Prediction of Recurrent Pregnancy Loss by a New Thrombophilia Based Genetic Risk Score (TiC-RPL)

Recurrent pregnancy loss (RPL) is a clinical problem affecting 1-5% of couples of reproductive age. The contribution of thrombophilia to RPL is disputed. This controversy is partly due to low sensitivity of the genetic variants currently used to evaluate hereditary thrombophilia: the Leiden mutation (identified as rs6025) in the coagulation factor 5 (F5L) gene and mutation G20210A (identified as rs1799963) in the prothrombin (PT) gene.

Our objective was to determine whether a wider algorithm that includes clinic and genetic variants associated with thrombophilia could be more useful in the prediction for RPL than FVL and PT alone.

Study Overview

• Status: Completed
• Conditions: Miscarriage, Recurrent

Detailed Description

Recurrent pregnancy loss can affect up to 5% of women in child-bearing age and is considered one of the most common causes of female sterility. In recent years, the association between thrombophilia and pregnancy failure has been observed in a number of studies, varying according to the nature of the thrombophilia (for example the antiphospholipid syndrome as opposed to the hereditary forms) or the type of pregnancy loss (either isolated or recurrent, or early or late). It has therefore been accepted that thrombophilia is detected in a significant number of idiopathic pregnancy losses, reaching 66% of the cases in some series.

Since the 1990's, a number of studies have associated recurrent pregnancy loss with FVL mutations (most frequently) and G20210 PT. In a systematic review, it was confirmed that women with thrombophilia have a higher risk of developing thromboembolism and complications in pregnancy. Another recent meta-analysis of prospective cohort studies concluded that women who were carriers of FVL had a higher risk of late pregnancy loss, at 52%, as opposed to non-carriers (OR=1.52), though the differences in absolute risk were discreet (4.2% and 3.2%, respectively). However, the analysis of these 2 single nucleotide polymorphisms (SNPs) showed low discriminative capacity and diagnostic sensitivity.

This study hypothesize that the use of the Thrombo inCode® in the screening for hereditary thrombophilia in patients with recurrent pregnancy loss can improve the diagnostic sensitivity and predictive capacity of the routine genetic panel, based on FVL and G20210A PT. Thus, the Thrombo inCode® model can accurately identify more patients with clinical-genetic risk of thromboembolism and therefore establish the appropriate preventive measures.

A transversal observational case-control study will be carried out, with retrospective data analysis. The screening for hereditary thrombophilia will be performed through the Thrombo inCode® panel in cases and controls. The results produced from a single genetic analysis will allow comparison to the centres' routine protocol (FV Leiden and G20210A PT) with the complete Thrombo inCode® panel, that also includes the previously-mentioned classical variants.

• Study Type: Observational
• Enrollment (Actual): 364

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Institut d'Investigació Sant Pau
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28029
    • Instituto Salud Carlos III
  • Valencia, Spain, 46015
    • IVI-RMA Valencia
  • Valencia, Spain, 46026
    • Instituto de Investigaciones Sanitarias La Fe
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra
  • Select State
    • Esplugues de Llobregat, Select State, Spain, 08950
      • Gendiag.exe, S.L.
• United Kingdom
  • London, United Kingdom, W1G9RQ
    • IVI-RMA-London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 37 years (Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

The study will include women with recurrent pregnancy loss (> 2 consecutive or > 3 non-consecutive) before the 20th week of pregnancy (cases) and women with at least 1 pregnancy at term (controls).

Description

CONTROLS

Inclusion Criteria:

• Women >18 and < 38 years old at the time of the first pregnancy.
• Women with successful implantation and at least one full-term pregnancy
• No chronic pathology

Exclusion Criteria:

• Personal or family history of thrombosis
• Personal history of obstetric complications Miscarriage or foetal death Pre-eclampsia or eclampsia Intrauterine growth restriction Placental abruption
• Concomitant anticoagulant treatment and/or antiplatelet treatments during pregnancy

CASES

Inclusion Criteria:

• Repeated clinical miscarriages and/or foetal death (≥ 2 consecutive or ≥ 3 non- consecutive) before the 20th weeks of pregnancy, from spontaneous or assisted pregnancies.
• Recurrent miscarriage with the same gametic origin.

Idiopathic origin:

Women < 38 years old Non-severe seminal factor (sperm concentration > 2 mill/ml) Normal karyotypes in both spouses (or in the male and the donor in the case of ovocyte donation) Antiphospholipid syndrome negative Normal or corrected thyroid function BMI < 30

Exclusion Criteria:

• Diabetes
• Chronic pathologies
• Hydrosalpinx
• Concomitant anticoagulant or antiplatelet treatment

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Controls; No intervention
Cases; No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent Pregnancy Loss	Repeated clinical pregnancy loss and/or foetal death (≥ 2 consecutive or ≥ 3 non-consecutive) before the 20th weeks of pregnancy	20 weeks
Pregnancy at term	Pregnancy with life-birth	20 weeks

Collaborators and Investigators

• Sponsor: Ferrer inCode, S.L.
• Collaborators: Instituto Valenciano de Infertilidad, IVI VALENCIA; Instituto de Investigacion Sanitaria La Fe; Clinica Universidad de Navarra, Universidad de Navarra; Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau; Instituto de Salud Carlos III; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; IVI-RMA London; Gendiag.exe, S.L.
• Investigators: Study Director: Eduardo S Salas, MD, PhD, Ferrer inCode, S.L.

Publications and helpful links

General Publications

• Soria JM, Morange PE, Vila J, Souto JC, Moyano M, Tregouet DA, Mateo J, Saut N, Salas E, Elosua R. Multilocus genetic risk scores for venous thromboembolism risk assessment. J Am Heart Assoc. 2014 Oct 23;3(5):e001060. doi: 10.1161/JAHA.114.001060.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: October 23, 2017
• First Submitted That Met QC Criteria: November 3, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): November 8, 2017
• Last Update Submitted That Met QC Criteria: November 3, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Genetic risk score; Thrombophilia screening
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Hematologic Diseases; Pregnancy Complications; Recurrence; Abortion, Spontaneous; Abortion, Habitual; Thrombophilia
• Other Study ID Numbers: FerrerinCode

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No