Although mild itching could be related to physiological pregnancy-related changes, severe and prolonged itching (pruritus) could signify obstetric cholestasis. Cholestasis describes the condition of slowed biliary excretion from the liver and might have adverse fetal outcomes.
Intrahepatic cholestasis is presented with itching observed in the late stages of pregnancy.
Increased reproductive hormones, including estrogen and progesterone, decrease bile flow in the liver and increase bile acid levels in the blood.
Elevated bile acid levels may lead to preterm delivery and sudden fetal demise.
Intrahepatic cholestasis symptoms and laboratory abnormalities generally resolve rapidly in the first few days after birth.
Intense itching symptoms observed in the late second and early third trimesters of pregnancy could indicate intrahepatic cholestasis (ICP) (chole-bile (Latin), stasis-standing (Greek)).
ICP is the most common liver disease in pregnancy. Intrahepatic cholestasis occurs in 0.2% to 27% of pregnancies worldwide, varying with ethnicity and geography. Symptoms are specific to the late stages of the pregnancy and rapidly resolve after delivery.
Who is more susceptible to developing an ICP?
Women diagnosed with ICP in previous pregnancies carry a 60-70% increased risk of developing the condition in subsequent pregnancies.
Recent studies showed that mutations of some genes, including ABCB4 or MDR, are associated with ICP risk. A common occurrence in the family clusters and first-degree relatives also supports the genetic susceptibility to the disease. A survey analyzing more than 1,700 women showed that 10-15% of ICP-developing women had a similar history in their mothers, sisters, or daughters.
Some environmental factors, such as cold weather and low vitamin D and selenium levels, also increase the ICP risk.
Overall, a higher incidence is observed in women with advanced age, chronic liver diseases, an ICP history in previous pregnancies, and pregnancies with more than one fetus.
What lies behind the ICP scenario?
Although the complete pathophysiology of the condition is not entirely understood, genetic and hormonal factors are the main contributing factors.
Bile synthesis from the liver is essential for the digestion of lipids, and it flows within the digestive canal.
Estrogen impairs the synthesis and metabolism of bile acids and decreases bile flow. Thus, the highest estrogen levels in the late stages of pregnancy increase the chances of ICP development. With increased reproductive hormone levels, multiple gestations also carry the risk for the condition; twin pregnancies show a 5-fold higher ICP incidence than singleton gestations. Moreover, ovarian stimulation drugs used for in-vitro fertilization also increase the ICP risk, especially in the early stages of pregnancy.
Progesterone, another reproductive hormone, also was linked to ICP pathogenesis by occupying liver transport systems with its metabolites.
How to identify the cholestasis of pregnancy?
The main complaint indicating ICP is mild to intense itching or pruritus, which presents after the 30th gestational week. Itching typically worsens at night and mainly involves palms and soles. Symptoms could be so excruciating that women may have visible scratch marks on the skin.
In addition to the itching, other cholestasis-related symptoms, including pain in the right and upper side of the abdomen, dark urine, and pale stool may occur. Jaundice might be observed in 14-25% of cases.
Nausea, fatigue, loss of appetite, and insomnia are other complaints related to ICP.
Why is pregnancy cholestasis alarming?
ICP symptoms affect mothers' quality of life, but it requires more attention for affecting fetal well-being.
According to the meta-analysis investigating over 5,000 ICP-diagnosed women, ICP is associated with several obstetric complications, including preterm birth and neonatal ICU admission rates. Elevated bile acids may induce uterine contractions and increase the incidence of preterm labor.
However, sudden fetal death is the most concerning complication of ICP. ICP-diagnosed pregnancies carry a 46% increased risk of sudden fetal demise, especially in cases with high bile acid levels (>100 μmol/L). Although still not completely understood, it is assumed that accumulating bile acids transported through the placenta may have toxic effects on the fetal heart and blood vessels, thus causing arrhythmias and asphyxia.
What is the management of ICP?
Increased serum bile acid levels (>10 μmol/L) are the most sensitive marker for ICP diagnosis. Other liver function tests also might be affected. However, they have little diagnostic significance.
Ursodeoxycholic acid (UDCA) is the most effective drug used in the management of ICP symptoms. UDCA reduces itching symptoms in two to three weeks, reduces bile acid levels, and decreases fetal adverse effects, including preterm birth, fetal distress, and the need for NICU.
Antihistamines might be used for itching symptoms, but it does not affect bile acid levels.
According to the American College of Obstetricians and Gynecologists, patients unresponsive to UDCA treatment and with a previous history of ICP-related intrauterine fetal demise could be considered for delivery before 37 weeks of gestation.
What are the prognoses of ICP?
Maternal physical symptoms and laboratory abnormalities rapidly resolve following the delivery and typically disappear in the first two to three days after birth. However, in the later years, women and children may develop certain conditions associated with the ICP history.
According to a Swedish study, women diagnosed with ICP develop hepatobiliary diseases, including hepatitis C, chronic hepatitis, cirrhosis, gallstone disease, or cholangitis, more often than those without an ICP history.
Another study from Finland showed that children born to ICP-diagnosed mothers had altered lipid profiles at the age of 16; males showed higher body mass indexes, and females exhibited increased waist and hip circumference.
- Intrahepatic cholestasis is the most common liver disease in pregnant women.
- Intense itching is the main complaint in ICP cases.
- Elevation of bile acids in the blood significantly increases the risks of premature delivery and sudden fetal death.
- Ursodeoxycholic acid (UDCA) is the most effective treatment for reducing symptoms and complication risks.
Itching is a subjective and common symptom and might be physiological in pregnancy. Here are some frequently asked questions about intrahepatic cholestasis of pregnancy:
When should a mother-to-be be alarmed by itching?
Intense itching during late pregnancy, predominantly localized on palms and soles and worsening at night, could be a sign of ICP.
What could happen if ICP is neglected?
As a result of the slowed bile circulation, bile acids build up in the blood. If left untreated, bile acid levels may increase, and measurements over 100 μmol/L may lead to premature birth and sudden fetal demise.
How is this condition being managed?
Ursodeoxycholic acid (UDCA) is the most effective drug to alleviate the itching symptoms and normalize bile acid levels. Furthermore, this treatment reduces fetal and obstetric risks associated with intrahepatic cholestasis.
Are itching symptoms permanent?
Itching symptoms rapidly resolve in the first days following the baby's birth. However, ICP may reoccur in subsequent pregnancies. Moreover, women with an ICP history carry the risk of some liver and heart diseases, including gallstone disease, hepatitis C, and liver cancer.
Can women with an ICP history breastfeed?
Mothers diagnosed with an ICP during pregnancy can breastfeed their babies after birth. Bile acid levels rapidly drop after birth. UDCA, a drug used for ICP treatment, passes to the milk at very low levels and is assumed safe for breastfed babies.
Can ICP-diagnosed mothers use contraception after birth?
All types of non-hormonal contraceptions are suitable for use. However, due to the estrogen and progesterone content, oral contraceptives should be initiated after liver tests will normalize. It should be noted that symptoms may relapse. Therefore, hormonal contraception should be promptly discontinued if itching and other cholestasis-related symptoms develop.
- National Library of Medicine. ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population.
- National Library of Medicine. New Insights on Intrahepatic Cholestasis of Pregnancy.
- National Library of Medicine. The pathophysiology of intrahepatic cholestasis of pregnancy.
- National Library of Medicine. Perinatal outcomes of intrahepatic cholestasis of pregnancy in twin versus singleton pregnancies: is plurality associated with adverse outcomes?
- National Library of Medicine. Intrahepatic cholestasis of pregnancy is common among patients' first-degree relatives.
- National Library of Medicine. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study.
- National Library of Medicine. Maternal cholestasis during pregnancy programs metabolic disease in offspring.
- National Library of Medicine. Evaluating the effectiveness and safety of Ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy.
- National Library of Medicine. ACOG Committee Opinion No. 764: Medically Indicated Late-Preterm and Early-Term Deliveries.
- UpToDate. Intrahepatic cholestasis of pregnancy.