Download Slide 1

Continue Biologics
Throughout Pregnancy
Uma Mahadevan MD
Associate Professor of Medicine
Co-Medical Director
UCSF Center for Colitis and Crohn’s Disease
Key Points

Once pregnant, even with inactive disease,
there is an increased risk of complications
– Moderate to severe disease increases risk



Preterm birth is associated with significant
infant mortality, morbidity and developmental
delay
Transfer of biologics across the placenta
begins as soon as week 6 of gestation
Interrupted anti-TNF therapy leads to
antibody formation and loss of response
BEING IN REMISSION ON
LOW RISK MEDICATION IS
THE BEST OPTION FOR A
HEALTHY PREGNANCY
Increase in Preterm birth with
moderate to high disease
activity
Crude Relative Risk
95% CI
LBW
LBW at term
1.1
0.3-4.0
0.9
0.1-8.5
Preterm birth
Congenital
Anomalies
3.4
1.1-10.6
0.4
0.0-3.9
Preterm birth (>37 wks gestation)
Leading cause of mortality in newborns
Higher rates CP, sensory deficits, learning disabilities, respiratory
illness
Norgard B, et al. Am J Gastroenterol. 2007;102:1947–1954.
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
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
RESULTS
Women Enrolled (4/25/2012)
1115
Pregnancies Ended
•Still pregnant
•Missing outcomes
•Excluded/Withdrew
896
94
55
17/53
Unexposed
•No medications
326
32
Group A (AZA/6MP)
204
Group B (Biologics)
291
Group AB (Combination)
75
Infliximab (+multiple exp)
Adalimumab
Certolizumab
Natalizumab
193
104
37
5
(214)
(126)
(47)
(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)
Adjusted for none/mild vs. mod/severe disease activity
* P <0.05
Adverse Pregnancy
Outcomes: Crohn’s Disease
Group A
RR (CI)
Group B
Group AB
Any
Complication
0.99(0.62-1.58)
1.04 (0.70-1.55)
0.73 (0.36-1.47)
Spontaneous
Abortion
1.16 (0.24-5.56)
1.76 (0.48-6.40)
--
Preterm Birth
1.21 (0.61-2.39)
0.85 (0.45-1.62)
1.16 (0.48-2.80)
Low Birth Weight
0.68 (0.25-1.80)
1.01 (0.48-2.11)
0.27 (0.04-2.05)
IUGR
2.33 (0.44-12.4)
1.67 (0.34-8.06)
1.37 (0.13-14.7)
Cesarean section
1.02 (0.79-1.32)
1.06 (0.85-1.32)
0.90 (0.63-1.29)
NICU
1.08 (0.55-2.13)
1.17 (0.65-2.09)
0.91 (0.35-2.35)
Congenital Anom
1.75 (0.51-6.02)
2.03 (0.68-6.08)
1.92 (0.45-8.26)
Adjusted for none/mild vs. mod/severe disease activity
* P <0.05
Adverse Pregnancy Outcomes:
Ulcerative Colitis
Group A
RR (CI)
Group B
Group AB
Any
Complication
0.93(0.54-1.62)
0.97 (0.54-1.75)
2.97 (1.76-5.02)*
Spontaneous
Abortion
2.98 (0.79-11.3)
4.85 (1.48-15.9)*
4.27 (0.80-22.8)
Preterm Birth
0.73 (0.27-1.94)
0.69 (0.24-1.97)
3.81 (1.80-8.06)*
Low Birth Weight
0.62 (0.17-2.19)
1.08 (0.36-3.25)
3.35 (1.16-9.64)*
IUGR
0.00(0.00- )
0.00 (0.00- )
1.81 (0.22-15.1)
Cesarean section
0.97 (0.67-1.43)
1.03 (0.69-1.53)
1.37 (0.81-2.30)
NICU
1.09 (0.51-2.36)
0.97 (0.40-2.33)
3.90 (1.94-7.85)*
Congenital Anom
0.90 (0.33-2.47)
0.68 (0.20-2.30)
1.82 (0.42-8.00)
Adjusted for none/mild vs. mod/severe disease activity
* P <0.05
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
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



20
B: Fetal
r2=0.87, p<0.04
IgG (g/L)
15
10
5
0
0
10
20
30
40
50
Gestational age (weeks)
Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins
During human pregnancy. Am J Reprod Immunol 1996; 36(5):248-55.
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
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
Infections:
Adjusted for Preterm Birth
By Month 4
RR (CI)
By Month 9
By Month 12
Group A
(AZA)
1.08 (0.65-1.82)
1.18 (0.87-1.59)
0.98 (0.77-1.24)
Group B
(Bio)
1.09 (0.68-1.74)
1.06 (0.79-1.42)
0.89 (0.70-1.12)
Group AB
(Combo)
1.28 (0.64-2.55)
1.24 (0.82-1.87)
1.27 (0.96-1.69)
Mahadevan. Gastroenterologyh 2012
Infections Adjusted for Preterm
Birth: Excluding Certolizumab
Adjusted for
preterm birth
By Month 4
RR (CI)
By Month 9
Group B
1.09 (0.67-1.78)
1.07 (0.79-1.45) 0.91 (0.72-1.15)
Group AB
1.00 (0.44-2.29)
1.23 (0.80-1.91) 1.35 (1.011.80)*
*This
By Month 12
was not seen when infliximab and
adalimumab were each excluded from the
analysis.
Infections by Exposure
Group
Unexposed
Group A (n)
Group B
Group AB
Ear infxn (119)
Uri (32)/cold 1
pneumonia (1)
bladder (1)
conjunctivitis (1)
croup (1)
Eye(3)
impetigo (2)
low plt count (1)
Nasopharyngitis
(1)
sinus (1)
skin infec eye (1)
staph (1)
thrush (1)
unknown (2)
uti (1)
viral (4)
Ear infxn (85)
Uri (14)
Pneumonia (4)
Conjunctivitis (2)
Eye (1)
Fingernail (1)
Murmur (1)
Sinus (2)
Strep throat (1)
Viral (2)
Yeast infxn neck (1)
Ear Infxn (104)
URI (29)/Cold
(2)
sepsis (1)
pneumonia (1)
abscess LN (1)
bronchiolitis (1)
bronchitis (1)
cellulitis (1)
eye (2)
fingernail (1)
GI (2)
rsv (2)
sinus (1)
staph (1)
thrush (2)
unknown (2)
uti (2)
viral (1)
Ear infxn (31)
URI 11/cold (1)
sepsis (2)
croup (1)
eye (1)
rsv (1)
uti (2)
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
Avoid combination therapy with ADA/IFX
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 issues
Mahadevan 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

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
We do not recommend cessation
of therapy in non-pregnant pts

WCOG Statement 1.17:
– Pts with mod to severe luminal CD who have responded to
induction anti-TNF should be considered for scheduled retreatment…This strategy is more effective than episodic
therapy for maintaining response. [EL 1b]

WCOG Statement 1.19:
– Pts with UC refractory to conventional therapy which has
responded to infliximab should best be considered for
continuing therapy since scheduled re-treatment is
effective for maintaining response and reducing the risk of
colectomy [EL 1b]
D’Haens Am J Gastroenterol 2011:106:199-212
Summary

We teach all our patients the importance of
compliance with biologic therapy
– Risk of antibody formation
– Risk of attenuated response

Pregnant women should not be different!
– No increase in the risk of birth defects
– No increase in infections in newborns except with
combo therapy
– Clear risk of increased adverse events with increased
disease activity.

Postpartum is important too!
Treat the patient , not your
own fears
…and if you are still not
convinced…
Consensus Statement




The risks and benefits of biologic therapy during
the third trimester should be individually
considered
Combination therapy with a biologic and
immunomodulator should be avoided in
pregnancy if possible
Certolizumab can be continued throughout
pregnancy on schedule
Further studies are needed to determine the
impact of significant levels of anti-TNF agents on
newborn immune development and infection risk