1. Prof. Mahmoud Midan

2. Definition  Obstetric cholestasis is a multifactorial condition of pregnancy characterised by pruritus in the absence of a skin rash with abnormal liver function tests (LFTs), and both of which resolve after birth.  Usually occurring in the last trimester of pregnancy. It can, however, occur earlier in gestations.  Obstetric cholestasis is a multifactorial condition of pregnancy characterised by pruritus in the absence of a skin rash with abnormal liver function tests (LFTs), and both of which resolve after birth.  Usually occurring in the last trimester of pregnancy. It can, however, occur earlier in gestations. Investigations to exclude other causes of pruritus and of abnormal LFTs should be performed. Investigations to exclude other causes of pruritus and of abnormal LFTs should be performed.

3. Background  Prevalence is influenced by genetic and environmental factors and varies between populations worldwide.  In England, obstetric cholestasis affects 0.7% of pregnancies in multiethnic populations and 1.2– 1.5% of women of Indian–Asian or Pakistani– Asian origin.  In Chile, 2.4% of all pregnancies are affected.  In Indian:- 5% of all pregnancies are affected.

4. History  In 1987, Wilson reported the first case of intrahepatic cholestasis of pregnancy in an African-American patient.

5. Histology  The periportal areas show no change, and the hepatocellular architecture remains undisturbed.  The centrilobular areas, however, reveal dilated bile canaliculi, many containing bile plugs.  Ultrastructurally, there appears to be some destruction and atrophy of microvilli in the bile canaliculi.  These changes tend to regress after pregnancy.

6. Risk Factors 1. Personal or family history of obstetric cholestasis. 2. Multiple pregnancy. 3. Carriage of hepatitis C. 4. Presence of gallstones. 1. Personal or family history of obstetric cholestasis. 2. Multiple pregnancy. 3. Carriage of hepatitis C. 4. Presence of gallstones.

7. Diagnosis 1. Unexplained pruritus and Abnormal (LFTs) 2. Raised bile acids. These acids are deposited in the skin and probably cause the extreme pruritus. 1. Unexplained pruritus and Abnormal (LFTs) 2. Raised bile acids. These acids are deposited in the skin and probably cause the extreme pruritus. 1. Other causes of itching and of liver dysfunction should be excluded. 2. Postnatal resolution of pruritus and abnormal LFTs should be confirmed. 1. Other causes of itching and of liver dysfunction should be excluded. 2. Postnatal resolution of pruritus and abnormal LFTs should be confirmed. And/ Or Grade C

8. Pruritus in pregnancy It is common, affecting 23% of pregnancies, of which a small proportion will have obstetric cholestasis.

9. Pruritus of Cholestasis 1- worse at night 2- often widespread and may involve the palms of the hands and/or the soles of the feet. 1- worse at night 2- often widespread and may involve the palms of the hands and/or the soles of the feet. 1. Other evidence of cholestasis should be sought, including pale stool, dark urine and jaundice. 2. Other causes of pruritus must be excluded such as eczema or atopic eruption of pregnancy. 1. Other evidence of cholestasis should be sought, including pale stool, dark urine and jaundice. 2. Other causes of pruritus must be excluded such as eczema or atopic eruption of pregnancy.

10. Pruritus in pregnancy (cont.) If a rash is present, polymorphic eruption of pregnancy or pemphigoid gestations (blisters) should be considered.

11. Jaundice  Approximately, 2 weeks later, clinical jaundice will develop in 50 % of cases.  The jaundice is usually mild, soon plateaus, and remains constant until delivery.  The pruritus worsens with the onset of jaundice, and the patient's skin can become excoriated.  The symptoms usually abate within 2 days after delivery.

12. Laboratory abnormalities Unexplained abnormalities in 1- Transaminases, 2-Gamma-Glutamyl Transferase 3. Bile salts are considered sufficient to support the diagnosis of obstetric cholestasis. Unexplained abnormalities in 1- Transaminases, 2-Gamma-Glutamyl Transferase 3. Bile salts are considered sufficient to support the diagnosis of obstetric cholestasis. 1. Alkaline phosphatase (non specific as it is placental in origin so, it is not reflect liver disease). 2. Bilirubin is raised only infrequently. 1. Alkaline phosphatase (non specific as it is placental in origin so, it is not reflect liver disease). 2. Bilirubin is raised only infrequently. And/ Or Pregnancy-specific reference ranges for LFTs should be used (20% of non pregnant value)

13. Differential Diagnosis Other causes of pruritus and abnormal LFTs should be sought:- 1.viral screen for hepatitis A, B, and C, EBV, CMV. 2.primary biliary cirrhosis (for example, anti-smooth muscle and antimitochondrial antibodies). (liver ultrasound) 3.Pre-eclampsia and acute fatty liver of pregnancy are pregnancy-specific causes of abnormal LFTs that might form part of the differential diagnosis in atypical or early cases. Other causes of pruritus and abnormal LFTs should be sought:- 1.viral screen for hepatitis A, B, and C, EBV, CMV. 2.primary biliary cirrhosis (for example, anti-smooth muscle and antimitochondrial antibodies). (liver ultrasound) 3.Pre-eclampsia and acute fatty liver of pregnancy are pregnancy-specific causes of abnormal LFTs that might form part of the differential diagnosis in atypical or early cases.

14. Maternal morbidity 1. Intense pruritus and Consequent sleep deprivation. 2. Increase Rate Of CS. 3. Increase Risk Of PPH. 4. If cholestasis lasts for several wks, liver dysfunction may result in: i. Decreased vitamin K re-absorption or ii. Decreased prothrombin production, leading to a prolongation of the prothrombin time.

15. Fetal risks

16. Preterm birth Spontaneous preterm birth (range 4-12%) Iatrogenic preterm birth (range 7–25%) Grade B

17. Meconium Passage Grade B

18. Still Birth For England and Wales in 1980, the perinatal mortality rate was 13.4, 8.3 in 2002 and 5.4 in 2008 Small Grade B

19. Caesarean Section  Caesarean section rates are high, ranging from 10% to 36%.  It is difficult to establish the relative roles played of obstetric cholestasis itself, of induction of labour/other obstetric indications and of obstetrician/patient anxiety.

20. Postpartum haemorrhage  Despite physiological reasons and a high caesarean section rate, which might suggest an increased risk of postpartum haemorrhage, evidence from current practice does not show this.

21. Monitoring  Measure LFTs weekly until delivery  If LFTs return to normal, obstetric cholestasis is not likely to be the correct diagnosis.  If LFTs escalate very rapidly, additional diagnoses need to be considered and the frequency of monitoring increased.  A coagulation screen should be performed.  blood pressure measurement and urine check, allow monitoring of the condition and exclusion of other diagnoses.

22. Can fetal death be predicted and prevented?  Poor outcome cannot currently be predicted by biochemical results and delivery decisions should not be based on results alone.  No specific method of antenatal fetal monitoring for the prediction of fetal death can be recommended.  Ultrasound and CTG are not reliable methods for preventing fetal death in cholestasis.  Continuous fetal monitoring in labour should be offered. Grade B Grade D Grade C

23. It Is Difficult to predict fetal death??  Until the pathophysiology of obstetric cholestasis and fetal death is more clearly defined and the level of risk is clarified, prediction and prevention of fetal death will remain challenging.  Fetal death is usually sudden. There is no evidence of placental insufficiency. Fetal growth restriction and oligohydramnios are not features of the disease.

24. Management  Women with obstetric cholestasis should be booked in under consultant-led, team based care and give birth in a hospital unit.

25. Should women with obstetric cholestasis be offered elective early delivery ??  A discussion should take place with women regarding induction of labour after 37+0 weeks of gestation.  Women should be informed of the increased risk of perinatal morbidity from early intervention (after 37+0 weeks of gestation).  Women should be informed of the inability to predict stillbirth if the pregnancy continues.  Women should be informed that the case for intervention (after 37+0 weeks of gestation) may be stronger in those with more severe biochemical abnormality (transaminases and bile acids). Grade B

26. Treatment  There is no evidence that any specific treatment improves fetal or neonatal outcomes.  All such therapies should be discussed with the individual woman with this in mind.  There is no evidence that any specific treatment improves fetal or neonatal outcomes.  All such therapies should be discussed with the individual woman with this in mind.

27. Topical emollients (calamine lotion and aqueous cream with menthol). Safe but their efficacy is unknown Grade C

28. Systemic treatments  Aim:- relieve pruritus 1. Colestyramine. 2. Antihistamines such as chlorphenamine may provide some but not significant impact on pruritus. 3. Activated charcoal and guar gum do not relieve pruritus.  Aim:- relieve pruritus 1. Colestyramine. 2. Antihistamines such as chlorphenamine may provide some but not significant impact on pruritus. 3. Activated charcoal and guar gum do not relieve pruritus.

29. Cholestyramine (Cholestran Pack 4 gm). A total of 8 to 16 g/day in three to four divided doses A. A poorly tolerated bile acid-chelating agent. B. May improve pruritus in some women C. May also exacerbate vitamin K deficiency (fetal ICH), check PT weekly D. No randomised trials and is not in clinical use.

30. S-adenosyl methionine  There is insufficient evidence to demonstrate whether it is effective for either control of maternal symptoms or for improving fetal outcome It is not recommended Grade A

31. Ursodeoxycholic acid (UDCA)  Improves pruritus and liver function.  No robust data concerning protection against stillbirth and safety to the fetus or neonate.  Improves pruritus and liver function.  No robust data concerning protection against stillbirth and safety to the fetus or neonate. Mechanism of action:-  enhance bile acid clearance across the placenta, This may protect the hepatocyte membrane from the damaging toxicity of bile salts. Grade A

32. Dexamethasone  should not be first-line therapy for treatment of obstetric cholestasis, nor should it be used outside of a randomised controlled trial without a thorough consultation with the woman.  The results are conflicting, with some improvement in symptoms and biochemistry in some women.  should not be first-line therapy for treatment of obstetric cholestasis, nor should it be used outside of a randomised controlled trial without a thorough consultation with the woman.  The results are conflicting, with some improvement in symptoms and biochemistry in some women. 10 mg orally for 7 days and then stopping over 3 days Grade D

33. Role of vitamin K  Obstetric cholestasis can result in:- 1. Reduced absorption of dietary fats due to failure of excretion of bile salts into the GIT and reduced micelle formation. 2. Increased fat excretion (subclinically or clinically apparent as steatorrhoea) has been reported to affect the absorption of fat- soluble vitamins including vitamin K, which is required for the manufacture of coagulation factors 11,V11, 1X and X.

34. vitamin K  When the prothrombin time is prolonged, the use of water- soluble vitamin K (menadiol sodium phosphate) is indicated.  When prothrombin time is normal, vitamin K in low doses should be used only after careful counselling about the likely benefits but small theoretical risk.  Postnatal vitamin K must be offered to the babies in the usual way  When the prothrombin time is prolonged, the use of water- soluble vitamin K (menadiol sodium phosphate) is indicated.  When prothrombin time is normal, vitamin K in low doses should be used only after careful counselling about the likely benefits but small theoretical risk.  Postnatal vitamin K must be offered to the babies in the usual way 5- 10 mg daily oral, aiming to improve both maternal and neonatal levels, which are assumed to be deficient, and therefore reduce postpartum haemorrhage and fetal or neonatal bleeding Grade D

35. POSTNATAL  LFTs should be deferred for at least 10 days postnatally (6-8 wks)  In normal pregnancy, LFTs may increase in the first 10 days of the puerperium.  Postnatal resolution of symptoms and of biochemical abnormalities is required to secure the diagnosis. Grade D Evidence level III

36. contraceptive choices Usually avoiding Estrogen- containing methods. Usually avoiding Estrogen- containing methods.

37. Recurrence  Intrahepatic cholestasis tends to recur in subsequent pregnancies, but the severity may vary from one pregnancy to the next.  In their Chilean study, Gonzalez et al. reported a recurrence rate of 70 % in singleton pregnancies.