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Pregnancy Intrahepatic Cholestasis

Editor: Ashish Sharma Updated: 6/4/2023 6:57:31 PM

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder in the late second and early third trimester of pregnancy. It is also known as obstetric cholestasis (OC) and is characterized by pruritus with increased serum bile acids and other liver function tests. The pathophysiology of ICP is still not completely understood. The symptoms and biochemical abnormality rapidly resolve after delivery. ICP is associated with an increased risk of adverse obstetrical outcomes, which include stillbirth, respiratory distress syndrome, meconium passage, and fetal asphyxiation.[1] This activity will cover the clinical presentation, diagnosis, and management of this condition.

Etiology

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Etiology

The etiology of intrahepatic cholestasis of pregnancy (ICP) is poorly understood and is thought to be complicated and multifactorial. Genetic susceptibility, hormonal, and environmental factors have been proposed as possible mechanisms. There appears to be a relation between cholestatic properties of reproductive hormones in genetically susceptible women and ICP. The supportive evidence for the genetic susceptibility hypothesis lies in the fact that the disease has been observed more in familial clustering patterns, first-degree relatives, and a higher risk of disease recurrence with subsequent pregnancies.[2][3] Recent studies have shown evidence of mutations in genes (ABCB4) encoding hepatobiliary canalicular translocator proteins called multidrug resistance 3 (MDR3) and pedigrees with the mode of inheritance being a sex-limited, dominant pattern.[4][5] Some other genes which seem to play a role in the development of ICP are ATP8B1(FIC1), ABCB11 (BSEP), ABCC2, and NR1H4 (FXR).[6][7][8][9] A different form of intrahepatic cholestasis called progressive familial intrahepatic cholestasis (PFIC) is considered a broad term for the most severe forms of the different genetically discreet diseases and also has various autosomal recessive genetic mutations as mentioned above.[10] Further analysis of PFIC is out of scope for the current topic.

The role of reproductive hormones in developing ICP has also appeared in multiple studies. Many studies showed an association of high levels of estrogen conditions such as multitone pregnancy, ovarian hyperstimulation effect, and late second-trimester presentation of ICP.[11] ICP typically occurs in the late second trimester when the estrogen levels are the highest in pregnancy. ICP shows similar characteristics seen in women taking contraceptive pills high in estrogen quantity.[12] High circulating estrogen levels may induce cholestasis in genetically predisposed women in ICP.[12] The role of progesterone is only partially apparent; however, recent studies, including some animal model studies, have demonstrated that progesterone sulfated metabolites are partial agonists of farnesoid X receptor FXR (also called bile acid receptor).[13] The progesterone sulfate metabolites alter the hepatobiliary transport system by impairing the functioning of the main hepatic bile acid receptor.[13]

Environmental and seasonal factors have also correlated with ICP. ICP is noted to be more prevalent in women with a low level of selenium and vitamin D. It is also common in some countries in winters when selenium and vitamin D may be low.[14][12][15]

Chronic underlying liver disease correlates with ICP; however, it is not yet clear whether chronic liver diseases contribute to developing ICP or are revealed by pregnancy.[16]

Epidemiology

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease related to pregnancy.[17] The Incidence and prevalence of ICP vary with ethnicity and geographic distribution. ICP incidence rate is between 0.2 to 2% of pregnancies.[1] It is more common in South American and northern European continents. Research has described ICP in 0.2 to 0.3% of pregnancies in the USA.[18] A higher incidence of ICP is observable with a prior history of ICP, chronic liver disease, chronic hepatitis C, multifetal pregnancy, and advanced maternal age.[19][15] The recurrence rate of ICP in subsequent pregnancies is high (60 to 70 percent).[20] Turunen K et al. did a survey of 544 former ICP patients and 1235 controls which showed 12.8% of mothers (odds ratio 9.2), 15.9% of sisters (odds ratio 5.3), and 10.3% of daughters (odds ratio 4.8) of women with a history of ICP had liver dysfunction during pregnancy. Similarly, estimates for the relative risk for the siblings of affected women were 12% in another study.[21][2]

Pathophysiology

Genetic susceptibility and reproductive hormones, especially estrogen, are found to be the principal contributing factors to the development of intrahepatic cholestasis of pregnancy (ICP). See details in the etiology section. Estrogen reduces the expression of nuclear hepatic bile acid receptors and hepatic biliary canalicular transport proteins in genetically susceptible women causing impairment of hepatic bile acid homeostasis and subsequent increased level of bile acids.[13] Downregulation of placental expression of bile acid transporters organic anion transporting polypeptides OATP1A2 and OATP1B3 in ICP placenta in one report also indicates a role in pathophysiology.[22]

Histopathology

Histopathology shows the widening of the bile canaliculi with bile plugs in hepatocytes and canaliculi in predominantly zone 3 and centrilobular cholestasis with inflammation.[23][20] Liver biopsy is rarely a requirement for the diagnosis of intrahepatic cholestasis of pregnancy (ICP).

History and Physical

Classically, intrahepatic cholestasis of pregnancy (ICP) presents in the late second trimester to the early third trimester. The most common complaint is generalized intense pruritus, which usually starts after the 30th week of pregnancy. Pruritus can be more common in palms and soles and is typically worse at night. Other symptoms of cholestasis, such as nausea, anorexia, fatigue, right upper quadrant pain, dark urine, and pale stool, can be present. Clinical jaundice is rare but may present in 14 to 25% of patients after 1 to 4 weeks of the onset of pruritus.[24] Some patients also complain of insomnia secondary to pruritis. Generally, the physical examination is unremarkable except for scratch marks on the skin from pruritus. Pruritis is a cardinal symptom of ICP and may precede biochemical abnormalities. In patients who undergo in vitro fertilization, ovarian hyperstimulation can cause transient symptoms in the first trimester compared to persistent symptoms in the second and third trimester in ICP.[11] Family history of liver dysfunctions during pregnancy in other female relatives requires inclusion because of the role of genetics in pathophysiology.

Evaluation

The diagnosis of intrahepatic cholestasis of pregnancy (ICP) is via the presence of clinical symptom that is pruritus in the third trimester with elevated maternal total serum bile acids and excluding other diagnoses, which can cause similar symptoms and lab abnormalities. Raised liver function tests in the absence of pruritus require investigation for another cause.  The most sensitive and specific marker for ICP is the total serum bile acid (91 and 93 percent) using a cut-off value of 10 micromol/L.[25] Most studies use an upper limit of bile acids between 10 and 14 micromoles/L for the diagnosis of ICP. The risk for fetal complications increases in severe cholestasis with increased serum bile acid levels, usually over 40 micromol/L. Other liver function tests, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) usually mildly elevated and do not exceed two times the upper limit of normal value in pregnancy. Serum alkaline phosphatase can be elevated physiologically sometimes up to four times the upper normal value but has little diagnostic significance in ICP. Elevated bilirubin can present in 25% percent of cases but rarely exceeds 6 mg/dL.[26] High prothrombin time can be present because of vitamin K deficiency (decreased fat-soluble vitamins), but postpartum hemorrhage is rare.[27]

Kremer et al., in their animal model study, found that autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, which is pruritogenic, was markedly increased in patients with ICP versus pregnant controls and cholestatic patients with versus without pruritus.[28] Kremer et al., in their other study, which included 145 women, also reported that increased serum autotaxin activity represents a highly sensitive, specific, and robust diagnostic marker of ICP, distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP.[29] Serum autotaxin can be used as a helpful test in excluding other causes of pruritus and elevated bile acid levels.

Treatment / Management

Once the diagnosis of intrahepatic cholestasis of pregnancy (ICP) is confirmed, immediate treatment is necessary, and the primary goal of therapy is to decrease the risk of perinatal morbidity and mortality and to alleviate maternal symptoms.

Ursodeoxycholic acid (UDCA) is the drug of choice for the treatment of ICP.[30] The initial starting dose of UDCA is not well established, but it is reasonable to start at 300 mg BID and can be increased to 300 mg three times a day until delivery. Usually, maternal symptoms will alleviate in about two weeks, and the bile acid levels will decline in two to three weeks. If there is no improvement in the patient's symptoms or bile acid levels, the dose can be titrated every week or two to a maximum dose of 21 mg/kg/day.[1] UDCA is well tolerated by most patients; some of the common side effects are nausea, vomiting, and diarrhea. It has no detrimental impact on the fetus. The mechanism of action of ursodeoxycholic acid is unknown, but studies have shown that after treatment, a significant reduction in total serum bile acids occurs. In a meta-analysis, patients with ICP who received UDCA had better outcomes than those who received an alternative agent. Patients using UDCA had better resolution of pruritus, reduction in liver function tests, and bile acid levels, and decreased incidence of premature birth, fetal distress, respiratory distress syndrome, and need for neonatal intensive care unit admission.[31][32](A1)

For patients with no improvement of ICP, refractory to UDCA, other medications such as rifampin, cholestyramine, and S-adenosyl-L-methionine are options.[33] Rifampin increases bile acid detoxification and excretion and can be an adjunct to ursodeoxycholic acid. Cholestyramine is an anion exchange resin that decreases the ileal absorption of bile salts, thereby increasing their fecal excretion. S-adenosyl-L-methionine is often administered using a twice-daily intravenous regimen, making it a less attractive option in the management of intrahepatic cholestasis of pregnancy. One study found UDCA more effective than S-adenosyl-L-methionine at improving liver function tests but equally effective at improving pruritus.[34] An antihistamine such as chlorpheniramine is often used in ICP to alleviate pruritis. Antihistamines do not affect serum bile acids but may reduce the sensation of pruritus in some women.(A1)

Antepartum Management of ICP

In patients with intrahepatic cholestasis of pregnancy, the importance of regular antepartum fetal testing is not proven to be useful to identify fetuses at risk of demise. None of the existing antenatal tests has been shown to either predict or reduce the risk of adverse perinatal outcomes. Nevertheless, most providers find it reassuring to have regular antenatal testing for patients with ICP. Although there is a dearth of high-quality evidence to support antenatal screening in pregnant women with ICP, the consensus is to use weekly biophysical profiles (BPP) to detect fetal compromise.

Timing of Delivery

Many authors have advocated elective early delivery of women with intrahepatic cholestasis of pregnancy to reduce the risk of sudden fetal demise. The timing of delivery should depend on balancing the risk of fetal death as opposed to the potential risks of prematurity. In a meta-analysis of 23 studies done by Ovadia et al., it was noted that the prevalence of stillbirth after 24 weeks of gestation was 3.44% (95% CI 2.05–5.37) for females with intrahepatic cholestasis of pregnancy compared with 0.3 to 0.4% from pooled national average data among included countries. The elevated total bile acid concentrations (greater than 100 micromol/L) were highly predictive of stillbirth in single pregnancies (area under the receiver operating characteristic curve 0.83 [95% CI 0.74 to 0.92], and the conclusion was that in women with total bile acid concentrations of 100 micromol/L or more, delivery should probably occur by 35 to 36 weeks of gestation.[35] In women with ICP, The Royal College of Obstetricians and Gynecologists recommends induction of labor after 37+0 weeks of gestation whereas, The American College of Obstetricians and Gynecologists recommends delivery between 36+0 to 37+0 weeks of pregnancy.[36](B3)

Consider delivery before 37 weeks of gestation in women with ICP if they have one of the following:[36](B3)

  • Maternal symptoms along with jaundice not improving with medications, and needing escalating doses of UDCA
  • Previous history of intrauterine fetal demise before 37 weeks secondary to ICP
  • Total serum bile acid concentration of more than 100 micromol/L

Intrahepatic cholestasis of pregnancy is not an indication for cesarean delivery. Postpartum - pruritus typically disappears in the first two to three days following delivery, and serum bile acid concentrations will normalize eventually. ICP is not a contraindication to breastfeeding, and mothers with a history of ICP in pregnancy can breastfeed their infants. Postpartum monitoring and follow-up of bile acids and liver function tests should be done in 4-6 weeks to ensure resolution. Women with the persistent abnormality of liver function tests after 6 to 8 weeks require investigation for other etiologies.

Differential Diagnosis

The differential diagnosis of cholestasis in pregnancy categorizes into two groups, conditions causing pruritis and conditions, causing elevated liver function.

Conditions Causing Pruritis

  • Pemphigoid gestationis
  • Pruritis gravidarum
  • Prurigo in pregnancy
  • Atopic dermatitis
  • Allergic reactions

Conditions Causing Impaired Liver Function

  • HELLP syndrome (hemolysis, elevated liver enzymes, low platelets)
  • Acute fatty liver of pregnancy
  • Viral hepatitis
  • Primary biliary cirrhosis
  • Drug-induced liver damage

Prognosis

Maternal prognosis is benign in intrahepatic cholestasis of pregnancy (ICP) and symptoms, and abnormal liver biochemistry resolves rapidly after delivery. In some women, the abnormal LFTs may remain persistent and should be investigated further for any other etiology. In a large cohort study, women with ICP were found to have a high incidence of hepatobiliary disorders later in life and, hepatitis C, chronic hepatitis, hepatic fibrosis or cirrhosis, and gallstones or cholangitis were seen more commonly in these women compared to the general population.[16] For fetal prognosis, see the section on the complication. Children born to women with ICP were also found to be at more risk of developing high body mass index and dyslipidemia at the age of 16.[37] The recurrence rate of ICP in subsequent pregnancies is high (60 to 70 percent).[20]

Complications

Intrahepatic cholestasis of pregnancy (ICP) can cause a significant risk for the fetus, and it is one of the treacherous risk factors for sudden fetal demise.[21] ICP is also associated with an increased risk of adverse obstetrical outcomes. Maternal bile acids cross the placenta and can accumulate in the fetus and amniotic fluid, causing fatal complications. Ovadia et al. conducted an aggregate meta-analysis, including 23 studies that compared perinatal outcomes of women with intrahepatic cholestasis of pregnancy (n=5557) vs. healthy controls (n=165136). The meta-analysis result shows evidence of the associations of intrahepatic cholestasis of pregnancy with increased fetal complications, as listed below.[35][21]

  • Sudden intrauterine demise (odds ratio 1.46 [95% CI 0.73–2.89])
  • Meconium-stained amniotic fluid (2.60 [1.62–4.16])
  • Spontaneous preterm birth (3.47 [3.06–3.95])
  • Iatrogenic preterm birth (3.65 [1.94–6.85])
  • Neonatal ICU admission (2.12 [1.48–3.03])

Maternal bile acids are transported through the placenta to the fetus and accumulate in the amniotic fluid to cause complications. The incidence of preterm labor also increases in women with ICP, the cause is unknown, but possibly related to bile acid accumulation in the uterine myometrium causing increased uterine activity. Sudden fetal death is the most concerning complication of ICP; the cause of fetal death is not well understood; still, it possibly has a relationship to the toxic effects of bile acids on the fetal heart, causing arrhythmias and chorionic vasospasm causing deprivation of maternal oxygenated blood to the fetus causing asphyxia.[38] The risk of fetal death increases with increasing levels of bile acids, notably higher with bile acid levels of more than100 micromol/L.[39]

Consultations

Uncomplicated cases of intrahepatic cholestasis of pregnancy (ICP) are manageable by obstetrician-gynecologist; however, a maternal-fetal medicine specialist (MFM) and gastroenterologist consultation, when available, should always be considered in the patients with the complicated ICP and with other preexisting chronic liver diseases. A geneticist also can be consulted for sequence analysis when there is suspicion of the familial clustering of disease.

Deterrence and Patient Education

In patients with a history of intrahepatic cholestasis of pregnancy (ICP), exogenous estrogen administration can lead to cholestasis. Estrogen-containing oral contraceptives should be avoided in these patients if possible or should be used in the smallest possible dose. Due to the high risk of recurrence of this disease, patients should be monitored cautiously with subsequent pregnancies.

Pearls and Other Issues

Pruritis in the late second and third trimester is a cardinal symptom of intrahepatic cholestasis of pregnancy along with elevated serum bile acids level.

Encephalopathy or other liver failure symptoms in ICP are rare and should prompt investigation for etiology other than ICP.

Combined oral contraceptive pills can cause cholestasis in some postpartum patients. A non-hormonal alternative for contraception merits consideration in such patients. Center for disease control and prevention okays to consider combined OCPs in patients with a history of ICP because of benefits outweigh the risks.[40]

Enhancing Healthcare Team Outcomes

The management of intrahepatic cholestasis of pregnancy (ICP) must be an interprofessional team approach. Typically, whenever feasible, an interprofessional team should include an obstetrician, maternal-fetal medicine specialist (MFM), gastroenterologist, anesthetist, and the nursing team.

A weekly biophysical profile for fetal health monitoring should take place in patients with ICP with elevated total bile acid level (over 100 micromol/L). Delivery between 36 to 37 weeks should be considered to avoid fetal complications in a patient with severely elevated total bile salt acid levels and other risk factors, as mentioned above. Once the condition gets diagnosed, the patient should be closely monitored by the nurse and obstetrician to ensure that the ICP is not worsening. A team approach to patient management is vital if one wants to improve outcomes.

References


[1]

Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstetrics and gynecology. 2014 Jul:124(1):120-133. doi: 10.1097/AOG.0000000000000346. Epub     [PubMed PMID: 24901263]


[2]

Turunen K, Helander K, Mattila KJ, Sumanen M. Intrahepatic cholestasis of pregnancy is common among patients' first-degree relatives. Acta obstetricia et gynecologica Scandinavica. 2013 Sep:92(9):1108-10. doi: 10.1111/aogs.12168. Epub 2013 Jun 6     [PubMed PMID: 23663193]


[3]

Pataia V, Dixon PH, Williamson C. Pregnancy and bile acid disorders. American journal of physiology. Gastrointestinal and liver physiology. 2017 Jul 1:313(1):G1-G6. doi: 10.1152/ajpgi.00028.2017. Epub 2017 Apr 27     [PubMed PMID: 28450276]


[4]

Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Seminars in liver disease. 2010 May:30(2):134-46. doi: 10.1055/s-0030-1253223. Epub 2010 Apr 26     [PubMed PMID: 20422496]

Level 3 (low-level) evidence

[5]

Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, Ruggiero G, Zampino R, Bertolotti M, Loria P, Carulli L. ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2013 Mar:45(3):226-32. doi: 10.1016/j.dld.2012.08.011. Epub 2012 Sep 27     [PubMed PMID: 23022423]

Level 2 (mid-level) evidence

[6]

Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clinics and research in hepatology and gastroenterology. 2016 Apr:40(2):141-53. doi: 10.1016/j.clinre.2015.12.008. Epub 2016 Jan 25     [PubMed PMID: 26823041]


[7]

Keitel V, Vogt C, Häussinger D, Kubitz R. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology. 2006 Aug:131(2):624-9     [PubMed PMID: 16890614]

Level 3 (low-level) evidence

[8]

Sookoian S, Castaño G, Burgueño A, Gianotti TF, Pirola CJ. Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy. Journal of hepatology. 2008 Jan:48(1):125-32     [PubMed PMID: 17997497]

Level 2 (mid-level) evidence

[9]

Van Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J, Shevchuk V, Moore GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J, Parker MG, White R, Williamson C. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology. 2007 Aug:133(2):507-16     [PubMed PMID: 17681172]

Level 2 (mid-level) evidence

[10]

Bull LN, Thompson RJ. Progressive Familial Intrahepatic Cholestasis. Clinics in liver disease. 2018 Nov:22(4):657-669. doi: 10.1016/j.cld.2018.06.003. Epub 2018 Aug 3     [PubMed PMID: 30266155]


[11]

Mutlu MF, Aslan K, Guler I, Mutlu I, Erdem M, Bozkurt N, Erdem A. Two cases of first onset intrahepatic cholestasis of pregnancy associated with moderate ovarian hyperstimulation syndrome after IVF treatment and review of the literature. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2017 Jul:37(5):547-549. doi: 10.1080/01443615.2017.1286302. Epub 2017 Mar 20     [PubMed PMID: 28319428]

Level 3 (low-level) evidence

[12]

Gabzdyl EM, Schlaeger JM. Intrahepatic cholestasis of pregnancy: a critical clinical review. The Journal of perinatal & neonatal nursing. 2015 Jan-Mar:29(1):41-50. doi: 10.1097/JPN.0000000000000077. Epub     [PubMed PMID: 25633399]


[13]

Abu-Hayyeh S, Papacleovoulou G, Lövgren-Sandblom A, Tahir M, Oduwole O, Jamaludin NA, Ravat S, Nikolova V, Chambers J, Selden C, Rees M, Marschall HU, Parker MG, Williamson C. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology (Baltimore, Md.). 2013 Feb:57(2):716-26. doi: 10.1002/hep.26055. Epub 2013 Jan 8     [PubMed PMID: 22961653]

Level 3 (low-level) evidence

[14]

Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World journal of gastroenterology. 2009 May 7:15(17):2049-66     [PubMed PMID: 19418576]


[15]

Floreani A, Gervasi MT. New Insights on Intrahepatic Cholestasis of Pregnancy. Clinics in liver disease. 2016 Feb:20(1):177-89. doi: 10.1016/j.cld.2015.08.010. Epub 2015 Oct 9     [PubMed PMID: 26593298]


[16]

Marschall HU, Wikström Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology (Baltimore, Md.). 2013 Oct:58(4):1385-91. doi: 10.1002/hep.26444. Epub 2013 Aug 6     [PubMed PMID: 23564560]

Level 2 (mid-level) evidence

[17]

. Clinical Updates in Women's Health Care Summary: Liver Disease: Reproductive Considerations. Obstetrics and gynecology. 2017 Jan:129(1):236. doi: 10.1097/AOG.0000000000001858. Epub     [PubMed PMID: 28002308]


[18]

Allen AM, Kim WR, Larson JJ, Rosedahl JK, Yawn BP, McKeon K, Hay JE. The Epidemiology of Liver Diseases Unique to Pregnancy in a US Community: A Population-Based Study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2016 Feb:14(2):287-94.e1-2. doi: 10.1016/j.cgh.2015.08.022. Epub 2015 Aug 21     [PubMed PMID: 26305066]


[19]

Batsry L, Zloto K, Kalter A, Baum M, Mazaki-Tovi S, Yinon Y. Perinatal outcomes of intrahepatic cholestasis of pregnancy in twin versus singleton pregnancies: is plurality associated with adverse outcomes? Archives of gynecology and obstetrics. 2019 Oct:300(4):881-887. doi: 10.1007/s00404-019-05247-0. Epub 2019 Jul 25     [PubMed PMID: 31346701]


[20]

Hepburn IS, Schade RR. Pregnancy-associated liver disorders. Digestive diseases and sciences. 2008 Sep:53(9):2334-58. doi: 10.1007/s10620-007-0167-9. Epub 2008 Feb 7     [PubMed PMID: 18256934]

Level 3 (low-level) evidence

[21]

Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O, Swiet M, Johnston DG. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG : an international journal of obstetrics and gynaecology. 2004 Jul:111(7):676-81     [PubMed PMID: 15198757]

Level 2 (mid-level) evidence

[22]

Wang H, Yan Z, Dong M, Zhu X, Wang H, Wang Z. Alteration in placental expression of bile acids transporters OATP1A2, OATP1B1, OATP1B3 in intrahepatic cholestasis of pregnancy. Archives of gynecology and obstetrics. 2012 Jun:285(6):1535-40. doi: 10.1007/s00404-011-2183-4. Epub 2011 Dec 28     [PubMed PMID: 22203093]


[23]

Bacq Y. Liver diseases unique to pregnancy: a 2010 update. Clinics and research in hepatology and gastroenterology. 2011 Mar:35(3):182-93. doi: 10.1016/j.clinre.2010.11.011. Epub     [PubMed PMID: 21310683]


[24]

Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World journal of gastroenterology. 2008 Oct 14:14(38):5781-8     [PubMed PMID: 18855975]


[25]

Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. The Cochrane database of systematic reviews. 2019 Jul 5:7(7):CD012546. doi: 10.1002/14651858.CD012546.pub2. Epub 2019 Jul 5     [PubMed PMID: 31283001]

Level 1 (high-level) evidence

[26]

Lee NM, Brady CW. Liver disease in pregnancy. World journal of gastroenterology. 2009 Feb 28:15(8):897-906     [PubMed PMID: 19248187]


[27]

Maldonado M, Alhousseini A, Awadalla M, Idler J, Welch R, Puder K, Patwardhan M, Gonik B. Intrahepatic Cholestasis of Pregnancy Leading to Severe Vitamin K Deficiency and Coagulopathy. Case reports in obstetrics and gynecology. 2017:2017():5646247. doi: 10.1155/2017/5646247. Epub 2017 Jun 7     [PubMed PMID: 28680707]

Level 3 (low-level) evidence

[28]

Kremer AE, Martens JJ, Kulik W, Ruëff F, Kuiper EM, van Buuren HR, van Erpecum KJ, Kondrackiene J, Prieto J, Rust C, Geenes VL, Williamson C, Moolenaar WH, Beuers U, Oude Elferink RP. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010 Sep:139(3):1008-18, 1018.e1. doi: 10.1053/j.gastro.2010.05.009. Epub 2010 Jun 19     [PubMed PMID: 20546739]

Level 3 (low-level) evidence

[29]

Kremer AE, Bolier R, Dixon PH, Geenes V, Chambers J, Tolenaars D, Ris-Stalpers C, Kaess BM, Rust C, van der Post JA, Williamson C, Beuers U, Oude Elferink RP. Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy. Journal of hepatology. 2015 Apr:62(4):897-904. doi: 10.1016/j.jhep.2014.10.041. Epub 2014 Nov 5     [PubMed PMID: 25450205]


[30]

Kremer AE, Namer B, Bolier R, Fischer MJ, Oude Elferink RP, Beuers U. Pathogenesis and Management of Pruritus in PBC and PSC. Digestive diseases (Basel, Switzerland). 2015:33 Suppl 2():164-75. doi: 10.1159/000440829. Epub 2015 Dec 7     [PubMed PMID: 26641452]


[31]

Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, Nicastri PL, Locatelli A, Floreani A, Hernandez I, Di Martino V. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology. 2012 Dec:143(6):1492-501. doi: 10.1053/j.gastro.2012.08.004. Epub 2012 Aug 11     [PubMed PMID: 22892336]

Level 1 (high-level) evidence

[32]

Kong X, Kong Y, Zhang F, Wang T, Yan J. Evaluating the effectiveness and safety of ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy: A meta-analysis (a prisma-compliant study). Medicine. 2016 Oct:95(40):e4949. doi: 10.1097/MD.0000000000004949. Epub     [PubMed PMID: 27749550]

Level 1 (high-level) evidence

[33]

Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver international : official journal of the International Association for the Study of the Liver. 2006 Oct:26(8):943-8     [PubMed PMID: 16953834]

Level 1 (high-level) evidence

[34]

Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC, Ghidini A. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG : an international journal of obstetrics and gynaecology. 2004 Jan:111(1):17-21     [PubMed PMID: 14687046]

Level 1 (high-level) evidence

[35]

Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Ilio C, Chambers J, Kohari K, Bacq Y, Bozkurt N, Brun-Furrer R, Bull L, Estiú MC, Grymowicz M, Gunaydin B, Hague WM, Haslinger C, Hu Y, Kawakita T, Kebapcilar AG, Kebapcilar L, Kondrackienė J, Koster MPH, Kowalska-Kańka A, Kupčinskas L, Lee RH, Locatelli A, Macias RIR, Marschall HU, Oudijk MA, Raz Y, Rimon E, Shan D, Shao Y, Tribe R, Tripodi V, Yayla Abide C, Yenidede I, Thornton JG, Chappell LC, Williamson C. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet (London, England). 2019 Mar 2:393(10174):899-909. doi: 10.1016/S0140-6736(18)31877-4. Epub 2019 Feb 14     [PubMed PMID: 30773280]


[36]

. ACOG Committee Opinion No. 764: Medically Indicated Late-Preterm and Early-Term Deliveries. Obstetrics and gynecology. 2019 Feb:133(2):e151-e155. doi: 10.1097/AOG.0000000000003083. Epub     [PubMed PMID: 30681545]

Level 3 (low-level) evidence

[37]

Papacleovoulou G, Abu-Hayyeh S, Nikolopoulou E, Briz O, Owen BM, Nikolova V, Ovadia C, Huang X, Vaarasmaki M, Baumann M, Jansen E, Albrecht C, Jarvelin MR, Marin JJ, Knisely AS, Williamson C. Maternal cholestasis during pregnancy programs metabolic disease in offspring. The Journal of clinical investigation. 2013 Jul:123(7):3172-81. doi: 10.1172/JCI68927. Epub 2013 Jun 24     [PubMed PMID: 23934127]

Level 3 (low-level) evidence

[38]

Williamson C, Miragoli M, Sheikh Abdul Kadir S, Abu-Hayyeh S, Papacleovoulou G, Geenes V, Gorelik J. Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. Digestive diseases (Basel, Switzerland). 2011:29(1):58-61. doi: 10.1159/000324130. Epub 2011 Jun 17     [PubMed PMID: 21691106]


[39]

Brouwers L, Koster MP, Page-Christiaens GC, Kemperman H, Boon J, Evers IM, Bogte A, Oudijk MA. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. American journal of obstetrics and gynecology. 2015 Jan:212(1):100.e1-7. doi: 10.1016/j.ajog.2014.07.026. Epub 2014 Jul 18     [PubMed PMID: 25046809]

Level 2 (mid-level) evidence

[40]

Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, Simmons KB, Pagano HP, Jamieson DJ, Whiteman MK. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2016 Jul 29:65(3):1-103. doi: 10.15585/mmwr.rr6503a1. Epub 2016 Jul 29     [PubMed PMID: 27467196]