Korean J Gastroenterol.  2021 Aug;78(2):94-104. 10.4166/kjg.2021.111.

A Recent Update on Endoscopic Drainage of Advanced Malignant Hilar Obstruction

• Lee TH
• Moon JH
• Park SH

• KMID: 2519378
• DOI: http://doi.org/10.4166/kjg.2021.111

Abstract

Malignant hilar obstruction (MHO) is considered an aggressive perihilar obstruction caused by cholangiocarcinoma, gallbladder cancer, or metastatic malignancies and has a poor prognosis. Although surgical resection is the only curative treatment method, the majority of patients with MHO do not undergo surgery due to an advanced inoperable state at presentation. Currently, effective biliary drainage provides the necessary palliation for symptomatic improvement. Among the drainage methods, percutaneous access may be preferred, especially for advanced MHO because of the technical difficulty involved with other techniques. Recently, primary endoscopic palliation using plastic or metal stents has been shown to have higher technical feasibility and clinical success without increasing adverse events even in patients with high-degree MHO. The development of various accessories, endoscopic ultrasonography, and advances in techniques have facilitated primary endoscopic intervention. However, some aspects continue to be debated such as the palliation methods, appropriate stents, the number of stents, the deployment methods, and additional local ablation therapies. Therefore, this review discusses the current optimal endoscopic treatment methods for advanced MHO based on reported literature.

Keyword

Hilar; Obstruction; Endoscopy; Drainage

Figure

• 

  Fig. 1 (A) Stent-by-stent deployment of metallic stents (Bonastent, Standard SciTech Inc., Seoul, Korea): two self-expandable metal stents were deployed parallelly into both IHDs and the distal tip of the two stents were positioned at the same level within CBD (left). (B) Stent-in-stent deployment of metallic stents in Bismuth type IV (Bonastent, Standard SciTech Inc.); The second stent was placed through the central portion of the first stent (X-marked stent). Following the deployment of the second stent, the bilateral metal stents were in a Y-configuration (right).

Reference

1. Jarnagin WR, Fong Y, DeMatteo RP, et al. 2001; Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 234:507–519. DOI: 10.1097/00000658-200110000-00010. PMID: 11573044. PMCID: PMC1422074.

2. Lee TH. 2013; Technical tips and issues of biliary stenting, focusing on malignant hilar obstruction. Clin Endosc. 46:260–266. DOI: 10.5946/ce.2013.46.3.260. PMID: 23767037. PMCID: PMC3678064.

3. Kim JH. 2011; Endoscopic stent placement in the palliation of malignant biliary obstruction. Clin Endosc. 44:76–86. DOI: 10.5946/ce.2011.44.2.76. PMID: 22741117. PMCID: PMC3363064.

4. Bismuth H, Castaing D, Traynor O. 1988; Resection or palliation: priority of surgery in the treatment of hilar cancer. World J Surg. 12:39–47. DOI: 10.1007/BF01658484. PMID: 2449769.

5. Rerknimitr R, Angsuwatcharakon P, Ratanachu-ek T, et al. 2013; Asia-Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma. J Gastroenterol Hepatol. 28:593–607. DOI: 10.1111/jgh.12128. PMID: 23350673.

6. Aghaie Meybodi M, Shakoor D, Nanavati J, et al. 2020; Unilateral versus bilateral endoscopic stenting in patients with unresectable malignant hilar obstruction: a systematic review and meta-analysis. Endosc Int Open. 8:E281–E290. DOI: 10.1055/a-1067-4326. PMID: 32118102. PMCID: PMC7035140.

7. Dumonceau JM, Tringali A, Papanikolaou IS, et al. 2018; Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline - Updated October 2017. Endoscopy. 50:910–930. DOI: 10.1055/a-0659-9864. PMID: 30086596.

8. Qumseya BJ, Jamil LH, Elmunzer BJ, et al. 2021; ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction. Gastrointest Endosc. 94:222–234.e22. DOI: 10.1016/j.gie.2020.12.035. PMID: 34023067.

9. Moole H, Dharmapuri S, Duvvuri A, et al. 2016; Endoscopic versus percutaneous biliary drainage in palliation of advanced malignant hilar obstruction: a meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2016:4726078. DOI: 10.1155/2016/4726078. PMID: 27648439. PMCID: PMC5014937.

10. Lee TH, Moon JH, Park SH. 2020; Biliary stenting for hilar malignant biliary obstruction. Dig Endosc. 32:275–286. DOI: 10.1111/den.13549. PMID: 31578770.

11. Wagner HJ, Knyrim K, Vakil N, Klose KJ. 1993; Plastic endoprostheses versus metal stents in the palliative treatment of malignant hilar biliary obstruction. A prospective and randomized trial. Endoscopy. 25:213–218. DOI: 10.1055/s-2007-1010295. PMID: 7686100.

12. Raijman I. 2003; Biliary and pancreatic stents. Gastrointest Endosc Clin N Am. 13:561–592. vii–viii. DOI: 10.1016/S1052-5157(03)00069-2. PMID: 14986787.

13. Maillot N, Aucher P, Robert S, et al. 2000; Polyethylene stent blockage: a porcine model. Gastrointest Endosc. 51:12–18. DOI: 10.1016/S0016-5107(00)70379-8. PMID: 10625788.

14. Speer AG, Cotton PB, MacRae KD. 1988; Endoscopic management of malignant biliary obstruction: stents of 10 French gauge are preferable to stents of 8 French gauge. Gastrointest Endosc. 34:412–417. DOI: 10.1016/S0016-5107(88)71407-8. PMID: 2460394.

15. Pedersen FM. 1993; Endoscopic management of malignant biliary obstruction. Is stent size of 10 French gauge better than 7 French gauge? Scand J Gastroenterol. 28:185–189. DOI: 10.3109/00365529309096068. PMID: 8441913.

16. Kadakia SC, Starnes E. 1992; Comparison of 10 French gauge stent with 11.5 French gauge stent in patients with biliary tract diseases. Gastrointest Endosc. 38:454–459. DOI: 10.1016/S0016-5107(92)70476-3. PMID: 1511821.

17. van Berkel AM, Boland C, Redekop WK, et al. 1998; A prospective randomized trial of Teflon versus polyethylene stents for distal malignant biliary obstruction. Endoscopy. 30:681–686. DOI: 10.1055/s-2007-1001388. PMID: 9865556.

18. England RE, Martin DF, Morris J, et al. 2000; A prospective randomised multicentre trial comparing 10 Fr Teflon Tannenbaum stents with 10 Fr polyethylene Cotton-Leung stents in patients with malignant common duct strictures. Gut. 46:395–400. DOI: 10.1136/gut.46.3.395. PMID: 10673303. PMCID: PMC1727856.

19. Terruzzi V, Comin U, De Grazia F, et al. 2000; Prospective randomized trial comparing Tannenbaum Teflon and standard polyethylene stents in distal malignant biliary stenosis. Gastrointest Endosc. 51:23–27. DOI: 10.1016/S0016-5107(00)70381-6. PMID: 10625790.

20. Davids PH, Groen AK, Rauws EA, Tytgat GN, Huibregtse K. 1992; Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet. 340:1488–1492. DOI: 10.1016/0140-6736(92)92752-2. PMID: 1281903.

21. Kaassis M, Boyer J, Dumas R, et al. 2003; Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc. 57:178–182. DOI: 10.1067/mge.2003.66. PMID: 12556780.

22. Schmassmann A, von Gunten E, Knuchel J, Scheurer U, Fehr HF, Halter F. 1996; Wallstents versus plastic stents in malignant biliary obstruction: effects of stent patency of the first and second stent on patient compliance and survival. Am J Gastroenterol. 91:654–659. PMID: 8677925.

23. Park DH, Lee SS, Moon JH, et al. 2009; Newly designed stent for endoscopic bilateral stent-in-stent placement of metallic stents in patients with malignant hilar biliary strictures: multicenter prospective feasibility study (with videos). Gastrointest Endosc. 69:1357–1360. DOI: 10.1016/j.gie.2008.12.250. PMID: 19481654.

24. Dowsett JF, Vaira D, Hatfield AR, et al. 1989; Endoscopic biliary therapy using the combined percutaneous and endoscopic technique. Gastroenterology. 96:1180–1186. DOI: 10.1016/0016-5085(89)91639-9. PMID: 2925062.

25. Polydorou AA, Cairns SR, Dowsett JF, et al. 1991; Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion. Gut. 32:685–689. DOI: 10.1136/gut.32.6.685. PMID: 1711994. PMCID: PMC1378890.

26. Chahal P, Baron TH. 2010; Expandable metal stents for endoscopic bilateral stent-within-stent placement for malignant hilar biliary obstruction. Gastrointest Endosc. 71:195–199. DOI: 10.1016/j.gie.2009.08.006. PMID: 19945101.

27. Kawamoto H, Tsutsumi K, Fujii M, et al. 2007; Endoscopic 3-branched partial stent-in-stent deployment of metallic stents in high-grade malignant hilar biliary stricture (with videos). Gastrointest Endosc. 66:1030–1037. DOI: 10.1016/j.gie.2007.06.055. PMID: 17963891.

28. Lee JH, Kang DH, Kim JY, et al. 2007; Endoscopic bilateral metal stent placement for advanced hilar cholangiocarcinoma: a pilot study of a newly designed Y stent. Gastrointest Endosc. 66:364–369. DOI: 10.1016/j.gie.2006.12.061. PMID: 17643714.

29. Perdue DG, Freeman ML, DiSario JA, et al. 2008; Plastic versus self-expanding metallic stents for malignant hilar biliary obstruction: a prospective multicenter observational cohort study. J Clin Gastroenterol. 42:1040–1046. DOI: 10.1097/MCG.0b013e31815853e0. PMID: 18719507.

30. Raju RP, Jaganmohan SR, Ross WA, et al. 2011; Optimum palliation of inoperable hilar cholangiocarcinoma: comparative assessment of the efficacy of plastic and self-expanding metal stents. Dig Dis Sci. 56:1557–1564. DOI: 10.1007/s10620-010-1550-5. PMID: 21222156.

31. Stern N, Sturgess R. 2008; Endoscopic therapy in the management of malignant biliary obstruction. Eur J Surg Oncol. 34:313–317. DOI: 10.1016/j.ejso.2007.07.210. PMID: 18276101.

32. Pedersen FM, Lassen AT, Schaffalitzky de Muckadell OB. 1998; Randomized trial of stent placed above and across the sphincter of Oddi in malignant bile duct obstruction. Gastrointest Endosc. 48:574–579. DOI: 10.1016/S0016-5107(98)70038-0. PMID: 9852446.

33. Cosgrove N, Siddiqui AA, Adler DG, et al. 2017; A comparison of bilateral side-by-side metal stents deployed above and across the sphincter of Oddi in the management of malignant hilar biliary obstruction. J Clin Gastroenterol. 51:528–533. DOI: 10.1097/MCG.0000000000000584. PMID: 27348319.

34. Kitamura K, Yamamiya A, Ishii Y, Mitsui Y, Nomoto T, Yoshida H. 2017; Side-by-side partially covered self-expandable metal stent placement for malignant hilar biliary obstruction. Endosc Int Open. 5:E1211–E1217. DOI: 10.1055/s-0043-117955. PMID: 29202005. PMCID: PMC5699902.

35. Ogura T, Okuda A, Fukunishi S, Higuchi K. 2018; Side-by-side stent deployment above the papilla to treat hepatic hilar obstruction using a new covered metal stent. Dig Liver Dis. 50:972. DOI: 10.1016/j.dld.2018.04.015. PMID: 29784580.

36. Polydorou AA, Chisholm EM, Romanos AA, et al. 1989; A comparison of right versus left hepatic duct endoprosthesis insertion in malignant hilar biliary obstruction. Endoscopy. 21:266–271. DOI: 10.1055/s-2007-1012966. PMID: 2482169.

37. De Palma GD, Galloro G, Siciliano S, Iovino P, Catanzano C. 2001; Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc. 53:547–553. DOI: 10.1067/mge.2001.113381. PMID: 11323577.

38. De Palma GD, Pezzullo A, Rega M, et al. 2003; Unilateral placement of metallic stents for malignant hilar obstruction: a prospective study. Gastrointest Endosc. 58:50–53. DOI: 10.1067/mge.2003.310. PMID: 12838220.

39. Iwano H, Ryozawa S, Ishigaki N, et al. 2011; Unilateral versus bilateral drainage using self-expandable metallic stent for unresectable hilar biliary obstruction. Dig Endosc. 23:43–48. DOI: 10.1111/j.1443-1661.2010.01036.x. PMID: 21198916.

40. Sherman S. 2001; Endoscopic drainage of malignant hilar obstruction: is one biliary stent enough or should we work to place two? Gastrointest Endosc. 53:681–684. DOI: 10.1067/mge.2001.114714. PMID: 11323609.

41. Nomura T, Shirai Y, Hatakeyama K. 1997; Cholangitis after endoscopic biliary drainage for hilar lesions. Hepatogastroenterology. 44:1267–1270. PMID: 9356838.

42. Freeman ML, Overby C. 2003; Selective MRCP and CT-targeted drainage of malignant hilar biliary obstruction with self-expanding metallic stents. Gastrointest Endosc. 58:41–49. DOI: 10.1067/mge.2003.292. PMID: 12838219.

43. Hintze RE, Abou-Rebyeh H, Adler A, Veltzke-Schlieker W, Felix R, Wiedenmann B. 2001; Magnetic resonance cholangiopancreatography-guided unilateral endoscopic stent placement for Klatskin tumors. Gastrointest Endosc. 53:40–46. DOI: 10.1067/mge.2001.111388. PMID: 11154487.

44. Khan SA, Davidson BR, Goldin R, et al. 2002; Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 51 Suppl 6(Suppl 6):VI1–VI9. DOI: 10.1136/gut.51.suppl_6.vi1. PMID: 12376491. PMCID: PMC1867742.

45. Chang WH, Kortan P, Haber GB. 1998; Outcome in patients with bifurcation tumors who undergo unilateral versus bilateral hepatic duct drainage. Gastrointest Endosc. 47:354–362. DOI: 10.1016/S0016-5107(98)70218-4. PMID: 9609426.

46. Naitoh I, Ohara H, Nakazawa T, et al. 2009; Unilateral versus bilateral endoscopic metal stenting for malignant hilar biliary obstruction. J Gastroenterol Hepatol. 24:552–557. DOI: 10.1111/j.1440-1746.2008.05750.x. PMID: 19220678.

47. Lee TH, Kim TH, Moon JH, et al. 2017; Bilateral versus unilateral placement of metal stents for inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective, randomized study (with video). Gastrointest Endosc. 86:817–827. DOI: 10.1016/j.gie.2017.04.037. PMID: 28479493.

48. Puli SR, Kalva N, Pamulaparthy SR, et al. 2013; Bilateral and unilateral stenting for malignant hilar obstruction: a systematic review and meta-analysis. Indian J Gastroenterol. 32:355–362. DOI: 10.1007/s12664-013-0413-3. PMID: 24214663.

49. Ashat M, Arora S, Klair JS, Childs CA, Murali AR, Johlin FC. 2019; Bilateral vs unilateral placement of metal stents for inoperable high-grade hilar biliary strictures: a systemic review and meta-analysis. World J Gastroenterol. 25:5210–5219. DOI: 10.3748/wjg.v25.i34.5210. PMID: 31558868. PMCID: PMC6747295.

50. Lee TH, Lee SJ, Moon JH, Park SH. 2014; Technical tips and issues of biliary stenting, focusing on malignant hilar obstruction. Minerva Gastroenterol Dietol. 60:135–149. PMID: 24780948.

51. Lee TH, Moon JH, Choi HJ, et al. 2016; Third metal stent for revision of malignant hilar biliary strictures. Endoscopy. 48:1129–1133. DOI: 10.1055/s-0042-112574. PMID: 27487289.

52. Lee TH, Moon JH, Kim JH, et al. 2013; Primary and revision efficacy of cross-wired metallic stents for endoscopic bilateral stent-in-stent placement in malignant hilar biliary strictures. Endoscopy. 45:106–113. DOI: 10.1055/s-0032-1325928. PMID: 23212727.

53. Lee TH, Park DH, Lee SS, et al. 2013; Technical feasibility and revision efficacy of the sequential deployment of endoscopic bilateral side-by-side metal stents for malignant hilar biliary strictures: a multicenter prospective study. Dig Dis Sci. 58:547–555. DOI: 10.1007/s10620-012-2346-6. PMID: 22886596.

54. Paik WH, Park YS, Hwang JH, et al. 2009; Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach. Gastrointest Endosc. 69:55–62. DOI: 10.1016/j.gie.2008.04.005. PMID: 18657806.

55. Cheng JL, Bruno MJ, Bergman JJ, Rauws EA, Tytgat GN, Huibregtse K. 2002; Endoscopic palliation of patients with biliary obstruction caused by nonresectable hilar cholangiocarcinoma: efficacy of self-expandable metallic Wallstents. Gastrointest Endosc. 56:33–39. DOI: 10.1067/mge.2002.125364. PMID: 12085032.

56. Dumas R, Demuth N, Buckley M, et al. 2000; Endoscopic bilateral metal stent placement for malignant hilar stenoses: identification of optimal technique. Gastrointest Endosc. 51:334–338. DOI: 10.1016/S0016-5107(00)70364-6. PMID: 10699784.

57. Chennat J, Waxman I. 2010; Initial performance profile of a new 6F self-expanding metal stent for palliation of malignant hilar biliary obstruction. Gastrointest Endosc. 72:632–636. DOI: 10.1016/j.gie.2010.04.037. PMID: 20579991.

58. Kim JY, Kang DH, Kim HW, et al. 2009; Usefulness of slimmer and open-cell-design stents for endoscopic bilateral stenting and endoscopic revision in patients with hilar cholangiocarcinoma (with video). Gastrointest Endosc. 70:1109–1115. DOI: 10.1016/j.gie.2009.05.013. PMID: 19647244.

59. Hwang JC, Kim JH, Lim SG, Kim SS, Yoo BM, Cho SW. 2011; Y-shaped endoscopic bilateral metal stent placement for malignant hilar biliary obstruction: prospective long-term study. Scand J Gastroenterol. 46:326–332. DOI: 10.3109/00365521.2010.536253. PMID: 21082874.

60. Naitoh I, Hayashi K, Nakazawa T, et al. 2012; Side-by-side versus stent-in-stent deployment in bilateral endoscopic metal stenting for malignant hilar biliary obstruction. Dig Dis Sci. 57:3279–3285. DOI: 10.1007/s10620-012-2270-9. PMID: 22732832.

61. Lee TH, Moon JH, Choi JH, et al. 2019; Prospective comparison of endoscopic bilateral stent-in-stent versus stent-by-stent deployment for inoperable advanced malignant hilar biliary stricture. Gastrointest Endosc. 90:222–230. DOI: 10.1016/j.gie.2019.03.011. PMID: 30905729.

62. Law R, Baron TH. 2013; Bilateral metal stents for hilar biliary obstruction using a 6Fr delivery system: outcomes following bilateral and side-by-side stent deployment. Dig Dis Sci. 58:2667–2672. DOI: 10.1007/s10620-013-2671-4. PMID: 23625287.

63. Kim KM, Lee KH, Chung YH, et al. 2012; A comparison of bilateral stenting methods for malignant hilar biliary obstruction. Hepatogastroenterology. 59:341–346. DOI: 10.1016/S0016-5085(12)61289-X. PMID: 22353496.

64. Shim SR, Lee TH, Yang JK, et al. Endoscopic bilateral stent-in-stent versus stent-by-stent deployment in advanced malignant hilar obstruction: a meta-analysis and systematic review. Dig Dis Sci. 2021 Feb 24. [Epub ahead of print]. DOI: 10.1007/s10620-021-06885-8. PMID: 33625611.

65. Lee TH, Choi JH, Park do H, et al. 2016; Similar efficacies of endoscopic ultrasound-guided transmural and percutaneous drainage for malignant distal biliary obstruction. Clin Gastroenterol Hepatol. 14:1011–1019.e3. DOI: 10.1016/j.cgh.2015.12.032. PMID: 26748220.

66. Paik WH, Lee TH, Park DH, et al. 2018; EUS-guided biliary drainage versus ERCP for the primary palliation of malignant biliary obstruction: a multicenter randomized clinical trial. Am J Gastroenterol. 113:987–997. DOI: 10.1038/s41395-018-0122-8. PMID: 29961772.

67. Nakai Y, Kogure H, Isayama H, Koike K. 2019; Endoscopic ultrasound-guided biliary drainage for unresectable hilar malignant biliary obstruction. Clin Endosc. 52:220–225. DOI: 10.5946/ce.2018.094. PMID: 30472818. PMCID: PMC6547346.

68. Cheon YK. 2010; The role of photodynamic therapy for hilar cholangiocarcinoma. Korean J Intern Med. 25:345–352. DOI: 10.3904/kjim.2010.25.4.345. PMID: 21179270. PMCID: PMC2997961.

69. Cheon YK, Cho YD, Baek SH, et al. 2004; Comparison of survival of advanced hilar cholangiocarcinoma after biliary drainage alone versus photodynamic therapy with external drainage. Korean J Gastroenterol. 44:280–287. PMID: 15564808.

70. Cheon YK, Lee TY, Lee SM, Yoon JY, Shim CS. 2012; Longterm outcome of photodynamic therapy compared with biliary stenting alone in patients with advanced hilar cholangiocarcinoma. HPB (Oxford). 14:185–193. DOI: 10.1111/j.1477-2574.2011.00424.x. PMID: 22321037. PMCID: PMC3371201.

71. Inoue T, Ibusuki M, Kitano R, et al. 2020; Endobiliary radiofrequency ablation combined with bilateral metal stent placement for malignant hilar biliary obstruction. Endoscopy. 52:595–599. DOI: 10.1055/a-1133-4448. PMID: 32208498.

72. Bokemeyer A, Matern P, Bettenworth D, et al. 2019; Endoscopic radiofrequency ablation prolongs survival of patients with unresectable hilar cholangiocellular carcinoma - a case-control study. Sci Rep. 9:13685. DOI: 10.1038/s41598-019-50132-0. PMID: 31548703. PMCID: PMC6757045.

73. Tal AO, Vermehren J, Friedrich-Rust M, et al. 2014; Intraductal endoscopic radiofrequency ablation for the treatment of hilar non-resectable malignant bile duct obstruction. World J Gastrointest Endosc. 6:13–19. DOI: 10.4253/wjge.v6.i1.13. PMID: 24527176. PMCID: PMC3921441.

74. Kim EJ, Cho JH, Kim YJ, et al. 2019; Intraductal temperature-controlled radiofrequency ablation in malignant hilar obstruction: a preliminary study in animals and initial human experience. Endosc Int Open. 7:E1293–E1300. DOI: 10.1055/a-0970-9005. PMID: 31595223. PMCID: PMC6779589.

75. Schmidt A, Bloechinger M, Weber A, et al. 2016; Short-term effects and adverse events of endoscopically applied radiofrequency ablation appear to be comparable with photodynamic therapy in hilar cholangiocarcinoma. United European Gastroenterol J. 4:570–579. DOI: 10.1177/2050640615621235. PMID: 27536367. PMCID: PMC4971790.

76. Yang J, Wang J, Zhou H, et al. 2018; Efficacy and safety of endoscopic radiofrequency ablation for unresectable extrahepatic cholangiocarcinoma: a randomized trial. Endoscopy. 50:751–760. DOI: 10.1055/s-0043-124870. PMID: 29342492.

77. Mohan BP, Chandan S, Khan SR, et al. Photodynamic therapy (PDT), radiofrequency ablation (RFA) with biliary stents in palliative treatment of unresectable extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Clin Gastroenterol. 2021 Mar 12. [Epub ahead of print]. DOI: 10.1097/MCG.0000000000001524. PMID: 33780214.