Immunology in RPL: Facts and Fiction

Recurrent miscarriage (RM) affects 1-3% of couples during childbearing age and has a major impact on wellbeing and psychosocial status. Gynecologists are faced with both, patients suffering from childnessless as well as patients willing to try every available treatment. Therefore proper diagnosis and risk factor associated treatment options are mandatory.

Beside established risk factors like chromosomal disorders in patients and in the conceptus according to the mothers age, uterine malformations, endocrine dysfunctions, infectious diseases and thrombophilia also immunologic changes like antiphospholipid syndrom (APLS) are known. However, current guidelines do not recommend routine immunologic diagnostics more than antiphospholipid antibodies.

The central role of the maternal immune system for disturbed pregnancies such as recurrent miscarriage (RM) is apparent and our understanding of the complex interaction of the different immunological players and the adaptation of the maternal immune system to the semi-allogeneic embryo increases daily. Furthermore, there is growing evidence for immunological abnormalities in RM patients, including autoimmune and allogeneic factors like the above mentioned APlS, celiac disease, (autoimmune) thyroid disorders as well as changes in uterine and peripheral natural killer cells (uNK, pNK). PNK and uNK can be distinguished according to differences in receptor expression. Some studies indicate an association of elevated pNK and uNK with recurrent miscarriage (RM). We were able to demonstrate that patients with RM without a previous live birth (pRM) showed higher absolute pNK than RM patients with previous live births (sRM). In addition, the rate of highly elevated uNK was increased in RM patients with idiopathic RM as compared to non-iRM patients.

Beside our effort to identify possible immunologic risk factors in patients with RM, the question remains unsolved, whether these changes represent the cause or the consequence of RM.

Treatment strategies like aspirin and low molecular weight heparin (LMWH) are often seen as standard medication in RM, although only a few placebo-controlled trials have proven their benefit in respect to live birth rate whereas many recently published placebo-controlled trials failed to prove any benefit. In addition, treatment options like TNFalpha inhibitors, i.v. IgG and granulocyte colony-stimulating factor (G-CSF) might be beneficial in some cases of RM, larger clinical trials must be completed to further prove or disprove benefits of these drugs in the treatment of RM patients. But also possible new aspects like the high prevalence of Vitamin D (Vit D) deficiency in RM patients must be taken into account. Especially due to the fact that Vit D acts as an immune regulatory effector and plays a major role in the regulation of auto- and cellular immune abnormalities.

We suggest that immunological diagnosis and treatment options should be implemented only in well-designed clinical trials in specialized centers to establish a standardized immunological work-up in RM patients. In addition, further research reports and international guidelines are urgently needed to provide insights into the pathophysiology of pregnancy disrupted by repeated miscarriage.