Intrahepatic cholestasis of pregnancy

Abstract

INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder.1 The incidence of ICP varies by country and ethnicity, ranging from 0.4% to 10%, with the highest rates found in women of Araucanian-Indian descent.2 A retrospective review of 43,876 pregnancies in Australia found that the overall incidence was 0.7%. Though their cohort of pregnant women was 72% white, they observed higher rates of South Asian, Asian, and indigenous Australian ethnicities than in the general population.2 ICP is defined as pruritus with elevated bile acids (BA), typically greater than 10 mmol/L. The pruritus is not associated with a rash and can affect the whole body but is often worse over the palms of the hands and soles of the feet. It is often worse at night.1 ICP typically presents in the second or third trimester but can present as early as the first trimester and is associated with elevated liver biochemistries in up to 84% of cases in a retrospective review.2,3 ICP is associated with adverse fetal outcomes such as preterm premature rupture of membranes, meconium-stained amniotic fluid, and preterm labor when BA levels are greater than 40 mmol/L. The risk of stillbirth is associated with a BA concentration of > 100 mmol/L.4 Women with ICP are often treated with ursodeoxycholic acid (UDCA), which decreases fetal bile acid levels and can improve pruritus. Because of the risk of stillbirth, guidelines recommend early delivery. Women with ICP have an increased risk of developing other liver diseases, such as cholelithiasis.5 DIAGNOSTICS ICP is typically defined as gestational pruritus and with BA levels above 10 mmol/L. ICP is considered mild with BA between 10 and 40 mmol, moderate between 40 and 100 mmol/L, and severe above 100 mmol/L. Prevalence of neonatal intensive care unit (NICU) admission, meconium-stained amniotic fluid, and preterm labor is increased in moderate ICP.4,6,7 Severe ICP is associated with a higher prevalence of stillbirth4 There is no current consensus in guidelines if BA should be drawn fasting or postprandially though it is known that bile acids increase after meals. Adverse perinatal outcomes are associated with the peak bile acid levels, so postprandial bile acid levels hold the most prognostic value. In a study measuring both fasting and postprandial bile acid levels in women with known ICP after standardized meals, the diagnosis of ICP would have been missed for all women with mild ICP (BA level between 10 and 40 mmol/L) if BA levels had only been taken fasting. Similarly, fasting labs missed severe ICP in most cases. In contrast, postprandial measurements of those with severe ICP were > 90% sensitive. The optimal timing for BA measurement is 20 minutes after lunch to optimize sensitivity and specificity of diagnosing ICP and accurately stratifying severity category.6 Serial measurements of bile acids can be useful in severe cases to help guide the timing of delivery. Guidelines do not recommend specific timing of repeat testing other than to advise against weekly BA measurements.8 RISK FACTORS Several risk factors for ICP have been identified. Gestational diabetes, pregestational diabetes, pregnancy of multiples, ICP in a previous pregnancy, and higher body mass index have all been found to be risk factors for ICP.2,3,9 Known prior hepatobiliary disease, especially cholelithiasis, chronic hepatitis, and hepatitis C (HCV), increased the risk for ICP in a large Swedish database cohort.5 A 2017 systemic review and meta-analysis found that the risk of ICP was higher in women infected with HCV.10 The mechanism underlying this association is not known, though the authors propose several potential theories, including persistent viremia impairing both hepatocytes, biliary epithelium, or bile acid transporters, though note that data from in vitro studies have been contradictory in elucidating the role HCV has on bile acid transporters.10 Women with ICP are also more likely to have hypertensive disorders of pregnancy7,9 and gestational diabetes.9 The overlap of ICP and gestational diabetes in retrospective studies and in gene identification studies could be related to the involvement of bile acids in glucose homeostasis. In women with ICP, even when not meeting the criteria for gestational diabetes, there is a correlation between higher glucose levels and higher infant birth weight, suggesting that dysregulation of bile acids may contribute to the development of gestational diabetes.9 Genetics There is strong evidence that there are genetic underpinnings for ICP, such as the increased prevalence in certain ethnic groups and familial clustering of ICP,3 although exact genetic loci have not yet been identified. Genes involved in progressive familial intrahepatic cholestasis, such as ATP-binding casesette subfamily B4 (ABCB) and ABCB11, have been linked to some severe cases of ICP. However, large registry trials from Finland, the United Kingdom, Sweden, and Italy did not find mutations in the ABCB4 gene to be strongly linked with ICP. Similarly, further studies have not found mutations in the ABCB11 gene to account for more than ~1% of ICP cases. These genetic defects may account for the small proportion of early presenting, severe ICP or may be the cause of a clinically distinct form of cholestasis.11 Since there are known genetic underpinnings for other chronic cholestasis diseases, genetic testing is recommended for women whose bile acids remain elevated after delivery, as this is not consistent with a diagnosis of ICP. To try to elucidate culprit genes for the majority of cases of ICP, a genome-wide association study of women with ICP was conducted and identified 11 significant genetic loci. The genes involved were the alpha 1 antitrypsin gene, genes involving hepatic metabolic homeostasis, and genes linked to the development of insulin resistance and monogenic diabetes. The other loci were on noncoding regulatory areas of genes involving bile acid biosynthesis and homeostasis (ABCB transporter genes), cholesterol absorption, uptake, and transport. The genes identified in this genome-wide association study show that genetic risk for ICP overlaps with genetic risk for cholelithiasis and diabetes based on the genes identified.12 OUTCOMES Fetal complications In ICP, the bile acids cross the placenta and accumulate in the fetal compartment. Risks of spontaneous and iatrogenic preterm labor, as well as meconium-stained amniotic fluid, are associated with peak BA level > 40 mmol/L.4,7 There were no increased odds of adverse perinatal events when BA levels were less than 40 mmol/L.7 Bile acids increase both myometrial contraction and colonic motility, which is the likely mechanism underlying the increased risk of preterm labor and meconium-stained amniotic fluid.13 The prevalence of stillbirth is highest in women whose BA level is greater than 100 mmol/L.4 When BA concentration is below 100 mmol/L, the incidence of stillbirth is no different than in the general population.4 The proposed mechanisms for fetal demise in ICP are arrhythmias from BA toxicity on cardiac muscle or BA-induced vasoconstriction of chorionic blood vessels leading to anoxia.13 Women with ICP tend to have an earlier gestational age at delivery, either due to spontaneous preterm birth as a complication of ICP or due to iatrogenic preterm birth following society guidelines for early delivery. Infants born of women with ICP tend to have lower birth weight and more NICU admissions.2 A recent retrospective review found that many of the complications associated with ICP are complications of prematurity.1 ICP pregnancies delivered after 37 weeks are less likely to experience these adverse events.1 Another study found that when adjusting for neonatal age, there was no association between ICP and neonatal birth weight or NICU admission.7 These findings suggest that many of the more commonly reported adverse events are related to prematurity rather than cholestasis. Maternal complications Maternal outcomes are generally good. The pruritus typically resolves within 48 hours of delivery, and liver biochemistries tend to normalize by 4 weeks.5 ICP is linked with cholelithiasis, which is likely related to the genetic overlap of both diseases.5 A large Swedish registry trial found that women with ICP were 2.5 times more likely to develop hepatobiliary disease than matched controls.5 TREATMENT UDCA is the most common medication used for the treatment of ICP. It reduces fetal serum bile acid concentration by upregulating placental bile acid transport.4 A Cochrane review of 26 trials of potential treatments for ICP concluded that UDCA improves pruritus in women with ICP compared to placebo but found insufficient evidence of any effect on fetal outcomes due to the small number of events in the studies. Other treatments, such as cholestyramine, S‐adenosylmethionine, and rifampin, have been used for refractory pruritus, but this Cochrane review found that there was insufficient evidence of benefit for these treatment options.14 A systematic review and meta-analysis which analyzed individual participant data from published studies as well as from unpublished cohorts of women with ICP found that UDCA lowered the risk of preterm birth with a number needed to treat of 15 and was associated with decreased odds of meconium-stained amniotic fluid.4 Even this analysis, which included birth outcomes of 6974 women with ICP, was underpowered to detect a benefit for stillbirths. Since the standard practice of early delivery for women with ICP, stillbirth remains a rare event.4 UDCA had no effect on the need for induction of labor, postpartum hemorrhage, or preeclampsia.4 Guidelines from the American College of Obstetrics and Gynecology recommend delivery at 36 weeks when BA levels are >100 mmol/L and between 36 and 39 weeks gestational age for BA levels < 100 mmol/L.9 Society of Maternal and Fetal Medicine recommends stratification based on bile acid level, with those with BA > 40 mmol/L delivering closer to 36 weeks and those with pruritus but BA < 10 mmol/L not to be delivered before 37 weeks.1,8 Cholestasis affects the absorption of fat-soluble vitamins, including Vitamin K, an essential co-factor for the blood clotting process. Due to the concern for perinatal bleeding, guidelines have recommended Vitamin K supplementation in cases of abnormal lab results of clotting parameters, such as an elevated prothrombin time. A recent study of pregnant women with ICP found that though a majority of women had low Vitamin K levels (59.2%), concomitant abnormalities in their clotting parameters were not detected.15 Similarly, a significant difference in bleeding rates during delivery has not been found for women with ICP.15 SUMMARY ICP presents as pruritus typically in the third trimester and is associated with adverse fetal outcomes such as preterm labor, meconium-stained amniotic fluid, and stillbirth.7 The risk of these adverse fetal outcomes is correlated with peak bile acid levels.6 The risk of preterm labor and meconium-stained amniotic fluid is associated with peak BA > 40, and the risk of stillbirth is associated with peak BA > 100.4 UDCA is beneficial for the treatment of pruritus, and data suggests it lowers the risk of spontaneous preterm birth and meconium-stained amniotic fluid.4 To reduce the risk of stillbirth, guidelines have recommended early delivery for women with ICP.1 Many of the reported adverse perinatal outcomes associated with ICP are actually complications of preterm birth, such as low birth weight and NICU utilization.1 Newer guidelines recommend stratifying early delivery based on peak bile acid level to balance the risks of iatrogenic preterm birth with risks of adverse fetal effects from ICP (Figure 1).FIGURE 1: Printed with permission from ©Mount Sinai Health System. Abbreviations: BMI, body mass index; ICP, intrahepatic cholestasis of pregnancy; UDCA, ursodeoxycholic acid.

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