introduction/clinical features/investigation/management/recent advances

1. Intern Dr. Hinasha Thapa
Intern Dr. Jiwan Pandey
Intern Dr. Jonas Malla
Intern Dr. Kajol Shrestha
Shree Birendra Hospital

2. Case presentation

3. • 22 yrs, Primigravida at 36+3 Weeks of Gestation presented with
chief complaints of:
• Amenorrhoea for 8 months.
• Itching all over the body for 1 month.

4. • Patient was apparently well with 8 months of amenorrhoea when
she started having itching all over the body.
– Itching was sudden in onset.
– Started from palms and soles then became generalized.
– Progressively increasing.
– Continuous since then.
– Aggravated by cold water and sweat and no relieving factors.
– No diurnal variation.

5. • She does not give history of:
 Skin rashes
 Bruises and contusions
 Fever, Nausea and vomiting
 Yellowish discolouration of skin and eyes
 Dark discolouration of urine
 Pale stool
 Fatigue
 Pain abdomen
 Per vaginal bleeding
 Per vaginal leaking

6.  Increase in BP
 Headache
 Blurring of Vision
 Epigastric pain
 Swelling of legs
• She is perceiving good fetal movements.

7. • She is a booked case of SBH and under regular ANC visits.
1st Trimester 2nd Trimester 3rd Trimester
Uneventful Uneventful •History of generalized itching
of body.
•She was admitted on
2074/03/29 and was kept for
observation.
•She was managed
conservatively.
• On 17th day of admission
(2074/04/15), IOL was done.

8. – Primigravida
– LMP: 2073/7/16
– EDD: 2074/4/23
– WOG: 36+3
– Menarche: 14 yrs
– Pads changed/day: 2-3 homemade pads fully soaked/day
– Menstrual flow: 5-6 days
– Menstrual cycle: 28-30 days
– Dysmenorrhoea +
– Clots +

9. – Barrier method used by her husband.
– No history of HTN, COPD, TB, DM, Thyroid abnormalities
– No surgical interventions done till date
– HTN in father since 2 years.

10. – She is a non vegetarian.
– She has normal bowel and bladder habit.
– She has normal sleep and appetite.
– She does not give history of smoking and alcohol intake
– No history of documented allergy towards food or drug till date.

11. Examination
General Examination
• Weight: 51 kg
• Height : 151 cm
• Conscious, co-operative, well oriented to time, place and person.
• No signs of Pallor, Icterus, Edema and Dehydration
• No scratch marks over the body.
• Vitals parameter:
– P: 90 beats/min, regular
– BP: 80/60 mm of Hg
– T: 97 F
– R: 22 breaths/min, thoracoabdominal

12. Systemic examination
• CNS: Grossly intact
• Chest: B/L vesicular sound heard and no added sound heard
• CVS: 1st and 2nd heart sound heard and no murmur
• P/A:
– Uterus: 34 weeks size
– Cephalic presentation
– Head: free
– Contractions: Nil
– FHS:140 bpm, Regular

13. On 2074/03/29
• USG Obs Scan at 36+3 WOG by date reveals:
– Single live intrauterine pregnancy of 32+6 weeks, EFW:2188 gm,
cephalic presentation, AFI:16.6cm
• LFT
– Total Bilirubin: 0.9 mg/dl (0.3-1.2 )
– Direct Bilirubin: 0.4 mg/dl (<0.2)
– ALT: 196 U/l (upto 46 )
– AST: 164 U/l (upto 46)
– ALP: 271 U/l (42-128)

14. • CBC: WNL
• Urine RE/ME: WNL
• RBS: 64 mg/dl
• Urea:14 mEq/l
• Creatinine: 0.7 mEq/l
• Na+: 136 mEq/l
• K+: 3.7 mEq/l

15. • Then, she was managed conservatively:
– 2074/03/29: Tab. Ursodeoxycholic Acid 300mg tds
– 2074/3/30:
• Tab. Ursodeoxycholic Acid (Udihep)150mg tds
• Tab. Chlorpheniramine (Avil) 25 mg HS
• Calamine lotion LA X bd
• Cap. Ifol 1 cap od
• Tab. Calvit 500mg bd
– 2074/04/04: Arginine Sachet bd
– 2071/04/05: Tab. Avil and calamine lotion was stopped.

16. • USG on 2074/04/02 reveals:
– Single live intrauterine pregnancy of 33+5 weeks, EFW:2320 gm,
Cephalic presentation, AFI:16.5cm
• LFT
– Total Bilirubin: 0.5 mg/dl (0.3-1.2 l)
– Direct Bilirubin: 0.3 mg/dl (<0.2)
– ALT: 117U/l (upto 46 )
– AST: 57 U/l (upto 46)
– ALP: 259 U/l (42-128)

17. • USG on 2074/04/05 reveals:
– Single live intrauterine pregnancy of 36+2 weeks, EFW: 3091 gm,
Cephalic presentation, AFI:12.94cm, Placenta: Anterior
– Normal Fetal Doppler Study:
• Bilateral MCA, Umbilical and placental and fetal end
demonstrates normal flow velocity.
• No evidence of reverse flow seen.
• LFT (2074/04/08)
– Total Bilirubin: 0.4 mg/dl (0.3-1.2 l)
– Direct Bilirubin: 0.2 mg/dl (<0.2)
– ALT: 26 U/l (upto 46 )

18. • On Examination:
 P/A- Uterus: Term size, cephalic, 4/5
- FHS: 144 bpm, Regular
- Contractions: Nil
 P/V- Os: Closed
- Cervix: Soft, posterior, uneffaced,
-Head station: High up
- Bishop’s score: 2

19. On Shrawan 15 at 38+6 WOG (17th Day of admission), induction
was done at 4am with Tab misoprostol 25 µg at posterior fornix.
From 4am Syntocin was started( 5U Syntocin in 500ml RL)
Again after reassessment (Bishop’s score 5) and monitoring fetal status
Next 3 doses of Tab. Misoprostol was kept at posterior fornix every 6
hour interval ( 10 am, 4pm, 10pm)
After reassessment and reassurance Fetal status with CTG
on next day(18th day)

20. OUTCOME:
• Alive Male baby of weight 2880 gm at 9:38 am on 2074/04/16 with
APGAR score 3/10 and 6/10 at 1 and 5 minutes respectively.
• Placental weight: 500gm
• TBL: 250 ml
• Umbilical cord: 25 cm
• Baby was sent to NICU for observation.
There was progression of labor
2nd dose of Syntocin was started
Full term vaginal delivery with episiotomy at 39 WOG

21. Yesterday was her 1st day of puerperium
• Chief Complaints: No fresh complaints
• On Examination:
– General Condition: Fair
– No signs of Pallor, Icterus, Edema and Dehydration
– Vitals:
• P: 74 bpm
• BP: 100/70 mm of Hg
• T: 97.8 F
• RR: 20 breaths/ min
– Systemic Examination: NAD

22. • P/A:
– Soft, non tender
– Uterus: Well contacted at 20 weeks size
– BS +nt
• P/V: Normal Lochia
• She was discharged yesterday.

24. Obstetric Cholestasis
Intrahepatic Cholestasis of Pregnancy
Jaundice of Pregnancy
Prurigo Gravidarum
Synonyms

25. Defination
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder
characterized by pruritus, elevated serum aminotransferases and
bile acid levels with onset in the second or third trimester of
pregnancy, and spontaneous relief of signs and symptoms within
two to three weeks after delivery.

26. • Central and western Europe : 0.4–1%of pregnancy
• Chile and Bolivia : 5–15% of pregnancy
• India : 1.2- 1.5% of pregnancy

27. • Most common presentation is itching.
– Mostly in palms and soles but can occur all over the body
– Without rashes
– Mostly in the evening
– Usually doesn’t respond to anti-histamines.

28. • Less common presentation are:
– Nausea
– Decrease in appetite
– Jaundice
– Right upper quadrant pain
– Darker urine
– Lighter stools
– Fatigue

31. • Genetics :
– Genetic mutations in the hepatocellular transport protein ABCB4
which controls secretion of phosphatidylcholine into bile.
– Genetic changes to bile salt transport molecules, high levels of
estrogen glucuronides have been shown to inhibit the bile salt
export pump (BSEP) ABCB11, and high levels of progesterone
to inhibit the ABCB4 (MDR3) phospholipid transporter.

33. 1. Serum bile acid levels :
– Increased (most sensitive indicator ), may increases upto 10
fold.
2. Transaminases:
– (moderate (<3 fold))
– ALT is most sensitive then AST.
3. Alkaline Phosphatase:
– Elevated but have poor diagnostic value.
4. Bilirubin:
– Hyperbilirubinemia up to 100 μmol/l (5 mg/dl) is only detected
in 10–20% of the cases.
5. γ-GT :
– High if mutations in the MDR3 gene are suspected.

34. • Lipid profile:
– The increase of LDL-cholesterol and triglycerides, which is
observed during pregnancy, is more pronounced in cholestatic
patients including ICP, whereas HDL-cholesterol may decrease

35. • An abdominal ultrasound is considered in ICP patients with
abdominal symptoms or raised liver enzymes.
- also to rule out liver abnormalities and presence of gall bladder
stones.

36. • Liver Biopsy
– Liver biopsy in general is unnecessary.
– Histology would show mild focal irregular intrahepatic cholestasis
with bile plugs in the canaliculi and small amounts of bile
pigment in centrilobular hepatocytes and macrophages. Necrosis
or inflammation is absent.

37. • Viral marker screening
• Hepatitis A,B,C, E
• EBV and CMV viruses

38. Vitamin K deficiency
Increased risk of PPH
Recurrence (45–70%
Maternal outcomes

39. Fetal outcomes

40. Still birth
(up to 0.4–4.1%)

41. Fetal Distress:
(21-42%)

42. Meconium staining of amniotic fluid:
(up to 27%)

43. Preterm delivery
(up to 19–60%)

44. 1. Counselling
– Risk of the fetus
– Close surveillance
2.Liver function tests: weekly
3. Fetal well-being
Monitor at regular interval
CTG
USG
Umbilical artery Doppler blood flow
Fetal growth and liquor volume

45. Important steps in management
Symptoms relief
Reducing the bile acids in
blood
Delivery
Topical emollients:
calamine lotion and
aqueous cream with
menthol
Antihistamines
Bile acid-chelating
agent:
Cholestyramine
Ursodeoxycholic
acid
At 37-38 weeks or when
fetal lung maturity is
evident
Close monitoring during
induction and labor
Where the Prothrombin time is prolonged, the use of water-soluble vitamin K (Menadiol
sodium phosphate) 5–10 mg daily is indicated.

46. • Lower fat intake.
• Have frequent baths.
• Avoid hot environment.
• Wear loose cotton clothes.

47. • Usually rapid complete recovery occurs
• Sometimes LFT may return to normal in 4-6 weeks
• If persistent abnormalities we should suspect CLD like primary
biliary cirrhosis, primary sclerosing cholangitis, or chronic hepatitis C
which all may be associated with development of pruritus during late
pregnancy.

49. • Once obstetric cholestasis is diagnosed, it is reasonable to measure
LFTs weekly until delivery.
• During Postnatal periods, LFTs should be deferred at least 10 days.

50. • No specific method of antenatal fetal monitoring for the prediction of
fetal death can be recommended.
• Ultrasound and Cardiotocography are not reliable methods for
preventing fetal death in obstetric cholestasis.
• Continuous fetal monitoring should be offered.

51. • Topical emollients
- topical emollients are safe but their
efficacy is unknown
-bland topical options include
diprobase, calamine lotion and
aqueous cream with menthol.

52. Systemic treatment
- Cholestyramine
Cholestyramine is an anion exchange resin that binds bile acid
and interfere with entero-hepatic circulation
however its efficacy in counter-acting pruritus is minimal and can
cause vitamin k deficiency
- Anti-histamines
Various anti-histamines such as diphenhydramine and
chlorpheniramine have been used.
They may provide some sedation at night but do not have a
significant impact on pruritus.

53. - There is insufficient evidence to demonstrate whether S-adenosyl
methionine is effective for the control of maternal symptoms for
improving fetal outcome.
- However recent research shows intravenous administration of 800
mg/day for 2 weeks produces substantial reduction in pruritus and
an improvement in abnormal liver function indices.
- Moreover, it decreases the incidence of premature labor.

54. Ursodeoxycholic acid
improves pruritus and liver
function in women with obstetric
cholestasis.

55. • Dexamethasone should not be first-line therapy for treatment of
obstetric cholestasis.
Decreases the synthesis of fetal and maternal ACTH hormone and
secretion of oestrogen pre-cursors
Reduction in maternal oestrogens levels may be possible mechanism
by which it may improve cholestasis

56. • Women should be advised that where the prothrombin time is
prolonged, the use of water soluble vitamin k in dose of 5-10 mg
daily is indicated.
• Women should be advised when the prothrombin time is normal,
water soluble vitamin k should be used in low doses only after
careful counselling.

57. • Women should be informed of the increased risk of perinatal
morbidity from early interventions.
• Women should be informed of the increased risk of maternal
morbidity from interventions at 37th week of gestation.
• Women should be informed that the case for intervention may be
stronger in those with severe bio-chemical abnormality.

58. SBH Guidelines
The pregnancy was continued till
39 weeks of gestation and then
induction of labor was done.
The pregnancy is to be continued
till 37 weeks as it decreases the
risk of fetal complications.
Prothrombin time was not sent for
investigation.
Prothrombin time can be
derranged in Intrahepatic
Cholestatis of Pregnancy and
should be measured.

60. • Combined Ursodeoxycholic acid (UDCA) and rifampicin is 2nd line
treatment.
• Enhances bile acid detoxification as well as bilirubin concentration.
• Increase excretion of bilirubin glucuronides by increasing MRP2
expression.
• Phenobarbitone increases the excretion of bile salt.
European journal of obstetric and

61. • Progesterone sulfate are prognostic indicator of ICP
• Sulfated progesterone metabolites (PM2DiS,PM3S and PM3DiS )
are found to be increased in maternal serum during ICP.
• Furthermore, UDCA treatment reduces ICP associated elevation of
disulfated progesterone metabolites.
Role of Progesterone Metabolites in diagnosis of
ICP

62. One study shows that PM3S(metabolites of
progesterone) increase in ICP
activates TGR5 dependent pathway
Causes pruritus
Increased concentration of sulfated Progesterone also saturate
the maximal transport capacity of transport protein for bile acid
so progesterone containing drugs shouldn’t be used.

64. • Intrahepatic cholestasis of pregnancy is associated with dyslipidemia.
METHODS
Plasma lipid concentration
Assessed in
Non fasting blood samples
• 63 women with intrahepatic cholestasis of pregnancy
• 43 in pruritus gravidarum
• 20 in healthy pregnant
• 4-6 in postpartum

65. • Elevation of Low density lipoprotein (LDL) cholesterol and reduction
of high density lipoprotein (HDL) cholesterol in Intrahepatic
Cholestasis of Pregnancy compared to Pruritus gravidarum.

66. Lipoproteins + constituent lipids
contribute to
- Oxidative stress
- Influence cell membrane fluidity
- Permeability of canalicular epithelium
- Function of hepatobiliary transporters and receptors
- Promotes synthesis of cholestatic metabolites of placental steroid
hormones

68. • To determine incidence, obstetrical and fetal complication rates of
ICP in patients managed expectantly to 40 weeks gestation.
- Course of pregnancy was monitored to 40 weeks gestation or
spontaneous onset of labor, whichever come first.
- Compared with a cross matched group of healthy pregnant women.
Methods
Purposes

69. - No significant difference between groups in gestational age at delivery,
preterm labor, intrauterine fetal death, CS or Respiratory Distress
syndrome.
- Significantly higher intrapartum non reassuring fetal heart rate pattern
and meconium- stained amniotic fluid in ICP group.
- Intrapartum fetal asphyxia is more likely.
Conclusion
Result

70. UDCA:
- Decrease in alanine aminotransferase (ALT) and bilirubin.
-Significant effects on pruritus.
-Not on fetal complication rate.
Dexamethasone:
- Less effective in reducing bile acid and bilirubin.

71. THANK YOU