Daniele Di Mascio1, Johanna Quist-Nelson2, Melissa Riegel2, Brandon George3, Gabriele Saccone4, Romana Brun5, Christian Haslinger5, Christina Herrera6,7,8, Tetsuya Kawakita9, Richard H Lee10, Pierluigi Benedetti Panici1, Vincenzo Berghella2. 1. Department of Maternal and Child Health and Urological Sciences, "Sapienza" University of Rome, Rome, Italy. 2. Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Sidney Kimmel Medical College - Thomas Jefferson University, Philadelphia, PA, USA. 3. Jefferson College of Population Health, Thomas Jefferson University, Philadelphia, PA, USA. 4. Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples "Federico II", Naples, Italy. 5. Division of Obstetrics, University Hospital Zurich, Zurich, Switzerland. 6. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA. 7. Intermountain Healthcare Division of Maternal Fetal Medicine, Salt Lake City, UT, USA. 8. Division of Maternal Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 9. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Medstar Washington Hospital Center, Washington, DC, USA. 10. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
Abstract
BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is characterized by the elevation of total bile acids (TBAs). The primary concern in women with ICP is the increased risk of stillbirth. ICP is generally considered as "mild" when TBA levels range from 10 to 39 µmol/L and "severe" with levels greater than 40 µmol/L, although levels of TBA ≥100 µmol/L have been also considered as a further threshold of severity. OBJECTIVE: To quantify the association between different severities of ICP (TBA 10-39, 40-99, and ≥100 µmol/L) and perinatal death. DATA SOURCES: Medline, Embase, Scopus, Web of Sciences, and ClinicalTrial.gov were searched from the inception of each database to February 2019. METHODS OF STUDY SELECTION: Randomized, cohort, case-control, or case series studies reporting maternal and perinatal outcomes on women with ICP by the three prespecified TBA levels (10-39, 40-99, and ≥100 µmol/L) were included. We excluded multiple gestations and trials which included an intervention. The analysis was performed with Pearson chi-square and Fisher's exact test as appropriate. Continuous outcomes were compared using metaregression with inverse variance weighting using reported sample sizes and standard deviations. Pairwise comparisons used a Bonferroni correction to control for multiple testing. TABULATION, INTEGRATION, AND RESULTS: Six articles including 1280 singleton pregnancies affected by ICP were included in the systematic review. Out of the 1280 singleton pregnancies affected by ICP included, 118 had ICP with TBA ≥100 µmol/L. Perinatal death was more common in women with TBA ≥100 µmol/L (0.4% for TBA 10-39 μmol/L versus 0.3% for TBA 40-99 μmol/L versus 6.8% for TBA ≥ 100 μmol/L, p < .0001). Of the 8 perinatal deaths in the TBA ≥100 µmol/L group, 3 occurred ≥34 weeks. TBA ≥100 µmol/L increased the risk of spontaneous preterm birth (PTB) (5.4% versus 8.6% versus 18.2% respectively, p < .0001) and iatrogenic PTB (10.8% versus 21.6% versus 35.8% respectively, p<.0001) as well as meconium-stained amniotic fluid (9.0% versus 18.4% versus 31.6% respectively, p < .0001). CONCLUSIONS: Maternal TBA ≥100 µmol/L is associated with a 6.8% incidence of perinatal death, most of which (5.9% overall) are stillbirths, while TBA <100 µmol/L are associated with an incidence of perinatal death of 0.3%. It may be reasonable to consider late preterm delivery (at about 35-36 weeks) in women with TBA ≥100 µmol/L.
BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is characterized by the elevation of total bile acids (TBAs). The primary concern in women with ICP is the increased risk of stillbirth. ICP is generally considered as "mild" when TBA levels range from 10 to 39 µmol/L and "severe" with levels greater than 40 µmol/L, although levels of TBA ≥100 µmol/L have been also considered as a further threshold of severity. OBJECTIVE: To quantify the association between different severities of ICP (TBA 10-39, 40-99, and ≥100 µmol/L) and perinatal death. DATA SOURCES: Medline, Embase, Scopus, Web of Sciences, and ClinicalTrial.gov were searched from the inception of each database to February 2019. METHODS OF STUDY SELECTION: Randomized, cohort, case-control, or case series studies reporting maternal and perinatal outcomes on women with ICP by the three prespecified TBA levels (10-39, 40-99, and ≥100 µmol/L) were included. We excluded multiple gestations and trials which included an intervention. The analysis was performed with Pearson chi-square and Fisher's exact test as appropriate. Continuous outcomes were compared using metaregression with inverse variance weighting using reported sample sizes and standard deviations. Pairwise comparisons used a Bonferroni correction to control for multiple testing. TABULATION, INTEGRATION, AND RESULTS: Six articles including 1280 singleton pregnancies affected by ICP were included in the systematic review. Out of the 1280 singleton pregnancies affected by ICP included, 118 had ICP with TBA ≥100 µmol/L. Perinatal death was more common in women with TBA ≥100 µmol/L (0.4% for TBA 10-39 μmol/L versus 0.3% for TBA 40-99 μmol/L versus 6.8% for TBA ≥ 100 μmol/L, p < .0001). Of the 8 perinatal deaths in the TBA ≥100 µmol/L group, 3 occurred ≥34 weeks. TBA ≥100 µmol/L increased the risk of spontaneous preterm birth (PTB) (5.4% versus 8.6% versus 18.2% respectively, p < .0001) and iatrogenic PTB (10.8% versus 21.6% versus 35.8% respectively, p<.0001) as well as meconium-stained amniotic fluid (9.0% versus 18.4% versus 31.6% respectively, p < .0001). CONCLUSIONS: Maternal TBA ≥100 µmol/L is associated with a 6.8% incidence of perinatal death, most of which (5.9% overall) are stillbirths, while TBA <100 µmol/L are associated with an incidence of perinatal death of 0.3%. It may be reasonable to consider late preterm delivery (at about 35-36 weeks) in women with TBA ≥100 µmol/L.