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

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
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

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…
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

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
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 Nov;94(11):
Bennett RA Gastroenterology Jun;100(6):
Polito JM, Gastroenterology 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
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

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
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.

12. 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).

13. 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

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
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:

16. 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:

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: Dominitz JA, et al. Am J Gastroenterol. 2002;97: Porter RJ, Stirrat GM. Br J Obstet Gynaecol. 1986;93: Fonager K, et al. Am J Gastroenterol. 1998;93: Mahadevan U, et al. Gastroenterol. 2007;133: Kornfield D et al. Am J Obstet Gynecol. 1997;177:

18. Increase in Preterm birth with moderate to high disease activity
Crude Relative Risk
95% CI
LBW
1.1
LBW at term
0.9
Preterm birth
3.4
Congenital Anomalies
0.4
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.

19. 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

20. 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.

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
Corticosteroids marginal increas in risk of oral cleft malformation if used early in pregnancy and preterm birth described
1. Beaulieu Inflamm Bowel Dis 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
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

23. 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.

24. 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):
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/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 Dec 21
(4) Nazareth M, 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
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

27. 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.

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
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.

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 Pharmacol Ther 1998; 2. Kane S. Gastroenterol Clin 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

32. 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 Ilnyckyji A. Am J Gastroenterol. 1999

33. She delivers a healthy baby boy!

34. 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

35. 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

36. 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): ; Sau A, et al. BJOG. 2007;114(4): ; Moretti ME, et al. Ann Pharmacother. 2006;40(12): ; Gardiner SJ, et al. Br J Clin Pharmacol. 2006;62(4):

37. 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 ; 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

38. 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