Role of the placenta in serum autotaxin elevation during maternal cholestasis

Intrahepatic cholestasis of pregnancy (ICP) is frequently accompanied by pruritus, whose etiology has been associated with an enhanced production of lysophosphatidic acid (LPA) by the combined action of phospholipase A1/A2 (PLA1/PLA2) and autotaxin (ATX). Here, we have investigated whether the placenta is involved in LPA release to maternal circulation during ICP. Serum levels of ATX and LPA (determined by ELISA) were elevated in women with ICP, and a correlation between both parameters was found. No relationship between serum levels of ATX or LPA and bile acids was found. Expression levels of ATX and PLA2 were determined by RT-qPCR and Western blot. Placenta ATX but not PLA2 was significantly upregulated in ICP, and a tendency to increase was found at the protein level. A correlation between serum ATX and placental ATX mRNA levels was found. In human placenta at term, ATX was clearly detected (by immunofluorescence) in Hofbauer cells, but only faintly in trophoblast cells. In pregnant rats, the expression of Atx and Pla2 in placenta was lower than in liver. When obstructive cholestasis was imposed by bile duct ligation from day 14 of gestation until term, placenta Atx and Pla2 expression was markedly enhanced, and overexpression was confirmed at the protein level for Pla2, whereas Atx protein was not detected. In conclusion, the placenta substantially participates in LPA production during gestation. This contribution is markedly higher during maternal cholestasis and hence, may be involved in ICP-associated pruritus. NEW & NOTEWORTHY Fetal placental macrophages and, to a lesser extent, trophoblast cells express high levels of autotaxin at term. An increased expression of mRNA and protein autotaxin, the key secretory enzyme responsible for the production of lysophosphatidic acid in serum, has been observed in placentas of women with cholestasis of pregnancy, which supports that the placenta can contribute to an increased production of this pruritogenic compound in women suffering from this liver disease

Relationship between hypercholanemia and the frequency of meconium-stained amniotic fluid (MSAF).

<p>Frequency of the presence of MSAF in pregnancies complicated by cholestasis of pregnancy classified according to gestational age (GA) at diagnosis (A) or at delivery (B), severity of hypercholanemia (mild: 10–19.9 μmol/L; moderate: 20–39.9 μmol/L; severe: ≥40 μmol/L) at diagnosis in women not treated (C) or women treated with ursodeoxycholic acid (UDCA), (D), and at delivery in those treated with UDCA (E).</p

Demographic and clinical characteristics of patients.

<p>Demographic and clinical characteristics of patients.</p

Evaluation of the index to predict the risk of meconium-stained amniotic fluid (MSAF).

<p>Balance between sensitivity and specificity for different cut-off values of meconium risk factor (MRF), calculated taking into account the severity of hypercholanemia and gestational age at diagnosis (A). Proportion of cases of MSAF in pregnancies with complications due to cholestasis of pregnancy according to a MRF cut-off value of 3 in women not treated or treated with ursodeoxycholic acid (UDCA) (B).</p

Flow chart of ICP cases included in the study.

<p>Flow chart showing the intrahepatic cholestasis of pregnancy (ICP) cases at the Mother’s and Children’s Hospital, Buenos Aires, from June 2009 to December 2013, and reasons for the exclusion of some patients from the study.</p

Flow chart of management of patients.

<p>Flow chart showing distribution of women with intrahepatic cholestasis of pregnancy (ICP) depending on whether they were not treated or treated with ursodeoxycholic acid (UDCA), together with days of treatment.</p

Relationship between hypercholanemia and body weight at birth.

<p>Gestational age and body weight of neonates born from women with intrahepatic cholestasis of pregnancy (ICP) with high or low weights at birth for their gestational age.</p

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.Fil: Ovadia, Caroline. King's College London; Reino UnidoFil: Sajous, Jenna. King's College London; Reino UnidoFil: Seed, Paul T.. King's College London; Reino UnidoFil: Patel, Kajol. King's College London; Reino UnidoFil: Williamson, Nicholas J.. King's College London; Reino UnidoFil: Attilakos, George. University College London; Estados UnidosFil: Azzaroli, Francesco. Universidad de Bologna; ItaliaFil: Bacq, Yannick. Universite de Tours; FranciaFil: Batsry, Linoy. Universitat Tel Aviv; IsraelFil: Broom, Kelsey. Healthcare Group; AustraliaFil: Brun Furrer, Romana. University Hospital Zurich; SuizaFil: Bull, Laura. University of California; Estados UnidosFil: Chambers, Jenny. Imperial College London; Reino UnidoFil: Cui, Yue. Chongqing Medical University; ChinaFil: Ding, Min. Chongqing Medical University; ChinaFil: Dixon, Peter H.. King's College London; Reino UnidoFil: Estiú, Maria C.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital Materno Infantil Ramon Sarda; ArgentinaFil: Gardiner, Fergus W.. Royal Flying Doctor Service; AustraliaFil: Geenes, Victoria. King's College London; Reino UnidoFil: Grymowicz, Monika. Medical University of Warsaw; PoloniaFil: Günaydin, Berrin. Gazi University School of Medicine; TurquíaFil: Hague, William M. University of Adelaide; AustraliaFil: Haslinger, Christian. University Hospital Zurich; SuizaFil: Hu, Yayi. Sichuan University; ChinaFil: Indraccolo, Ugo. Alto Tevere Hospital of Città di Castello; ItaliaFil: Juusela, Alexander. Newark Beth Israel Medical Center; Estados UnidosFil: Kane, Stefan C. Royal Women's Hospital; Australia. University of Melbourne; AustraliaFil: Kebapcilar, Ayse. Selcuk University; TurquíaFil: Kebapcilar, Levent. Selcuk University; TurquíaFil: Tripodi, Valeria Paula. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research