1. Case #2 Biologics and Pregnancy

2. History of Present Illness 26 F with Crohn’s disease Developed persistent diarrhea in 2008 – colonoscopy demonstrated Crohn's disease primarily involving terminal ileum but also some active colitis in the sigmoid colon. – Failed 5-ASA and immunomodulators. – Developed perianal abscess progressing to fistula in 2009, requiring surgery. – Started on infliximab in 2009 but this was complicated by anaphylaxis Began adalimumab in 2010 and was doing well Became pregnant in 2011 while on adalimumab

3. Discussion When is a good time to get pregnant after a flare? Now that she is pregnant, what would you do with her anti-TNF agent? – Continue – Continue with immunomodulator – Stop – Switch

4. Increase in Preterm birth with moderate to high disease activity Crude Relative Risk 95% CI LBW1.10.3-4.0 LBW at term 0.90.1-8.5 Preterm birth 3.41.1-10.6 Congenital Anomalies 0.40.0-3.9 Norgard B, et al. Am J Gastroenterol. 2007;102:1947–1954. Danish population based study: Pregnancies with disease activity at any time (n=71) were compared to pregnancies without any disease activity (n=86)

5. 571 IBD pregnancies in Spain (53% CD; 21% active disease during pregnancy) 253 pregnancies in patients exposed to IM (187) or anti-TNF (66) during/within 6 months of pregnancy – 74% IM monotherapy; 11% anti-TNF agent; 15% combination therapy Azathioprine safety: Spanish cohort Exposed (253) Unexposed (318)P Crohn’s Disease73%37%< 0.001 IBD Surgery37%6%<0.001 History: Tobacco Use21%13%0.01 Active IBD27%19%0.015 Exposed (253) Unexposed (318) Any complication25%32% Spontaneous Abortion9%12% Preterm Delivery5%9% Low Birth Weight5%9% ICU Admission2%3% Malformations1%0.4% All P-values NS Casanova MJ, et al. Am J Gastroenterol. 2013 Mar;108(3):433-40Am J Gastroenterol. ICU, intensive care unit Conclusion: There was no increased risk of poor pregnancy outcomes in Spanish IBD patients on immunosuppressant therapy Thiopurines only predictor of favorable GPO OR 1.67, 1.03-2.7

6. 30 patients on azathioprine (28 patients, median dose 1.93 mg/kg) or 6-MP (two patients, doses 1.32 and 0.94 mg/kg) During pregnancy, median 6-TGN decreased over time (p=0.001). while 6-MMP increased, without causing maternal myelotoxicity or hepatotoxicity. After delivery, both 6-TGN and 6-MMP levels returned to preconception baseline levels. Jharap B et al Gut 2013 Feb 19. [Epub ahead of print Thiopurines and fetal anemia; Should we test newborns?

7. Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). (n=25) Median 6TGN infant: mother = 42:92 pmol/8x10 8 No 6-MMP was detected in the newborns except 1 Pancytopenia and high alk phos (severe pre-eclampsia) 63% had anemia at birth: (n=16) Median Hb 9.25 mmol/l [8.25-9.60] 6-TGN 230 vs 90 in infants with anemia Congenital Anomalies: 2/31 (6.5%) clubfoot, ptosis Jharap B et al Gut 2013 Feb 19. [Epub ahead of print) Thiopurines and fetal anemia; Should we test newborns?

8. Adverse Pregnancy Outcomes: The Piano Study Group A (aza) RR (CI) Group B (bio)Group AB (combo) Any Complication 1.2 (0.8-1.8)1.2 (0.8-1.7)1.7 (1.0-2.8) Spontaneous Abortion 0.5 (0.2-1.5)1.3 (0.6-2.9)1.4 (0.5-4.1) Preterm Birth 1.0 (0.6-1.8)0.8 (0.5-1.3)2.4 (1.3-4.3) Low Birth Weight 0.7 (0.4-1.6)1.2 (0.6-2.1)1.5 (0.7-3.3) IUGR 0.8 (0.2-2.8)1.0 (0.3-2.8)0.5 (0.1-3.9) Cesarean section 1.0 (0.7-1.4)1.4 (1.0-1.9)1.3 (0.8-2.0) NICU 1.1 (0.6-1.8)1.2 (0.7-1.9)1.3 (0.7-2.5) Congenital Anom 0.8 (0.4-1.7)0.9 (0.4-1.7)0.9 (0.3-2.5) * P <0.05 Adjusted for none/mild vs. mod/severe disease activity

9. Biologics: Placental Transfer Infliximab: – Study of 10 mothers on IFX – In all cases, infant and cord IFX level were greater than mother. 6 months to clear Adalimumab – Study of 10 mothers on ADA – In all cases, infant and cord ADA level was greater than mother. Up to 4 months to clear – ¾ pts who stopped ADA 35 days prior to delivery had a flare Certolizumab – Study of 10 mothers – In all cases, infant and cord levels were less than 2 mcg/ml even if mom dosed the week of delivery Mahadevan Clin Gastroenterol Hepatol. 2013 Mar

10. Placental Transfer 28 live births (17 IFX, 11 ADA) – Mean GA 39 [32-42] – Pts with active disease continued tx (5) – 10 pts on thiopurines, continued through pregnancy IFX: 12/17 d/c week 18-27 – Mean cord level 6.4 + 1.6 µg/ml (2.8 vs. 10 p=0.02 if >10 weeks) – 14 restarted (week 8-27 postpartum) – 1 allergic rxn, 2 changed to ADA: 3/12 (25%) ADA: All 11 pts stopped week 22 – Mean cord level 1.7 + 0.4 µg/ml – 2/11 relapsed – [18%] (CS wk 30; C section week 37) – all resumed therapy f/u 9 mos 22 % (5/23) had a flare or need to change therapy postpartum. – Account for preterm birth, continuing thiopurines, presence of detectable levels even when discontinued <30 weeks. Zelinkova Clin Gastroenterol Hepatol. 2013 Mar

11. Consecutive cohort of patients (n=128), 105 CD, 23 UC where IFX restarted after median drug holiday of 15 months (at least >6 months). – Success at week 14, 1 year and end of follow up (median 4years), ATI and trough level (TL) assessed Results – Restarting IFX successful in 84.5% (short term), 70% (at 1 yr) and in 61% (end of FU) – IFX discontinued in 12% due to infusion reaction. IMM at restart prevents infusion reactions. Multivariate analysis 11 Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday Response (%) Short termYear1End of FUHR (95% CI) ATI (at 2 nd infusion) detectable N=3171%54.8%38.7%0.14 (0.026-0.74) p=0.021 IMM at restart N=8491.6%74.7%66.6%6 (1.3-2.7) p=0.019 Reason for discontinuation (remission &/or pregnancy) 90%77.5%66.6%2.70 (1.09-6.67) p=0.033 TL (at 2 nd infusion) > 2 μg/ml N=4393%74%70% 2.94 (1.18-7.69) p=0.021 Baert F et al. Presented at DDW 2013, May 19, Abstract 492 Conclusion : Restarting IFX after drug holiday is safe with success predicted by absence of early ATI formation, IMM at recommencement and not having had previous infusion reactions

12. Her adalimumab was stopped in the first trimester (4/11) She began developing perianal disease which progressed throughout pregnancy – No therapy was given initially due to concern for pregnancy – She developed large draining skin defects throughout her perineum, perivaginal area, perianal area, sacrum, inner thighs, and umbilicus.

13. Discussion What type of diagnostic tests would you do in this pregnant patient now in her second trimester? – Labs? Stool tests? – Imaging? – Endoscopy? How do you manage surgical needs in the pregnant patient? Would you start anti-TNF denovo in pregnancy? In third trimester?

14. She underwent urgent surgery + seton placements in July 2011, September 2011, and multiple times in 2012 as well She underwent cesarean section 11/11 She was not started on therapy despite ongoing perianal disease until 3/2012 when she presented to our office

18. What medication would you offer her at this point (anaphylaxis to infliximab; off adalimumab for 7 months) What concerns do you have about lactation and azathioprine/anti-TNF therapy?

19. Breast Feeding While Taking AZA/6MP 8 lactating women received Aza 75-200 QD – Milk and plasma at 30, 60 min and every hour x 5 Variation in bioavailability reflected in wide range in milk an plasma first 3 hours Major excretion in breast milk within 4 hours of drug intake Worst case scenario: max concentration 0.0075 mg/kg – In most cases, will be <10% of maximum concentration Christensen S et al. Aliment Pharmacol Ther. 2008:28, 1209-1213.

20. Breastfeeding Infliximab Breastmilk 1/200 th mother’s level (n=1) 1 Peak concentrations in BM 100 ng/ml Induction therapy: (n=1) infant levels 1700 ng/ml (maternal level 78,300 ng/ml) 3 Adalimumab Breastmilk 1/200 th mother’s level(n=1) 2 ADA undetectable in infant serum (n=1) 3 Certolizumab Not detected in breastmilk (n=1) 1. Benhorin J Crohn’s Colitis 2011; Ben-Horin CGH 2010 3. Friitzsche J Clin Gastro 2012

21. She was started on certolizumab 400 mg week 0,2,4 and q 4 weeks, increased to 400 mg every 2 weeks She was started on azathioprine 50 mg increase to 100 mg She began to slowly improve

22. Questions for Discussion When (if ever) do you stop anti-TNF in pregnancy – IF you stop, what are you worried about? – Should you have azathioprine on board too particularly if you plan to stop? Does it matter if the patient is flaring or not? What precautions are needed for mom and baby?