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

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 certolizumab pegol and azathioprine Wants to have children Husband is healthy Prior subtotal colectomy with ileal sigmoid anastomosis. Perianal disease

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

Before Pregnancy Ensure health disease control – obtimise disease control Vaccinations inc live vaccines if not on immunosuppression Papsmears up to date Optimise vit levels – D, B12, folate and iron Cancer screening up to date Find right obsteriian – needs high risk and happy to be on immunosuppresnats Preconception counseling offers an opportunity for the clinician to address specific patient concerns regarding the risk of transmission of inflammatory bowel disease (IBD) to their offspring, to optimize control of disease activity and nutritional status, and discontinue medications that may adversely affect pregnancy Vitamin B12, folate and iron also required

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… Keep dialogue open and ask patients Increase aware ness of advrse effect of disease on prengan Educate about disease control 1. Mounitfield et al. JCC 2010 2. Julsgaard et al. IBD 2011 & 2010

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%

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 Rates higher in jewish community. Is strongest risk factor but rates still low. These rates are 3-20 times higher than in general population Clinical features of the disease also demonstrate a heritable pattern with concordance in disease location (eg, ileal versus colonic Crohn’s disease) and type (eg, fibrostenotic Crohn’s disease, fistulas) [19-24]. Subsequent generations may demonstrate "genetic anticipation" with the development of earlier onset of IBD and more severe disease as compared with their parents 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

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

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

Voluntary Childlessness is increased in patients with IBD Multifactorial – fear of passing on disease, fear of fetal exposure to IBD therapies, fear of not being able to look after child, also being councelled not to have children by doctor Mari et al. IBD 2007

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 Author / year N Crohn’s Control Fielding ’70 77 32% Khosla ’84 54 married 12% 10% gen pop Mayberry ’86 275 42% subfertility 28% Baird ’90 177 Involuntary 5% Voluntary 14% 8% 14% Hudson ’97 Surg:20% Med: 8% Older studies suggest that may have increased risk but likely secondary to counselling regarding avoiding having children. Recent studies suggest no difference although may be slight increase in those having had surgery.

Infertility: Ulcerative Colitis Author / year N Ulcerative colitis Control Willoughby 1980 147 6.8% Olsen 2002 290 FR = 1.01 pre-operative FR*= .20 post-operative NS P = <.0001 Johnson 2004 213 13.3% non-operative 38.6% post IPAA Lepisto 2007 160 18% non-operative 32% post IPAA Pregnancy after 2 years: 91% non-operative 56% post IPAA Cornish 419 Systematic Review 12% pre-operative 25% post-operative Risk of surgery is demonstrated in our UC patients: due to scarring and formation of adnexal adhesions. Olsen study – vs 661 controls those that had ileal pouch anal anastomosis fecundability dropped to 0.2 compared to normal population level of 1 (ability to conceive per menstrual cycle) Confirmed by Johnson and who showed a 38.6% infertility rate in UC patients after IPAA versus 13.3% in UC patients managed non‐operatively (p<0.001).

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

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

Disease Activity Trends During Pregnancy in women with CD 73% n=93 34% 33% 32% Disease activity in women with CD is compared. The bars at the left show that of 186 women with inactive disease at the time of conception, 27% experienced relapse in the period of gestation and puerperium. The first trimester and the puerperium are the most likely times for relapse. This rate may not be appreciably different from the 12-month relapse rate of women with CD who are not pregnant. The bars at the right show that approximately one third of women with active disease will have worsened activity, one third will continue at the same level of severity, and one third will improve.55 Again, these data suggest that for the health of both mother and baby, it is important to attempt to induce remission before conception or to wait for a period of remission before attempting to conceive. The effect of pregnancy on both UC and CD should be discussed fully by the clinician and the patient. No Relapse Relapse Worsened Activity Continued Activity Decreased Activity Inactive Active Miller JP. J R Soc Med. 1986;79:221-225.

Disease Activity Trends During Pregnancy in women with UC 66% 45% 34% 27% 24% The bars at the left of this graph report the effect of pregnancy on UC disease activity in 528 women with inactive disease at the time of conception. These women have about 1 out of 3 chances of relapsing during the 12 months of gestation and puerperium. This is similar to the relapse rate for women with UC who are not pregnant. Thus, there is no evidence that pregnancy triggers relapse in women with inactive disease. The bars at the right report the effect of pregnancy on UC disease activity in 227 women with active disease at the time of conception. In this group, 45% will have worsened activity, 24% will continue to have disease activity at an unchanged level, and 27% will improve. Thus, nearly three quarters of women with active disease at the time of conception will continue to have active disease at some point in their pregnancy.55 These data suggest that for the health of both mother and baby, it is important to attempt to induce remission before conception or to wait for a period of remission before attempting to conceive. The effect of pregnancy on UC should be discussed fully by the clinician and the patient. No Relapse Relapse Worsened Activity Continued Activity Decreased Activity Inactive Active Miller JP. J R Soc Med. 1986;79:221-225.

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 Obstet Gynaecol. 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

Increase in Preterm birth with moderate to high disease activity Crude Relative Risk 95% CI LBW 1.1 0.3-4.0 LBW at term 0.9 0.1-8.5 Preterm birth 3.4 1.1-10.6 Congenital Anomalies 0.4 0.0-3.9 Preterm birth (<37 wks gestation) Leading cause of mortality in newborns Higher rates CP, sensory deficits, learning disabilities, respiratory illness And fetal loss 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.

Currently on certolizumab pegol 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 High risk patient, previous surgery so medicaitons continued

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 Natalizumab Asacol HD Metronidazole* a Controlled evidence in humans b No evidence of risk in human studies c. In adquate evidence in humans so benefits may outweight risks d. Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are ineffective X. CI in pregnancy Cyclosporin – higher rates of prematurity and low birth weight but survival high. Tacrolimus – safe. Slight increase prematuriy but no excess congenital malformations, low birth weight, neontal complications Methorexate teratogenic and embryotoxic resulting in choroosal dmage and miscarriage. If conceptions occurs therapeutic abortion should be discussed but not necessarity performed. Need stop immediately and high dose folate replacement. Stop MTX 6 weeks before conception. Both women and men. *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.

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 Corticosteroids marginal increas in risk of oral cleft malformation if used early in pregnancy and preterm birth described 1. Beaulieu Inflamm Bowel Dis. 2009 Jan;15(1):25-8

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 Azathiprine category D secondaryto anecdotal reports of high abortion rates and in animal studies 10 fold doseas higher than normal may increase risk of congintal malformation, prematuriy, low birth weight and chormosomal abnormalities. Normal doses risk of low birth weight. In IBD shown no rates of prematuriy, spontaneous abortion, congintal abnormlaities or infections. Recent study of 30 patints showed 60% of babies anaemic – unsure what clinical outcome this means 1) Coelho: Gut. 2011; 2) Goldstein LH, et al. Birth Defects Res A Clin Mol Teratol. 2007; 3) Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. 1998; 4) Francella A, et al. Gastroenterology. 2003; 5) Cleary. Birth Defects Research 2009; 6) Jharap et al. GUT. 2013

Anti-TNF-alpha Therapies Certolizumab pegol PEG PEGylated humanized Fab′ fragment 2 × 20 kDa PEG Infliximab Adalimumab Fab′ Fab IgG1Fc INF and ADA are IgG1 antibodies Certolizumab is a Fab’ fragment Likely passive diffusion Chimeric Human Monoclonal antibody Adapted from: Hanauer SB. Rev Gastroenterol Disord. 2004;4(Suppl. 3):S18-S24.

Placental Transfer of IgG Ab 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 Fetal immunity is acquired by active transfer of Fc portion of IgG from maternal to fetal circulation by specific neonatal FcR (IgG1>IgG4>IgG3>IgG2) Smooth linear rise in fetal IgG as early as 13 weeks (earliest examined), after 32 weeks, significant increase in ratio (elevated levels in newborn) INF and ADA are IgG1 antibodies Certolizumab is a Fab’ fragment Likely passive diffusion Image Courtesy of Sunanda Kane MD: Malek A, Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol 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

Infliximab/Adalimumab/Certolizumab pegol (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 delivery 3 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 reported 4 Katz JA, et al. Am J Gastroenterol. 2004;99:2385 (2) Lichtenstein. Gastroenterol 2010;138, S-475 (3) Jurgens Inflamm Bowel Dis. 2009 Dec 21 (4) Nazareth M, Mahadevan U. Am J Gastroenterol 2008;103:S449-50

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 Last dose infliximab at week 32 weeks gestation • No real delay if patient gets next dose immediately after delivery (assume delivery around week 40 gestation) – Last dose adalimumab at week 34 - 36 Stopping earlier may lead to flares• If needed, can continue throughout on schedule Child who got disseminated TB fro BCG vaccine

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

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 Surgery – in severely ill patient continued illness is greater risk to fetus than surgical intervntion. If surgery required temporary ileostmy is preferred to reduce the risk of post-operative complications after primary anastomosis.

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 Pharmacol Ther 1998; 2. Kane S. Gastroenterol Clin North Am 2003;

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

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 Also those that have ilal pouch-anal anastomosis shold have caesarian as have broderline continence and depends more on intact, optinal sphincer function to maintain faecal continece than pt with itnact rectum. Those with colostomy, ileostomy or continent ileostomy can deliver vaginally Episiotomy should be avoided if possible – but better than uncontrolled laceration. Overall patients with IBD have more problems with faecal incontinecnce after vaginal delivery compared to controls. 1 Brandt LJ. Am J Gastroenterol. 1995 2. Ilnyckyji A. Am J Gastroenterol. 1999

She delivers a healthy baby boy!

Lets assume she is back on her medication… Lets assume she is back on her medication…. Can she breast-feed whilst taking certolizumab pegol 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

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 Pediatr 2009; 2. Moffatt Am J Gastro June 2009

Safety of IBD Medications in Breast-Feeding Low Risk to Use When Warranted Limited Data Available Contraindicated Oral mesalamine Tacrolimus Natalizumab Methotrexate Topical mesalamine Sulfasalazine Certolizumab Adalimumab Cyclosporine Metronidazole Ciprofloxacin Infliximab Corticosteroids 6-MP/AZA If wish to lower chances with perdnioslone can give 4 hour delay AZA 6MP ndetectable or almost no level in milk same as infliximab and thought to be same for adalimumab and certolizumab 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.

Breastfeeding Azathioprine Infliximab and Adalimumab Certolizumab 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) 5 6 ADA not detected in infant (n = 1) 6 Certolizumab Not detected in breast milk (n = 1) Dose normally less than 10 % of this. 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

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