Intrahepatic Cholestasis of Pregnancy
/Further reading for today: SMFM consult series #53 — it’s free!
And check out the ObG Project’s summary too!
What is cholestasis?
ICP or IHCP is a strange condition occurring in the 2nd and 3rd trimesters of pregnancy, and is characterized by two primary things: intense pruritis, and elevated serum bile acid levels.
The intense itching is the characteristic symptom -- rashless, unrelenting, and affecting even the palmar surfaces of the hands and the soles of the feet.
Women at risk of ICP include women who have had a history of ICP, women with hepatic disorders such as hepatitis C, nonalcoholic cirrhosis or pancreatitis, and women with gallstones and cholecystitis.
Recurrence risk in subsequent pregnancy may be as high as 90%, but there’s limited data on this risk overall.
ICP is also associated with multiple gestations, advanced maternal age, and there is likely a familial component to ICP as well.
Incidence of ICP is around 0.3 - 0.5%, but has been reported as affecting up to 15% of pregnancies.
It seems silly to care about a disorder that causes itching in pregnancy, and ICP really doesn’t seem to affect the mother otherwise -- however, ICP is associated with severe adverse perinatal outcomes, particularly stillbirth, meconium-stained fluid, and preterm birth.
Many other conditions can cause itching in pregnancy!
Differential diagnoses include atopic eruption of pregnancy (AEP), polymorphic eruption of pregnancy (PEP), and pemphigoid gestationis (PG).
AEP is associated with an eczematous rash that breaks out on the face, eyelids, neck, antecubal and popliteal fossa, trunk, and extremities -- think of the terrible eczema you saw in kids on your pediatrics rotation, but now put it on a pregnant woman!
PEP, or it’s former name PUPPS (pruritic urticarial papules and plaques of pregnancy, or PUPPS), is also associated with a rash that often breaks out in plaques on the abdomen and thighs, but will spare the arms generally. This is the most common dermatosis of pregnancy.
Finally, PG is super rare, but as you might remember from your dermatology rotations or Step 1 studying, “pemphigus” is derived from the Greek word meaning pustules. The characteristic skin change of this disorder are vesicles and bullae, and though rare, requires consultation with dermatology immediately!
There are even other conditions that can cause itching without a rash in pregnancy - renal failure, HIV, multiple sclerosis, and psychiatric disease include just a few of the broad differential.
However, any patient with generalized pruritis in the 2nd or 3rd trimester should receive an evaluation for possible ICP.
How do we evaluate for ICP?
There shouldn’t be a rash!
The exam should also look for potential other hepatic causes that might raise bile acids - dark urine, jaundice or scleral icterus, abdominal pain and colic are not common with ICP.
Bile acids are the laboratory of choice to evaluate for cholestasis of pregnancy.
Total serum bile acids > 10 micromol/L is the general cutoff for diagnosis of ICP.
Some labs will ask for a fasting draw, which can be impractical for a pregnancy evaluation. Trials reviewing this have demonstrated that differences in random and fasting bile acid levels are pretty small in pregnant women, so feel free to draw away at the time of suspicion!
This also helps because many times, bile acid measurements occur at specialty labs and take a few days to return.
Evaluation should also look at transaminases as these may also be elevated in ICP.
What is the antenatal management of ICP?
The primary adverse outcome we’re trying to avoid is stillbirth. Stillbirth risk seems to correlate with increasing bile acid levels:
Diagnosis is called with BA > 10 micromol/L;
BA > 40 micromol/L has been demonstrated to have a higher incidence of stillbirth in some studies, as well as higher risk of other poor neonatal outcomes such as meconium, respiratory distress, and preterm birth;
A large meta-analysis demonstrated the highest risk for stillbirth and other adverse outcomes seems to exist for women with BAs > 100 micromol/L.
For maternal benefit, the drug of choice is ursodeoxycholic acid, or ursodiol.
Ursodiol is effective in improving laboratory abnormalities (i.e., BAs, LFTs) and itching while not increasing any adverse fetal effects.
However, ursodiol likely does not decrease adverse fetal outcomes in ICP, so even though the bile acids will go lower, the peak value is still important to keep in mind.
Dosing of ursodiol should be 10-15mg/kg per day, divided into 2-3 daily doses.
This often comes out around 300mg BID or TID, or 500mg BID.
Alternative medications for maternal benefit to reduce bile acid levels include cholestyramine and S-adenosyl-methionine (a dietary supplement in the US, sold as “SAMe”).
Symptomatic treatment of itching can safely be targeted with oral antihistamines.
Topical antipruritics are likely unhelpful given the widespread nature of the itching!
Serial testing of bile acids is not necessarily recommended, but might be considered on a case-by-case basis as peak values are what have been reported in studies as being most significant with respect to stillbirth risk.
It’s worthwhile to note that it’s not uncommon for pruritis in ICP can precede rising bile acid levels by even a few weeks! So in women who initially have a negative test, repeat bile acids and transaminase levels are very reasonable.
Some may also practice in this particular scenario by diagnosing ICP clinically, and starting ursodiol empirically even in the absence of elevated bile acids. SMFM notes this is a reasonable approach, but certainly be aware of your differential diagnosis and keep an open eye for other pathologies.
For fetal benefit, our only defense against stillbirth is the use of antenatal testing!
Antenatal testing should begin with diagnosis of ICP, at a gestational age when delivery would be performed in response to an abnormal test.
SMFM notes that most obstetric providers will perform some sort of antenatal testing, though the optimal frequency is unknown and even the effectiveness of testing is uncertain:
The mechanism for stillbirth in ICP is thought to be a sudden event, rather than a chronic placental vascular process -- so surveillance doesn’t necessarily predict stillbirth well.
Considerations for an antenatal testing schedule should be gestational age, severity of cholestasis (i.e., peak bile acid level), and patient values.
Ultimately to avoid stillbirth, delivery should be undertaken at an earlier gestational age:
In women with a clinical diagnosis of ICP (i.e., no bile acid elevation), delivery should not occur at less than 37 weeks.
In women with ICP and bile acids less than 100, delivery is reasonable between 36’0 - 39’0.
Data here is more challenging and less convincing on risk of stillbirth and when it occurs. It’s reasonable to consider managing women with lower values (ie., < 40) towards the later end of this window, and women with higher values (i.e., > 40) towards the earlier end.
In women with ICP and bile acids > 100, delivery can be offered as early as 36’0.
This is based on data suggesting in this high risk group, the risk of stillbirth substantially increases past this gestational age.
SMFM even mentions in this group delivery between 34’0 - 36’0, provided that one of the following criteria is met:
Excruciating pruritis unremitting to pharmacotherapy;
History of ICP-associated stillbirth < 36 weeks in prior pregnancy;
Preexisting or acute hepatic disease with clinical or lab evidence of worsening hepatic function.
SMFM does advocate for the use of steroids for fetal lung maturity prior to delivery at 37’0 or earlier!