Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss

To investigate efficacy and safety of Hydroxychloroquin in improving pregnancy outcome in women with unexplained recurrent pregnancy loss .

Recurrent pregnancy loss (RPL) remains a significant challenge in obstetrical practice. It is not only emotionally devastating for expectant women but is also medically challenging. Approximately 1-3% of women have recurrent spontaneous abortion, defined as ≥3 pregnancy losses before the age of viability .The European Society of Human Reproduction and Embryology (ESHRE 2021) defined RPL as three or more consecutive losses. The American College of Obstetrics and Gynecology (ACOG 2020) defined RPL as two or more consecutive losses and the American Society for Reproductive Medicine (ASRM 2021) defined RPL as two or more failed pregnancies.

RPL maybe due to uterine anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation/platelet defects . Many of these causes are treatable . However, in about 40%-50% of pregnancy-loss cases, there is no identifiable cause. As such, the term "unexplained recurrent pregnancy loss" (URPL) is the spontaneous loss of three or more consecutive pregnancies without an identifiable risk factor .

Endometrial environment plays a crucial place in embryo implantation and early placental development. In normal pregnancy, the survival of the semi-allogeneic fetus is dependent on the induction of maternal immune tolerance, with decrease regulatory T cells and Th-2 anti-inflammatory profile in peripheral blood and endometrium .

Several reports show a misbalance of immune cells and cytokines expression such as increased Th1 to Th2 cytokine ratio in women with recurrent miscarriage and implantation failure .The excess activation of the proinflammatory pathways may inhibit the proliferation and invasion of the extravillous trophoblast and induce the activation of the immune cells with a direct damage to the trophoblast . So several studies have highlighted the immune deregulation to explain URM , Consequently, it has been hypothesized that immunomodulatory drugs could be a relevant therapy in URM .Among them, various treatments have been recently used, as HCQ . .

Heparin-based drugs are essential in treating thrombosis and embolisms and preventing thromboembolic phenomena. Heparin works primarily by inhibiting thrombin (factor IIa) and factor Xa. Heparin use is associated with the risk of bleeding, osteoporosis and heparin-induced thrombocytopenia so requiring close monitoring .Apart from its antithrombotic effects, heparin has anti-inflammatory effect which consist to prevent the endothelial cells adhesion to the endothelium; heparin can bind selectins and integrins and interfere with complement activation. But these anti-thrombotic treatments have been used for several years to enhance live birth rates in URM, but failed to reach significant efficacy .

Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines , Few in vitro studies showed a potential benefit of hydroxychloroquine in early trophoblastic migration and implantation. Hydroxychloroquine restored trophoblastic fusion and differentiation and restored the annexin A5 expression .

Hydroxychloroquine is widely used during the pregnancy, in particular in patients with systemic lupus erythematous. The main severe adverse effects in mothers include the allergic reactions, potential heart toxicity, and retinopathy. The retinal toxicity mainly concerns treatment duration of more than 5 years and the risk remain low in patients with regular follow-up . Audio-vestibular and ophthalmological studies of children at 12 months of life born from mothers under hydroxychloroquine during pregnancy showed no apparent abnormality and were similar to non-exposed children.

Eligibility Criteria:
Inclusion Criteria:

* Women aged between 18 and 35 years inclusive.
* Women with at least three previous consecutive miscarriages in the first trimester of pregnancy of unknown origin with no uterine cavity abnormality that might explain recurrent miscarriage at 3D ultrasonography
* Women who have given their informed consent.
* Patient who did received standard treatment and failed in an ongoing pregnancy

Exclusion Criteria:

* Previous history VTE (venous thromboembolization)
* Persistent positive APL antibodies: lupus anticoagulant and/or APL (anticardiolipin or anticardiolipin IgG or IgM) titers \>99th percentile or \>40 with at least 12 weeks interval between two positive determinations (persistent antibodies) or a specific clinical setting of APS (thrombotic or obstetrical, apart from RM in the first trimester of pregnancy) .
* Known contraindication to a treatment by HCQ (retinopathy, hypersensitivity to chloroquine or HCQ, G6PD deficiency, acute intermittent porphyria, chronic liver or kidney insufficiency, extensive cutaneous psoriasis not controlled by local treatment, significant chronic digestive or haematologic disease) .
* Indication to a treatment by HCQ (rheumatoid arthritis, Lupus, solar eczema) or previous exposure for \>5years to HCQ.
* BMI \> 35
* Condition may have an effect on immune reaction e.g. history of HCV or HBV .
* Endocrinopathies such as ( DM ,thyroid disorders , hyperprolactinemia ) .
* History of hormonal contraception or intrauterine device usage in last 3 months preceeding .