In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.
Classification of evidence levels (1++ to 4) and grades of recommendations (A-D) are defined at the end of the "Major Recommendations" field.
How Is Obstetric Cholestasis Diagnosed?
C - Pregnancy-specific reference ranges for liver function tests (LFTs) should be used.
C - Other causes of itching and of liver dysfunction should be excluded.
C - Women with persistent pruritus and normal biochemistry should have LFTs repeated every 1–2 weeks.
C - Postnatal resolution of pruritus and LFTs should be confirmed.
Other causes of pruritus must be excluded. The skin should be inspected and care must be taken to differentiate dermatographia artefacta (skin trauma from intense scratching),which may be seen in obstetric cholestasis, from other common skin conditions such as eczema or atopic eruption of pregnancy (previously referred to as eczema of pregnancy, prurigo and pruritic folliculitis). If a rash is present, polymorphic eruption of pregnancy or pemphigoid gestations (blisters) should be considered.
Other evidence of cholestasis should be sought, including pale stool, dark urine and jaundice, and other risk factors identified such as a personal or family history of obstetric cholestasis, multiple pregnancy, carriage of hepatitis C and presence of gallstones.
In clinical practice, otherwise unexplained abnormalities in transaminases, gamma-glutamyl transferase and/or bile salts are considered sufficient to support the diagnosis of obstetric cholestasis. The increase in alkaline phosphatase in pregnancy is usually placental in origin and so does not normally reflect liver disease. A thorough history and examination should be carried out, including a drug history, before abnormal LFTs are determined to be otherwise unexplained. Bilirubin is raised only infrequently and most women will have increased levels of one or more of the remaining LFTs. Although a wide variety of cutoff points have been used for defining abnormality in LFTs and bile salts, the upper limit of pregnancy-specific ranges should be applied. For transaminases, gamma-glutamyl transferase and bilirubin, the upper limit of normal throughout pregnancy is 20% lower than the non-pregnant range. Many laboratories will use pregnancy-specific ranges for bile salts, but this should not be assumed. Bile acid levels can rise significantly after a meal, so while fasting might give lower values and help the diagnosis to be avoided in a few women with otherwise normal LFT, in the majority of studies and in clinical practice random levels are generally used. Some women will have pruritus for days or weeks before the development of abnormal liver function: in those with persistent unexplained pruritus and normal biochemistry, LFTs should be measured every 1–2 weeks. Isolated elevation of bile salts may occur but this is uncommon; normal levels of bile salts do not exclude the diagnosis.
Other causes of pruritus and abnormal LFTs should be sought. This may include carrying out a viral screen for hepatitis A, B, and C, Epstein Barr and cytomegalovirus, a liver autoimmune screen for chronic active hepatitis and primary biliary cirrhosis (for example, anti-smooth muscle and antimitochondrial antibodies) and liver ultrasound. Pre-eclampsia and acute fatty liver of pregnancy are pregnancy-specific causes of abnormal LFTs that might form part of the differential diagnosis in atypical or early cases.
How Should Obstetric Cholestasis Be Monitored?
D - Postnatally, LFTs should be deferred for at least 10 days.
Typically, transaminases will range from just above the upper limit of normal to several hundreds. Regular LFTs, along with a general review, blood pressure measurement and urine check, allow monitoring of the condition and exclusion of other diagnoses. If LFTs return to normal, obstetric cholestasis is not likely to be the correct diagnosis. If LFTs escalate very rapidly, additional diagnoses need to be considered and the frequency of monitoring increased: although this situation can be consistent with obstetric cholestasis, it is not typical. A coagulation screen should be performed.
What Is the Risk of Stillbirth for Pregnancies Complicated by Obstetric Cholestasis?
B - In a hospital setting, the current additional risk of stillbirth in obstetric cholestasis above that of the general population has not been determined but is likely to be small.
What Additional Risks Are Associated with Pregnancies Complicated by Obstetric Cholestasis?
B - Obstetricians should be aware (and should advise women) that the incidence of premature birth, especially iatrogenic, is increased.
B - Women should be advised of the increased likelihood of meconium passage in pregnancies affected by obstetric cholestasis.
B - Women with obstetric cholestasis should be booked in under consultant-led, team-based care and give birth in a hospital unit.
Can Fetal Death Be Predicted and Prevented?
B - Poor outcome cannot currently be predicted by biochemical results and delivery decisions should not be based on results alone.
D - No specific method of antenatal fetal monitoring for the prediction of fetal death can be recommended.
C - Ultrasound and cardiotocography are not reliable methods for preventing fetal death in obstetric cholestasis.
Should Women with Obstetric Cholestasis Be Offered Elective Early Delivery?
B - Women should be informed of the increased risk of perinatal morbidity from early intervention (after 37+0 weeks of gestation).
B - Women should be informed of the increased risk of maternal morbidity from intervention at 37+0 weeks of gestation.
Stillbirths in obstetric cholestasis have been reported across all gestations. As gestation advances, the risk of delivery (prematurity, respiratory distress, failed induction) versus the uncertain fetal risk of continuing the pregnancy (stillbirth) may justify offering women induction of labour after 37+0 weeks of pregnancy. The decision should be made after careful counselling. The case for intervention at this gestation may be stronger in those with more severe biochemical abnormality.
What Treatment, if Any, Should Be Used to Treat Obstetric Cholestasis and What Benefit Can Be Expected?
There is no evidence that any specific treatment improves fetal or neonatal outcomes. All such therapies should be discussed with the individual woman with this in mind.
C - Topical emollients are safe but their efficacy is unknown.
A - There is insufficient evidence to demonstrate whether S-adenosyl methionine (SAMe) is effective for either control of maternal symptoms or for improving fetal outcome, and it is not recommended.
Ursodeoxycholic Acid (UDCA)
A - UDCA improves pruritus and liver function in women with obstetric cholestasis.
D - Dexamethasone should not be first-line therapy for treatment of obstetric cholestasis, nor should it be used outside of a randomised controlled trial (RCT) without a thorough consultation with the woman.
What is the Role of Vitamin K?
D - Women should be advised that when prothrombin time is normal, water-soluble vitamin K (menadiol sodium phosphate) in low doses should be used only after careful counselling about the likely benefits but small theoretical risk.
What Follow-up Should Be Offered to Women Who Have Had a Pregnancy Affected by Obstetric Cholestasis?
As a minimum, healthcare practitioners must ensure that LFTs return to normal, pruritus resolves, all investigations carried out during the pregnancy have been reviewed and the mother has fully understood the implications of obstetric cholestasis. The latter will include reassurance about the lack of long-term sequelae for mother and baby and discussion of the high recurrence rate (45%–90%), contraceptive choices (usually avoiding estrogen-containing methods) and the increased incidence of obstetric cholestasis in family members. Local policy will dictate how this is best organised, but LFTs at 6 weeks after delivery and an appointment at 8 weeks is a suggested model. Appropriate follow-up should be arranged by a medical practitioner with appropriate skills.
Grades of Recommendations
A - At least one meta-analysis, systematic review or randomised controlled trial rated as 1++, and directly applicable to the target population; or
A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results
B - A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
C - A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 2++
D - Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
Good Practice Point - Recommended best practice based on the clinical experience of the guideline development group
Classification of Evidence Levels
1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias
1– Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias
2++ High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal
2+ Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal
2– Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal
3 Non-analytical studies, e.g., case reports, case series
4 Expert opinion