Comparison of pregnancy outcomes of frozen embryo transfers in women undergoing artificial endometrial preparation with and without short and long-acting gonadotropin releasing hormone agonists

Supraphysiological estradiol and progesterone levels during controlled ovarian stimulation impair endometrial receptivity by shortening the duration of implantation window during fresh embryo transfer cycles (1). According to the evidence, it is suggested that cryopreserved/thawed embryo transfer (FET) may improve assisted reproductive technology outcome rather than fresh embryo transfer (2, 3).

Endometrial preparation is a curial step in FET cycles, which should be synchronized with the developmental stage of embryos. Several FET protocols have been introduced; however, a consensus related to the optimal protocol for frozen-thawed embryo transfer is still lacking. The FET strategies include natural cycles following spontaneous ovulation and hormone-mediated cycles with or without gonadotropin-releasing hormone (GnRH) agonist (4-7).

The natural cycle is an effective method of contraception, which is more preferable due to no requirement for hormone therapy, patient convenience, and cost-effectiveness. Nonetheless, timing and monitoring of spontaneous ovulation is very critical and can increase the cancelation rate of FET cycle (8). Artificial hormone-mediated cycles without GnRH agonist enable physicians to choose the day of embryo transfer; however, this method has lower advantages in women with irregular cycles. Pituitary suppression using GnRH agonist before hormone-replacement therapy is a convenient method for the inhibition of spontaneous ovulation (9); nonetheless, it is less patient-friendly and more expensive.

To the best of our knowledge, there has been no study that compares pregnancy outcomes among the patients undergoing short- and long-acting types of GnRH agonist in FET cycles. The present study aimed to compare pregnancy outcomes among the patients undergoing artificial hormone-mediated cycles with and without short- and long-acting GnRH agonist.

Materials and Methods

The present retrospective study was conducted on patients who underwent FET cycles during April 2016 and May 2017 at Mehr medical institute in Rasht, Iran. In this study, all FET cycles were included, and outcomes were compared among the three groups, including group A (n=103) that received artificial hormone-mediated cycles without GnRH agonist, as well as groups B (n=100) and C (n=93) that received artificial hormone-mediated cycles with short- and half-dose long-acting GnRH agonist, respectively. Patients with thin endometrium or homogenous hyperechogenic endometrium were excluded from the study. The eligibility of subjects for each group was decided by physicians. Written informed consent was obtained from all the participants.

Artificial hormone-mediated cycles without gonadotropin-releasing hormone agonist protocol

All the patients were given oral contraceptives in the preceding cycle of FET. In artificial hormone-mediated cycles (i.e., group A),estradiol valerate (2 mg, Aburaihan, Iran) was commenced at 6 mg/day since days 2 to 9 and continued at 8 mg/day up to clinical pregnancy approval. First transvaginal ultrasound monitoring of endometrial development was performed on day 13 and continued every other day. When endometrial thickness (EnT) reached approximately 7 mm, vaginal (400 mg, Fertigest, Aburaihan, Iran) and intramuscular (IM) 100 mg (50 mg, Fertigest, Aburaihan, Iran) progesterone supplementation was administrated for 3 to 5 days with respect to the cleavage stage of embryos.

Artificial hormone-mediated cycles with short-acting gonadotropin-releasing hormone agonist

In short-acting GnRH agonist cycles (i.e., group B), buserelin acetate (Cinnafact, Cinnagen, Iran) was administrated at a dose of 0.3 mg/day since day 21 of the preceding cycle to day 2 of FET cycle and continued with a dose of 0.2 mg/day up to day 6. Endometrial preparation was started with estradiol valerate and followed by progesterone supplementation in the same pattern as in group A.

Artificial hormone-mediated cycles with long-acting gonadotropin-releasing hormone agonist

In long-acting GnRH agonist cycles (i.e., group C), a single half-dose of depot GnRH agonist (Decapeptyl 1.875 mg, Ferring, Germany) was administrated on day 21 of the preceding cycle. Endometrial preparation was started with estradiol valerate and followed by progesterone supplementation in the same pattern as in group A. The embryo transfer was canceled, if EnT had no response to further estradiol treatment (10 mg, IM estradiol valerate, Aburaihan, Iran) and remained

The rates of ongoing pregnancy, clinical pregnancy, biochemical pregnancy, implantation, fertilization, and EnT, as well as the number of embryos and blastocyst transfer, were recorded in this study. The ratio of the number of gestational sacs to the total number of transferred embryos was considered as implantation rate. Patients with the polycystic ovarian syndrome (PCOS) were assessed for ongoing pregnancy rate in the groups. Biochemical pregnancy was approved by positive β human chorionic gonadotropin hormone test 2 weeks after embryo transfer. Clinical pregnancy was approved after the assessment of fetal heartbeat at 7 weeks of gestation. Ongoing pregnancy was distinguished as a viable pregnancy at 12 weeks of gestation.

Statistical analysis was performed using SPSS software (version 21). Normally distributed variables were analyzed using the analysis of variance, and the Kruskal-Wallis test was utilized for the analysis of non-normal variables. Categorical variables were assessed by the Chi-square goodness of fit test. According to univariate logistic regression, variables with P-value less than 0.2 were considered as confounding factors and evaluated by multivariate logistic regression. P-value less than 0.05 was considered statistically significant.

Results

The three groups were comparable in the baseline characteristics, such as body mass index, age, antimullerian hormone (AMH), types and etiologies of infertility, and duration of infertility (Table 1).

Clinical results of patients are summarized in Table 2. Differences in EnT (P=0.053), fertilization rate (P=0.88), total number of transferred embryos (P=0.77), embryo transfer day (P=0.09), blastocyst (P=0.49), and grade A transferred embryos (P=0.8) were not statistically significant among the groups. There were no significant differences in the rates of implantation (P=0.94), biochemical (P=0.67), clinical (P=0.82), and ongoing (P=0.96) pregnancy. The patients with PCOS did not show any significant differences in clinical pregnancy rate among the three groups (A: 31.57%, B: 41.66%, and C: 30.76%; P=0.72) (Table 2).

The crude odds ratios for clinical pregnancy rate were 0.874 (95% confidence interval [CI]; 0 .483-1.581) and 1.052 (95% CI; 0.569-1.946) for groups B and C, when compared to the group A. The results of univariate logistic regression indicated that AMH, as well as number of blastocysts and grade A transferred embryos, were reported with a significance level less than 0.2. After adjustment to these variables, the odds ratio for groups B and C were 0.940 (95% CI, 0.527-2.067) and 1.043 (95% CI, 0.527-2.067), respectively. The obtained aforementioned results are summarized in Table 3.

Discussion