The Pregnant Patient with Inflammatory Bowel Disease
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The Pregnant Patient with Inflammatory Bowel Disease
Britt Christensen, MDScott Plevy, MD
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Case 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
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Relationships and Fertility in IBD
Peak incidence of IBD overlaps the prime child bearing years
Fertility and pregnancy outcome is of great concern to the IBD patient
Addressing these issues is part of our goals of management
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Before Pregnancy
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Biggest Risk in IBD Pregnancy is Active Disease
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 What will happen if you are off all meds? The reality of the timing of this approach…
1. Mounitfield et al. JCC 20102. Julsgaard et al. IBD 2011 & 2010
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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%
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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
One parent has CD: 5%
One parent has UC: 1.6%
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
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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 non-IBD 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 normal rates of fertility
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Fear of Infertility in IBD Patients
CD vs. U
C
Operat
ed vs
Not-
Operat
ed
Female
vs. M
ale0.00%
20.00%
40.00%
60.00%
Mountifield et al. IBD 2009
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Voluntary Childlessness is increased in patients with IBD
CD UC NCHS0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
Mari et al. IBD 2007
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Infertility: Crohn’s DiseaseHudson: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 ControlFielding ’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%
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Infertility: Ulcerative ColitisAuthor / year N Ulcerative colitis ControlWilloughby1980
147 6.8%
Olsen2002
290 FR = 1.01 pre-operativeFR*= .20 post-operative
NSP = <.0001
Johnson2004
213 13.3% non-operative38.6% post IPAA
Lepisto2007
160 18% non-operative32% post IPAAPregnancy after 2 years:91% non-operative56% post IPAA
Cornish2007
419Systematic Review
12% pre-operative25% post-operative
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Case
She and her partner are unable to conceive naturally (decreased fecundity)
Undergoes in vitro fertilization
She successfully conceives with IVF
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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 pregnancyb) If their disease is in remission they have a 70%
chance of flairing during pregnancyc) If their disease is in remission they have a 70%
chance of staying in remission during pregnancyd) If their disease is active they have a 70% chance
of their disease worsening during pregnancy
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Disease Activity Trends During Pregnancy in women with CD
73%
33% 32%34%
Inactive Active
NoRelapse
Relapse WorsenedActivity
ContinuedActivity
DecreasedActivity
n=186 n=93
Miller JP. J R Soc Med. 1986;79:221-225.
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Disease Activity Trends During Pregnancy in women with UC
66%
45%34%
24% 27%
Inactive Active
NoRelapse
Relapse WorsenedActivity
ContinuedActivity
DecreasedActivity
n=227n=528
Miller JP. J R Soc Med. 1986;79:221-225.
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Pregnancy Outcomes and IBD Preterm birth
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
1Baird 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
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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)
Preterm birth (<37 wks gestation)
Leading cause of mortality in newbornsHigher rates CP, sensory deficits, learning disabilities, respiratory illness
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Currently on certolizumab pegol and azathioprine: What do you do with her medications now that she is pregnant?
a) Continue both medications throughout pregnancyb) Continue both medication and then cease
certolizumab at 30 weeksc) Cease azathioprine but continue certolizumb
throughout pregnancyd) Cease certolizumab but continue azathioprine
throughout pregnancye) Cease both medications whilst patient is pregnant
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Category B Category C Category D Category XLoperamide Ciprofloxacin Azathioprine† MethotrexateMesalamine Cyclosporine 6-Mercaptopurine† ThalidomideBalsalazide Diphenoxylate
Corticosteroids OlsalazineSulfasalazine Tacrolimus
Anti-TNF agents NatalizumabAsacol HDMetronidazole*
*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.
Safety of IBD Medications During Pregnancy
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Corticosteroids (C) Case-control study in 1st trimester
Increased risk of oral clefts Overall risk of malformations low In transplant setting:
Adrenal suppression in newborn Premature rupture of membranes
Compatible with breast feeding Budesonide (Entocort)
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
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Azathioprine/6-MP 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
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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′ fragment2 × 20 kDa
PEG
Anti-TNF-alpha Therapies
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Placental Transfer of IgG Ab
0
5
10
15
20
0 10 20 30 40 50Gestational age (weeks)
IgG
(g/L
)
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: (n= 10)Infant and cord IFX level were greater than mother. 6 months to clear
Adalimumab (n = 10)ADA level was greater than mother. 4 months to clear¾ pts who stopped ADA 35 days prior to delivery had a flare
Certolizumab (n = 10)Infant and cord levels less than 2 mcg/ml even if mom dosed the week of delivery
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Infliximab/Adalimumab/Certolizumab pegol (B)
Infliximab (B) 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
Adalimumab (B) 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) Limited published data Thought likely safe as minimal transfer across placenta
Natalizumab (C): IgG4 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
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Timing of Biological Therapies in Pregnancy
Elective switching of therapies is not recommended
Outcomes of moms on biological therapies not different than moms who are off these therapies (recognizing differences in disease severity)
Trying to time dosing based on third trimester is an unproven strategy, and not based on known pharmacokinetics
No live virus vaccine for first 6 months for infants exposed to IFX or ADA during pregnancy
Focus on newborn- consider testing for immune conversion with vaccinations
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Case She continues on her azathioprine and
anti-TNF agent (certolizumab pegol)
At 18 weeks EGA, presents with rectal pain, bleeding.
EXAM: Anal stricture, significant induration of
perianal area.
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Management of Flares in the Pregnant IBD Patient
Medication choices are similar Avoid new aza/6mp in pregnancy Avoid metronidazole, corticosteroids in T1
Imaging MRI preferred to CT, but NO gadolinium in T1 Small bowel US if available
Endoscopy Unsedated flexible sigmoidoscopy preferred
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Surgery During Pregnancy Indications similar to non-pregnant patient
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;
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Case
Undergoes loop ileostomy. Tolerates procedure well. Medications stopped (diverted) “feels great” Follows up with OB and GI Planned elective Caesarean delivery
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Mode of DeliveryMode of delivery is per OB discretion except… Avoid episiotomy: may predispose to perineal
disease (17.9%) without prior disease 103 Vaginal delivery (87% episiotomy)1
Caesarean section if active perianal disease 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 Borderline continence that depends more on intact
optimal sphincter function 1 Brandt LJ. Am J Gastroenterol. 1995 2. Ilnyckyji A. Am J Gastroenterol. 1999
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She delivers a healthy baby boy!
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Lets assume she is back on her medication…. Can she breast-feed whilst
taking certolizumab pegol and azathioprine?
a) Yes – both medications are considered safe b) She must cease her azathioprine but can
breast-feed whilst taking certolizumabc) She must cease her certolizumab but can
breast-feed whilst taking azathioprined) She must cease both medications if she wishes
to breast-feed
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Breastfeeding
Breastfeeding (non-IBD moms) associated with a protective effect in the development of early onset IBD1
Breastfeeding not associated with an increased risk of disease flare; possible protective effect against disease flare in the post-partum Manitoba, population based study2
1. Barclay J Pediatr 2009; 2. Moffatt Am J Gastro June 2009
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Low Risk to Use When Warranted
Limited Data Available Contraindicated
Oral mesalamine TacrolimusNatalizumab
MethotrexateTopical mesalamine
Sulfasalazine CertolizumabAdalimumab
CyclosporineMetronidazole Ciprofloxacin
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):2269-2272. ; Gardiner SJ, et al. Br J Clin Pharmacol. 2006;62(4):453-456.
Safety of IBD Medications in Breast-Feeding
Corticosteroids6-MP/AZA
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Breastfeeding Azathioprine
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. Infliximab and Adalimumab
Breast milk 1/200th mother’s level (n = 1) 5 6
ADA not detected in infant (n = 1) 6
Certolizumab 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
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Summary: IBD and the Pregnant Patient
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:
5-ASA Corticosteroids (1st T risk of cleft palate) Antibiotics (metronidazole after T1, Clavulanate/piperacillin) Azathioprine/6-MP Anti-TNF (notable that certolizumab doesn’t cross placenta)
Most medications are safe for breast feeding as well