INTRODUCTION
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent liver disease seen only in pregnancy and it affects approximately 0.1–2% of pregnant women [1]. Intrahepatic cholestasis of pregnancy presents mainly with maternal pruritus, increased serum bile acids (BA) and liver dysfunction usually in the third trimester [2, 3]. Enterohepatic circulation of BA ceases and serum BA concentration increases in ICP [4]. Although maternal symptoms resolve after delivery, there are studies in the literature that these affected women are at risk for hepatobiliary disease in later life [5]. Fetal risks such as preterm delivery, fetal hypoxia, meconium-stained amniotic fluid and sudden intrauterine fetal loss increased in pregnant women with ICP [6, 7] and these increased fetal risks are found to be associated with higher BA levels [8].
Ursodeoxycholic acid (UDCA) is a natural bile acid that is found in humans and is usually used to treat hepatobiliary diseases. It is also the most recommended agent in the world for ICP disease [9]. It improves cholestasis by several mechanisms. It increases biliary BA excretion, stimulates hepatocellular secretion, stabilizes plasma membranes and protects cholangiocytes and hepatocytes from cytotoxicity of bile acids [10]. Although UDCA is the most used agent for ICP treatment worldwide, its benefit on fetal outcome is unclear. A Cochrane systematic review of the effectiveness of UDCA for ICP disease concluded that it improves maternal symptoms mildly, however evidence for fetal adverse outcomes was not shown with certainty [11].
In the literature there is insufficient data on fetal and fetomaternal circulation and Doppler ultrasonography (USG) parameters in pregnant women complicated with ICP and the effect of UDCA treatment on these parameters. In this study we aimed to evaluate umbilical artery (UA), uterine arteries (UtA) and middle cerebral artery (MCA) Doppler parameters in pregnant women with ICP and compare these parameters with pregnant women without disease, and to determine the effect of UDCA treatment on these Doppler parameters in pregnant women with ICP.
MATERIAL AND METHODS
This prospective cohort study was performed at Dr. Sami Ulus Women’s and Children’s Health Teaching and Research Hospital, in Türkiye between September 2022 and February 2023. This study was approved by the local Ethical Committee of the Hospital (Ethics Number: E-22/09-411). The universal principles of the Helsinki Declaration were applied and informed consent was obtained from all participants. Pregnant women with a diagnosis of ICP and consecutive pregnant women without disease during the same period were recruited for the study.
Intrahepatic cholestasis of pregnancy was diagnosed when a pregnant woman had unexplained pruritus without skin lesions and with increased serum BA (≥ 10 mmol/L) and/or elevated liver function tests. For all study populations with abnormal liver function test results, viral marker measurements and liver ultrasonography were done for exclusion of other hepatotobiliary diseases such as biliary obstruction, gallstones or hepatitis. Pregnant women with other causes of liver disease were excluded from the study. Pregnant women with chronic systemic disease, multiple gestation and fetuses with malformation or diagnosis of intrauterine growth retardation (defined as estimated fetal weight < 10th percentile and/or abdominal circumference < 10th percentile) and pregnant women with obstetric complications (e.g., preeclampsia, premature rupture of membranes, gestational diabetes mellitus) were also excluded from the study.
Demographic and the laboratory data of pregnant women in study population were recorded at first evaluation. Gestational age was determined according to the first day of the last menstrual period (LMP) and measurement of the crown–rump length (CRL) at first trimester. If there was a difference of more than seven days between them, ultrasound dating was taken as gestational age [12]. All pregnant women in study population were followed to delivery and obstetric outcome in terms of gestational week at delivery, birth weight (BW), and Neonatal Intensive Care Unit (NICU) admission was recorded. UDCA (2 × 300 mg daily) was given to all women in the study group when ICP was diagnosed.
The same perinatologist performed Doppler measurements using a Mindray DC-40 ultrasound device for all pregnant women in the study group. The systole/diastole (S/D) ratio, pulsatility index (PI), and resistance index (RI) were measured for UA, right and left UtAs, MCA and peak systolic velocity (PSV) for MCA with Doppler USG. UA measurement was done on the free loop between the fetal and placental ends of the cord. UtA measurements were performed bilaterally where it originates from iliac artery at isthmus level. Middle Cerebral Artery Doppler measurement was done with visualizing the circle of Willis on the axial section of the brain and one of the MCAs was used for the study. The insonation angle was tried to keep to zero degrees as possible and 30 degrees were not exceeded. Cerebro-placental ratio (CPR) was defined by dividing the MCA PI by the UA PI. Measurements were done during fetal inactivity and in the absence of fetal breathing and uterine contraction. Doppler measurements were done in the control group and prior to UDCA treatment at first diagnosis of the disease and after 48–72 hours of treatment in the ICP group.
RESULTS
Totally 60 pregnant women (30 with ICP disease and 30 without disease) were recruited to the study. Demographic parameters were found to be similar between the groups. Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly higher in the ICP group. The serum mean BA level was 38.75 ± 25.70 in the ICP group at diagnosis. Demographic and laboratory parameters of study population are shown in Table 1.
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Table 1. Comparison of demographic and laboratory findings of study groups |
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|
Variables |
Control group (n = 30) |
ICP group (n = 30) |
p value |
|
Age [years] |
27.93 ± 5.25 |
28.40 ± 5.03 |
0.727 |
|
GW at assessment |
34.87 ± 2.92 |
33.39 ± 3.05 |
0.060 |
|
Gravidity |
2.0 (1.0–6.0) |
2.0 (1.0–6.0) |
0.195 |
|
Parity |
0.0 (0.0–2.0) |
0.0 (0.0–4.0) |
0.186 |
|
BMI [kg/m2] |
27.5 ± 5.24 |
28.7 ± 4.53 |
0.35 |
|
ALT [U/L] |
13.0 (8.0–43.0) |
95.5 (16.0–374.0) |
< 0.0001 |
|
AST [U/L] |
17.0 (12.0–76.0) |
67.5 (15.0–232.0) |
< 0.0001 |
|
Hemoglobin [g/dL] |
11.52 ± 1.01 |
11.59 ± 1.16 |
0.801 |
|
WBC × 103 mL |
10.41 ± 3.01 |
10.72 ± 3.64 |
0.720 |
|
Platelets × 103 mL |
223.60 ± 63.19 |
253.13 ± 66.52 |
0.083 |
|
Fasting TBA [mmol/L] |
– |
38.75 ± 25.70 |
– |
|
GW at delivery |
38.8 (35.0–41.0) |
36.0 (32.0–38.0) |
< 0.0001 |
|
Birth weight [g] |
3410.66 ± 504.84 |
2982.50 ± 455.96 |
0.001 |
|
NICU admission; n [%] No Yes |
26 (86.7%) 4 (13.3%) |
25 (83.3%) 5 (16.7%) |
0.718 |
|
ALT — alanine aminotransferase; AST — aspartate aminotransferase; BMI — body mass index; GW — gestational week; ICP — intrahepatic cholestasis of pregnancy; NICU — Neonatal Intensive Care Unit; p < 0.05 was considered statistically significant; TBA — total bile acid; WBC — white blood cell |
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In our study group no intrauterine fetal loss was observed. BW and gestational week at delivery were lower in the ICP group when compared with the control group. Neonatal Intensive Care Unit admission rate was similar between the groups. The obstetric outcome of the pregnant women with ICP and healthy pregnant women are also presented in Table 1.
There was no statistically significant difference in the S/D ratio, PI and RI values of the UA, MCA and right and left UtAs Doppler between pregnant women with ICP and the control group. CPR values were also similar between the groups. The obstetric Doppler measurements of the pregnant women with and without ICP are presented in Table 2.
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Table 2. Comparison of Doppler index values in intrahepatic cholestasis of pregnancy (ICP) and control groups |
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|
Doppler parameters |
Control group (n = 30) |
ICP group (n = 30) |
p value |
|
UA-S/D |
2.34 ± 0.48 |
2.48 ± 0.48 |
0.264 |
|
UA-PI |
0.85 ± 0.24 |
0.92 ± 0.17 |
0.205 |
|
MCA-S/D |
3.46 ± 0.46 |
3.24 ± 0.52 |
0.097 |
|
MCA-PSV |
39.30 ± 10.04 |
41.36 ± 9.01 |
0.407 |
|
MCA-PI |
1.86 ± 0.47 |
1.85 ± 0.51 |
0.948 |
|
CPR |
2.28 (1.29–3.7) |
2.11 (0.74–3.90) |
0.395 |
|
Right UtA-PI |
0.67 (0.40–1.20) |
0.66 (0.33–1.60) |
0.848 |
|
Left UtA-PI |
0.64 (0.37–1.14) |
0,66 (0.32–1.60) |
0.787 |
|
UA — umbilical artery; S/D — systole/diastole; MCA — middle cerebral artery; PSV — peak systolic velocity; CPR — cerebro-placental ratio; PI — pulsatility index; RI — resistance index; UtA — uterine artery; p < 0.05 was considered statistically significant |
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The obstetric Doppler parameters before and after treatment with UDCA in the ICP group are shown in Table 3. There was no significant difference in Doppler findings for the ICP group before and after treatment with UDCA.
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Table 3. Comparison of Doppler index values before and after treatment in intrahepatic cholestasis of pregnancy (ICP) group |
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|
Doppler parameters |
Before treatment (n = 30) |
After treatment (48 hours) (n = 30) |
p value |
|
UA-S/D |
2.47 (1.73–3.50) |
2.41(1.80–3.00) |
0.34 |
|
UA-PI |
0.90 (0.61–1.35) |
0.92 (0.68–1.40) |
0.94 |
|
MCA-S/D |
3.35 (1.98–4.20) |
3.00 (1.80–3.90) |
0.358 |
|
MCA-PSV |
41.36 ± 9.01 |
42.02 ± 8.66 |
0.077 |
|
MCA-PI |
1.85 ± 0.51 |
1.87 ± 0.43 |
0.05 |
|
CPR |
2.10 ± 0.72 |
2.18 ± 0.64 |
0.36 |
|
Right UtA-PI |
0.66 (0.33–1.60) |
0.67 (0.44–1.40) |
0.87 |
|
Left UtA-PI |
0.66 (0.32–1.60) |
0.61 (0.44–1.40) |
0.16 |
|
CPR — cerebro-placental ratio; MCA — middle cerebral artery; p < 0.05 was considered statistically significant; PI — pulsatility index; PSV — peak systolic velocity; RI — resistance index; S/D — systole/diastole; UA — umbilical artery; UtA — uterine artery |
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DISCUSSION
In this study, we evaluated fetal and maternal circulation with routine Doppler USG parameters in pregnant women with ICP disease and compared the results with pregnant women without disease, and we also aimed to evaluate the effect of UDCA treatment on these parameters. We found that fetomaternal Doppler parameters were similar between pregnant women complicated with ICP and without disease and UDCA had no effect on these parameters.
Intrahepatic cholestasis of pregnancy is a benign and temporary disease for pregnant women and after birth the symptoms resolve, and prognosis is excellent. However, ICP disease is associated with significant fetal risks such as preterm delivery, meconium-stained amniotic fluid, sudden intrauterine fetal demise and NICU admission and fetal complications are found to be more common with higher BA concentrations [13, 14]. In a recent Swedish cohort study, preterm labor and fetal asphyxia were found to be significantly increased when maternal serum BA concentrations were more than 40 μmol/L [8] and a UK cohort study also supported these findings that increased stillbirths were only increased in pregnant women with ICP when bile acids increased more than 40 μmol/L [15]. The long-term outcome of these children is not well known, and data is insufficient in the literature [16].
Increased bile acids and their toxic metabolites are thought to be a reason for increased fetal morbidity associated with ICP. In animal studies it was shown that bile acids might have toxic effects on myometrium and placenta. In an animal study, Williamson et al. [17] reported that elevated serum taurocholate might cause fetal dysrhythmia by impairing cardiac conduction and destroy synchronous contraction by altering the function of gap junctions in cardiomyocytes. In another animal study it was found that tauro-conjugated cholic acid administration to adult and neonatal rat cardiomyocytes caused arrhythmias and abnormal contraction and neonatal rat cardiomyocytes were found to be more sensitive than adult cardiomyocytes [18].
Although in the literature it is known that ICP is associated with increased fetal risks, there are limited studies and data is conflicting about obstetric Doppler findings in pregnant women with ICP. Guerra et al. [19] found that obstetric Doppler patterns were similar in pregnant women with a diagnosis of ICP. Suri et al. [20] showed that a S/D ratio above 2 SD was significantly higher in pregnancies with ICP compared with gestation matched reference values of the umbilical artery of a normal healthy pregnant population, however adverse fetal outcome was not associated with Doppler findings. Kurtulmuş et al. [21] found that UA and MCA Doppler S/D ratio, PI, and RI in pregnant women with ICP were not different when compared with healthy pregnant women. In our study there was no statistically significant difference between Doppler findings in the ICP group and the control group. CPR was found to be similar between groups. To our knowledge, this is the first study that evaluated CPR in pregnant women with ICP disease.
Different pharmacological agents, such as UDCA, cholestyramine, dexamethasone, s-adenosylmethionine and, most recently, rifampicin have been used for pregnant women with ICP diagnosis [7]. Although the effectiveness of these agents has not been shown with evidence-based studies, UDCA is the most frequently suggested agent in the treatment of ICP in most guidelines. UDCA is thought to remove more hydrophobic endogenous bile salts from the BA pool, protects hepatocyte membranes from bile acid toxicity, and causes BA clearance from the placenta [22]. There are a few studies on UDCA effects on neonatal outcome in ICP disease in the literature. In a recent placebo controlled RCT, Chappell et al. [23] found that UDCA treatment showed a small reduction in pruritus in pregnant women with ICP of any severity, but no effect on adverse perinatal outcomes that included intrauterine fetal demise, preterm delivery and NICU admission. In a systematic review of the Cochrane library, the authors reported that UDCA treatment may cause a decrease in pruritus to a small extent in pregnant women with ICP, however definitive evidence for improvement in perinatal outcomes was not found and further large-scale trials are needed to determine fetal risks or benefits [11].
Although in clinical studies the impact of UDCA treatment on adverse fetal outcomes has not been demonstrated clearly, in an in vitro study UDCA was shown to protect rat cardiomyocytes from damage due to BAs [24]. Vasavan et al. [25] found an increased fetal NT-proBNP concentration, which is used as a marker for ventricular dysfunction in untreated ICP disease when compared with normal healthy pregnant women and pregnant women with treated ICP disease and they suggested that the cardiac phenotype of ICP fetuses showed arrhythmic activity and that UDCA may have cardioprotective effects on the fetus.
In this study we evaluated UDCA treatment effects on maternal and fetal Doppler parameters and found that Doppler parameters were not affected at 48 hours after UDCA treatment. The influence of UDCA treatment on fetal Doppler parameters has not previously been studied and this is the first study that evaluated UDCA treatment effects on fetal and maternal Doppler parameters. We found lower BW and gestational week at birth in pregnant women with ICP compared to healthy pregnant women, similar to the literature, due to our policy of early timing of birth in these pregnant women. Stillbirth or neonatal death was not observed in each group. Neonatal Intensive Care Unit admission rate was similar between the groups.
CONCLUSIONS
In conclusion, the pathogenesis of increased fetal morbidity and especially sudden intrauterine fetal demise in ICP is not fully understood. In this study we aimed to evaluate Doppler USG parameters of fetomaternal circulation in pregnant with ICP to understand the fetal pathophysiology associated with disease and we found that Doppler results were similar in the ICP group and healthy group so it is not useful in monitoring fetal health in pregnant with ICP. We also showed that UDCA treatment had no effect on these parameters in the short term. However further multicenter prospective studies with larger patient series are needed to evaluate fetomaternal circulation in ICP disease and the effect of UDCA treatment in both short and long term on fetomaternal Doppler parameters in pregnant with ICP to confirm our results.
Article information and declarations
Data availability statement
Data used in this study can be provided on reasonable request.
Ethics statement
This study was approved by the local Ethical Committee of our Hospital (Ethics Number: E-22/09-411).
Author contributions
Zehra Vural Yilmaz: first author, conception and design the study, analyses and interpretation of data, drafting of the manuscript.
Oguz Ozdemir: acquisition of data, analysis and interpretation of data.
Gozde Yasemin Kurt: acquisition of data, drafting the manuscript.
Caganay Soysal: conception and design of the study, supervision.
Elif Yilmaz: statistical analysis, critical revision of the manuscript for important intellectual content.
Funding
None.
Acknowledgments
None.
Conflict of interest
Authors declare no conflict of interest.
Supplementary material
None.
