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Intrauterine Administration of Human Chorionic Gonadotropin Improves

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Intrauterine Administration of Human Chorionic Gonadotropin Improves Archives of Gynecology and Obstetrics (2019) 299:1165–1172 https://doi.org/10.1007/s00404-019-05047-6 GYNECOLOGIC ENDOCRINOLOGY AND REPRODUCTIVE MEDICINE Intrauterine administration of human chorionic gonadotropin improves the live birth rates of patients with repeated implantation failure in frozen‑thawed blastocyst transfer cycles by increasing the percentage of peripheral regulatory T cells Xuemei Liu1 · Ding Ma1 · Wenjuan Wang1 · Qinglan Qu1 · Ning Zhang1 · Xinrong Wang1 · Jianye Fang1 · Zhi Ma1 · Cuifang Hao1 Received: 8 August 2018 / Accepted: 5 January 2019 / Published online: 19 January 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Introduction Repeated implantation failure (RIF) frustrates both patients and their clinicians. Our aim was to observe the efects of intrauterine administration of human chorionic gonadotropin (hCG) on pregnancy outcomes of patients who received frozen-thawed embryo transfer (FET). Methods A prospective cohort study was conducted to evaluate the impact of intrauterine administration of hCG on preg- nancy outcomes in FET cycles of patients with RIF from January 1st 2016 to December 31st 2016. The treatment group (n = 153, 152 cycles) received an infusion of 500 IU of hCG diluted in normal saline 3 days before embryo transfer. The control group (n = 152, 151 cycles) received embryo transfer with a previous intrauterine injection of normal saline without hCG. Early morning fasting blood samples were obtained from each patient for the measurement of peripheral regulatory T cells (Tregs) on the day of embryo transfer. The outcome parameters including Tregs in each group were compared. Results The patients in the hCG-treated group had signifcantly higher clinical pregnancy rates, implantation rates and live birth rates than the controls (37.5% versus 25.17%, 29.19% versus 19.4%, 26.97% versus 17.22%, respectively). They also had signifcantly higher percentages of peripheral Tregs than the controls (6.1 ± 0.6% versus 5.4 ± 1.0%). In addition, the clinical pregnancy rate, implantation rate and live birth rate in patients who received blastocyst transfer were signifcantly higher in the hCG-treated group when compared to the control group (41.38% versus 26.44%, 42.22% versus 26.14%, 33.33% versus 17.24%, respectively). We also showed that the clinical pregnancy rate, implantation rate and live birth rate were signifcantly higher in hCG-treated group when compared to the control group (49.12% versus 28.07%, 49.15% versus 28.07%, 40.35% versus 17.54%, respectively) of RIF patients with blastocyst transfer under 35 years, while there was on diference in patients above 35 years. Conclusions Intrauterine administration of hCG signifcantly improves the clinical pregnancy rate, implantation rate and live birth rate in FET cycles of patients with RIF by increasing Tregs. The treatment improves the pregnancy outcomes much more for younger RIF patients transferred blastocysts. Keywords Human chorionic gonadotropin · Tregs · Embryo transfer · Live birth rate Introduction Successful implantation is a complex process involving Xuemei Liu and Ding Ma contributed equally to this work. the receptive endometrium and a high quality embryo. * Any problem stemming from these two main players can Xuemei Liu adversely afect the cross-talk between the embryo and [email protected] the endometrium, which can result in implantation failure. 1 Reproductive Medicine Center, Yantai Yuhuangding When transferred embryos of good quality fail to implant Hospital, Afliated Hospital of Qingdao University, 20 after several in vitro fertilization (IVF) treatment cycles, RIF Yuhuangding East Rd, Yantai 264000, Shandong, China Vol.:(0123456789)1 3 1166 Archives of Gynecology and Obstetrics (2019) 299:1165–1172 is determined. RIF remains a variable defnition, but the def- whether intrauterine administration of hCG improved preg- inition of failure of implantation after three or more embryo nancy outcomes by increasing Tregs in RIF patients who transfers or transfer of ten or more high-quality embryos has received FET. been taken as criteria by many researchers [1]. The causes of implantation failure include maternal factors and embryonic causes [2]. However, for many of patients with RIF the cause Materials and methods cannot be identifed, which creates frustration both patients and their clinicians. Subjects It is well known that the progression of pregnancy requires immunological tolerance at the maternal–fetal A total of 305 RIF patients who had an indication for a interface. A cascade of cytokines mediates this dialogue frozen-thawed embryo transfer cycle were enrolled in the and is important in the cross-talk between the immune and study from January 1st 2016 to December 31st 2016. Each endocrine systems. hCG is the frst known human embryo- patient gave written consent at the time of treatment for the derived signal which infuences immunological tolerance future use of their clinical data. At our center, RIF is defned and angiogenesis at the maternal–fetal interface. It, as the as implantation failure after three or more transfers of high- earliest embryonic product, could be a key regulator in trig- quality embryos. gering the complex process of embryo implantation. In addition, hCG can prolong endometrial receptivity, support Ethics appropriate endometrial angiogenesis, and modulate endo- metrial tissue remodelling to promote embryo implantation This study was a prospective cohort study that was approved [3–5]. by the Ethical Committee of Yantai Yuhuangding Hospital. The hCG-subunits are already secreted by two-cell stage This study was performed according to the ethical guide- embryos and increase to high concentrations at the blasto- lines regarding studies in which human gametes or embryos cyst stage [6]. Therefore, hCG already activates the embryo- are used as materials. These guidelines are issued by the endometrial dialogue before the embryo arrives in the uter- Ethics Committee of the China Society of Obstetrics and ine cavity on day 5 and 6 as a blastocyst. It may function as a Gynecology. modulator of embryo-maternal communication and maternal Inclusion criteria were as follows: a history of RIF, immune response during implantation [7, 8]. However, IVF age ≤ 45 years, BMI 19–30 kg/m2, basal FSH < 10 IU/L, patients lack the efect of hCG on the uterus prior to embryo normal uterine cavity as assessed through hysteroscopy, and transfer, especially blastocyst transfer. IVF decreases hCG normal maternal and paternal karyotypes. Exclusion crite- signalling to the endometrium during the early days of the ria were the following: severe uterine malformation, severe embryo development, which could contribute to the rela- uterine adhesions, chromosomal abnormality, antiphospho- tively low implantation rate [9, 10]. Therefore, there have lipid syndrome, hydrosalpinx (if not surgically removed or been many recent studies where researchers have attempted ligated), any contraindication to pregnancy, thyroid or adre- to inject hCG into uterine cavity before embryo transfer and nal dysfunction, neoplasia, severe impairment of renal or conclude that this treatment signifcantly improves embryo hepatic function, and use of medications that might interfere implantation and clinical pregnancy rates [11–14]. However, with study evaluations (e.g., hormonal medication, prosta- others show no benefcial efect before blastocyst transfer glandin inhibitors, psychotropic agents). [10, 15]. This could be because there is not enough time for hCG to have any signifcant benefcial efect on the endome- Study design trium before implantation [3, 9]. On the other hand, the percentages of Tregs are sig- All enrolled patients were thoroughly informed about the nifcantly lower in patients with RIF [16]. Tregs are nec- novelty and unknown efcacy of intrauterine injection hCG essary for the maintenance of maternal–fetal tolerance. in improving pregnancy outcomes. All patients were not per- hCG increases Tregs in periphery and attracts Tregs to the formed preimplantation genetic screening. Each patient was maternal–fetal interface during pregnancy [4]. Moreover, a included with only one treatment cycle. The patients were recent study has showed that hCG could upregulate Tregs randomized into two groups using a computerized random [16]. Based on these fndings, we hypothesized that if we digit generator based on their registration number. In the inject hCG into the uterine cavity before embryo transfer treatment group (n = 153, 153 cycles), 500 IU of hCG was for RIF patients, it may improve embryo implantation by injected into the uterine cavity 3 days before embryo trans- increasing Tregs. However, few studies conducted to date fer. The patients in the control group (n = 152, 152 cycles) have examined Tregs in peripheral blood of patients with received an intrauterine injection of saline without hCG RIF after injecting hCG. So, this study aimed to determine before embryo transfer. Maternal peripheral blood samples 1 3 Archives of Gynecology and Obstetrics (2019) 299:1165–1172 1167 were collected from each patient in sterile heparinized tubes catheter (K-Soft-5000 catheter; Cook Medical, Inc., USA). on the day of embryo transfer for the measurement of Tregs. Three days after the hCG injection, the embryos were then The outcome parameters were compared between the two transferred. groups. All intrauterine injection and transfer procedures were performed by the same physician to avoid inter-operator Procedure variability. The embryologist
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