysiology of
Cholesterol
Cholic Acid Chenodeoxycolic Acid
BSEP
M
DRP
Primary Bile Salts
Fecal Excretion
(0.5g/d)
Taurine, Glycine
Primary Bile Salts (0.5g/d)
Primary Bile Acid
Secondary Bile Acid
Taurine, Glycine
Secondary Bile Salts
- Litho, Deoxycholic Acid
Bacterial Action
Enterohepatic
Circulation (15-30g/d)
Farnesoid
Receptor X
Cholic Acid Chenodeoxycolic Acid
Primary Bile Salts (0.5g/d)
Sulphate
metabolites of
progesterone
?
Estrogen
Antonín Pařízek et. al, PLoS One. 2016; 11(8): e0159203.

19. ICPDiagnosis of
Obstetric cholestasis
is diagnosed when
otherwise unexplained
pruritus occurs in
pregnancy and abnormal
liver function tests (LFTs)
and/or raised bile acids occur
in the pregnant woman and
both resolve after delivery.
RCOG Green Top Guideline No.43, 2011
ICP-
Diagnosis
of
exclusion
PRURITIS
• Prurigo of pregnancy
• Pruritic urticarial
papules and plaques
of pregnancy (PUPPP)
• Pruritic folliculitis
LIVER ABNORMALITIES
• Viral hepatitis
• Auto immune hepatitis
• Acute fatty liver
• Cholelithiasis
• Drug induced hepatitis

20. ICPLiver Function Tests in the Diagnosis of
Bile Acids
AST
ALT
ALP
GGT
BR
Bile Acids
Most consistent predictor of poor fetal outcome.
RCOG 2011: Walker I et al. Ann Clin Biochem 2002;39: 105–13
Upper limit - 10 micromol/L.
Levels above 40 micromol/L strongly correlate with poor
fetal outcome.
Low BA does not preclude risk of fetal distress.
Glantz, A.et al, Hepatology 2014, 40: 467–474.
Increase of conjugated primary bile acids - taurocholate
of cholic > chenodeoxycholic acid.

21. Alkaline phosphatase is produced in large quantities by the
placenta in pregnancy and is usually not useful to diagnose
ICP.
Williamson and Geenes, Obstet Gynecol 2014;124:120–33
Gamma glutamyl transferase may be elevated or normal.
More often elevated in patients with ABCA3 mutation.
Not useful for diagnosis.
Sookoian S et. al, J Hepatol 2008;48:125–32.
• Bilirubin may be raised in up to 10% of patients with ICP,
causing cholestatic jaundice.
• Conjugated hyperbilirubinemia.
Glantz, A.et al, Hepatology 2014, 40: 467–474.
• Prothrombin time may be prolonged in ICP with steatorrhea
due to Vit. K deficiency.
• 5 case series in literature with prevalence of prolonged PT from
2 to 22%.
RCOG 2011
Alkaline phosphatase is produced in large quantities by the
placenta in pregnancy and is usually not useful to diagnose
ICP.
Williamson and Geenes, Obstet Gynecol 2014;124:120–33
Gamma glutamyl transferase may be elevated or normal.
More often elevated in patients with ABCA3 mutation.
Not useful for diagnosis.
Sookoian S et. al, J Hepatol 2008;48:125–32.

22. Aspartate and Alanine Aminotransferase
• AST/ ALT may rise before or after bile acid elevation with
poor correlation between the two.
• Resolve post partum.
Walker I et al, BMJ 2013;347
• Alanine transaminase (ALT) more sensitive than AST.
• May be raised twofold to 30-fold.
Williamson et al, Obstet Gynecol 2014;124:120–33

24. Retrospective study- 215 women with BA >/- 10 umol/L
Mild
(BA 10-39 umol/L) n=8
Moderate
(BA 40-99 umol/L) n=86
Severe
(>100 umol/L)n=21
Gestational age at delivery 272 265 259
Preterm birth 9 (8.3%) 11 (12.8%) 8 (38.1%)
Spontaneous labor onset 28 (25.9%) 10 (11.6%) 4 (19%)
Induced/ Elective CS 80 (74.1%) 76 (88.4%) 17 (81%)
Meconium stained fluid 15 (13.8%) 19 (22.1%) 10 (47.6%)
Asphyxia - 2 (2.3%) -
Perinatal death - - 2 (9.5%)
NICU stay 1 (0.9%) 2 (2.3%) 2(9.5%)
PPH 3 (2.8%) 11 (12.8%) 2 (9.5%)
Am J Obstet Gynecol 2015;212:100.e1-7

25. ICPComplications of
Maternal Complications
USUALLY SAFE
Post Partum Hemorrhage
Cholestasis —> Liver abnormality —>
Deficiency of Vit. K dependent clotting
factors —-> Prolonged PT.
Reported in only 5 case series with
incidence of PPH ranging from 2 to
22%. (RCOG 2011, Evidence Level IV)
Prophylaxis: Vitamin K
Fetal Complications
Stillbirth
Meconium
staining
Asphyxia
Prematurity

26. Stillbirth
Meconium
staining
Asphyxia
Prematurity
1.5 to 7%, as high as 20% in some
studies.
Puljik A. Et al, Am J Obstet Gynecol 2015;212:667.
Bile acid level >/- 40 umol/L may
indicate high risk.
Brouwers L, Am J Obstet Gynecol 2015;212:100.
Placental chorionic
vein spasm
Lethal arrhythmias
by depositing in
cardiomyocytes
Apgar of <7 at 5 minutes post
partum
Studies show up to 20% incidence,
with positive correlation to BA
level.
Oztekin D et al, Arch Gynecol Obstet (2009) 280:975–979
May be caused by bile acids stimulating
colonic motility or by fetal distress itself.
RCOG- 2011
Positively correlated with serum bile
acid level . Risk may decrease with
UDCA treatment.
Estiú MC et. al, PLoS ONE 2012(4): e0176504.
Spontaneous preterm delivery - 4-12 %
Roncaglia N et. al, Eur J Obstet Gynecol Reprod Biol 2002;100:167–70.
Iatrogenic preterm delivery - 7 -25%
- “obstetrician anxiety”.
RCOG -2011
Bile acids may increase the
sensitivity to oxytocin receptors.
Germain AM et. al, Am J Obstet Gynecol 2003;189:577-82.

27. ICPTreatment ofUrsodeoxycholic Acid
Women should be informed of the lack of robust data
concerning protection against stillbirth and safety to the
fetus or neonate.
(BEST PRACTICE RECOMMENDATION)
Ursodeoxycholic acid (UDCA) improves pruritus and
liver function in women with obstetric cholestasis.
(GRADE A)
RCOG Green Top Guideline No.43, 2011
Ursodeoxycholic acid, should be
given at 10–15mg/kg, to women with
IHCP for symptomatic improvement
(strong recommendation, moderate level of evidence).
ACG Practice Guideline 2016
Usually comes in tablets of 300 mg , given TDS
for a total dose of 900 mg/ day.
(For an average 60 kg woman, 15 mg/kg)

28. Ancient
Chinese used to treat
liver ailments with a drug
“yutan” made from dried bile of
adult bears, from which UDCA
was isolated and named in 1927.
Ursus : Bear (Latin)
Pharmacology of UDCAUDCA up regulates transport proteins
(MDR, BSEP)
Enhances canalicular excretion of bile acids
Williamson. Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2014.
K.N. Lazaridis et al. / Journal of Hepatology 35 (2001) 134±146 135
Ursodeoxycholic acid: hydrophilic bile acid
Accounts for 4% of BA in humans, made by bacterial
epimerization of chenodeoxycholic acid.
30-60% absorbed in intestine
Liver via enterohepatic circulation
Conjugated to taurine, glycine
Displaces the hydrophobic, toxic BA, makes bile rich
in UDCA, and reduces hepatic damage.

29. ICPTreatment ofS-Adenosine Methionine
- Not recommended (Level A )
- Three of four studies of 86 patients showed no difference in pregnancy
outcome, pruritis, or LFTs.
- Twice daily IV application - poor acceptability.
NOT RECOMMENDED - RCOG 2011
Dexamethasone
- Avoid first line use, or outside of an RCT without consultation with
patient. (Level D)
- Three observational reports on the use of dexamethasone (10 mg orally for
7 days and then stopping over 3 days) in 23 women for the treatment of
obstetric cholestasis.
- Conflicting results, no data on safety profile.
Cholestyramine
- Poorly tolerated bile chelating agent.
- Not subjected to RCT, not in clinical use.
- Causes Vit. K deficiency and coagulation defects.
Topical emollients and anti
histaminics may be used as adjuvants.
Vitamin K
• PROLONGED PT - water-soluble
vitamin K (menadiol sodium
phosphate) 5–10mg/d
(Best Practice Recommendation)
• NORMAL PT - may give after
counselling about possible benefit.
(Level D)

30. J Obstet Gynaecol Can 2014;36(7):632–641
11 RCTs (N=625) 6 NRSs (N=211)
Improved LFT in 82% Improved LFT in 100%
Reduced Pruritis in 73% Reduced Pruritis in 100%
Reduced prematurity, less NICU stay, decreased meconium staining
Significant
Difference

31. RCOG Green Top Guideline No.43, 2011
Recommendation Grade Comment
Obstetric cholestasis is diagnosed when otherwise
unexplained pruritus occurs in pregnancy and
abnormal liver function tests (LFTs) and/or raised
bile acids occur in the pregnant woman and both
resolve after delivery.
Best Practice
Recommendation
Differentiate dermatographica artefacts
from other dermatological conditions.
Exclude underlying liver disease.
Pregnancy-specific reference ranges for LFTs
should be used.
C
Normal bile acid does not exclude
diagnosis.
Other causes of itching and of liver dysfunction
should be excluded.
C
Screen for viral hepatitis, auto immune
liver disease.
Women with persistent pruritus and normal
biochemistry should have LFTs repeated every 1–2
weeks. Repeat LFTs for diagnosed ICP every 1-2
weeks.
C
Transaminases can range from normal to
several hundreds. A return to normal LFT
or a rapidly worsening LFT indicates a
likely wrong diagnosis.
Postnatal resolution of pruritus and abnormal
LFTs should be confirmed.
C
Defer LFT for at least 10 days post
delivery as there may be transient rise.
ICPManagement of

32. ICPManagement ofRCOG - 2011
Recommendation Level
Poor outcome cannot currently be predicted by
biochemical results and delivery decisions should
not be based on results alone.
B
No specific method of antenatal fetal monitoring for
the prediction of fetal death can be recommended.
D
Ultrasound and cardiotocography are not reliable
methods for preventing fetal death in obstetric
cholestasis.
C
Continuous fetal monitoring in labour should be
offered. Best Practice
Recommendation
Women should be informed of the
inability to predict stillbirth if the
pregnancy continues.
A discussion should take place with
women regarding induction of
labour after 37+0 weeks of
gestation.
Women should be informed that the
case for intervention (after 37+0
weeks of gestation) may be stronger
in those with more severe
b i o c h e m i c a l a b n o r m a l i t y
(transaminases and bile acids).
Best Practice Recommendations

33. Viral Hepatitis

34. VIRAL HEPATITISEpidemiology of
• Global Incidence (General Population): 5%
• Viral hepatitis accounted for 1.34 million deaths in 2015.
WHO Global hepatitis report, 2017
Hepatitis A
• Hyperendemic in India
• Occurs mainly in
children
• 90-100% population
immune by
adolescence
• Accounted for 11,000
deaths (0.8%) in 2015
(WHO-2015)
Hepatitis B
• Intermediate
endemicity in India.
• 2 to 4 % carrier
frequency.
• Genotypes A and D are
common.
Hepatitis C
• Prevalence in India: 1%
• Genotypes 2 and 3 are
common (susceptible to
IFN and ribavirin)
Hepatitis D
• Infrequent in India
• 5 to 10% of HBV
related liver disease.
Hepatitis E
• Most dangerous in
pregnancy, high
mortality , 60% of ALF
in pregnancy.
• Occurs in epidemics.
Acharya et al, J Gastroenterol Hepatol. 2009;18:822–7
No difference in incidence/
prevalence of hepatitis amongst
pregnant and non pregnant
population.

35. VIRAL HEPATITISClinical Features of
Feature HAV HBV HCV HDV HEV
Incubation (days)
Onset
Age
15-45, mean 30
Acute
Children
30-180, mean 60-90
Insidious/Acute
Any age
15-160, mean 50
Insidious
Any age
30-180, mean 60-90
Insidious or acute
Any age
14-60, mean 40
Acute
Young adults
Transmission
Feco-oral
Percutaneous
Perinatal
Sexual
+++
Unusual
-
+/- (Anal)
-
+++
+++
++
-
+++
+/-
+/-
-
+++
+
++
+++
-
-
-
Clinical
Severity
Fulminant
Chronicity
Carrier
Cancer
Prognosis
Mild
0.1%
None
None
None
Excellent
Occasional severe
0.1-1%
1-10%, 90% neonates
0.1 to 30%
+(Neonatal)
Worsens with age
Moderate
0.1%
85%
1-3 %
+
Moderate
Occasionally severe
5-20%
Common
Variable
+/-
Acute-good
Chronic- poor
Mild
1-2%
None
None
None
Good, Except in
Fulminant
Harrison’s Principles of Internal Medicine, 19th edition

36. Clinical Features of VIRAL HEPATITIS
Incubation
Prodrome
Jaundice
Convalescence
Complete Recovery
• Anorexia, NV, fatigue, malaise,
low grade fever (A,E > B,C),
arthralgia.
• Biochemical abnormalities (LFT)
begin to derange.
1-2 weeks —>
Dark urine
Clay coloured stool
• Reduced constitutional symptoms
• Enlarged tender liver
• Splenomegaly and cervical adenopathy in 10-20%
• Biochemical abnormalities may persist
• Liver enlargement may persist
• Prolonged in Hep B,C
• 1-2 months (A, E)
• 3-4 months (B,C)
Harrison’s Principles of Internal Medicine, 19th edition

37. Laboratory Features of VIRAL HEPATITIS
Harrison’s Principles of Internal Medicine, 19th edition
AST, ALT
• Variable increase, from 400-4000 IU
• Rise during prodrome, precede the rise of bilirubin
• Poorly correlate with degree of liver damage.
Bilirubin
• Typically rises from 5 to 20 mg / dl
• Both indirect and direct.
CBC
• Neutropenia and lymphopenia, followed by
relative lymphocytosis.
Prothrombin Time
• May be prolonged due to severe hepatocellular
necrosis.
• May be prolonged with relatively low rise of
transaminases.

38. HBV
ds-DNA virus
Hepatitis B
surface antigen
Freely circulating
Core Antigen
Only in
hepatocytes
E Antigen
Indicates high viral
load, active
replication
Harrison’s Principles of Internal Medicine, 19th edition

39. HBVAcute Infection
Typical serologic course of acute hepatitis B virus
infection with recovery.
85-90%
Progression to chronic hepatitis B virus
infection. (HBsAg for more than 20 weeks)
10-15%, risk inversely
proportional to age
CDC 2007

40. HBV
CDC 2007

41. Cesarean section does
not reduce rate of transmission.
Breast feeding- safe
HBVVertical Transmission of
HBsAg Positive- Chronically infected
Risk of transmission - 20%
(In absence of neonatal prophylactic
measures)
HBsAg and HbeAg Positive
Risk of transmission - 90%
Acute HBV- First trimester - 10% risk
of transmission.
Third trimester - 90% risk.
HBV has not shown to be
teratogenic. May cause IUGR.
Mast EE et. al, MMWR Recomm Rep 2005;54(RR-16):1–31.
Immunoprophylaxis with
immunoglobulin at birth reduces risk
of transmission to 5 to 10%
M/C cause of chronically
infected individuals
- 95% chance of becoming
chronic
- 25-30% risk of fatal liver
disease

42. Vertical Transmission of HBV
ACOG Recommendations 2007 (Level A)
Routine prenatal screening of all pregnant women by HBsAg testing.
Newborns of HBV+ should receive combined immunoprophylaxis (HBIG+ hepatitis B
vaccine) within 12 hours of birth.
Universal vaccination
Breastfeeding safe in:
• Women with HAV infection with appropriate hygienic precautions
• HBV+ mothers- if the infant receives immunoprophylaxis
• Women with HCV infection.

43. HBVProphylaxis against
Vaccine Age Group Dose Volume No. Of Doses Schedule
Engerix
(GlaxoSmithKline)
0-19 y 10 ug 0.5 mL 3 Infants: Birth, 1-4 mo, 6-18 mo
20 y and older 20 ug 1 mL 3 0, 1, 6 mo
Recombivax HB
(Merck and Co.)
0-19 y 5 ug 0.5 mL 3 Infants: Birth, 1-4 mo, 6-18 mo
20 y and older 10 ug 1 mL 3 0, 1, 6 mo
Vaccination of all infants at birth
is universally recommended
Advisory Committee on Immunization Practices , 2006
Hepatitis vaccine can be delayed safely up to 24
hours after birth and must be given before 7 days.
CDC/ACIP 2006
HepB vaccine is generally considered safe in
pregnancy despite lack of studies on long term
neonatal outcomes.
Pregnant women at high risk should be vaccinated
according to usual adult regimen.
ACOG 2007
Infants born to HBsAg positive mothers should receive
immunoglobulin (250 IU) and vaccination within 12 hours of
birth followed by 2 more doses of vaccine within 6 months.
ACOG 2007
Immunoglobulin should be given within 24 hours of exposure
via blood products or 14 days of sexual exposure in adults.
Pregnant women who think they have been exposed should be
offered immunoglobulin.
ACOG 2007

44. Prophylaxis against HBV
AIIMS Neonatology Protocol:
All infants: 0.5 mL of Pentavalent Vaccine at 0, 6 , 10, 14 weeks
HBV+ Mothers: Also give Immunoglobulin IM on opposite thigh (100 IU)
Follow- Up(Babies of HBV + Mothers)
Test for HBsAg and Anti Hbsag Antibody at 18 months
Anti HBs >/-10 mIU/mL
HbsAg negative
- no action
Anti HBs </-10 mIU/mL
HbsAg negative
- Revaccination (3 doses)
Anti HBs </-10
mIU/mL
HbsAg positive
- Follow-up

45. HBVInitiation of Antiviral Treatment in
Purpose of Treatment
Women with advanced disease To reduce vertical transmission
Traditional immunoprophylaxis
reduces transmission to 5-10%.
Antiviral therapy in women with
high viral load- reduces it further.

46. HBV
ACOG/CDC 2015
Vaccination is safe in pregnancy.
Consider for high risk populations like
sex workers, intravenous drug abusers.

47. WHO- 2015
(Including Pregnant Women )
Women with advanced disease

48. Women with advanced disease
Start antiviral therapy irrespective of gestation if a pregnant women has
- cirrhosis
- Persistent raised ALT and HBV DNA >/-200,000 IU/mL
Stop therapy till one year after
- Persistent undetectable HBV DNA and
- Persistent normal ALT and
- Seroconversion (HbeAg- / HbeAb+)
Lifelong therapy if cirrhosis

49. Sarkar and Terrault, Hepatology, Vol. 60, No. 2, 2014
To reduce vertical transmission

50. To reduce vertical transmission
WHO, ACOG, RCOG:
No recommendations currently.
Sarkar and Terrault, Hepatology, Vol. 60, No. 2, 2014

51. HBVDrugs for
Drug Dose Pregnancy Lactation Effect on Mother Effect on Fetus
Tenofovir
300 mg
OD
B Unknown
Nephropathy, Fanconi syndrome,
Osteomalacia, Lactic acidosis
Reduced bone
mineral density?
Telbivudine
600 mg
OD
B Unknown
Creatine kinase elevation, myopathy,
peripheral neuropathy, lactic acidosis
No studies
Entecavir
0.5 to 1 mg
OD
C Unknown Lactic acidosis No studies
Lamivudine
100 mg
OD
C Unknown Pancreatitis, lactic acidosis No studies
Adefovir
10 mg
daily
C Unknown
Acute renal failure, nephrogenic diabetes
insipidus, renal failure, lactic acidosis
No studies
Pegylated IFN
2a
180 ug
weekly
C Unknown
Flulike symptoms, cytopenias, autoimmune
disorders (checkTSH), psychiatric disorders.
Avoid in pregnancy.
Abortion, IUGR,
thrombocyopoenia
Brown et al, J. Hepatol.,57(2012),953-959.

52. HBV
200 pregnant women with HBeAg + and HBV DNA >20,000 IU/mL
100 participants received tenofovir 300
mg OD from 30-32 weeks POG till 4
weeks post partum
100 participants - control - no
treatment
Followed till 4 weeks postpartum. All
infants received immunoprophylaxis.
Primary
Outcomes -
Significant
68% had HBV DNA <200,000
IU/mL at delivery
2% had HBV DNA <200,000 IU/
mL at delivery
5% mother to infant
transmission at PPD-28
18% mother to infant
transmission at PPD-28
2% infants had birth defects 1% infants had birth defects
Secondary
Outcome - Not
Significant
Pan et. al, N Engl J Med (2016)374;24

53. HCV
Chronic infection(50%)
B- cell lymphoma
Cirrhosis
Cryoglobulinemia
HCC
Asymptomatic infection (75%)
Acute viral hepatitis (20%)
No change in rate during pregnancy
Diagnosis
Antibiodies to HCV (2nd/3rd gen ELISA) - screening test.
HCV RNA (PCR) - more specific. Varies with periods of intermittent viremia.
ss-RNA virus
Harrison’s Principles of Internal Medicine, 19th edition

54. HCVVertical Transmission of
Mast EE et al. J Infect Dis 2005;192: 1880–9.
High
HCV RNA titre
HIV
co-infection
Prolonged
membrane rupture
Internal
fetal monitoring
Risk factors for transmission
Risk of transmission increases
up to 10 - 44%
>/- 6 hours
Maternal viremia is a uniform requisite for vertical transmission.
Zanetti AR, et al. Intervirology 1998; 41:208–12.
Seroprevalence world wide : 0.6 to 6% (INDIA: 1%)
Rate of vertical transmission: 2 to 8%
Okamoto M, et al. J Infect Dis 2000;182:1511–4

55. Vertical Transmission of
No preventive measure to prevent vertical transmission.
Routine screening of all women not recommended
ACOG 2007, WHO 2015
HCV
Routine Testing
Recommended ONLY for :
1. Persons who ever injected illegal drugs
(even once)
2. Persons notified that they received blood
products before 1987 or from a donor who later
tested positive for hepatitis C virus (HCV)
3. Recipients of transfusions or organ transplants,
particularly if received before July 1992
4. Persons ever on long-term hemodialysis
5. Persons with persistently elevated alanine
amino- transferase (ALT) or other evidence of
liver disease
6. Persons seeking evaluation or care for a
sexually transmitted infection, including HIV
7. Persons born from 1945-1965
8. Children of HCV positive mothers
CDC 2006
Ribavirin : Class X
IFN : Class C
Defer treatment during pregnancy.
Diagnosis of infant after birth done with HCV RNA.
If using antibodies to HCV, defer until 12* -18# months
post partum.
AIIMS: follow up at 6 months for HCV RNA testing.
*CDC 2006, #RCOG 2011
Caesarean section does not reduce the risk of
transmission. Breast feeding not contraindicated.
ACOG 2007

56. Universal Screening versus risk based screening
40-70% women do not report identifiable
risk factors.
Blasig A et al, Revue canadienne de sante publique. 2011; 102:98–102
85–95% of HCV+ children in the U.S. have
not been identified due to failure to identify
maternal infections.
Delgado-Borrego A et al, The Journal of pediatrics. 2012; 161:915–21.
Difficult to ascertain risk factors.
RISK
BASED SCREENING
UNIVERSAL
SCREENING
Not cost effective in a population where the
seroprevalence is 1%
Plunkett BA, AJOG. 2005; 192:1153–61.
Lack of effective therapy in pregnancy.
No evidence based intervention to limit
MTCT.

57. Treatment of HCV
Peg-Interferon-a
Abortifacient in Rhesus
monkeys, serious post partum
depression
Category C
Yazdani Brojeni P et. al, Reprod Toxicol 2012; 33:
265-268
Ribavirin:
Nucleotide inhibitor.
Teratogenic and embryogenic.
Category X
U.S. National Library of MedicineRibavirin,
2015
Sustained Viral Response
Undetectable HCV RNA 12 weeks after treatment. Only in 40-80%
EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol 2015; 63: 199-236
The past of Antiviral therapy
Direct Acting Antivirals
• Inhibit HCV protease and
RNA dependent RNA
polymerase
• Sustained viral response of
60-100%
• No studies on safety in
pregnancy.
World J Hepatol 2016 April 28; 8(12): 557-565
KEY MESSAGE
HCV: Treat after delivery.

58. Treatment of HCV
Drug
Pregnancy
Category
Transfer
across
placenta
Transfer
to milk
Comment
Boseprevir,
Telaprevir(1st GEN)
B Yes Yes Used only with IFN and Ribavirin, C/I in pregnancy
Sofosbuvir B Yes Yes No teratogenicity/ embryo toxicity in animal studies
Ledipasvir B Yes Yes No teratogenicity/ embryo toxicity in animal studies
Simeprevir C Yes Yes Skeletal defects in animal studies
Dasabuvir B Minimal Yes No teratogenicity/ embryo toxicity
Prasad M, Am J Perinatol. 2013 February ; 30(2):

59. HEV accounts for 70-80% of ALF in pregnancy in epidemic numbers.
WHO 2016
Mortality rate - 20 to 58%
Acharya, Shalimar J Clin Exp Hepatol 2013;3:213–224
Pregnant women are more susceptible to HEV
infection. Risk increases with trimester.
Gurley ES, Am J Public Health. 2012;102:2248–2254.
Pathogenesis
of ALF: unknown
Diagnosis:
Indirect test:
IgM Antibody (current)
IgG Antibody (past)
Direct test:
HEV RNA
Pregnant women are more prone to ALF.
(10-20% vs 1-2 % in general population).
AggarwalR.J Clin Exp Hepatol. 2013;3:125–133.
HEV

60. Shalimar, Acharya, J CLIN EXP HEPATOL 2013;3:213–224
Pregnant women are more susceptible to acquire HEV, more like to
develop ALF, and more likely to die.
HEV

61. HEV
1015 patients with acute liver failure
PREGNANT
FEMALES
NON PREGNANT
FEMALES
MALES
MORTALITY RATE 53.8% 57.2% 57.9% NOT SIGNIFICANT
ALF ATTRIBUTABLE TO HEV 59.4% 30.4% 23.1% SIGNIFICANT
The mortality of pregnant patients with ALF is similar to that of other
populations. Pregnancy per se should not be regarded as a poor prognostic
factor for a patient with ALF.
Bhatia et. al, Hepatology 2008;48:1577-1585

62. HEVClinical Course of
Prodrome Jaundice
Liver
Failure
Death
4-8 weeks from various studies
Bhatia V et al. Hepatology. 2008;48:1577–1585
Infection, Sepsis
Encephalopathy,
Coagulopathy, DIC

63. HEVComplications of
Premature
labor (90%)
Spontaneous
abortion (8%)
APH(23%) PPH (14%)
ALF (70-80%), hepatic encephalopathy
(30%), death (20-58%)
Maternal
complications
Fetal
complications
Risk of vertical transmission: 30-100%
HEV RNA- major risk factor.
Kumar RM, Eur J Obstet Gynecol Reprod Biol. 2001;100:9–15
Neonates can suffer from hepatitis,
hypoglycaemia, ALF, icterus, fever,
diarrhoea, stillbirth.
Neonatal mortality: 17%
Acharya, Shalimar J Clin Exp Hepatol 2013;3:213–224
Sookian S, Annals of Hepatology 5(3) 2006: 231-236,
AggarwalR.J Clin Exp Hepatol. 2013;3:125–133.

64. HEVProphylaxis against
Vaccines - Yet to be approved.
Baculovirus expressed 56
kDa vaccine - Studied in Nepalese
males
Shrestha MP et. Al, N Engl J Med. 2007;356:895–903.
HEV 239 vaccine - Licensed in
Chinese population- Pregnant women
inadvertently received the vaccine with
no side effects
Zhu FC et. Al, Lancet. 2010;376:895–902.
Advocate safe hand washing practices and water
hygiene.

65. HAV• RNA virus, feco-oral transmission
• Causes acute self limiting infections, very low mortality (<1% case fatality rate).
• 10–15% of symptomatic individuals can have prolonged or relapsing disease lasting up to 6 months
Glikson M, Medicine 1992;71:14–23.
Effects on Pregnancy
GENERALLY SAFE
-Preterm labor, PPROM, vaginal bleeding - reported in a
case series.
Elinav E, Gastroenterology 2006; 130(4): 1129-1134.
-Fetal ascites, meconium peritonitis in a single case
of HAV at 13 weeks POG.
McDuffie RS, Jr. et al, Am J Obstet Gynecol 1999; 180(4):
1031-1032.
•
Vaccination
• Single Antigen Vaccine - inactivated HAV
• Combination - with recombinant HBV
• Not C/I in pregnancy. 95-100% immunogenic.
ACOG 2007
Post Exposure prophylaxis
• Immunoglobulin 0.02 ml/kg IM, as soon as
possible, up to 2 weeks after h/o close or sexual
contact with HAV infected person.
• Safe in pregnancy.
• 80-90% efficacy.
ACIP 2006

66. Acute Liver FailureALF: Encephalopathy within 4 weeks of onset of symptoms
in the absence of preexisting liver disease.
Tandon et. al, J Gastroenterol Hepatol 1999;14:403-404.
40%
4%
10% 5% 5%
1%
34%
Acute E Acute A Acute B
Dual Acute Chronic Markers only Drugs/ Toxins
No cause identified
Bhatia et. al, Hepatology 2008;48:1577-1585
Etiology of ALF in Pregnant Women (AIIMS 1986-2006)
• Most common: HEV
• M/C drug: ATT - izoniazid
• Dual acute : (A,E) , (B,E) ,
(C,E)
• Mortality Rate: ~50%

67. ALF including HEV
Admit to ICU - history, examination
Monitor 2 hourly :
Non invasive cardiac
SpO2
BP
Blood Glucose
Daily Neurological
Assessment:
Encephalopathy,
decerebration, pupil
grade, focal deficit
Daily Investigations
CBC, LFT, KFT,
Coagulation Profile
First Line Investigations
HEV: IgM / HEV RNA
HBV: HbsAg, IgM to HbCAg
HAV: IgM
HCV: IgM , RNA
Second Line Investigations
AIHA: ANA, Anti-smooth
muscle, Anti-LK Antibodies
Wilson’s: 24 hr Copper,
ceruloplasmin
Upper Abdomen USG
Fetal Monitoring
Supportive therapy
• Fluid balance
• No transfusion of
blood products unless
active bleeding
• Ventilation
• Mannitol for cerebral
edema
• Antibiotic prophylaxis
Termination
• Pregnancy managed
conservatively - avoid
active induction
• Induction with
Oxytocin/
Prostaglandin if
rupture of membrane/
chorioamnitis
• Blood and blood
products as required
• Orthotopic transplant -
not at AIIMS - 25% in
the US
Bhatia et. al, Hepatology 2008;48:1577-1585
AIIMS Gastroenterology Protocol
ALL SURGERIES CONTRAINDICATED IN
ALF - NO CESAREAN SECTION
Management of

68. Acute Fatty Liver of Pregnancy

69. Defect in mitochondrial
FAO, LCHAD (79%)
(long-chain 3-hydroxyacyl-CoA )
Microvesicular
steatosis Hepatic failure Death
ACG Guideline, Hepatology 2016
Hay, Hepatology 2008
AFLP
• Life threatening condition, rapidly
causes liver failure with high mortality.
• Incidence: 0.005-0.01%
• Reduced capacity to oxidize
long-chain fatty acids in liver
and placenta,
• metabolic stress
• fetal homozygosity for
LCHAD deficiency,
Causes accumulation of
hepatotoxic LCHAD
metabolites.
• Mean Gestational Age: 36 weeks POG
• May occur in 2nd trimester or post partum.
• Risk factors: Twin pregnancy, low BMI
• Non- specific symptoms: 1
to 2 weeks of NV,
abdominal pain, malaise,
headache.
• Increased transaminases
and bilirubin.
• 50% have coexistent
preeclampsia.
Encephalopathy,
coagulopathy, DIC,
hypoglycaemia, renal
failure.
• 7-18% maternal
mortality
• 9-23 % fetal/
perinatal mortality
Within 4
weeks

70. AFLPSwansea Criteria
Six or more criteria required in the absence of another cause
Vomiting
Abdominal pain
Polydipsia/polyuria
Encephalopathy
Elevated bilirubin >14 "mol/l
Hypoglycaemia <4 mmol/l
Elevated urea >340 "mol/l
Leucocytosis >11×106 cells/l
Ascites or bright liver on ultrasound scan
Elevated transaminases (AST or ALT) >42 IU/l
Elevated ammonia >47 "mol/l
Renal impairment; creatinine >150 "mol/l
Coagulopathy; prothrombin time >14s or APPT>34s
Microvesicular steatosis on liver biopsy
Differentiate
between AFLP and
HELLP
Knight et. al, Gut 2008

71. AFLPManagement of
Infant should be monitored for
manifestations of deficiency of LCHAD
including hypoketotic hypoglycemia and
fatty liver. Monitor for Vit. K deficiency.
Coagulopathy: Blood, FFP, Plt, cryoprecipitate,
recombinant factor 7. Monitor PT, APTT, CBC.
Thromboelastography may better predict
coagulopathy.
Ko HH, Canadian Journal of Gastroenterology. 2006;20(1):25-30.
Counsel about future risk of
recurrence (25%) and offer LCHAD
testing to mother and baby.
Hypoglycemia: Monitor glucose and
administer IV dextrose accordingly.
Monitor serum lipase/ amylase
if suspicion of pancreatitis.
Transfer critical patients to a liver unit. Expect rapid
recovery within 2-3 days of delivery.
Prophylactic Antibiotics
Infection is second leading cause of
mortality after hemorrhage.
PROMPT DELIVERY
Consider vaginal delivery only
if labor is established and
delivery expected within 24
hours.
NO ROLE OF EXPECTANT
MANAGEMENT
ACG 2016, Strong Recommendation, Level IV
evidence
ACG 2016

72. Next Generation Management of Hemorrhage:
Recombinant Factor VIIa

73. Recombinant activated human factor VII produced by transfection of the human factor VII gene
into cultured hamster cells is commercially available (Novo-Seven).
APPROVED FOR: haemophilia, Glanzmann’s thrombasthenia, congenital factor 7 deficiency.
Mechanism of Action:
Physiological concentration: Activates
extrinsic cascade.
Supraphysiological concentration: Binds to
platelets via GP Ib/IX/ X complex —>
promotes Factor X activation and thrombin
generation.
Off label use in liver disorders of
pregnancy and PPH shows
much promise.
Small trials and case reports using RFVIIa at 5 to
120 ug /kg show success in intractable PPH.
Next Generation Management of Hemorrhage:
Recombinant Factor VIIa

74. HELLP

75. HELLP
Hemolysis
Elevated
Liver
Enzymes
Low
Platelets
Unique pregnancy related liver disorder first described in 1982 by Weinstein.
Weinstein L. Am J Obstet Gynecol 1982;142:159-167.
Incidence:
2%-12% of preeclampsia
0.2%-0.6% of all pregnancies
Barton JR et. al, Clin Pernatol 2004;31:807- 833
Most patients present between 27 and 36 weeks’ gestation, but 25% in postpartum
period.
Hay, Hepatology 2008;47:1067-1076
RAPID PROGRESSION
• 35%-50% decrease in platelets per 24 hours; mean daily reduction of 40,000/mL platelets
• LDH and aminotransaminases can continue to rise until 24 to 48 hours postpartum.
Hammoud et al, Clinical Liver Disease, September 2014

76. Nausea,
Vomiting
Viral
Like
Illness
Jaundice
Right
Upper
Quadrant
Pain,
90%
May indicate
impending liver
capsule hepatoma
rupture
10-40%
50%
Hammoud et al, Clinical Liver Disease, September 2014
HELLPClinical Symptoms Of
Severe hypertension and proteinuria: common
but not necessary for the diagnosis of HELLP.
(15-20% have no HTN/proteinuria)
No consistent relationship of these 2
parameters with the laboratory abnormalities
of HELLP.
Sibai BM, Am J Obstet Gynecol 2006;169:1000-6.

77. HELLPEtiology of
?Aberrant
placental
development
Vascular
endothelial
injury
Fibrin
deposition in
blood vessels
Platelet
activation,
consumption
Hemorrhage,
necrosis in liver
from zone 1 to
capsule
Subcapsular
hematoma
Microangiopathic
haemolytic
anemia
Hay, Hepatology 2008;47:1067-1076

78. HELLP
Tennessee Classification Mississippi Classification
Platelets < 100,000/mL (LP)
Class 1:
Platelets <50,000 / mL
AST or ALT >/-70 units/L
LDH >/- 600 units/L
AST >/- 70 units/L (EL)
Class 2:
Platelets 50,000-1,00,000 / mL
AST or ALT >/-70 units/L
LDH >/- 600 units/L
LDH >/- 600 units/L (H)
Class 3:
Platelets >1,00,000 / mL
AST or ALT >/-40 units/L
LDH >/- 600 units/L
Diagnosis of
Other Evidence of Hemolysis
• Progressively worsening anemia
• Decreased haptoglobin
• Increasing indirect bilirubin
• P/S with disrupted RBCs
Sibai BM, Am J Obstet Gynecol. 1990 Feb;162(2):311-6.Martin JN Jr, Am J Obstet Gynecol. 1991 Jun; 164:1500-9.

79. ACG-2016
HELLPManagement of
Admit
Treat hypertension
Management of DIC
Seizure prophylaxis
Fetal monitoring
Delivery: Definitive therapy
• >34 weeks POG
• Multiorgan dysfunction
• Fetal distress
Cesarean Section
(40-50%)
Normal delivery
if labor already
well established
<34 weeks: Consider
steroid therapy for
24-48 hours to improve
lung maturity.
Most patients will deteriorate 1-10 days after
diagnosis with conservative management.
HELLP syndrome should be managed by prompt delivery, especially after 34
weeks gestation
(strong recommendation, Level IV).
Platelet transfusion to 40,000–50,000 cells/"l should be considered before
delivery, especially if cesarean section is likely
(conditional recommendation, Level IV).
ACG Guideline 2016

80. Understanding and managing HELLP syndrome: The integral role of
aggressive glucocorticoids for mother and child
James N. Martin Jr, MD, Carl H. Rose, MD, Christian M. Briery, MD
Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS
American Journal of Obstetrics and Gynecology (2006) 195, 914–34

81. HELLP behaves like a SIRS - like
inflammatory form of severe
preeclampsia.
Redman CWG, Semin Nephrol 2004;24:565-70.
NICE 2011:
Do not use corticosteroids for maternal benefit in HELLP.
Meta-analysis showed marginal improvement in platelet count, with no significant improvement in
maternal / perinatal outcome.
Woudstra DM et al, Cochrane Database Syst Rev. 2010 Sep 8;(9):CD008148.
Corticosteroids were found to reduce morbidity of 64% for
class 1 HELLP syndrome 54% for class 2, and 40% for class 3
to 49%, 22%, and 21%, respectively from this study.
More rapid normalization of platelet counts and LDH values and a clinically significant reduction of
indicated transfusion, need for intubation or intensive respiratory therapy, invasive hemodynamic
monitoring, infectious or bleeding-related morbidity, and length of postpartum hospital course.
Crane JM, J Obstet Gynaecol Can 2003;25:650-5.
]

82. Complications of HELLP
Maternal Mortality
Ranges from 1 to 24%
Hay, Hepatology 2008;47:1067-1076
DIC - 21%
Abruption - 16%
Acute renal failure- 7.7%
Pulmonary edema- 6%
Subcapsular liver hematoma,
rupture - 0.9%
Morbidity/ Near Miss Mortality
Haddad et al, Am J Obstet Gynecol 2000;183:444-8.
Wound hematoma-6%
Perinatal Mortality
Perinatal mortality is 11%, due
to prematurity, dysmaturity due
to placental insufficiency, or the
consequences of severe
maternal complications.
Hay, Hepatology 2008;47:1067-1076
Hepatic encephalopathy-1.1%
Retinal detachment-0.7%
Sepsis- 4.3%
Massive Blood Transfusion -
55%

83. HELLPLiver Hematoma in
Rare: 1 in 40,000- 1 in 250,000 deliveries.
Right upper
quadrant pain
Shoulder pain
Nausea, vomiting
Abdominal
distensionHypovolemic
shock
Clinical Examination
MRI (T2)
Transabdominal ultrasound
Non contrast CT
Laboratory
findings
Imaging
Evaluation
IV Fluid
Blood and blood
products
Percutaneous
embolisation of
hepatic arteries
Ascitic / pleural tap
Conservative Management
Packing
Drainage
Hepatic artery
ligationHepatic resection
Liver
transplant
Laparotomy
Wicke et al, AJOG(2004) 190, 106e112

84. Subsequent pregnancies—
• Pre-eclampsia (20 to 60%)
• Recurrent HELLP (2 to 19%)
• Prematurity
• IUGR
• Abruptio placentae
• Perinatal mortality.
Baxter JK, Obstet Gynecol Surg 2004;59:838-845
HELLPPrognosis and Follow-up of
85%-90% of patients achieve
-Platelets 100,000/mL or greater within 6 to 8 days of delivery or within 72 hours of platelet nadir
-Total LDH/ transaminases trend toward normal within 96 hours postpartum.
Martin JN Jr, Am J Obstet Gynecol 1991;164:1500-13
Renal Dysfunction
In absence of acute renal failure, renal function usually normalises after
pregnancy.
Increased risk of chronic hypertension.
Jacquemyn Y, Gynecol Obstet Invest 2004;57:117-20
No persistent liver dysfunction after HELLP has been reported in studies.
Martin JN Jr et al, AJOG 2006;195,914–34
Stroke in patients with HELLP syndrome left residual defects in 10 of
13 patients (77%) who survived the acute insult.
Martin JN Jr, Obstet Gynecol 2005;104:246-54

85. ALFPrognostic Models for
Study by Acharya et al, AIIMS
Risk Factors at Admission:
(i) Age >/- 40 years
(ii) Bilirubin >/- 15 mg/dL
(iii) Prothrombin time prolongation >/-
25 s
(iv) Clinical features of cerebral edema.
Linear increase of risk of mortality with
increasing risk factors, up to 93% with 3
factors.
Acharya SK et. al, Hepatology. 1996;23:1448–1455
ALF Early Dynamic Model
• Arterial ammonia
• Serum bilirubin
• INR
• Hepatic encephalopathy > grade II
Measured dynamically over 3 days.
Khuroo MS, J Viral Hepat. 2003;10:224–231.

86. Chronic Liver Diseases in
Pregnancy

87. Cirrhosis and Portal HTNLow incidence in women of reproductive age group
+ reduced fertility in cirrhosis —>
Rare in pregnancy.
Complications
-Prematurity
-Spontaneous abortions
-Maternal-fetal mortality
Variceal bleeding - deadliest complication.
Non- cirrhotic portal HTN- better
prognosis
Rasheed SM et. al, Int J Gynaecol Obstet 2013;121:247–51.
ACUTE VARICEAL BLEEDING
• Incidence: 50%
• Mortality rate: 10- 50%.
• Pathophysiology: Due to expanded blood
volume, increased intra abdominal pressure,
straining during second stage, coagulopathy
due to liver failure.
• Management: Endoscopic banding, TIPSS,
sclerotherapy, octreotide infusion
• Delivery: Vaginal- cut short second stage.
Cesarean if high risk of bleeding.
Joshi D et al, Lancet 2010; 375: 594–605
•

88. Cirrhosis and Portal HTN
• Assess severity, inform
prognosis
• Maximize nutrition: Replace
fats soluble vitamins and
minerals.
• Endoscopy for surveillance/
therapeutic.
• High-risk team
• Frequent visits
• Monthly investigations
• Continue all medications
• Monitor nutritional status
Esposti, Clinical Liver Disease, 2014
• Monitor: LFT, PT-INR
• Ensure availability of platelets
and blood products at time of
delivery
• Cesarean/ operative delivery
if risk of esophageal rupture
• Antibiotic prophylaxis
• Splenectomy during LSCS*
Third trimester/deliveryPregnancyPreconception Evaluation
Upper endoscopy and endoscopic ligation of large varices at 28 weeks
ACG 2016 - Strong Recommendation.

89. DRUGS COMMONLY USED IN CIRRHOTIC PATIENTS
Drug Category Use in pregnancy
Lactulose B Frequently used
Spironolactone C Feminization of male fetes
Hydrochlorthiazide B
Furosemide C
Ciprofloxacin C Skeletal abnormalities
Metronidazole B
Rifaximin C No data available
Propanolol C Fetal bradycardia, FGR, hypoglycaemia
Octreotide B Theoretical risk of uterine ischemia

90. Liver TransplantationFertility - restored in 80% in 1 year, as early as few months
Cundy TF, Gut 1990;31:337–8.
Maximum chances of graft rejection are within 6 months, decrease with time.
Counsel to wait at least 1 year before planning pregnancy- lower dose of immunosuppressants,
acute cellular rejection, and opportunistic infections.
McKay DB et. al, Am J Transplant 2005;5:1592–9.
Pregnancy Outcomes
Similar live birth rate to general
population.
Increased rate of preeclampsia, cesarean
delivery, prematurity, LBW.
Deshpande NA et al, Liver Transpl 2012;18:621–9.
Continue immunosuppressive drugs except for
mycophenolic acid
(Strong recommendation, Level II Evidence) ACG 2016
Case series show minimal to no adverse effects in breast
fed babies of mothers taking tacrolimus and cyclosporine.
Br J Clin Pharmacol 2013;76:988–96, Expert Rev Clin Immunol 2013;9:623–6,
Clin J Am Soc Nephrol 2013;8:563–7
Transplantation 2012;94:e38–40

91. Auto-Immune HepatitisType Antibodies Comment
Type 1 ANA, SMA Most common, all age groups.
Type 2 Anti- LKM1
Young women, most severe.
Extrahepatic manifestations
Type 3
Anti-SLA/
LP, Anti
RO/LA
Non conventional antibodies.
Candia L, Semin Arthritis Rheum, 2000; 35:49-56
Increased incidence of
amenorrhea, anovulation, infertility
in women with AIH.
Henghan, Gut 2001;48:97–102
More women with AIH are
becoming pregnant as treatment
improves.
Cases may be diagnosed de novo
in pregnancy.
ACG-2016
Spectrum
Asymptomatic ALF Cirrhosis

92. AIH
AIH causes increased fetal loss and prematurity especially if treatment is
inadequate or stopped.
Westbrook RH et. al, J Autoimmun 2012;38:J239–44.
Presentation
Diagnosis
de novo
20%
antepartum flares
30-50%
post partum flares
Schramm C, Am J Gastroenterol 2006;101:556–60. Werner M. Scand J Gastroenterol 2007;42: 986–91.
Flare: Increase in AST/ ALT above twice UNL +/- increased globulin +/-
symptoms of acute hepatitis.
Henghan, Gut 2001;48:97–102

93. Treatment Guidelines AIH
Induction: Corticosteroids +/- Azathriopine
Maintenance: Corticosteroids + Azathriopine ,
Azathriopine Monotherapy
Manns MP, American Association for the Study of Liver Diseases. Hepatology 2010;51:2193–213.
Women who were on corticosteroids/
azathriopine before pregnancy should be
continued on the same after conception.
(Strong Recommendation, Level IV Evidence) ACG 2016
In women not receiving any treatment during
pregnancy, corticosteroid is preferred for acute
flares.
Manns MP, American Association for the Study of Liver Diseases. Hepatology 2010;51:2193–213.
Corticosteroid: Category C
No increase in cleft palate or adverse
effects in 51,000 steroid exposed
pregnancies
Lamers MM, t al. J Hepatol 2010;53:191–8.
AZA: Category D.
Earlier case reports of thymic atrophy,
leukemia, anaemia in newborn. Latest
evidence: no adverse effects.
Birth Defects Res A Clin Mol Teratol 2009;85:647–54, Curr Opin
Pharmacol 2013;13:470–5, Am J Gastroenterol 2013;108:433–
40, J Obstet Gynaecol 2013;33:1–8.

94. Hyperemesis Gravidarum

95. RCOG Green-Top Guideline No. 69 - June 2016
Nausea and vomiting of pregnancy
(NVP)
• Nausea and/or vomiting during
early pregnancy where there are
no other causes.
• Starts at 4- 7 weeks
• Peaks at 9th week
• Resolves by the 20th week in 90%
of women.
RCOG - 2016
Hyperemesis Gravidarum
Severe protracted NV with
1. weight loss of more than 5% of
prepregnancy weight
2. dehydration, and
3. electrolyte imbalances.
Miller F. Am J Obstet Gynecol 2002;186 Suppl 2:S182–3.
• NVP ~80% incidence.
• HG ~0.3–3.6%
• HG recurrence rate -15 to 80%
Einarson TR,. J Popul Ther Clin Pharmacol 2013;20:e171–
83.
*Trogstad LI et. al, BJOG 2005;112:1641–5
#Fejzo MS et al. Reproductive Sciences 2010; 17:191A–
192A.

96. Classifying the severity of
NVP
• PUQE -objective validated
questionnaire developed
by Motherisk Program in
Canada
• Correlates with hydration
status and tracks progress
with treatment.
RCOG Green-Top Guideline No. 69 - June 2016
Ebrahimi N, et al,. J Obstet Gynaecol Can 2009;31:803–7.
Pregnancy-Unique Quantification of Emesis (PUQE) index

97. History Examination
• Previous history of NVP/HG
• Quantify severity using PUQE score: nausea,
vomiting, hypersalivation, spitting, loss of weight,
inability to tolerate food and fluids, effect on quality
of life
• History to exclude other causes:
– abdominal pain
– urinary symptoms
– infection
– drug history
– chronic Helicobacter pylori infection
• Temperature
• Pulse
• Blood pressure
• Oxygen saturations
• Respiratory rate
• Abdominal examination
• Weight
• Signs of dehydration - dry mucosa, sunken
eyes, reduced urine output
• Other examination as guided by history
RCOG Green-Top Guideline No. 69 - June 2016

98. MANAGEMENT
ALGORITHM
RCOG Green-Top Guideline No. 69 - June 2016

99. ACOG Practice Bulletin No. 153, Sept. 2015
A – Based on consistent evidence
• Take prenatal vitamins for 3
months before conception.
• Treatment NVP with vitamin B6 or
vitamin B6 plus doxylamine is safe
and effective and should be
c o n s i d e r e d f i r s t - l i n e
pharmacotherapy.
• In patients with HG who also have
suppressed thyroid-stimulating
hormone levels, treatment of
hyperthyroidism should not be
undertaken without evidence
(such as goiter, thyroid
autoantibodies, or both) of
intrinsic thyroid disease.
B- Based on inconsistent evidence
• Treatment of NVP with ginger reduces nausea and can be considered as a
nonpharmacologic option.
•
• Early treatment of nausea and vomiting of pregnancy is recommended to
prevent progression to hyperemesis gravidarum.
• Methylprednisolone is beneficial but should be used for last resort cases.
C- Based on Expert opinion and consensus
• Intravenous hydration should be used for the patient who cannot tolerate
oral liquids for a prolonged period or if clinical signs of dehydration are
present. Correction of ketosis and vitamin deficiency should be strongly
considered. Dextrose and vitamins should be included in the therapy when
prolonged vomiting is present, and thiamine should be administered before
dextrose infusion to prevent Wernicke encephalopathy.
• Enteral tube feeding (nasogastric or nasoduodenal) should be initiated as
first-line treatment to provide nutritional support to the woman with
hyperemesis .

100. Maternal Complications of HG
Hyponatremia
Central Pontine
Myelinosis due to
rapid correction
Vit B6/B12 deficiency
Wernicke’s
encephalopathy
Hypokalemia -
skeletal muscle
weakness and cardiac
arrhythmias
Mallory Weiss
Esophageal tears
Venous
thromboembolism
Psychological
Morbidity

101. • Wernicke’s encephalopathy due to vitamin B1 (thiamine) deficiency
presents with blurred vision, unsteadiness and confusion/memory
problems/drowsiness. O/E: Nystagmus, ophthalmoplegia, hyporeflexia
or areflexia, gait and/or finger–nose ataxia.
• Potentially fatal, completely preventable. Complete remission occurred
in only 29% and permanent residual impairment was common.
Togay-Işikay C et. al,. Aust N Z J Obstet Gynaecol 2001;41:453–6.
• Overall pregnancy loss rate including intrauterine deaths and
terminations was 48%.
Chiossi G et. Al, Obstet Gynecol Surv 2006;61:255–68.
Thiamine supplementation is recommended for all
women with protracted vomiting.
•Oesophageal gastroduodenoscopy
is safe in pregnancy and indicated if
there is haematemesis or severe epigastric
pain.
ACG 2016 GUIDELINE
Debby A et. al, J Reprod Med 2008;53:347–51.
• A therapeutic trial with a proton pump
inhibitor is appropriate for treatment and
prevention and is safe in pregnancy.
Gill Sk et al, Am J Gastroenterol 2009;104:1541–5.

102. RCOG Green-Top Guideline No. 69 - June 2016
Urine dipstick:
quantify ketonuria as
1+ ketones or more
Urea and electrolytes:
– hypokalaemia/
hyperkalaemia
– hyponatraemia
– dehydration
– renal disease
Full blood count:
– leucocytosis
– haematocrit
(increase due to
dehydration)
Blood glucose
monitoring:
– exclude diabetic
ketoacidosis if diabetic
Ultrasound scan:
– confirm pregnancy
– exclude multiple
pregnancy and trophoblastic
disease (H.mole)
– TFTs
– LFTs: exclude other liver
disease
– calcium and phosphate
– amylase: exclude
pancreatitis
– ABG: alkalosis
There is hyponatraemia, hypokalaemia,
low serum urea, raised haematocrit and
ketonuria with a metabolic
hypochloraemic alkalosis. If severe, a
metabolic acidaemia may develop.
• Abnormal TFT in two
third of patients.
• Structural similarity
between B-hCG and
TSH —> Increases free
T3/T4 —> Decreases
TSH
• Clinically euthyroid,
b i o c h e m i c a l l y
hyperthyroid.

103. Abnormal liver enzyme values occur in
approximately 50% of patients who are
hospitalized with hyperemesis.
The severity of nausea and vomiting in patients
with HG correlates with the degree of liver
enzyme elevation.
• Mild aminotransferase elevation (up to 200 U/l) -
most common liver laboratory abnormality.
• Increased alkaline phosphatase up to twice
normal values
• Mild hyperbilirubinemia (mixed direct and
indirect fractions) up to 4 mg/dl.
The treatment for HG with or without
liver laboratory abnormalities remains the
same.
-RCOG 2011
Liver Abnormalities in Hyperemesis Gravidarum
Chiossi G et. Al, Obstet Gynecol Surv 2006;61:255–68.

104. RECOMMENDED ANTI- EMETICS
RCOG Green-Top Guideline No. 69 - June 2016

105. Recommendation
Level of
Recommendation
There are safety and efficacy data for first-line antiemetics such as antihistamines (H1 receptor
antagonists) and phenothiazines and they should be prescribed when required for NVP and HG
C
Combinations of different drugs should be used in women who do not respond to a single antiemetic.
Best Practice
Recommendation
For women with persistent or severe HG, the parenteral or rectal route may be necessary and more
effective than an oral regimen.
Best Practice
Recommendation
Ginger may be used as a complementary therapy in mild to moderate NVP in patients not wishing to
take drugs.
A
Women should be asked about previous adverse reactions to antiemetic therapies. Drug-induced
extrapyramidal symptoms and oculogyric crises can occur with the use of phenothiazines and
metoclopramide. If this occurs, there should be prompt cessation of the medications.
B
Pyridoxine is not recommended for NVP and HG C
Corticosteroids should be reserved for cases where standard therapies have failed. A

106. HYDRATION THERAPY
Recommendation Level of Recommendation
Normal saline with additional potassium chloride in each bag, with
administration guided by daily monitoring of electrolytes, is the most
appropriate intravenous hydration.
D
Dextrose infusions are not appropriate unless the serum sodium levels
are normal and thiamine has been administered.
D
RCOG Green-Top Guideline No. 69 - June 2016
100 mg thiamine should be
supplemented per day if dextrose is
given.

107. HELLP: Deliver
after 34 weeks.
May delay for
steroid cover if
</-34 weeks.
Hepatitis B:
Universal screening
Universal Vaccination - Even for
pregnant women if high risk
behaviour
Immunoprophylaxis of infants of
HBV+ mothers
Antivirals - tenofovir - at 28-30
weeks to reduce MTCT
ALF: M/c cause:
HEV : ICU care
conservative
management, no
cesarean.
ICP: Bile acids
correlate with fetal
prognosis. UDCA for
treatment.
AFLP:
Immediate
termination.
Hepatitis C:
Risk based
screening, no
Rx in
pregnancy
Cirrhosis:
Screening and
banding at 28
weeks
AIHA: continue all
immunosuppressant
except
mycophenolic acid.HG: Self resolving
liver abnormalities.
Supportive care.
Take Home Messages
Liver disease
occurs in 3-5 % of
pregnancies.
AST/ALT and PT
derangements should be
evaluated
thoroughly.