Hydroxychloroquine for Prevention of Recurrent Miscarriage.
- Conditions
- Recurrent MiscarriageFirst Trimester Abortion
- Interventions
- Drug: Placebo
- Registration Number
- NCT03165136
- Lead Sponsor
- University Hospital, Brest
- Brief Summary
Recurrent miscarriage (RM) defined by \>=3 consecutive losses affects 1% of fertile couples. Most women have recurrent early loss with a failure of development before 10 weeks' gestation. Standard investigations fail to reveal any apparent cause in \>50% of couples.
No study has demonstrated any benefit of any medication in women with Unexplained RM, in the presence or absence of an inherited thrombophilia.
Moreover, the benefit of aspirin and/or heparin has not been proved in women with Antiphospholipid (APL) antibody without other clinical manifestations of Antiphospholipid Syndrome.
Hydroxychloroquine (HQ) is a molecule whose properties (anti-thrombotic, vascular-protective, immunomodulatory, improved glucose tolerance, lipid-lowering, anti-infectious) could be useful against mechanisms of Unexplained RM.
There is no data concerning the benefit of HQ in RM in the presence or absence of antiphospholipid antibodies or any inherited thrombophilia.
Administration in (Systemic Lupus erythematosus (SLE) women and for Malaria prevention provides extensive safety data during pregnancy.
Oral administration makes possible treatment since the preconception period. For all of that and its low cost, hydroxychloroquine should be evaluated in RM whatever the woman thrombophilic status.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 300
- women aged from 18 to 38 years,
- women trying to conceive,
- women with at least 3 previous consecutive miscarriage in the first pregnancy trimester, of unknown origin (normal parental karyotypes, no uterine cavity abnormality, no antiphospholipid syndrome with other clinical events than RM in the first trimester of pregnancy.)
- women who have given their informed consent
- ongoing pregnancy,
- Normal pregnancy since the last miscarriage,
- Uterine cavity abnormality,
- Abnormal parental karyotype,
- Antiphospholipid syndrome defined as both persistent positive antiphospholipid antibodies (40 IU or more of anticardiolipin or anti beta2 GPI IgG or IgM, and/or lupus anticoagulant) and a specific clinical setting (thrombotic or obstetrical, apart from RM)
- women with a contraindication or an indication to a treatment by hydroxychloroquine
- Previous exposure > 4 years to chloroquine or hydroxychloroquine
- impossible follow up
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo A similar placebo will be orally administrated every day. Hydroxychloroquine Hydroxychloroquine The treatment will be orally administrated, at a daily dose of 400 mg of hydroxychloroquine . The treatment will be started before conception and will be stopped at the end of the tenth week of gestation or before in case of pregnancy loss.
- Primary Outcome Measures
Name Time Method A live and viable birth At delivery In case of preterm and/or low birth weight, we define the viability by the decision to transfer the newborn to a neonatal intensive care unit
- Secondary Outcome Measures
Name Time Method gestation time (in weeks of amenorrhea) at delivery, At delivery up birth weight (in grams) at delivery At delivery survival of the newborn At 28 days of the newborn psychomotor development of the child (normal/abnormal) at 12 months of age height (in centimeters) at 12 months of age weight (in grams) at 12 months of age Cranial perimeter (in centimeters) at 12 months of age a live and viable birth (for the subgroup analyses) At delivery occurrence of pregnancy complications (Recurrent Miscarriage-any other premature termination of pregnancy-placental vascular disease) Since the beginning of pregnancy up to delivery
Trial Locations
- Locations (18)
Hôpital Bichat
🇫🇷Paris, France
CHU Estaing
🇫🇷Clermont-Ferrand, France
Hopital Saint Antoine
🇫🇷Paris, France
CHU Besançon
🇫🇷Besançon, France
Centre Hospitalier Annecy Genevois
🇫🇷Annecy, France
Hopital Port Royal Cochin
🇫🇷Paris 14, France
Hôpital sud de Rennes
🇫🇷Rennes, France
CH d'Auch
🇫🇷Auch, France
CHU de Saint Etienne - Hôpital Nord
🇫🇷Saint Etienne, France
CHRU de Lille
🇫🇷Lille, France
Hôpital Nord - Unité mère-enfant
🇫🇷Marseille, France
CH de Mont de Marsan
🇫🇷Mont-de-Marsan, France
CH de Bigorre
🇫🇷Tarbes, France
CHU de Nantes
🇫🇷Nantes, France
Nouvel Hôpital Civil
🇫🇷Strasbourg, France
CHRU de Brest
🇫🇷Brest, France
Centre hospitalier de Cornouaille
🇫🇷Quimper, France
CHG François Mitterand
🇫🇷Pau, France