Considerations After an Intrahepatic Cholestasis of Pregnancy
Considerations After Pregnancy Intrahepatic Cholestasis

Considerations After an ICP Pregnancy

The exact cause of Intrahepatic Cholestasis of Pregnancy (ICP) is unknown but is thought to be caused by a combination of genetic, environmental and hormonal factors. Genes such as ABCB4 which control for bile acid transport in the liver have been identified in cases that occur in families and this gene is probably responsible for about 15% of ICP pregnancies.1 These same genes also can cause liver disorders outside of pregnancy including Progressive familial intrahepatic cholestasis (PFIC) and gallstones.1

It is often assumed that ICP is a pregnancy specific disorder that resolves when the pregnancy is over and causes no life-long health concerns. Recent research indicates this is not always the case. Patients who have had pregnancies with this condition are at greater risk for developing disorders of the liver and biliary tract.2,3,4,5 Intrahepatic Cholestasis of Pregnancy may also develop due to an underlying liver condition.6

There is still much to be learned about ICP after a pregnancy and many questions still to be researched. We present a summary of much of the current literature below.

Future Medical Risks After Intrahepatic Cholestasis of Pregnancy (ICP)

Several studies have followed patients after Intrahepatic Cholestasis of Pregnancy (ICP) to monitor future disease development. The good news is that many of these studies showed overall life expectancy in patients with a history of this is not reduced.7,8 The majority of effects on further health history in these patients appears to be disorders of the gastrointestinal system.

Intrahepatic Cholestasis of Pregnancy has been linked with the later development of hepatobiliary disease, including gallbladder diseases (gallstones and inflammation/cholangitis), pancreatitis, non-alcoholic fatty liver disease (NAFLD) and liver cirrhosis.9  Patients with a history of ICP were 5 times more likely to have gastrointestinal issues such as alcoholic liver disease and pancreatitis.8 Other studies have also shown about a 1.5 times increased risk of liver disorders after it compared to patients without ICP.3

The most common gastrointestinal disorder after an ICP pregnancy is gallstones, and patients with it are more likely to need removal of their gallbladder.10 Removal of the gallbladder does not decrease the risk for recurrence of this in a future pregnancy, since ICP is caused by abnormal flow of bile in the liver.5 At least one gene that can cause Intrahepatic Cholestasis of Pregnancy, ABCB4, also increases the risk of gallstones.10

Monrose et al discuss in their study that it cannot be proven that it causes permanent liver damage. It is instead theorized that “ICP may unmask undiagnosed liver disease or may be an important risk factor for liver disease”3

One study showed a slightly increased risk of liver cancer and hepatobiliary cancer in patients with ICP.2 Most of these cancers of the biliary tract occurred in patients who also had either gallstones or a history of inflammation of the gallbladder (cholangitis). Liver cancer was also more common in patients who also had Hepatitis C. A later study which followed patients with Intrahepatic Cholestasis of Pregnancy (ICP) for 27-46 years after their pregnancies showed no increased risk of hepatobiliary cancer.8 If there is a correlation, it seems to be minor as this is an extremely rare cancer and should not be a common concern.

Studies have also shown a correlation between ICP and autoimmune disorders. The strongest link seems to be between ICP and hypothyroidism.2

It is reassuring to note that studies have not found a correlation with overall future cancer development or an increase in cardiovascular diseases.4,8

What is responsible for these increased conditions?

The same process that causes Intrahepatic Cholestasis of Pregnancy may be responsible for further hepatobiliary and autoimmune issues. The same genes at play in ICP are known to cause other hepatobiliary disease.

“The explanation might be the genetic predisposition rather than the history of ICP itself. The shared risk factors, such as mutations in particular genes, might influence the pathogenesis of ICP as well as other diseases of the digestive system. Both ICP and gallstone diseases are associated with the ABCB4 gene”.4

Patients who have previously been diagnosed with Hepatitis C are at increased risk of developing Intrahepatic Cholestasis of Pregnancy (ICP). Many of the patients with ICP who go on to develop liver cirrhosis are thought to also have Hepatitis C.

Underlying Liver Disorders

The other question is whether a patient might have an underlying liver condition that causes an increased risk of developing Intrahepatic Cholestasis of Pregnancy. Some of these disorders can present with itching, dark urine and elevated bile acids in pregnancy. In some cases, the underlying disorder causes elevated bile acids and not a “true ICP”. Primary Biliary Sclerosis (PBC) and Primary Sclerosing Cholangitis (PSC) are two conditions that can present with elevated bile acids early in pregnancy. In fact, a study has shown that ⅓ of diagnoses of PBC are made during pregnancy in patients who were previously unaware they had the disorder.11

Hepatitis C has been strongly linked to the development of ICP. There is a higher risk of Intrahepatic Cholestasis of Pregnancy in patients with autoimmune hepatitis, alpha-1 antitrypsin deficiency, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis (PFIC). Some of these conditions may be unknown to the patient, and the pregnancy with ICP might be the first sign that there is an underlying liver disorder.12 In some disorders the symptoms may be subtle, and the patient may be unaware of the underlying condition.13

Given these risks of underlying liver disorders, the current recommendation is for repeat liver function testing 6-12 weeks after a pregnancy in all patients with Intrahepatic Cholestasis of Pregnancy (ICP). Should the testing continue to be elevated, referral should be made to a hepatologist for further evaluation. This evaluation usually includes a full history, a family history, liver ultrasound and a panel of blood testing to look for any underlying conditions.9 Patients with ICP are also recommended to have screening for Hepatitis C.10

There are some clues as to who might have more risk of an underlying disorder. These include: severe Intrahepatic Cholestasis of Pregnancy, first trimester onset of ICP, familial history of several members with ICP or gallstones under the age of 40, and elevated GGT in pregnancy that does not go back to normal postpartum.12

One of the questions that needs to be further investigated is whether an ICP pregnancy that is caused by an underlying liver disorder needs different management. Often in these cases, the cholestasis occurs in the first trimester or is very severe. Since little is known about the risks to these specific patients in pregnancy, there should be consideration for individualized treatment. Many of these patients will have bile acids that are severely elevated over 100 µmol/L early in pregnancy.13

A large 2019 meta-analysis showed that the risks in an ICP pregnancy were highly correlated with levels of the bile acid elevations. Risks for preterm labor were increased when bile acid levels were over 40 µmol/L and risk for stillbirth was also increased with higher levels and most pronounced when levels reached 100 µmol/L.14 Therefore, it likely does not matter if the elevated bile acids are a result of Intrahepatic Cholestasis of Pregnancy or an underlying liver disorder, because elevation of the bile acids appears to cause the risk to the fetus. A case report documenting an IUFD in a patient with BRIC with an early onset argues for more aggressive treatment in patients with early and severe onset disease from underlying liver abnormalities.13

Risk for future Intrahepatic Cholestasis of Pregnancy (ICP)

Up to 90% recurrence risk for ICP in a future pregnancy has been noted.15 Other risk factors linked with the development of it include hormonal treatment such as in IVF pregnancies or elevated hormones in twin pregnancies. These risks might not occur in the next pregnancy and might reduce the chance of recurrence. Patients should be aware ICP is likely to recur and should monitor for symptoms. There is no standard of care for management of the next pregnancy after Intrahepatic Cholestasis of Pregnancy. Some physicians may choose to monitor bile acid levels at the start of a pregnancy and others might choose to follow the clinical course.

Risk to children from pregnancies complicated by ICP

There have been a few different studies that look at the long-term risks to the children that are born from a pregnancy that is complicated by ICP. The findings of these studies are reassuring.

One study looked at the health of female offspring from ICP pregnancies followed to around the age of 30. The only statistically increased disease was a history of seizures (epilepsy). The exact cause of this difference is unknown. Otherwise, the health of daughters from an ICP pregnancy was not affected by their mother’s ICP.16

A separate study also looked at the health of male offspring and found the only statistically significant difference was an increase in hives (urticaria) in the ICP group. This was not thought to significantly affect their health. The conclusions of both studies were that the children’s health was the same as people born after non-ICP pregnancies.17

We do know that some cases of ICP are caused by genetic mutations. These could be inherited by the offspring. Both of the studies of the daughters and sons of ICP pregnancies showed some increases in liver disorders. Female offspring had an increased risk of gallstones, elevated liver tests, acute hepatitis and fatty liver disease. None of these risks was statistically significant. Male offspring showed an increased risk of acute hepatitis and gallstones. Again this difference was not significant.The offspring were only followed until an average age of 30. If they were followed longer, it is possible these differences might have become statistically significant. There might be more risk of a long term liver health issue in these offspring, possibly due to inheriting the genes that cause ICP and other liver disorders.16,17

Other studies have considered whether a pregnancy with ICP predisposes the offspring to metabolic disorders such as obesity, diabetes or elevated cholesterol. In a study of 45 ICP cases, it was shown that at the age of 16, female offspring had increased hip and waist girth and decreased HDL cholesterol. Male offspring at the age of 16 were shown to have an increased BMI and fasting insulin level. These findings were then compared with findings from a study involving a mouse model of a cholestasis pregnancy which showed that mice from these pregnancies may be predisposed to a metabolic syndrome including obesity and diabetes. None of these pregnancies were treated with Ursodeoxycholic acid which might play a role in stopping this programming towards a metabolic syndrome.18 In fact, a separate study looking at lipid alteration in cord blood of infants born to ICP pregnancies showed that while ICP can change the lipid profile in fetuses exposed, these changes were reversed with the use of Ursodeoxycholic acid. A further mouse model confirmed that these metabolic changes may be reversed by the use of UDCA.19

In the prior discussed studies following the ICP populations for many years after delivery, there were no differences in BMI or diabetes in those studies that followed offspring to the age of 30.

Contraception

Intrahepatic Cholestasis of Pregnancy (ICP) is thought to be due to a combination of factors of pregnancy, and one of these is the increased amounts of hormones including estrogen and progesterone. There have been concerns raised in the past about whether it is safe to take birth control after a pregnancy with ICP.

There are some case reports in the literature of patients with prior ICP having a return of a cholestasis picture with the use of birth control. In recent studies, it seems more likely that this will occur in patients who have some genetic predisposition to Intrahepatic Cholestasis of Pregnancy. Patients who have mutations in the genes that encode for the bile acid transporters are more likely to react to birth control, as the hormones are thought to disrupt the flow of bile. If a patient has a mutation in the bile transporter genes, they are found to have a 3 times increased risk of developing cholestasis with birth control. These mutations are more common in patients who had early or severe ICP or patients with a strong family history of ICP. The cholestasis from the birth control resolves within weeks to months of stopping the medication and does not seem to pose any long-term risk.20

If a patient has cholestasis from use of birth control or has continued itching postpartum, it is recommended that they be evaluated by a physician or hepatologist for underlying liver disorders.20

Cyclic itching after Intrahepatic Cholestasis of Pregnancy (ICP)

Some patients with a history of ICP will have itching after pregnancy around the time of their menstrual cycle. This phenomenon has not been well studied and needs further research. Given that the hormones of pregnancy are able to affect bile acid transport and cause ICP in pregnancy, it is possible that the fluctuations in the hormones during the menstrual cycle are also able to cause cholestasis.

It is recommended that any patient who has episodes of itching after pregnancy be evaluated by a gastroenterologist (GI specialist) for other liver disorders such as benign recurrent intrahepatic cholestasis (BRIC) progressive familial intrahepatic cholestasis (PFIC), autoimmune hepatitis, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that can cause itching.11

Genetic Screening

Several genes that encode for bile acid transport have been linked to the development of Intrahepatic Cholestasis of Pregnancy including ABCB11, ABCB4 and ATP8B1. These genes can also cause liver and gallbladder issues later in life.

It is currently recommended by the American Association for the Study of Liver Diseases that patients with the following have genetic screening:

  • Severe ICP (Bile acids greater than 100 µmol/L)
  • Recurrent Intrahepatic Cholestasis of Pregnanc (ICP)
  • Early onset ICP (usually first trimester)

It is thought that much of the risk for further liver and gallbladder disorders might come from the effects of these genes. There is a higher risk of benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis (PFIC) in patients with these gene mutations. Both of these syndromes can cause episodes of itching outside of pregnancy.11

Conclusions:

Intrahepatic Cholestasis of Pregnancy (ICP), while often limited to pregnancy, could be an indicator of an underlying liver disorder. Patients with multiple family members with liver/gallbladder conditions, early or severe ICP should consider follow up with a liver specialist postpartum. These patients should also consider genetic screening for mutations that can cause ICP.

Women with Intrahepatic Cholestasis of Pregnancy are at most risk for gallbladder disease and diseases of the gastrointestinal system in the future. Overall life expectancy is not reduced and risk overall for cancer is not increased. There is also an increased risk of autoimmune hypothyroidism in patients with ICP.

Several gene mutations have been indicated in the development of ICP including ABCB11, ABCB4 and ATP8B1. These genes encode for biliary transport. Up to 15% of cases of Intrahepatic Cholestasis of Pregnancy (ICP) are thought to be due to these mutations.

Studies of the offspring of pregnancies complicated by ICP show no significant health differences when followed out to the age of 30. One study did show some metabolic effects in the children but these were reversed with use of ursodeoxycholic acid in pregnancy.

Patients with Intrahepatic Cholestasis of Pregnancy should be screened for Hepatitis C due to a strong correlation.

Hormonal contraception can be used by most patients with a history of ICP. There is a small subset of patients who will have a return of itching and cholestasis symptoms with the use of hormonal contraception. These patients are more likely to have an underlying genetic mutation in one of the genes that codes for bile acid transport and should see GI for further evaluation.

References
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