Obstetrics and Gynecology
Intrahepatic cholestasis of pregnancy
1. What every clinician should know
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease specific to pregnancy presenting usually in the third trimester with intense pruritus and elevated maternal serum bile acids (BA).
There is marked geographic variation in the incidence of ICP, with the disease known to occur in as few as 1:10,000 deliveries in European populations and more frequently in South Asian, South American, and Scandinavian populations. Occurrence is as frequently as 14% in some Chilean populations.
In addition, seasonal variation has been demonstrated, with ICP occurring more frequently in the winter months. A higher incidence is seen in multiple gestations, following in vitro virtilization, in patients of advanced maternal age, and in patients with a prior history of ICP. Hepatitis C has also been reported as a risk factor for ICP and may be associated with early onset of the disease. While maternal morbidity is usually mild, ICP has been associated with multiple adverse fetal outcomes, including preterm labor, meconium stained amniotic fluid, fetal distress, and intrauterine fetal demise.
A higher incidence of ICP is seen in multiple gestations, following in vitro fertilization, in patients of advanced maternal age, and in those with a prior history of ICP. Hepatitis C has also been reported as a risk factor for ICP and may be associated with early onset of the disease.
While the exact cause of ICP is unknown, it is likely a combination of genetic, hormonal, and exogenous factors. Sex hormones (estrogen and progesterone) have known cholestatic effects through inhibition of the hepatocellular bile salt export pump. This may explain why those women carrying multiple gestations are at an increased risk of ICP (higher endogenous sex steroids) and why the disease resolves relatively quickly after delivery (withdrawal of hormones).
In addition, several genetic studies have identified mutations in genes involved in hepatobiliary transport, cholesterol metabolism, and protein trafficking that all may be associated with the development of ICP. Other studies have proposed a role for dietary factors (selenium deficiency), seasonable variability, and geographic variations.
Fetal complications are likely due to the over accumulation of BA in the fetal circulation. Increased maternal serum BA leads to a breakdown of bile acid transport from the fetal to maternal compartment, resulting in deleterious fetal effects.
Animal studies have found impaired cardiac myocyte contractility when exposed to high levels of taurocholate (a bile acid). Therefore, one etiology of fetal death in ICP may be an acute cardiac event. Other studies have demonstrated human chorionic vein constriction with the administration of cholic acid, which is theoretically a possible mechanism for acute fetal asphyxia and subsequent demise. Still further studies have demonstrated an increase in fetal colonic motility with the administration of cholic acid. Though meconium passage is known to occur more frequently in cases of ICP, there is insufficient evidence in the literature to suggest a role for meconium in fetal death.
2. Diagnosis and differential diagnosis
ICP presents in the third trimester 80% of the time. The disease typically manifests with intense pruritus originating on the palms and soles and later extending to the trunk and extremities. In rare, severe cases, pruritus can involve the face, neck, ears, and mucosal surfaces. Skin lesions are notably absent. Most patients report a nocturnal exacerbation of the pruritus with associated insomnia and fatigue. Mild jaundice is seen in 20% of patients, often associated with dark urine and hyperbilirubinemia. Some patients may also report mild nausea and anorexia. Due to malabsorption, some women may have a deficiency of fat soluble vitamins (including vitamin K), thereby increasing their risk of postpartum hemorrhage
Findings of maternal fever, abdominal pain, profuse vomiting, mental status changes, coagulopathy, or hypertensions should prompt an immediate and thorough evaluation for other causes of liver dysfunction in pregnancy (acute hepatitis, cholelithiasis, cholecystitis, acute fatty liver of pregnancy, or pre-eclampsia/HELLP).
While imaging is not necessary for diagnosis of ICP, some clinicians may want to obtain a maternal abdominal (right upper quadrant) ultrasound to evaluate for other possible causes of liver disease (i.e., cholelithiasis). In addition, regular ultrasound evaluation of fetal growth is recommended once a diagnosis of ICP is established.
Liver biopsy, though also unnecessary for an ICP diagnosis, will show centrilobar cholestasis with minimal or no inflammatory changes, canaliculi containing bile plugs, and bile pigment in hepatocytes.
Physical exam is notable for a paucity of findings. Excoriations may be present, but there are no distinct skin lesions noted with ICP. As mentioned above, mild jaundice may be noted. Symptoms usually resolve within days of delivery. Note that the severity of maternal signs and symptoms do not seem to consistently correlate with fetal prognosis.
Patients with ICP do not display evidence of fever, abdominal pain, profuse vomiting, mental status changes, coagulopathy, or hypertension. Such findings should prompt an immediate and thorough evaluation for other causes of liver dysfunction in pregnancy, including acute hepatitis, cholelithiasis, cholecystitis, acute fatty liver of pregnancy, and pre-eclampsia/HELLP.
We recommend sending 1) total serum bile acids (BA); 2) alanine aminotransferase (ALT); 3) aspartate aminotransferase (AST); and 4) total and direct bilirubin. Consideration should be given to sending a hepatitis panel as well. BA may be elevated 10 - 25 fold and is often the first and sometimes only lab abnormality. Of note, there is significant inter-laboratory variability in the normal lab value cut offs. Generally, bile acids greater than 10 umol/L is considered abnormal. AST and ALT may be increased 2 - 20 fold. Total and direct bilirubin may also be significantly elevated.
Serum abnormalities have been noted to be present up to 4 weeks prior to symptom development and as late as 3 weeks after symptom development. Lab abnormalities usually resolve within 4 - 8 weeks of delivery.
Those presenting with ICP prior to the third trimester should be tested for Hepatitis C, as ICP is known to occur more commonly in affected patients.
Multiple medications have been used to manage cholestasis over the last several years, including steroids, bile acid-binding resins (cholestyramine), bile acid sequestrants, antihisamines, and opioid antagonists, all with variable and less than satisfying results regarding resolution of maternal symptoms, laboratory improvements, and/or improved perinatal outcome.
Ursodeoxycholic Acid (UDCA) is a newer agent that has been shown to mitigate maternal pruritus and enzyme elevations, as well as reverse abnormalities in bile acid transport across the placenta. UDCA is a hydrophilic bile acid that alters the overall distribution of bile acids in the bile acid pool and may therefore aid in the removal of bile acids from the fetal compartment. Whether it is able to alter fetal prognosis remains unclear. Regardless, UDCA is generally well tolerated and is considered the first line treatment for ICP. We recommend initiation of treatment with either 500mg po BID or 300mg po TID to a maximum of 15mg/kg/day until delivery.
Unfortunately, due to the unpredictable nature of fetal complications, there is little consensus among practitioners regarding the appropriate level of antepartum testing and/or timing of delivery. Considering that most cases of fetal demise occur after 37 weeks gestation, most clinicians have adopted a practice of early delivery, with or without documentation of fetal lung maturity.
We recommend, upon diagnosis of ICP prior to 37 weeks gestation, initiation of UDCA (500mg po BID or 300mg po TID) and an antihistamine as needed for control of pruritus. In addition, we recommend initiation of fetal kick counts, biweekly fetal testing (either by NST or BPP), and ultrasound growth evaluations every 2 - 4 weeks.
Regarding timing of delivery, we would recommend delivery at or by 37 weeks gestation. If delivery is opted for prior to this time (e.g., 36 week gestation), we would recommend documentation of fetal lung maturity (FLM) by amniocentesis. If FLM is noted to be immature, we would recommend either administration of a course of antentatal steroids followed by subsequent delivery or delay of delivery for 1 week (until 37 weeks gestation).
The diagnosis of ICP should not impact the mode of delivery, and an induction of labor, if no contraindications exist, should be considered appropriate.
While the diagnosis of ICP typically involves both symptoms and elevated BA levels, there is evidence that symptoms may precede laboratory abnormalities by up to three weeks. In the case of intense pruritus without documentation of elevated bile acids or other explanation for the symptoms, we would recommend initiation of biweekly fetal testing and weekly maternal laboratory evaluation. If bile acids become elevated, we would then recommend following the standard clinical course of UDCA administration, fetal testing and early delivery.
If amniocentesis indicates immature fetal lung function, the provider has two possible options. The first would be to administer a course of antenatal steroids to expedite fetal lung maturation and proceed with delivery. The other option is to continue fetal testing and maternal treatment for another week and then proceed with delivery. We do not see a need for repeating the amniocentesis.
4. Prognosis and outcome
Maternal prognosis is generally considered good. Symptoms usually resolve within days and lab values normalize within weeks of delivery. We recommend following lab values in the postpartum period to document this resolution. Affected women generally have no hepatic sequelae, although they are at an increased risk for later development of cholelithiasis.
Overall, there is a 40 - 60% chance of recurrence of ICP in subsequent pregnancies. Due to malabsorption, some women may have a deficiency of fat soluble vitamins (including vitamin K), thereby increasing their risk of postpartum hemorrhage.
From a fetal perspective, ICP has been associated with preterm delivery, increased perinatal mortality, nonreassuring fetal heart rate patterns, and meconium stained amniotic fluid. When untreated, perinatal mortality ranges from 2 - 15%. Unfortunately, the severity of maternal signs and symptoms do not seem to correlate well with fetal prognosis. In addition, fetal monitoring has been described as normal up until a few days prior to fetal demise. The majority of fetal deaths occur after 37 weeks gestation, hence the rationale for early delivery.
5. What is the evidence for specific management and treatment recommendations
Reyes, H. "Intrahepatic choleststasis: a puzzling disorder of pregnancy". J Gastro Hepatol. vol. 12. 1997. pp. 211-6.
Berg, B, Helm, G, Petersohn, L, Tryding, N. "Cholestasis of pregnancy: clinical and laboratory studies". Acta Obstet Gynecol Scand. vol. 65. 1986. pp. 107-13.
Heinonen, S, Kirkinene, P. "Pregnancy outcome with intrahepatic cholestasis". Obstet Gynecol. vol. 94. 1999. pp. 189-93.
Locatelli, A, Rongaclia, N, Arrehgini, A, Bellini, P, Vergani, P. "Hepatitis C virus infection is associated with a higher incidence of cholestasis of pregnancy". Br J of Obstet Gynecol. vol. 106. 1999. pp. 498-500.
Reid, R, Ivey, KJ, Rencort, RH, Storey, B. "Fetal complications of obstetric cholestasis". Br Med J. vol. 1. 1976. pp. 870-2.
Joshi, D, James, A, Quaglia, A, Westbrook, RH, Henegan, MA. "Liver disease in pregnancy". Lancet. vol. 375. 2010. pp. 594-605.
Lammert, F, Marschall, HU, Glantz, A, Siegfried, M. "Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management". J Hepatol. vol. 33. 2000. pp. 1012-21.
Kenyon, A, Piercy, CN, Girling, J, Williamson, C, Tribe, RM. "Obstetric cholestasis, outcome with active management: a series of 70 cases". Br J Obstet Gynecol. vol. 109. 2002. pp. 282-8.
Pan, C, Perumalswami, P. "Pregnancy-related liver diseases". Clin Liver Dis. vol. 15. 2011. pp. 199-208.
Mullalay, BA, Hansen, WF. "Intrahepatic cholestasis of pregnancy: review of the literature". Obstet Gynecol Surv. vol. 57. 2001. pp. 47-52.
Reyes, H, Sjovall, J. "Bile acid and progesterone metabolites in intrahepatic cholestasis of pregnancy". Ann Med. vol. 32. 2000. pp. 94-106.
Rioseco, AJ, Ivankovic, MB, Manzur, A. "Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome". Am J Obstet Gynecol. vol. 170. 1994. pp. 890-5.
Fisk, NM, Storey, GN. "Fetal outcome in obstetric cholestasis". Br J Obstet Gynecol. vol. 95. 1988. pp. 1137-43.
Alsulyman, OM, Ouzounian, JG, Ames-Castro, M, Goodwin, TM. "Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management". Am J Obstet Gynecol. vol. 175. 1996. pp. 957-60.
Steiger, B, Fattinger, K, Madon, J, Kullak-Ublick, GA, Meier, PJ. "Brug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver". Gastroenterol. vol. 118. 2000. pp. 422-30.
Williamson, C, Gorelik, J, Eaton, B, Lab, M, de Swiet, M. "The bile acid taurocholate impairs rat cardiomyocyte function: a proposed mechanism for intrauterine fetal death in obstetric cholestasis". Clin Sci. vol. 100. 2001. pp. 363-9.
Sepulveda, WH, Gonzalez, C, Cruz, MA, Rudolph, MI. "Vasoconstrictive effects of bile acids on isolated human placental chorionic veins". Eur J Obstet Gynecol Reprod Biol. vol. 42. 1991. pp. 211-5.
Pathak, B, Sheibani, L, Lee, RH. "Cholestasis of pregnancy". Obstet Gynecol Clin N Am. vol. 37. 2010. pp. 269-82.
Knox, TA, Olans, LB. "Liver disease in pregnancy". N Eng J Med. vol. 335. 1996. pp. 569-76.
Davidson, K. "Intrahepatic cholestasis of pregnancy". Semin Perinatol. vol. 22. 1998. pp. 104-11.
Steven, MM. "Pregnancy and liver disease". Gut. vol. 22. 1981. pp. 592-614.
Copyright © 2017, 2014 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
Clinical Pain Advisor Articles
- Replacing Sleep, Sedentary Behavior With Physical Activity Beneficial in Knee Osteoarthritis
- The Role of Psychological Factors in Phantom Limb Pain Reviewed
- FDA Outlines Plan for New Analgesic Guidance to Combat Opioid Crisis
- Ozone vs Corticosteroids May Provide Longer-Lasting Effects for Plantar Fasciitis
- Rates of Concurrent Opioid, Sedative-Hypnotic Prescription Fills in Veterans
- Ketamine: Mechanisms of Action, Uses in Pain Medicine, and Side Effects
- Cannabis May Be Effective for Migraine Treatment
- Medicinal Cannabis May Not Have Opioid-Sparing Effects in Chronic Noncancer Pain
- Integrating Psychological Interventions Into Chronic Pain Management
- Chronic Neck Pain: Generators, Clinical Examination, MRI Findings, and Differential Diagnosis
- Pregabalin May Not Improve Analgesia During Medical Abortion
- Investigational Treatment Shows Promise in Chronic Low Back Pain
- Rheumatologist-Assessed vs Criteria for Inflammatory Back Pain in Psoriatic Arthritis
- Incorporating Guidelines Into Clinical Practice: An Interview With Gary L. LeRoy, MD
- Pain Severity May Partly Mediate the Association Between Depression and Physical Performance in Knee OA