Intrahepatic Cholestasis of Pregnancy

1. Intrahepatic Cholestasis of Pregnancy Carla Morrow DNP, CNM Dallas Midwife Associates

2. ICP • Characterized by pruritus and an elevation in serum bile acid concentrations, typically developing in the late second and or third trimester and rapidly resolving after delivery.

3. Incidence/Epidemiology • Most common liver disease unique to pregnancy • Worldwide varies from <1% to 27.6% • Variations are not understood • In US rates range from .32% in Bridgeport Hospital in Connecticut to 5.6% in primarily Hispanic population in LA • Araucanos Indians in Chile have highest incidence worldwide @ 27.6 %

4. Incidence/Epidemiology • More common in • Winter months • Multiple Gestations • Chronic Hep C • Prior family history of ICP • Advanced maternal age

5. Etiology • Not completely understood • Genetic Some evidence suggesting gene mutations • Estrogen • A role for Estrogen in ICP has been supported • Highest in 2nd 3rd trimester • Twins • Replicated in women on OCPs • Resolves rapidly after delivery of placenta

6. Etiology • Progesterone • Alterations in progesterone metabolism may also play a role • Unknown if administering exogenous progesterone contributes • Environmental Factors – Seasonal and geographic variabilities in ICP suggest that environmental factors could modulate the expression of the disease • Underlying liver disease

7. Presentation • Pruritus • Late 2nd and 3rd trimester • Generally palms of hands and soles of feet • Worse at night • Right upper quadrant pain • Nausea, poor appetite, steatorrhea (pale, oily stools that float)

8. Physical Exam • Scratch Marks, excoriations • There will be no primary skin lesions • Jaundice in 14 to 25% of patients typically developing 1-4 weeks after onset of itching

9. Lab Findings • Serum Bile Acids is the Key lab findings present in >90 percent of cases • Use the total bile acid result • Non pregnant adult First Trimester • 0.3-4.8 0-4.9 • Second Trimester Third Trimester • 0-9.1 0-11.3 • Serum Total and direct bilirubin (elevated in 25% of cases) • Serum aminotransferases (elevated in 60% of cases) • Postprandial serum total bile acid levels are generally higher than fasting levels

10. Lab Findings • Serum aminotransferases (ALT) (elevated in 60% of cases) • Lab value not affected by pregnancy • Non pregnant adult • 7-41 U/L • First Trimester • 3-30 U/L • Second Trimester • 2-33 U/L • Third Trimester • 2-25 U/L

11. Diagnosis • Based on the presence of pruritis associated with total serum bile acid levels, elevated aminotransferases or both • Severe cholestasis is consistent defined as bile acids over 40 mmol/L and accounts for 20% of cases • Because Pruritus can precede the rise in serum bile acids, it is recommended repeating lab tests weekly • However if ursodeoxycholic (Ursodiol) acid is started empirically, elevated bile acid and transaminase levels may never be detected

12. Pruritus • Affects 23% of all pregnancies, but only a small proportion are due to ICP • Pruritus has also been associated with preeclampsia and fatty liver disease in pregnancy • The lack of primary skin lesions in ICP helps differentiate from most pregnancy specific pruritic dermatosis • and skin conditions that are unrelated to pregnancy

13. Morbidity and Mortality Maternal bile acids cross the placenta and can accumulate in the fetus and amniotic fluid • Risks • Stillbirth (.91% versus 0.32%) In in 100 versus about 1 in 350 • Preterm birth (13.4% versus 4.0%) • Meconium stained fluid (18.7% versus 10.8%) • NICU admission (2.12% versus 1.48%)

14. Stillbirth Risks • The risk of fetal demise increases with higher serum total bile acid levels especially >100 mml/L • <40-99 (.28%) .92 + .28 = 1.2 • >100 (3.44%) .92 + 3.44 = 4.36

15. Maternal Treatment • Reducing bothersome symptoms • Reducing perinatal morbidity and mortality • All patients are offered Ursodeoxycholic acid (Ursodiol) • May initiate treatment with classic symptoms (pruritis palms of hands/soles of feet)

16. Ursodiol Complete resolution of symptoms in approximately 42% of patients and improvement in 61% Improves lab abnormalities associated with ICP May improve perinatal outcome and has no known fetal and neonatal toxicity Optimal starting dose 300 mg three times a day until delivery Well tolerated by most, but may have nausea and dizziness Improvement in itching within 2 weeks Lab values improve within 3-4 weeks

17. Pregnancy Management • Antepartum fetal assessment • Twice weekly BPPs/NSTs • Daily fetal kick count AND NONE OF THIS MAY BE USEFUL

18. Timing of Delivery • Early delivery to to reduce the risk of fetal demise. The timing should be guided by balancing the risk of fetal death the the expectant management against the potential risk of premature delivery. • Deliver 36-37 weeks • consider delivery prior to 36 weeks in women with ICP and Excruciating and unremitting pruritus • Jaundice • Prior history of fetal demise before 36 weeks • Total serum bile acids >100

19. Delivery • No special considerations related to delivery • Continuous fetal monitoring recommended • Labor induction does not necessarily lead to increased cesarean section compared with expectant management • No increased risk of PPH

20. Maternal Outcome • Postpartum – Pruritus usually disappears in the first few days following delivery. • Breastfeeding – No a contraindication to breastfeeding Ursodiol is discontinued when labor begins. • Follow-up – CMP and bile acids 6-8 weeks after the delivery. • Studies suggest that ICP may be associated with subsequent diagnosis of gallstone disease • Reoccurrence in 60-70% of subsequent pregnancies • Contraception – May not be a good candidate for OCPs

21. Special Populations • Women with history of ICP undergoing IVF may have transient symptoms • Progesterone supplementation – Risks/Benefits and if develops ICP, should discontinue the use of progesterone

23. Midwifery Role • Physical Exam and History • Obtain CMP, Bile Acids • Referral • May be candidate for co-care • CNMs with hospital privileges can usually manage these patients.

24. For Referrals/Consultation call: 214-974-3937

25. References • Clinical Updates in Women’s Health Care Summary: Liver Disease: Reproductive Considerations. Obstet Gynecol 2017; 129:236 • Geenes V., Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15:2049 • Laifer SA, Stiller RJ. Siddiqui DS, et al. Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. J Maternal Fetal Med 2001; 10:131 • Lee RH, Goodwin RM, Greenspoon j, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatal 2006; 26:527 • Abedin P. Weaver JB. Egginton E. Intraheaptic cholestasis of pregnancy: prevalence and ethnic Distribution

26. References • Savander M, Ropponen A, Avela K, et al. Genetic evidence fo heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003; 52: 1025 • Floreani A. Gervasi MT. New Insignts on Intraheaptic Cholestasis of Pregnancy. Clin Liver Dis 2016; 20:177 • Lunzer m. Barnes p, Byuth K, O’Halloran M. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis. Gastroenterology 1986; 91:825 • Bicocca MJ, Sperlin JD, Chauhan SP. Intrahepatic cholestasis of pregnanc; Review of six national and regional guidelines. Eur J Obset Gynecol Reprod Biol 2018: 231:180 • https://www.smfm.org/publicaitons/96-understanding-intrahepatic-cholestasis of-pregnancy (Accessed on April 2, 2019)