Transcript IBD and Pregnancy: Overlapping Pathways

Management of
Pregnant Women with
IBD
Uma Mahadevan MD
Associate Professor of Medicine
Co-Medical Director
UCSF Center for Colitis and Crohn’s Disease
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?
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
THE PREGNANT PATIENT
Pregnancy Outcomes:
Population Based Studies
IBD
UC
CD
Preterm Birth
X
X
XX
LBW
X
SGA
XX
X
1.
2.
3.
4.
Kornfeld et al. Am J Obstet Gynecol. 1997 (n=756 IBD)
Fonager et al. Am J Gastroenterol. 1998 (n=510 CD)
Norgard et al. Am J Gastroenterol. 2000 (n=1531 UC)
Dominitz et al. Am J Gastroenterol. 2002 (n=107 UC, 155 CD) – Knight, no c
Increase in Preterm birth with
moderate to high disease
activity
LBW
LBW at term
Preterm birth
Congenital
Anomalies
Crude Relative Risk
95% CI
1.1
0.3-4.0
0.9
0.1-8.5
3.4
1.1-10.6
0.4
0.0-3.9
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.
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
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
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 2010:16:847-855
2. Savoye Am J Gastro:105:2010pp 473-4
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
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
1. Ilnyckyji A, Am J Gastroenterol 1999;94:3274-8
2. Juhasz ES, Dis Colon Rectum 1995;38:159-65.
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, 1.011.54) but not girls, (OR = 0.99, 95% CI 0.76-1.29)

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 1.11-1.49)
– 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. 1.06 (1.15 among girls)
Higher for UC than CD
1.
Decker Pediatrics 2010:125:e1433-40 2.Malmborg Inflamm Bowel Dis 2011
3.Bager Inflamm Bowel Dis. 2011 Jul 7. 4.Andersen Inflamm Bowel Dis
2012
Pelvic Floor Disorders

Spontaneous vaginal birth vs. C section (n=1011)
– Stress incontinence (OR 2.9, 1.5-5.5)
– Prolapse to or beyond the hymen (OR 5.6, 95% CI 2.214.7)

Operative vaginal birth significantly increased the
odds for all pelvic floor disorders, especially
prolapse
– (OR 7.5, 95% CI 2.7-20.9).

Forceps deliveries and perineal lacerations, but not
episiotomies, were associated with pelvic floor
disorders 5-10 years after a first delivery.
Handa Obstet Gynecol. 2011 Oct;118(4):777-84
Handa Obstet Gynecol. 2012 Jan 5.
Medication Use in Pregnancy
Medication Safety
Medication
FDA
Category
Comment
Lactation
5ASA
Asacol, olsalazine
B
C
Asacol: DBP
Compatible
(rare diarrhea)
Corticosteroids
Budesonide
C
C
Low risk T1:
Cleft palate
Compatible
Azathioprine/6MP D
Low risk
Compatible:
Ideally wait 4
hours after dose
Methotrexate
Contraindicated Contraindicated
X
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: 0.98-2.04
– Increased rate of VSD/ASD
OR 3.18, 95% CI: 1.45-6.04
 N=9 (4 SLE, 4 IBD, 1 nephrotic syndrome)

– Increased rate of preterm, LBW, SGA

Likely disease effect
Coelho: Gut. 2011 Feb;60(2):198-203.
Cleary. Birth Defects Research 85:647-654, 2009
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)
1. Barclay J Pediatr 2009
2. Moffatt Am J Gastro June 2009
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.
Anti-TNF-alpha Therapies
Infliximab
Adalimumab
Fab′
Certolizumab
pegol
Fab
PEG
IgG1
Fc
Chimeric
Human
Monoclonal
antibody
PEGylated
humanized
Fab′ fragment
2 × 20 kDa
PEG
Adapted from: Hanauer SB. Rev Gastroenterol Disord. 2004;4(Suppl. 3):S18-S24.
Anti-TNF’s: Safety

Infliximab (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. 2009
Dec 21 ; Nazareth M, Mahadevan U. Am J Gastroenterol 2008;103:S449-50
Breastfeeding

Infliximab




Adalimumab



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
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
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



20
B: Fetal
r2=0.87, p<0.04
IgG (g/L)
15
10
5
0
0
10
20
30
40
50
Gestational age (weeks)
Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins
During human pregnancy. Am J Reprod Immunol 1996; 36(5):248-55.
Image Courtesy of Sundana Kane MD


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
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 U Clin Gastro Hep 2012 epub ahead of print
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
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
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

+/- Unexposed medications
– Group AB: Combination therapy

+/- Unexposed medications
Mahadevan Gastroenterology 2012
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
104
37
5
(214)
(126)
(47)
(6)
Multiple Exposure: 27
•IFX/ADA (16) IFX/CZP (5) ADA/CZP (5) ADA/CZP/NAT (1)
Disease Activity by
Trimester: CD
%
TRIMESTER AND MONTHS POSTPARTUM
Two hospitalizations
Disease Activity by
Trimester: UC
%
TRIMESTER AND MONTHS POSTPARTUM
No hospitalization
Adverse Pregnancy
Outcomes
Group A (aza)
RR (CI)
Group B (bio)
Group AB
(combo)
Any
Complication
0.98(0.69-1.40)
1.09 (0.80-1.48)
1.28 (0.82-1.98)
Spontaneous
Abortion
2.03 (0.74-5.55)
2.56 (1.07-6.12)*
1.29 (0.79-2.11)
Preterm Birth
1.06 (0.62-1.81)
0.89 (0.54-1.47)
1.83 (1.01-3.31)*
Low Birth Weight
0.69 (0.32-1.48)
1.17 (0.66-2.09)
1.05 (0.41-2.68)
IUGR
0.96 (0.28-3.27)
1.01 (0.35-2.98)
1.25 (0.26-5.88)
Cesarean section
1.07 (0.86-1.33)
1.23 (1.02-1.48)*
1.14 (0.86-1.53)
NICU
1.09 (0.66-1.81)
1.20 (0.77-1.88)
1.71 (0.96-3.07)
Congenital Anom
1.05 (0.50-2.21)
1.07 (0.55-2.08)
1.36 (0.52-3.56)
Adjusted for none/mild vs. mod/severe disease activity
* P <0.05
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
Mahadevan U. Am J Gastroenterol. 2011 Feb;106(2):214-23
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