Treatment of IBD in the Pregnant Patient
Transcription
Treatment of IBD in the Pregnant Patient
Treatment of IBD in the Pregnant Patient Miguel Regueiro, M.D. Associate Professor of Medicine Associate Chief for Education Cli i l Head Clinical H d and d Co-Director, C Di t IBD C Center t Director, Gastroenterology, Hepatology, Nutrition Fellowship University of Pittsburgh School of Medicine Question 1 • Which of the following drugs should NOT be actively transported across the placenta in the third trimester of pregnancy 1. 1 2. 3 3. 4. Infliximab Adalimumab Certolizumab Natalizumab Question 2 • Which of the following drugs is COMPATIBLE with breastfeeding 1. 1 2. 3 3. 4. 5 5. Infliximab Azathioprine Sulfasalazine All of the above N None off the th above b Question 3 • All of the following are CATEGORY B risk in pregnancy, EXCEPT: 1. 1 2. 3 3. 4. 5 5. Infliximab Adalimumab Certolizumab Natalizumab M Mesalamine l i Effect of Pregnancy on CD: Disease Activity at Conception N = 186 73% N = 93 27% No Relapse Relapse Inactive Miller JP. J R Soc Med. 1986;79(4):221-225. 33% 32% 34% Worsened Continued Decreased Activity Activity Activity Active Disease activity during pregnancy in women with IBD Percenta age of patie ents Exposure: IBD disease activity acti it d during ing conception, conception each trimester t imeste and the postpartum period (1 month) – Inactive, mild, moderate, severe 100 80 60 40 20 0 100 Disease activity in Crohn’s disease Inactive Mild Disease activity y in ulcerative colitis Moderate 80 60 40 20 0 Severe Concept T1 T2 T3 PP Trimester Mahadevan U, et al. Gastroenterol. 2007;133:1106-1112 Pregnancy Outcomes: Population Based Studies Preterm Birth Low Birth Wt Small Gest Age Caesarean Section 1. 2. 3. 4 4. N = 756 IBD N = 510 CD N = 1531 UC N = 107 UC UC, 155 CD 1. Kornfeld D, et al. Am J Obstet Gynecol. 1997;177(4):942-946. 2. Fonager K, et al. Am J Gastroenterol. 1998;93(12):2426-2430. 3. Nørgård B, et al. Am J Gastroenterol. 2000 Nov;95(11):3165-3170. 4. Dominitz JA, et al. Am J Gastroenterol. 2002 Mar;97(3):641-648. IBD UC CD X X X XX XX X X IPAA: Cumulative Incidence of Pregnancy Within 5 Years 1.0 Cumulaative Incidence of P Pregnancyy 0.8 Before diagnosis Reference Before surgery After surgery 0.6 04 0.4 0.2 0.0 0 12 24 36 48 Time to Pregnancy (months) Reprinted from Olsen KØ, et al. Gastroenterology. 2002;122:15-19 with permission from American Gastroenterological Association. 60 Pregnancy Risk Categories Pregnancy-Risk A: B: C: D: X: Controlled human studies do not show risk to fetus; chance of risk remote No evidence of risk to fetus in human studies; chance of risk remote but possible Inadequate studies in humans; risk cannot be ruled out but benefits may outweigh risks out, Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are ineffective Contraindicated in pregnancy Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. Safety of IBD Medications During Pregnancy Category B Category C Category D Category X Loperamide Ciprofloxacin Azathioprine† Methotrexate Mesalamine Cyclosporine 6-Mercaptopurine† Thalidomide Balsalazide Diphenoxylate Corticosteroids Olsalazine Sulfasalazine Tacrolimus Anti-TNF agents Metronidazole* Natalizumab Corticosteroids Rifaximin *Safe for use after first trimester. †Increasing use in pregnancy. Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. Physician’s Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003. Aminosalicylates (B,C) • Meta-analysis Meta analysis 7 studies: 642 5ASA vs 1158 no med – – – – – Congenital anomalies: OR 1.16 (0.76, 1.77) Stillbirth OR 2.38 (0.65, 8.72) SAB OR 1.14 1 14 (0.65, (0 65 2 2.01) 01) Preterm delivery 1.35 (0.85, 2.13) LBW OR 0.93 (0.46, 1.85) • Sulfasalazine given w/ folic acid 1 mg BID • Folic acid: neural tube defects, CV, GU, cleft palate • Case reports of congenital malformation • Placental and Breast Transfer Occurs • Potential allergic reaction newborn: watery diarrhea • SAS not associated with kernicterus or displacement of bilirubin from albumin • Olsalazine: Pregnancy category C. All others, B Rahimi Reprod Toxicol 2008 Corticosteroids (C) • Case-control studyy in 1st Trimester – Increased risk of oral clefts – Overall risk of malformations low – In transplant setting: • Adrenal suppression in newborn • Premature rupture of membranes • Compatible with breast feeding • Entocort (budesonide) – Orallyy inhaled budesonide not associated with increase risk of fetal abnormalities – 8 CD patients treated with oral budesonide (Binion) Antibiotics • Metronidazole ((B)) /Ciprofloxacin p ((C)) – Low risk of teratogenicity • Metronidazole: prospective controlled study, 2 meta-analysis – However, 2nd, 3rd T use, 1st T cleft lip, palate • Ciprofloxacin: prospective controlled study low risk of defects – Affinity for bones, arthropathy in children – Breast feeding not advised on metronidazole, probably compatible tibl with ith ciprofloxacin i fl i – Minimal benefit in CD and UC with longer use-avoid • Rifaximin: Pregnancy g yC – teratogenicity in animal studies – Safety in humans in pregnancy/breastfeeding unknown Human Studies: 6MP/AZA (D) • Transplantation Experience – Frequency of Congenital Abnormality in renal tx 0.0-11.8% in 27 clinical series – No recurrent pattern of anomalies seen – No increase in anomalies (Armenti 1994) in kidney transplant • No congenital anom in rheumatic ds, SLE • Experience in IBD – Alstead (1990): 14 pts: 7 entire pregnancy: no CA – Khan (2000): 8 preg/6 pt pt. No complications – Francella (2003): Retrospective • 79F(24 UC), 76M(27 UC). 325 pregnancies • No difference in outcomes with 6mp exposure • Only 15 patients on 6mp throughout pregnancy Azathioprine • 189 pregnant women on AZA who contacted one of seven teratogen information services were compared to a cohort of 230 pregnant women who took non-teratogenic treatments • Rate of major malformations did not differ with six neonates each: – AZA (3.5%) vs control ( 3.0%) (P = .775; OR 1.17; CI: 0.37, 3 69) 3.69). Goldstein LH, et al. Birth Defects Res A Clin Mol Teratol. 2007;79(10):696-701. So…although 6MP/AZA listed as category D….. ….the evidence suggests minimal to no increase risk in pregnancy. pregnancy Biologic Therapy in IBD Infliximab (B) Adalimumab (B) Certolizumab (B) Natalizumab (C) Outcomes of Women Exposed to Infliximab During Pregnancy P Proportio n of Patie ents (%) 80 70 67 67 66 67 60 Live births 50 Miscarriages 40 Therapeutic termination 30 20 17 16 20 19 17 15 11 13 10 0 General population Crohn’s disease Katz JA, et al. Am J Gastroenterol. 2004;99(12):2385-2392. Ventura SJ, et al. Vital Health Stat 21. 2000;21(56):1-47. Hudson M, et al. Int J Gynaecol Obstet. 1997;58(2):229-237. All infliximab Infliximab patients patients with (N = 96) CD (N = 82) Infliximab in Pregnancy 10 Crohn’s disease patients i t ti intentionally ll exposed d to t infliximab during pregnancy 8 women received maintenance infusions 2 women received initial infusions 10 Live Births Congenital malformations (N=0) IUGR (N=0) SGA (N=0) Preterm (N=3) LBW (N=1) 8 Caesarean sections: 2 active luminal, 3 perianal disease, 1 preterm Mahadevan U, et al. Aliment Pharmacol Ther. 2005;21:733-738. Infliximab in Cord Blood Pt # * Breastfed 1 2 3* 4* 5* 6 7* 8* Mother INF 15.1 (mcg/ml) 1.4 19.2 3.8 4.8 14.5 16.5 2.2 Cord Blood INF 2.0 26.5 3.3 8.8 20.5 26.5 8.4 -- 2.9 Newborn 25.3 23.6 4.2 8.7 28.2 27.5 10.6 INF at Birth W:2 Month INF Undetectable 5 2 7 2 3 4 5 -- High Serum Infliximab Levels in Newborn of a Mother Treated During Pregnancy Breast fed 7 wks –2 Time (weeks) from birth Infliximab + + + infusions (10 mg/kg) + + 0 2 4 Breast feed resumed Wk 11 6 10 13 + Birth 41 wks Immune studies at 6 months: T and B lymphocytes normal IgG, IgM and IgA levels normal Infliximab level Mother serum Baby serum Breast milk Vasiliauskas EA, et al. Clin Gastroenterol Hepatol. 2006;4(10):1255-1258 µg/mL 40 9.3 8.4 40 0 20.8 0 11.7 0 Adalimumab (B) O Organization i ti for f T Teratology t l IInformation f ti Specialists reports 27 women enrolled in a prospective study of adalimumab in pregnancy and an additional 47 adalimumab exposed pregnant women in a registry The rate of spontaneous abortion, stillbirth, congenital malformation and preterm t d delivery li was similar i il to t the th diseased comparison and the general population. population Chambers CD The OTIS Autoimmune Diseases in Pregnancy Project. Personal communication. July 13, 2007 . Certolizumab (B) Natalizumab (C) Certolizumab:: data on file Certolizumab – Pegylated – should not cross placenta – 16 pregnancies: 4 healthy ea t y infants, a ts, 8 IAB,, 1 S SAB,, 1 p preterm, ete , 2 unknown Natalizumab ((C): ) – IgG4, placental transfer in third trimester – 143 pregnant patients exposed to tysabri – No birth defects reported Mahadevan ACG 2008 Safety of IBD Medications in Breast-Feeding Low Risk to Use When Warranted Limited Data Available Contraindicated Oral mesalamine Topical mesalamine Sulfasalazine Corticosteroids Tacrolimus Natalizumab Certolizumab Adalimumab Methotrexate Cyclosporine Metronidazole Ci Ciprofloxacin? fl i ? 6-MP/AZA* I fli i b Infliximab (*new evidence suggests safe) Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003. de Boer NK, et al. Am J Gastroenterol. 2006;101(6):1390-1392. Sau A, et al. BJOG. 2007;114(4):498-501. Moretti ME, et al. Ann Pharmacother. 2006;40(12):2269-2272. Gardiner SJ, et al. Br J Clin Pharmacol. 2006;62(4):453-456. Question 1 • Which of the following drugs should NOT be actively transported across the placenta in the third trimester of pregnancy 1. 1 2. 3 3. 4. Infliximab Adalimumab Certolizumab Natalizumab Question 2 • Which of the following drugs is COMPATIBLE with breastfeeding 1. 1 2. 3 3. 4. Infliximab Azathioprine Sulfasalazine All of the above Question 3 • All of the following are CATEGORY B risk in pregnancy, EXCEPT: 1. 1 2. 3 3. 4. 5 5. Infliximab Adalimumab Certolizumab Natalizumab – category C M Mesalamine l i Summary • Disease control at conception p improves p pregnancy outcomes • anti-TNF therapies are safe and thiopurines are probably safe during pregnancy • Infliximab and adalimumab do cross the placenta in the third trimester. Preliminary p y evidence suggests that certolizumab does not cross • Most IBD medications can be continued during breastfeeding UPMC IBD CENTER Leonard Baidoo, MD Beth Rothert RN, BSN Arthur “Tripp” Tripp Barrie, Barrie MD MD, PhD Linda Kontur RN David Binion, MD Jennifer Rosenberry, RN Richard Duerr Duerr, MD Di Diane Sabilla, S bill RN Janet Harrison, MD Marilyn Pesci, RN Miguel Regueiro Regueiro, MD Joann Fultz Wolfgang Schraut, MD, PhD Kristy Rosenberry, RN M Marc Schwartz, S h t MD Linda Nelson Jason Swoger, MD, MPH Katie Wyant, CRNP A d Andrew W Watson, t MD 29