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Original Article
Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy
Relación entre el prurito y la autotaxina en la colestasis intrahepática del embarazo
Sami Cifcia, Kader Irakb, Mehmet Bayramb, Nergiz Ekmenc,
Corresponding author
dr_nergisekmen@hotmail.com

Corresponding author.
, Cemal Kazezoglud, Zuat Acare, Hadi Sasanif
a Basaksehir Cam and Sakura City Hospital, Department of Gastroenterology, Istanbul, Turkey
b SBU Istanbul Kanuni Sultan Süleyman Training and Research Hospital, Department of Gastroenterology, Istanbul, Turkey
c Gazi University Medical Faculty, Department of Gastroenterology, Ankara, Turkey
d SBU Istanbul Kanuni Sultan Süleyman Training and Research Hospital, Department of Biochemistry, Istanbul, Turkey
e SBU Sarıyer Hamidiye Etfal Training and Research Hospital, Department of Perinatology, Istanbul, Turkey
f Tekirdag Namık Kemal University, Faculty of Medicine, Department of Radiology, Tekirdag, Turkey
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Intrahepatic cholestasis of pregnancy &#40;ICP&#41; is a disease that usually occurs in the third trimester and presents with pruritus and elevation in liver enzymes&#46; Pruritus disappears on its own shortly after birth and serum biochemical parameters return to their normal range&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">1</span></a> The etiology of ICP has still not been elucidated today&#44; and its incidence varies greatly depending on ethnicity and geographic location&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">2</span></a> An increase in maternal serum bile salts is observed in ICP<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">3</span></a> and therefore&#44; ursodeoxycholic acid &#40;UDCA&#41; has been the most frequently used medication among treatment options&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">1</span></a> The diagnosis is confirmed by the exclusion of diseases that can explain pruritus&#44; elevated levels of liver enzymes&#44; and fasting serum bile acid &#40;SBA&#41; level being above 10<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a> Severe ICP is the case if the SBA level is greater than 40<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L and is associated with an increased risk of fetal complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Autotaxin &#40;ATX&#41; was first defined in various pathological mechanisms such as tumor cell proliferation and metastasis formation as an autocrine cell motility factor in melanoma cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;8</span></a> ATX plays a crucial role in Lysophosphatidic acid &#40;LPA&#41; production by converting lysophosphatidylcholine to LPA&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> LPA is a small but powerful bioactive phospholipid with a wide range of effects on a multitude of cell types&#44; from cell migration to cytokine production and platelet activation through the inter-cell signal transmission associated with the G protein&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">8&#44;10&#44;11</span></a> It has been shown that in vitro LPA signaling contributes to the production of chemokine from human trophoblast cells&#44; and these chemokines regulate the migration&#44; proliferation&#44; and angiogenesis of human endometrial epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">It has also been shown that LPA plays an important role in a wide variety of reproductive processes&#44; including functional maturation of the endometrium to support embryonic growth&#44; also known as decidualization&#44; as well as implantation&#44; and continuation of pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> It has been found that ATX and LPA concentrations in the peripheral blood of pregnant women gradually increase during pregnancy and rapidly return to their pre-pregnancy level following birth&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> There is a high degree of correlation between blood LPA level and ATX levels&#44; and it has been stated that it could be required for the continuation of pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> In parallel&#44; it is assumed that placental trophoblasts and syncytiotrophoblasts are the sources of elevated ATX levels&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> Besides&#44; it has been stated that fatty tissue&#44; enteroendocrine cells&#44; and liver may also contribute to ATX synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> While examining the effects of ATX on the physiology of pregnancy&#44; a cause-effect relationship was attempted to be established with pregnancy-specific diseases such as pre-eclampsia &#40;PE&#41; and ICP&#46; This relationship has been tried to be explained in various studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">18&#8211;22</span></a> but the results contradict each other&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this study&#44; we aimed to investigate the relationship between pregnancy complications &#40;such as preterm delivery&#44; pruritus&#41; and serum ATX levels in intrahepatic cholestasis of pregnancy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Participants of the study</span><p id="par0025" class="elsevierStylePara elsevierViewall">In 2018&#44; 102 pregnant women were analyzed&#44; who were referred to the gastroenterology outpatient clinic of the hospital with a pre-diagnosis of ICP&#46; Of these patients&#44; 82 pregnant women were diagnosed with ICP&#44; who had a fasting SBA level of &#62;10<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L&#44; did not have a hepatobiliary obstruction in abdominal ultrasonography &#40;USG&#41;&#44; and had a pruritus&#46; Exclusion criteria were as follows&#58; being under the age of 18&#44; being at less than 12 weeks of gestation and more than 40 weeks and 6 days&#44; having multiple pregnancies of triplets or more&#44; giving birth decision within 48<span class="elsevierStyleHsp" style=""></span>h after admission&#44; and having fetal-lethal anomaly&#46; Thirteen pregnant women who had one or more of these criteria were excluded from the study&#46; Sixty-nine pregnant women fulfilling the criteria were enrolled in the study&#46; Twenty healthy pregnant women who did not have any disease followed-up by the obstetrics outpatient clinic were included in the study as a control group&#46; Age&#44; gestational week&#44; SBA pruritus score&#44; biochemical tests of patients&#44; birth week&#44; and birth weight of infants were recorded&#46; Patient information was accessed from the hospital information processing system and patient files&#46; This is a prospective study and the ethics committee approval was granted by the Clinical Research Ethics Committee of the institution under number 2018&#47;07&#46; Patient selection in the study is shown with a flow chart &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Pruritus score</span><p id="par0030" class="elsevierStylePara elsevierViewall">Verbal Rating Scale &#40;VRS&#41; was used to assess the itch intensity&#46; Four different symptom intensities of patients were evaluated through VRS as 0&#58; absent&#44; 1&#58; mild&#44; 2&#58; moderate&#44; 3&#58; severe itching&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">23</span></a> According to this itch scale&#44; which is divided into four categories&#44; the patients were asked verbally for the severity of itching&#44; and the responses received were recorded numerically&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Examination of biochemical parameters</span><p id="par0035" class="elsevierStylePara elsevierViewall">Following 12-hour fasting for biochemical assays&#44; blood samples taken to dry tubes with gel were delivered to the laboratory within one hour at the latest&#46; 500<span class="elsevierStyleHsp" style=""></span>&#956;l of a serum sample from the first tube&#44; centrifuged for 10<span class="elsevierStyleHsp" style=""></span>min at 1500<span class="elsevierStyleHsp" style=""></span>rpm for serum collection&#44; was reserved for the Eppendorf and stored at &#8722;20&#176; for ATX analysis for further studies&#46; Routine biochemistry assays &#40;alanine transaminase&#44; aspartate aminotransferase&#44; total and direct bilirubin&#44; etc&#46;&#41; from serum samples obtained from other tubes were studied with the original kits on Cobas 8000&#174; model biochemistry and hormone modular analyzer series by Roche &#40;Roche Diagnostics&#44; California&#44; US&#41;&#46; Serum bile acids were analyzed by colorimetric method&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">After the collection of all samples&#44; stored serum samples were thawed at room temperature for ATX analysis&#46; ATX level was quantitatively analyzed under conditions as per the procedure including the recommendations of the manufacturer company with the ELISA &#40;Enzyme-linked immunosorbent assay&#41; method based on the sandwich method using the Human Autotaxin ELISA Kit &#40;Cat no&#58; SG-10887&#41; by SinoGeneClon Biotech Co&#46;&#44; Ltd&#46; Results were expressed in pg&#47;mL&#46; In the repeatability study carried out&#44; the intra-assay and inter-assay coefficients of variation &#40;&#37; CV&#41; were &#60;8&#37; and &#60;10&#37;&#44; respectively&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The data were analyzed using the Statistical Package for the Social Sciences v22 &#40;SPSS&#44; Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46; In the section of descriptive statistics&#44; categorical variables were presented by providing numbers and percentages&#44; and continuous variables were presented with mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41; and median &#40;minimum&#8211;maximum&#41;&#46; Comparative data were shown as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard error&#46; The fitness of continuous variables to normal distribution was evaluated using visual &#40;histogram and probability plots&#41; and analytical methods &#40;Kolmogorov&#8211;Smirnov&#47;Shapiro&#8211;Wilk tests&#41;&#46; In the data that do not conform to the normal distribution as a result of the normality analysis&#44; the Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test was used for comparative analyses between the two groups&#44; while independent Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used in non-compliant cases&#46; Pearson&#39;s chi-square &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span>&#41; test was used in comparison analysis for categorical variables between independent groups&#46; Pearson and Spearman correlation analyzes were performed for correlation analysis between categorical and continuous variables&#46; Data were presented with a 95&#37; confidence interval and all tests of significance were two-tailed&#46; <span class="elsevierStyleItalic">p</span> values of &#60;0&#46;05 were considered statistically significant&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">Eighty-nine patients were enrolled in the study&#44; which consists of 69 patients for ICP and 20 for the control group&#46; The mean age of the control group and the ICP group was similar &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;888&#41;&#46; The mean gestational week at the time of admission of the ICP group &#40;31&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;85&#41; and the gestational week of the control group &#40;27&#46;15<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;69&#41; were similar&#46; The mean birth week &#40;36&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;65&#41; in pregnant women with ICP was significantly lower than the control group &#40;38&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;13&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The mean birth weight &#40;2756&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>563&#46;22&#41; of the infants of pregnant women with ICP was found significantly lower than the control group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; There was a statistically significant difference between the groups for total SBA&#44; ALT&#44; AST&#44; total bilirubin&#44; and direct bilirubin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; The mean serum ATX concentration was higher in ICP&#44; while the difference between the control groups was not statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46; All data have been summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">In the correlation study between SBA and ATX in ICP and some biochemical parameters and clinical manifestations&#44; a weak correlation was found out between SBA and AST&#44; ALT&#44; and the level of pruritus &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014 <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;295&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;023 <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;257&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006 <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;362&#44; respectively&#41;&#46; There was no correlation between ATX and other parameters &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Moreover&#44; it was observed that there was no correlation between the gestational week at diagnosis and SBA and ATX levels &#40;<a class="elsevierStyleCrossRefs" href="#fig0015">Figs&#46; 3 and 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">It was found out that 65&#46;2&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45&#41; of the patients with ICP had a normal birth and 34&#46;8&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41; had a premature birth&#46; Total SBA&#44; ATX concentration&#44; mean ALT and AST were higher at the time of diagnosis in pregnant women with ICP who gave a premature birth&#44; but the difference between them was not statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; The findings are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">ATX is a lysophospholipase D required for angiogenesis and neuronal development in the embryogenesis process&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">24</span></a> High levels of ATX mRNA have been reported in the human placenta <a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a> and it has been suggested that this enzyme is expressed from syncytiotrophoblasts by immunohistochemical analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> Besides&#44; lysophospholipase D levels have been reported to increase during pregnancy and show a positive correlation with gestational age&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">ATX has been the subject of research in other cholestatic liver diseases&#44; as well as in patients with ICP&#44; to explain the etiopathogenesis of pruritus&#46; In a study involving patients with primary biliary cholangitis &#40;PBC&#41;&#44; it was stated that ATX and its product LPA might be one of the causes of cholestatic pruritus&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a> Another study indicated that SBA and ATX activation significantly increased in PBC&#44; a correlation was found between fasting SBA and ATX levels and there was a decrease in these levels in correlation with the ileal bile acid transporter &#40;IBAT&#41; inhibitor&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a> In a study conducted by Kremer et al&#46;&#44; ATX level was found to be high in non-pregnancy-related cholestatic pruritus and had not any relationship with other itchy diseases&#59; also&#44; it was claimed that ATX was involved in cholestasis related itching&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a> This allowed us to think more about the origin of ATX in cholestatic pruritus&#44; and to question the level of ATX synthesis outside the placenta&#44; especially in the liver&#44; and its contribution to itching&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Although there are some studies trying to explain the relationship between ATX and pregnancy-related diseases&#44;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">14&#44;18&#8211;22</span></a> these are not yet sufficient to eliminate contradictions&#46; Here&#44; patients with preeclampsia can be given as an example&#46; In one study<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> it was found that ATX levels were higher in preeclamptic patients compared to the control group&#44; while other studies indicated the exact opposite results&#44; in which the serum ATX levels decrease in patients with PE&#59; also&#44; there may be a decrease in trophoblast-associated ATX expression due to placental pathology in early-onset preeclampsia&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">14&#44;19</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Just as with PE&#44; there are contradictory cases in terms of ATX in patients with ICP&#46; Upon examination of few studies in the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">20&#8211;22</span></a> Kremer et al&#46; claimed that there was a strong correlation between ATX and ICP&#44; and there might be a relationship between ATX level and preterm births&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> In a later study by the same author&#44; it was reported that though the elevated serum ATX level in ICP&#44; there was no difference in ATX mRNA levels in placental tissue between healthy pregnancies and patients with ICP&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> However&#44; in a study by Macias et al&#46;&#44; it was reported that ATX mRNA expression was higher in the placenta of patients with ICP&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In our study&#44; although the mean serum ATX level in patients with ICP was higher than in the control pregnant women&#44; no statistically significant difference was found between them&#46; It was noteworthy that while the serum ATX levels increased as the gestational week progressed&#44; the difference in serum ATX level was not statistically significant in our study&#44; although the gestational week was lower than the ICP group&#46; Additionally&#44; in general&#44; although we found the number of the preterm birth and low birth weight babies significantly higher in patients with ICP&#44; we could not find a relationship between them and the ATX level&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Despite claiming that ATX &#40;and relevant products&#41; and LPA may be a mediator for itching&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> in our study&#44; there was no relation between ATX level and pruritus intensity&#46; A weak correlation was detected between SBA level and pruritus intensity&#46; According to this knowledge&#44; we think that there is a need for future studies investigating the relationship between the pruritis in ICP and LPA&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">There were some limiting factors in this study&#46; The study population was relatively small&#59; therefore&#44; it was not able to examine the effect of UDCA on serum bile acid and serum ATX levels&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In conclusion&#44; in the current study&#44; ATX was not found to be correlated with biochemical and clinical endpoints in patients with ICP and in this point&#44; the current study contributed to the literature&#46; Noting the physiological role of ATX in the continuation of pregnancy&#44; we indicate the need for larger studies on this subject&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Author&#39;s distribution</span><p id="par0105" class="elsevierStylePara elsevierViewall">All authors were involved in the study concept and design&#44; analysis and interpretation of the data&#44; and the drafting and critical revision of the manuscript for important intellectual content&#46; Study concept&#44; design and drafting&#58; SC&#59; Data acquisition&#58; KI&#44; MB&#44; CK&#44; ZA&#59; Statistical analysis and interpretation of the data&#58; NE&#44; SC&#59; Critical review and editing&#58; NE&#44; HS&#46; SC is the article guarantor&#46; All authors read and approved the final manuscript&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115"><span class="elsevierStyleBold">Availability of data and</span> materials</span><p id="par0110" class="elsevierStylePara elsevierViewall">Patient&#39;s data was obtained from hospital data system&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethical approval</span><p id="par0115" class="elsevierStylePara elsevierViewall">Clinical Research Ethics Committee of Kanuni Sultan S&#252;leyman Training and Research Hospital under number 2018&#47;07&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declared that this study has received no financial support&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declared no conflicts of interest&#46;</p></span></span>"
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    "fechaRecibido" => "2020-07-18"
    "fechaAceptado" => "2020-08-16"
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            1 => "Intrahepatic cholestasis"
            2 => "Pregnancy"
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          "titulo" => "Abbreviations"
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          "palabras" => array:11 [
            0 => "ICP"
            1 => "UDCa"
            2 => "SBa"
            3 => "ATX"
            4 => "LPA"
            5 => "PE"
            6 => "USG"
            7 => "VRS"
            8 => "ELISA"
            9 => "PBC"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Intrahepatic cholestasis of pregnancy is a temporary&#44; pregnancy-specific disease that resolves with delivery&#44; characterized by itching &#40;pruritus&#41;&#44; as well as high transaminase and serum bile acid levels in the third trimester of pregnancy&#46; Due to the effects of Autotaxin on the physiology of pregnancy&#44; we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Sixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study&#46; Fasting serum bile acid&#44; pruritus intensity&#44; serum parameters&#44; gestational week of the patients at the time of diagnosis were recorded&#44; and birth week and birth weight were monitored&#46; Autotaxin serum level was measured enzymatically&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The mean serum bile acid level &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#59; 38&#46;74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&#46;92<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L&#41; in patients with intrahepatic cholestasis of pregnancy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#41; was detected to be higher than healthy pregnant women &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#59; 5&#46;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;88<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Weak correlation was detected between serum bile acid level and itch intensity &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#44; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;295&#41;&#44; while no relation was detected between Autotaxin and itch intensity &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;446&#44; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;09&#41;&#46; Although mean Autotaxin &#40;intrahepatic cholestasis of pregnancy&#58; 678&#46;10<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>424&#46;42<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; control&#58; 535&#46;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>256&#46;47<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#41; levels were high in patients with intrahepatic cholestasis of pregnancy&#44; it was not statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;157&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In our study&#44; we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women&#46; These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Patients and methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La colestasis intrahep&#225;tica del embarazo es una enfermedad temporal espec&#237;fica del embarazo caracterizada por picaz&#243;n &#40;prurito&#41;&#44; niveles elevados de transaminasas y &#225;cidos biliares s&#233;ricos elevados en el tercer trimestre del embarazo que se resuelve con el parto&#46; Debido a los efectos de la autotaxina en la fisiolog&#237;a del embarazo&#44; nuestro objetivo fue investigar la actividad de la autotaxina en pacientes con colestasis intrahep&#225;tica del embarazo&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En el estudio se incluyeron 69 pacientes con diagn&#243;stico de colestasis intrahep&#225;tica del embarazo y 20 mujeres embarazadas sanas&#46; Registramos los &#225;cidos biliares s&#233;ricos en ayunas&#44; la intensidad del prurito&#44; los par&#225;metros s&#233;ricos y la semana de gestaci&#243;n de las pacientes en el momento del diagn&#243;stico&#44; y controlamos la semana del parto y el peso al nacer&#46; Los niveles s&#233;ricos de autotaxina se midieron de forma enzim&#225;tica&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se observ&#243; que el nivel medio de &#225;cidos biliares en suero era mayor en pacientes con colestasis intrahep&#225;tica del embarazo &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#59; 38&#44;74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&#44;92<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l&#41; que en mujeres embarazadas sanas &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#59; 5&#44;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;88<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l&#41; &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Se detect&#243; una correlaci&#243;n d&#233;bil entre el nivel de &#225;cidos biliares en suero y la intensidad del prurito &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;014&#59; r<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;295&#41;&#44; mientras que no se observ&#243; ninguna relaci&#243;n entre la autotaxina y la intensidad del prurito &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;446&#59; r<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;09&#41;&#46; Aunque los niveles medios de autotaxina fueron altos en pacientes con colestasis intrahep&#225;tica del embarazo &#40;678&#44;10<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>424&#44;42 frente a 535&#44;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>256&#44;47<span class="elsevierStyleHsp" style=""></span>pg&#47;ml en los controles&#41;&#44; la diferencia no fue estad&#237;sticamente significativa &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;157&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Observamos que el nivel de autotaxina s&#233;rica no supuso una diferencia significativa en pacientes con colestasis intrahep&#225;tica del embarazo en comparaci&#243;n con las mujeres embarazadas sanas&#46; Estos hallazgos sugieren que se requieren estudios cl&#237;nicos m&#225;s amplios para determinar los efectos fisiopatol&#243;gicos de la autotaxina en el embarazo&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
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            "titulo" => "Pacientes y m&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The relationship between SBA and ATX&#46;</p>"
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                  \t\t\t\t">2&#46;90<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;29&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">31&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;85&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">27&#46;15<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;69&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Birth weight &#40;g&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">T&#46; Bilirubin &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">D&#46; Bilirubin &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;105&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;393<span class="elsevierStyleSup">a</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;058&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;634<span class="elsevierStyleSup">a</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Pruritus Level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;462<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;326&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;006</span><span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delivery week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;902<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;0&#46;054&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;659<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Birth weight &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;249<span class="elsevierStyleSup">a</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;055&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;653<span class="elsevierStyleSup">a</span>&nbsp;\t\t\t\t\t\t\n
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                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Premature deliveryYes &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41; No &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>sd&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">28&#46;84<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;64&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pregnancy week</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&#46;60<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;047</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bile acid level</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&#46;42<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>30&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;467</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;08<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>44&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autotaxin level &#40;pg&#47;mL&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">669&#46;24<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>426&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;814</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">694&#46;71<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>428&#46;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALT &#40;IU&#47;L&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">104&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>101&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;151</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">146&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>133&#46;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AST &#40;IU&#47;L&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>47&#46;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;071</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#46;70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>57&#46;499&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total bilirubin &#40;mg&#47;dL&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;24<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;431</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#46;39&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos