Cholestasis of Pregnancy Part 1: Research Review

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This post will be reviewing an article regarding Intrahepatic Cholestasis of Pregnancy (ICP). It discusses causes, symptoms, labs, complications, and treatment options.

Diken Z, Usta IM, Nassar AH. A Clinical Approach to Intrahepatic Cholestasis of Pregnancy. American Journal of Perinatology, EFirst (2013).

Introduction
First described in 1883, Intrahepatic Cholestasis of Pregnancy (ICP) is a disease unique to pregnancy
Prevalence ranges from 0.3 to 5.6% of pregnancies in the US
Due to abnormal formation or secretion of bile acids

Etiology (Causes)
Risk factors include ethnicity, twin gestation, assisted reproductive techniques, hepatitis C, advanced maternal age, family history of biliary disease, preeclampsia, and having ICP in a prior pregnancy. Tends to recur in 40-60% of subsequent pregnancies
Women with ICP also seem more likely to have gallstones, drug sensitivities, and more severe and prolonged vomiting
Multiple factors: environmental influences, nutritional deficiencies, hormonal changes, and genetic variations
Higher prevalence in winter
Deficiency in Selenium, leading to defective bile formation. Found in garlic, onions, sunflower seeds, and mushrooms
Hormonal changes. Typically occurs at end of pregnancy when levels of estrogen and progesterone are highest. Can explain higher incidence in twin gestations. ICP may also recur in women with history of ICP using oral contraceptives.
Genetic causes. 12 fold increased risk of sisters of affected patients developing ICP. Only a small percentage of patients show genetic mutation associated with ICP.

Clinical Presentation
Usually beginning in second or third trimester with itching and skin lesions caused by scratching, has been seen as early as 8 weeks
Itching of palms of hands and soles of feet that spreads to the whole body, usually worse at night
No associated rashes or lesions other than those caused by scratching
Itching is common even in healthy, normal pregnancies. ICP must be confirmed by lab testing and to rule out hepatitis and gallbladder disease.
Itching thought to be due to build up of bile acids in skin
Occasionally also see mild jaundice (yellowing of skin), steatorrhea (greasy stools), abdominal pain, and weight loss

Lab Abnormalities
Most frequent abnormality is an elevated total bile acid concentration (TBA)
TBA over 11 found to be highest predictive marker in diagnosis of ICP
Mild: TBA 10-40
Severe: TBA over 40
Can also see abnormal liver function tests, but there is no standard level used for diagnosis
Liver tests usually normalize 2-8 weeks after delivery

Associated Obstetric Complications
Definite association between ICP and a higher frequency of fetal distress, preterm labor and delivery, unexplained fetal demise (fetal death), and meconium staining (baby has a bowel movement while inside)
Intrauterine mortality rate of 7%, with 90% of cases occurring after 37 weeks gestation
Higher incidence of ICP with preeclampsia, acute fatty liver of pregnancy, and gestational diabetes
May also see maternal postpartum hemorrhage due to malabsorption of Vitamin K (vitamin used by body for clotting blood)
Uncertain if adverse pregnancy outcome can be avoided below a certain TBA threshold
Appears to be an increased complication rate when TBA >40 and especially >100
Excessive maternal bile acids cross the placenta and accumulate in fetus, cord blood, meconium, and amniotic fluid
Excessive bile acids were found to cause abnormal cardiac activity in rate, which could partially explain fetal cardiac abnormalities and sudden cardiac death in infants
Studies have found bile-depletes surfactant levels in the fetal lungs, leading to increased risk of respiratory distress and breathing difficulties even in babies with mature lungs

Treatment
Goal to minimize maternal symptoms and decreased adverse fetal outcomes
First line treatment ursodeoxycholic acid (UDCA) also known as Actigall and Ursodiol. Decreases maternal itching, normalizes bile acid levels, decreases rate of preterm birth, fetal distress, respiratory distress in the infant, and admission to neonatal intensive care.
Dose of UDCA is 10-20 mg/kg/day in two divided doses (usually 15 mg/kg). Improvement in 1-2 weeks. No  reported cases of fetal toxicity with UDCA.
Dexamethasone decreased itching and bile acids the first week, but was followed by a rise in bile acids until the end of the 3 week study period. Dexamethasone is not an effective treatment and is not recommended.
SAMe given daily by IV was less effective on it’s own than UDCA, but when combined was found to have a synergistic effect when used together. May be useful in severe cases when combined with UDCA.

Fetal Well Being
No ideal method of fetal surveillance in patients with ICP, as nonstress tests have been unable to predict fetal outcome in several studies
No need for frequent growth ultrasounds in women with ICP, as growth restriction is not common and uteroplacental insufficiency (placenta not pumping blood and nutrients like it should) is not a usual complication with ICP

Expectant vs. Active Management
Expectant Management
Intrauterine mortality rate of 7%, with 90% of cases occurring after 37 weeks gestation
Carries higher risk of adverse pregnancy outcomes and higher incidence of fetal death even after reassuring antenatal testing
Cause of fetal death is not due to the placenta being affected resulting in a chronic problem, but instead a sudden cardiac arrest in the baby
May be reasonable when TBA levels less than 40, as some studies find no rise in fetal complications until TBA levels exceed 40
Mild ICP. Manage at outpatient. Antihistamines for itching. Start UDCA. Weekly non-stress tests. Weekly liver function tests, TBA, and prothrombin time (if increased, start 10mg Vitamin K daily). Wait for spontaneous labor and delivery.

Active Management
Closer fetal surveillance, amniocentesis at 36 weeks to detect meconium and fetal lung maturity, and induction of labor by 37 weeks
Presence of meconium detected by amniocentesis associated with 86-100% risk of fetal death in patients with ICP
Severe ICP. TBA levels >40. Start UDCA. Twice weekly non-stress test and biophysical profile. Twice weekly liver function tests, TBA levels, and prothrombin time. Consider course of betamethasone in <34 weeks gestation. Consider inpatient management. Consider amniocentesis at 36 weeks. If meconium fluid found during amniocentesis, deliver promptly. If no meconium, deliver at 37 weeks.

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