O-025 A randomised controlled trial on post-warming incubation and transfer with hyaluronic acid and prolactin before single vitrified-warmed blastocyst transfer
Abstract Study question Does combined treatment with hyaluronic acid (HA) and prolactin (PRL) for post-warming cultures and embryo transfer increase live births after single vitrified-warmed blastocyst transfer (SVBT)? Summary answer Combined treatment with HA and PRL significantly increased live births and decreased early pregnancy loss compared with treatment with HA alone or no treatment. What is known already Systematic reviews have shown that the addition of HA to embryo transfer media improves live birth rates. Therefore, addition of HA to transfer media is currently recommended. Human endometrial tissues secrete PRL, which is accompanied by the differentiation of decidual cells during the mid-secretory phase. Human embryos express PRL receptors during the morula and blastocyst stages. Although in vitro experiments have demonstrated that PRL treatment at the blastocyst stage improves trophoblast migration by stimulating epithelial–mesenchymal transition and focal adhesion, the clinical benefits of PRL treatment have not been evaluated. Study design, size, duration This three-arm, double-blind, randomised controlled trial (RCT) was conducted at an in vitro fertilisation centre between October 2020 and May 2021. A total of 1,236 couples undergoing SVBTs in their ovulatory cycles were randomised at a ratio of 1:1:1 into one of three groups using a computer-generated random number sequence. The primary outcome was the live birth rate. Secondary outcomes included pregnancy-, maternal-, and perinatal-related variables. Subgroup analyses of pregnancy outcomes were performed. Participants/materials, setting, methods After removing the zona pellucida of the warmed blastocysts, the blastocysts were incubated in a medium without HA and PRL (control group), an HA-enriched transfer medium (EmbryoGlue; EG group), or EG supplemented with PRL (EGP group) for 2 h prior to transfer in the same medium. All SVBTs were performed using either natural or letrozole cycles. Implantation, clinical pregnancy, ongoing pregnancy, early pregnancy loss, miscarriage, stillbirth, ectopic pregnancy, and multiple pregnancy rates were assessed. Main results and the role of chance The live birth rate in the EGP group (39.1%, 160/409) was higher than that in the control (31.4%, 128/40; adjusted odds ratio [AOR], 1.39; P = 0.0279) and EG (31.7%, 130/410; AOR, 1.41; P = 0.0347) groups. Although implantation and clinical pregnancy rates were comparable among the three groups (P = 0.6049 and P = 0.1225, respectively), the ongoing pregnancy rate in the EGP group (43.5%) was higher than that in the control (35.1%; AOR, 1.41; P = 0.0207) and EG (35.9%; AOR, 1.39; P = 0.0334) groups. Furthermore, the rate of early pregnancy loss was lower in the EGP group (5.3%) than in the control (13.0%; AOR, 0.40; P = 0.0114) and EG (13.3%; AOR, 0.37; P = 0.0061) groups. Miscarriage, stillbirth, ectopic pregnancy, and multiple pregnancy rates were comparable between groups. The incidences of maternal and perinatal complications were comparable between groups. Subgroup analyses demonstrated that EGP treatment was effective for blastocysts derived from young patients, morphologically good blastocysts, and Day 4/5 blastocysts. However, live birth rates did not improve in poor prognosis blastocysts or advanced-age patients, even after EGP treatment. Conversely, EG conferred significant benefits for Day 6/7 blastocyst transfers. Limitations, reasons for caution This RCT was a single-centre study, necessitating further multicentre studies to ascertain the generalisability of our findings to other clinics. Data on maternal and neonatal outcomes were collected using self-reported parental questionnaires, which could be error-prone. Furthermore, follow-up studies of children’s physical and cognitive development are required. Wider implications of the findings This RCT demonstrated the effectiveness of combined HA and PRL treatment in improving live birth rates by reducing early pregnancy loss in a very specific subgroup of patients and blastocysts. Continuous development of methods for enhancing the implantation capacity of poor-prognosis blastocysts is required. Trial registration number Yes
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