Comparative analysis of the effectiveness of programs and perinatal outcomes after frozen-thawed embryo transfer depending on post-transfer support medications

The widespread application of advanced cryopreservation techniques has become a breakthrough in assisted reproductive technologies (ART) over the past decade. In frozen-thawed embryo transfer cycle, endometrial receptivity is preserved, ovarian hyperstimulation syndrome is excluded, one embryo can be transferred after preimplantation genetic testing during the implantation window; all these factors contribute to the preservation of fertility and an increase in the number of live births [1, 2]. Perinatal outcomes of cryopreserved embryo transfer have advantages due to the decreased frequency of low birth weight for gestational age, preterm birth, placenta previa, placental abruption and perinatal mortality in comparison with the transfer of fresh embryos [3–5]. However, cryopreserved embryo transfer is accompanied by an increased risk of macrosomia and hypertensive disorders of pregnancy [6, 7]. It still remains unknown whether these differences result from taking hormone replacement therapy in the protocols for preparing the endometrium for the transfer of thawed embryos or from the absence of corpus luteum [8, 9]. The choice of a progestogen for adequate secretory transformation and subsequent post-transfer support is another important issue [10, 11].

The role of progestogens in reducing late pregnancy complications, such as preeclampsia, is currently studied. The data of the previous retrospective studies show a decrease in the frequency of preeclampsia after taking dydrogesterone to support the luteal phase in ART programs [12, 13].

There were some studies that compared the effectiveness of the use of dydrogesterone and micronized vaginal progesterone in the cycles of in vitro fertilization [6, 14–16]. However, there is no evidence base in favor of certain progestogens to support the luteal phase after the transfer of thawed embryos nowadays.

It is necessary to conduct further prospective randomized trials to determine the optimal programs of endometrial preparation with subsequent post-transfer support to improve the outcomes of ART.

The aim of the study is to evaluate the effectiveness of frozen-thawed embryo transfer programs and pregnancy outcomes depending on the type of progestogen used for secretory endometrial transformation and post-transfer support.

Materials and methods

This was a retrospective study of the outcomes of frozen-thawed own embryo transfers with hormone replacement therapy cycle in the period from February 2021 to May 2022 in the Assisted Reproduction Department, Urals Scientific Research Institute for Maternal and Child Care. The study included 334 women diagnosed with female infertility who were prescribed the following hormonal preparations to prepare the endometrium for the transfer of thawed embryos: estrogens (estradiol valerate at a dosage of 6 mg/day from the 2^nd–4^th day of the menstrual cycle) aimed at achieving proliferative changes in the endometrium, and progestogens for the secretory transformation and decidualization of the endometrium (till the endometrium becomes at least 7 mm thick and up to 12 weeks gestation). All the patients were divided into two groups: the first group consisted of 224 patients who took dydrogesterone (30 mg/day orally) for full secretory transformation of the endometrium, the second group included 110 patients who were prescribed micronized vaginal progesterone (600 mg/day). The preparation of the endometrium did not include methods of surgical, instrumental (cavity irrigation), or biological (intrauterine administration of platelet-enriched plasma) preparation of the uterine cavity and endometrium.

There were the following main outcome indicators: the presence of clinical pregnancy, live birth, obstetric complications (the frequency of miscarriage, preterm birth).

Statistical analysis

Statistical processing of the study results was carried out using Microsoft Excel (2010) application software packages, Stat Soft Statistica 6.0 (Stat Soft, USA), SPSS Statistics version 22.0 (IBM Microsoft, USA). The assessment of the compliance of the sample with the normal distribution was carried out using the Kolmogorov–Smirnov test. If the distribution of the sampling was normal, the data were presented in the form of a mean value (M) and a standard deviation (SD). Qualitative variables were represented as absolute values and relative values in percentage, statistical significance was assessed using the chi-squared test (χ²), if the absolute frequencies were less than 10, then the Yates’ correction was applied. The null hypothesis was rejected at p<0.05. In order to evaluate the final results of each of the clinical outcomes, the effect size was calculated using the odds ratio (OR) with a 95% confidence interval (CI).

Results and discussion

The average age of patients in group 1 was 34.3 (0.63) years, and it was 33.8 (0.75) years in group 2; demographic indicators were comparable in the study groups (p=0.063).

The assessment of the accompanying somatic pathologies revealed that in both groups the endocrine, nutritional and metabolic diseases occupy a leading place: 54/224 in the 1^st group (24.10%) and 14/110 (12.72%) in the 2^nd group, with a statistically significant difference (p=0.016). The diseases of the gastrointestinal tract occurred in 16/224 patients (7.14%) in group 1, and in 10/110 (9.09%) patients in group 2 (p>0.05). In addition, obesity was the fourth leading somatic pathology in the group of patients who used micronized vaginal progesterone, namely, 8/110 (7.27%) (Table 1).

Most frequently the patients of both groups had the following gynecological diseases: postoperative uterine scar requiring medical care, 42/224 (18.75%) in group 1 versus 18/110 (16.36%) in group 2, p=0.594; polycystic ovary syndrome, 26/224 (11.60%) in group 1 versus 10/110 (9.09%) in group 2, p=0.486; uterine leiomyoma, 20/224 (8.92%) in group 1 versus 4/110 (3.63%) in group 2, p=0.079. There were no statistically significant differences in gynecological pathologies in all groups (p>0.05). 

Infertility factors of patients in each group were analyzed in this study (Table 2).

The most common factor of infertility in patients of group 1 who received dydrogesterone to support the luteal phase was tubal factor (N97.1), 88/224 patients (39.28%). The next most frequent factors were anovulatory factor (N97.0), 52/224 patients (23.21%), and male factor (N97.4), 42/224 patients (18.75%). Among the patients who used micronized vaginal progesterone, the most frequent factors were female infertility associated with male factor (N97.4), 28/110 (34.54%), and anovulation (N97.0), 32/110 (29.09%). The patients of group 1 were statistically significantly more likely to have female infertility associated with tubal factor (p=0.005) and combined forms of infertility (p=0.014) than the patients of group 2. Taking into account the statistical significance of differences in infertility factors, we analyzed the embryological stage of frozen-thawed embryo transfer programs in these groups. There were no statistically significant differences in the number of transferred embryos in patients of groups 1 and 2. One embryo was transferred in the group of patients who received dydrogesterone in 130/224 (58.03%) cases, and in the group of patients who used micronized vaginal progesterone in 54/110 (49.09%) cases (p=0.123); two frozen-thawed embryos were transferred to the uterine cavity in the rest of the cases (Table 3).

All transferred embryos were at the blastocyst stage, their cryopreservation took place on the 5^th–6^th day of embryo development. Preimplantation testing of embryos was not carried out. After embryos were thawed, they were assessed according to the scoring system developed by Gardner. We analyzed embryo transfers using the data on the quality of blastocysts (Table 4). The frequency of transferred embryos of excellent and good quality (AA, AB, BA, BB) in the group of patients who received dydrogesterone was 244/318 (76.73%), and it was 130/166 (78.31%) in the 2^nd group of patients (p>0.05). All other embryos were of satisfactory quality: 74/318 (23.27%) cases in group 1; 36/166 (21.68%) cases in group 2 (p=0.694). There were no statistically significant differences in the quality of transferred embryos in all cases.

The outcomes of ART programs were evaluated on the basis of clinical pregnancy rate in the study groups (Table 5).

Conclusion

Our study was aimed at evaluating the effectiveness of ART programs and perinatal outcomes after the transfer of frozen-thawed embryos depending on the progestogen used for secretory endometrial transformation, endometrial decidualization and post-transfer support.

The data obtained in the study showed comparable effectiveness of progestogens in the clinical pregnancy rate and perinatal outcomes in the cycle of preparation for frozen-thawed embryo transfer; however, no statistically significant differences were revealed. The patients who received dydrogesterone were more likely to have preterm birth, but the differences in the rate of live birth and obstetric complications were not statistically significant.

It is possible to use both micronized vaginal progesterone and dydrogesterone in cycles of hormone replacement therapy for preparing the endometrium for frozen-thawed embryo transfer.

It is necessary to conduct further multicenter studies on a large sample of patients to draw conclusions on the possibility of personal use of progestogens in ART programs with frozen-thawed embryo transfer, as well as the assessment of pregnancy complications and perinatal outcomes.