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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