P–401 Frozen-thawed embryo-transfer adjuvant therapy: one size DOES NOT fit all
Authors: Riviello E , Riva A , Bottai A , Buzzaccarini G , Marin L , Noventa M , Dell. Vella E , Coronella M L , Ambrosini G , Andrisani A 
Published: August 2021

Abstract

Study question
Does adjuvant therapy after frozen-thawed embryo-transfer (FRET) with CardioAspirin and Prednisone enhance clinical pregnancy rate (CPR) and live birth rate (LBR)?

Summary answer
Adjuvant therapy enhanced CPR and LBR in study-group. A significant correlation was found confronting blastocyst FRET in study-group versus controls.

What is known already
Embryo implantation is a rate-limiting step of FRET cycles. It’s a complex process resulting from a balance between inflammation pathways and maternal immune tolerance. Low-dose aspirin unlocks Prostaglandin-F2 synthesis by Cyclooxygenase–1, thus increasing uterine vascular permeability and attachment reaction while reducing vasoconstriction. Pregnancy results from a balance between helper and regulatory T-cells (Treg), the latter protect the embryo from maternal immune attack. Treg cells’ immunosuppressive function is pivotal in pregnancy establishment. Prednisone increases the proportion of Treg cells thus inhibiting inflammation. Many therapy schedules for implantation enhancement are currently used worldwide, although there is no consistent shared evidence.

Study design, size, duration
Retrospective cohort-control study including 237 subjects who underwent FRET after artificial endometrial-preparation from January 2018 to March 2020. Estrogenic stimulation was either oral or transdermic. The study-group received luteal support (vaginal Progesterone 600 mg/die) and adjuvant therapy (CardioAspirin and Prednisone 25–5 mg); the control-group received luteal support only. Pregnancy test (PT) was scheduled 10–14 days post-transfer (blastocysts or cleavage stage embryos). Second PT and ultrasound were performed 7 days later if the first was positive.

Participants/materials, setting, methods
Patients referred to Padua University Hospital’s Human Reproduction Pathophysiology Unit. Exclusion criteria: &gt;50/&lt;18 years, fresh embryo-transfer cycles, oocyte-thawing cycles, natural/natural-modified cycles. Male factor was the prevalent fertility issue. Single embryo-transfer was performed in both groups. Mean endometrial thickness was 9 mm trilaminar in both groups. Statistical analysis were carried out using JMP Pro 14 software. Categorical variables were analyzed using Chi-square test or Fisher’s exact test where appropriate.

Main results and the role of chance
In the study-group, 87 subjects were given luteal support and adjuvant therapy, while in the control-group, 150 subjects received luteal support only. Groups were homogeneous for age, number of embryos transferred, endometrial thickness, endometrial features (trilaminarity) and fertilization tecniques (108 IVF/ 127 ICSI). CPR and LBR were significantly higher in the study-group. CPR was 31.4% in study-group versus 14.8% in controls (p = 0.002), LBR was 27.4% in study-group versus 11.6% in controls (p = 0.002). Since heterogeneity between groups was found regarding the type of embryo transferred (55.3% cleavage-stage versus 44.7% blastocyst, p &lt; 0.01), the groups were split analyzed basing upon the type if embryo transferred. In the cleavage-stage FRET condition no relevant correlation was found between groups. However in blastocyst-FRET group CPR (34.5% study-group versus 18% controls, p = 0.04) and LBR (30.9% study-group versus 12% controls, p = 0.017) were significantly higher in the study-group, thus showing that adjuvant therapy could improve CPR and LBR.

Limitations, reasons for caution
Limited sample size negatively impacts the study’s power. It would be appropriate to expand the sample to obtain more reliable results.
Wider implications of the findings: Although no unanimous consent exists for tout-court adjuvant therapy administration, scientific literature shows that such therapy can help patients with repeated implantation failures or anti-nuclear-antibodies positivity. Assuming that a single-therapy-regimen could perfectly fit all patients is not realistic. We have to move towards patient-tailored adjuvant therapy thinking.

Trial registration number
Not applicable