This document discusses inflammatory bowel disease (IBD) in pregnancy and covers several topics. It defines the two main types of IBD as ulcerative colitis and Crohn's disease. It discusses the prevalence and incidence of IBD, how pregnancy can affect disease course, and how active IBD may increase risks of adverse pregnancy outcomes like preterm birth. The document reviews common IBD medications including biologics, their safety in pregnancy, and considerations for use. It also discusses potential IBD complications and examines the question of whether aspirin has a role in preventing venous thromboembolism. Finally, it addresses considerations for mode of delivery for women with IBD.

1. Inflammatory bowel disease in pregnancy:
biologics, aspirin, mode of delivery
Chad A. Grotegut MD
Duke University

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The disclosures
 None

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IBD in pregnancy: the plan
 IBD review
 etiology and definitions
 prevalence and incidence
 effects of pregnancy on IBD
 effects of IBD on pregnancy
 classes of medications
 Biologics
 IBD complications
 VTE prevention- is there a role for aspirin?
 Mode of delivery

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IBD etiology
Genetic
predisposition
Immune system
Environmental
triggers
IBD
Adapted from The facts about inflammatory bowel disease. Crohn’s and Colitis Foundation of America. 2014.

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IBD basics
 Ulcerative colitis
 mucosal layer
inflammation
 continuous
 rectal involvement
 Crohn’s disease
 transmural
inflammation
 skip areas
 mouth to anus
 often has small bowel
involvement
 50% involves rectum
 perianal disease

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Ulcerative colitis
 Typically classified:
 mild
 moderate
 severe
 fulminant
 Classic symptoms
 bloody diarrhea
 urgency
 tenesmus

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Ulcerative colitis
 GI Complications
 massive GI hemorrhage
 fulminant colitis / toxic megacolon
 perforation or stricture / obstruction
 colon cancer
 Extraintestinal complications
 eye – uveitis / scleritis
 skin – erythema nodosum / pyoderma gangr.
 arthritis
 lung disease
 venous thromboembolism

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Crohn’s disease
 Variable symptoms
 fatigue
 diarrhea
 abdominal pain
 weight loss
 fever
 rectal bleeding
 fistulas
 perianal abscesses
 aphthous ulcers

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Crohn’s disease
 Classified
 severity:
 mild, moderate, severe
 phenotype:
 inflammatory, stricturing, penetrating
 location
 GI Complications
 strictures / obstructions
 perianal fistulas / abscesses
 Extraintestinal manifestations

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Epidemiology
 Approximately 1.6 million Americans have IBD
 ~70,000 new cases diagnosed in the US each year
 United States prevalence
 Ulcerative colitis: 238 per 100,000 population
 Crohn’s: 201 per 100,000 population
 United States incidence
 Ulcerative colitis: 2-19 per 100,000 person-years
 Crohn’s: 3-20 per 100,000 person-years
Crohn’s and Colitis Foundation of America. 2014.
Loftus EV et al. Gastroenterol. 2004

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Incidence ulcerative colitis by age
Adapted from Loftus et al, ACG 2014 Annual Scientific Meeting, Oct 2014
0
5
10
15
20
25
Age Ranges
CrudeIncidenceRate
(per100,000person-years)
0-19 20-29 30-39 40-49 50-59 60-69 70-79
Female
Male

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Incidence Crohn’s disease by age
Adapted from Loftus et al, ACG 2014 Annual Scientific Meeting, Oct 2014
0
5
10
15
20
25
Age Ranges
CrudeIncidenceRate
(per100,000person-years)
0-19 20-29 30-39 40-49 50-59 60-69 70-79
Female
Male

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IBD risk factors
 Age
 onset: 15-40
 possible bimodal, second peak 50-80
 Gender
 slight female predominance in Crohn’s disease
 Race/ethnicity
 Israeli Jews > N.American Jews > Asian/African
Jews
 White > African American/Hispanic
 Genetic susceptibility
 Smoking
See Appendix for list of references

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IBD risk factors continued
 Diet
 Physical activity
 Obesity
 Infections
 Nursing/perinatal events
 Antibiotics
 Isotretinoin
 NSAIDs
 OCPs / HRT
 Psychosocial
 Sleep duration
See Appendix for list of references

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Inheritance / transmission
 Positive family history most important predictor of
lifetime risk
 10-25% of individuals with IBD have a first degree
relative with IBD
 Offspring of first degree relative - lifetime risk
 3-20 times over general population
 Offspring of parent with IBD
 5-10% lifetime risk
 Both parents with IBD
 ~30-35% lifetime risk

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Scope of the problem, the numbers
 Nationwide inpatient sample, 2008-2010
 ~16,250 deliveries to women with IBD
among 12.5 million deliveries
 ~130 women with IBD per 100,000
deliveries
Grotegut CA. Unpublished data, 2014

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Effects of pregnancy on IBD
 Key issue: want quiescent disease at time of
conception
 Flare risk in pregnancy
 IBD in remission at conception
 20-25% flare risk, similar to non-pregnant population
 IBD active at conception
 ~50-70% continued or worsening symptoms
 confounding factors
 medication cessation
 smoking cessation
 smoking may be protective in UC
 No correlation of symptoms from one pregnancy to
another
Kane S et al. in Pregnancy in Gastrointestinal Disorders, 2nd ed. Am College Gastrolog.y 2007

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UC: active disease at conception
Abhyankar A et al. Allimentary Pharm & Ther. 2013
• Women with active UC at time of conception are more likely to have
active UC during the pregnancy
• 55% of women with active disease at conception, disease
remained active or experienced flares
• 29% of women with inactive disease at conception had a UC
flare

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Crohn’s: active disease at conception
Abhyankar A et al. Allimentary Pharm & Ther. 2013
• Women with active Crohn’s at time of conception are more likely to
have active Crohn’s during the pregnancy
• 46% of women with active disease at conception, disease
remained active or experienced flares
• 23% of women with inactive disease at conception had a UC
flare

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Effects of IBD on pregnancy
 Increased risk of poor pregnancy outcomes compared
to women without IBD
 preterm delivery
 low birth weight
 cesarean delivery
 Active disease seems to increase the risk of adverse
outcomes
 especially those with active disease at conception

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Effects of IBD on pregnancy continued
 Unclear what drives the association with adverse
pregnancy outcomes
 disease
 disease flares
 generalized inflammatory state
 medications
 other factors
 Most consistent outcome associated with IBD disease
activity in pregnancy is with preterm birth

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IBD disease activity and preterm birth
Broms G. Inflamm Bowel Dis. 2014

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IBD disease activity and preterm birth
Broms G. Inflamm Bowel Dis. 2014

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Prematurity: IBD vs. control
Cornish J et al. Gut. 2007

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Cesarean: IBD vs. control
Cornish J et al. Gut. 2007

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IBD medication classes
 Medication classes:
 corticosteroids
 aminosalicylates
 antibiotics
 immunomodulators
 biologics
 Most commonly used IBD medications are largely not
associated with adverse outcomes or congenital
anomalies

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IBD medication and risk
Active disease, not therapy, poses the
greatest risk to pregnancy
Kane S et al. Practical Gastroenterology. 2007

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Corticosteroids
 Utilized for flares
 Not used for maintenance
 Most common flavors:
 prednisone
 prednisolone
 budesonide
 Obstetricians comfortable with their use
 Considerations
 small increase risk for oral clefting
 gestational diabetes

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Aminosalicylates
 Sulfasalazine and 5-aminosalicylic acid (5-ASA)
 Anti-inflammatory properties
 Induce remission and maintenance
 Used primarily in UC but not as effective in Crohn’s
 Oral or rectal
 Most common flavors:
 sulfasalazine
 balsalazide
 mesalamine
 olsalazine

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Aminosalicylates continued
 Sulfasalazine
 prodrug of 5-ASA linked to sulfapyridine
 allows passage to colon
 potentially interferes with folic acid metabolism
 folic acid 2 mg daily, preconception
 Enteric-coated mesalamine (i.e. Asacol)
 DBP associated with skeletal malformations in
animals at high doses
 consider switching to another 5-ASA agent
 Aminosalicylates take-home
 safe in pregnancy, folic acid
van Assche et al. J Crohns Colitis. 2010
US FDA. Asacol delayed release tablets, safety labeling changes. 2010

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Antibiotics
 Primarily used for flares and complications
 pouchitis
 perianal disease
 associated infections
 Not utilized for maintenance
 Common flavors:
 metronidazole
 ciprofloxacin

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Immunomodulators
 Modifies the immune system
 Primarily used to maintain remission
 The flavors:
 azathioprine
 6-mercaptopurine (6-MP)
 cyclosporine
 methotrexate
 thalidomide

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Immunomodulators continued
 Azathioprine and 6-mercaptopurine
 azathiprine is a prodrug converted to 6-MP
 both classified as FDA pregnancy D
 initial concern for anomalies in transplant populations
 current data suggest no increased risk
 discontinuation results in high rate of relapse
 87% of complete responders relapsed with
discontinuation
 active disease associated with PTB
 recommend to continue
Akbari M et al. Inflamm Bowel Dis. 2013
George J et al. Am J Gastroenteroll. 1996

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Immunomodulators continued
 Azathioprine and 6-MP and congenital anomalies
Adapted from Akbari M et al. Inflamm Bowel Dis. 2013
0.1 1 10
Combined
Shim
Coelho
Cleary
Norgard
Francella
Odds Ratio, Congenital anomalies

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Immunomodulators continued
 Cyclosporin
 used for flares in severe steroid-refractory UC
 experience in pregnancy largely among transplant
recipients
 not associated with congenital anomalies
Adapted from Bar et al. Transplantation. 2001
0.1 1 10
Odds Ratio, Congenital anomalies
Combined
(six studies)

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Immunomodulators continued
 Methotrexate
 no
 wait 3-6 months for conception following
discontinuation
 Thalidomide
 no

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The biologics
Korzenik JR and Podolsky DK. Nature Rev. 2006

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The biologics
 Tumor necrosis factor-α (TNF-α)
 cell-signaling protein
 involved in systemic inflammation
 neutrophil chemoattractant
 produced by numerous cell types
 activated macrophages
 other immune cells
 endothelial cells
 fibroblasts
 soluble and transmembrane forms
 associated with human disease
 rheumatologic conditions
 inflammatory bowel disease

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The biologics
 Anti-TNF-α agents
 monoclonal antibody directed at TNF-α
 binds soluble and membrane-bound TNF-α
 prevents TNF-α signaling
 the flavors:
 infliximab (Remicade)
 adalimumamb(Humira)
 certolizumab pegol
(Cimzia)
Feagan BG. Medscape multispecialty. Dec 2014

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The biologics continued
 Infliximab (Remicade)
 induction and maintenance of remission
 IgG antibody
 crosses placenta
 detected in cord blood
 potential neonatal issues
 not associated with congenital anomalies
 may increase risk of infection
 may lead to decreased response to vaccination
 live vaccines should not be given to newborns exposed to
perinatal infliximab
 dosed every 8 weeks for maintenance
 time last dose 8-10 weeks prior to delivery
Zelinkova Z et al. Clin Gastroenterol Hepatol. 2013
Mahadevan U et al. Clin Gastroenterol Hepatol. 2013

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The biologics continued
 Certolizumab pegol (Cimzia)
 PEGylated Fc-free anti_TNF therapy
 Commonly used in Rheumatologic disorders but
also used in Crohn’s disease
 Does not cross the placenta
 Lacks the Fc portion which is important for placental IgG
transfer
 Do not switch agents for purpose of pregnancy
Clowse MEB et al. J Rheumatol. 2015

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Anti-TNF-α therapies and pregnancy outcomes
Narula et al. Inflammatory Bowel Diseases. 2014

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IBD complications
 Anemia
 Bowel stricture / obstruction
 Fulminant colitis / toxic megacolon
 Perianal abscesses
 Fistulas
 Primary sclerosing cholangitis
 Colorectal cancer
 up to 18% by 30 years
 Venous thromboembolism
Eaden et al. Gut. 2001
Zitomersky NL et al. Inflamm Bowel Dis. 2011

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IBD complications
 Anemia
 Bowel stricture / obstruction
 Fulminant colitis / toxic megacolon
 Perianal abscesses
 Fistulas
 Primary sclerosing cholangitis
 Colorectal cancer
 up to 18% by 30 years
 Venous thromboembolism
Eaden et al. Gut. 2001
Zitomersky NL et al. Inflamm Bowel Dis. 2011

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IBD and VTE (non-pregnant)
• Absolute VTE risk among hospitalized IBD to ambulatory IBD and
controls:
• 37.5 per 1000 person years, hospitalized IBD flare
• 6.4 per 1000 person years, ambulatory IBD flare
• 1.4 per 1000 person years, remission IBD
• 0.6 per 1000 person years, control
Nguyen GC et al. Gastroenterology. 2014
Grainge MJ et al. Lancet. 2010
VTE relative risk estimates among IBD compared to general population:

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IBD and VTE (non-pregnant) continued
 Venous thromboembolism
 three-fold increased risk compared to general
population
 RR > 15-20 during flares
 among those with IBD, six-fold higher risk during
hospitalized flare vs. outpatient flare
 moderate-to-severe flare is considered a substantial
provoking factor
 new focus on IBD patients who have additional risk
factors for VTE
 pregnancy
 cesarean delivery
 acquired / inherited thrombophilia
Zitomersky NL et al. Inflamm Bowel Dis. 2011
Nguyen GC et al. Gastroenterol. 2014

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IBD and VTE (non-pregnant) continued
 VTE prophylaxis and IBD (non-pregnant)
 not addressed in the ACCP Chest guidelines
 Canadian Association of Gastroenterology
 recommend anticoagulant prophylaxis during:
 moderate to severe outpatient flare with history of
VTE
 hospitalization for flare
 hospitalization for other indication, including those in
remission (weak rec, low-qual evid)
 major abdominal-pelvic surgery
 substitute mechanical prophylaxis with indications and
severe IBD-related GI bleeding
Eaden et al. Gut. 2001
Zitomersky NL et al. Inflamm Bowel Dis. 2011

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IBD, VTE, and pregnancy
 Canadian Association of Gastroenterology
 anticoagulant prophylaxis for “women with IBD
who have undergone cesarean delivery while
hospitalized”
 ACCP recommends post-cesarean anticoagulant
prophylaxis for women with one major or at least two
minor risk factors for VTE
 IBD not specifically considered as a risk factor for VTE in
the current ACCP guidelines
 Pregnancy as an additional risk factor for VTE, should
women with IBD receive prophylaxis during
pregnancy?
Nguyen GC et al. Gastroenterol. 2014
Bates SM et al. Chest. 2012

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IBD, VTE, and pregnancy continued
Medical condition Pregnancies
n=376,154
Antepartum
IRR1 VTE
Postpartum
IRR1 VTE
IBD 1472 3.46 (1.11, 10.7) 4.56 (1.88, 11.0)
Cancer 5012 1.97 (0.87, 4.44) 1.21 (0.49, 2.96)
Cardiac disease 354 -- 6.58 (1.63, 26.5)
SLE 188 -- 6.69 (0.95, 47.0)
Chronic HTN 11,718 0.90 (0.42, 1.94) 0.25 (0.08, 0.79)
Diabetes 4022 3.08 (1.42, 6.39) 0.88 (0.33, 2.38)
Sultan AA et al. Blood. 2013
1IRR = Incidence rate ratio
Controls for age, BMI, parity, smoking

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IBD, VTE, and pregnancy continued
 Overall VTE rate:
 AP: 84 per 100,000 person years
 PP: 338 per 100,000 person years
 IBD VTE rate:
 AP: 288 per 100,000 person years
 PP: 1514 per 100,000 person years
 Cancer VTE rate:
 AP: 169 per 100,000 person years
 PP: 446 per 100,000 person years
Sultan AA et al. Blood. 2013

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IBD, VTE, and pregnancy continued
 Nationwide inpatient sample, 2005
 delivery discharges
Medical
condition
Non-IBD
deliveries
n=965,473
UC deliveries
n=387
Crohn’s deliveries
n=694
VTE rate 0.2 %
2.1%
aOR 8.44 (3.71, 19.20)
1.5 %
aOR 6.12 (2.91, 12.9)
Nguyen GC et al. Clin Gastroenterol Hepatol. 2009
aOR controls for age, race/ethnicity, insurance, hospital type, mode of delivery

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IBD, VTE, and pregnancy continued
 RCOG
 Includes IBD as an intermediate risk factor for
consideration of anticoagulation prophylaxis

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8/17/2017 The Society for Maternal-Fetal Medicine 53
RCOG. Green-top guideline 37a. 2009
RCOG guidelines for VTE risk reduction

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Low-dose aspirin
 Low-dose aspirin for VTE prophylaxis
 classically thought that did not prevent venous
thrombosis
 5-ASA drugs do not seem to have anti-platelet
activity
 Aspirin has been shown to prevent VTE in high-risk
populations
 No pregnancy data on VTE prevention with aspirin
Zitomersky et al. Inflamm Bowel Dis. 2011
PEP trial Collaborative Group. Lancet. 2000

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Aspirin and VTE prevention (non-pregnant)
 PEP Trial
 RCT of 13,356 patients
having surgery for hip
fracture
 1992-1998
 Europe, South Africa,
Australia, NZ
 160 mg ASA vs. placebo
 43% reduction PE
 29% reduction DVT
PEP trial Collaborative Group. Lancet. 2000

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Aspirin and VTE prevention (non-pregnant)
 WARFASA trial
 RCT of 100 mg ASA vs. placebo following primary
VTE
 ASA HR 0.58 (0.36, 0.93) for recurrent VTE
 6.6% vs. 11.2% per year
Becattini C et al. NEJM. 2012

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Low-dose aspirin and IBD
 NSAIDs and risk for IBD relapse
 Conflicting data about NSAID use and IBD flare
 NSAIDs have effects that may alter IBD
 interaction between gut flora and immune cells through
effects on intestinal mucosa
 alter platelet aggregation
 release of inflammatory mediators
 microvascular response to stress
 Nurses’ Health Study
Ananthakrishnan AN et al. Ann Intern Med. 2012

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Low-dose aspirin and IBD- Nurses’ Health Study
Ananthakrishnan AN et al. Ann Intern Med. 2012

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Low-dose aspirin and IBD- Nurses’ Health Study
Ananthakrishnan AN et al. Ann Intern Med. 2012

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Low-dose aspirin and IBD continued
 NSAIDs and risk for IBD relapse
 Takeucki et al
 IBD subjects placed on NSAIDs, aspirin, selective
COX-2 inhibitor, or acetaminophen
 NSAIDS associated with relapse and increases in
intestinal inflammation
 Aspirin, COX-2 inhibitor, and acetaminophen:
 no relapse
 no increases in intestinal inflammation
 Aspirin does not seem to be associated with IBD
onset of relapse
 unclear if antenatal low-dose aspirin would
decrease VTE in pregnancy
Takeuchi K et al. Clin Gastroentol Hepatol. 2006

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Mode of delivery
 Mode of delivery considerations
 Presence of perianal disease in Crohn’s disease
 concern for complicated perianal / sphincter injury
 concern for healing
 History of IPAA in ulcerative colitis
 concern for anal sphincter injury
 concern for pouch dysfunction

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Mode of delivery
 Perianal flare and mode of delivery
Cheng AG et al. Inflamm Bowel Dis. 2014
p=0.89

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Mode of delivery
Ananthakrishnan AN et al. Dig Dis Sci. 2014
HR 0.19 (0.04, 1.05)
 Mode of delivery and risk for perianal surgery

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Mode of delivery continued
 Discuss preference with patient and their GI and
colorectal surgeon
 Active perianal disease consider cesarean
 IPAA not necessarily an indication for cesarean

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IBD and pregnancy
 Summary
 active disease, not therapy, poses the greatest risk
to pregnancy
 review medication list
 avoid discontinuing most meds
 folic acid
 biologics are safe in pregnancy
 discuss timing of last dose with GI
 be cognizant of VTE risk
 consider other risk factors
 anticoagulation candidate?
 is there a role for low-dose aspirin in IBD patients?
 mode of delivery and active perianal disease

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IBD and pregnancy
 Questions