Author: Dr. Laura Bonebrake

What we know about risks and outcomes

Intrahepatic cholestasis of pregnancy (ICP) is classically known as a disorder that first occurs in the second or third trimesters of pregnancy.¹ At ICP Care, we have had members diagnosed much earlier in pregnancy, including in the first trimester.  There are cases in the literature showing onset of symptoms of ICP as early as 5 weeks of gestation.²

A recent meta-analysis showed the risks of stillbirth and preterm labor are strongly correlated with the level of bile acid elevation. Most risks occur when bile acids exceed 40 µmol/L.³ Unfortunately, there are few published studies or cases describing outcomes of early onset ICP pregnancies. This post covers what is currently known about the risks and outcomes of early onset ICP pregnancies and discusses areas of future research.

What counts as early onset?

There is not a clear definition of what qualifies as an early diagnosis for cholestasis. A common criteria used in published literature is 28-30 weeks.^4,5

Patients may have itching (pruritus) and other symptoms for weeks before bile acids become elevated.¹  Studies typically determine risk using time of official diagnosis with elevated bile acids rather than the time of symptom onset. Most studies from this review use 10 µmol/L as the diagnostic level.

Risks of early onset?

Risks of any ICP pregnancy include preterm labor, meconium passage, infant respiratory distress/NICU admission and stillbirth.¹ Many but not all of these seem to be increased with earlier diagnosis.

Meconium Passage: Meconium is passed when a fetus has a bowel movement inside the uterus. ICP is known to increase meconium passage. Early onset cases, especially with diagnosis before 28 weeks, increase the risk of meconium passage more than later onset cases.^7,8 Meconium passage was found in 12.6% of all ICP cases in one study. For ICP diagnosed before 28 weeks, however, this risk increased to almost 30%.⁷

Bile acid elevation:

Multiple studies have shown that early onset cases tend to have a more severe elevation of bile acid levels than cases diagnosed later in pregnancy.^5,7,9 This is significant as higher bile acid levels result in more adverse outcomes for many of the known risks.3 Stillbirth and preterm birth are both linked most significantly with bile acids levels over 40 µmol/L and 100 µmol/L respectively.

A higher percentage of early onset cases have a genetic cause or an underlying liver disorder. In these cases, bile acids can increase more rapidly during pregnancy, which may account for higher levels. While it is unclear if these cases should truly be diagnosed as classic ICP, they are still included in many studies since the bile acid elevation drives risk. Whether the true cause of the bile elevation is ICP or the underlying liver disorder, these cases should be managed based upon highest (or peak) bile acid levels. There are case reports of severe elevations of bile acids in the setting of underlying liver disorders that have led to stillbirth.⁹

Preterm Labor:

Preterm labor appears to increase in patients with ICP due to increased contractility of the uterus from bile acid exposure. Preterm labor and delivery was increased in several studies with early onset cases of ICP.^4,5,10 In late onset ICP cases, preterm labor is only increased when bile acids are over 40 µmol/L.³  Preterm labor seems independently linked to the earlier onset, regardless of bile acid levels.¹¹

Respiratory Distress of the Infant:

ICP infants have a 2-3 times increased risk of needing admission to the NICU for respiratory distress (RDS), even when delivered at the same gestational age as non-ICP infants. This is thought to be due to the effect of elevated bile acid levels on the production of surfactant which is needed to help the lungs expand after birth.¹²

Early onset of ICP is linked to a higher incidence of RDS than cases diagnosed later in pregnancy, even when delivered at the same gestational age.^10,12 Administration of steroids before birth to improve lung maturity did not reduce the risk of RDS in this early onset population unfortunately.¹²  Early onset cases should plan for delivery at a hospital that has a NICU or Special Care Nursery which can provide respiratory support.

Stillbirth

No studies have shown an increase in the incidence of stillbirth with an earlier diagnosis of ICP. However, we cannot fully conclude that this risk isn’t present. Stillbirth is a rare occurrence, even in ICP pregnancies. Most of the studies of early onset cases are limited to less than 100 patients which makes it hard to distinguish a difference in stillbirth from the limited participants in the studies.

What might cause ICP to occur so early?

The exact cause of ICP is unknown but it is thought to be from a combination of hormonal, genetic and environmental factors.

Possible causes of first trimester onset of ICP:

• IVF and increased hormones: Many case reports of first trimester onset occur with higher levels of estrogen. This can be linked to IVF or multiple gestations such as twin pregnancies.^13,14 Some patients who develop early ICP have a history of developing pruritus while taking birth control containing estrogen and might have a predisposition to be more highly affected by hormones.⁸
• Genetic Factors: Several genes that encode bile acid transporter channels have been implicated in development of ICP. A case report showed a first trimester onset of severe ICP with bile acids above 200 in a patient with a mutation in the ABCB4 gene.¹⁵ Over 15% of cases of ICP are caused by this mutation.
• Underlying liver disorders: ICP is linked to liver disorders including Primary Biliary Sclerosis (PBC), autoimmune hepatitis, Hepatitis C, and alpha-1 antitrypsin deficiency among several others.¹⁶ Some of these disorders cause itching outside of pregnancy as well. Many times the person is unaware of an underlying liver condition until ICP is diagnosed. It is thought that the extra stress or hormones of the pregnancy bring to light the underlying disorder.^16,17

Follow-up of early onset

All cases of ICP should have liver function tests and possibly bile acids measured postpartum to ensure that they return to normal.¹⁸ This is especially important if itching continues.

Due to the possible genetic or underlying liver disorder causes of early onset cases, patients should consider either genetic testing or follow-up with a hepatology specialist for screening.¹⁹

Conclusions:

Early onset ICP (around 28-30 weeks) increases the risk of meconium passage, preterm labor and respiratory distress in the infant. Though there is not a clear link to increased stillbirth in early onset cases, there is insufficient data to fully determine the relationship of length of bile acid exposure and the risk of stillbirth and more studies in this area are needed. Early onset cases tend to be more severe with higher bile acid levels.

There is much more research needed on early onset cases, especially those in the first trimester. SMFM argues for an individualized approach to treatment of ICP.¹ Madazli et al argue that ”gestational age at diagnosis seems to be an important independent factor predicting adverse perinatal outcomes in patients with ICP and should be taken into consideration in the management of such pregnancies”.⁴

Current management of ICP pregnancies mostly depends on the level of elevation of the bile acids. Most of the risks appear to be associated with elevations higher than 40 µmol/L. Treatment in an early onset case should be tailored to take into account both the levels of elevation as well as the length of exposure. The increased risk of respiratory distress in these infants must also be considered when trying to determine an optimal delivery window.

Dr. Laura Bonebrake

MD, FACOG

ICP Care Medical Advisory Board Member