Cytokines in recurrent miscarriage

Cytokines act at all stages of pregnancy from implantation to parturition. This review examines their relevance in recurrent miscarriage. However, recurrent miscarriage may be due to an inherently abnormal embryo (e.g., chromosomal abberations) or maternal factors (e.g., uterine anomalies or antiphospholipid antibodies). In the former, cytokines are not causitive, but may be part of the mechanism of abortion. In the antiphospholipid syndrome, cytokines such as TNFα and IL-6 may be responsible for the associated thrombosis. Hence, an appropriate cytokine milieu could be responsible for whether the antibodies are pathogenic or merely an epiphenomenon. Natural killer cells seem to have a key role in immunosurveillance of the invading trophoblast. However, if activated by TNFα, natural killer cells may induce apoptosis in the trophoblast possibly leading to miscarriage. This action is inhibited by TGFβ. Early ultrasound scanning and embryoscopy have revealed structural anomalies in karyotypically normal embryos which have terminated in first trimester missed abortion. Teratogens such as cyclophosphamide cause fetal demise by excessive apoptosis. Excessive apoptosis may be mediated by TNFα, TGFβ and other cytokines. GM-CSF has been reported to prevent teratogenesis in laboratory animals. Both immunomodulation and hormonal support (progesterone or hCG supplements) have been used to improve the live birth rate in recurrently aborting women. Each may modulate the balance between various cytokines. Although neither hormonal support or immunopotentiation have been proven to be beneficial, the results and the role of cytokines themselves can only be assessed in trials of karyotypically normal embryos.