Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations

Abstract

Background & Aims: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of stillbirth. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in patients with ICP who were or were not treated with ursodeoxycholic acid (UDCA). Methods: Bile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCAtreated). Fetal electrocardiogram traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability (HRV) parameters were measured in 2 behavioral states (quiet and active sleep). Results: In untreated ICP, fetal total serum bile acid (TSBA) concentrations (r = 0.49, p = 0.019), hydrophobicity index (r = 0.20, p = 0.039), glycocholate concentrations (r = 0.56, p = 0.007) and taurocholate concentrations (r = 0.44, p = 0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r = 0.40, p = 0.026) and alanine aminotransferase (r = 0.40, p = 0.046) also positively correlated with fetal NT-proBNP. There were no significant correlations between maternal or fetal serum bile acid concentrations and fetal HRV parameters or NT-proBNP concentrations in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r = 0.46, p = 0.027) and UDCA-treated ICP (r = 0.54, p = 0.026). Measures of HRV in active sleep and quiet sleep were significantly higher in untreated ICP cases than controls. HRV values in UDCA-treated cases did not differ from controls. Conclusions: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterized by increased NT-proBNP concentration, PR interval length and HRV. UDCA treatment partially attenuates this phenotype. Lay summary: The risk of stillbirth in intrahepatic cholestasis of pregnancy (ICP) is linked to the level of bile acids in the mother which are thought to disrupt the baby's heart rhythm. We found that babies of women with untreated ICP have abnormally functioning hearts compared to those without ICP, and the degree of abnormality is closely linked to the level of harmful bile acids in the mother and baby's blood. Babies of women with ICP who received treatment with the drug UDCA do not have the same level of abnormality in their hearts, suggesting that UDCA could be a beneficial treatment in some ICP cases, although further clinical trials are needed to confirm this.

Ursodeoxycholic Acid in Intrahepatic Cholestasis of Pregnancy: A Systematic Review and Individual Participant Data Meta-analysis

“…12 There is experimental evidence that ursodeoxycholic acid treatment reduces the impact of pathological processes that are implicated in the causes of stillbirth in women with intrahepatic cholestasis of pregnancy, such as placental vasospasm 24 and fetal arrhythmia (abnormal heart rate variability and the elevation of umbilical venous N-terminal pro-brain natriuretic peptide are associated with elevated maternal and fetal bile acid concentrations). 25,26 However, clinical trials powered to detect alterations in stillbirth rates would require participant numbers that are likely to be unfeasible given the disease prevalence. 27 We therefore aimed to use data from existing literature to examine whether ursodeoxycholic acid affects adverse perinatal outcomes, predominantly stillbirth and preterm birth.…”

ENDOCRINOLOGY IN PREGNANCY: Metabolic impact of bile acids in gestation

“…Activation of TGR5 by bile acids, or other agonists such as progesterone sulfates, may also play a role in the pruritus associated with ICP (87,93,94). As well as maternal effects, bile acids have been directly implicated in fetal arrhythmias, with fetal PR interval elongation and abnormal calcium dynamics reported (95,96,97,98). FXR function has also been linked to the pathophysiology of ICP.…”

Intrahepatic cholestasis in pregnancy: Increased surveillance and the role of bile acids in a patient with history of fetal demise

“…During pregnancy, serum bile acids within the fetus are slightly higher than those in the maternal circulation where they are ultimately transferred for excretion [6]. In ICP, the feto-maternal concentration gradient is reversed and is known to increase risk of fetal complications such as stillbirth, spontaneous preterm birth, and vasospasms leading to abnormal electrocardiogram (ECG) findings [7]. In particular, it has been shown that fetal cardiomyocytes have increased susceptibility to and incidence of tachycardia, bradycardia, atrial flutter, and supraventricular tachycardia when exposed to elevated bile acids [8].…”