Abstract
Background & AimsIntrahepatic 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).MethodsBile 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 UDCA-treated). 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).ResultsIn 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.ConclusionsElevated 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 summaryThe 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.
Highlights
Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse pregnancy outcomes; when maternal total serum bile acid (TSBAs) concentrations were >−40 lmol/L the likelihood of spontaneous preterm birth, prolonged neonatal unit admission and fetal asphyxia were significantly increased in a prospective Swedish cohort, and stillbirth was increased in a UK cohort.[2,3]
Maternal and fetal serum bile acid concentrations and fetal bile acid hydrophobicity index (HI) are positively correlated with fetal NT-proBNP concentrations One-way analysis of variance (ANOVA) demonstrated significant differences in peak maternal and fetal TSBA concentrations, and fetal NT-proBNP concentrations at delivery between participant cohorts (Fig. 2A-C)
This study has demonstrated a fetal cardiac phenotype that is associated with severity of ICP in untreated pregnancies
Summary
Intrahepatic cholestasis of pregnancy (ICP), the most common gestational liver disease, is diagnosed in women with pruritus and elevated maternal total serum bile acid (TSBA) concentrations.[1,2] ICP is associated with adverse pregnancy outcomes; when maternal TSBA concentrations were >−40 lmol/L the likelihood of spontaneous preterm birth, prolonged neonatal unit admission and fetal asphyxia were significantly increased in a prospective Swedish cohort, and stillbirth was increased in a UK cohort.[2,3] More recently, the prevalence of stillbirth was shown to increase from 0.28% to 3.44% in singleton pregnancies with maternal TSBA concentrations of >−100 lmol/L; the prevalence of stillbirth in the control cohort of this study was found to be 0.31%.4The mechanism of ICP-associated stillbirth is unknown, with post-mortem findings indicating that infants are appropriately grown.[5]. 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. 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. Conclusions: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal
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