Delayed Fulminant Hepatic Failure from Dydrogesterone-Related In Vitro Fertilization Therapy Requiring Liver Transplantation During Pregnancy

Abstract

BACKGROUND Drug-induced liver failure is a rare complication of pregnancy and occasionally requires liver transplantation. However, fulminant liver failure arising from in vitro fertilization (IVF) therapy involving progestogens (e.g. dydrogesterone) is extremely rare and has not been reported in pregnancy. Furthermore, dydrogesterone-mediated hepatic dysfunction has not previously necessitated liver transplantation and is usually conservatively managed. We report the first Australian case of a pregnant woman with delayed fulminant liver failure and in utero fetal death requiring a liver transplant from dydrogesterone use. CASE REPORT A 35-year-old multiparous (G₅P₂) woman presented with painless jaundice and transaminitis (alanine aminotransferase and aspartate aminotransferase of 2800 U/L and 2990 U/L respectively). She was pregnant at 14 weeks' gestation after successful IVF in Thailand four months before involving dydrogesterone therapy. She was diagnosed with delayed, subfulminant liver failure arising from previous dydrogesterone use. Initially, she was not encephalopathic and conservative management strategies were instituted. Her hepatic dysfunction progressed and she deteriorated clinically with encephalopathy, necessitating an emergent liver transplantation. Fetal death was confirmed in utero four days before transplantation. A combined orthotopic liver transplant and hysterotomy with fetal evacuation were performed without complication. CONCLUSIONS Fulminant liver failure in pregnancy due to idiosyncratic drug reactions are rare. Dydrogesterone may cause significant, albeit delayed, liver dysfunction in pregnancy necessitating the need for liver transplantation. Early recognition of progressive liver failure despite best supportive care efforts should prompt early considerations for liver transplantation. Delays in liver transplantation with prolonged hyperbilirubinemia and coagulopathy may exacerbate fetal death in utero.

Figure 1.

Longitudinal biochemical data illustrating the patient’s progressive hepatic failure since her hospital admission (day 0). Transplantation occurred at day 24 with subsequent post-transplant biochemical data illustrated thereafter by gray shading. (A) Alanine aminotransferase (ALT, blue) and aspartate aminotransferase (AST, red) parameters showing initial significant transaminitis with progressive normalization post-liver transplantation. Hepatic failure was further illustrated by progressive (B) hyperbilirubinemia (red), thrombocytopenia (blue), (C) hypoalbuminemia, and (D) coagulopathy (international normalized ratio [INR]). Post-transplantation, all parameters normalized.

Figure 2.

Representative macroscopic and microscopic images of the patient’s liver and placenta. (A) Gross morphology of the liver with submassive hepatic necrosis demonstrating capsular wrinkling and flattening (*) with developing regenerative nodularity (arrow) in portions of the liver. (B) Histologic examination of the liver demonstrating submassive hepatic necrosis characterized by complete loss of hepatocytes and inflammation (right and upper portion of image), with early regenerative nodularity (lower left portion of image). (Original magnification ×40.) (C) Histologic examination of the placenta demonstrating evidence of chorioamnionitis characterized by subchorionic fibrin (*) with admixed neutrophils and neutrophilic infiltration of the chorionic plate (arrows). (Original magnification ×400.) (D) Histologic examination of the placenta demonstrating extensive accumulation of intervillous blood with perivillous fibrin deposition (*) and early ischemic change of villi (arrows). (Original magnification ×200.)