Guideline No. 452: Diagnosis and Management of Intrahepatic Cholestasis of Pregnancy

Objective

To summarize the current evidence and to make recommendations for the diagnosis and management of intrahepatic cholestasis of pregnancy.

Target Population

Pregnant people with intrahepatic cholestasis of pregnancy.

Options

Diagnosing the condition using fasting or non-fasting bile acids, classifying disease severity, determining what treatment to offer, establishing how to monitor for antenatal fetal wellbeing, identifying when to perform elective birth.

Benefits, Harms, and Costs

Individuals with intrahepatic cholestasis of pregnancy are at increased risk of adverse perinatal outcomes including preterm birth, neonatal respiratory distress and admission to a neonatal intensive care unit, with an increased risk of stillbirth when bile acid levels are ≥100 μmol/L. There is inequity in bile acid testing availability and timely access to results, along with uncertainly of how to treat, monitor. and ultimately deliver these pregnancies. Optimization of diagnostic and management protocols can improve maternal and fetal postnatal outcomes.

Evidence

Medline, PubMed, Embase, and the Cochrane Library were searched from inception to March 2023, using medical subject headings (MeSH) and keywords related to pregnancy, intrahepatic cholestasis of pregnancy, bile acids, pruritis, ursodeoxycholic acid, and stillbirth. This document presents an abstraction of the evidence rather than a methodological review.

Validation Methods

The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations).

Intended Audience

Obstetric care providers, including obstetricians, family physicians, nurses, midwives, maternal–fetal medicine specialists, and radiologists.

Social Media Abstract

Intrahepatic cholestasis of pregnancy requires adequate diagnosis with non-fasting bile acid levels which guide optimal management and delivery timing.

SUMMARY STATEMENTS

• 1.

  Intrahepatic cholestasis of pregnancy is a common pregnancy condition manifesting in the late-second or third trimesters (moderate).

• 2.

  The etiology of intrahepatic cholestasis is complex, involving a combination of hormonal factors, genetic susceptibility, and environmental influences (low).

• 3.

  Intrahepatic cholestasis remains a diagnosis of exclusion and is based on the presence of maternal pruritis, predominantly of the palms and soles, along with elevated non-fasting bile acids (>19 μmol/L) (moderate).

• 4.

  The perinatal sequelae of intrahepatic cholestasis of pregnancy includes increased risks of preeclampsia, gestational diabetes, preterm birth, neonatal respiratory distress, and neonatal intensive care unit admission (moderate). Patients with intrahepatic cholestasis and bile acids ≥100 μmol/L have a significantly increased risk of stillbirth compared with the general population (moderate).

• 5.

  The mainstay of symptomatic treatment of pruritis is with ursodeoxycholic acid (10–15 mg/kg/d), given daily in 2–3 divided doses, which may also reduce the risk of preterm birth, but not stillbirth (high).

• 6.

  Antenatal fetal monitoring has not been shown to improve perinatal outcomes (moderate).

• 7.

  Symptoms as well as intrahepatic cholestasis-associated biochemical abnormalities are expected to resolve within 1–2 weeks postpartum, although they may persist up to 4 weeks in some individuals (moderate).

• 8.

  Individuals who have been diagnosed with intrahepatic cholestasis are at increased risk of future cholecystitis, cholelithiasis, pancreatic disease, goiter, and hypothyroidism (low).

• 9.

  Recurrence of intrahepatic cholestasis in future pregnancies is around 70%–90% (low).

• 10.

  In patients with a history of intrahepatic cholestasis of pregnancy choosing hormonal contraception, progestin-only options are associated with the lowest risk of non-pregnant cholestasis (moderate).

RECOMMENDATIONS

• 1.

  Clinicians should include intrahepatic cholestasis of pregnancy in the differential diagnosis of any pregnant person with pruritis, particularly of the palms of the hands or soles of feet, in the late-second or third trimester (strong, moderate).

• 2.

  Laboratory investigations for intrahepatic cholestasis should include non-fasting bile acids, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and bilirubin. Additional testing or imaging should be guided by clinical findings and differential diagnoses (strong, moderate).

• 3.

  Clinicians and health care authorities should advocate for universally available serum bile acid testing with timely access to results (strong, low).

• 4.

  Clinicians should adopt the contemporary definition of intrahepatic cholestasis as raised non-fasting bile acid levels >19 μmol/L (strong, moderate).

• 5.

  Repeat testing of non-fasting laboratory investigations should be performed every 2–4 weeks to monitor disease progression and ascertain the highest recorded bile acid level (strong, low).

• 6.

  Atypical presentations of intrahepatic cholestasis should be referred for specialist consultation by a maternal–fetal medicine or internal medicine physician (strong, low).

• 7.

  Clinicians should counsel patients diagnosed with intrahepatic cholestasis regarding increased risks of preeclampsia, gestational diabetes, preterm birth, neonatal respiratory distress, and neonatal intensive care unit admission. Furthermore, there is a significant increase in the risk of stillbirth if bile acid levels are ≥100 μmol/L, and some evidence demonstrating a modest increase in stillbirth risk with bile acid levels >40 μmol/L from 38 weeks gestation onward (strong, low).

• 8.

  While topical emollients and antihistamines may be prescribed, clinicians should offer treatment of pruritis in cholestasis of pregnancy with ursodeoxycholic acid (strong, moderate).

• 9.

  The following therapies for intrahepatic cholestasis have been shown to be ineffective and should not be prescribed by clinicians to treat the condition: dexamethasone, cholestyramine, phenobarbital, S-adenosylmethionine, activated charcoal, and epomediol (strong, moderate).

• 10.

  All pregnant individuals should be advised to monitor fetal movements as the mainstay of fetal wellbeing surveillance in intrahepatic cholestasis and to seek timely care if indicated (strong, moderate).

• 11.

  While additional fetal monitoring is not mandated in intrahepatic cholestasis, local units may offer monitoring after discussion and shared decision-making (conditional, low); in patients with bile acid levels between 40ؘ–99 μmol/L monitoring can include obstetric ultrasound for biophysical profile or electronic fetal heart rate monitoring every 1–2 weeks, and in patients with bile acid levels ≥100 μmol/L monitoring can include obstetric ultrasound for biophysical profile or electronic fetal heart rate monitoring weekly or twice weekly.

• 12.

  Based on expert opinion, clinicians should counsel their patients regarding optimal delivery timing based on the highest recorded non-fasting bile acid level: 20–39 μmol/L at 39⁰–39⁶ weeks gestation (conditional, low); 40–69 μmol/L at 38⁰–38⁶ weeks gestation (conditional, low); 70–99 μmol/L at 36⁰–37⁶ weeks gestation (conditional, moderate); and ≥100 μmol/L by 36 weeks gestation (strong, high) or earlier in patients with comorbidities or other risks factors (i.e., multiple pregnancy, preeclampsia, gestational diabetes, previous stillbirth secondary to intrahepatic cholestasis and/or severe persistent maternal pruritus).

• 13.

  Patients with intrahepatic cholestasis should be offered continuous electronic fetal heart rate monitoring in labour (conditional, low).

• 14.

  Clinicians should confirm resolution of pruritis in intrahepatic cholestasis at the 6-week postpartum visit and repeat bile acid and liver transaminase testing in those where symptoms persist (conditional, low).

• 15.

  Clinicians should pursue further workup or specialist consultation for patients with persistent intrahepatic cholestasis symptoms or biochemical abnormalities beyond the postpartum period (conditional, low).

• 16.

  Clinicians should inform patients affected by intrahepatic cholestasis that they and their family members are at a higher risk of intrahepatic cholestasis in future pregnancies (conditional, low).