I would like to thank the authors for their comprehensive and thorough review. Recurrent miscarriages with unknown aetiology always pose a big challenge to clinicians. I would like to point out that you have failed to include adenomyosis/endometriosis as a potential cause of recurrent miscarriages. I do appreciate the fact that some of these potential causes cannot be classified as known or unknown due to the lack of quality evidence.
There are insufficient evidence to suggest any direct association between endometriosis and recurrent miscarriages. However, there is new evidence emerging in the literature indicating a link.
- Recurrent implantation failure after assisted reproduction. This can possibly be explained by alterations in humoral and cell-mediated immunity in women with endometriosis.
- The autoimmune nature of endometriosis can affect egg quality by elevating the intra-abdominal levels of inflammatory cytokines that the ovaries are directly exposed to. This causes a condition known as oxidative stress and raises the level of a ‘toxic’ chemical called ROS (reactive oxygen species) that the eggs are exposed to. This can be treated to improve egg quality.
- Patients with lesions of endometriosis stages I–II had more autoantibodies than those with stages III–IV, and may be immunologically more active. This result may be significant for future treatments such as in vitro fertilisation and embryo transfer.
- The presence of either diffuse or ‘adenomyoma’ type of adenomyosis was associated with a marked increase in the density of macrophages and natural killer cells in the endometrial stroma, compared to those women with mild focal adenomyosis or no disease. These findings point to an immunological mechanism by which adenomyosis might interfere with successful embryo implantation.
However, prospective randomised controlled studies evaluating the effect of surgical treatment of endometriosis on fertility parameters have not shown a reduction in spontaneous abortion rates after endometriosis treatment.