Management of Pregnant Women with IBD
Uma Mahadevan MDAssociate Professor of MedicineCo-Medical DirectorUCSF 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 X X
LBW X X X
SGA X
1. Kornfeld et al. Am J Obstet Gynecol. 1997 (n=756 IBD)2. Fonager et al. Am J Gastroenterol. 1998 (n=510 CD)3. Norgard et al. Am J Gastroenterol. 2000 (n=1531 UC)4. 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
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
Norgard B, et al. Am J Gastroenterol. 2007;102:1947–1954.
Danish population based study: Pregnancies with disease activity at any time (n=71) were compared to pregnancies without any disease activity (n=86)
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 PTB1. Bengtson Inflamm Bowel Dis 2010:16:847-8552. 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;94:3274-82. 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, 1.01-1.54) 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
2.2-14.7) 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
5ASAAsacol, olsalazine
BC Asacol: DBP
Compatible(rare diarrhea)
CorticosteroidsBudesonide
CC
Low risk T1:Cleft palate
Compatible
Azathioprine/6MP
D Low risk Compatible:Ideally wait 4 hours after dose
Methotrexate X Contraindicated
Contraindicated
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 effectCoelho: 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 20092. Moffatt Am J Gastro June 2009
Breast Feeding While Taking AZA/6MP8 lactating women received Aza 75-200
QD– Milk and plasma at 30, 60 min and every
hour x 5Variation 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.
Adapted from: Hanauer SB. Rev Gastroenterol Disord. 2004;4(Suppl. 3):S18-S24.
Monoclonal antibody
Infliximab Adalimumab
IgG1Fc
Fab
HumanChimeric
Fab′
Certolizumab pegol
PEG
PEGylated humanized
Fab′ fragment
2 × 20 kDa PEG
Anti-TNF-alpha Therapies
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 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 2010 3. Friitzsche J Clin Gastro 2012
Placental Transfer of IgG Ab
0
5
10
15
20
0 10 20 30 40 50
Gestational age (weeks)
IgG
(g
/L)
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
Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulinsDuring human pregnancy. Am J Reprod Immunol 1996; 36(5):248-55.
r2=0.87, p<0.04
B: Fetal
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
Jauniaux Human Reprod vol 10:12:3297-3300
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
RESULTSWomen Enrolled (4/25/2012) 1115
Pregnancies Ended• Still pregnant• Missing outcomes• Excluded/Withdrew
8969455
17/53
Unexposed• No medications
32632
Group A (AZA/6MP) 204
Group B (Biologics) 291
Group AB (Combination) 75
Infliximab (+multiple exp)AdalimumabCertolizumabNatalizumab
193 (214)104 (126)
37 (47)5 (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)
* P <0.05Adjusted for none/mild vs. mod/severe disease activity
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 issuesMahadevan 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