何瑶;李玥;谭蓓;高翔;梁洁;钱家鸣;吴开春;

• 1:中华医学会消化病学分会炎症性肠病学组
• 2:中山大学附属第一医院消化科
• 3:北京协和医院消化内科
• 4:中山大学附属第六医院消化科

摘要(Abstract)：

炎症性肠病大多于中青年发病,会面临生育问题,故加强妊娠前咨询、优化妊娠期管理可改善不良妊娠结局,提高患者生命质量。本共识基于循证医学依据和Delphi方法,在妊娠前指导和管理、妊娠期管理、分娩方式、哺乳期管理和婴儿疫苗接种共5个方面达成初步共识,为临床工作提供指导。

关键词(KeyWords)： 炎症性肠病;妊娠期;疾病管理;专家共识

Abstract:

Keywords:

基金项目(Foundation): 卫生部行业专项基金(201002020);; 国家支撑项目基金(2015BA13B07);; 中国医学科学院医学与健康科技创新工程(2016-I2M-3-001)

作者(Author): 何瑶;李玥;谭蓓;高翔;梁洁;钱家鸣;吴开春;

Email:

DOI:

参考文献(References)：

• [1] Martin L,Peche W,Peterson K,et al. Population Based Paternity Rate and Partner Birth Outcomes Among Utah Men With Inflammatory Bowel Disease[J]. Am J Gastroenterol,2017,112:1722-1727.
• [2] Tavernier N, Fumery M, Peyrin-Biroulet L, et al.Systematic review:fertility in non-surgically treated inflammatory bowel disease[J]. Aliment Pharmacol Ther,2013,38:847-853.
• [3] Mayberry JF,Weterman IT. European survey of fertility and pregnancy in women with Crohn's disease:a case control study by European collaborative group[J]. Gut,1986,27:821-825.
• [4] Marri SR,Ahn C,Buchman AL. Voluntary childlessness is increased in women with inflammatory bowel disease[J].Inflamm Bowel Dis,2007,13:591-599.
• [5] Ording Olsen K,Juul S,Berndtsson I,et al. Ulcerative colitis:female fecundity before diagnosis,during disease,and after surgery compared with a population sample[J]. Gastroenterology,2002,122:15-19.
• [6] Waljee A. Waljee J,Morris AM,et al. Threefold increased risk of infertility:a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis[J]. Gut,2006,55:1575-1580.
• [7] Rajaratnam SG,Eglinton TW,Hider P,et al. Impact of ileal pouch-anal anastomosis on female fertility:metaanalysis and systematic review[J]. Int J Colorectal Dis,2011,26:1365-1374.
• [8] Ananthakrishnan AN,Martin C,Kane S,et al. Paternal Disease Activity Is Associated With Difficulty in Conception Among Men With Inflammatory Bowel Diseases[J]. Clin Gastroenterol Hepatol,2019,17:203-204.
• [9] Orholm M,Munkholm P,Langholz E,et al. Familial occurrence of inflammatory bowel disease[J]. N Engl J Med,1991,324:84-88.
• [10] Peeters M,Nevens H,Baert F,et al. Familial aggregation in Crohn's disease:increased age-adjusted risk and concordance in clinical characteristics[J]. Gastroenterology,1996,111:597-603.
• [11] Jolving LR,Nielsen J,Beck-Nielsen SS,et al. The Association Between Maternal Chronic Inflammatory Bowel Disease and Long-term Health Outcomes in Children-A Nationwide Cohort Study[J]. Inflamm Bowel Dis, 2017, 23:1440-1446.
• [12] Orholm M,Fonager K,Sorensen HT. Risk of ulcerative colitis and Crohn's disease among offspring of patients with chronic inflammatory bowel disease[J]. Am J Gastroenterol,1999,94:3236-3238.
• [13] Bennett RA,Rubin PH,Present DH. Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease[J]. Gastroenterology,1991,100:1638-1643.
• [14] Laharie D,Debeugny S,Peeters M,et al. Inflammatory bowel disease in spouses and their offspring[J]. Gastroenterology,2001,120:816-819.
• [15] Julsgaard M,Norgaard M,Hvas CL,et al. Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis[J]. Inflamm Bowel Dis,2011,17:1573-1580.
• [16] Nielsen MJ,Norgaard M,Holland-Fisher P,et al. Self-reported antenatal adherence to medical treatment among pregnant women with Crohn's disease[J]. Aliment Pharmacol Ther,2010,32:49-58.
• [17] de Lima A,Zelinkova Z,Mulders AG,et al. Preconception Care Reduces Relapse of Inflammatory Bowel Disease During Pregnancy[J]. Clin Gastroenterol Hepatol, 2016, 14:1285-1292. e1.
• [18] Mountifield R,Andrews JM,Bampton P. It is worth the effort:Patient knowledge of reproductive aspects of inflammatory bowel disease improves dramatically after a single group education session[J]. J Crohns Colitis,2014,8:796-801.
• [19] Reddy D,Murphy SJ,Kane SV,et al. Relapses of inflammatory bowel disease during pregnancy:in-hospital management and birth outcomes[J]. Am J Gastroenterol,2008,103:1203-1209.
• [20] Pedersen N,Bortoli A,Duricova D,et al. The course of inflammatory bowel disease during pregnancy and postpartum:a prospective European ECCO-EpiCom Study of 209 pregnant women[J]. Aliment Pharmacol Ther,2013,38:501-512.
• [21] Miller JP. Inflammatory bowel disease in pregnancy:a review[J]. J R Soc Med,1986,79:221-225.
• [22] Bengtson MB,Solberg IC,Aamodt G,et al. Relationships between inflammatory bowel disease and perinatal factors:both maternal and paternal disease are related to preterm birth of offspring[J]. Inflamm Bowel Dis, 2010, 16:847-855.
• [23] Mahadevan U,Sandborn WJ,Li DK,et al. Pregnancy outcomes in women with inflammatory bowel disease:a large community-based study from Northern California[J]. Gastroenterology,2007,133:1106-1112.
• [24] Naganuma M,Kunisaki R,Yoshimura N,et al. Conception and pregnancy outcome in women with inflammatory bowel disease:A multicentre study from Japan[J]. J Crohns Colitis,2011,5:317-323.
• [25] Stephansson O,Larsson H,Pedersen L,et al. Congenital abnormalities and other birth outcomes in children born to women with ulcerative colitis in Denmark and Sweden[J].Inflamm Bowel Dis,2011,17:795-801.
• [26] Cornish J,Tan E,Teare J,et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy[J].Gut,2007,56:830-837.
• [27] Lin HC,Chiu CC,Chen SF,et al. Ulcerative colitis and pregnancy outcomes in an Asian population[J]. Am J Gastroenterol,2010,105:387-394.
• [28] Bortoli A,Pedersen N,Duricova D,et al. Pregnancy outcome in inflammatory bowel disease:prospective European case-control ECCO-EpiCom study, 2003—2006[J].Aliment Pharmacol Ther,2011,34:724-734.
• [29] Ito A,Iizuka B,Omori T,et al. Relationship between the Clinical Course of Ulcerative Colitis during Pregnancy and the Outcomes of Pregnancy:A Retrospective Evaluation[J]. Intern Med,2018,57:159-164.
• [30] Ujihara M,Ando T,Ishiguro K,et al. Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis[J]. BMC Res Notes,2013,6:210.
• [31] Bressler B,Marshall JK,Bernstein CN,et al. Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis:the Toronto consensus[J]. Gastroenterology,2015,148:1035-1058. e3.
• [32] Neurath MF,Travis SP. Mucosal healing in inflammatory bowel diseases:a systematic review[J]. Gut,2012,61:1619-1635.
• [33] Hanan IM. Inflammatory bowel disease in the pregnant woman[J]. Compr Ther,1998,24:409-414.
• [34] Kelley KE,Hernandez-Diaz S,Chaplin EL,et al. Identification of phthalates in medications and dietary supplement formulations in the United States and Canada[J]. Environ Health Perspect,2012,120:379-384.
• [35] Hernandez-Diaz S,Su YC,Mitchell AA,et al. Medications as a potential source of exposure to phthalates among women of childbearing age[J]. Reprod Toxicol,2013,37:1-5.
• [36] Dalrymple JM,Stamp LK,O'Donnell JL,et al. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis[J]. Arthritis Rheum,2008,58:3299-3308.
• [37] Dara P,Slater LM,Armentrout SA. Successful pregnancy during chemotherapy for acute leukemia[J]. Cancer,1981,47:845-846.
• [38] Kozlowski RD,Steinbrunner JV,MacKenzie AH, et al.Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease[J]. Am J Med,1990,88:589-592.
• [39] Martinez Lopez JA,Loza E,Carmona L. Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system(fertility,pregnancy,and breastfeeding)[J]. Clin Exp Rheumatol,2009,27:678-684.
• [40] Hernandez-Diaz S,Werler MM,Walker AM,et al. Folic acid antagonists during pregnancy and the risk of birth defects[J]. N Engl J Med,2000,343:1608-1614.
• [41] Smithells RW,Newman CG. Recognition of thalidomide defects[J]. J Med Genet,1992,29:716-723.
• [42] Peng X,Zhi M,Wei M,et al. Thalidomide results in diminished ovarian reserve in reproductive age female IBD patients[J]. Medicine(Baltimore),2017,96:e6540.
• [43] O'Morain C,Smethurst P,Dore CJ,et al. Reversible male infertility due to sulphasalazine:studies in man and rat[J].Gut,1984,25:1078-1784.
• [44] Mahadevan U,Terdiman JP,Aron J,et al. Infliximab and semen quality in men with inflammatory bowel disease[J].Inflamm Bowel Dis,2005,11:395-399.
• [45] Villiger PM,Caliezi G,Cottin V,et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis[J]. Ann Rheum Dis,2010,69:1842-1844.
• [46] Teruel C,Lopez-San Roman A,Bermejo F,et al. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines[J]. Am J Gastroenterol,2010,105:2003-2008.
• [47] Dejaco C,Mittermaier C,Reinisch W,et al. Azathioprine treatment and male fertility in inflammatory bowel disease[J]. Gastroenterology,2001,121:1048-1053.
• [48] Norgard B,Czeizel AE,Rockenbauer M,et al. Populationbased case control study of the safety of sulfasalazine use during pregnancy[J]. Aliment Pharmacol Ther,2001,15:483-486.
• [49] Rahimi R,Nikfar S,Rezaie A,et al. Pregnancy outcome in women with inflammatory bowel disease following exposure to5-aminosalicylic acid drugs:a meta-analysis[J]. Reprod Toxicol,2008,25:271-275.
• [50] Norgard B,Fonager K,Pedersen L,et al. Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy:a Danish cohort study[J]. Gut,2003,52:243-237.
• [51] Akbari M,Shah S,Velayos FS,et al. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease[J]. Inflamm Bowel Dis,2013,19:15-22.
• [52] Coelho J,Beaugerie L,Colombel JF,et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines:cohort from the CESAME Study[J]. Gut,2011,60:198-203.
• [53] Casanova MJ,Chaparro M,Domenech E,et al. Safety of thiopurines and anti-TNF-alpha drugs during pregnancy in patients with inflammatory bowel disease[J]. Am J Gastroenterol,2013,108:433-440.
• [54] Langagergaard V,Pedersen L,Gislum M,et al. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy:A Danish nationwide cohort study[J].Aliment Pharmacol Ther,2007,25:73-81.
• [55] Kanis SL,de Lima-Karagiannis A,de Boer NKH,et al. Use of Thiopurines During Conception and Pregnancy Is Not Associated With Adverse Pregnancy Outcomes or Health of Infants at One Year in a Prospective Study[J]. Clin Gastroenterol Hepatol,2017,15:1232-1241. e1.
• [56] Kane SV,Acquah LA. Placental transport of immunoglobulins:a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy[J]. Am J Gastroenterol,2009,104:228-233.
• [57] Mahadevan U,Wolf DC,Dubinsky M,et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease[J]. Clin Gastroenterol Hepatol,2013,11:286-292,e24.
• [58] Cheent K,Nolan J,Shariq S,et al. Case Report:Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease[J]. J Crohns Colitis,2010,4:603-605.
• [59] Mahadevan U,Martin CF,Sandler RS,et al. PIANO:a1000 patient prospective registry of pregnancy outcomes in women with ibd exposed to immunomodulators and biologic therapy[J]. Gastroenterology,2012,142:S149.
• [60] Julsgaard M,Kjeldsen J,Baumgart DC. Vedolizumab safety in pregnancy and newborn outcomes[J]. Gut,2017,66:1866-1867.
• [61] Mahadevan U,Vermeire S,Lasch K,et al. Vedolizumab exposure in pregnancy:outcomes from clinical studies in inflammatory bowel disease[J]. Aliment Pharmacol Ther,2017,45:941-950.
• [62] Park-Wyllie L,Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids:prospective cohort study and meta-analysis of epidemiological studies[J]. Teratology,2000,62:385-392.
• [63] Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts[J]. Cmaj,2011,183:796-804.
• [64] Martel MJ,Rey E,Beauchesne MF,et al. Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension:nested case-control study[J]. BMJ,2005,330:230.
• [65] Bar Oz B,Hackman R,Einarson T,et al. Pregnancy outcome after cyclosporine therapy during pregnancy:a metaanalysis[J]. Transplantation,2001,71:1051-1055.
• [66] Branche J,Cortot A,Bourreille A,et al. Cyclosporine treatment of steroid-refractory ulcerative colitis during pregnancy[J]. Inflamm Bowel Dis,2009,15:1044-1048.
• [67] Piper JM,Mitchel EF,Ray WA. Prenatal use of metronidazole and birth defects:no association[J]. Obstet Gynecol,1993,82:348-352.
• [68] Koss CA,Baras DC,Lane SD,et al. Investigation of metronidazole use during pregnancy and adverse birth outcomes[J]. Antimicrob Agents Chemother,2012,56:4800-4805.
• [69] Linseman DA,Hampton LA,Branstetter DG. Quinolone-induced arthropathy in the neonatal mouse. Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin[J]. Fundam Appl Toxicol,1995,28:59-64.
• [70] Bernstein CN,Blanchard JF,Houston DS,et al. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease:a population-based cohort study[J]. Thromb Haemost,2001,85:430-434.
• [71] Pomp ER,Lenselink AM,Rosendaal FR,et al. Pregnancy,the postpartum period and prothrombotic defects:risk of venous thrombosis in the MEGA study[J]. J Thromb Haemost,2008,6:632-637.
• [72]中华医学会消化病学分会炎症性肠病学组.中国住院炎症性肠病患者静脉血栓栓塞症防治的专家共识意见[J].中华炎性肠病杂志,2018,2:75-82.
• [73] Killeen S,Gunn J,Hartley J. Surgical management of complicated and medically refractory inflammatory bowel disease during pregnancy[J]. Colorectal Dis,2017,19:123-138.
• [74] Panes J,Bouzas R,Chaparro M,et al. Systematic review:the use of ultrasonography,computed tomography and magnetic resonance imaging for the diagnosis,assessment of activity and abdominal complications of Crohn's disease[J].Aliment Pharmacol Ther,2011,34:125-145.
• [75] Schreyer AG,Menzel C,Friedrich C,et al. Comparison of high-resolution ultrasound and MR-enterography in patients with inflammatory bowel disease[J]. World J Gastroenterol,2011,17:1018-1025.
• [76] Stern MD,Kopylov U,Ben-Horin S,et al. Magnetic resonance enterography in pregnant women with Crohn's disease:case series and literature review[J]. BMC Gastroenterol,2014,14:146.
• [77] Birchard KR,Brown MA,Hyslop WB,et al. MRI of acute abdominal and pelvic pain in pregnant patients[J]. AJR Am J Roentgenol,2005,184:452-458.
• [78] Tremblay E, Therasse E, Thomassin-Naggara I, et al.Quality initiatives:guidelines for use of medical imaging during pregnancy and lactation[J]. Radiographics,2012,32:897-911.
• [79] Schulze H,Esters P,A Dignass. Review article:the management of Crohn's disease and ulcerative colitis during pregnancy and lactation[J]. Aliment Pharmacol Ther,2014,40:991-1008.
• [80] Nguyen GC,Seow CH,Maxwell C,et al. The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy[J]. Gastroenterology,2016,150:734-757. e1.
• [81] van der Woude CJ,Ardizzone S,Bengtson MB,et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease[J]. J Crohns Colitis,2015,9:107-124.
• [82] Shergill AK,Ben-Menachem T,Chandrasekhara V,et al.Guidelines for endoscopy in pregnant and lactating women[J]. Gastrointest Endosc,2012,76:18-24.
• [83] Ludvigsson JF,Lebwohl B,Ekbom A,et al. Outcomes of Pregnancies for Women Undergoing Endoscopy While They Were Pregnant:A Nationwide Cohort Study[J]. Gastroenterology,2017,152:554-563. e9.
• [84] De Lima A,Galjart B,Wisse PH,et al. Does lower gastrointestinal endoscopy during pregnancy pose a risk for mother and child?—a systematic review[J]. BMC Gastroenterol,2015,15:15.
• [85] Abdul Sultan A,West J,Ban L,et al. Adverse Pregnancy Outcomes Among Women with Inflammatory Bowel Disease:A Population-Based Study from England[J]. Inflamm Bowel Dis,2016,22:1621-1630.
• [86] Foulon A,Dupas JL,Sabbagh C,et al. Defining the Most Appropriate Delivery Mode in Women with Inflammatory Bowel Disease:A Systematic Review[J]. Inflamm Bowel Dis,2017,23:712-720.
• [87] Ananthakrishnan AN,Cheng A,Cagan A,et al. Mode of childbirth and long-term outcomes in women with inflammatory bowel diseases[J]. Dig Dis Sci,2015,60:471-477.
• [88] Grouin A,Brochard C,Siproudhis L,et al. Perianal Crohn's disease results in fewer pregnancies but is not exacerbated by vaginal delivery[J]. Dig Liver Dis,2015,47:1021-1026.
• [89] McConnell RA,Mahadevan U. Pregnancy and the Patient with Inflammatory Bowel Disease:Fertility,Treatment,Delivery,and Complications[J]. Gastroenterol Clin North Am,2016,45:285-301.
• [90] Burke KE,Haviland MJ,Hacker MR,et al. Indications for Mode of Delivery in Pregnant Women with Inflammatory Bowel Disease[J]. Inflamm Bowel Dis, 2017, 23:721-726.
• [91] Smink M,Lotgering FK,Albers L,et al. Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands[J]. BMC Gastroenterol,2011,11:6.
• [92] Bernstein CN,Banerjee A,Targownik LE,et al. Cesarean Section Delivery Is Not a Risk Factor for Development of Inflammatory Bowel Disease:A Population-based Analysis[J]. Clin Gastroenterol Hepatol,2016,14:50-57.
• [93] Mahadevan U,McConnell RA,Chambers CD. Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease[J]. Gastroenterology, 2017,152:451-462. e2.
• [94] Branski D,Kerem E,Gross-Kieselstein E,et al. Bloody diarrhea—a possible complication of sulfasalazine transferred through human breast milk[J]. J Pediatr Gastroenterol Nutr,1986,5:316-317.
• [95] Van Assche G,Dignass A,Reinisch W,et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease:Special situations[J]. J Crohns Colitis,2010,4:63-101.
• [96] Ng SW,Mahadevan U. Management of inflammatory bowel disease in pregnancy[J]. Expert Rev Clin Immunol,2013,9:161-73; quiz 174.
• [97] Christensen LA, Dahlerup JF, Nielsen MJ, et al.Azathioprine treatment during lactation[J]. Aliment Pharmacol Ther,2008,28:1209-1213.
• [98] Sau A,Clarke S,Bass J,et al. Azathioprine and breastfeeding:is it safe?[J]. BJOG,2007,114:498-501.
• [99] Sammaritano LR,Bermas BL. Rheumatoid arthritis medications and lactation[J]. Curr Opin Rheumatol,2014,26:354-360.
• [100] Moretti ME,Verjee Z,Ito S,et al. Breast-feeding during maternal use of azathioprine[J]. Ann Pharmacother,2006,40:2269-2272.
• [101] Gotestam Skorpen C,Hoeltzenbein M,Tincani A,et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy,and during pregnancy and lactation[J].Ann Rheum Dis,2016,75:795-810.
• [102] Zelinkova Z,De Boer IP,Van Dijke MJ,et al. Azathioprine treatment during lactation[J]. Aliment Pharmacol Ther,2009. 30:90-91; author reply 91.
• [103] Nielsen OH,Maxwell C,Hendel J. IBD medications during pregnancy and lactation[J]. Nat Rev Gastroenterol Hepatol,2014,11:116-127.
• [104] Niebyl JR. Antibiotics and other anti-infective agents in pregnancy and lactation[J]. Am J Perinatol,2003,20:405-414.
• [105] WHO. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans:Vol. 50 Pharmaceutical Drugs[M]. Lyon:International Agency for Research on Cancer,1990:77-114.
• [106] Yamada T,Mogi M,Kage T,et al. Enhancement by cyclosporin A of metastasis from hamster cheek pouch carcinoma[J]. Arch Oral Biol,1992,37:593-596.
• [107] Pistilli B,Bellettini G, Giovannetti E, et al. Chemotherapy,targeted agents,antiemetics and growth-factors in human milk:how should we counsel cancer patients about breastfeeding?[J]. Cancer Treat Rev,2013,39:207-211.
• [108] Johns DG,Rutherford LD,Leighton PC,et al. Secretion of methotrexate into human milk[J]. Am J Obstet Gynecol,1972,112:978-980.
• [109] Gisbert JP. Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregn-ancy and breast-feeding[J]. Inflamm Bowel Dis,2010, 16:881-895.
• [110] Morton A. Cyclosporine and lactation[J]. Nephrology(Carlton),2011,16:249.
• [111] Ben-Horin S,Yavzori M,Kopylov U,et al. Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease[J]. J Crohns Colitis,2011,5:555-558.
• [112] Kattah MG,Milush JM,Burt T,et al. Anti-TNF and thiopurine therapy in pregnant IBD patients does not significantly alter a panel of B-cell and T-cell subsets in 1-yearold infants[J]. Clin Transl Gastroenterol,2018,9:143.
• [113] Esteve-Sole A,Deya-Martinez A,Teixido I,et al. Immunological Changes in Blood of Newborns Exposed to Anti-TNFalpha during Pregnancy[J]. Front Immunol, 2017,8:1123