Pregnancy in IBD CDDW 2014 Brian Bressler MD, MS, FRCPC Director, Advanced IBD Training Program Clinical Assistant Professor of Medicine Division of Gastroenterology University of British Columbia
Bressler Financial Interest Disclosure (over the past 24 months) Commercial Interest Abbvie Janssen Ferring Shire Warner Chilcott Takeda Relationship Advisory Board, Speaker Advisory Board, Speaker Speaker Advisory Board, Speaker Advisory Board Advisory Board
CanMEDS Roles Covered in this Session: ü ü ü ü Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.) Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.) Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal patient care.) Manager (as Managers, physicians are integral participants in healthcare organizations, organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.) Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to advance the health and well-being of individual patients, communities, and populations.) Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.) Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.)
Objectives 1. Know what to tell IBD patients wanting to get pregnant a. discussion of fecundity/infertility b. explain the risks of flaring, risk of complications 2. Understand the safety of medical therapy in pregnant IBD patients
IBD Patients Fear Infertility n 43% IBD patients fear infertility CD more than UC (47% v. 26%) Females more than males (54% v. 33%) n 14% were childless n 24% with children had fewer kids than desired or planned n Reasons for voluntary infertility included: Fear of IBD-related congenitial abn, genetic risk of IBD, medication toxicity, medical advice IBD 2009; 15:720.
RISK OF IBD IN OFFSPRING n First degree relatives 10-15 fold increase n Both parents with IBD 33% risk n Concordance of Type of Disease Gastroenterology 2001 Laharie D.
Are Patients with Crohn s Infertile? n Involuntary Rates similar to controls (4-14%) Higher in surgically managed patients (20% v. 8%) n Voluntary Rates higher than controls (14-30%) Higher in medically managed patients (36% v. 23%) Int J. Gynec & Obs 1997;58:229. Gastro 1990; 99:987.
Are Patients with UC Infertile? n Involuntary Overall similar rates to controls (2-15%) Higher in surgically managed patients (30% v. 13%) n Voluntary Rates higher than controls (21-25%) Higher in surgically managed patients (45% v. 21%) Int J. Gynec & Obs 1997;58:229. Gastro 1990; 99:987.
Female Infertility After IPAA Before After IPAA pts Diseases of Colon & Rectum 2004:47:1119
Open vs. Laparoscopic IPAA Ann Surgery 2012 One year pregnancy rate 30% (open) and 56% (laparoscopic) 6 mo and 1 yr rate for 29 yo 64% and 85%
Pregnancy & Risk of an IBD Flare n If in remission at conception: similar to 1-year risk in non-pregnant patients 25% CD (highest in 1 st trimester) 33% UC n If have active disease at conception UC 45% get worse, 25% better, 25% same CD 1/3 worse, 1/3 better; 1/3 same AJG 2007; 102:1414. Gut 1984; 25:52.
Outcome of IBD on Pregnancy n n Meta-analysis (3907 IBD pts v. 320,521 controls) Results reported as OR (odds ratios) IBD CD UC Prematurity (<37 wks) 1.87 1.97 1.34 Low Birth Weight (<2500 g) 2.1 2.82 NS Caesarean Section 1.5 1.65 NS Small for Gestational Age NS NS NS Still Births NS NS NS Gut 2007; 56:830
Norgard B, et al. Am J Gastro 2007 Impact of disease activity on pregnancy outcomes Danish population study comparing 71 pregnant patients with disease Activity to 86 patients without disease activity
FERTILITY SULFASALAZINE Oligospermia Reduced Motility Abnormal Morphology Not dose-dependent METHOTREXATE Reversible oligospermia AZATHIOPRINE No effect on semen quality 1.5-2 mg/kg INFLIXIMAB Counter negative effects of TNFα Gastroenterology 2001 Vol 121(5) Inflamm Bowel Dis 2005 11(4) Journal of Crohn s and Colitis 2012 Vol 6 (8)
SAFETY OF IBD MEDICATIONS FDA Category A B Description Adequate and well controlled studies showing no risk No risk demonstrated in human studies C D Animal studies; benefits may be acceptable despite potential risks Human studies; benefit from the drug may be acceptable despite potential risks X Human studies show risk; RISK >>> BENEFIT
FDA classification
5-ASA FDA Class B FDA Class C Dipentum Asacol Asacol coating contains DBP (debutyl phthalate) SULFASALAZINE Needs folate supplementation Animal studies at doses >190 times the human dose Skeletal malformations and male reproductive system
200 x Reproductive Toxicology 2013
Thiopurine/Pregnancy Outcomes Meta analysis Birth Weight Preterm Birth Akbari et al. Inflamm Bowel Dis 2013
Thiopurine exposure and Congential Abnormalities Maternal Paternal Akbari et al. Inflamm Bowel Dis 2013
Thiopurines and Breast Feeding n Major excretion in breast milk within 4 hours of taking medication n Worst case scenario: max concentration 0.0075mg/kg Christensen S et al. APT 2008
Infliximab Exposure * Flare Mahadevan et al. Clin Gastro Hep 2013
ADA Exposure
Does this matter?
Infliximab in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy Proportion of Patients (%) 80 70 60 50 40 30 20 10 0 67 66 67 67 17 16 17 General Population 11 Crohn s Disease 15 19 20 13 All Infliximab Patients (N=96) Infliximab Patients with CD (N=82) Live births Miscarriages Therapeutic termination Adapted from Katz JA, et al. Am J Gastroenterol 2004;99:2385-92; Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59; Hudson et al. Int J Gynaecol Obstet 1997;58:229-37.
Infections n Fatal case of disseminated BCG infection in an infant born to mother on infliximab for CD Infant died at 4.5 months of age Cheet K. JCC 2010 Don t give infants live vaccines
Immune Response to Vaccines n Influenza vaccine Pediatric IBD patients on infliximab and immunomodulators had higher rates of inadequate response compared to healthy controls 1 Among adults on infliximab, proportion with protective titer not different from controls; however, mean antibody titer was significantly lower 2 n Pneumococcal vaccine Infliximab +/- methotrexate had lower response to pneumococcal vaccine 3 1. Mamula P, et al. Clin Gastroenterol Hepatol 2007;5:851-6; 2. Gelnick A. Ann Rheum Dis 2005;64:181; 3. Visvanathan S, et al. J Rheumatol 2007;34:952-7.
BREASTFEEDING MEDICATION Sulfasalazine 5-ASA Methotrexate AZA or 6-MP? SAFE Sulfapyridine secreted into breast milk < 10% of therapeutic dose - Compatible Contraindicated <1% of maternal dose - Compatible Majority excreted in first 4 hours Corticosteroids <0.1% of maternal dose of prednisolone - Compatible Infliximab Adalimumab Cyclosporine Not detected in breast milk Compatible No data Diarrhea Secreted at high concentrations Not recommended
Summary/Conclusions n Fertility and pregnancy are common concerns to patients with IBD Talk to your patients! n Involuntary infertility is more common in IBD patients managed surgically n Voluntary infertility is higher in surgically managed UC patients and medically managed CD patients n Female infertility is significantly decreased after IPAA
Summary/Conclusions (2) n IBD outcomes are better if pt is in remission at the time of conception n IBD pregnancies (mostly CD) have increased odds of prematurity, low birth weight, C- section, and congenital abnormalities n Safety signals suggests Adalimumab and Infliximab are reasonable medications to use in pregnancy n Fetal exposure may occur if given anti-tnf agents in 3 rd Trimester
Canadian National Working Group for IBD meeting and Pregnancy: 2nd Salon 3 on the 19th floor