Ursodeoxycholic acid for intrahepatic cholestasis of pregnancy: good for the mother, not bad for the baby
- 1Division of Hepatology, Mayo Clinic, Phoenix, Arizona, USA
- 2Department of OB-Gyn, Loyola University Chicago, Maywood, Illinois, USA
- Correspondence to: Dr Elizabeth J Carey
Division of Hepatology, Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA;
Commentary on: Bacq Y, Sentilhes L, Reyes HB, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012;143:1492–501.
Intrahepatic cholestasis of pregnancy (ICP) is a heritable disease of pregnancy resulting in elevation of serum bile acids, pruritus and increased risk of poor fetal outcomes. It always resolves after delivery, but pruritus can be a cause of severe distress for the mother, and the fetus is at increased risk of intrauterine demise. The prevalence of ICP varies greatly by ethnicity and geography: rates of over 25% have been reported in South American Indians, although in most areas the prevalence is less than 2%.1 ,2
Ursodeoxycholic acid (UDCA) is a naturally occurring hydrophilic bile acid used in a variety of cholestatic liver diseases. The exact mechanism of benefit is not completely understood, but it is thought to work by increasing secretion of bile acids, inhibiting apoptosis and decreasing inflammation, and reducing the toxicity of bile acids. UDCA has been studied in ICP, but its benefit remains controversial. The present study aimed to determine the effect of UDCA on maternal symptoms, maternal biochemistry and fetal outcomes.
Bacq and colleagues performed a systematic review of nine published randomised controlled trials (RCTs) comparing UDCA to other medications, placebo or no treatment. The authors searched MEDLINE on PubMed, the Cochrane Library and manually for clinical trials and meta-analyses comparing UDCA to other treatments or placebo in ICP. The main outcomes were pruritus, liver test results and fetal outcomes. They also contacted the corresponding author of each RCT to collect unpublished information which allowed for standardisation of the end-point definitions.
Nine RCTs met the inclusion criteria: (1) comparing UDCA alone to placebo or other treatments and (2) publication as full papers in the English language peer-reviewed journals. UDCA compared with all controls was associated with improved maternal outcomes: reduced or resolved pruritus, decrease or normalisation of alanine aminotransferase (ALT) and reduced levels of serum bile acids. When UDCA was compared with placebo alone, reduced pruritus, decreased or normalised ALT and reduced serum bile acids were noted.
UDCA compared with all controls was associated with improved fetal outcomes as well: less prematurity, less meconium staining and/or fetal asphyxia, less respiratory distress syndrome (RDS) and fewer admissions to the neonatal intensive care unit (NICU). These results were not demonstrated when UDCA was compared with placebo only.
This present study demonstrates that treatment with UCDA in ICP improves maternal symptoms and laboratory findings, and likely improves fetal outcomes as well. Although these findings had previously been reported, the sample sizes were small, heterogeneity of study design hampered interpretation and a previous meta-analysis failed to demonstrate a significant effect.3 With any pharmacological intervention in pregnancy, safety concerns abound and clinicians may not be willing to prescribe medication if any uncertainty about its safety or efficacy exists.
For the mother, ICP is a benign disease which always resolves after pregnancy without long-term sequelae. However, pruritus is common and often severe, so identification of safe and effective treatment is essential. Previous studies have noted a correlation between bile acid levels and fetal complications.4 ,5 This meta-analysis confirmed that treatment with UCDA results in decreased bile acid levels, a potential surrogate marker for fetal complications.
Compared with all controls, UCDA resulted in less iatrogenic prematurity, meconium staining, asphyxia, RDS and NICU admission, suggesting benefit to the fetus in addition to the reduction of maternal symptoms. The significance of fetal benefit was lost when UCDA was compared with placebo only, likely related to the low number of placebo controls present. Fetal demise, the most feared complication of ICP, is a rare event and only two cases were noted, both in a placebo group. The authors acknowledge that the small number of events precluded analysis; whether this devastating outcome is prevented by UDCA remains unknown.
This systematic review clearly outlines the maternal benefit of UDCA in ICP while strongly suggesting fetal benefit as well. Given the rarity of the disease and the difficulty in performing RCTs during pregnancy, it is unlikely that more convincing evidence will emerge in the near future. Importantly, previous reports that UDCA in pregnancy does not pose a risk to the fetus were confirmed. This meta-analysis should provide reassurance to all clinicians that UDCA can be used in ICP as it improves maternal outcomes without evidence of risk to the fetus.