Prevalence of Inherited and Acquired Thrombophilia in Females Post Multiple Assisted Reproductive Technology (ART) Attempts
Authors: Rafei Hind , Eissa Hisham , Amin Sherif , Ramzy Amira , Mobarek Dalia 
Published: October 2019

Abstract
Introduction: A link between thrombophilia and female infertility has been previously reported and the role of thrombophilia in multiple ART failures has been debated. Most meta-analyses of existing studies yield inconclusive and contradictory results that no antithrombotic therapy could, to-date, be indicated in thrombophilia patients with ART failure(s) without clinical thrombosis. As analysis of a large cohort is therefore warranted, we embarked on this study to identify the true prevalence of thrombophilia in a large number of women who presented for infertility and recurrent ART failures evaluation to detect the true prevalence of thrombophilia.
Methods: This is an IRB-approved retrospective cohort analysis of Egyptian women with 3 or more ART attempts referred to our center NSA-Diagnostic Laboratories from 1/1/2009 to 1/1/2015. Females with known venous thromboembolism (VTE) prior to infertility evaluation were excluded. Aspirin use and results of thrombophilia testing were collected on all patients. Thrombophilia testing included Factor V Leiden mutation (FVL), prothrombin gene mutation, Plasminogen Activator Inhibitor-1 (PAI-1), Factor XIII level, b-Fib, HPA, ACE, ApoB, ApoE, anticardiolipin IgG and IgM (ACLG, ACLM respectively), Protein C deficiency, Protein S deficiency, antithrombin (AT), lupus anticoagulant (LA), CD16, CD56, methylenetetrahydrofolate reductase (MTHFR) A or C, and homocysteine level. Thrombophilia was categorized into simple and complex reflecting 1 and >1 homozygous mutations detected, respectively. Demographic characteristics and the prevalence of the different mutations were analyzed. Statistical analysis was performed using SPSS software version 20.0.
Results: Inclusion criteria and all data were available in 2585 female subjects. Age range was 21-43. While all subjects had at least one or more mutation(s) of any kind, 305 subjects (11.8%) did not have any homozygous mutations. Simple thrombophilia (one homozygous mutation) was found in 894 patients (34.6%). Complex thrombophilia (more than one homozygous mutation) with 2, 3, 4, and 5 concomitant abnormalities was encountered: in 35.8%, 13.5%, 3.9% and 0.4%, respectively. Prevalence of homozygous and heterozygous mutations was as follows: FVL (2.9%; 21.9%), prothrombin gene mutation (0.1%; 4.0%), PAI (17.4%; 67.5%), factor XIII (1.2%; 23.7%), b-Fib (39.2%; 2.7%), HPA (10%; 30%), ACE (49.6%; 49.2%), ApoB (0.1%; 0%), ApoE (62.7%; 21.3%). ACLG was positive in 1.2%, ACLM in 3.6%, Protein C deficiency in 0.4%, Protein S deficiency in 0.2%, AT in 1.0%, LA in 1.8%, CD16 in 0.1%, CD56 in 1.1% and hyperhomocysteinemia in 0.7%. Heterozygous and homozygous MTHFR A (45.1%; 9.8%), MTHFR C (35.3%; 7.7%) mutations were noted. When compared to historical controls in the literature, similar prevalence was found for Protein C/S deficiencies, higher prevalence for FVL and Prothrombin gene mutation, and a lower prevalence for hyperhomocysteinemia in our cohort. No VTE was reported in subjects from the time of testing until data collection and follow up. Prophylactic anticoagulation with low molecular weight heparin and low dose aspirin in subjects were noted. All subjects with successful pregnancies post identification of thrombophilia were prescribed prophylactic anticoagulation with low molecular weight heparin through pregnancy and for 6 weeks postpartum. Low dose aspirin and first trimester steroids were also used. Analysis of full term pregnancy as an outcome is underway.
Discussion: Thrombophilia prevalence in infertile Egyptian women presenting to our center with multiple failed ART attempts is higher for certain mutations than reported in the literature. Our cohort is unique in that women did not have a history of clinically evident VTE and had a higher prevalence of complex homozygous mutations. Our study has implications on the evaluation of female patients with infertility and helps set up the stage for future prospective and interventional trials using antithrombotic therapy.

Disclosures
No relevant conflicts of interest to declare.