NEW YORK (360Dx) – A group of researchers led by Guy's and St. Thomas' NHS Foundation Trust and King's College London has developed a method to clarify the adverse pregnancy outcomes and measure the risk of stillbirth in patients with intrahepatic cholestasis of pregnancy (ICP) by using a metadata analysis of patient cohorts from multiple studies. The researchers believe that the analysis can help clinicians stratify patient risk groups depending on the total concentration levels of bile in their systems.
In research described earlier this month in The Lancet, the team found that women who had a serum bile acid concentration of 100 or more micromoles per liter were as much as twice as likely of having a stillbirth as women with lower bile acid concentrations.
Clinicians typically diagnose ICP in patients who have itching sensations without developing rashes during pregnancy. ICP is a liver disorder — occurring in an estimated 1 percent of women of North European Ancestry — that causes build-up of bile acids in a patient's bloodstream and usually occurs within the third trimester of pregnancy.
To be sure that the condition exists, doctors perform a blood-based test to measure the level of enzymatic activity of certain bile acid biomarkers in the patient's bloodstream. However, researchers still do not perfectly understand the link between specific biochemical markers and the patient's risk for stillbirth.
"There's no established treatment for ICP, so clinicians have to think about delivery or drug treatments," Catherine Williamson, the senior author of the study and a professor of human health at Guy's and St. Thomas' and King's College London, explained. She and her colleagues sought to quantify the dangerous perinatal effects of ICP in women with increased serum bile acid concentrations. They also set out to investigate whether elevated bile acid concentrations were linked to the risk of stillbirth and preterm birth.
The group first performed a review of several databases and collected 109 full-text studies published from each of the databases' inception to June 2018, identifying perinatal outcomes for patients with ICP when they could examine serum bile acid concentrations.
When examining the studies, the team narrowed down results to studies defining ICP based on itching and elevated serum bile acid concentrations, with or without raised liver aminotransferase (ATF) concentrations. Eligible studies included case-control, cohort, population-based studies, randomized controlled trials with at least 30 participants, and reported bile acid concentrations and perinatal outcomes.
Williamson and her team then performed a random effects metadata analysis to determine the risk of dangerous perinatal outcomes in patients. They extracted aggregate data for several maternal and perinatal outcomes from case-control studies, including maximum serum bile acid concentrations and liver function tests, ALT concentration, aspartate amino-transferase (APT) concentration, and bilirubin concentration.
The group then asked for individual patient data (IPD) from study authors in order to examine links between biochemical markers and adverse outcomes. To identify whether a certain threshold of total bile acid concentration was linked to increased incidences of stillbirth, the team performed stepwise logistic regression between bile acid categories at 20 micromoles per liter intervals.
Williamson and her team curated data from a final total of 23 studies that reported ICP and control pregnant groups, in addition to comparing perinatal outcomes in ICP with controls. According to the study authors, the studies came from 15 countries across five continents in the aggregate data meta-analysis.
Williamson noted that stillbirth pregnancies only occurred in 45 of 4,936 ICP cases, compared to 519 of 163,947 cases from the control patient data.
For singleton pregnancies, the researchers saw stillbirth in three out of 2,310 ICP cases of women with serum total bile acids of less than 40 micromoles per liter, versus four out of 1,412 cases with total bile acids of between 40 and 99 micromoles per liter, and versus 18 of 524 cases for bile acids of 100 micromole or more.
In the analysis, the team found that women with ICP had a slightly higher BMI and were more likely to be of Asian ethnicity. In addition, a higher proportion of individuals with ICP had pre-eclampsia and gestational diabetes than controls.
Compared to controls, women with ICP also had a higher risk of spontaneous preterm birth and iatrogenic preterm birth. IPD analysis highlighted that — in singleton pregnancies — stillbirth was associated with maximum total bile acid concentration, but not with ALT, APT, and bilirubin.
According to the study, women with singleton pregnancies who had total bile acids with 100 micromoles or more per liter were significantly associated with an increased risk of stillbirth. However, the team did not find a higher stillbirth risk for women with singleton ICP with total bile acids of less than 40 micromoles per liter or 40 to 99 micromoles per liter.
"Because most women with IHC have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery," the study authors noted.
While the risk of preterm birth in female patients with ICP was significant, the researchers did not find any strong link between preterm birth on serum biochemistry. At the same time, they saw that an increase in preterm birth was linked to elevated levels of total bile acid concentrations.
"What's new is understanding where the threshold bile acid concentration for stillbirth risk is and understanding the relationships between the number of weeks of pregnancy and risk of ICP," Williamson explained. "The ability to tell 90 percent of people [that] they're not at risk and 10 percent that they are is crucial for diagnosis and treatment."
"Metadata analysis is a limited technique to aggregate data, but probably the best way to address stillbirth," Stephen Chasen, a professor of clinical obstetrics and gynecology and maternal fetal medicine specialist at Weill Cornell and New York Presbyterian, who is not affiliated with the Lancet study, said.
Williamson said there were several challenges to collecting the data from the wide swath of studies and patient cohorts for the study. In particular, the team was confronted with inconsistent definitions of perinatal outcomes regarding neonatal asphyxia in certain cases, which led to issues comparing different studies.
In addition, William's group struggled to adjust for results that may have been skewed by incomplete reporting in some studies. While the team successfully performed meta-regression for study-level outside influences — including multifetal pregnancy proportions and study quality — it could not account for individual patient elements such as coexistent pre-eclampsia and gestational diabetes.
"Without data on the timings of peak bile acid concentration and associated stillbirth gestation, this study cannot provide further mechanistic evidence to support these models," the study authors noted. "As such, we suggest managing women with [ICP] and singleton pregnancies on the basis of their peak bile acid concentration."
Williamson also noted that her team was intrigued that the inatrogenic — relating to illness caused by medical examination or treatment — stillbirth rate in the analysis was relatively high when the mother’s bile acid concentration was lower than 40 micromoles per liter. She explained that many clinicians will decide to deliver women with ICP before term if they worry that the risk of the fetus remaining in utero is higher than the risk of early delivery.
Williamson pointed out that previous studies have indicated fetal risk is higher when the maternal serum bile acid levels are above 40 micromoles per liter. She therefore believes that doctors in the cases examined in the metadata analysis may have been worried about the patient's liver and decided to deliver the baby early.
"There are obviously downsides to delivering women weeks from their due date, as newborns are at risk of respiratory and breathing complications, and they can spend lots of time in the neonatal ICU," Chasen said. "If it's to prevent stillbirth, that's one thing, but based on this data, I think patients and doctors can agree that … performing it in order to shorten the duration of itching … cannot be justified."
While Williamson said the study's results highlight the need to develop improved bedside testing methods, she did not expand on her team's plans to develop a point-of-care assay for bile acid concentrations. However, she noted that her team has been performing whole-genome sequencing on women with severe early onset disease and plan to release the results soon.
Chasen pointed out that multiple research groups outside the US are also examining how therapy can prevent stillbirth. However, he argued that the studies are very challenging to perform, since stillbirth is such a rare event, "even in the ICP subsets that are associated with or may increase the link of the condition."
"I think [Williamson's] data shows that it's really extreme elevation of bile acids that probably account for the excess rate of stillbirth in this population," Chasen pointed out. "This study can get [doctors] to that level of stratifying women by following [the level of ] bile acids to determine their risk."
Williamson said her team will use the study's findings to stratify care of pregnant patients in future studies. One route involves examining female patients' genetic susceptibility and underlying diagnosis to improve their health after pregnancy. The group is looking at the frequency of pathological mutations in genes known to cause cholestasis.
According to Williamson, another study will pursue rapid ways of evaluating stillbirth risk for more rapid bile acid testing. The team aims to find out whether maternal fasting or the time period during pregnancy that researchers take the blood test may have an impact on the bile acid concentration rate together with the lowest false positive rate.
"We want to understand how bile acid concentrations in the circulation of the mother and baby can influence the risk of stillbirth and other adverse pregnancy outcomes," Williamson noted.