Objective
The purpose of this study was to evaluate the fetal mechanical PR interval in intrahepatic cholestasis of pregnancy (ICP).
Study Design
Fetal echocardiography was performed for women with ICP and control subjects. Clinical characteristics, total bile acids, and liver profile tests were compared between groups.
Results
Fourteen women with ICP and 7 control subjects were enrolled. Total bile acids (28.3 vs 6.2 μmol/L; P < .001), aspartate aminotransferase (53 vs 23 IU/L; P = .002), alanine aminotransferase (63 vs 19 IU/L; P = .002), and the PR interval (124 vs 110 msec; P = .006) were significantly higher in fetuses with ICP than in control fetuses. On multivariable linear regression analysis, only the presence of ICP was associated significantly with an increase in the PR interval (95% confidence interval, 4–24 msec; P = .01).
Conclusion
The fetal cardiac conduction system is altered in ICP. Further investigation is needed to determine whether fetal echocardiography can help to predict which fetuses are at risk for death that is associated with ICP.
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease unique to pregnancy, which is characterized by pruritus in conjunction with elevations in the serum total bile acid (TBA) concentration, abnormalities in liver function tests, or both.
ICP is associated with adverse obstetric outcomes (eg, preterm birth, meconium passage, postpartum hemorrhage, and asphyxial events). Most notable is the risk for fetal death, which has been reported to affect 2-4% of ICP pregnancies. Although the exact mechanism of fetal death that is associated with ICP is unknown, there is evidence to suggest that it may be related to a fetal cardiac event. A series of in vitro murine studies by Williamson et al assessed the effect of bile acids on cardiomyocytes. Taurocholate, a bile acid when added to the culture, resulted in loss of cardiomyocyte contractile function. Recovery of function was noted when the cardiomyocytes were removed from the taurocholate medium. This effect was dose-dependent, with increased loss of the cell integrity as the concentration of taurocholate was increased. In another in vitro murine model, taurocholate had an arrhythmogenic effect on cardiomyocytes. In humans with ICP, there is a disproportionally increased concentration of taurocholate in maternal serum. It is hypothesized that these bile acids are passed from the mother to the fetus; therefore, the mechanism of fetal death in ICP may be through a fetal cardiac event that is caused by the effect of bile acids on the fetal cardiac conduction system.
In adult populations, the PR interval has been identified as a potential marker for the development of arrhythmias, which include atrial fibrillation, heart block, and tachyarrhythmias. Prolongation of the PR interval has been associated with an increased interatrial and intraatrial conduction time and a higher late diastolic threshold, which may increase the risk for tachyarrhythmias. Data from the Framingham Heart Study demonstrated that individuals with a prolonged PR interval carry an increased risk of the development of atrial fibrillation, a need for a pacemaker, and overall death. Doppler interrogation of the PR interval in the human fetus is feasible, and its measurement has been validated in normal populations. Furthermore, in fetuses of mothers with SS-A antibody positivity, the PR interval has been measured in utero to assess for first-degree heart block, which may progress to complete heart block.
The purpose of this pilot study was to determine whether the fetal mechanical PR interval is altered in ICP.
Materials and Methods
This study was approved by the Institutional Review Board at Los Angeles County and University of Southern California Medical Center. Pregnant patients were recruited from the Los Angeles County and University of Southern California Obstetric Clinic from September 2006 to December 2009. Patients were recruited if their treating physician suspected ICP based on the symptom of generalized pruritus without a rash. For the purpose of the study, ICP was diagnosed when a patient had the combination of the aforementioned pruritus and a serum TBA concentration >10 μmol/L. Control subjects consisted of those women with pruritus who had a TBA concentration <10 μmol/L and of additional recruited healthy pregnant patients who never complained of pruritus and had a TBA concentration <10 μmol/L. After informed consent was obtained, all patients and control subjects had blood drawn for the measurement of serum TBA concentration, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and direct bilirubin. TBA levels were measured by tandem mass spectrometry (Quest Diagnostics, San Luis Obispo, CA). For both patients and control subjects, exclusion criteria consisted of known multiple gestation, pregestational liver disease, systemic lupus erythematosus, anti-SSA antibody positivity, age <18 years of age, and fetuses with a known cardiac anomaly or arrhythmia because of other identifiable causes. During the study period, women with ICP that was diagnosed at <37 weeks’ gestation were treated medically with ursodeoxycholic acid (300 mg 3 times daily) and, at the discretion of the providing physician, with an oral antihistamine (eg, diphenhydramine. Data analysis was based on the first set of serum studies, which was obtained before the initiation of pharmacotherapy for those women with ICP. Women with clinical ICP were delivered at 37 weeks’ gestation or at the time of diagnosis, if identified at >37 weeks’ gestation.
Gestational age was determined by last menstrual period, confirmed by ultrasound scanning. After enrollment, an echocardiogram confirmed the absence of structural cardiac anomalies or existing arrhythmia. Echocardiographic studies were performed with a 3.5-MHz transducer with 1 of 2 scanners (Philips SONOS 5500 and Philips iE33; Koninklijke Philips Electronics N.V., Eindhoven, The Netherlands). Doppler echocardiography was performed on the enrollees by a single sonographer (M.E.), who was blinded to the enrollment group. Pulsed Doppler signals were obtained over the junction of the anterior leaflet of the mitral valve and the left ventricular outflow tract at the apical 5-chamber view of the heart. The mechanical PR interval was measured from the onset of the mitral A wave to the onset of ventricular systole ( Figure 1 ).
