Stop biologics prior to delivery !

M NachuryCHU Lille, France

JF ColombelMount Sinai School of Medicine, New York, USA

Are biologics (non) teratogenic ?

We don’t know !!

Evolving knowledge of the teratogenicity of medications in human pregnancy

• Safety information for 468 drugs approved by the FDA from 1980 to 2000 reviewed to determine if revisions in risks had been made in the last 10 years

• Teratogenic risk « undetermined » for 168 (97.7%) of drug treatments approved between 2000 and 2010

• For drugs approved between 1980 and 2000, only 23 (5%) changed a full category risk or more in the past 10 years

• « we estimate the mean time necessary to assign a more precise teratogenic risk to treatments initially judged to have an ‘undetermined’ risk to be 27 years »

Adam MP et al. Am J Med Genetics 2011

Effects of teratogens may occur many years after the prenatal exposure

Herbst AL et al. N Engl J Med 1971

Forty years ago, in 1971, Herbst et al. reported a new association between maternal diethylstilbestrol use duringpregnancy and occurrence of adenocarcinoma of the vagina in their daughters 15 to 20 years later in the New England Journal of Medicine.

The VACTERL controversy

• Request adressed to the FDA for adverse events for IFX, ADA and etanercept from 1999-2005

• Search for congenital abnormalities. • Out of >120.000 adverse events: 41 children with 61

congenital anomalies: 22 mothers etanercept and 19 IFX • 34 different types of birth defects, 19 of which are part of the

VACTERL; 9/19 occured more than historical controls (p<0.01)– Vertebral defects– Anal atresia– Cardiac abnormalities– Tracheoesophageal fistula– Esophageal atresia– Renal abnormalities– Limb abnormalities

Carter JD et al. J Rheumatol 2008

If the biologics are continued, will my baby be exposed ?

YES !!

Increase of fetal serum IgG concentration during pregnancy

Malek A et al. Am J Reprod Immunol 1996

Serum IgG is detectable in the foetus as early as 13 weeks of gestation, and its concentration increases steadily until birth.

At birth, a child has more serum IgG than its mother

maternal IgG

fetal IgG

Malek A et al. Am J Reprod Immunol 1996

IgG transcytosis by FcRn in the syncitiotrophoblast

FcRn

transcytosis

Recycling of anti-TNfs through FcRn protects them from catabolism

Binding ofmaternal Ig

Releaseof maternal Ig

Infliximab levels in neonates often surpassed these in the mother and remained detectable up to 6 mos after birth

Mahadevan U et al. Gastroenterology 2007

Stopping IFX therapy at gestational week 30 is not enough

Zelinkova Z et al. Aliment Pharmacol Ther 2011

Discontinuation of Adalimumab in the second trimester does not prevent neonatal exposure to this agentZelinkova Z et al. UEGW 2012

Important observations to keep in mind…

• Recycling of anti-TNFs through neonatal Fc receptor protects them from catabolism

• The biological half life of anti-TNFs in the newborn is longer than in adults because of high expression of the FcRn during first months of life

• Persistance of IFX in the blood of children for as long as 6mos

• The PK of anti-TNFs in pregnancy is changed leading to longer biological half-life

If my baby is exposed to biologics, does that matter ?

We don’t know !!

TNF is involved in mouse growth and lymphoid tissue development

Injection of anti-TNF in pregnantmice- Severe but transient growth retardation (± 35%).- Normal growth hormone bloodlevels.- Decrease of IGF-1 blood levels (±50%).- Marked atrophy of thymus, spleenand lymph nodes.

De Kossodo S et al. J Exp Med 1992

• 28 year old lady with refractory Crohn's Disease treated with infliximab throughout her pregnancy. • Her baby was born healthy and received a Bacillus Calmette-Guérin (BCG) vaccine aged 3 months. • Soon after this the infant became unwell and died aged 4.5 months. • At post-mortem the cause of death was attributed to an unusual complication of the BCG vaccine, known as disseminated BCG.

The wake-up call

Cheent K et al. J Crohns Colitis 2012

• 11 children born to 10 patients with IBD• 3 mothers used anti-TNF during pregnancy (1 ADA and 2 IFX); ttt was stopped at week 24 (ADA) and 26 (IFX)• 7 mothers were on AZA (n=4) or 5-ASA (n=3)• All children received BCG vaccination within the first 5 days of life according to the local standard protocol (Slovakia)• All 3 children born to mothers treated with anti-TNF developed adverse reactions : 2 axillar and 1 generalized lymphadenopathy• No adverse reactions in children from the control group

And more…

Zelinkova Z et al. UEGW 2012

Infections in Piano

Month 4

RR (CI)

Month 9 Month 12

IS alone 1.1 (0.4,2.6) 1.3 (0.6, 2.7) 0.9 (0.3, 2.6)

Anti-TNF alone 0.7 (0.3, 2.1) 1.5 (0.7, 2.9) 1.4 (0.5, 3.6)

Combo 1.8 (0.7, 4.5) 1.2 (0.5, 3.0) 2.5 (1.1-6.0)

Mahadevan U et al. DDW 2012

If I stop biologics prior delivery will my disease flare ?

Good chance that it will not

CD activity may be lower during pregnancy

Agret F et al. Aliment Pharmacol Ther 2005

Smokers

Non smokers

Total

70 pregnancies in 61 patients with CD

HBI was significantly lower during pregnancy than the yearbefore or after

IBD activity may be lower during and after pregnancy

Riis et al. Am J Gastro 2006

Prospective study of 177 pregnancies in women with IBD (109 UC 68 CD)

Risk of relapse is low when the patient is in a state of « deep

remission »

Kaplan Meier time-to-relapse curves according to multivariate models including deleterious factors*

* Deleterious factors were: no previous surgery, steroid use within 12-6 months before infliximab withdrawal, male gender, haemoglobin ≤14.5 g/dl, leukocyte count >6 109/l, hsCRP ≥5 mg/l, faecal calprotectin ≥300 µg/g, CDEIS >0, infliximab trough ≥2 mg/l

0.0

0.4

0.6

0.2

0.8

1.0

0 6 12 18 24 30

Prop

ortio

nw

ithou

t rel

apse

Months since infliximab withdrawal

No. of deleterious factors

<4

4

5–6

>6

hsCRP< 5mg/lCalprotectin <300g/g

Risk of relapse after IFW withdrawal in patients on combo therapy (Stori)

Louis E et al. Gastroenterology 2012

More Good news:The patient can be successfully

retreated after stopping

Stori: What happened to relapsers ?

39/39 negative for ATI

38/43 : remission42/43 : response

STORI

Conclusion

Considering the current knowledge, everything should be tried to limit the intra-uterine and postnatal

exposure of children to anti-TNFs

For patients in whom the quiescent disease during pregnancyallows interruption of treatment, intra-uterine andpostnatal exposure of newborns to IFX should be

avoided by stopping IFX at the beginning of the secondtrimester

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