Insights into the treatment of inflammatory bowel disease in pregnancy

Patients diagnosed with inflammatory bowel disease (IBD) are most commonly diagnosed in late adolescence or early adulthood, with half of patients being diagnosed before age 32, thus impacting peak years of reproduction and family planning. While controlled IBD has no negative effects on the ability to conceive, there is overall a trend towards voluntary childlessness due to patients’ concerns for adverse fetal outcomes from underlying IBD and from adverse medication effects. Active disease at the time of conception is associated with worsening disease activity during pregnancy and carries a higher risk of poor fetal outcomes. It is therefore important to maintain remission during pregnancy, which is often achieved with pharmacologic therapy. The goal of this paper is to provide a comprehensive review of the current literature and safety data for pharmacologic treatment of IBD in pregnancy, in breastfeeding women, and in men planning to have children.

[1]  P. Michl,et al.  High frequency of secondary, but not primary ocular manifestations of inflammatory bowel disease in patients treated at a tertiary care center , 2018, European journal of gastroenterology & hepatology.

[2]  M. Neurath,et al.  Drug Levels in the Maternal Serum, Cord Blood and Breast Milk of a Ustekinumab-Treated Patient with Crohn's Disease. , 2018, Journal of Crohn's & colitis.

[3]  U. Mahadevan,et al.  The Debate is Over: Continue Anti-Tumor Necrosis Factor Therapy Throughout Pregnancy , 2018, The American Journal of Gastroenterology.

[4]  D. Franchimont,et al.  Outcome of Pregnancies in Female Patients With Inflammatory Bowel Diseases Treated With Vedolizumab , 2018, Journal of Crohn's & colitis.

[5]  Sean T. McCarthy,et al.  An International External Interobserver and Derivation Study for the Detection of Advanced Neoplasia in IPMNs Using Confocal Laser Endomicroscopy , 2018, American Journal of Gastroenterology.

[6]  M. Lukáš,et al.  Safety of Anti-TNF-Alpha Therapy During Pregnancy on Long-term Outcome of Exposed Children: A Controlled, Multicenter Observation. , 2018, Inflammatory bowel diseases.

[7]  Christopher F. Martin,et al.  Exposure Concentrations of Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and Development. , 2018, Gastroenterology.

[8]  D. Rizopoulos,et al.  Anti-TNF Levels in Cord Blood at Birth are Associated with Anti-TNF Type , 2018, Journal of Crohn's & colitis.

[9]  W. Sandborn,et al.  Pregnancy Outcomes Reported During the 13‐Year TREAT Registry: A Descriptive Report , 2018, The American Journal of Gastroenterology.

[10]  S. Feldman,et al.  Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis , 2018, Inflammatory bowel diseases.

[11]  A. Barkun,et al.  Continuous Anti‐TNF&agr; Use Throughout Pregnancy: Possible Complications For the Mother But Not for the Fetus. A Retrospective Cohort on the French National Health Insurance Database (EVASION) , 2018, The American Journal of Gastroenterology.

[12]  A. Kimball,et al.  Su1799 - Pregnancy Outcomes in Women Exposed to Ustekinumab , 2018 .

[13]  L. Peyrin-Biroulet,et al.  Sexual and reproductive issues and inflammatory bowel disease: a neglected topic in men , 2018, European journal of gastroenterology & hepatology.

[14]  B. Abraham,et al.  A109 PREGNANCY OUTCOMES IN WOMEN EXPOSED TO USTEKINUMAB IN THE CROHN’S DISEASE CLINICAL DEVELOPMENT PROGRAM , 2018 .

[15]  D. Murphy,et al.  Ustekinumab Drug Levels in Maternal and Cord Blood in a Woman With Crohn's Disease Treated Until 33 Weeks of Gestation. , 2018, Journal of Crohn's & colitis.

[16]  J. Gisbert,et al.  Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study , 2018, The American Journal of Gastroenterology.

[17]  L. Peyrin-Biroulet,et al.  P817 Live-vaccines and lactation in newborn exposed in utero to anti-TNF: A multi-centre French experience in inflammatory bowel disease , 2018 .

[18]  Nima Hamidi,et al.  Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies , 2017, The Lancet.

[19]  P. Michl,et al.  Family planning in inflammatory bowel disease: childlessness and disease-related concerns among female patients , 2017, European journal of gastroenterology & hepatology.

[20]  X. Mariette,et al.  Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study , 2017, Annals of the rheumatic diseases.

[21]  B. Bibby,et al.  Vedolizumab Concentrations in the Breast Milk of Nursing Mothers With Inflammatory Bowel Disease. , 2017, Gastroenterology.

[22]  T. Ma,et al.  Effects of In Utero Exposure to Di-n-Butyl Phthalate on Testicular Development in Rat , 2017, International journal of environmental research and public health.

[23]  S. Kane,et al.  Sexuality, Fertility, and Pregnancy in Crohn's Disease. , 2017, Gastroenterology clinics of North America.

[24]  J. Thorp,et al.  Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study , 2017, Annals of the rheumatic diseases.

[25]  I. Kema,et al.  Maternal use of prednisolone is unlikely to be associated with neonatal adrenal suppression—a single-center study of 16 cases , 2017, European Journal of Pediatrics.

[26]  D. Tanyingoh,et al.  The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease , 2017, Alimentary pharmacology & therapeutics.

[27]  H. Poulsen,et al.  Risk of Adverse Pregnancy Outcome After Paternal Exposure to Methotrexate Within 90 Days Before Pregnancy. , 2017, Obstetrics and gynecology.

[28]  M. Dubinsky,et al.  Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease , 2017, Alimentary pharmacology & therapeutics.

[29]  Wen-lin Xiao,et al.  The relationship between maternal corticosteroid use and orofacial clefts-a meta-analysis. , 2017, Reproductive toxicology.

[30]  G. Rogler,et al.  Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease , 2016, Inflammatory bowel diseases.

[31]  C. J. van der Woude,et al.  Preconception Care Reduces Relapse of Inflammatory Bowel Disease During Pregnancy. , 2016, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[32]  C. J. Woude,et al.  The Effects of Active IBD During Pregnancy in the Era of Novel IBD Therapies , 2016, The American Journal of Gastroenterology.

[33]  U. Kopylov,et al.  Perception of Reproductive Health in Women with Inflammatory Bowel Disease. , 2016, Journal of Crohn's & colitis.

[34]  B. Nørgård,et al.  Reassuring results on birth outcomes in children fathered by men treated with azathioprine/6-mercaptopurine within 3 months before conception: a nationwide cohort study , 2016, Gut.

[35]  Steven J Brown,et al.  Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. , 2016, Gastroenterology.

[36]  S. Feldman,et al.  Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis , 2016, Drug Safety.

[37]  U. Mahadevan,et al.  Pregnancy and the Patient with Inflammatory Bowel Disease: Fertility, Treatment, Delivery, and Complications. , 2016, Gastroenterology clinics of North America.

[38]  A. Madill,et al.  What Factors Might Drive Voluntary Childlessness (VC) in Women with IBD? Does IBD-specific Pregnancy-related Knowledge Matter? , 2016, Journal of Crohn's & colitis.

[39]  A. Bitton,et al.  The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy. , 2016, Gastroenterology.

[40]  D. Wolf,et al.  Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol , 2015, The Journal of Rheumatology.

[41]  S. Tenjarla,et al.  Release of 5-Aminosalicylic Acid (5-ASA) from Mesalamine Formulations at Various pH Levels , 2015, Advances in Therapy.

[42]  A. Bitton,et al.  Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus. , 2015, Gastroenterology.

[43]  Hsiu-Ju Chang,et al.  Does the level of reproductive knowledge specific to inflammatory bowel disease predict childlessness among women with inflammatory bowel disease? , 2015, Canadian journal of gastroenterology & hepatology.

[44]  D. Tanyingoh,et al.  Intrapartum corticosteroid use significantly increases the risk of gestational diabetes in women with inflammatory bowel disease. , 2015, Journal of Crohn's & colitis.

[45]  C. J. van der Woude,et al.  The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. , 2015, Journal of Crohn's & colitis.

[46]  G. Lichtenstein,et al.  Safety of anti-TNF therapy in inflammatory bowel disease during pregnancy , 2014, Expert opinion on drug safety.

[47]  Christopher F. Martin,et al.  Erratum: Pregnancy outcomes amongst mothers with inflammatory bowel disease exposed to systemic corticosteroids: Results of the PIANO registry (Gastroenterology (2014) 146:5 (Suppl 1) (S1)) , 2014 .

[48]  P. Deepak,et al.  Maternal and foetal adverse events with tumour necrosis factor‐alpha inhibitors in inflammatory bowel disease , 2014, Alimentary pharmacology & therapeutics.

[49]  F. Granath,et al.  Birth Outcomes in Women with Inflammatory Bowel Disease: Effects of Disease Activity and Drug Exposure , 2014, Inflammatory bowel diseases.

[50]  Christopher F. Martin,et al.  1 Achievement of Developmental Milestones Among Offspring of Women With Inflammatory Bowel Disease: The PIANO Registry , 2014 .

[51]  Alok Jain,et al.  959 Vaccination Outcomes in Inflammatory Bowel Disease , 2014 .

[52]  G. Shaw,et al.  Corticosteroid use and risk of orofacial clefts , 2014, Birth defects research. Part A, Clinical and molecular teratology.

[53]  M. Hoeltzenbein,et al.  No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. , 2014, Rheumatology.

[54]  O. Nielsen,et al.  IBD medications during pregnancy and lactation , 2014, Nature Reviews Gastroenterology &Hepatology.

[55]  L. Punzi,et al.  Influence of tumor necrosis factor α inhibitors on testicular function and semen in spondyloarthritis patients. , 2014, Fertility and sterility.

[56]  L. Peyrin-Biroulet,et al.  Systematic review: fertility in non‐surgically treated inflammatory bowel disease , 2013, Alimentary pharmacology & therapeutics.

[57]  A. Abhyankar,et al.  Commentary: impact of disease activity at conception on disease activity during pregnancy in patients with inflammatory bowel disease – authors' reply , 2013, Alimentary pharmacology & therapeutics.

[58]  J. Gisbert,et al.  The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO‐EpiCom Study of 209 pregnant women , 2013, Alimentary pharmacology & therapeutics.

[59]  J. Mclaughlin,et al.  Inflammatory bowel disease and pregnancy: lack of knowledge is associated with negative views. , 2013, Journal of Crohn's & colitis.

[60]  S. Hernández-Díaz,et al.  Medications as a potential source of exposure to phthalates among women of childbearing age. , 2013, Reproductive toxicology.

[61]  D. Hommes,et al.  Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease , 2013, Gut.

[62]  S. Shah,et al.  Systematic Review and Meta-analysis on the Effects of Thiopurines on Birth Outcomes from Female and Male Patients with Inflammatory Bowel Disease , 2013, Inflammatory bowel diseases.

[63]  Cynthia J. Vaughn Drugs and Lactation Database: LactMed , 2012 .

[64]  A. Puchner,et al.  Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. , 2012, Clinical and experimental rheumatology.

[65]  M. Lebwohl,et al.  Review of treatment options for psoriasis in pregnant or lactating women: from the Medical Board of the National Psoriasis Foundation. , 2012, Journal of the American Academy of Dermatology.

[66]  J. Mclaughlin,et al.  Patients' knowledge of pregnancy‐related issues in inflammatory bowel disease and validation of a novel assessment tool (‘CCPKnow’) , 2012, Alimentary pharmacology & therapeutics.

[67]  Christopher F. Martin,et al.  865 PIANO: A 1000 Patient Prospective Registry of Pregnancy Outcomes in Women With IBD Exposed to Immunomodulators and Biologic Therapy , 2012 .

[68]  D. Furst,et al.  Rheumatoid arthritis and pregnancy: Disease activity, pregnancy outcomes, and treatment options during pregnancy and lactation , 2011 .

[69]  A. Hviid,et al.  Corticosteroid use during pregnancy and risk of orofacial clefts , 2011, Canadian Medical Association Journal.

[70]  P. Moayyedi,et al.  Glucocorticosteroid Therapy in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis , 2011, The American Journal of Gastroenterology.

[71]  W. Reinisch,et al.  Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding. , 2011, Journal of Crohn's & colitis.

[72]  J. Gisbert,et al.  Successful use of infliximab for perianal Crohn's disease in pregnancy. , 2011, Inflammatory bowel diseases.

[73]  M. Lebwohl,et al.  Obesity and psoriasis: from the Medical Board of the National Psoriasis Foundation. , 2010, Journal of the American Academy of Dermatology.

[74]  S. Shariq,et al.  Case Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease. , 2010, Journal of Crohn's & colitis.

[75]  J. Gisbert,et al.  Outcomes of Pregnancies Fathered by Inflammatory Bowel Disease Patients Exposed to Thiopurines , 2010, The American Journal of Gastroenterology.

[76]  M. Serghini,et al.  [Fertility and inflammatory bowel diseases]. , 2010, La Tunisie medicale.

[77]  P. Villiger,et al.  Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis , 2010, Annals of the rheumatic diseases.

[78]  H. Sørensen,et al.  Crohn's disease is a risk factor for preterm birth. , 2010, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[79]  P. Saulnier,et al.  Hypoglycaemic seizure and neonatal acute adrenal insufficiency after maternal exposure to prednisone during pregnancy: a case report , 2010, European Journal of Pediatrics.

[80]  M. Vatn,et al.  Relationships between inflammatory bowel disease and perinatal factors: Both maternal and paternal disease are related to preterm birth of offspring , 2010, Inflammatory bowel diseases.

[81]  C. O'Morain,et al.  The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. , 2010, Journal of Crohn's & colitis.

[82]  J. Andrews,et al.  Fear and fertility in inflammatory bowel disease: A mismatch of perception and reality affects family planning decisions , 2009, Inflammatory bowel diseases.

[83]  Dawn B. Beaulieu,et al.  Budesonide induction and maintenance therapy for Crohn's disease during pregnancy , 2009, Inflammatory bowel diseases.

[84]  P. Voulgari,et al.  Fertility and Reproduction in Male Patients with Ankylosing Spondylitis Treated with Infliximab , 2008, The Journal of Rheumatology.

[85]  C. Heijnen,et al.  Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment , 2008, Journal of leukocyte biology.

[86]  A. Kornbluth,et al.  Relapses of Inflammatory Bowel Disease During Pregnancy: In-Hospital Management and Birth Outcomes , 2008, The American Journal of Gastroenterology.

[87]  S. Nikfar,et al.  Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis. , 2008, Reproductive toxicology.

[88]  Ken Kleinman,et al.  The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[89]  D. Corley,et al.  Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. , 2007, Gastroenterology.

[90]  R. Sharpe,et al.  In Utero Exposure to Di(n-butyl) Phthalate and Testicular Dysgenesis: Comparison of Fetal and Adult End Points and Their Dose Sensitivity , 2007, Environmental health perspectives.

[91]  A. Buchman,et al.  Voluntary childlessness is increased in women with inflammatory bowel disease , 2007, Inflammatory bowel diseases.

[92]  S. Targan,et al.  Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[93]  C. O'Morain,et al.  Does Pregnancy Change the Disease Course? A Study in a European Cohort of Patients with Inflammatory Bowel Disease , 2006, The American Journal of Gastroenterology.

[94]  E. Louis,et al.  The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. , 2006, Journal of Crohn's & colitis.

[95]  J. Auwerx,et al.  Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ , 2005, The Journal of experimental medicine.

[96]  J. Terdiman,et al.  Infliximab and Semen Quality in Men With Inflammatory Bowel Disease , 2005, Inflammatory bowel diseases.

[97]  G. Lichtenstein,et al.  Outcome of Pregnancy in Women Receiving Infliximab for the Treatment of Crohn's Disease and Rheumatoid Arthritis , 2004, The American Journal of Gastroenterology.

[98]  E. Loftus Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. , 2004, Gastroenterology.

[99]  M. Neurath,et al.  CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. , 2003, The Journal of clinical investigation.

[100]  E. Chakravarty,et al.  The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. , 2003, The Journal of rheumatology.

[101]  E. Boyko,et al.  Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study , 2002, American Journal of Gastroenterology.

[102]  T. Einarson,et al.  Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. , 2001, Transplantation.

[103]  T. Einarson,et al.  Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. , 2000, Teratology.

[104]  B. Korelitz,et al.  6MP for fathers with IBD at the time of conception: the value of a large clinical experience over unrelated controls , 2000, American Journal of Gastroenterology.

[105]  S. Hanauer,et al.  Intravenous cyclosporin in ulcerative colitis: a five-year experience , 1999, American Journal of Gastroenterology.

[106]  Marteau,et al.  Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules , 1998, Alimentary pharmacology & therapeutics.

[107]  B. Korelitz,et al.  Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease , 1998, American Journal of Gastroenterology.

[108]  G. Brooks,et al.  Overtraining affects male reproductive status , 1993, Fertility and sterility.

[109]  D. Baird,et al.  Increased risk of preterm birth for women with inflammatory bowel disease. , 1990, Gastroenterology.

[110]  G. Nelis DIARRHOEA DUE TO 5-AMINOSALICYLIC ACID IN BREAST MILK , 1989, The Lancet.

[111]  S. Riley,et al.  Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. , 1987, Gut.

[112]  E. Kerem,et al.  Bloody diarrhea--a possible complication of sulfasalazine transferred through human breast milk. , 1986, Journal of pediatric gastroenterology and nutrition.

[113]  C. O'Morain,et al.  Reversible male infertility due to sulphasalazine: studies in man and rat. , 1984, Gut.

[114]  K. Das,et al.  Sulfasalazine. Adverse effects and desensitization. , 1983, Digestive diseases and sciences.

[115]  U. Zor,et al.  Enhanced thromboxane A2 and prostacyclin production by cultured rectal mucosa in ulcerative colitis and its inhibition by steroids and sulfasalazine. , 1981, Gastroenterology.

[116]  G. Birnie,et al.  Incidence of sulphasalazine-induced male infertility. , 1981, Gut.

[117]  R. Lauwerys,et al.  ENVIRONMENTAL POLLUTION BY CADMIUM AND MORTALITY FROM RENAL DISEASES , 1981, The Lancet.

[118]  M. Leonard,et al.  Psoriasis, methotrexate, and oligospermia. , 1980, Archives of dermatology.

[119]  C. Vogel,et al.  Secretion of methotrexate into human milk. , 1972, American journal of obstetrics and gynecology.

[120]  Christopher F. Martin,et al.  Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines , 2018, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[121]  N. Chescheir Focus on Clinical Practice and Quality. , 2017, Obstetrics and gynecology.

[122]  D. Rimar,et al.  Effect of infliximab on male fertility: Comment on the article "Fertility in male patients with seronegative spondyloarthropathies treated with infliximab" by Saougou et al., Joint Bone Spine 2013;80, 34-37. , 2014, Joint, bone, spine : revue du rhumatisme.

[123]  P. Voulgari,et al.  Fertility in male patients with seronegative spondyloarthropathies treated with infliximab. , 2013, Joint, bone, spine : revue du rhumatisme.

[124]  M. Chatzinoff,et al.  Sulfasalazine-induced abnormal sperm penetration assay reversed on changing to 5-aminosalicylic acid enemas , 2005, Digestive Diseases and Sciences.

[125]  B. Feagan,et al.  Methotrexate for induction of remission in refractory Crohn's disease. , 2005, The Cochrane database of systematic reviews.

[126]  S. Kane,et al.  Gastroenterology Expert Column: IBD and Pregnancy , 2004 .

[127]  A. Källén,et al.  Rectal pharmacokinetics of budesonide , 2004, European Journal of Clinical Pharmacology.

[128]  G. Koren,et al.  The safety of mesalamine in human pregnancy: a prospective controlled cohort study. , 1998, Gastroenterology.

[129]  R. Clark,et al.  Effects of corticosterone on reproduction in male Sprague-Dawley rats. , 1997, Reproductive toxicology.

[130]  R. Brattsand,et al.  Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. , 1996, Alimentary pharmacology & therapeutics.

[131]  S. Yaffe,et al.  Disposition of salicylazosulfapyridine (Azulfidine) and metabolites in human breast milk. , 1980, Developmental pharmacology and therapeutics.