P–706 Impaired fibrinolysis during estrogen substitution in relation to frozen-thawed embryo transfer
Authors: Dalsgaard T , Vestergaar. Jensen M , Rau. Frahm M , Stille. Kirkegaard K , Hvas A M , Bret. Knudsen U 
Published: August 2021

Abstract

Study question
Is the clot lysis time prolonged in women undergoing estrogen substitution in artificial cycle during frozen-thawed embryo transfer (AC-FET)?

Summary answer
Women receiving AC-FET have a prolonged clot lysis time that could result in increased venous thromboembolic risk during estrogen substitution.

What is known already
High doses of estrogen are used for women treated with AC-FET; this in contrast to women treated with natural cycle frozen-thawed embryo transfer (NC-FET). Based on previous research on hormone replacement therapy in other settings, estrogen substitution is probably associated with an increased risk of thromboembolism. Moreover, it has formerly been shown that pregnant women followed assisted reproductive technology (ART) treatment as compared to natural fertilization, has an increased risk of thrombosis. However, changes in fibrinolysis has never been examined in women undergoing estrogen substitution during treatment with AC-FET.

Study design, size, duration
Prospective cohort study of women receiving AC-FET with oestrogen/progesterone substitution or NC-FET. Blood samples were obtained four times: 1) prior to hormone substitution (baseline), 2) confirmation of biochemical pregnancy, 3) gestational week 8 and 4) gestational week 13 (5 weeks after cessation of hormone substitution). Inclusion criteria: women aged &gt; 18 years assigned for FET. Exclusion criteria: egg donor recipients, known bleeding disorders, indication for thromboprophylaxis and treatment with anti-platelet medication or non-steroid-anti-inflammatory drugs.

Participants/materials, setting, methods
We included women at the Department of Obstetrics and Gynaecology, Horsens Fertility Clinic, Denmark, from August 2019 – November 2020. In total, 34 participants were included: 19 women treated with AC-FET and 15 women receiving NC-FET. We examined fibrinolysis measured by a dynamic fibrin clot lysis assay that can assess the capacity for fibrin formation and fibrinolysis. This detailed information of the fibrinolytic activity are used as a surrogat marker of thromboembolic risk.

Main results and the role of chance
Our results showed a significantly longer lysis time (908 ± 234 vs 1157 ± 218) (p &lt; 0.001) within the AC-FET group after hormone substitution compared to baseline. Moreover, we found a higher area under the curve (AUC) (919 ± 305 vs 1167 ± 391) (p = 0.006) within the AC-FET group. However, we observed no changes in mean lag phase or maximum absorbency after estrogen substitution within the AC-FET group. Since we observed a significantly higher AUC within the AC-FET group after estrogen substitution, this is probably due to the prolonged lysis time, indicating hypofibrinolysis. No significant changes was found comparing the NC-FET group with the AC-FET group.

Limitations, reasons for caution
Our data are based on a small study population. Additionally, we cannot exclude that the coagulation parameters could be affected by estrogen prior to study enrollment as we had no wash out period.
Wider implications of the findings: Our findings indicate prothrombotic changes in the AC-FET group. It is relevant to individually consider the indication for AC-FET and restrict the use of unnecessary hormone exposure. These data should be followed by a populations-based study to clarify how this potentially increased venous thromboembolic risk will manifest itself clinically.

Trial registration number
NCT04359576