Defects in protective cytokine profiles in spontaneous miscarriage in the first trimester

Objective

To study differences in cytokine expression profiles between women with ongoing pregnancy and those experiencing spontaneous miscarriage, among women who presented with threatened miscarriage before week 16 of gestation.

Design

Prospective cohort study.

Setting

Academic hospital.

Patient(s)

In this prospective cohort study, 155 pregnant women, comprising normal pregnant women recruited from antenatal clinics (n = 97) and women with threatened miscarriage recruited from an emergency walk-in clinic (n = 58).

Intervention(s)

None.

Main Outcome Measure(s)

Sixty-five serum cytokines quantified using multiplex immunoassay correlated with miscarriage outcomes.

Result(s)

Among women presenting with threatened miscarriage, those who eventually miscarried had significantly lower levels of interleukin (IL)-2, IL-12p70, IL-17A, B-cell–activating factor, B lymphocyte chemoattractant, basic nerve growth factor, interferon-γ, tumor necrosis factor–related apoptosis-inducing ligand, thymic stromal lymphopoietin, and tumor necrosis factor-α and higher levels of vascular endothelial growth factor A, IL-21, and stromal cell–derived factor 1α than those with ongoing pregnancy. Comparisons between normal pregnancies and women with threatened miscarriage who eventually miscarried revealed significant differences across 7 cytokines: B-cell–activating factor; B lymphocyte chemoattractant; basic nerve growth factor; IL-17A; fractalkine/CX3CL1; vascular endothelial growth factor A; and CCL22. Vascular endothelial growth factor A exhibited a negative correlation with the progesterone level (r = −0.270). The cluster of significant cytokines alludes to T cell proliferation, B-cell proliferation, natural killer cell–mediated cytotoxicity, and apoptosis as important pathways that determine pregnancy outcomes. Bioinformatic analysis further revealed alteration of the suppressor of cytokine signaling proteins family of Janus kinase-signal transducer and activator of transcription signaling axis by cytokines as a plausible key molecular mechanism in spontaneous miscarriage.

Conclusion(s)

This study demonstrates that the regulated balance between the proinflammatory and anti-inflammatory pathways is crucial to maintaining pregnancy. A better understanding of the cytokines associated with immunomodulatory effects may lead to novel targets for the prediction and treatment of spontaneous miscarriage.