The Genetic and Epigenetic Nexus of Intrahepatic Cholestasis of Pregnancy in the In Vitro Fertilization Era: A Perspective on the Iranian Population

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder associated with significant fetal risks. Its incidence is notably increased in pregnancies conceived via in vitro fertilization (IVF). This elevated risk is attributed to the supraphysiological hormonal environment created during controlled ovarian hyperstimulation, which may act as a trigger in genetically susceptible individuals. The etiology of ICP involves a complex interplay between a predisposing genetic background, primarily mutations in hepatobiliary transporter genes like ABCB4 and ABCB11, and regulatory epigenetic mechanisms. Epigenetic modifications, such as DNA methylation and microRNA-mediated silencing, are increasingly recognized as key mediators that could translate the hormonal stimulus of IVF into the clinical phenotype of cholestasis. While the genetic architecture of ICP has been explored in several ethnic groups, a significant knowledge gap exists for the Iranian population—a population with a unique genetic heritage and a growing reliance on assisted reproductive technologies (ART). This review examines the genetic and epigenetic underpinnings of ICP, focusing on how the hormonal milieu of IVF unmasks latent predispositions. We highlight the urgent need for research within the Iranian population to develop tailored genetic screening protocols for ART candidates, aiming to mitigate the risk and improve perinatal outcomes in this high-risk group.