Stop biologics prior to delivery ! M Nachury CHU Lille, France JF Colombel Mount Sinai School of...
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![Page 1: Stop biologics prior to delivery ! M Nachury CHU Lille, France JF Colombel Mount Sinai School of Medicine, New York, USA.](https://reader031.fdocuments.us/reader031/viewer/2022020417/56649f2f5503460f94c489da/html5/thumbnails/1.jpg)
Stop biologics prior to delivery !
M NachuryCHU Lille, France
JF ColombelMount Sinai School of Medicine, New York, USA
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Are biologics (non) teratogenic ?
We don’t know !!
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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
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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.
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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
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If the biologics are continued, will my baby be exposed ?
YES !!
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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.
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At birth, a child has more serum IgG than its mother
maternal IgG
fetal IgG
Malek A et al. Am J Reprod Immunol 1996
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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
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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
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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
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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
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If my baby is exposed to biologics, does that matter ?
We don’t know !!
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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
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• 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
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• 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
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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
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If I stop biologics prior delivery will my disease flare ?
Good chance that it will not
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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
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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)
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Risk of relapse is low when the patient is in a state of « deep
remission »
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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
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More Good news:The patient can be successfully
retreated after stopping
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Stori: What happened to relapsers ?
39/39 negative for ATI
38/43 : remission42/43 : response
STORI
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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
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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