Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

• Autores: Ovadia, Caroline; Seed, Paul T.; Sklavounos, Alexandros; Geenes, Victoria; Di Illio, Chiara; Chambers, Jenny; Kohari, Katherine; Bacq, Yannick; Bozkurt, Nuray; Brun Furrer, Romana; Bull, Laura; Estiú, Maria C.; Grymowicz, Monika; Gunaydin, Berrin; Hague, William M.; Haslinger, Christian; Hu, Yayi; Kawakita, Tetsuya; Kebapcilar, Ayse G.; Kebapcilar, Levent; Kondrackienė, Jūratė; Koster, Maria P. H.; Kowalska, Kańka; Kupčinskas, Limas; Lee, Richard H.; Locatelli, Anna; Macias, Rocio I.R.; Marschall, Hanns Ulrich; Oudijk, Martijn A.; Raz, Yael; Rimon, Eli; Shan, Dan; Shao, Yong; Tribe, Rachel; Tripodi, Valeria Paula; Yayla Abide, Cigdem; Yenidede, Ilter; Thornton, Jim G.; Chappell, Lucy C.; Williamson, Catherine
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: BILE ACIDS; INTRAHEPATIC CHOLESTASIS OF PREGNANCY
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Background Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. Methods We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and populationbased studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. Findings We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73–2·89]; I²=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74–0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35–0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02–0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08–0·72) of 1412 cases with total bile acids of 40–99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52–10·50]; p=0·26), and versus 18 (3·44%; 2·05–5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83–105·30]; p<0·0001). Interpretation The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy 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. Funding Tommy’s, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.
Fil: Ovadia, Caroline. King's College; Reino Unido
Fil: Seed, Paul T.. King's College; Reino Unido
Fil: Sklavounos, Alexandros. King's College; Reino Unido
Fil: Geenes, Victoria. King's College; Reino Unido
Fil: Di Illio, Chiara. King's College; Reino Unido
Fil: Chambers, Jenny. King's College; Reino Unido
Fil: Kohari, Katherine. University of Yale; Estados Unidos
Fil: Bacq, Yannick. Universite de Tours; Francia
Fil: Bozkurt, Nuray. Gazi University School Of Medicine; Turquía
Fil: Brun Furrer, Romana. University Hospital of Zurich; Suiza
Fil: Bull, Laura. University of California; Estados Unidos
Fil: Estiú, Maria C.. Ramón Sardá Mothers and Childrens Hospital; Argentina
Fil: Grymowicz, Monika. Warsaw Medical University; Polonia
Fil: Gunaydin, Berrin. Gazi University School of Medicine; Turquía
Fil: Hague, William M.. University of Adelaide; Australia
Fil: Haslinger, Christian. University Hospital of Zurich; Suiza
Fil: Hu, Yayi. Sichuan University; China
Fil: Kawakita, Tetsuya. MedStar Washington Hospital Center; Estados Unidos
Fil: Kebapcilar, Ayse G.. Selcuk University; Turquía
Fil: Kebapcilar, Levent. Selcuk University; Turquía
Fil: Kondrackienė, Jūratė. Lithuanian University of Health Sciences; Lituania
Fil: Koster, Maria P. H.. No especifíca;
Fil: Kowalska, Kańka. Institute of Mother and Child; Polonia
Fil: Kupčinskas, Limas. Lithuanian University of Health Sciences; Lituania
Fil: Lee, Richard H.. University of Southern California; Estados Unidos
Fil: Locatelli, Anna. Università degli Studi di Milano; Italia
Fil: Macias, Rocio I.R.. Universidad de Salamanca; España
Fil: Marschall, Hanns Ulrich. University of Gothenburg; Suecia
Fil: Oudijk, Martijn A.. University of Amsterdam; Países Bajos
Fil: Raz, Yael. Tel Aviv Medical Center; Israel
Fil: Rimon, Eli. Tel Aviv Medical Center; Israel
Fil: Shan, Dan. Sichuan University; China
Fil: Shao, Yong. The First Affiliated Hospital of Chongqing Medical University; China
Fil: Tribe, Rachel. King's College; Reino Unido
Fil: Tripodi, Valeria Paula. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Yayla Abide, Cigdem. University of Health Sciences; Turquía
Fil: Yenidede, Ilter. University of Health Sciences; Turquía
Fil: Thornton, Jim G.. University of Nottingham; Estados Unidos
Fil: Chappell, Lucy C.. King's College; Reino Unido
Fil: Williamson, Catherine. King's College; Reino Unido