In 2019, families affected by intrahepatic cholestasis of pregnancy (ICP) saw the publication of a study which questioned the benefits of the frontline medication, ursodeoxycholic acid (Ursodiol)². The year 2020…well, we all know how that went. Now 2021 has come, and two new studies have been published that offer new evidence which support the benefits and the continued use of ursodeoxycholic acid to treat ICP.

Study 1

The first of the two studies is a meta-analysis, which included data from the 2019 study, as well as other studies and additional previously unpublished data1. One of the constant problems for any research into Cholestasis of Pregnancy is that there are never enough data points to get really solid evidence. This meta-analysis tried to overcome this problem.

What we already knew

Ursodeoxycholic acid has uncertain benefits

The 2019 study (PITCHES), was the first randomized, controlled trial to compare outcomes in ICP pregnancies treated with Ursodiol versus placebo. The study found a modest reduction in itching in pregnant patients, but wasn’t able to find any evidence to prove benefit to the baby². The study measured a composite outcome of stillbirth, admission to NICU, preterm delivery, and a number of secondary outcomes such as bile acid levels. The composite outcome was not impacted by the use of Ursodiol in this study. Stillbirth, however, did not happen with enough frequency to allow for analysis. Stillbirth is the outcome ICP families care about most, and given the lack of certainty around this outcome, many of us continued to believe that Ursodiol was still our best available treatment for intrahepatic cholestasis of pregnancy.

What we learned from the new meta-analysis on the use of Ursodiol

With higher powered meta-analysis, Ursodeoxycholic acid appears to improve outcomes

In this new study, many of the measures of fetal outcome were improved with the use of ursodeoxycholic acid, including the composite (meaning calculated together) outcome of stillbirth and preterm birth, spontaneous (meaning not induced) preterm birth in singleton pregnancies, total preterm birth for singletons and multifetal pregnancies, and meconium staining of the amniotic fluid.

Not all outcomes were improved

Ursodiol did not reduce the amount of early preterm birth (before 34 weeks). Probably more importantly, when the study looked at stillbirth alone (rather than as a composite of stillbirth and preterm birth), no benefit was found. This doesn’t mean that no benefit exists. The age-old problem of not enough data was once again the culprit. Stillbirth is a rare event, and there were just not enough of them to allow for accurate analysis. We do know that stillbirth can still happen, even when treated with Ursodiol, and this study does not allow us to conclude that ursodeoxycholic acid is able to fully eliminate the risk of stillbirth.

Higher bile acids mean higher risk

Confirming the results of many previous studies, higher bile acids resulted in higher risk of stillbirth. Stillbirth levels for the lower bile acid groups were similar to those found in previous meta-analysis³. Ursodiol showed the most benefit for pregnancies in which bile acids were over 40μmol/L, so medication is especially important for those cases.

Study 2

The second 2021 study, “Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations,” gives us more insight into how the medicine ursodeoxycholic acid (Ursodiol) may function when used to treat intrahepatic cholestasis of pregnancy⁴. While we still don’t have all the answers, we hope this translates to lower risk for this high risk condition.

What we already knew

Not all bile acids are equal⁵

There are many types of bile acids which occur naturally in the body. Some of these are more toxic than others. This can be measured by something called the hydrophobicity index (HI). A higher HI means the bile acid is more toxic. Ursodiol is a pill form of a naturally-occuring bile acid called Ursodeoxycholic Acid (UDCA). UDCA has a very low HI, which means it isn’t toxic in the way that other bile acids are.

ICP causes issues with the unborn baby’s heart⁶

There has been a lot of research to support this, however these issues aren’t usually predicted by traditional fetal monitoring. The current thinking at the time of writing is that stillbirth is the result of a sudden cardiac event caused by changes to the unborn baby’s heart cells. These changes have been linked to the elevated bile acids.

There are other markers of fetal distress not measured by fetal monitoring⁷

There is a marker called NT-proBNP which is a good indicator of fetal distress, even when the distress isn’t apparent on fetal monitoring. The marker can be used to diagnose heart failure and dysfunction. This can be measured by testing umbilical vein blood at birth. We know that this marker is higher, on average, in babies born to people with ICP.

The bile acid pool is altered by ICP⁸

Not only are the total bile acids higher, the types of bile acids that make up the pool are different in patients with ICP. The majority of the bile acid pool is made up of glycocholic acid and taurocholic acid. The bad news is that these have a really high HI, which makes them very toxic.

What we learned from this study

ICP causes higher levels of NT-proBNP (marker of fetal distress), but not when it is treated.

From this study, we learned that higher bile acids are linked with higher levels of that marker of fetal distress, NT-proBNP, as well as other indicators of baby’s heart function, but only when ICP is untreated. When ICP was treated with Ursodeoxycholic acid (Ursodiol), higher bile acids were no longer linked with higher NT-proBNP.

Why?

When a patient is treated with Ursodiol, this changes the bile acid pool. In ICP, as we already saw, most of the bile acid pool is made of really toxic bile acids. Ursodiol replaces these toxic bile acids in the patient’s blood, so even though the total bile acids are still high, they are no longer as problematic. In treated ICP, most of the bile acid pool is made up of Ursodeoxycholic acid instead of the more toxic bile acids. It may be that the bile acid HI (level of toxicity) is more important than the total bile acids in determining risk.

The protective effect is not 100%

There is another way to measure heart function, called the PR interval. This measures how well signals are moving from the top chambers of the heart (atria) to the lower chambers (ventricles). If signals aren’t travelling well, this indicates a problem with heart function. In this study, higher PR intervals were linked with higher bile acids for both treated and untreated ICP, meaning that Ursodiol doesn’t completely protect the baby’s heart against all changes.

What we hope but can’t yet prove

We hope that the decreased fetal distress translates to decreased stillbirth. Logically, we can see how it might. We know that NT-proBNP indicates fetal distress. We know that fetal distress sometimes leads to stillbirth. We know that Ursodiol lowers the levels of NT pro-BNP. However, we do not yet know if this plays out in the real world to actually reduce stillbirth. This is because stillbirth is a rare event, and there are not enough of them to analyze in studies.

Even though we still have no proof that Ursodiol reduces stillbirth, what we learned in these studies is good news for those of us with ICP. This is the first reliable, measurable evidence we have of fetal benefit from the use of ursodeoxycholic acid. The Society for Maternal-Fetal Medicine has continued to be supportive of the use of Ursodiol in ICP pregnancies, even when the fetal benefit was unclear in 2019. Now that there is more evidence from these studies showing benefit, this is a medication that should be used in pregnancies with ICP.

Over the past two years, patients and providers have been riding a pendulum of shifting recommendations and advice. If your provider is not aware of the most recent evidence, don’t be surprised. Share these important studies, and engage in a discussion of the benefits of treatment with Ursodiol.