Predicting fetal outcome in intrahepatic cholestasis of pregnancy: Is the bile acid level sufficient?
Authors: Robert S. Egerman, Caroline A. Riely
Journal: Hepatology (2004)

Liver disorders during pregnancy range from those being a benign nuisance to others of catastrophic importance. While sailing comfortably through an uncomplicated pregnancy, the parturient, her fetus, and her care providers may unexpectedly find themselves facing an unforgiving tempest. This conundrum is exemplified by intrahepatic cholestasis of pregnancy (ICP), which starts with modest itching and can end in intrauterine fetal demise.1 ICP, intrahepatic cholestasis of pregnancy. The frequency of ICP among pregnancies in the United States is 0.1%. It is considerably higher in women from Scandinavia or Chile, where the prevalence is roughly 1% and 10%, respectively. Family history is an important risk factor, as is a personal history of hepatitis C.2 The diagnosis is typically based on clinical findings, although a number of perturbations in aminotransferases, bilirubin, and bile acids can be detected. In a study from Sweden in the current issue of HEPATOLOGY, Glantz et al. demonstrate a correlation between fetal complications and serum bile acid levels, but no association between maternal symptoms and levels of serum bile acids in these pregnancies.3 Indeed, ICP may be present in the absence of elevated bile acids.4 Adverse effects of ICP to the gravida include intractable pruritus and its associated fatigue and discomfort, and can also include coagulopathy and postpartum hemorrhage.5 The adverse effects of ICP on the fetus include increased risks of meconium stained amniotic fluid, preterm delivery, fetal distress and fetal death. The mechanisms behind such untoward events are unclear. Elevated sulfated progesterone compounds as well as impaired excretion of bile acids are found in pregnancies complicated by ICP.6, 7 Progesterone given to delay premature delivery has been associated with ICP.8 High levels of maternal bile acids produce abnormalities in placental transport, placental hormone production, chorionic vessel constriction and possibly fetal cardiac function.9-11 The authors of the Swedish study have shown a correlation between serum bile acid levels and obstetric complications in ICP. The serum bile acid test remains underutilized in cholestasis of any etiology. One reason for such underutilization is the delay in getting the results. A quick survey of two national clinical chemistry laboratories showed that the sample must be sent to a reference lab, where the determination is done either daily or three times a week. Thus, the result will be returned in as little as 2 or as many as 6 days. The authors of this study used cardiotocography or nonstress fetal heart rate monitoring to ascertain fetal well-being but found this test to be less helpful than the serum bile acid measurement. The usual tool to predict uteroplacental insufficiency and identify fetuses at risk for antepartum demise is fetal heart rate monitoring. However, antenatal testing, like adult cardiac assessment, involves more than one modality. The weekly fetal heart rate nonstress testing (used in this study) is the least sensitive test when compared to the fetal biophysical profile (a sonographic in utero physical examination) and the fetal heart rate contraction stress testing.12 To date, no ideal method of fetal surveillance has been determined for ICP,13 and fetal antenatal testing has had limited predictability in the setting of this disorder. Intended to recognize a failing placenta, fetal cardiac monitoring cannot forecast an acute event such as an umbilical cord entanglement or a sudden fetal cardiac decompensation or arrhythmia. Such disparity is highlighted in a case where reassuring fetal heart rate monitoring had been documented within a short period before a fetal death.14 The unpredictability of antenatal testing in pregnancies complicated by ICP provides a challenge to the obstetric provider. Consideration is given to delivering the fetus a few weeks before the estimated date of confinement in an attempt to reduce the risk of an in utero death.15 Preferably, the delivery is performed after fetal pulmonary maturation has been documented, but it may be sooner if antenatal fetal heart monitoring is nonreassuring, a finding that warrants an expeditious delivery.16 Glantz et al. report that adverse perinatal outcomes in pregnancies complicated by ICP are limited to those with increased maternal serum bile acids (>40 mmol/L); furthermore, they note that increasing bile acid concentrations correlate with worsening perinatal events. The authors conclude that directing focused surveillance on pregnancies with critically high levels of bile acids will curtail health care expenditures with no attendant increase in poor fetal outcomes. Indeed, perinatal outcomes were demonstrably worse among those women with higher bile acid levels when compared to those with no or low bile acid levels. While the frequency of asphyxia was similar among parturients with absent or low levels of bile acids, this frequency is markedly higher than that seen in uncomplicated pregnancies.17, 18 This discrepancy highlights the fact that all the women recruited for this particular study had pruritus during pregnancy. An appropriate comparison group would include a group of uncomplicated pregnancies, with patients having no complaints of itching. If the question of efficacy of antepartum testing is to be addressed in patients with no or low levels of maternal serum bile acids, a randomized, prospective study is warranted to compare them to parturients without ICP. This study demonstrates the need for a greater understanding of the pathogenesis of ICP and of the effects of maternal bile acids on the fetal placental unit. Despite the limitations of antenatal fetal testing, ICP must be recognized as a condition that is associated with increased perinatal mortality, irrespective of maternal bile acid levels, and intense fetal surveillance is warranted. If management regarding antenatal testing is to rely solely on levels of bile acids, a logistical problem is created: a patient is diagnosed with ICP by her obstetric provider in the mid third trimester. A known fetal risk is evident but the serum bile acid results are not readily available. Antenatal testing is likely to begin immediately. Should testing be discontinued if the bile acid result is at a less-than-critical level? What if these levels change over the course of the week despite weekly planned assessments of bile acids? Can the results be extrapolated to other populations? As of yet, we do not have these answers.