10 WORLD GASTROENTEROLOGY NEWS JULY 2016 Editorial | Expert Point of View | Gastro 2016: EGHS-WGO | WDHD News | WGO & WGOF News | WGO Global Guidelines | Calendar of Events Due to this risk, optimal timing of delivery by 36-37 weeks is considered by most obstetricians, with earlier delivery when jaundice and total bile acid levels are >40 μmol/L 3, 6. The risk of stillbirth has been demonstrat-ed to increase beyond 36 weeks. The intriguing physiopathologic expla-nation for stillbirth associated with higher levels of bile acids, points to fetal cardiac arrest associated with bile acids entrance to cardiomyocytes in abnormal amounts, resulting in pro-longed PR interval and fetal cardiac arrest. A role for bile acids entering the fetal lungs and depleting surfac-tant is also a possible explanation for neonatal respiratory distress syndrome of newborn of mothers with ICP 3. Table 2 summarizes the main clinical studies evaluating the fetal prognosis of ICP patients. Once the diagnosis is made, man-agement should be oriented to reduce the maternal symptoms and offering adequate obstetric care to avoid fetal distress and stillbirth. Maternal outcomes are excellent, with no long-term sequelae. Malab-sorption due to persistent cholestasis has been described due to vitamin K deficiency, leading to intrapartum and postpartum hemorrhage 1. Pruri-tus and abnormal liver tests usually disappear within 1-3 weeks after delivery. If liver tests abnormalities persists after a few weeks of delivery, other chronic liver disease should be ruled out. Nevertheless, recent data has shown that ICP patients at long term follow-up may have an increased risk of gallstone disease, pancreatitis, cirrhosis, hepatobiliary cancer, and autoimmune mediated and cardio-vascular diseases when compared to women without ICP 20, 21. Pregnancies complicated by ICP are also associated with a higher risk of preeclampsia and gestational diabetes. Management of ICP Patients For maternal pruritus, antihistamines and topical therapy with emol-lients may provide some relief 2, 3, 6. Although cholestyramine may be effective, it may decrease the absorp-tion of fat-soluble vitamins, leading to vitamin K deficiency and fetal coagulopathy. Considering the previous beneficial experience in primary biliary cirrhosis with the use of Ursodeoxycholic acid (UDCA), an oral hydrophilic tertiary bile acid, our Chilean group was the first one to publish an open clinical trial showing the beneficial effects of UDCA in ICP 22. In this trial, nine patients with severe ICP received oral UDCA 15mg/kg/day (divided twice a day) obtaining relief of pruritus in most mothers and improvement of liver tests without any adverse effect. After discontinuing UDCA, pruri-tus and biochemical abnormalities reappeared, but they improved again after re-challenge with oral UDCA. Since then, other clinical series and then controlled studies have shown that UDCA administration provides a significant improvement in maternal pruritus, biochemical abnormali-ties and the fetal prognosis, with no adverse effects for the mother or child 3, 8, 16. In a recent meta-analysis reviewing nine published, randomized con-trolled trials comparing UDCA to other drugs, and analyzing the data on 454 patients with ICP 23, UDCA was demonstrated to be effective in reducing pruritus, improving liver test results, and reducing serum levels of total bile salts (P< 0,0001 for all these variables) UDCA was also associated with fewer premature births (P < 0.01), less fetal distress (P < 0.01), less frequent respiratory distress syndrome (P < 0.01), and fewer neonates in the intensive care unit (P = 0.046). Since only two cases of intrauterine fetal death were observed (both in the placebo groups) this small number precluded specific analysis on this issue but strongly suggested that UDCA improves fetal outcome. Fi-nally, the systematic review confirmed that UDCA (10–15 mg/kg maternal body weight) was well tolerated by the mother, with rare and mild side effects (diarrhea), and was very safe for the fetus. UDCA therapy normalized serum bile acid patterns in babies with minimal accumulation in amniotic fluid and cord blood. Our long-term study of 26 children born to mothers with ICP and treated with UDCA, and followed for up to 12 years, showed a normal development 24. In summary, much has been learned in the last two decades about this initially considered rare disease. Its etiology is likely multifactorial, with the influence of many environmental factors over a genetically predisposed subject. ICP patients with a sig-nificant increase in serum total bile acids (>40 umol/L and especially >100 umol/L), are the ones with a higher risk of fetal morbimortality, and should be identified to define an active maternal management. UDCA is currently the main medication in the management of ICP, due to its safety (both for the mother and fetus), with beneficial effects on maternal pruritus, liver function tests, and fetal morbidity. “Significant advances had been made in the last two decades in the study of this disease, but ICP is still, and will continue to be for a long time, a puzzling disease of pregnancy.” References 1. Reyes H: Review: intrahepatic cholestasis. A puzzling disorder of pregnancy. J Gastroenterol Hepatol 1997; 12: 211-216. 2. Tran TT, Ahn J, Reau NS. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gas-troenterol. 2016 ;111:176-194.
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