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

Tharni Vasavan; Sahil Deepak; Indu Asanka Jayawardane; Maristella Lucchini; Catherine Martin; Victoria Geenes; Joel Yang; Anita Lövgren-Sandblom; Paul Townsend Seed; Jenny Chambers; Sophia Stone; Lesia Kurlak; Peter Hendy Dixon; Hanns-Ulrich Marschall; Julia Gorelik; Lucy Chappell; Pam Loughna; Jim Thornton; Fiona Broughton Pipkin; Barrie Hayes-Gill; William Paul Fifer; Catherine Williamson

doi:10.1016/j.jhep.2020.11.038

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

Tharni Vasavan, Sahil Deepak, Indu Asanka Jayawardane, Maristella Lucchini, Catherine Martin, Victoria Geenes, Joel Yang, Anita Lövgren-Sandblom, Paul Townsend Seed, Jenny Chambers, Sophia Stone, Lesia Kurlak, Peter Hendy Dixon, Hanns-Ulrich Marschall, Julia Gorelik, Lucy Chappell, Pam Loughna, Jim Thornton, Fiona Broughton Pipkin, Barrie Hayes-GillWilliam Paul Fifer, Catherine Williamson

Women & Children's Health

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is associated with increased stillbirth risk. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in ICP with or without ursodeoxycholic acid (UDCA) treatment.

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 UDCA-treated). Fetal ECG traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability parameters (RMSSD, SDNN) were measured in two behavioural states (quiet and active sleep). Partial correlation coefficients (r) and median [IQR] are reported.

RESULTS: In untreated ICP, fetal total serum bile acids (TSBA, r=0.49, p=0.019), their hydrophobicity index (r=0.20, p=0.039), glycocholate (r=0.56, p=0.007) and taurocholate (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. No significant correlations to NT-proBNP were observed 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). Fetal RMSSD in active sleep (9.6 [8.8,11.3] vs. 8.7 [7.6,9.6] ms, p=0.028) and SDNN in quiet sleep (11.0 [9.5,14.9] vs. 7.9 [5.1,9.7] ms, p=0.013) and active sleep (25.4 [21.0,32.4] vs. 18.2 [14.7,25.7] ms, p=0.003) were significantly higher in untreated ICP cases than controls. Heart rate variability values in UDCA-treated cases did not differ to controls.

CONCLUSIONS: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterised by increased NT-proBNP concentration, PR interval length and heart rate variability. UDCA treatment partially attenuates this phenotype.

Original language	English
Pages (from-to)	1-10
Journal	Journal of Hepatology
Volume	0
Issue number	0
Early online date	1 Dec 2020
DOIs	https://doi.org/10.1016/j.jhep.2020.11.038
Publication status	E-pub ahead of print - 1 Dec 2020

Keywords

Pregnancy
female
ursodeoxycholic acid
intrahepatic cholestasis of pregnancy
cholic acid
stillbirth
heart rate
bile
ventricular dysfunction

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Vasavan, T., Deepak, S., Jayawardane, I. A., Lucchini, M., Martin, C., Geenes, V., Yang, J., Lövgren-Sandblom, A., Seed, P. T., Chambers, J., Stone, S., Kurlak, L., Dixon, P. H., Marschall, H.-U., Gorelik, J., Chappell, L., Loughna, P., Thornton, J., Pipkin, F. B., ... Williamson, C. (2020). Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations. Journal of Hepatology, 0(0), 1-10. Advance online publication. https://doi.org/10.1016/j.jhep.2020.11.038

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

abstract = "BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is associated with increased stillbirth risk. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in ICP with or without ursodeoxycholic acid (UDCA) treatment.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 UDCA-treated). Fetal ECG traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability parameters (RMSSD, SDNN) were measured in two behavioural states (quiet and active sleep). Partial correlation coefficients (r) and median [IQR] are reported.RESULTS: In untreated ICP, fetal total serum bile acids (TSBA, r=0.49, p=0.019), their hydrophobicity index (r=0.20, p=0.039), glycocholate (r=0.56, p=0.007) and taurocholate (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. No significant correlations to NT-proBNP were observed 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). Fetal RMSSD in active sleep (9.6 [8.8,11.3] vs. 8.7 [7.6,9.6] ms, p=0.028) and SDNN in quiet sleep (11.0 [9.5,14.9] vs. 7.9 [5.1,9.7] ms, p=0.013) and active sleep (25.4 [21.0,32.4] vs. 18.2 [14.7,25.7] ms, p=0.003) were significantly higher in untreated ICP cases than controls. Heart rate variability values in UDCA-treated cases did not differ to controls.CONCLUSIONS: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterised by increased NT-proBNP concentration, PR interval length and heart rate variability. UDCA treatment partially attenuates this phenotype.",

keywords = "Pregnancy, female, ursodeoxycholic acid, intrahepatic cholestasis of pregnancy, cholic acid, stillbirth, heart rate, bile, ventricular dysfunction",

author = "Tharni Vasavan and Sahil Deepak and Jayawardane, {Indu Asanka} and Maristella Lucchini and Catherine Martin and Victoria Geenes and Joel Yang and Anita L{\"o}vgren-Sandblom and Seed, {Paul Townsend} and Jenny Chambers and Sophia Stone and Lesia Kurlak and Dixon, {Peter Hendy} and Hanns-Ulrich Marschall and Julia Gorelik and Lucy Chappell and Pam Loughna and Jim Thornton and Pipkin, {Fiona Broughton} and Barrie Hayes-Gill and Fifer, {William Paul} and Catherine Williamson",

note = "Copyright {\textcopyright} 2020. Published by Elsevier B.V.",

year = "2020",

month = dec,

day = "1",

doi = "10.1016/j.jhep.2020.11.038",

language = "English",

volume = "0",

pages = "1--10",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "0",

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Vasavan, T, Deepak, S, Jayawardane, IA, Lucchini, M, Martin, C, Geenes, V, Yang, J, Lövgren-Sandblom, A, Seed, PT, Chambers, J, Stone, S, Kurlak, L, Dixon, PH, Marschall, H-U, Gorelik, J, Chappell, L, Loughna, P, Thornton, J, Pipkin, FB, Hayes-Gill, B, Fifer, WP & Williamson, C 2020, 'Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations', Journal of Hepatology, vol. 0, no. 0, pp. 1-10. https://doi.org/10.1016/j.jhep.2020.11.038

TY - JOUR

T1 - Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations

AU - Vasavan, Tharni

AU - Deepak, Sahil

AU - Jayawardane, Indu Asanka

AU - Lucchini, Maristella

AU - Martin, Catherine

AU - Geenes, Victoria

AU - Yang, Joel

AU - Lövgren-Sandblom, Anita

AU - Seed, Paul Townsend

AU - Chambers, Jenny

AU - Stone, Sophia

AU - Kurlak, Lesia

AU - Dixon, Peter Hendy

AU - Marschall, Hanns-Ulrich

AU - Gorelik, Julia

AU - Chappell, Lucy

AU - Loughna, Pam

AU - Thornton, Jim

AU - Pipkin, Fiona Broughton

AU - Hayes-Gill, Barrie

AU - Fifer, William Paul

AU - Williamson, Catherine

PY - 2020/12/1

Y1 - 2020/12/1

N2 - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is associated with increased stillbirth risk. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in ICP with or without ursodeoxycholic acid (UDCA) treatment.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 UDCA-treated). Fetal ECG traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability parameters (RMSSD, SDNN) were measured in two behavioural states (quiet and active sleep). Partial correlation coefficients (r) and median [IQR] are reported.RESULTS: In untreated ICP, fetal total serum bile acids (TSBA, r=0.49, p=0.019), their hydrophobicity index (r=0.20, p=0.039), glycocholate (r=0.56, p=0.007) and taurocholate (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. No significant correlations to NT-proBNP were observed 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). Fetal RMSSD in active sleep (9.6 [8.8,11.3] vs. 8.7 [7.6,9.6] ms, p=0.028) and SDNN in quiet sleep (11.0 [9.5,14.9] vs. 7.9 [5.1,9.7] ms, p=0.013) and active sleep (25.4 [21.0,32.4] vs. 18.2 [14.7,25.7] ms, p=0.003) were significantly higher in untreated ICP cases than controls. Heart rate variability values in UDCA-treated cases did not differ to controls.CONCLUSIONS: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterised by increased NT-proBNP concentration, PR interval length and heart rate variability. UDCA treatment partially attenuates this phenotype.

AB - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is associated with increased stillbirth risk. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in ICP with or without ursodeoxycholic acid (UDCA) treatment.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 UDCA-treated). Fetal ECG traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability parameters (RMSSD, SDNN) were measured in two behavioural states (quiet and active sleep). Partial correlation coefficients (r) and median [IQR] are reported.RESULTS: In untreated ICP, fetal total serum bile acids (TSBA, r=0.49, p=0.019), their hydrophobicity index (r=0.20, p=0.039), glycocholate (r=0.56, p=0.007) and taurocholate (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. No significant correlations to NT-proBNP were observed 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). Fetal RMSSD in active sleep (9.6 [8.8,11.3] vs. 8.7 [7.6,9.6] ms, p=0.028) and SDNN in quiet sleep (11.0 [9.5,14.9] vs. 7.9 [5.1,9.7] ms, p=0.013) and active sleep (25.4 [21.0,32.4] vs. 18.2 [14.7,25.7] ms, p=0.003) were significantly higher in untreated ICP cases than controls. Heart rate variability values in UDCA-treated cases did not differ to controls.CONCLUSIONS: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterised by increased NT-proBNP concentration, PR interval length and heart rate variability. UDCA treatment partially attenuates this phenotype.

KW - Pregnancy

KW - female

KW - ursodeoxycholic acid

KW - intrahepatic cholestasis of pregnancy

KW - cholic acid

KW - stillbirth

KW - heart rate

KW - bile

KW - ventricular dysfunction

U2 - 10.1016/j.jhep.2020.11.038

DO - 10.1016/j.jhep.2020.11.038

M3 - Article

C2 - 33276032

SN - 0168-8278

VL - 0

SP - 1

EP - 10

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 0

ER -

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

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Keywords

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