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Stop biologics prior to delivery !

Stop biologics prior to delivery !. M Nachury CHU Lille, France JF Colombel Mount 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.

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Stop biologics prior to delivery !

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  1. Stop biologics prior to delivery ! M Nachury CHU Lille, France JF Colombel Mount Sinai School of Medicine, New York, USA

  2. Are biologics (non) teratogenic ? We don’t know !!

  3. 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

  4. Effects of teratogens may occur many years after the prenatal exposure Forty years ago, in 1971, Herbst et al. reported a new association between maternal diethylstilbestrol use during pregnancy and occurrence of adenocarcinoma of the vagina in their daughters 15 to 20 years later in the New England Journal of Medicine. Herbst AL et al. N Engl J Med 1971

  5. 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

  6. If the biologics are continued, will my baby be exposed ? YES !!

  7. Increase of fetal serum IgG concentration during pregnancy Serum IgG is detectable in the foetus as early as 13 weeks of gestation, and its concentration increases steadily until birth. Malek A et al. Am J Reprod Immunol 1996

  8. At birth, a child has more serum IgG than its mother maternal IgG fetal IgG Malek A et al. Am J Reprod Immunol 1996

  9. IgG transcytosis by FcRn in the syncitiotrophoblast Binding of maternal Ig transcytosis FcRn Release of maternal Ig Recycling of anti-TNfs through FcRn protects them from catabolism

  10. 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

  11. Stopping IFX therapy at gestational week 30 is not enough Discontinuation of Adalimumab in the second trimester does not prevent neonatal exposure to this agent Zelinkova Z et al. UEGW 2012 Zelinkova Z et al. Aliment Pharmacol Ther 2011

  12. 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

  13. If my baby is exposed to biologics, does that matter ? We don’t know !!

  14. TNFa is involved in mouse growth and lymphoid tissue development Injection of anti-TNFa in pregnant mice - Severe but transient growth retardation (± 35%). - Normal growth hormone blood levels. - Decrease of IGF-1 blood levels (± 50%). - Marked atrophy of thymus, spleen and lymph nodes. De Kossodo S et al. J Exp Med 1992

  15. The wake-up call • 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. Cheent K et al. J Crohns Colitis 2012

  16. And more… • 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 Zelinkova Z et al. UEGW 2012

  17. Infections in Piano Mahadevan U et al. DDW 2012

  18. If I stop biologics prior delivery will my disease flare ? Good chance that it will not

  19. CD activity may be lower during pregnancy 70 pregnancies in 61 patients with CD Non smokers Total Smokers HBI was significantly lower during pregnancy than the year before or after Agret F et al. Aliment Pharmacol Ther 2005

  20. IBD activity may be lower during and after pregnancy Prospective study of 177 pregnancies in women with IBD (109 UC 68 CD) Riis et al. Am J Gastro 2006

  21. Risk of relapse is low when the patient is in a state of « deep remission »

  22. Risk of relapse after IFW withdrawal in patients on combo therapy (Stori) hsCRP< 5mg/l Calprotectin <300mg/g Kaplan Meier time-to-relapse curves according to multivariate models including deleterious factors* No. of deleterious factors <4 4 Proportionwithout relapse 1.0 5–6 0.8 >6 0.6 0.4 Months since infliximab withdrawal 0.2 * 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 6 12 18 24 30 Louis E et al. Gastroenterology 2012

  23. More Good news:The patient can be successfully retreated after stopping

  24. Stori: What happened to relapsers ? STORI 39/39 negative for ATI 38/43 : remission 42/43 : response

  25. 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 pregnancy allows interruption of treatment, intra-uterine and postnatal exposure of newborns to IFX should be avoided by stopping IFX at the beginning of the second trimester

  26. 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

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