1. No category

Treatment of IBD in the
Pregnant Patient
Miguel Regueiro, M.D.
Associate Professor of Medicine
Associate Chief for Education
Cli i l Head
Clinical
H d and
d Co-Director,
C Di
t
IBD C
Center
t
Director, Gastroenterology, Hepatology, Nutrition
Fellowship
University of Pittsburgh School of Medicine
Question 1
•
Which of the following drugs should NOT
be actively transported across the
placenta in the third trimester of
pregnancy
1.
1
2.
3
3.
4.
Infliximab
Adalimumab
Certolizumab
Natalizumab
Question 2
•
Which of the following drugs is
COMPATIBLE with breastfeeding
1.
1
2.
3
3.
4.
5
5.
Infliximab
Azathioprine
Sulfasalazine
All of the above
N
None
off the
th above
b
Question 3
•
All of the following are CATEGORY B
risk in pregnancy, EXCEPT:
1.
1
2.
3
3.
4.
5
5.
Infliximab
Adalimumab
Certolizumab
Natalizumab
M
Mesalamine
l i
Effect of Pregnancy on CD:
Disease Activity at Conception
N = 186
73%
N = 93
27%
No
Relapse
Relapse
Inactive
Miller JP. J R Soc Med. 1986;79(4):221-225.
33%
32%
34%
Worsened Continued Decreased
Activity
Activity
Activity
Active
Disease activity during
pregnancy in women with IBD
Percenta
age of patie
ents
„
Exposure: IBD disease activity
acti it d
during
ing conception,
conception each trimester
t imeste
and the postpartum period (1 month)
– Inactive, mild, moderate, severe
100
80
60
40
20
0
100
Disease activity in Crohn’s disease
Inactive
Mild
Disease activity
y in ulcerative colitis
Moderate
80
60
40
20
0
Severe
Concept
T1
T2
T3
PP
Trimester
Mahadevan U, et al. Gastroenterol. 2007;133:1106-1112
Pregnancy Outcomes:
Population Based Studies
Preterm Birth
Low Birth Wt
Small Gest Age
Caesarean Section
1.
2.
3.
4
4.
N = 756 IBD
N = 510 CD
N = 1531 UC
N = 107 UC
UC, 155 CD
1. Kornfeld D, et al. Am J Obstet Gynecol. 1997;177(4):942-946.
2. Fonager K, et al. Am J Gastroenterol. 1998;93(12):2426-2430.
3. Nørgård B, et al. Am J Gastroenterol. 2000 Nov;95(11):3165-3170.
4. Dominitz JA, et al. Am J Gastroenterol. 2002 Mar;97(3):641-648.
IBD
UC
CD
X
X
X
XX
XX
X
X
IPAA: Cumulative Incidence of
Pregnancy Within 5 Years
1.0
Cumulaative Incidence
of P
Pregnancyy
0.8
Before diagnosis
Reference
Before surgery
After surgery
0.6
04
0.4
0.2
0.0
0
12
24
36
48
Time to Pregnancy (months)
Reprinted from Olsen KØ, et al. Gastroenterology. 2002;122:15-19 with permission from American
Gastroenterological Association.
60
Pregnancy Risk Categories
Pregnancy-Risk
A:
B:
C:
D:
X:
Controlled human studies do not show risk to fetus;
chance of risk remote
No evidence of risk to fetus in human studies; chance
of risk remote but possible
Inadequate studies in humans; risk cannot be ruled
out but benefits may outweigh risks
out,
Positive evidence of fetal risk; benefits might outweigh
risks in life-threatening situations when safer drugs are
ineffective
Contraindicated in pregnancy
Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
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
Tacrolimus
Anti-TNF
agents
Metronidazole*
Natalizumab
Corticosteroids
Rifaximin
*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.
Aminosalicylates (B,C)
• Meta-analysis
Meta analysis 7 studies: 642 5ASA vs 1158 no med
–
–
–
–
–
Congenital anomalies: OR 1.16 (0.76, 1.77)
Stillbirth OR 2.38 (0.65, 8.72)
SAB OR 1.14
1 14 (0.65,
(0 65 2
2.01)
01)
Preterm delivery 1.35 (0.85, 2.13)
LBW OR 0.93 (0.46, 1.85)
• Sulfasalazine given w/ folic acid 1 mg BID
• Folic acid: neural tube defects, CV, GU, cleft palate
• Case reports of congenital malformation
• Placental and Breast Transfer Occurs
• Potential allergic reaction newborn: watery diarrhea
• SAS not associated with kernicterus or displacement of
bilirubin from albumin
• Olsalazine: Pregnancy category C. All others, B
Rahimi Reprod Toxicol 2008
Corticosteroids (C)
• Case-control studyy 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
• Entocort (budesonide)
– Orallyy inhaled budesonide not associated with
increase risk of fetal abnormalities
– 8 CD patients treated with oral budesonide (Binion)
Antibiotics
• Metronidazole ((B)) /Ciprofloxacin
p
((C))
– Low risk of teratogenicity
• Metronidazole: prospective controlled study, 2 meta-analysis
– However, 2nd, 3rd T use, 1st T cleft lip, palate
• Ciprofloxacin: prospective controlled study low risk of defects
– Affinity for bones, arthropathy in children
– Breast feeding not advised on metronidazole, probably
compatible
tibl with
ith ciprofloxacin
i fl
i
– Minimal benefit in CD and UC with longer use-avoid
• Rifaximin: Pregnancy
g
yC
– teratogenicity in animal studies
– Safety in humans in pregnancy/breastfeeding unknown
Human Studies: 6MP/AZA (D)
• Transplantation Experience
– Frequency of Congenital Abnormality in renal tx
0.0-11.8% in 27 clinical series
– No recurrent pattern of anomalies seen
– No increase in anomalies (Armenti 1994) in kidney
transplant
• No congenital anom in rheumatic ds, SLE
• Experience in IBD
– Alstead (1990): 14 pts: 7 entire pregnancy: no CA
– Khan (2000): 8 preg/6 pt
pt. No complications
– Francella (2003): Retrospective
• 79F(24 UC), 76M(27 UC). 325 pregnancies
• No difference in outcomes with 6mp exposure
• Only 15 patients on 6mp throughout pregnancy
Azathioprine
• 189 pregnant women on AZA who contacted one
of seven teratogen information services were
compared to a cohort of 230 pregnant women
who took non-teratogenic treatments
• Rate of major malformations did not differ with
six neonates each:
– AZA (3.5%) vs control ( 3.0%) (P = .775; OR 1.17; CI: 0.37,
3 69)
3.69).
Goldstein LH, et al. Birth Defects Res A Clin Mol Teratol. 2007;79(10):696-701.
So…although 6MP/AZA listed
as category D…..
….the evidence suggests
minimal to no increase risk
in pregnancy.
pregnancy
Biologic Therapy in IBD
Infliximab (B)
Adalimumab (B)
Certolizumab (B)
Natalizumab (C)
Outcomes of Women Exposed
to Infliximab During Pregnancy
P
Proportio
n of Patie
ents (%)
80
70
67
67
66
67
60
Live births
50
Miscarriages
40
Therapeutic
termination
30
20
17 16
20
19
17
15
11
13
10
0
General
population
Crohn’s
disease
Katz JA, et al. Am J Gastroenterol. 2004;99(12):2385-2392.
Ventura SJ, et al. Vital Health Stat 21. 2000;21(56):1-47.
Hudson M, et al. Int J Gynaecol Obstet. 1997;58(2):229-237.
All infliximab
Infliximab
patients
patients with
(N = 96)
CD (N = 82)
Infliximab in Pregnancy
10 Crohn’s disease patients
i t ti
intentionally
ll exposed
d to
t
infliximab during pregnancy
8 women received
maintenance infusions
2 women received
initial infusions
10 Live Births
Congenital
malformations
(N=0)
IUGR
(N=0)
SGA
(N=0)
Preterm
(N=3)
LBW
(N=1)
8 Caesarean sections: 2 active luminal, 3 perianal disease, 1 preterm
Mahadevan U, et al. Aliment Pharmacol Ther. 2005;21:733-738.
Infliximab in Cord Blood
Pt #
* Breastfed
1
2
3*
4*
5*
6
7*
8*
Mother INF
15.1
(mcg/ml)
1.4
19.2 3.8 4.8 14.5 16.5
2.2
Cord Blood
INF
2.0
26.5 3.3 8.8 20.5 26.5
8.4
--
2.9
Newborn
25.3
23.6 4.2 8.7 28.2 27.5 10.6
INF at Birth
W:2
Month INF
Undetectable
5
2
7
2
3
4
5
--
High Serum Infliximab Levels in Newborn
of a Mother Treated During Pregnancy
Breast fed 7 wks
–2
Time (weeks) from birth
Infliximab
+ + +
infusions (10 mg/kg)
+
+
0
2
4
Breast feed resumed Wk 11
6
10
13
+
Birth 41 wks
Immune studies at 6 months:
T and B lymphocytes normal
IgG, IgM and IgA levels normal
Infliximab
level
Mother
serum
Baby serum
Breast milk
Vasiliauskas EA, et al. Clin Gastroenterol Hepatol. 2006;4(10):1255-1258
µg/mL
40
9.3
8.4
40
0
20.8
0
11.7
0
Adalimumab (B)
„
„
O
Organization
i ti for
f T
Teratology
t l
IInformation
f
ti
Specialists reports 27 women enrolled in a
prospective study of adalimumab in
pregnancy and an additional 47 adalimumab
exposed pregnant women in a registry
The rate of spontaneous abortion,
stillbirth, congenital malformation and
preterm
t
d
delivery
li
was similar
i il to
t the
th
diseased comparison and the general
population.
population
Chambers CD The OTIS Autoimmune Diseases in Pregnancy Project. Personal
communication. July 13, 2007 .
Certolizumab (B) Natalizumab (C)
„
Certolizumab:: data on file
Certolizumab
– Pegylated – should not cross placenta
– 16 pregnancies:
„
„
4 healthy
ea t y infants,
a ts, 8 IAB,, 1 S
SAB,, 1 p
preterm,
ete , 2
unknown
Natalizumab ((C):
)
– IgG4, placental transfer in third trimester
– 143 pregnant patients exposed to tysabri
– No birth defects reported
Mahadevan ACG 2008
Safety of IBD Medications in
Breast-Feeding
Low Risk to Use
When Warranted
Limited Data
Available
Contraindicated
Oral mesalamine
Topical mesalamine
Sulfasalazine
Corticosteroids
Tacrolimus
Natalizumab
Certolizumab
Adalimumab
Methotrexate
Cyclosporine
Metronidazole
Ci
Ciprofloxacin?
fl
i ?
6-MP/AZA*
I fli i b
Infliximab
(*new evidence suggests safe)
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.
Question 1
•
Which of the following drugs should NOT
be actively transported across the
placenta in the third trimester of
pregnancy
1.
1
2.
3
3.
4.
Infliximab
Adalimumab
Certolizumab
Natalizumab
Question 2
•
Which of the following drugs is
COMPATIBLE with breastfeeding
1.
1
2.
3
3.
4.
Infliximab
Azathioprine
Sulfasalazine
All of the above
Question 3
•
All of the following are CATEGORY B
risk in pregnancy, EXCEPT:
1.
1
2.
3
3.
4.
5
5.
Infliximab
Adalimumab
Certolizumab
Natalizumab – category C
M
Mesalamine
l i
Summary
• Disease control at conception
p
improves
p
pregnancy outcomes
• anti-TNF therapies are safe and thiopurines are
probably safe during pregnancy
• Infliximab and adalimumab do cross the
placenta in the third trimester. Preliminary
p
y
evidence suggests that certolizumab does not
cross
• Most IBD medications can be continued during
breastfeeding
UPMC IBD CENTER
Leonard Baidoo, MD
Beth Rothert RN, BSN
Arthur “Tripp”
Tripp Barrie,
Barrie MD
MD, PhD
Linda Kontur RN
David Binion, MD
Jennifer Rosenberry, RN
Richard Duerr
Duerr, MD
Di
Diane
Sabilla,
S bill RN
Janet Harrison, MD
Marilyn Pesci, RN
Miguel Regueiro
Regueiro, MD
Joann Fultz
Wolfgang Schraut, MD, PhD
Kristy Rosenberry, RN
M
Marc
Schwartz,
S h
t MD
Linda Nelson
Jason Swoger, MD, MPH
Katie Wyant, CRNP
A d
Andrew
W
Watson,
t
MD
29