Clinical aspects of IMID and IMID drugs during pregnancy

1. Clinical aspects of IMID and IMID drugs during pregnancy Prof Franck Carbonnel CHU de Bic�tre Assistance Publique H�pitaux de Paris Universit� Paris Sud

3. Clinical aspects of IMID during pregnancy

4. Effect of pregnancy on IBD The rate of disease flare during pregnancy (26%�34%) appears to be similar to the rate of flare in the nonpregnant IBD population.

5. Disease activity may even be slightly lower during pregnancy

6. IBD activity may even be slightly lower during and after pregnancy

7. Fetal outcome in IBD: lessons from the meta-analysis 12 studies, 3907 women with IBD (CD 1952, UC 1113) and 320 531 controls In women with IBD : 1.9-fold significant increase in incidence of prematurity (CD and UC) 2.1-fold significant increase in incidence of low birth weight (<2500 g) (CD)  1.5-fold significant increase in incidence of caesarean section (CD) 2.4-fold significant increase in incidence of congenital abnormalities (UC)

8. IMID drugs during pregnancy

9. IMID drugs during pregnancy IBD drugs and during pregnancy Relapse during pregnancy IBD drugs and lactation IBD drugs and male infertility

10. Drugs and Safety information during pregnancy Voluntary reports of adverse events during post-marketing surveillance Uncontrolled observational studies (controlled data)

11. FDA Categories for use of medication in pregnancies

12. Conventional drugs and risks during pregnancy

13. Conventional drugs and risks during pregnancy

14. Methotrexate and pregnancy Methotrexate is teratogenic and should not be used in women considering conception. Patients must wait at least 3�6 months from the discontinuation of the drug before attempting conception.

15. Conventional drugs and risks during pregnancy

16. Azathioprine and pregnancy Pregnancy Category D Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies Multiple case series in transplant recipients (Polifka Teratology 2002) or IBD patients (Alstead Gastroenterology 1990; Francella A, Gastroenterology 2003; Khan Digestion 2000; Moskovitz Am J Gastroenterol 2004) have not noted increase in congenital anomalies. No evidence of recurrent patterns of congenital anomalies emerged

19. Pregnancy outcome in patients with Inflammatory Bowel Disease treated with Thiopurines : cohort from the CESAME study J Coelho, L Beaugerie, JF Colombel, X H�buterne, E Lerebours, M Lemann, P Baumer, J Cosnes, A Bourreille, JP Gendre, P Seksik, A Blain, EH Metman, A Nisard, G Cadiot, M Veyrac, B Coffin, F Carrat, P Marteau � For the CESAME group study (France)

20. Patients and methods (2) Classification of pregnancies into 1 of 3 groups Comparison of pregnancy between the groups (Fisher�s exact test)

21. Results (1) Pregnancies and fetal outcome according to exposure groups

22. Results (2) Details on the 6 cases of congenital abnormalities

23. Complications during pregnancies and after birth

24. Conventional drugs and risks during pregnancy

25. IgG placental transport over time

27. Infliximab TREAT registry (Lichtenstein G et al clin Gastro & Hepatol 2006) 36 pregnancies with prior infliximab exposure No fetal malformations Rates of miscarriage (11.1 vs 7.1%) and neonatal complications (8.3 vs 7.1%) not different between IFX treated and IFX-naive patients IFX safety database (Katz J et al Am J Gastro 2004) 96 pregnancies with IFX exposure (82 CD, 1UC) from 3 M before conception up to the first trimester Miscarriage : fausse couche. Miscarriage : fausse couche.

28. Intentional infliximab use during pregnancy in Crohn�s disease 8 women maintenance IFX throughout pregnancy 1 woman started IFX in third trimester for severe flare 1 woman started IFX in first trimester but did not continue

29. Infliximab levels in infants born to women with IBD

30. Effect of maternal peripartum infliximab use on neonatal immune response 8 infants born to women (7 Crohn's, 1 UC) received IFX in third trimester and 3 of the infants were breastfed 6 patients had available results: - all normal IgG and IgA levels - low IgM levels in 4/6 patients All 8 patients had appropriate protective response to tetanus vaccine 7/8 appropriate response to H Influenzae, while one 7 month old failed to develop protective antibody levels

31. The VACTERL controversy Request adressed to the FDA for adverse events for IFX, ADA and etanercept from 1999-2005 Search for congenital abnormalities. Out of >120.000 adverse events: 41 children with 61 congenital anomalies 22 mothers etanercept 19 IFX 34 different types of birth defects, 19 of which are part of the VACTERL 9/19 occured more than historical controls (p<0.01)

32. The VACTERL controversy Vertebral defects Anal atresia Cardiac abnormalities Tracheoesophageal fistula Esophageal atresia Renal abnormalities Limb abnormalities

34. Adalimumab OTIS : prospective cohort study of women with RA or CD exposed to ADA during the first trimester of pregnancy followed 1 year post partum.

35. Adalimumab

36. Relapse during pregnancy (focus on third trimester) Conventional corticosteroids and 5-ASA derivatives can be used and are preferred therapy In refractory patients anti-TNF agents and the calcineurin inhibitors can be used UM � patients on sulfasalazine should be on increased folic acid due to the anti-folate properties of the drug. Slight risk of cleft palate with steroid use in first trimesterUM � patients on sulfasalazine should be on increased folic acid due to the anti-folate properties of the drug. Slight risk of cleft palate with steroid use in first trimester

37. Conventional drugs and risks during pregnancy

38. Conventional drugs and risks during pregnancy

39. Medication during lactation Corticosteroids � gestational diabetesCorticosteroids � gestational diabetes

40. Semen quality and immune suppression

41. Summary There is a slightly decreased disease activity during pregnancy There is an increased rate of adverse outcome during pregnancies of women with IBD There appears to be no increased risk related to the use of salicylates, corticosteroids, ciclosporine, azathioprine, anti TNF agents during pregnancy Anti TNF agents after the second trimester and should be interrupted if possible. More data are needed concerning the development and immunity of children born to mothers treated with IBD drugs during pregnancy IBD drugs can be used safely during lactation Salazosulfapyridine causes oligospermia

42. Take home messages on pregnancy in IBD patients Before pregnancy Achieve disease remission before conception! Discuss necessity of drugs to maintain disease remission If possible: monotherapy and avoid cumulating therapies During pregnancy Monitor patient q8-12 weeks (blood monitoring in case of azathioprine and/or anti-TNF therapy) Stop anti-TNF around week 22 Discuss way of delivery: Cesarean section recommended in severe perianal CD or UC with IPAA pouch After delivery Discuss with patient if and when drugs should be restarted Be careful for flare in weeks following delivery Discuss breastfeeding

43. Take home messages on pregnancy in IBD patients Before pregnancy Achieve disease remission before conception! Discuss necessity of drugs to maintain disease remission If possible: monotherapy and avoid cumulating therapies During pregnancy Monitor patient q8-12 weeks (blood monitoring in case of azathioprine and/or anti-TNF therapy) Stop anti-TNF around week 22 Discuss way of delivery: Cesarean section recommended in severe perianal CD or UC with IPAA pouch After delivery Discuss with patient if and when drugs should be restarted Be careful for flare in weeks following delivery Discuss breastfeeding