Use of fenofibrate for intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic liver disease characterized by elevated total serum bile acids (BAs), elevated liver transaminases and alkaline phosphatase, and pruritus that typically presents in the third trimester. In ICP, perinatal outcomes correlate with the degree of BA elevation. BA levels ≥40 μmol/L are associated with spontaneous preterm birth, meconium-stained amniotic fluid, and neonatal intensive care unit admission.[1]Glantz A. Marschall H.U. Mattsson L.A. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates.Hepatology. 2004; 40: 467-474Crossref PubMed Scopus (609) Google Scholar,[2]Ovadia C. Seed P.T. Sklavounos A. Greenes V. Di Ilio C. Chambers J. et al.Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.Lancet. 2019; 393: 899-909Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar BA levels of 100 μmol/L or more are associated with an increased risk of stillbirth.[2]Ovadia C. Seed P.T. Sklavounos A. Greenes V. Di Ilio C. Chambers J. et al.Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.Lancet. 2019; 393: 899-909Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar The first-line treatment for ICP is ursodeoxycholic acid (UDCA).[3]Bicocca M.J. Sperling J.D. Chauhan S.P. Intrahepatic cholestasis of pregnancy: review of six national and regional guidelines.Eur J Obstet Gynecol Reprod Biol. 2018; 231: 180-187Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar The role of UDCA in ICP is controversial, as previous studies have provided conflicting results. A randomized trial of 605 patients showed that UDCA was not effective in reducing a composite of perinatal outcomes (perinatal death, preterm birth, and neonatal unit admission) in patients with ICP.[4]Chappell L.C. Bell J.L. Smith A. Linsell L. Juszczak E. Dixon P.H. et al.Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.Lancet. 2019; 394: 849-860Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar A subsequent meta-analysis has shown that UDCA is associated with a reduced risk of spontaneous preterm birth in patients with ICP and BA ≥40 μmol/L.[5]Ovadia C. Sajous J. Seed P.T. Patel K. Williamsonn N.J. Attilakos G. et al.Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.Lancet Gastroenterol Hepatol. 2021; 6: 547-558Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Studies indicate that UDCA’s effect on maternal pruritus is minimal.[4]Chappell L.C. Bell J.L. Smith A. Linsell L. Juszczak E. Dixon P.H. et al.Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.Lancet. 2019; 394: 849-860Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar,[5]Ovadia C. Sajous J. Seed P.T. Patel K. Williamsonn N.J. Attilakos G. et al.Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.Lancet Gastroenterol Hepatol. 2021; 6: 547-558Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Fibrates have emerged as a therapeutic option for patients with other cholestatic liver diseases refractory to UDCA monotherapy. In primary biliary cholangitis (PBC) patients with incomplete response to UDCA, combination therapy with bezafibrate and UDCA has been shown to improve pruritus and prognostic markers of cholestasis compared to UDCA plus placebo.[6]Corpechot C. Chazouillères O. Rousseau A. Le Gruyer A. Haberseetzer F. Mathurin P. et al.A placebo-controlled trial of bezafibrate in primary biliary cholangitis.N Engl J Med. 2018; 378: 2171-2181Crossref PubMed Scopus (343) Google Scholar,[7]de Vries E. Bolier R. Goet J. Parés A. Verbeek J. de Vree M. Drenth J. van Erpecum K. van Nieuwkerk K. van der Heide F. Mostafavi N. Helder J. Ponsioen C. Oude Elferink R. van Buuren H. Beuers U. Netherlands association for the study of the liver-cholestasis working group. Fibrates for itch (FITCH) in fibrosing cholangiopathies: a double-blind, randomized, placebo-controlled trial.Gastroenterol. 2021 Feb; 160: 734-743.e6Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Herein, we report on the use of fenofibrate to treat pruritus refractory to UDCA treatment in two patients with ICP. Patient A is a 33-year-old G4P0121 at 28w3d gestation with a history of pre-eclampsia, chronic hypertension, transient ischemic attack, and hypothyroidism. Labs revealed aspartate aminotransferase (AST) 50 IU/L, alanine aminotransferase (ALT) 69 IU/L, alkaline phosphatase (ALP) 158 IU/L and total bilirubin (TB) 0.4 mg/dl. She was normotensive with a platelet count of 214x103/μl. A right upper quadrant ultrasound was unremarkable. At 31w1d, repeat labs showed AST 189 IU/L, ALT 480 IU/L, ALP 218 IU/L, TB 0.9 mg/dl. BA levels were 27 μmol/L. She reported generalized pruritus for the preceding two weeks. She was not taking any herbal supplements, nor any new medications. Antimitochondrial, anti-smooth muscle, and EBV/CMV antibodies were negative. Given her elevated BA levels and otherwise negative workup, the patient was diagnosed with ICP. She was started on UDCA at 31w2d (increased from 300 to 600 mg twice daily over four days) and hydroxyzine as needed for pruritus. However, she had persistent itching with BA levels increasing to 75 μmol/L at 31w6d. At 32w3d, BA levels decreased to 43 μmol/L, but her liver transaminases and ALP remained elevated (AST 149 IU/L, ALT 420 IU/L, ALP 211 IU/L, TB 0.6 mg/dl). She was started on micronized fenofibrate 134 mg daily and continued on UDCA. Two weeks after the initiation of fenofibrate (34w3d), laboratory values improved (BA 10 μmol/L, AST 20 IU/L, ALT 35 IU/L, ALP 170 IU/L, TB 0.3 mg/dl) with significant improvement in her pruritus (Fig. 1A). She underwent an uncomplicated cesarean section at 37w0d delivering a 3,230 g infant with APGARs 9/9. There were no neonatal complications. Patient A presented again 17.5 months later during her next pregnancy (G5P1122) at 30w2d with a two-day history of severe generalized pruritus. Her liver panel was unremarkable (AST 21 IU/L, ALT 19 IU/L, ALP 112 IU/L, TB 0.3 mg/dl). BA levels were 12 μmol/L. She was started on UDCA (500 mg BID) and fenofibrate (non-micronized; 160 mg daily) with rapid improvement in pruritis. She underwent planned, uncomplicated caesarean at 37w2d, delivering a 2,835 g infant with APGARS of 7/8. Patient B is a 31-year-old G1P0101 with a pregnancy complicated by monozygotic dichorionic twins with selective reduction of fetus A at 29w3d due to progressive ventriculomegaly and obstructive hydrocephalus. At 15w2d, Patient B reported new-onset pruritus of her hands and feet (AST 23 IU/L, ALT 21 IU/L, and BA 5 μmol/L). Her pruritus worsened over the next three weeks with BA levels increasing to 31 μmol/L. She was started on UDCA 300 mg three times daily at 19w4d, leading to an initial decrease in her BA levels to 10 μmol/L but minimal improvement in her pruritus. Throughout the remainder of her pregnancy, she had fluctuating levels of BAs with persistent pruritus, despite increasing doses of UDCA to 500 mg TID. Her BA levels rose to 33 μmol/L at 31w0d, so she was started on non-micronized fenofibrate 160 mg daily at 32w6d in addition to UDCA. She had persistent pruritus but underwent a cesarean at 34w0d for breech presentation and preterm prelabor rupture of membranes, with delivery of fetus A (demised) and fetus B with APGARs 6/8 and weight of 2,115 gm. At the time of delivery, BAs were 7 μmol/L, and fenofibrate and UDCA were discontinued (Fig. 1B). While the use of fibrates has been well documented in cholestatic liver diseases, to our knowledge, this is the first report of fibrate use in ICP. The safety of fenofibrate in pregnancy has not been well established due to a lack of well-controlled studies. The FDA notes that fenofibrate should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. In ICP, this benefit likely comes when patients experience intractable pruritus or when BA levels are rising and refractory to UDCA. Observational studies are needed to further investigate the role of fenofibrate in ICP. The authors received no financial support to produce this manuscript. The authors report no relevant conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details. JG provided intellectual contributions and wrote the manuscript. CC and MT provided intellectual contributions and critical revision of manuscript for important intellectual content. AS provided the intellectual basis for the content of the manuscript and provided clinical decision making under the direction of NP. 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