Continue Biologics Throughout Pregnancy

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Continue Biologics Throughout Pregnancy

• Uma Mahadevan MD
• Associate Professor of Medicine
• Co-Medical Director
• UCSF Center for Colitis and Crohns Disease

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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

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Being in remission on low risk medication is the
best option for a healthy pregnancy
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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
Preterm birth (gt37 wks gestation) Leading cause
of mortality in newborns Higher rates CP, sensory
deficits, learning disabilities, respiratory
illness
Norgard B, et al. Am J Gastroenterol.
200710219471954.
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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

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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
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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 (214) 104 (126) 37 (47) 5 (6)
Multiple Exposure 27 IFX/ADA (16) IFX/CZP (5) ADA/CZP (5) ADA/CZP/NAT (1) Multiple Exposure 27 IFX/ADA (16) IFX/CZP (5) ADA/CZP (5) ADA/CZP/NAT (1)
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Disease Activity by Trimester CD

TRIMESTER AND MONTHS POSTPARTUM
Two hospitalizations
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Disease Activity by Trimester UC

TRIMESTER AND MONTHS POSTPARTUM
No hospitalization
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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 lt0.05
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Adverse Pregnancy Outcomes Crohns 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)
P lt0.05
Adjusted for none/mild vs. mod/severe disease
activity
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Adverse Pregnancy OutcomesUlcerative 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)
P lt0.05
Adjusted for none/mild vs. mod/severe disease
activity
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Anti-TNF-alpha Therapies
Infliximab
Adalimumab
Fab'
Fab
IgG1Fc
Human
Chimeric
Monoclonal antibody
Adapted from Hanauer SB. Rev Gastroenterol
Disord. 20044(Suppl. 3)S18-S24.
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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

B Fetal
r20.87, plt0.04
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
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• 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

Jauniaux Human Reprod vol 10123297-3300
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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
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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 lt30 weeks.

Zelinkova Clin Gastro Hep Oct 2012
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Infections

• Fatal case of disseminated BCG infection in an
  infant born to a mother on INF for Crohns
  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 Crohns Colitis 2010
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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
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Infections Adjusted for Preterm Birth Excluding
Certolizumab
Adjusted for preterm birth By Month 4 RR (CI) By Month 9 By Month 12
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 (1.01-1.80)
This was not seen when infliximab and adalimumab
were each excluded from the analysis.
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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)
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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
Feb106(2)214-23
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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

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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 re-treatmentThis
  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

DHaens Am J Gastroenterol 2011106199-212
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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!

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• Treat the patient , not your own fears
• and if you are still not convinced

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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