Ursodeoxycholic acid use is associated with significant risk of morbidity and mortality in infants with cholestasis

Abstract

The off-label use of medications is a “right” for pediatricians, owing to lack of enough safety and effectiveness drug trials in pediatric age group. Pediatricians have to rely on their personal judicial use of medications in children. We studied off-label use of ursodeoxycholic acid (UDCA) retrospectively during 2005 to 2015 among those who attended the Pediatic Hepatology Unit, Cairo University. We analyzed data of 779 neonates and infants with cholestasis. 15% dropped out. Males comprised 374 (56.5%). Cholestasis was due to surgical causes in 129 (19.5%), neonatal hepatitis in 445 (67.2%), and paucity of intrahepatic bile ducts in 88 (13.3%). Three hundred sixty (54.4%) received UDCA (15–30 mg/kg/d), and 302 (45.6%) did not. Both groups were matched as regards causes and severity of cholestasis. Those who received UDCA had worse outcome (P < .001), and more complications (P < .001). A total of 73.1% (221) achieved cure without UDCA compared to only 45.8% (165) of those on UDCA (P < .001). UDCA is not effective and not safe in Egyptian neonates and infants with cholestasis. UDCA use compromises chance of cure, and is associated with serious morbidity, progression of disease, and death. UDCA off-label use mortality was absolutely preventable. Off- label use of UDCA in neonates and children should be utterly prohibited. Information of use of off-label medications, effectiveness, and safety, should be recorded, analyzed, and made available within context of Off-label Use Registry Studies with informed consent of parents.

Conservative Management of Alloimmune Hemolysis and Cholestasis With Extreme Laboratory Abnormalities

“…However, authors of recent work have raised alarms about the use of ursodiol in infants, including an association with increased mortality. 33 Both of our patients and many of the published cases (Table 1) received IVIg. IVIg remains a recommended intervention for HDFN and hyperbilirubinemia, 34 although there are limited data supporting its efficacy for HDFN.…”

Efficacy and safety of ursodeoxycholic acid in children with cholestasis: A systematic review and meta-analysis

“…In addition, a long-term, double-blind, randomized controlled trial found that the risk of developing cirrhosis, varicose veins, bile duct cancer, liver transplantation and death was twice in patients receiving high-dose UDCA (28 to 30 mg/kg/d) compared with patients receiving the placebo [ 50 , 51 ]. There was no long-term, double-blind, randomized controlled trial conducted to evaluate the effect of UDCA on the long-term prognosis of children with cholestasis, but a retrospective study has shown that UDCA (15 to 40 mg/kg/d) had no benefit to neonates and infants with cholestasis (obstructive and non-obstructive) and put them at a higher risk of treatment failure [ 15 , 16 ]. And it was associated with disease progression, severe complications (hepatocyte failure, ascites, vanishing bile duct syndrome, and so forth.)…”

“…However, some researchers believed that UDCA was ineffective and unsafe in infants and neonates with cholestasis and might be associated with severe complications (cirrhosis, hepatocyte failure, and so forth. ), disease progression and death, especially when taking higher doses (20–40 mg/kg) /d) [ 15 – 17 ].…”

Obeticholic Acid, FXR Agonists, Liver Disease and Plasma Biomarkers

“…The risks that occur in the prolonged administration of ursodeoxycholic acid are beyond the scope of this report. The recent report by Kotb [20] of the increased mortality in a large group of infants and children receiving ursodeoxycholic acid for liver disease compared with a control group should alert physicians to currently unaddressed problems with its prolonged use.…”