87Several studies have found an increased risk for SA following anti-TNF expo-
sure during pregnancy. Using the British Society for Rheumatology Biologics
Register (BSRBR) to determine outcomes of 130 pregnancies in RA patients
exposed to anti-TNF medications (including exposure to IFX, ADA, and etaner-
cept) prior to or during pregnancy, the authors found a slightly, but not signifi-
cantly, increased rate of SA in those exposed to anti-TNF medications at the time
of conception; however, this rate was most pronounced in the cohort on concomi-
tant methotrexate (MTX) or leflunomide (LEF) (33%) compared to the group
exposed to anti-TNF without MTX or LEF (24%), to those exposed to anti-TNF
medications prior to conception (17%), and to those in the TNF-naïve group (10%)
[ 49 ]. Another retrospective database study including 86 pregnancies in women
with autoimmune diseases who were counseled by the Israeli Teratology
Information Service regarding exposure to anti-TNF medications (35 IFX, 25 etan-
ercept, 23 ADA), 97.6% exposed only in the first trimester, found an increased rate
of SA in the TNF-exposed group (10.8%) compared to the rate in a group of women
who were not exposed to potentially teratogenic agents (2.9%), but not signifi-
cantly increased compared to pregnancies in a disease-matched cohort (5.8%) [ 50 ].
Similarly, a recent study of pregnancy outcomes of women with IBD in Japan
included 24 pregnancies with exposure to anti-TNF agents (23 IFX, 1 ADA), 7
pregnancies in women with thiopurine monotherapy, 10 pregnancies in women
treated with combined IFX and thiopurines, and 31 pregnancies in nonexposed
women and also found an increased rate of SA in the TNF-exposed groups (mono-
therapy and combination therapy groups) compared to the other non-TNF-exposed
groups (17.7% vs. 0%, P = 0.009) [ 51 ]. In all three of these studies, there were no
differences between the groups in fetal outcomes.
A prospective observational cohort study comparing adverse events reported to
the European Network of Teratology Information Services (ENTIS) in 495 preg-
nancies in women with autoimmune diseases exposed to anti-TNF medications
(including IFX, ADA, CZP, GOL, and ETA) in the first trimester to outcomes of
1532 pregnancies in women not exposed to anti-TNF agents but who had con-
tacted ENTIS for other non-medication-related concerns found no increased risk
of SA or stillbirth with TNF exposure but, however, did find a higher incidence of
preterm birth (ORadj 1.69, 95% CI 1.1–2.5) [ 52 ]. In addition, the study found an
increased risk of major birth defects in the TNF-exposed cohort compared to the
nonexposed cohort (5.0 % vs. 1.5%, adjusted odds ratio [ORadj] 2.20, 95% CI
1.01–4.8); however, there was no distinct pattern of birth defects to suggest a
drug-related effect.
With respect to risk factors associated with adverse pregnancy and neonatal out-
comes, a retrospective study including 124 IBD patients with 133 pregnancies fol-
lowed in Groupe d’Etude Thérapeutique des Affections due Tube Digestif (GETAID)
centers with exposure to anti-TNF medications during pregnancy or less than
3 months prior to pregnancy showed no difference in the pregnancy or neonatal
outcomes compared to a control group [ 46 ]. However, on multivariate analysis, the
risk factors associated with adverse pregnancy outcomes included current smoking
(P = 0.004), occurrence of a flare during pregnancy (P = 0.006), a stenotic Crohn’s
6 Biologics in Pregnancy and Breastfeeding