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The Pregnant Patient with Inflammatory Bowel Disease

The Pregnant Patient with Inflammatory Bowel Disease. Britt Christensen, MD Scott Plevy, MD. Case. 26 yo woman with Crohn’s Dx since age 11 I leal and colonic involvement Prior surgery, ileal sigmoid anastomosis. Perianal disease, large skin tags, anal stricture

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The Pregnant Patient with Inflammatory Bowel Disease

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  1. The Pregnant Patient with Inflammatory Bowel Disease Britt Christensen, MD Scott Plevy, MD

  2. Case • 26 yo woman with Crohn’s Dx since age 11 • Ileal and colonic involvement • Prior surgery, ileal sigmoid anastomosis. • Perianal disease, large skin tags, anal stricture • Maintained on certolizumabpegol and azathioprine • Wants to have children • Husband is healthy

  3. Relationships and Fertility in IBD • Peak incidence of IBD overlaps the prime child bearing years • Fertility and pregnancy outcome is of great concern to the IBD patient • Addressing these issues is part of our goals of management

  4. Before Pregnancy

  5. Biggest Risk in IBD Pregnancy is Active Disease • Education regarding adverse effect of disease on pregnancy outcomes • High rates of “non-adherence” due to concerns regarding medications (12-40%, often without physician knowledge) 1 2 • Counseling regarding use of IBD medications during pregnancy and lactation • What will happen if you are off all meds? • The reality of the timing of this approach… 1. Mounitfield et al. JCC 2010 2. Julsgaard et al. IBD 2011 & 2010

  6. What are the chances of her child inheriting IBD? a) No increased risk – the chances are the same as the general population risk b) 1.5% c) 5% d) 20% e) 35%

  7. Inheritance of IBD • Non-mendelian inheritance: Multifactorial with a role for as yet undefined environmental triggers • Risk of CD and UC in offspring of patients with IBD1 • One parent has CD: 5% • One parent has UC: 1.6% • Both parents have IBD: 35% 2 • Genetic anticipation: Familial CD younger onset than sporadic cases (22 y vs 27 y) 3 • Clinical features demonstrate heritable pattern • Smoking may be an environmental trigger in susceptible family members • Orholm M Am J Gastroenterol. 1999 Nov;94(11):3236-8. • Bennett RA Gastroenterology. 1991 Jun;100(6):1638-43. • Polito JM, Gastroenterology. 1996 Sep;111(3):580-6

  8. Which statement is incorrect in regards to fertility and IBD? a) Many patients with IBD are fearful of infertility b) IBD patients have as many children as non-IBD patients c) Patients with Crohn’s Disease who have had surgery have higher rates of infertility d) Patients who have had IPAA surgery have infertility rates of up to 30-40% e) Patients with both CD and UC who are in remission and have never had surgery have normal rates of fertility

  9. Fear of Infertility in IBD Patients Mountifield et al. IBD 2009

  10. Voluntary Childlessness is increased in patients with IBD Mari et al. IBD 2007

  11. Infertility: Crohn’s Disease Hudson:14% CD (n= 177) vs 14% general population Surgical therapy:20% Medical therapy: 8% The risk of fertility in CD prior to surgery appears to be similar to the general population

  12. Infertility: Ulcerative Colitis

  13. Case She successfully conceives with IVF • She and her partner are unable to conceive naturally (decreased fecundity) • Undergoes in vitro fertilization

  14. What are the chances of a patient with Crohn’s Disease fairing during pregnancy? • If their disease is active on conception they have a 70% chance of improving during pregnancy • If their disease is in remission they have a 70% chance of flairing during pregnancy • If their disease is in remission they have a 70% chance of staying in remission during pregnancy • If their disease is active they have a 70% chance of their disease worsening during pregnancy

  15. Disease Activity Trends During Pregnancy in women with CD n=186 73% n=93 34% 33% 32% NoRelapse Relapse WorsenedActivity Continued Activity DecreasedActivity Inactive Active Miller JP. J R Soc Med. 1986;79:221-225.

  16. Disease Activity Trends During Pregnancy in women with UC n=528 n=227 66% 45% 34% 27% 24% Relapse NoRelapse WorsenedActivity Continued Activity DecreasedActivity Inactive Active Miller JP. J R Soc Med. 1986;79:221-225.

  17. Pregnancy Outcomes and IBD • Preterm birth •  risk in both UC and CD1,2,5,6 •  in risk of low birth weight2-5 •  risk of maternal/delivery complications5 • C-section rate6 • 4 of 5 studies: no major impact on risk of congenital abnormalities1-5 • No impact on adverse new born outcomes5 6 1Baird DD, et al. Gastroenterology. 1990;99:987-994. 2Dominitz JA, et al. Am J Gastroenterol. 2002;97:641-648. 3Porter RJ, Stirrat GM. Br J ObstetGynaecol. 1986;93:1124-1131. 4Fonager K, et al. Am J Gastroenterol. 1998;93:2426-2430.5Mahadevan U, et al.Gastroenterol. 2007;133:1106-1112 6Kornfield D et al. Am J Obstet Gynecol. 1997;177:942-966

  18. Increase in Preterm birth with moderate to high disease activity • Preterm birth (<37 wks gestation) • Leading cause of mortality in newborns • Higher rates CP, sensory deficits, learning disabilities, respiratory illness 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.

  19. Currently on certolizumabpegol and azathioprine: What do you do with her medications now that she is pregnant? • Continue both medications throughout pregnancy • Continue both medication and then cease certolizumab at 30 weeks • Cease azathioprine but continue certolizumb throughout pregnancy • Cease certolizumab but continue azathioprine throughout pregnancy • Cease both medications whilst patient is pregnant

  20. 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 Natalizumab Asacol HD Metronidazole* Safety of IBD Medications During Pregnancy *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.

  21. Corticosteroids (C) • Case-control study 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 • Budesonide (Entocort) • Orally inhaled budesonide not associated with increase risk of fetal abnormalities • 8 CD patients treated with oral budesonide1 1. Beaulieu Inflamm Bowel Dis. 2009 Jan;15(1):25-8

  22. Azathioprine/6-MP • Transplant and rheumatology cohorts considered safe with no constant reports of abnormalities, prematurity or congenital defects • Almost all IBD studies show no increased risk of congenital abnormalities1-5 • No increased risk of miscarriage1 • Some studies suggest increased risk of prematurity and LBW but thought to be disease related2 5 • Recent study of 30 patients showed 60% of babies born mildly anemic – unsure if clinically relevant as no action required.6 1) Coelho: Gut. 2011; 2) Goldstein LH, et al. Birth Defects Res A ClinMolTeratol. 2007;3) Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. 1998; 4) FrancellaA, et al. Gastroenterology.2003;5) Cleary. Birth Defects Research 2009;6) Jharap et al. GUT. 2013

  23. Certolizumab pegol PEG PEGylated humanized Fab′ fragment 2 × 20 kDa PEG Anti-TNF-alpha Therapies Infliximab Adalimumab Fab′ Fab IgG1Fc Chimeric Human Monoclonal antibody Adapted from: Hanauer SB. Rev GastroenterolDisord. 2004;4(Suppl. 3):S18-S24.

  24. Placental Transfer of IgGAb • Infliximab: (n= 10) • Infant and cord IFX level were greater than mother. • 6 months to clear • Adalimumab (n = 10) • ADA level was greater than mother. 4 months to clear • ¾ pts who stopped ADA 35 days prior to delivery had a flare • Certolizumab (n = 10) • Infant and cord levels less than 2 mcg/ml even if mom dosed the week of delivery Image Courtesy of Sunanda Kane MD: MalekA, Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J ReprodImmunol 1996; 36(5):248-55. Mahadevan U Gastroenterol 2007;132:A-144; Mahadevan et al. Gastro vol 140 Is 5, suppl 1, P S-796 Mahadevan U Gastroenterology 2009;136:146

  25. Infliximab/Adalimumab/Certolizumabpegol (B) • Infliximab (B) • 100 infants exp, similar rate of live births, SAB’s1 • 117 exp vs. unexposed with similar rate of miscarriage (10 vs. 6.7%) and neonatal complications (6.9% vs. 10%)2 • Adalimumab (B) • 33 women enrolled in a prospective study in pregnancy and an additional 89 adalimumab exposed pregnant women in a registry. • No increase in birth defects, abortion, congenital malformation or preterm delivery3 • Certolizumab (B) • Limited published data • Thought likely safe as minimal transfer across placenta • Natalizumab (C): IgG4 • 143 pregnant patients exposed to natalizumab • No birth defects reported4 Katz JA, et al. Am J Gastroenterol. 2004;99:2385 (2) Lichtenstein. Gastroenterol 2010;138, S-475 (3) JurgensInflamm Bowel Dis. 2009 Dec 21 (4) NazarethM, Mahadevan U. Am J Gastroenterol 2008;103:S449-50

  26. Timing of Biological Therapies in Pregnancy • Elective switching of therapies is not recommended • Outcomes of moms on biological therapies not different than moms who are off these therapies (recognizing differences in disease severity) • Trying to time dosing based on third trimester is an unproven strategy, and not based on known pharmacokinetics • No live virus vaccine for first 6 months for infants exposed to IFX or ADA during pregnancy • Focus on newborn- consider testing for immune conversion with vaccinations

  27. Case • She continues on her azathioprine and anti-TNF agent (certolizumabpegol) • At 18 weeks EGA, presents with rectal pain, bleeding. • EXAM: • Anal stricture, significant induration of perianal area.

  28. Management of Flares in the Pregnant IBD Patient • Medication choices are similar • Avoid new aza/6mp in pregnancy • Avoid metronidazole, corticosteroids in T1 • Imaging • MRI preferred to CT, but NO gadolinium in T1 • Small bowel US if available • Endoscopy • Unsedated flexible sigmoidoscopy preferred

  29. Surgery During Pregnancy • Indications similar to non-pregnant patient • obstruction, perforation, hemorrhage or abscess • T2 best time to operate • Fetal mortality can be high with abortion-stillbirth rates as high as 18-40% • In severely ill patients, continued illness is greater risk to fetus than surgical intervention1 • A temporary ileostomy is generally preferred, to reduce risk of post-operative complications after primary anastomosis2 1. Subhani et al. Aliment PharmacolTher1998; 2. Kane S. GastroenterolClin North Am 2003;

  30. Case • Undergoes loop ileostomy. • Tolerates procedure well. • Medications stopped (diverted) • “feels great” • Follows up with OB and GI • Planned elective Caesarean delivery

  31. Mode of Delivery Mode of delivery is per OB discretion except… • Avoid episiotomy: may predispose to perineal disease (17.9%) without prior disease • 103 Vaginal delivery (87% episiotomy)1 • Caesarean section if active perianal disease • No history(1/39) or inactive (0/11) perianal disease at birth, risk of relapse very low • 4/4 with active perianal disease worsened post-vaginal delivery1 • J-Pouch: Relative Indication for Elective Caesarian • Borderline continence that depends more on intact optimal sphincter function 1 Brandt LJ. Am J Gastroenterol. 1995 2. IlnyckyjiA. Am J Gastroenterol. 1999

  32. She delivers a healthy baby boy!

  33. Lets assume she is back on her medication…. Can she breast-feed whilst taking certolizumabpegol and azathioprine? • Yes – both medications are considered safe • She must cease her azathioprine but can breast-feed whilst taking certolizumab • She must cease her certolizumab but can breast-feed whilst taking azathioprine • She must cease both medications if she wishes to breast-feed

  34. Breastfeeding • Breastfeeding (non-IBD moms) associated with a protective effect in the development of early onset IBD1 • Breastfeeding not associated with an increased risk of disease flare; possible protective effect against disease flare in the post-partum • Manitoba, population based study2 • Barclay J Pediatr2009; 2. Moffatt Am J Gastro June 2009

  35. Low Risk to Use When Warranted Limited Data Available Contraindicated Oral mesalamine Tacrolimus Natalizumab Methotrexate Topical mesalamine Sulfasalazine Certolizumab Adalimumab Cyclosporine Metronidazole Ciprofloxacin Infliximab Safety of IBD Medications in Breast-Feeding Corticosteroids 6-MP/AZA Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003; de Boer NK, et al. Am J Gastroenterol. 2006;101(6):1390-1392; SauA, et al. BJOG. 2007;114(4):498-501.; MorettiME, et al. Ann Pharmacother. 2006;40(12):2269-2272. ; Gardiner SJ, et al. Br J Clin Pharmacol. 2006;62(4):453-456.

  36. Breastfeeding • Azathioprine • Studies show undetectable levels in feeding infants and minimal detectable levels in milk with no consequences for baby1,2, 3 • Peak excretion first 3 hours with max infant ingestion less than 0.008mg/kg body weight/24 h4 • Can consider waiting 4 hours from dose to feed. • Infliximab and Adalimumab • Breast milk 1/200th mother’s level (n = 1) 56 • ADA not detected in infant (n = 1) 6 • Certolizumab • Not detected in breast milk (n = 1) Moretti ME et al. Ann. Pharmacother.2006.; 2. Gardiner SJ et al.Br. J. Clin. Pharmacol.2006; 3. Sau A et al.BJOG 2007; 4. Christensen et al. Aliment Pharmacol. Ther. 2008; 5.Benhorin J Crohn’s Colitis 2011; 6. Ben-Horin CGH 2010

  37. Summary: IBD and the Pregnant Patient • Control disease prior to planned pregnancy • Consider surgery prior to planning pregnancy (including temporary ostomy in some cases) • Communication to obstetrician and to pediatrician is essential • Most medications are compatible and safe in pregnancy: • 5-ASA • Corticosteroids (1st T risk of cleft palate) • Antibiotics (metronidazole after T1, Clavulanate/piperacillin) • Azathioprine/6-MP • Anti-TNF (notable that certolizumab doesn’t cross placenta) • Most medications are safe for breast feeding as well

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