P-371 The role of pharmacogenetics for individualized adjuvant therapy in patients with recurrent implantation failures
Authors: Fabregat Reolid A.M , Berenguer Alonso P , Lledó Bosch B , Ortiz Salcedo J.A , Bernabéu García A , Bernabéu Pérez R 
Published: June 2022

Abstract

Study question
In women with recurrent implantation failure (RIF), could we improve IVF/ICSI outcomes after administration of appropriate adjuvant therapies depending on patient's genetic profile?.

Summary answer
In RIF patients carrying polymorphisms detected in p53, IL-11 and VEGF genes, the addition of aspirin and intralipids administration appears to be beneficial.

What is known already
RIF is a distressing phenomenon of obscure etiology. Among the putative factors associated with this condition, we have immunological factors (the presence of antiphospholipid antibodies, certain cytokines or NK cells in maternal serum), genetic alterations in the parents or embryos, uterine abnormalities, or the presence of endometritis. Recently, certain genetic polymorphisms in genes involved in embryo implantation mechanisms at the endometrial (p53 and VEGF), immunological (IL-11 and Apo-E) and thrombotic levels (F5, F2 and MTHFR) have been identified.

Study design, size, duration
104 IVF cycles (2017-2021), corresponding to ninety-eight patients, were included in this retrospective study. RIF was defined as the failure of achieving an on-going pregnancy after the transfer of at least three good-quality embryos. Exclusion criteria were abnormal karyotype or sperm FISH, uterine malformations, or positive antiphospholipid antibodies. During the index cycle, these patients received different adjuvant therapies; the following were analyzed: hydroxychloroquine, intrauterine hCG instillation, scratching, intralipids, corticosteroids, aspirin, and low molecular weight heparin.

Participants/materials, setting, methods
To carry out the genetic profile, different SNPs were analyzed in p53  (rs1042522), VEGF (rs1570360), IL-11 (rs11668344), Apo-E (rs429358 and rs7412), F5 (rs6025), F2  (rs199963) and MTHFR  (rs1801133 and rs1801131) genes.Taqman® Life Technologies allelic discrimination real-time-PCR and TRP-PLUS kit were used for the detection of the different alleles. The following IVF outcome variables were considered: positive b-hCG, clinical (gestational sac) and on-going (10 week) pregnancy rate. SPSSv20.0 was used for statistical analysis.

Main results and the role of chance
Polymorphisms associated with a higher risk for RIF were PR and PP genotype for p53 gene, GG for VEGF, GG for IL-11, E4 isoform for Apo-E, GA and AA for F5, GA and AA F2, TT and CC for MTHFR gene. Accordingly, 64% of patients included in our study showed a high-risk genetic profile for RIF. Genotype variants for p53, IL-11 and VEGF were the most prevalent among this population. A multivariate binary logistic regression for possible confounding factors (maternal age, embryo quality, oocyte origin, number of embryos transferred, PGT-A and other adjuvants treatments) showed that those patients with PR/PP genotype for p53, GG for VEGF and GG for IL-11, obtained significantly higher positive b-hCG, clinical and on-going pregnancy rates when aspirin was administered compared to other genotypes (p &lt; 0.05). Furthermore, patients with GG genotype for VEGF, also obtained a significant improvement in positive b-hCG and clinical pregnancy rates after intralipids administration (p &lt; 0.05). None of the other adjuvant treatments employed showed significant differences regardless of the genetic profile.

Limitations, reasons for caution
The inherent limitations of a retrospective analysis of a limited sample size.

Wider implications of the findings
IVF/ICSI outcome of RIF patients was analyzed according to the adjuvant treatment received and considering their genetic profile. Pharmacogenetics seems promising in identifying patients at high risk for RIF and may add in the optimization of specific pharmacotherapy depending on the genetic background of each infertile woman.

Trial registration number
not applicable