Association of Adverse Perinatal Outcomes of Intrahepatic Cholestasis of Pregnancy With Biochemical Markers: Results of Aggregate and Individual Patient Data Meta-Analyses

Ovadia C., Seed P.T., Sklavounos A., Geenes B., Di Ilio C., Chambers J., Kohari K., Bacq Y., Bozkurt N., Brun-Furrer R., Bull L., Estiú M.C., Grymowicz M., Gunaydin B., Hague W.M., Haslinger C., Hu Y., Kawakita T., Kebapcilar A.G., Kebapcilar L., Kondrackienė J., Koster M.P.H., Kowalska-Kańka A., Kupčinskas L., Lee R.H., Locatelli A., Macias R.I.R., Marschall H.U., Oudijk M.A., Raz Y., Rimon E., Shan D., Shao Y., Tribe R., Tripodi V., Abide C.Y., Yenidede I., Thornton J.G., Chappell L.C., and Williamson C.

I ntrahepatic cholestasis of pregnancy has been associated with adverse perinatal outcomes, including preterm labor, fetal asphyxia, meconium-stained amniotic fluid, and stillbirth. Although studies have found an increased risk of these complications when the serum bile acid concentration is > 40 µmol/L, there currently are no studies to indicate a specific concentration threshold that is predictive of fetal death. The purpose of this systematic review and metaanalysis was to quantify adverse perinatal complications in relation to serum bile acid concentrations and to determine whether specific concentration levels were associated with the risk of stillbirth and preterm birth.
Studies for possible inclusion in the meta-analysis were identified by searching PubMed, Web of Science, and Embase databases from their origination until June 1, 2018. Only randomized controlled trials, and case control, cohort, and population-based studies were eligible; unpublished data from 2 hospitals in the United Kingdom were also included in the analysis. The studies had to define intrahepatic cholestasis based on pruritus and elevated serum bile acid concentrations to be included. Random effects metaanalysis of aggregate data was performed as well as individual patient data (IPD) meta-analysis using logistic regression methods. IPD were requested from the authors of the studies used for the analysis. The investigators assessed the risk of adverse outcomes in women with cholestasis and determined any association between elevated bile acid concentration and stillbirth.
In total, 109 full-text articles were reviewed, of which 23 studies met criteria for inclusion in the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165,136 controls), and 27 were used for the IPD meta-analysis (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 0.91% of intrahepatic cholestasis of pregnancy cases compared with 0·32% of control pregnancies in the aggregate data analysis, resulting in an odds ratio (OR) of 1·46 [95% confidence interval (CI): 0.73-2.89]. The IPD analysis found in singleton pregnancies that bile acid concentration was a better predictor of stillbirth than alanine or aspartate aminotransferase. An association was found between maximum serum bile acid concentration and risk of stillbirth, with the risk significantly increased for women with levels of ≥ 100 µmol/L (P < 0.0001). Women with bile acid concentration of <40 µmol/L had the lowest prevalence of stillbirth while the highest prevalence occurred in women a level of ≥ 100 µmol/L.
In the aggregate data meta-analysis, a diagnosis of intrahepatic cholestasis of pregnancy was also associated with increased risk of other adverse outcomes compared with women without the diagnosis. Risks of both spontaneous and iatrogenic preterm birth were increased (OR 3.47; 95% CI: 3.06-3.95 and OR 3.65; 95% CI: 1.94-6.85, respectively) as were risks of meconium-stained amniotic fluid (OR 2.60; 95% CI: 1.62-4.16) and neonatal intensive care unit admission (OR 2.12; 95% CI: 1.48-3.30).
In conclusion, these investigators found a significantly elevated risk of stillbirth in women with intrahepatic cholestasis of pregnancy when bile acid concentrations were ≥ 100 µmol/L. However, the majority of women with cholestasis have bile acid concentrations below that level so their risk of stillbirth is not considered significantly higher than pregnant women without the disorder. It is recommended that bile acid testing be done regularly until delivery in women with cholestasis to identify further increases that would put a woman at higher risk of stillbirth.

Preventability Review of Severe
Maternal Morbidity