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Case #2 Biologics and Pregnancy

Case #2 Biologics and Pregnancy. 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.

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Case #2 Biologics and Pregnancy

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  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 Danish population based study: Pregnancies with disease activity at any time (n=71) were compared to pregnancies without any disease activity (n=86) Norgard B, et al. Am J Gastroenterol. 2007;102:1947–1954.

  5. Azathioprine safety: Spanish cohort • 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 • 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 Casanova MJ, et al. Am J Gastroenterol. 2013 Mar;108(3):433-40 ICU, intensive care unit

  6. Thiopurines and fetal anemia; Should we test newborns? • 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

  7. Thiopurines and fetal anemia; Should we test newborns? • Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). (n=25) • Median 6TGN infant: mother = 42:92 pmol/8x108 • No 6-MMP was detected in the newborns except 1 • Pancytopenia and high alkphos (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)

  8. Adverse Pregnancy Outcomes: The Piano Study * 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. Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday • 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 • 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 Baert F et al. Presented at DDW 2013, May 19, Abstract 492

  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

  15. 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?

  16. 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.

  17. Breastfeeding • Infliximab • Breastmilk 1/200th 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 1/200th 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

  18. 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

  19. 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?

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