By Camille Hoffman, MD, MSc
Associate Professor, Maternal Fetal Medicine, University of Colorado Departments of Obstetrics and Gynecology and Psychiatry, Wheat Ridge, CO
Dr. Hoffman reports no financial relationships relevant to this field of study.
SYNOPSIS: While a diagnosis of intrahepatic cholestasis of pregnancy is associated with an increased risk for stillbirth, preterm birth, and neonatal respiratory issues, consensus on management within the obstetrics community has not been reached.
SOURCE: Ovadia C, Seed PT, Sklavounos A, et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: Results of aggregate and individual patient data meta-analyses. Lancet 2019;393:899-909.
The objective of this systematic review was to clarify the relationship between the range of serum bile acid concentrations and perinatal outcomes (i.e., stillbirth and preterm birth) in pregnant women diagnosed with intrahepatic cholestasis of pregnancy (ICP). Criteria defining ICP included pruritis and highest recorded total serum bile acid concentration (TBA) in singleton pregnancies. Trials involving at least 30 participants (i.e., no case reports or case series) were included in the analysis along with unpublished data from two United Kingdom hospitals. After criteria were applied, the authors analyzed 23 studies using 5,557 cases of ICP and 165,136 controls.
After review, the authors determined that the overall risk of stillbirth was not increased when compared to controls (odds ratio 1.4; 95% confidence interval, 0.73-2.89). When categorized by highest TBA concentration, stillbirth occurred in 3/2,310 (0.13%) ICP cases with TBAs < 40 µmol/L; 4/1,412 (0.28%) with TBAs 40-99 µmol/L; and 18/524 (3.44%) of cases with TBAs ≥ 100 µmol/L. In comparison, the risk of stillbirth in the control group was 519/163,947 (0.32%). Further assessment of these data indicated that both spontaneous preterm birth and iatrogenic preterm births were increased across all TBA categories from 32-34 weeks gestation and greater, and that preterm births (mostly iatrogenic) occurred in 16.5% of pregnancies with TBAs ≥ 100 µmol/L group and in 8.9% of pregnancies with TBA between 40-99 µmol/L.
The authors concluded that the risk of stillbirth was greatest in pregnant women with ICP whose peak TBAs were 100 µmol/L or greater. This risk began to increase most dramatically around 36 weeks gestation and beyond. Risks of both spontaneous and iatrogenic preterm birth were greater in women with ICP compared to controls, regardless of the TBA concentration.
Previous studies of ICP have attempted to identify both an ideal gestational age for delivery and a threshold of TBAs that increase the risk of stillbirth.1 Smaller studies suggest that TBAs > 40 µmol/L are associated with an increased risk of preterm birth2 and potentially stillbirth,3 although these studies are limited by small sample sizes and potentially exaggerated risks. Using a large data registry out of California to calculate a composite mortality risk by gestational week in cases of ICP, the ideal time to deliver is 36 weeks. These data do not account for disease severity or TBAs.2
This study is meaningful for two reasons. First, the authors painstakingly categorized disease severity and outcomes in more than 5,000 pregnancies affected by ICP. With this detailed stratification, they were able to clarify when adverse pregnancy outcomes were most likely to occur and determined that a TBA of ≥ 100 µmol/L significantly increased the risk of stillbirth. TBAs < 100 µmol/L did not hold this risk. Second, they performed survival analysis (Kaplan-Meir) to determine when the stillbirth (and preterm birth) risks become most significant by week of gestation. TBAs > 100 µmol/L were associated with an increase in stillbirth risk starting between 35-36 weeks gestation, and this risk continued to increase as gestation progressed. Current recommendations advise for delivery at 36 weeks based on existing, less sophisticated data. It is reasonable that this approach be continued for women with ICP and TBAs ≥ 100 µmol/L. However, for women with TBAs in the 40-99 µmol/L range, stillbirth risks do not appear to increase prior to 38 weeks and, for women with TBAs < 40 µmol/L, stillbirth risks do not appear to increase over the general population.
- Wikstrom Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: A 12-year population-based cohort study. BJOG 2013;120:717-723.
- Cui D, Zhong Y, Zhang L, Du H. Bile acid levels and risk of adverse perinatal outcomes in intrahepatic cholestasis of pregnancy: A meta-analysis. J Obstet Gynaecol Res 2017;43:1411-1420.
- Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004;40:467-474.