Elevated IL-6 and IL-22 in Early Pregnancy Are Associated with Worse Disease Course in Women with Inflammatory Bowel Disease

Abstract

Inflammatory bowel diseases (IBD), including Ulcerative Colitis (UC) and Crohn’s disease (CD), are inflammatory conditions of the intestinal tract that affect women in their reproductive years. Pregnancy affects Th1- and Th2-cytokines, but how these changes occur during pregnancy in IBD is unclear. We performed a longitudinal profiling of serum cytokines in a cohort of 11 healthy pregnant women and 76 pregnant women with IBD from the first trimester of pregnancy to the first 12 months post-partum. Participants were monitored for biochemical disease activity (C-reactive protein [CRP] and fecal calprotectin [FCP]) and clinical activities. Maternal cytokines were measured using ELISA. We identified changes in Th1 and Th17 cytokines throughout pregnancy in healthy pregnant women. During pregnancy, maternal serum cytokine expressions were influenced by IBD, disease activity, and medications. Active UC was associated with an elevation in IL-21, whereas active CD was associated with elevated IFN-γ, IL-6, and IL-21. Interestingly, T1 serum cytokine levels of IL-22 (>0.624 pg/mL) and IL-6 (>0.648 pg/mL) were associated with worse IBD disease activity throughout pregnancy in women with UC and CD, respectively. This shows serum cytokines in pregnancy differ by IBD, disease activity, and medications. We show for the first time that T1 IL-22 and IL-6 correlate with IBD disease course throughout pregnancy.

The Effect of In Utero Exposure to Maternal Inflammatory Bowel Disease and Immunomodulators on Infant Immune System Development and Function

“…Whether this decrease in TNF is attributable to IBD itself, or the immunosuppressive medications used to treat it, remains unclear. In individuals receiving biologics, azathioprine, or 5-aminosalycylates, TNF abundance was lower than in those not receiving any medical therapy, 110 but this difference was not observed in a subsequent study. 109 …”

“…In the third trimester of pregnancy in healthy women, TNF increased. 109 , 110 These findings were not appreciable in patients with IBD, who rather exhibited a progressive decrease in TNF. Whether this decrease in TNF is attributable to IBD itself, or the immunosuppressive medications used to treat it, remains unclear.…”

“…Antenatal cytokine profiles of individuals with IBD may differ from those of healthy controls, with current studies overall inconclusive. 109 , 110 Currently, the best data relates to TNF levels. In the third trimester of pregnancy in healthy women, TNF increased.…”

“…IBD flares in pregnancy have been associated with an increase in serum TNF. 110 Excessive circulating TNF was associated with recurrent pregnancy loss, with median TNF abundance derived from trophoblast antigen-stimulated PBMCs in the first trimester shown to be significantly higher in women who experience recurrent miscarriage. 111 A significant difference in median TNF was also observed in pregnancies with intrauterine growth restriction (IUGR) and placental insufficiency, as compared with pregnancies with IUGR without placental insufficiency, and pregnancies without IUGR.…”

“… 113 In IBD-specific studies, elevated TNF in patients with UC was additionally associated with an increased risk of caesarean section, although the indications for this (ie, elective vs emergency) were not provided, and infant birth weight was not impacted. 110 Overall, further studies including preconception serum cytokine analysis, individuals with other inflammatory disorders, and individuals with both active and inactive disease are required to extricate the impacts of immunosuppressive medications from those of an active inflammatory disorder.…”