Download Surgery During Pregnancy

The Pregnant Patient with
Inflammatory Bowel Disease
Britt Christensen, MD
Scott Plevy, MD
Case
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26 yo woman with Crohn’s Dx since age 11
Ileal and colonic involvement
Prior surgery, ileal sigmoid anastomosis.
Perianal disease, large skin tags, anal
stricture
Maintained on certolizumab pegol and
azathioprine
Wants to have children
Husband is healthy
Relationships and Fertility in IBD
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Peak incidence of IBD overlaps the prime
child bearing years
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Fertility and pregnancy outcome is of great
concern to the IBD patient
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Addressing these issues is part of our
goals of management
Before Pregnancy
Biggest Risk in IBD Pregnancy
is Active Disease
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Education regarding adverse effect of disease
on pregnancy outcomes
High rates of “non-adherence” due to concerns
regarding medications (12-40%, often without
physician knowledge) 1 2
Counseling regarding use of IBD medications
during pregnancy and lactation
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What will happen if you are off all meds?
The reality of the timing of this approach…
1. Mounitfield et al. JCC 2010
2. Julsgaard et al. IBD 2011 & 2010
What are the chances of her
child inheriting IBD?
a) No increased risk – the chances are
the same as the general population risk
b) 1.5%
c) 5%
d) 20%
e) 35%
Inheritance of IBD
• Non-mendelian inheritance: Multifactorial with a role for
as yet undefined environmental triggers
• Risk of CD and UC in offspring of patients with IBD1
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One parent has CD: 5%
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One parent has UC: 1.6%
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Both parents have IBD: 35% 2
• Genetic anticipation: Familial CD younger onset than
sporadic cases (22 y vs 27 y) 3
• Clinical features demonstrate heritable pattern
• Smoking may be an environmental trigger in susceptible
family members
1. Orholm M Am J Gastroenterol. 1999 Nov;94(11):3236-8.
2. Bennett RA Gastroenterology. 1991 Jun;100(6):1638-43.
3. Polito JM, Gastroenterology. 1996 Sep;111(3):580-6
Which statement is incorrect in
regards to fertility and IBD?
a) Many patients with IBD are fearful of
infertility
b) IBD patients have as many children as nonIBD patients
c) Patients with Crohn’s Disease who have
had surgery have higher rates of infertility
d) Patients who have had IPAA surgery have
infertility rates of up to 30-40%
e) Patients with both CD and UC who are in
remission and have never had surgery have
Fear of Infertility in IBD
Patients
60.00%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
CD vs. UC
Operated vs NotOperated
Female vs. Male
Mountifield et al. IBD 2009
Voluntary Childlessness is
increased in patients with IBD
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
CD
UC
NCHS
Mari et al. IBD 2007
Infertility: Crohn’s Disease
Hudson:14% CD (n= 177) vs 14% general population
Surgical therapy:20% Medical therapy: 8%
The risk of fertility in CD prior to surgery appears to be
similar to the general population
Author / year
N
Crohn’s
Fielding ’70
77
32%
Khosla ’84
54 married
12%
10% gen pop
Mayberry ’86
275
42% subfertility
28%
Baird ’90
177
Involuntary 5%
Voluntary 14%
8%
14%
Hudson ’97
177
14%
Surg:20% Med: 8%
14%
Control
Infertility: Ulcerative Colitis
Author / year
N
Ulcerative colitis
Willoughby
1980
147
6.8%
Olsen
2002
290
FR = 1.01 pre-operative
FR*= .20 post-operative
Johnson
2004
213
13.3% non-operative
38.6% post IPAA
Lepisto
2007
160
18% non-operative
32% post IPAA
Pregnancy after 2 years:
91% non-operative
56% post IPAA
Cornish
2007
419
Systematic
Review
12% pre-operative
25% post-operative
Control
NS
P = <.0001
Case
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She and her partner are unable to
conceive
naturally (decreased
She successfully
conceives
fecundity)
with IVF
Undergoes in vitro fertilization
What are the chances of a
patient with Crohn’s Disease
fairing during pregnancy?
a) If their disease is active on conception they have
a 70% chance of improving during pregnancy
b) If their disease is in remission they have a 70%
chance of flairing during pregnancy
c) If their disease is in remission they have a 70%
chance of staying in remission during pregnancy
d) If their disease is active they have a 70% chance
of their disease worsening during pregnancy
Disease Activity Trends During
Pregnancy in women with CD
n=186
n=93
73%
33%
No
Relapse
Relapse
Inactive
32%
34%
Worsened Continued Decreased
Activity
Activity
Activity
Active
Miller JP. J R Soc Med. 1986;79:221-225.
Disease Activity Trends During
Pregnancy in women with UC
n=528
n=227
66%
45%
34%
24%
No
Relapse
Relapse
Inactive
27%
Worsened Continued Decreased
Activity
Activity
Activity
Active
Miller JP. J R Soc Med. 1986;79:221-225.
Pregnancy Outcomes and IBD
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Preterm birth
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1Baird
 risk in both UC and CD1,2,5,6
 in risk of low birth weight2-5
 risk of maternal/delivery complications5
 C-section rate6
4 of 5 studies: no major impact on risk of
congenital abnormalities1-5
No impact on adverse new born outcomes5 6
DD, et al. Gastroenterology. 1990;99:987-994. 2Dominitz JA, et al. Am J Gastroenterol. 2002;97:641-648. 3Porter RJ,
Stirrat GM. Br J Obstet Gynaecol. 1986;93:1124-1131. 4Fonager K, et al. Am J Gastroenterol. 1998;93:2426-2430.5Mahadevan U,
et al. Gastroenterol. 2007;133:1106-1112 6Kornfield D et al. Am J Obstet Gynecol. 1997;177:942-966
Increase in Preterm birth with
moderate to high disease activity
Crude Relative Risk
95% CI
1.1
0.3-4.0
LBW
Preterm birth (<37 wks gestation)
0.9
0.1-8.5
LBW at term
1.1-10.6
Leadingbirth
cause of 3.4
mortality in newborns
Preterm
Higher rates CP, sensory
deficits, learning
0.4
0.0-3.9 disabilities,
Congenital
respiratory illness
Anomalies
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.
Currently on certolizumab pegol and
azathioprine: What do you do with her
medications now that she is pregnant?
a) Continue both medications throughout pregnancy
b) Continue both medication and then cease
certolizumab at 30 weeks
c) Cease azathioprine but continue certolizumb
throughout pregnancy
d) Cease certolizumab but continue azathioprine
throughout pregnancy
e) Cease both medications whilst patient is pregnant
Safety of IBD Medications During
Pregnancy
Category B
Category C
Category D
Category X
Loperamide
Ciprofloxacin
Azathioprine†
Methotrexate
Mesalamine
Cyclosporine
6-Mercaptopurine†
Thalidomide
Balsalazide
Diphenoxylate
Corticosteroids
Olsalazine
Sulfasalazine
Anti-TNF agents
Tacrolimus
Metronidazole*
Natalizumab
Asacol HD
*Safe for use after first trimester. †Increasing use in pregnancy.
Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins;
1998.
Physician’s Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.
Corticosteroids (C)
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Case-control study in 1st trimester
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Increased risk of oral clefts
Overall risk of malformations low
In transplant setting:
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Adrenal suppression in newborn
Premature rupture of membranes
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Compatible with breast feeding
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Budesonide (Entocort)
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Orally inhaled budesonide not associated with
increase risk of fetal abnormalities
8 CD patients treated with oral budesonide1
1. Beaulieu Inflamm Bowel Dis. 2009 Jan;15(1):25-8
Azathioprine/6-MP
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Transplant and rheumatology cohorts considered safe
with no constant reports of abnormalities, prematurity or
congenital defects
Almost all IBD studies show no increased risk of
congenital abnormalities1-5
No increased risk of miscarriage1
Some studies suggest increased risk of prematurity and
LBW but thought to be disease related2 5
Recent study of 30 patients showed 60% of babies born
mildly anemic – unsure if clinically relevant as no action
required.6
1) Coelho: Gut. 2011; 2) Goldstein LH, et al. Birth Defects Res A Clin Mol Teratol. 2007; 3) Briggs GG, et al. Drugs in Pregnancy and
Lactation. 5th ed. 1998; 4) Francella A, et al. Gastroenterology. 2003; 5) Cleary. Birth Defects Research 2009; 6) Jharap et al.
GUT. 2013
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.
Placental Transfer of IgG Ab
Infliximab: (n= 10)
Infant and cord IFX level
were greater than mother.
6 months to clear
20
IgG (g/L)
15
Adalimumab (n = 10)
ADA level was greater than
mother. 4 months to clear
¾ pts who stopped ADA 35
days prior to delivery had a
flare
10
5
Certolizumab (n = 10)
0
0
10
20
30
Gestational age (weeks)
40
50
Infant and cord levels less
than 2 mcg/ml even if mom
dosed the week of delivery
Image Courtesy of Sunanda Kane MD: Malek A, Evolution of maternofetal transport of immunoglobulins during human pregnancy.
Am J Reprod Immunol 1996; 36(5):248-55.
Mahadevan U Gastroenterol 2007;132:A-144; Mahadevan et al. Gastro vol 140 Is 5, suppl 1, P S-796 Mahadevan U Gastroenterology 2009;136:146
Infliximab/Adalimumab/Certolizumab
pegol (B)
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Infliximab (B)
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Adalimumab (B)
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33 women enrolled in a prospective study in pregnancy and an
additional 89 adalimumab exposed pregnant women in a registry.
No increase in birth defects, abortion, congenital malformation or
preterm delivery 3
Certolizumab (B)
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100 infants exp, similar rate of live births, SAB’s1
117 exp vs. unexposed with similar rate of miscarriage (10 vs. 6.7%)
and neonatal complications (6.9% vs. 10%) 2
Limited published data
Thought likely safe as minimal transfer across placenta
Natalizumab (C): IgG4
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143 pregnant patients exposed to natalizumab
No birth defects reported 4
(1) Katz JA, et al. Am J Gastroenterol. 2004;99:2385
(2) Lichtenstein. Gastroenterol 2010;138, S-475
(3) Jurgens Inflamm Bowel Dis. 2009 Dec 21
(4) Nazareth M, Mahadevan U. Am J Gastroenterol 2008;103:S449-50
Timing of Biological Therapies in
Pregnancy
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Elective switching of therapies is not recommended
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Outcomes of moms on biological therapies not different
than moms who are off these therapies (recognizing
differences in disease severity)
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Trying to time dosing based on third trimester is an
unproven strategy, and not based on known
pharmacokinetics
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No live virus vaccine for first 6 months for infants
exposed to IFX or ADA during pregnancy
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Focus on newborn- consider testing for immune conversion with
vaccinations
Case
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She continues on her azathioprine and
anti-TNF agent (certolizumab pegol)
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At 18 weeks EGA, presents with rectal
pain, bleeding.
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EXAM:
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Anal stricture, significant induration of
perianal area.
Management of Flares in the Pregnant
IBD Patient
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Medication choices are similar
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Imaging
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Avoid new aza/6mp in pregnancy
Avoid metronidazole, corticosteroids in T1
MRI preferred to CT, but NO gadolinium in T1
Small bowel US if available
Endoscopy
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Unsedated flexible sigmoidoscopy preferred
Surgery During Pregnancy
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Indications similar to non-pregnant patient
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obstruction, perforation, hemorrhage or abscess
T2 best time to operate
Fetal mortality can be high with abortion-stillbirth
rates as high as 18-40%
In severely ill patients, continued illness is greater
risk to fetus than surgical intervention1
A temporary ileostomy is generally preferred, to
reduce risk of post-operative complications after
primary anastomosis2
1. Subhani et al. Aliment Pharmacol Ther 1998; 2. Kane S. Gastroenterol Clin North Am 2003;
Case
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Undergoes loop ileostomy.
Tolerates procedure well.
Medications stopped (diverted)
“feels great”
Follows up with OB and GI
Planned elective Caesarean delivery
Mode of Delivery
Mode of delivery is per OB discretion except…
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Avoid episiotomy: may predispose to perineal
disease (17.9%) without prior disease
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Caesarean section if active perianal disease
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103 Vaginal delivery (87% episiotomy)1
No history(1/39) or inactive (0/11) perianal disease at
birth, risk of relapse very low
4/4 with active perianal disease worsened post-vaginal
delivery1
J-Pouch: Relative Indication for Elective Caesarian
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Borderline continence that depends more on intact
optimal sphincter function
1 Brandt LJ. Am J Gastroenterol. 1995 2. Ilnyckyji A. Am J Gastroenterol. 1999
She delivers a healthy baby
boy!
Lets assume she is back on her
medication…. Can she breast-feed whilst
taking certolizumab pegol and
azathioprine?
Yes – both medications are considered safe
b) She must cease her azathioprine but can
breast-feed whilst taking certolizumab
c) She must cease her certolizumab but can
breast-feed whilst taking azathioprine
d) She must cease both medications if she wishes
to breast-feed
a)
Breastfeeding
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Breastfeeding (non-IBD moms) associated
with a protective effect in the development
of early onset IBD1
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Breastfeeding not associated with an
increased risk of disease flare; possible
protective effect against disease flare in
the post-partum
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Manitoba, population based study2
1.
Barclay J Pediatr 2009; 2. Moffatt Am J Gastro June 2009
Safety of IBD Medications in
Breast-Feeding
Low Risk to Use
When Warranted
Limited Data
Available
Oral mesalamine
Topical mesalamine
Sulfasalazine
Corticosteroids
Tacrolimus
Natalizumab
Certolizumab
Adalimumab
Contraindicated
Methotrexate
Cyclosporine
Metronidazole
Ciprofloxacin
6-MP/AZA
Infliximab
Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003; de Boer NK, et al. Am J Gastroenterol.
2006;101(6):1390-1392; Sau A, et al. BJOG. 2007;114(4):498-501.; Moretti ME, et al. Ann Pharmacother. 2006;40(12):22692272. ; Gardiner SJ, et al. Br J Clin Pharmacol. 2006;62(4):453-456.
Breastfeeding
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Azathioprine
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Infliximab and Adalimumab
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Studies show undetectable levels in feeding infants and
minimal detectable levels in milk with no consequences
for baby1, 2, 3
Peak excretion first 3 hours with max infant ingestion less
than 0.008mg/kg body weight/24 h4
Can consider waiting 4 hours from dose to feed.
Breast milk 1/200th mother’s level (n = 1) 5 6
ADA not detected in infant (n = 1) 6
Certolizumab
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Not detected in breast milk (n = 1)
1. Moretti ME et al. Ann. Pharmacother. 2006.; 2. Gardiner SJ et al. Br. J. Clin. Pharmacol. 2006; 3. Sau A et al. BJOG 2007; 4.
Christensen et al. Aliment Pharmacol. Ther. 2008; 5.Benhorin J Crohn’s Colitis 2011; 6. Ben-Horin CGH 2010
Summary: IBD and the Pregnant
Patient
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Control disease prior to planned pregnancy
Consider surgery prior to planning pregnancy (including
temporary ostomy in some cases)
Communication to obstetrician and to pediatrician is
essential
Most medications are compatible and safe in pregnancy:
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5-ASA
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Corticosteroids (1st T risk of cleft palate)
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Antibiotics (metronidazole after T1, Clavulanate/piperacillin)
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Azathioprine/6-MP
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Anti-TNF (notable that certolizumab doesn’t cross placenta)
Most medications are safe for breast feeding as well