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Effect of GnRH-a pretreatment before frozen-thawed embryo transfer on pregnancy outcome of adenomyosis-associated infertile patients with 56 cm3 ≤ uterine volume ≤100 cm3

Background Whether gonadotrophin-releasing hormone agonist (GnRH-a) pretreatment before transferring frozen-thawed embryos (FETs) could improve the clinical outcome of adenomyosis-associated infertile patients with 56 cm3 ≤ uterine volume ≤100 cm3 is unclear. Methods Adenomyosis patients who underwent in vitro fertilization and frozen embryo transfers from January 2009 to December 2019 with 56 cm3 ≤ uterine volume ≤100 cm3 were included in this retrospective cohort study. The subjects were divided into two groups (GnRH-a treatment group vs. GnRH-a-free group). The effect of GnRH-a treatment before FET on pregnancy outcomes was explored by univariate and multivariate analysis. In the GnRH-a treatment group, uterine volume before and after GnRH-a pretreatment was also compared by t-tests. Results A total of 186 patients undergoing 263 cryopreserved embryo transfer cycles were included. There was no significant difference in terms of the clinical pregnancy rate between patients in the GnRH-a treatment group (24/45, 53.3%) and the GnRH-a-free group (86/218, 39.4%) (P=0.098). The miscarriage rate in the GnRH-a treatment group (3/24, 12.5%) was significantly lower than that in the GnRH-a-free group (32/86, 37.2%) (P=0.044). The live birth rate in the GnRH-a treatment group (21/45, 46.7%) was significantly higher than that in the GnRH-a-free group (54/218, 24.8%) (P=0.009). However, the uterine volume did not change significantly before (82.0±13.4 cm3) or after GnRH-a treatment (79.3±14.0 cm3), with a P=0.123. Conclusions GnRH-a pretreatment before FET reduced the miscarriage rate and improved the live birth rate among infertile women with adenomyosis whose uterine volume was 56–100 cm3.


Comment 4:
There is also a difference in the time of suppression with the GnRha before ET. Reply 4: Firstly, in the GnRH-a treatment group, patients with adenomyosis were pretreated with 1-3 GnRH-a injections before FET (every 28 days): the percentage of cycles with one, two and three GnRH-a injections before FET was 4/45 (8.9%), 15/45 (33.3%) and 26 /45 (57.8%), respectively. Secondly, the total number of cycles of GnRH-a pretreatment was 45 cycles, so due to the limited sample size we did not analyze the effects of the time of suppression with the GnRH-a before FET on pregnancy outcomes. However, according to our study, although the pretreatment time of GnRHa was different, the reproductive outcome of the GnRH-a treatment group was superior to that of the GnRH-a-free treatment group. Changes in the text: we have modified our text as advised (see Page 9, line 172-176 in Results part).
Comment 5: More details how the uterus is measured should be given. Reply 5: All TVS were performed by two highly skilled radiologists. The main criteria for sonographic diagnosis of adenomyosis included a globular uterus or asymmetric myometrial thickening; heterogeneous myometrium, with thin "venetian blind" shadows between areas of increased echogenicity; myometrial cysts; indistinctness of the margins of the endometrium and echogenic linear striations; and nodules extending from the endometrium into the myometrium.
TVS was conducted before GnRH-a pretreatment and 28 days after the last GnRH-a injection (before commencing FET cycle) for patients with GnRH-a pretreatment. For patients without GnRH-a pretreatment, TVS was conducted before commencing FET cycle. The volume of uterus was calculated by using a geometric formula for prolate ellipsoid volume: long diameter × width diameter × anteroposterior diameter × π/6. Furthermore, type of adenomyosis was divided into focal, diffuse according to the adenomyotic lesions. Focal adenomyosis (including adenomyoma) is classified when typical ultrasonographic adenomyotic signs are circumscribed in aggregates and surrounded by normal myometrium, while diffuse adenomyosis when typical alterations at TVS spread throughout the myometrium. Changes in the text: we added a paragraph to describe ultrasound measurement in method part (see Page 6-7, line 105-121).
Comment 6: Also, a comparison with a control group could be included stratified for age, treatment…. Reply 6: Thank you very much for the advice. Firstly, the total number of FET cycles pretreated with GnRH-a in our study was 45 cycles, and the sample size of GnRH-a treatment group after stratification would have been smaller, which would not be suitable for subgroup analysis after stratification due to the limited sample size and low power. Secondly, from our present study, the reproductive outcome of the GnRH-a treatment group was still significantly better than that of GnRH-a-free treatment group after correction for confounding factors by using logistic regression, and the difference was statistically significant. Both univariate analysis and multivariate analysis confirmed the effect of GnRH-a pretreatment on improving pregnancy outcomes in patients with adenomyosis infertility. Changes in the text: results of multivariate analysis are shown in results part (see Page 9-10, line 185-198) and table 2.
Comment 7: More data should be given on the patients'characteristics in both groups Reply 7: We have also added the following patients' characteristics in both groups: duration of infertility, gravidity times, parity times, adenomyotic lesions (diffuse/ focal). And No statistic difference was observed in those characteristics between two groups. Changes in the text: we added some data in the results (see Page 9, line 179-184) and table1.
Comment 8: check paper by native English speaking person Reply 8: This paper was edited by one or more of the highly qualified native English speaking editors at AJE (see editing certificate). Changes in the text: we have modified our text as advised (see editing certificate).

Reviewer B
It is a clinically interesting paper that GnRHa administration before ET to the uterus suffering from adenomyosis increases pregnancy rate and live birth rate, and even though there is no significant change in uterine volume. These facts are limited to cases of a particular uterine volume, but both are new discoveries. However, there are some problems with the description of research results. First, the definitions of the GnRHa-treated group and the control group are not described in methods of the main chapter (eg, whether it is the number of cycles or the actual number of people). In addition, although the characteristics of both groups are shown in Table 1, there are many results in which the% calculation method is incorrect. Furthermore, the items that should be described in "Results" are not described, while the results of the items that are not described in "Methods" are described in "Results". There are some other amendments, and if all of them are amended, this paper will be worth publishing. Below is a list of points to consider.