The Use of Fish Oil Supplementation in Treatment of Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a unique disease of the liver resulting in abnormal bile acid levels and liver function. The incidence of ICP ranges from 0.1 - 15.6%. Women diagnosed with ICP most often present with itching, which may be severe. More concerning, however, is the impact of ICP on adverse fetal and pregnancy outcomes, including preterm delivery, meconium exposure, fetal demise, and increased neonatal respiratory complications. The risk for fetal demise has been estimated to be 1-3%. The mechanism of fetal demise in ICP is unknown, and therefore cannot be reliably predicted. There is evidence to suggest that extremely elevated bile acids levels are associated with worse fetal outcomes, particularly levels greater than 40 μmol/L.

Ursodeoxycholic acid (UDCA) has anticholestatic effects, and is used to treat a variety of cholestatic liver diseases. Many studies have demonstrated superiority of UDCA over other agents, including dexamethasone and cholestyramine, for relief of maternal pruritus, improvement in transaminitis, reduction in serum bile acid concentrations, and improved pregnancy outcomes. As a result, UDCA is now widely used as first-line treatment for symptomatic relief in patients with ICP.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are two omega-3 long chain polyunsaturated fatty acids found in fish. DHA is known to play a key role in early fetal brain development, and has been associated with modest beneficial effects on neurodevelopmental and cognitive outcomes in children. In neonates with parental nutrition-induced cholestasis (PN-cholestasis), parental fish oil has been shown to be hepatoprotective not only for treatment of PN-cholestasis, but for prevention of cholestasis in premature infants at risk for the disease. Our hypothesis is that fish oil supplementation with DHA in women with ICP who are treated with UDCA will increase the rate of decline in serum total bile acid levels.

The incidence of ICP at a single hospital center in Queens, NY is estimated to be 5% secondary to a high concentration of patients from high-risk ethnic groups. High risk patients with bile acid levels greater than or equal to 40 μmol/L are managed aggressively with inpatient admission for continuous fetal monitoring, treatment with UDCA, and serial total bile acid levels weekly. These are patients are routinely offered early delivery after documented fetal lung maturity between 36 and 37 weeks gestation, or for any signs of fetal distress. This study is a prospective randomized controlled trial comparing weekly serum total bile acid levels in women admitted for inpatient management of ICP among women supplemented with a standard prenatal vitamin versus supplementation with a prenatal vitamin and DHA.

Study Overview

• Status: Withdrawn
• Conditions: Intrahepatic Cholestasis of Pregnancy
• Intervention / Treatment: Dietary supplement: Fish Oil Supplement Group

Detailed Description

Intrahepatic cholestasis of pregnancy (ICP) is a unique disease of the liver resulting in abnormal bile acid levels and liver function. In the literature, the incidence of ICP ranges from 0.1 - 15.6%.[1] Women diagnosed with ICP most often present with itching, which may be severe. More concerning, however, is the impact of ICP on adverse fetal and pregnancy outcomes, including preterm delivery, meconium exposure, fetal demise, and increased neonatal respiratory complications. The risk for fetal demise has been estimated to be 1-3%. The mechanism of fetal demise in ICP is unknown, and therefore cannot be reliably predicted. There is evidence to suggest that extremely elevated bile acids levels are associated with worse fetal outcomes, particularly levels greater than 40 μmol/L.[3] Ursodeoxycholic acid (UDCA) improves impaired hepatocellular secretion by stimulating canalicular bile acid transporter protein expression, and is now widely used as first-line treatment for symptomatic relief in patients with ICP. [1] Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are two omega-3 long chain polyunsaturated fatty acids found in fish. DHA is known to play a key role in early fetal brain development, and has been associated with modest beneficial effects on neurodevelopmental and cognitive outcomes in children.[2] In neonates with parental nutrition-induced cholestasis (PN-cholestasis), parental fish oil has been shown to be hepatoprotective not only for treatment of PN-cholestasis, but for prevention of cholestasis in premature infants at risk for the disease.[3-5] The incidence of ICP at a single hospital center in Queens, NY is estimated to be 5% secondary to a high concentration of patients from high-risk ethnic groups. High risk patients with bile acid levels greater than or equal to 40 μmol/L are managed aggressively with inpatient admission for continuous fetal monitoring, treatment with UDCA, and serial total bile acid levels weekly, and are routinely offered early delivery after documented fetal lung maturity between 36 and 37 weeks gestation, or for any signs of fetal distress. This study is a prospective randomized trial of women diagnosed with ICP prior to 36 weeks who are admitted to Elmhurst Hospital for inpatient observation. Women will be randomized to receiving a standard prenatal vitamin daily or a prenatal vitamin plus fish oil supplementation in addition to the standard UDCA 300mg by mouth three times daily. Dietary fish intake for each subject will be recorded. Total bile acid serum levels will be followed weekly, and fetal monitoring with daily non-stress tests will be performed on all women as per standard care for ICP at Elmhurst hospital. The primary outcome of interest is a 20% reduction in serum total bile acid levels in the treatment group compared to the control group at each time point. Secondary outcomes of interest include changes in maternal symptoms as measured using a validated itching score, changes in UDCA dosing, length of hospital stay, and neonatal outcomes including gestational age at delivery, Apgar scores, neonatal intensive care unit admissions, neonatal length of stay, meconium aspiration, birth weight, and perinatal mortality. Assuming 80% statistical power and a significance level of 0.05 to detect a 20% reduction in serum total bile acids in the treatment group compared to the placebo group, a total of 100 patients in each arm is needed.

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• All pregnant women aged 18 years or older admitted to Elmhurst Hospital Center (EHC) for inpatient management of ICP due to a serum total bile acid level > 40 μmol/L, or serum total bile acid level > 10 μmol/L with elevated AST or ALT, are eligible for enrollment

Exclusion Criteria:

• Women < 18 years
• Women with allergies to fish

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fish Oil Supplement Group; Receive the daily DHA pill and given a validated Itching Survey to assess maternal symptoms on admission and then weekly thereafter	Dietary supplement: Fish Oil Supplement Group; 1 liquid gel pill (440mg omega-3 fatty acids from fish oil) taken daily, enrollment to delivery; Other Names: DHA; Docosahexaenoic acid; Women's One A Day
No Intervention: Control Group; Given a validated Itching Survey to assess maternal symptoms on admission and then weekly thereafter.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bile acid levels	reduction in bile acid levels. Weekly (as part of standard hospital laboratory protocol for admission with intrahepatic cholestasis of pregnancy)	up to 9 months

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: Katherine Kohari, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7(7):CD000493. doi: 10.1002/14651858.CD000493.pub3.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: October 11, 2013
• First Submitted That Met QC Criteria: October 15, 2013
• First Posted (Estimate): October 18, 2013

Study Record Updates

• Last Update Posted (Estimate): October 18, 2013
• Last Update Submitted That Met QC Criteria: October 15, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: omega-3; eicosapentaenoic acid; fish oil; Intrahepatic cholestasis of pregnancy; Docosahexaenoic acid,
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Pregnancy Complications; Cholestasis; Cholestasis, Intrahepatic
• Other Study ID Numbers: GCO 12-1542