1. Management of Pregnant Women with IBD
Uma Mahadevan MD
Associate Professor of Medicine
Co-Medical Director
UCSF Center for Colitis and Crohn’s Disease

2. Objectives Is fertility altered among patients with IBD?
What adverse pregnancy outcomes are associated with IBD?
What medications are compatible with use during pregnancy and lactation?
What recommendations should be shared with the multidisciplinary team?

3. Fertility and Pre-pregnancy
Women with IBD have similar rates of conception to non-IBD women unless they have surgery
Once pregnant, even with inactive disease, there is an increased risk of complications
Moderate to severe disease may make this worse
Being in remission on low risk medication is the best option for a healthy pregnancy
Healthcare maintenance up to date
Pap smears
Colonoscopy
Vaccinations

4. THE PREGNANT PATIENT

5. Pregnancy Outcomes: Population Based Studies
IBD UC CD
Preterm Birth X
X X
LBW
SGA
Patients with IBD have an increased risk of preterm birth, low birth weight and small for gestational age infants. The risk of Cesarean section is high, but most of these seem elective rather than due to medical necessity.
Kornfeld et al. Am J Obstet Gynecol (n=756 IBD)
Fonager et al. Am J Gastroenterol (n=510 CD)
Norgard et al. Am J Gastroenterol (n=1531 UC)
Dominitz et al. Am J Gastroenterol (n=107 UC, 155 CD) – Knight, no c

6. 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
In subanalyses, birth outcomes in women with moderate-to-high disease activity at any time during pregnancy were compared with the outcomes in women with inactive disease. These relative risks of low birth weight, low birth weight at term, preterm birth and congenital anomalies were 1.1 (95%CI ), 0.9 (95% CI ), 3.4 (95% CI ), and 0.4 (95%CI ).
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. 6

7. IBD and Pregnancy: Overlapping Pathways
Preterm birth (>37 wks gestation)
Leading cause of mortality in newborns
Higher rates CP, sensory deficits, learning disabilities, respiratory illness
Animal models: During pregnancy, shift Th1:Th2 balance by placenta which produces Th2 cytokines (IL4) and progesterone.
Nasef. Translational Research 2012;160:65-83

8. Cytokine spectrum in Pregnancy
Early: dominant proinflammatory profile
Embryo invades and damages maternal uterus to implant
Middle:
Decrease in proinflammatory cytokines. Mother, fetus, placenta in synchrony
Late:
Increase in proinflammatory cytokines to activate parturition

9. Is Preterm Birth Due to Immune dysfunction?
Population based study Norway1
Preterm Birth
Maternal IBD: OR 2.15 (1.36, 3.39)
Paternal IBD: OR 3.02 (1.82, 5.01)
First degree relative of IBD patient with IBD: OR 4.29 (1.59, 11.63)
Process of labor involves remodeling of the cervix, rupture of membranes2
Process mediated by proinflammatory cytokines and prostaglandins.
Impaired innate immunity may affect these processes
Microbes induce both IBD and PTB
1. Bengtson Inflamm Bowel Dis 2010:16:
2. Savoye Am J Gastro:105:2010pp 473-4

10. Management of Flares Medication choices are similar
Avoid new aza/6mp in pregnancy
Avoid mnzl, CS in T1
Laboratory/Stool Tests
LFT’s (Alk Phos), ESR may be elevated
Albumin may be low; mild anemia normal
C. difficile
Imaging
MRI preferred to CT, though no gadolinium in T1
Ultrasound!
Endoscopy: Unsedated flexible sigmoidoscopy
Surgery: Indications similar to non-pregnant patient ; T2 best time

11. Method of Delivery
Delivery should be at the discretion of the obstetrician
Most women with IBD can have an uncomplicated vaginal delivery
Exceptions:
Women with active perianal disease should have a cesarean section. Women with inactive perianal disease may deliver vaginally without increased complications (1)
Women with an ileoanal J pouch should consider cesarean section, though vaginal delivery is possible (2)
Preserve sphincter function and continence later in life
Ilnyckyji A, Am J Gastroenterol 1999;94:3274-8
Juhasz ES, Dis Colon Rectum 1995;38:

12. C-section and risk of IBD?
CS delivery disturbs the normal bacterial colonization of the newborn's intestine
Swedish Case-Control study 1536 cases
CS risk of pediatric CD among boys (OR = 1.25, ) but not girls, (OR = 0.99, 95% CI )
Danish Population Based study
32.6 million person-yrs of follow-up CS increased risk of IBD at age 0-14 years (IRR 1.29, 95% CI )
Assuming causality, an estimated 3.2% of IBD cases before age 15 years were attributable to cesarean section.
Andersen: increase in IBD risk restricted nearly all to boys
IRR=1.26 (1.15,1.37) vs (1.15 among girls)
Higher for UC than CD
Decker Pediatrics 2010:125:e Malmborg Inflamm Bowel Dis Bager Inflamm Bowel Dis Jul 7. 4.Andersen Inflamm Bowel Dis 2012

13. Pelvic Floor Disorders
Spontaneous vaginal birth vs. C section (n=1011)
Stress incontinence (OR 2.9, )
Prolapse to or beyond the hymen (OR 5.6, 95% CI )
Operative vaginal birth significantly increased the odds for all pelvic floor disorders, especially prolapse
(OR 7.5, 95% CI ).
Forceps deliveries and perineal lacerations, but not episiotomies, were associated with pelvic floor disorders 5-10 years after a first delivery.
Handa Obstet Gynecol Oct;118(4):777-84
Handa Obstet Gynecol Jan 5.

14. Medication Use in Pregnancy

15. Medication Safety Medication FDA Category Comment Lactation 5ASA
Asacol, olsalazine B C
Asacol: DBP
Compatible
(rare diarrhea)
Corticosteroids
Budesonide
Low risk T1:
Cleft palate
Azathioprine/6MP D
Low risk
Compatible:
Ideally wait 4 hours after dose
Methotrexate X
Contraindicated

16. Azathioprine/6MP Swedish Medical Birth Register
476 women used AZA in early pregnancy
Most common indication was IBD (>300)
Rate of CA 6.2% AZA vs. 4.7% other
OR 1.41, 95% CI:
Increased rate of VSD/ASD
OR 3.18, 95% CI:
N=9 (4 SLE, 4 IBD, 1 nephrotic syndrome)
Increased rate of preterm, LBW, SGA
Likely disease effect
Coelho: Gut Feb;60(2):
Cleary. Birth Defects Research 85: , 2009

17. Breastfeeding
Breastfeeding (non-IBD moms) associated with a protective effect in the development of early onset IBD (1)
Breastfeeding not associated with an increased risk of disease flare; possible protective effect against disease flare in the post-partum
Manitoba, population based study (2)
Barclay J Pediatr 2009
Moffatt Am J Gastro June 2009

18. Breast Feeding While Taking AZA/6MP
8 lactating women received Aza 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 mg/kg
In most cases, will be <10% of maximum concentration
Christensen S et al. Aliment Pharmacol Ther. 2008:28,

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

20. Anti-TNF’s: Safety Infliximab (B) Adalimumab (B)
Katz: 100 infants exp, similar rate of live births, SAB’s
TREAT: 117 exp vs. unexposed with similar rate of miscarriage (10 vs. 6.7%) and neonatal complications (6.9% vs. 10%)
Adalimumab (B)
137 women enrolled in a prospective study in pregnancy and an additional 89 adalimumab exposed pregnant women in a registry. No increase in birth defects
Certolizumab (B) data on file
139 maternal exp pregnancies
Natalizumab (C): IgG4
143 pregnant patients exposed to natalizumab
No birth defects reported
Katz JA, et al. Am J Gastroenterol. 2004;99:2385; Lichtenstein. Gastroenterol 2010;138, S-475; Jurgens Inflamm Bowel Dis Dec 21 ; Nazareth M, Mahadevan U. Am J Gastroenterol 2008;103:S449-50

21. Breastfeeding Infliximab Adalimumab Certolizumab
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 Friitzsche J Clin Gastro 2012

22. Placental Transfer of IgG Ab
INF and ADA are IgG1 antibodies
Fc portion of IgG actively transported across placenta by specific neonatal FcR
Highly efficient transfer in 3rd T leads to elevated levels of drug in newborn
B: Fetal
r2=0.87, p<0.04
Estimated data
Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins
During human pregnancy. Am J Reprod Immunol 1996; 36(5):
Image Courtesy of Sundana Kane MD 22

23. Maternal IgG and IgA are potentially available to the embryo as early as the 6th week of gestation (coelomic fluid)
Maternal Ig present for the first 6 months of life to aid in fighting infection
Jauniaux Human Reprod vol 10:12:

24. Placental Transfer Infliximab: Adalimumab Certolizumab
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 U Clin Gastro Hep 2012 epub ahead of print

25. Placental Transfer: Another view
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
14 restarted (week 8-27)
1 allergic rxn, 2 changed to ADA: 3/12 (25%)
ADA: All 11 pts stopped week 22
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 Gastro Hep Oct 2012

26. Infections
Fatal case of disseminated BCG infection in an infant born to a mother on INF for Crohn’s disease
10 mg/kg q 8 weeks monotherapy
Healthy boy delivered 36 wks. No Breastfeeding
Did well until 3 months when received BCG
Failure to thrive, died at 4.5 months
Post-mortem: disseminated BCG
Cheet K J of Crohn’s Colitis 2010

27. PIANO: Pregnancy in Inflammatory Bowel Disease And Neonatal Outcomes
Patients classified by exposure to four groups of drugs taken b/w conception and delivery:
Unexposed: no immunomodulators/biologics
(mesalamine, steroids, antibiotics allowed)
Group A: AZA/6MP
+/- Unexposed medications
Group B: INF, ADA, CZP
Group AB: Combination therapy
Remember these are preliminary crude results and numbers may change when full cohort of 1000 women deliver
Mahadevan Gastroenterology 2012 27

28. RESULTS Women Enrolled (4/25/2012) 1115 Pregnancies Ended
Still pregnant
Missing outcomes
Excluded/Withdrew
896 94 55
17/53
Unexposed
No medications
326 32
Group A (AZA/6MP)
204
Group B (Biologics)
291
Group AB (Combination) 75
Infliximab (+multiple exp)
Adalimumab
Certolizumab
Natalizumab
193 (214)
104 (126)
37 (47)
5 (6)
Multiple Exposure: 27
IFX/ADA (16) IFX/CZP (5) ADA/CZP (5) ADA/CZP/NAT (1)

29. Disease Activity by Trimester: CD%
TRIMESTER AND MONTHS POSTPARTUM
Two hospitalizations

30. Disease Activity by Trimester: UC%
TRIMESTER AND MONTHS POSTPARTUM
No hospitalization

31. Adverse Pregnancy Outcomes
Group A (aza)
RR (CI)
Group B (bio)
Group AB (combo)
Any Complication
0.98( )
1.09 ( )
1.28 ( )
Spontaneous Abortion
2.03 ( )
2.56 ( )*
1.29 ( )
Preterm Birth
1.06 ( )
0.89 ( )
1.83 ( )*
Low Birth Weight
0.69 ( )
1.17 ( )
1.05 ( )
IUGR
0.96 ( )
1.01 ( )
1.25 ( )
Cesarean section
1.07 ( )
1.23 ( )*
1.14 ( )
NICU
1.09 ( )
1.20 ( )
1.71 ( )
Congenital Anom
1.05 ( )
1.07 ( )
1.36 ( )
Except for SA, outcomes are among live births only
Adjusted for none/mild vs. mod/severe disease activity
* P <0.05

32. Timing of biologics Debate: stop drug early or continue scheduled?
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 36-38
Stopping earlier may lead to flares
If needed, can continue throughout on schedule
Continue certolizumab throughout pregnancy
If mom flares, treat her!
No live virus vaccine for first 6 months for infants exposed to IFX or ADA during pregnancy
Never switch drugs during pregnancy purely for placental transfer issues
Rotavirus only live virus vaccine in US in first 6 months. (europe, BCG). All other vaccines can be given on schedule.
Mahadevan U. Am J Gastroenterol Feb;106(2):214-23

33. Communicate with Interdisciplinary team
Obstetrician:
Most IBD medications are low risk in pregnancy (exception methotrexate) and can be continued during pregnancy and lactation
Mode of delivery is per OB discretion except with active perianal disease at the time of delivery and perhaps J Pouch
Pediatrician
No live virus vaccines in the first 6 months if infant exposed to infliximab or adalimumab in utero
All other vaccines can be given on schedule
Monitor for infections