Beyond stillbirth: association of intrahepatic cholestasis of pregnancy severity and adverse outcomes

Sarker, Minhazur; Zamudio, Andrés Ramírez; DeBolt, Chelsea A.; Ferrara, Lauren

doi:10.1016/j.ajog.2022.06.013

Cited by 18 publications

(17 citation statements)

References 30 publications

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“…ICP is associated with increases in stillbirth, spontaneous and iatrogenic preterm birth, meconium aspiration, and neonatal respiratory distress 7,8 . The absolute increase in risk of these outcomes is small, particularly for stillbirth which according to a large individual patient data meta‐analysis only appears to be associated with very severe disease in which bile acids are above 100 μmol/L 9 …”

Section: Adverse Perinatal Outcomesmentioning

confidence: 99%

Intrahepatic cholestasis of pregnancy: Contemporary management

White

2023

Aust NZ J Obst Gynaeco

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Intrahepatic cholestasis of pregnancy: Contemporary managementIntrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy, occurring in up to 4% of women and varying in frequency according to ethnicity, fetal plurality, mode of conception, and concurrent hepatitis C virus infection. 1 It is characterised by itch and elevated serum bile acids. The association with adverse perinatal outcomes, particularly stillbirth, has previously led to a range of fetal surveillance strategies and interventions, not generally based on robust evidence, and often with adverse unintended consequences such as iatrogenic preterm birth. This issue of ANZJOG features a policy statement by Hague et al on behalf of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) presenting the consensus guidelines for the diagnosis and management of ICP. 2 This document is an excellent resource for Australian and New Zealand maternity care providers and should become the standard reference for those who diagnose and treat ICP. The full guideline is available on the SOMANZ website at https://www.somanz.org/content/uploads/2023/08/ SOMANZ-ICP-Consensus-Statement-1.6.23-Web-Version.pdf. ADVERSE MATERNAL OUTCOMESElevated transaminases are observed in around 80% of cases of ICP, although this generally resolves rapidly postpartum along with the ICP. 1 Fat malabsorption can lead to vitamin K deficiency with coagulopathy and bleeding complications, although this is rare and limited to severe cases. [3][4][5] The severe itch that some women experience may have significant negative psychosocial consequences. 6 Intrahepatic cholestasis of pregnancy: Contemporary management

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Section: Adverse Perinatal Outcomesmentioning

confidence: 99%

Intrahepatic cholestasis of pregnancy: Contemporary management

White

2023

Aust NZ J Obst Gynaeco

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“…The main complications related to this disease are presented in Figure 1 . They include, but are not limited to, neonatal respiratory distress syndrome (associated with the presence of BA in the lungs), meconium-stained amniotic fluid, preterm birth, and an increased risk of stillbirth [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

Section: Pathophysiology Etiology and Complications Of Icpmentioning

confidence: 99%

“…Fetal death in ICP may be caused by sudden vasoconstriction of the placental surface vessels or the development of arrhythmias induced by elevated BA levels, although pathophysiology has not been confirmed [ 38 , 39 , 40 ].…”

Section: Pathophysiology Etiology and Complications Of Icpmentioning

confidence: 99%

Bile Acids in Intrahepatic Cholestasis of Pregnancy

et al. 2022

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Intrahepatic cholestasis of pregnancy (ICP) is the most common, reversible, and closely related to pregnancy condition characterized by elevated levels of bile acids (BAs) in blood serum and an increased risk of adverse perinatal outcomes. Due to the complex interactions between the mother and the fetus in metabolism and transplacental BAs transport, ICP is classified as a fetal-maternal disease. The disease is usually mild in pregnant women, but it can be fatal to the fetus, leading to numerous complications, including intrauterine death. The pathophysiology of the disease is based on inflammatory mechanisms caused by elevated BA levels. Although ICP cannot be completely prevented, its early diagnosis and prompt management significantly reduce the risk of fetal complications, the most serious of which is unexpected intrauterine death. It is worth emphasizing that all diagnostics and management of ICP during pregnancy are based on BA levels. Therefore, it is important to standardize the criteria for diagnosis, as well as recommendations for management depending on the level of BAs, which undoubtedly determines the impact on the fetus. The purpose of this review is to present the potential and importance of BAs in the detection and rules of medical procedure in ICP.

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“…Gestational cholestasis was related to increased risks of pregnancy complications, such as gestational diabetes mellitus, later‐life cardiovascular diseases, later‐life autoimmune‐mediated conditions and later‐life biliary tree cancer 2,3 . Additionally, many of the findings in humans and animals showed that gestational cholestasis can lead to severe adverse fetal events, including spontaneous and iatrogenic preterm delivery, stillbirth, fetal death, and even neonatal death 4,5 . Numerous epidemiological studies suggested that adverse fetal events caused by gestational cholestasis were associated with elevated serum TBA levels 6–8 .…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Additionally, many of the findings in humans and animals showed that gestational cholestasis can lead to severe adverse fetal events, including spontaneous and iatrogenic preterm delivery, stillbirth, fetal death, and even neonatal death. 4,5 Numerous epidemiological studies suggested that adverse fetal events caused by gestational cholestasis were associated with elevated serum TBA levels. [6][7][8] Cholic acid (CA), a major primary bile acid, is the principal toxic bile acid species.…”

Section: Introductionmentioning

confidence: 99%

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species‐mediated activation of placental GCN2/eIF2α pathway

Lin

et al. 2023

The FASEB Journal

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Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA).Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown-rump length, and increased the incidence of FGR in a dose-dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down-regulating the protein but not the mRNA level of placental 11β-Hydroxysteroid dehydrogenase-2 (11β-HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA-induced down-regulation of 11β-HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA-induced placental barrier dysfunction by inhibiting activation of GCN2/ eIF2α pathway and subsequent down-regulation of 11β-HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA-induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS-mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding How to cite this article: Lin S, Ye M-Y, Fu Q-Y, et al. Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species-mediated activation of placental GCN2/eIF2α pathway. The

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Beyond stillbirth: association of intrahepatic cholestasis of pregnancy severity and adverse outcomes

Cited by 18 publications

References 30 publications

Intrahepatic cholestasis of pregnancy: Contemporary management

Intrahepatic cholestasis of pregnancy: Contemporary management

Bile Acids in Intrahepatic Cholestasis of Pregnancy

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species‐mediated activation of placental GCN2/eIF2α pathway

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