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Purpose <p>Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by pruritus and elevated maternal serum total bile acids. While clinical management has focused on bile acid-based risk stratification and delivery planning to reduce perinatal risks, emerging evidence suggests possible longer-term effects on offspring neurodevelopment. This review synthesizes current epidemiologic and mechanistic evidence linking ICP with offspring neurodevelopmental outcomes.</p> Methods <p>PubMed, Embase, and Web of Science were searched using controlled vocabulary and free-text terms. Relevant references were evaluated for inclusion in a stepwise approach.</p> Results <p>Large Nordic register-based studies report associations between in utero ICP exposure and increased risks of childhood neurodevelopmental diagnoses, particularly in earlier-onset disease. Follow-up cohorts suggest altered early-life growth trajectories related to biochemical severity. Mechanistically, elevated maternal bile acids are a plausible proximal exposure. Maternal bile acid overload can disrupt placental bile acid transport and handling, alter the feto-maternal bile acid gradient, and increase fetal bile acid burden. The placenta may further convert bile acid perturbations into inflammatory, oxidative stress, endoplasmic reticulum stress, and vasoactive signals that reshape the intrauterine milieu during sensitive windows of brain development. By contrast, downstream pathways involving microglial priming, neuroinflammation, and blood–brain barrier vulnerability are supported mainly by indirect evidence and require validation in pregnancy-relevant models.</p> Conclusion <p>Current evidence supports a life-course perspective on ICP beyond established perinatal risks. Maternal bile acids and placental dysfunction provide a coherent mechanistic framework for possible neurodevelopmental effects, but pregnancy-relevant mechanistic studies and longitudinal cohorts with refined exposure assessment are still needed.</p>

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Intrahepatic cholestasis of pregnancy and offspring neurodevelopment: bile acid-mediated mechanisms and long-term neurodevelopmental outcomes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月8日

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  • Siyu Dai,
  • Hao Zhao,
  • Yupei Xie,
  • Qian Chen,
  • Qiuhe Chen,
  • Yanhui Li,
  • Dan Shan,
  • Xi Tan,
  • Yayi Hu

摘要

Purpose

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by pruritus and elevated maternal serum total bile acids. While clinical management has focused on bile acid-based risk stratification and delivery planning to reduce perinatal risks, emerging evidence suggests possible longer-term effects on offspring neurodevelopment. This review synthesizes current epidemiologic and mechanistic evidence linking ICP with offspring neurodevelopmental outcomes.

Methods

PubMed, Embase, and Web of Science were searched using controlled vocabulary and free-text terms. Relevant references were evaluated for inclusion in a stepwise approach.

Results

Large Nordic register-based studies report associations between in utero ICP exposure and increased risks of childhood neurodevelopmental diagnoses, particularly in earlier-onset disease. Follow-up cohorts suggest altered early-life growth trajectories related to biochemical severity. Mechanistically, elevated maternal bile acids are a plausible proximal exposure. Maternal bile acid overload can disrupt placental bile acid transport and handling, alter the feto-maternal bile acid gradient, and increase fetal bile acid burden. The placenta may further convert bile acid perturbations into inflammatory, oxidative stress, endoplasmic reticulum stress, and vasoactive signals that reshape the intrauterine milieu during sensitive windows of brain development. By contrast, downstream pathways involving microglial priming, neuroinflammation, and blood–brain barrier vulnerability are supported mainly by indirect evidence and require validation in pregnancy-relevant models.

Conclusion

Current evidence supports a life-course perspective on ICP beyond established perinatal risks. Maternal bile acids and placental dysfunction provide a coherent mechanistic framework for possible neurodevelopmental effects, but pregnancy-relevant mechanistic studies and longitudinal cohorts with refined exposure assessment are still needed.