Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12‐year population‐based cohort study

Shemer, Elisabeth Wikström; Marschall, Hanns‐Ulrich; Ludvigsson, Jonas F.; Stephansson, Olof

doi:10.1111/1471-0528.12174

Cited by 222 publications

(131 citation statements)

References 31 publications

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“…Although the medical birth and patient registers are nationwide and are thus likely to have a high sensitivity for specific diagnoses such as ICP, we cannot rule out that a small number of women with ICP were not diagnosed with ICP. Given that ICP in Sweden has an overall prevalence of 1.5%, the existence of a small number of false‐negative ICP women among our controls, however, is unlikely to have affected our risk estimates more than marginally and if so should have pushed the risk estimates towards 1.…”

Section: Discussionmentioning

confidence: 98%

“…Pruritus in ICP spontaneously resolves and deranged liver function tests typically normalize within 4 weeks after delivery. Thus, ICP is usually a self‐limiting, benign condition for the mother, although the fetus is at increased risk of adverse outcome, in particular preterm delivery . In a small number of women with ICP, liver function does not return to normal, suggesting an underlying hepatobiliary disease that needs further diagnostic testing .…”

mentioning

confidence: 99%

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Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population-based cohort study

et al. 2013

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Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. We aimed to estimate the risk of developing hepatobiliary disease in women with ICP and the odds of developing ICP in women with prevalent hepatobiliary disease. We analyzed data of women with births between 1973 and 2009 and registered in the Swedish Medical Birth Register. By linkage with the Swedish Patient Register, we identified 11,388 women with ICP who were matched to 113,893 women without this diagnosis. Diagnoses of preexisting or later hepatobiliary disease were obtained from the Patient Register. Main outcome measures were hazard ratios (HRs) for later hepatobiliary disease in women with ICP and odds ratios (ORs) for developing ICP in preexisting hepatobiliary disease. Risk estimates were calculated through Cox and logistic regression analyses. Women with ICP were more often diagnosed with later hepatobiliary disease (HR 2.62; 95% confidence interval [CI] 2.47-2.77; increment at 1% per year), hepatitis C or chronic hepatitis (HR 4.16; 3.14-5.51 and 5.96; 3.43-10.33, respectively), fibrosis/ cirrhosis (HR 5.11; 3.29-7.96), gallstone disease or cholangitis (HR 2.72; 2.55-2.91, and 4.22; 3.13-5.69, respectively) as compared to women without ICP (P < 0.001 for all HRs). Later ICP was more common in women with prepregnancy hepatitis C (OR 5.76; 1.30-25.44; P 5 0.021), chronic hepatitis (OR 8.66; 1.05-71.48; P 5 0.045), and gallstone disease (OR 3.29; 2.02-5.36; P < 0.0001). Conclusion: Women with ICP have substantially increased risk for later hepatobiliary disease. Beyond gallstone-related morbidity we found a strong positive association between ICP and hepatitis C both before and after ICP diagnosis. Thus, we advocate testing for hepatitis C in women with ICP, in particular, since this potentially life-threatening infection can be treated successfully in the majority of patients. (HEPATOLOGY 2013;58:1385-1391 I ntrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, 1 with reported prevalence rates of between 0.4% and 1.5%.2,3 ICP is characterized by otherwise unexplained pruritus with elevated bile acids and/or transaminases in the late second and third trimester of pregnancy.2,3 Genetic predisposition (variants of hepatobiliary transport proteins), impaired turnover of reproductive hormones, and environmental factors play key roles in the etiology and pathogenesis of ICP. 2,3 By definition, ICP is a diagnosis of exclusion. Pruritus in ICP spontaneously resolves and deranged liver function tests typically normalize within 4 weeks after delivery. Thus, ICP is usually a self-limiting, benign condition for the mother, although the fetus is at increased risk of adverse outcome, in particular preterm delivery. 4,5 In a small number of women with ICP, liver function does not return to normal, suggesting an underlying hepatobiliary disease that needs further diagnostic testing.6 These women might have been misclassified as suffering from ICP only.Abbreviations: CI, confidence interva...

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population-based cohort study

et al. 2013

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“…ICP is observed in 0.5–2% of pregnancies in the United States, and carries with it an increased risk of fetal distress, spontaneous preterm delivery and stillbirth (Glantz et al , 2004; Geenes et al , 2014; Henderson et al , 2014; Williamson and Geenes, 2014). Likewise, women with ICP are more likely to have concomitant gestational diabetes or pre-eclampsia, and may be predisposed to develop subsequent liver disease, such as hepatitis C, fibrosis and gallstones (Marschall et al , 2013; Wikstrom Shemer et al , 2013). …”

Section: Introductionmentioning

confidence: 99%

Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064

Moscovitz

Kong

Buckley

et al. 2016

Toxicology and Applied Pharmacology

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The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis. The objective of this study was to determine whether short-term treatment of pregnant mice with GW4064 (a potent FXR agonist) restores Fxr signaling to the level observed in virgin mice. Plasma, liver and ilea were collected from virgin and pregnant mice administered vehicle or GW4064 by oral gavage. Treatment of pregnant mice with GW4064 induced ileal Fgf15, Shp and Ostα/β mRNAs, and restored hepatic Shp, Bal, Ntcp, and Bsep back to vehicle-treated virgin levels. Pregnant mice exhibited 2.5-fold increase in Cyp7a1 mRNA compared to virgin controls, which was reduced by GW4064. Similarly treatment of mouse primary hepatocytes with plasma isolated from pregnant mice induced Cyp7a1 mRNA by nearly 3-fold as compared to virgin plasma, which could be attenuated by co-treatment with either GW4064 or recombinant FGF19 protein. Collectively, these data reveal that repressed activity of intestinal and hepatic Fxr in pregnancy, as previously demonstrated, may be restored by pharmacological activation. This study provides the basis for a novel approach to restore bile acid homeostasis in patients with maternal cholestasis.

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“…In our case, the severity of bile acid elevation may be confounded by multiple factors including the patient's multifetal gestation, history of preeclampsia, the uncertain timeline of her acquisition of the hepatitis C virus, and the acute nature of the HCV infection. Specifically, Wikström Shemer et al have demonstrated an increased incidence of preeclampsia among pregnancies affected by ICP, with adjusted odds ratio 2.62 [11]. Additionally, a recent retrospective cohort study of 78 patients with ICP has revealed that severe ICP (total bile acid level greater than 40 micromol/L) is noted as a significant risk factor for preeclampsia in both singleton and twin pregnancies [12].…”

Section: Discussionmentioning

confidence: 99%

Intrahepatic Cholestasis of Pregnancy with Severe Elevation of Bile Acids in the Setting of Acute Hepatitis C Infection

Lawlor

Critchfield

2016

Case Reports in Obstetrics and Gynecology

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Intrahepatic cholestasis of pregnancy (ICP) is a complication of pregnancy resulting in elevation of serum bile acid levels. ICP is often associated with underlying liver disease, including hepatitis C. Bile acids in relationship to the acute infection of hepatitis C virus have not yet been delineated in the literature. A 26-year-old gravida 4 para 2103 with dichorionic, diamniotic twin gestation and history of intravenous drug abuse developed ICP in the setting of acute hepatitis C infection. In addition to clinical symptoms of pruritus and right upper quadrant pain, she developed severe elevation in bile acids, 239 micromol/L, and transaminitis aspartate aminotransferase 1033 U/L, and alanine aminotransferase 448 U/L. She received ursodeoxycholic acid and antenatal testing was performed. Patient delivered vaginally at 33-week gestation following preterm rupture of membranes. Neonates were admitted to NICU and had uncomplicated neonatal courses. In the setting of ICP with significant transaminitis and severe elevation of bile acids, consideration of acute viral hepatitis is important, especially considering the worsening opioid epidemic and concurrent increase in intravenous drug use in the United States. Further study is needed regarding the acute form of HCV infection and its effect on ICP and associated bile acids.

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Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12‐year population‐based cohort study

Cited by 222 publications

References 31 publications

Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population-based cohort study

Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population-based cohort study

Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064

Intrahepatic Cholestasis of Pregnancy with Severe Elevation of Bile Acids in the Setting of Acute Hepatitis C Infection

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