Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss

February 9, 2022 updated by: Ain Shams University

Hydroxychloroquine in Unexplained Recurrent Pregnancy Loss ,Double Blinded Randomized Controlled Trial .

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

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

70

Phase

  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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 .

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Group A (control group)

35 women in this group will receive only the standard treatment in the form of :

  • low- dose aspirin (LDA) 81 mg/day orally (Jusprin® 81mg which manufactured by Future Pharmaceutical Company),
  • LMWH (Enoxaparin, Clexane® which manufactured by SANOFI company) with a dose ( .5 mg/kg) subcutaneously injected/24 hr .

LDA ought to be begun before origination, while LMWH ought to be begun after confirmation of pregnancy by detecting fetal viability by ultrasound till age of viability (20wks)

-PLUS Placebo specially manufactured tablets in Ain shams faculty of pharmacy will start once known she is pregnan
Drug: Hydroxychloroquine
Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines ( Mekinian A et al ,2015 ) , 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.( Guller S et al ,2011 )
Other Names:
  • placebo - Aspirin (LDA) - Clexan (LMWH)
Experimental: Group B ( Hydroxychloroquine group )
This group included 35 women who will administered Hydroxychloroquine 200 mg (Hydroquine® 200mg which fabricated by MinaPharm Company) one tablets / day once known she is pregnant in addition to the standard therapy (LMWH + LDA )
Drug: Hydroxychloroquine
Besides anti-thrombotic effects, hydroxychloroquine have immunoregulatory properties and can block the production of pro-inflammatory cytokines ( Mekinian A et al ,2015 ) , 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.( Guller S et al ,2011 )
Other Names:
  • placebo - Aspirin (LDA) - Clexan (LMWH)
No Intervention: Study Director
Only those directing the study know the treatment that each participant receives Placebo OR Hydroxychloroquin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To investigate HCQ as a new edition in URPL protocol in change rate of pregnancy loss side by side with anticoagulant traditional treatment
Time Frame: one year to be completed
Describing 200 mg of HCQ daily in unexplained recurrent pregnancy loss start once she makes sure of pregnancy till 20 weeks of pregnancy
one year to be completed

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ain Shams University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

March 1, 2022

Primary Completion (Anticipated)

November 1, 2022

Study Completion (Anticipated)

January 1, 2023

Study Registration Dates

First Submitted

November 23, 2021

First Submitted That Met QC Criteria

February 9, 2022

First Posted (Actual)

February 14, 2022

Study Record Updates

Last Update Posted (Actual)

February 14, 2022

Last Update Submitted That Met QC Criteria

February 9, 2022

Last Verified

November 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HCQ in URPL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Data obtained through this study may be provided to new guide for recurrent pregnancy lss. Data or samples shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party

IPD Sharing Time Frame

Basline

IPD Sharing Access Criteria

Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact: yasmineabdoud@gmail.com

IPD Sharing Supporting Information Type

  • Study Protocol
  • Clinical Study Report (CSR)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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