Transcript Diapositive 1

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
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
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)
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–
–
–
–
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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
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
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
Binding of
maternal Ig
transcytosis
FcRn
Release
of maternal Ig
Recycling of anti-TNfs through FcRn protects them from catabolism
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
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
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 !!
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
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
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
Infections in Piano
Month 4
Month 9
Month 12
RR (CI)
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
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
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
Risk of relapse is low when the
patient is in a state of « deep
remission »
Risk of relapse after IFW withdrawal in
patients on combo therapy (Stori)
Kaplan Meier time-to-relapse curves according to multivariate models including
deleterious factors*
No. of deleterious factors
Proportion
without relapse
1.0
<4
0.8
4
0.6
hsCRP< 5mg/l
Calprotectin <300mg/g
0.4
0.2
5–6
0.0
>6
0
6
12
18
24
30
Months since infliximab withdrawal
* 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
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