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 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 during pregnancy 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 Search for congenital abnormalities. Out of > 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 of maternal Ig Release of 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 agent Zelinkova 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 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

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 9Month 12 IS alone1.1 (0.4,2.6)1.3 (0.6, 2.7)0.9 (0.3, 2.6) Anti-TNF alone0.7 (0.3, 2.1)1.5 (0.7, 2.9)1.4 (0.5, 3.6) Combo1.8 (0.7, 4.5)1.2 (0.5, 3.0)2.5 ( ) 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 year before 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 > /l, hsCRP ≥5 mg/l, faecal calprotectin ≥300 µg/g, CDEIS >0, infliximab trough ≥2 mg/l Proportion without relapse Months since infliximab withdrawal No. of deleterious factors <4 4 5–6 >6 hsCRP< 5mg/l Calprotectin <300  g/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 : remission 42/43 : 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 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

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