Hydroxychloroquine for Prevention of Recurrent Miscarriage.

Regarding the mechanisms of unexplained RM, on the basis of animal models and clinical studies, many hypotheses were raised:

• Reduced ovarian reserve,

• Progesterone defect: a double-blind trial did not show any benefit of progesterone therapy.

• Thrombotic mechanisms and/or endothelial dysfunction: An association with some inherited thrombophilias was suggested. A prothrombotic state outside of pregnancy was measured in women with previous RM and without known thrombophilia.

• Immunological disturbances (high titers of anti-thyroid or APL antibodies, maternal carriage of specific HLA alleles and immunological reactions against male-specific minor antigens, increased numbers of peripheral blood natural killer, overexpression of TOLL receptors, increase of TH1 and TH17 processes). Consequently, immunomodulatory treatments were proposed and assessed (no impact of intravenous immunoglobulins and no conclusive benefit of corticosteroids).

• Miscellaneous: BMI> 30 and chronic endometritis. Besides, the experience gained from previous clinical trials in RM leads us to emphasize, that subcutaneous administration of heparin limits its assessment among fertile women. Indeed, the treatment could not be administrated before conception and consequently the exposure was often too short (injections cannot be routinely initiated before 5 weeks).

Except psychological support, there is no treatment whose benefit has been proved in unexplained RM, in the presence or in the absence of an inherited thrombophilia. Moreover the absence of benefit of some treatments has been clearly demonstrated. Although the prognostic is not so poor (live-birth rates around 70%), proposed therapeutic interventions are sometimes excessive (regarding possible side effects and cost): as intravenous immunoglobulins, assisted procreation ...anti-TNF.

Consequently, for the management of these distressed patients, investigating other therapeutic options is highly needed.

Regarding recurrent miscarriage in women with high titers of antiphospholipid but without any other previous clinical event listed in the antiphospholipid syndrome, the benefit of antithrombotic treatment remains controversial (negative results of the HepASA trial) and hydroxychloroquine has never been assessed, although retrospective studies are encouraging.