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