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phenotype (P = 0.004), and prior pregnancy complications (P = 0.007), while the
only risk factor associated with newborn complications was having a disease dura-
tion of >10 years (P = 0.007). Prior exposure to anti-TNF therapy during pregnancy
was not found to be a risk factor. Because of the lack of consistent evidence showing
a risk for adverse pregnancy or neonatal outcomes, the use of anti-TNF medications
during pregnancy has been deemed to be low risk in rheumatologic and gastroen-
terological expert recommendations [ 29 , 30 , 53 , 54 ].
Anti-TNF Medications in Combination with Immunomodulators
Following the Study of Biologic and Immunomodulator Naïve Patients in Crohn’s
Disease (SONIC) trial, which showed improved remission rates with combination
anti-TNF and thiopurine medications compared to treatment with either agent
alone [ 55 ], as well as the recommendations for treating to target therapeutic end-
points in IBD, including treating with immunosuppressive therapy for patients
with characteristics of more aggressive disease [ 15 ], more IBD patients are fre-
quently on combination therapy. Several studies have included a cohort of women
receiving anti-TNF medications in combination with thiopurines to compare the
pregnancy and fetal outcomes with women on other treatment regimens. A sub-
analysis of a retrospective, multicenter trial found improved outcomes with com-
bination therapy as evidence by a higher rate of adverse pregnancy and fetal
outcomes, due to a higher rate of preterm delivery, in the anti-TNF monotherapy
cohort compared to the combined anti-TNF and thiopurine cohort (60.9% vs.
39.1%, P = 0.04 and 16% vs. 0%, P = 0.02) [ 45 ]. In the previously mentioned
PIANO registry, data from 2012 presented in abstract form included 1052 women
enrolled with 337 unexposed, 265 on thiopurine monotherapy, 102 on anti-TNF
therapy, and 59 on combination therapy and reported no increase in any complica-
tion associated with the use of anti- TNF medications; however, there was a signifi-
cant increase in fetal infections at 12 months of age in the infants exposed to
combination therapy compared to the infants in the unexposed group (RR 1.50,
1.08–2.09) [ 48 ]. Similarly, a recent prospective study including 80 pregnancies in
women with IBD including 39 women on combination therapy found a greater
than twofold increased risk for any infection in the first year of life for the infants
with in utero exposure to combination therapy compared to those exposed to anti-
TNF monotherapy (RR 2.7, 95% CI 1.09–6.78, P = 0.02) [ 26 ]. All of the noted
infections had a benign course without adverse sequelae.
This possible increased risk of infection in the newborn needs to be weighed
carefully against the need to continue combination therapy in the mother in
order to maintain disease remission. As such, two studies have shown no
increase in short- term relapse rates after transitioning from combination therapy
to anti-TNF monotherapy [ 56 , 57 ]; however, this needs to be completed early in
the preconception stage in order to ensure continued disease remission at the
time of conception [ 30 ].
J.K.J. Gaidos and S.V. Kane