Clinical trial NCT03336463: Prediction of Recurrent Pregnancy Loss by a New Thrombophilia Based Genetic Risk Score
Official title: Prediction of Recurrent Pregnancy Loss by a New Thrombophilia Based Genetic Risk Score
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Miscarriage, Recurrent
Keywords: Thrombophilia screening
Genetic risk score
Lead sponsor: Ferrer inCode, S.L.
Sponsor class: INDUSTRY
Collaborators: name: Clinica Universidad de Navarra, Universidad de Navarra
name: Instituto de Salud Carlos III
name: Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
name: Instituto Valenciano de Infertilidad, IVI VALENCIA
name: IVI-RMA London
name: Instituto de Investigacion Sanitaria La Fe
name: Gendiag.exe, S.L.
name: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
First posted: 2017-11-08
Enrollment: 364
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 37
Standard ages: ADULT
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
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).

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Recurrent Pregnancy Loss
timeFrame: 20 weeks
measure: Pregnancy at term
timeFrame: 20 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Esplugues de Llobregat
country: Spain
facility: Gendiag.exe, S.L.
state: Select State
city: Barcelona
country: Spain
facility: Institut d'Investigació Sant Pau
city: Madrid
country: Spain
facility: Instituto Salud Carlos III
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Valencia
country: Spain
facility: IVI-RMA Valencia
city: Valencia
country: Spain
facility: Instituto de Investigaciones Sanitarias La Fe
city: London
country: United Kingdom
facility: IVI-RMA-London
Study officials:
affiliation: Ferrer inCode, S.L.
name: Eduardo S Salas, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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.